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    ABSTRACT: Radiotherapy is commonly used to treat pain in malignant pleural mesothelioma (MPM). The purpose of this systematic review is to examine the evidence for this practice. Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases were searched. Eligible studies met the following criteria: MPM (histological or radiological diagnosis), radiotherapy given with the intent of improving pain, response rates to radiotherapy reported, dose and fractionation reported and the relationship between radiotherapy and pain response explored. All studies had independent review and were graded according to evidence level. Eight studies met the eligibility criteria. Two studies were prospective single arm phase II studies while the remainder were retrospective case series. All were graded as either Level 2 or Level 3 evidence. Due to marked heterogeneity among studies, quantitative synthesis of results was not possible. No high quality evidence currently exists to support radiotherapy in treating pain in MPM. Studies focusing on clear pain endpoints and improving target delineation are needed. Such studies should also use modern radiotherapy techniques and concentrate on dose escalation.
    Lung cancer (Amsterdam, Netherlands) 11/2013;
  • Nature Reviews Molecular Cell Biology 08/2013;
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    ABSTRACT: In advanced cancer, oncological treatment is influenced by performance status (PS), however this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (PS, patient reported outcomes) against an inflammation-based score (Glasgow Prognostic Score - mGPS). A new method of prognosis in advanced cancer (combining PS and mGPS) is tested and then validated. Two international biobanks of advanced cancer patients were analysed. Key prognostic factors (PS, patient reported outcomes (EORTC QLQ-C30) and mGPS (using C-reactive protein and albumin concentrations)) were examined. The relationship between these and survival was examined using Kaplan-Meier and Cox regression methods, in a test sample before independent validation. Data were available on 1825 patients (test) and 631 patients (validation). Median survival ranged from 3.2 months (test) - to 7.03 months (validation). On multivariate analysis, PS (HR 1.62-2.77) and mGPS (HR 1.51-2.27) were independently associated with, and were the strongest predictors of survival (p<0.01). Survival at 3 months varied from 82% (mGPS 0) to 39% (mGPS 2) and from 75% (PS 0-1) to 14% (PS 4). When used together survival ranged from 88% (mGPS 0, PS 0-1) to 10% (mGPS 2, PS 4), p<0.001. A systemic inflammation-based score, mGPS, and PS predict survival in advanced cancer. The mGPS is similar to PS in terms of prognostic power. Used together, PS and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of advanced cancer patients.
    Clinical Cancer Research 08/2013;
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    ABSTRACT: Cancer-related neuropathic pain is common; it can be disease related or related to the acute or chronic effects of cancer treatment. For example, chemotherapy-induced peripheral neuropathy occurs in 90% of patients receiving neurotoxic chemotherapy. Cancer treatments have become more effective; patients are living longer with cancer and there are more cancer survivors. However, side-effects (particularly neuropathy) have become more problematic. The key to management of cancer-related neuropathy is a considered assessment, remembering not to miss the opportunity of reversing the cause of the pain with appropriate oncological management. An increasing range of oncological therapies are available, including radiotherapy, chemotherapy, hormonal therapy, or one of the evolving approaches (e.g. immune therapies). Patients are often elderly and with comorbidities; therefore, all treatment decisions have to be made carefully and reviewed appropriately. Cancer pain is often of mixed aetiology or, if purely neuropathic, may be one of several pains experienced by a patient. For these reasons, opioids are used more frequently in patients with cancer-related neuropathic pain. Standard guidelines for the use of anticonvulsants (e.g. pregabalin and gabapentin), antidepressants (e.g. duloxetine and tricyclics), and topical treatments (e.g. capsaicin and lidocaine) may be applicable, but there is a lack of good-quality clinical trials in cancer-related neuropathic pain. Choice is dictated not just by age, drug interactions, and comorbidities, but also by the coexistence of many symptoms in patients with cancer. Treating more than one symptom with a particular neuropathic pain agent can avoid polypharmacy.
    BJA British Journal of Anaesthesia 07/2013; 111(1):105-11.
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    ABSTRACT: Improving cancer survival rates is a UK priority and equity of access to high quality cancer irrespective of geography is a key principle. Surgery, radiation therapy and systemic therapy remain the cornerstone of the multidisciplinary management of cancer. However, costs of cancer care continue to escalate. A recent review (1) estimated the global costs of cancer care caused by death and disability as US $895 billion (excluding indirect medical costs and based on 2008 figures). Approximately 49% of patients are cured by surgery, 40% by radiotherapy alone or in combination with other treatments and 11% by systemic therapy. With > 90,000 patients per annum treated with curative intent by radiotherapy in the UK, one would anticipate that access to modern radiotherapy techniques would have a high priority. However, there are substantial differences in the NHS uptake of new anti-cancer agents and advanced radiation technologies. In this article, these differences are explored and recommendations made for addressing them.
    International Journal of Clinical Practice 03/2013; 67(3):195-7.
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    ABSTRACT: Mouse double minute 2 (MDM2) participates in protein synthesis, folding, and ubiquitin-mediated degradation and is therefore a proteostasic hub protein. The MDM2 interactome contains over 100 proteins, yet stratification of dominant MDM2-interacting proteins has not been achieved. 8-plex iTRAQ (nanoLC-MS/MS) of MCF7 cells treated with the MDM2-binding ligand Nutlin-3 identified the most abundant cellular protein changes over early time points; 1,323 unique proteins were identified including 35 with altered steady-state levels within 2 h of Nutlin-3 treatment, identifying a core group of MDM2 related proteins. Six of these proteins were previously identified MDM2 interactors, and the effects of Nutlin-3 on the MDM2-nucleophosmin interaction (NPM) was further validated. This revealed that Nutlin-3 mediates the in vivo conversion of NPM from an oligomer to a monomer as an MDM2-dependent phenomenon, with Nutlin-3 stimulating MDM2 binding to a peptide motif derived from the oligomerization interface of NPM. These data form the first proteomic screen of Nutlin-3 in cells whereby we (i) identify the most abundant MDM2-interacting proteins whose steady-state levels change early after Nutlin-3 treatment; (ii) identify the first protein apart from p53, nucleophosmin (NPM), whose interaction with MDM2 can be stimulated allosterically by Nutlin-3; and (iii) raise the possibility that Nutlin-3 might act as a general agonist of other MDM2 protein-protein interactions.
    Journal of Proteome Research 10/2012;
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    ABSTRACT: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that integrates signals downstream of integrin and growth factor activation. Previously, we have shown that skin-specific loss of fak prevents chemically induced skin carcinogenesis in mice following phorbol ester treatment. In this study, we show that skin-specific deletion of fak prevents mobilization of stem cells within the bulge region of the hair follicle, which are the precursors of papillomas following phorbol ester treatment. We also show that phorbol ester treatment results in activation of-catenin within the skin and that FAK is required for β-catenin-induced stem cell mobilization. In addition, inhibition of Src kinase activity, a major binding partner of FAK also prevents stem cell mobilization. We show that FAK is required for the nuclear localization of β-catenin in the skin following phorbol ester treatment and the transcriptional activation of the β-catenin target gene c-Myc. This provides the first evidence of cross-talk between integrin and Wnt signalling pathways in the control of epidermal stem cells and the early events associated with skin carcinogenesis.
    Carcinogenesis 09/2012;
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    ABSTRACT: Preclinical and phase I data suggest gemcitabine to be a potent radiosensitiser. This multicentre study addressed whether the addition of low dose gemcitabine to radical radiotherapy improved 2 year event-free survival in patients with medically inoperable stages I-II non-small cell lung cancer. To determine whether low dose gemcitabine increased event-free survival in patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery. Patients with T1-2 N0-1 M0 NSCLC deemed unfit for surgery were randomised to 3D conformal radiotherapy delivering 55 Gy in 20 fractions over 4 weeks to known sites of cancer with (Arm B) or without (Arm A) 100mg/m(2) weekly gemcitabine. Study entry was terminated early because of slow accrual. 111 patients were randomised between March 2003 and December 2005, of whom 4 withdrew consent and 2 were lost to follow-up. Median age was 75 (range 49-88)years and 67 (63%) were male. 86 (81%) were PS 0-1 and 31 (30%) Charlson index 2 or greater. Event-free survival in arm A and B, respectively, was 42% and 46% at 2 years and 20% and 31% at 5 years (p=0.72), while overall survival was 56% and 52% at 2 years and 20% and 33% at 5 years (p=0.87). Two deaths from accelerated interstitial lung disease were seen in arm B, but toxicity was otherwise mild. No evidence of an improvement in event-free survival was seen with the addition of weekly gemcitabine at this dose for patients with early stage NSCLC unfit for surgery, although the power of the study was low.
    Lung cancer (Amsterdam, Netherlands) 06/2012; 77(3):532-6.
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    ABSTRACT: Nucleic acids are the foundation stone of all cellular processes. Consequently, the use of DNA or RNA to treat genetic and acquired disorders (so called gene therapy) offers enormous potential benefits. The restitution of defective genes or the suppression of malignant genes could target a range of diseases, including cancers, inherited diseases (cystic fibrosis, muscular dystrophy, etc.), and viral infections. However, this strategy has a major barrier: the size and charge of nucleic acids largely restricts their transit into eukaryotic cells. Potential strategies to solve this problem include the use of a variety of natural and synthetic nucleic acid carriers. Driven by the aim and ambition of translating this promising therapeutic approach into the clinic, researchers have been actively developing advanced delivery systems for nucleic acids for more than 20 years. A decade ago we began our investigations of solid-phase techniques to construct families of novel nucleic acid carriers for transfection. We envisaged that the solid-phase synthesis of polycationic dendrimers and derivatized polyamimes would offer distinct advantages over solution phase techniques. Notably in solid phase synthesis we could take advantage of mass action and streamlined purification procedures, while simplifying the handling of compounds with high polarities and plurality of functional groups. Parallel synthesis methods would also allow rapid access to libraries of compounds with improved purities and yields over comparable solution methodologies and facilitate the development of structure activity relationships. We also twisted the concept of the solid-phase support on its head: we devised miniaturized solid supports that provided an innovative cell delivery vehicle in their own right, carrying covalently conjugated cargos (biomolecules) into cells. In this Account, we summarize the main outcomes of this series of chemically related projects.
    Accounts of Chemical Research 03/2012; 45(7):1140-52.
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    ABSTRACT: Current drug-discovery strategies are typically 'target-centric' and are based upon high-throughput screening of large chemical libraries against nominated targets and a selection of lead compounds with optimized 'on-target' potency and selectivity profiles. However, high attrition of targeted agents in clinical development suggest that combinations of targeted agents will be most effective in treating solid tumors if the biological networks that permit cancer cells to subvert monotherapies are identified and retargeted. Conventional drug-discovery and development strategies are suboptimal for the rational design and development of novel drug combinations. In this article, we highlight a series of emerging technologies supporting a less reductionist, more agile, drug-discovery and development approach for the rational design, validation, prioritization and clinical development of novel drug combinations.
    Future medicinal chemistry 01/2012; 4(1):87-105.
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