Search

Background Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. Patients and methods ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. Results Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. Conclusions Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes. [ABSTRACT FROM AUTHOR]

Wolbachia endosymbiotic bacteria have been implicated in the inflammatory pathogenesis of filariasis. Inflammation induced by Brugia malayi female worm extract (BMFE) is dependent on Toll-like receptors 2 and 6 (TLR2/6) with only a partial requirement for TLR1. Removal of Wolbachia, lipids, or proteins eliminates all inflammatory activity. Wolbachia bacteria contain the lipoprotein biosynthesis genes Ltg and LspA but not Lnt, suggesting Wolbachia proteins cannot be triacylated, accounting for recognition by TLR2/6. Lipoprotein databases revealed 3-11 potential lipoproteins from Wolbachia. Peptidoglycan-associated lipoprotein (PAL) and Type IV secretion system-VirB6 were consistently predicted, and B. malayi Wolbachia PAL (wBmPAL) was selected for functional characterization. Diacylated 20-mer peptides of wBmPAL (Diacyl Wolbachia lipopeptide (Diacyl WoLP)) showed a near identical TLR2/6 and TLR2/1 usage compared with BMFE and bound directly to TLR2. Diacyl WoLP induced systemic tumor necrosis factor-a and neutrophilmediated keratitis in mice. Diacyl WoLP activated monocytes induce up-regulation of gp38 on human lymphatic endothehal cells and induced dendritic cell maturation and activation. Dendritic cells primed with BMFE generated a non-polarized Thl/Th2 CD4+ T cell profile, whereas priming with Wolbachia depleted extracts (following tetracycline treatment; BMFEtet) polarized to a Th2 profile that could be reversed by reconstitution with Diacyl WoLP. BMFE generated IgGi and IgG2c antibody responses, whereas BMFEtet or inoculation of TLR2 or MyD88-/- mice produced defective IgG2c responses. Thus, in addition to innate inflammatory activation, Wolbachia lipoproteins drive interferon-7dependent CD4+ T cell polarization and antibody switching. [ABSTRACT FROM AUTHOR]

Objectives Guidelines for the conduct of clinical trials emphasize the importance of keeping the interim results from the main endpoints confidential, in order to maintain the integrity of the trial and to safeguard patients' interests. However, is this essential in every situation? Materials and methods We review the evidence for these guidelines and consider recent randomised trials that have released interim results, to assess their impact on the success of the trial. However, because the strength of opinion to keep interim results confidential is so strong, there are limited examples of such trials. Results In the QUARTZ trial (which is assessing the value of whole brain radiotherapy in patients with brain metastases from non-small cell lung cancer) the decision to release interim results was taken in response to threatened closure due to poor accrual, whereas in the GRIT trial (which compared two obstetric strategies for the delivery of growth retarded pre-term fetuses) the regular release of interim results was pre-planned. Nevertheless there are a number of common factors between these two trials. In particular, the trial treatments were already in wide use, with no reliable randomised evidence on which treatment should be used for which patients, and there was diverse clinical opinion, which meant that accrual was likely to be challenging. In a situation where a quarter to a third of trials do not accrue their required number of patients, the QUARTZ trial continues to accrue patients, and the GRIT trial successfully accrued its target of nearly 600 babies. Conclusions This article therefore argues that there is a need to re-consider whether it is always essential to keep the interim results of randomized clinical trials confidential, and suggests some criteria that may help groups planning or running challenging trials decide whether releasing interim results would be a useful strategy. [ABSTRACT FROM AUTHOR]

Deformation caused by a volcano (e.g., from volcanic activity) can be a good indicator of volcanic processes; ground deformation measurements using geodetic tools can be useful to monitor this movement. This study concentrates on detecting short-term movements occurring during both low activity periods and the eruptive stages of a volcano on the island of Montserrat by using sub-daily (epoch-by-epoch) GPS data processing approaches. The GPS data are obtained from UNAVCO for stations surrounding the Soufrière Hills Volcano during the May 20, 2006, volcanic eruption period and during the Fall 2012 period (a period of lower activity). In order to analyze hidden periodicities within the data, Least Squares Spectral Analysis has been used. Our results show that the sub-daily peaks are located at near diurnal and semidiurnal tidal constituents (K1 and K2) with up to 5 mm amplitude. [ABSTRACT FROM AUTHOR]

Surgical excision of melanomas of less than 1 mm thickness is usually associated with a favorable outcome, compared to those that have extended deeper. However, some thin melanomas (<1 mm) are also paradoxically known to metastasize early and thus cofound thickness predictions. Numerous attempts have been made to identify phenotypic markers associated with this unusual behaviour pattern. So far no absolutely reliable marker has been identified. Fascin which is an actin-bundling protein has been shown to be associated with migratory abilities in in vitro studies of neural cells. In addition, in several tumour types including breast, ovarian and colonic carcinoma fascin expression has been shown by immunostaining to correlate with local invasive potential and subsequent metastasis. We investigated a series of pigmented skin lesions that included thin melanomas with the aggressive phenotype outlined above. Immunostaining of formalin-fixed paraffin-embedded clinical specimens for fascin, HMB-45, Mart1 and HLA-DR was achieved with antigen retrieval methods and ABC peroxidase methodology. Appropriate positive and negative tissue and reagent controls were used to ensure specificity of staining. Analysis of the staining included a quantitive assessment of stain intensity in cells at different depths in the lesions. A published algorythm applied to the Matlab analysis software program gave results as energy/pixel. Thin melanomas showed a significant expression of fascin compared to benign melanotic lesions and to other melanomas of <1 mm with clinical histories indicating the more usual phenotype and subsequent progression. In particular cells at the leading edge of the positive thin melanomas showed elevated expression of fascin. Fascin may prove to be a useful indicator of early metastatic potential. [ABSTRACT FROM AUTHOR]

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n  = 724) or SOC + docetaxel (n  = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P  = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P  = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59–0.81, P  < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P  > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden. [ABSTRACT FROM AUTHOR]

Background Following neoadjuvant chemotherapy for operable gastroesophageal cancer, lymph node metastasis is the only validated prognostic variable; however, within lymph node groups there is still heterogeneity with risk of relapse. We hypothesized that gene profiles from neoadjuvant chemotherapy treated resection specimens from gastroesophageal cancer patients can be used to define prognostic risk groups to identify patients at risk for relapse. Patients and methods The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (n =  202 with high quality RNA) samples treated with perioperative chemotherapy were profiled for a custom gastric cancer gene panel using the NanoString platform. Genes associated with overall survival (OS) were identified using penalized and standard Cox regression, followed by generation of risk scores and development of a NanoString biomarker assay to stratify patients into risk groups associated with OS. An independent dataset served as a validation cohort. Results Regression and clustering analysis of MAGIC patients defined a seven-Gene Signature and two risk groups with different OS [hazard ratio (HR) 5.1; P  <   0.0001]. The median OS of high- and low-risk groups were 10.2 [95% confidence interval (CI) of 6.5 and 13.2 months] and 80.9 months (CI: 43.0 months and not assessable), respectively. Risk groups were independently prognostic of lymph node metastasis by multivariate analysis (HR 3.6 in node positive group, P  =   0.02; HR 3.6 in high-risk group, P  =   0.0002), and not prognostic in surgery only patients (n = 118 ; log rank P  =   0.2). A validation cohort independently confirmed these findings. Conclusions These results suggest that gene-based risk groups can independently predict prognosis in gastroesophageal cancer patients treated with neoadjuvant chemotherapy. This signature and associated assay may help risk stratify these patients for post-surgery chemotherapy in future perioperative chemotherapy-based clinical trials. [ABSTRACT FROM AUTHOR]

The Global Positioning System (GPS) is a valuable tool in the measurement and monitoring of ionospheric total electron content (TEC). To obtain accurate GPS-derived TEC, satellite and receiver hardware biases, known as differential code biases (DCBs), must be estimated and removed. The Center for Orbit Determination in Europe (CODE) provides monthly averages of receiver DCBs for a significant number of stations in the International Global Navigation Satellite Systems Service (IGS) network. A comparison of the monthly receiver DCBs provided by CODE with DCBs estimated using the minimization of standard deviations (MSD) method on both daily and monthly time intervals, is presented. Calibrated TEC obtained using CODE-derived DCBs, is accurate to within 0.74 TEC units (TECU) in differenced slant TEC (sTEC), while calibrated sTEC using MSD-derived DCBs results in an accuracy of 1.48 TECU. [ABSTRACT FROM AUTHOR]

Background: Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented. Patients and methods: We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared with non-users, and extracted data on patients with early-stage cancer. Studies were assessed for design and quality, and a meta-analysis was conducted to quantify the adjuvant effect of metformin on recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS), to inform future trial design. Results: Of 7670 articles screened, 27 eligible studies were identified comprising 24 178 participants, all enrolled in observational studies. In those with early-stage colorectal cancer, metformin use was associated with a significant benefit in all outcomes [RFS hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.47-0.85; OS HR 0.69, CI 0.58-0.83; CSS HR 0.58, CI 0.39-0.86]. For men with early-stage prostate cancer, metformin was associated with significant, or borderline significant, benefits in all outcomes (RFS HR 0.83, CI 0.69-1.00; OS HR 0.82, CI 0.73-0.93; CSS HR 0.58, CI 0.37-0.93); however, there was significant heterogeneity between studies. The data suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin (RFS HR 0.45, CI 0.29-0.70). In breast and urothelial cancer, no significant benefits were identified. Sufficient data were not available to conduct analyses on the impact of metformin dose and duration. Conclusions: Our findings suggest that metformin could be a useful adjuvant agent, with the greatest benefits seen in colorectal and prostate cancer, particularly in those receiving radical radiotherapy, and randomised, controlled trials which investigate dose and duration, alongside efficacy, are advocated. [ABSTRACT FROM AUTHOR]

Background Perioperative epirubicin, cisplatin and fluorouracil (ECF) chemotherapy improves survival in operable oesophago-gastric cancer [Adjuvant Gastric Cancer Infusional Chemotherapy (MAGIC) trial HR 0.75 (0.6–0.93)]. HER2 amplification is reported to predict enhanced benefit from anthracyclines in breast cancer. We sought to define whether HER2 predicts benefit from ECF in oesophago-gastric cancer. Patients and methods Diagnostic biopsies and/or resection specimens were collected from 415 of 503 MAGIC trial patients (82.5%). HER2 was evaluated by immunohistochemistry (IHC) and brightfield dual in situ hybridisation (BDISH) in tissue microarrays. The prognostic and predictive impact of HER2 status was investigated. Results Concordance between HER2 over-expression (IHC3+) and amplification was 96%. Results of HER2 assessment in biopsy and resection specimens were concordant in 92.9% (145/156). HER2 positive rate (IHC3+, or IHC2+/BDISH positive) was 10.9% in the whole cohort and 10.4% in resection specimens. A further 4.0% of resections were IHC negative/BDISH positive. HER2 status was neither prognostic, nor (in pre-treatment biopsies) predicted enhanced benefit from chemotherapy [HER2 positive HR 0.74 (0.14–3.77); HER2 negative HR 0.58 (0.41–0.82), interaction P = 0.7]. However, the power of the predictive analysis was limited by the small number of HER2 positive pre-treatment biopsies. Conclusions HER2 status is not an independent prognostic biomarker in early oesophago-gastric adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract: A finite element model, using commercially available software, is presented to simulate the piezoelectrically induced stresses and strains in an optical fibre to be used as antenna. These stresses and strains are generated by a layer of piezoelectric polymer deposited on the cladding of a short fibre sample. The theoretical basis for the work is briefly explained and the modelling process is emphasised. Two types of fibre are investigated – circular fibre and D-fibre, and the results compared, analysed and discussed. It is shown that in the D-fibre, the stress and displacement increased by 1.46 and 115 times, respectively, in comparison with the circular fibre. [Copyright &y& Elsevier]