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  • Randomised phase II study of amrubicin as single agent or in combination with cisplatin versus cisplatin etoposide as first-line treatment in patients with extensive stage small cell lung cancer - EORTC 08062.

    O'Brien, M E R; Konopa, K; Lorigan, Paul C; Bosquee, L; Marshall, E; Bustin, F; Margerit, S; Fink, C; Stigt, J A; Dingemans, A; et al. (2011-10)
    The EORTC 08062 phase II randomised trial investigated the activity and safety of single agent amrubicin, cisplatin combined with amrubicin, and cisplatin combined with etoposide as first line treatment in extensive disease (ED) small cell lung cancer (SCLC).
  • Second cancer risk after chemotherapy for Hodgkin's lymphoma: a collaborative British cohort study.

    Swerdlow, A J; Higgins, C D; Smith, P; Cunningham, D; Hancock, B W; Horwich, A; Hoskin, P J; Lister, T A; Radford, John A; Rohatiner, A Z S; et al. (2011-11-01)
    We investigated the long-term risk of second primary malignancy after chemotherapy for Hodgkin's lymphoma (HL) in a much larger cohort than any yet published, to our knowledge.
  • 4D cone beam CT phase sorting using high frequency optical surface measurement during image guided radiotherapy.

    Price, Gareth J; Marchant, Thomas E; Parkhurst, James M; Sharrock, Phillip J; Whitfield, Gillian A; Moore, Christopher J; The Christie Hospital NHS Foundation Trust, Manchester (2011-03-16)
  • A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors.

    Jonker, D J; Rosen, L S; Sawyer, M B; de Braud, F; Wilding, G; Sweeney, C J; Jayson, Gordon C; McArthur, G A; Rustin, G; Goss, G; et al. (2011-06)
    This study was designed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of brivanib in patients with advanced/metastatic solid tumors.
  • Brain inflammation is induced by co-morbidities and risk factors for stroke.

    Drake, C; Boutin, H; Jones, M S; Denes, A; McColl, B W; Selvarajah, J R; Hulme, S; Georgiou, R F; Hinz, R; Gerhard, A; et al. (2011-08)
    Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE(-/-)) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a "primed" inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.
  • Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors.

    Martinez-Outschoorn, U E; Lin, Z; Trimmer, C; Flomenberg, N; Wang, C; Pavlides, S; Pestell, R G; Howell, Anthony; Sotgia, F; Lisanti, M P; et al. (2011-08-01)
    Previously, we proposed that cancer cells behave as metabolic parasites, as they use targeted oxidative stress as a "weapon" to extract recycled nutrients from adjacent stromal cells. Oxidative stress in cancer-associated fibroblasts triggers autophagy and  mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis, and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the "reverse Warburg effect." To further test the validity of this hypothesis, here we used an in vitro MCF7-fibroblast co-culture system, and quantitatively measured a variety of metabolic parameters by FACS analysis (analogous to laser-capture micro-dissection).  Mitochondrial activity, glucose uptake, and ROS production were measured with highly-sensitive fluorescent probes (MitoTracker, NBD-2-deoxy-glucose, and DCF-DA). Interestingly, using this approach, we directly show that cancer cells initially secrete hydrogen peroxide that then triggers oxidative stress in neighboring fibroblasts. Thus, oxidative stress is contagious (spreads like a virus) and is propagated laterally and vectorially from cancer cells to adjacent fibroblasts. Experimentally, we show that oxidative stress in cancer-associated fibroblasts quantitatively reduces mitochondrial activity, and increases glucose uptake, as the fibroblasts become more dependent on aerobic glycolysis.  Conversely, co-cultured cancer cells show significant increases in mitochondrial activity, and corresponding reductions in both glucose uptake and GLUT1 expression. Pre-treatment of co-cultures with extracellular catalase (an anti-oxidant enzyme that detoxifies hydrogen peroxide) blocks the onset of oxidative stress, and potently induces the death of cancer cells, likely via starvation.  Given that cancer-associated fibroblasts show the largest increases in glucose uptake, we suggest that PET imaging of human tumors, with Fluoro-2-deoxy-D-glucose (F-2-DG), may be specifically detecting the tumor stroma, rather than epithelial cancer cells.
  • Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs "fertilizer".

    Lisanti, Michael P; Martinez-Outschoorn, U E; Lin, Z; Pavlides, S; Whitaker-Menezes, D; Pestell, R G; Howell, Anthony; Sotgia, F; The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. (2011-08-01)
    In 1889, Dr. Stephen Paget proposed the "seed and soil" hypothesis, which states that cancer cells (the seeds) need the proper microenvironment (the soil) for them to grow, spread and metastasize systemically. In this hypothesis, Dr. Paget rightfully recognized that the tumor microenvironment has an important role to play in cancer progression and metastasis. In this regard, a series of recent studies have elegantly shown that the production of hydrogen peroxide, by both cancer cells and cancer-associated fibroblasts, may provide the necessary "fertilizer," by driving accelerated aging, DNA damage, inflammation and cancer metabolism, in the tumor microenvironment. By secreting hydrogen peroxide, cancer cells and fibroblasts are mimicking the behavior of immune cells (macrophages/neutrophils), driving local and systemic inflammation, via the innate immune response (NFκB). Thus, we should consider using various therapeutic strategies (such as catalase and/or other anti-oxidants) to neutralize the production of cancer-associated hydrogen peroxide, thereby preventing tumor-stroma co-evolution and metastasis. The implications of these findings for overcoming chemo-resistance in cancer cells are also discussed in the context of hydrogen peroxide production and cancer metabolism.
  • Understanding the metabolic basis of drug resistance: therapeutic induction of the Warburg effect kills cancer cells.

    Martinez-Outschoorn, U E; Lin, Z; Ko, Y H; Goldberg, A F; Flomenberg, N; Wang, C; Pavlides, S; Pestell, R G; Howell, Anthony; Sotgia, F; et al. (2011-08-01)
    Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, "fueling" oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream of to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the "root cause" of cancer, but rather it may provide the necessary clues to preventing chemo-resistance in cancer cells. Finally, we observed that this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus, simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer.
  • Reflections on attempted Anglo-Japanese collaboration on STAMPEDE: a randomized controlled trial for men with prostate cancer.

    Sydes, M R; Egawa, S; Sanders, K; Amos, C; Clarke, Noel W; Kimura, T; James, N D; Cancer Group, Medical Research Council Clinical Trials Unit, London (2011-08)
  • Prevalence of BRCA1 and BRCA2 mutations in triple negative breast cancer.

    Evans, D G; Howell, Anthony; Ward, D; Lalloo, F; Jones, J L; Eccles, D M; Genetic Medicine, St Mary's Hospital, Oxford Road, Manchester, UK. (2011-08)
  • The role of positron emission tomography in management of small cell lung cancer.

    Thomson, David J; Hulse, Paul; Lorigan, Paul C; Faivre-Finn, Corinne; Department of Clinical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2011-08)
    Accurate radiological staging of small-cell lung cancer (SCLC) is of paramount importance in selection of individual patients with limited stage disease for potentially curative treatment while avoiding toxic treatment in those with distant metastatic disease. [(18)F] flurodeoxy-D-glucose (FDG) positron emission tomography (PET) is an attractive tool for this purpose but there is limited evidence to support its use in the routine staging of SCLC. Whether therapeutic decisions based on FDG-PET imaging should be made remains uncertain. There is only preliminary evidence for use of FDG-PET as a prognostic biomarker, in the assessment of response to treatment and delineation of disease in conformal radiation planning.
  • Vaccines for the treatment of non-small cell lung cancer: investigational approaches and clinical experience.

    Mellstedt, H; Vansteenkiste, J; Thatcher, Nick; Cancer Centre Karolinska, Department of Oncology, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. (2011-07)
    Globally, lung cancer remains the most common malignancy and the leading cause of cancer-related death. Whilst resection is a therapeutic option for patients with early stage non-small cell lung cancer (NSCLC), most patients have locally advanced or metastatic disease at diagnosis, the treatment of which still presents a considerable challenge for medical oncologists. Therapeutic cancer vaccines offer a novel approach for the treatment of patients with NSCLC in both the adjuvant and advanced disease settings. Although early attempts to use such technologies were of limited success, increased knowledge of the molecular pathology of tumors, of the immune system in general, and of tumor immunity in particular, has facilitated the production of more sophisticated anticancer vaccines. A number of promising vaccine candidates based on different types of antigenic stimulus have now been evaluated in clinical studies. These include belagenpumatucel-L, a vaccine derived from four genetically modified, irradiated NSCLC cell lines and target protein-specific vaccines designed to induce responses against epidermal growth factor (EGF), melanoma-associated antigen A3 (MAGE-A3) and mucin 1 (MUC1). The purpose of this review is to describe the mode of action of the vaccine candidates that are most advanced in their clinical development for the treatment of NSCLC, and to summarize the most recent data from clinical studies of these vaccines.
  • Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients.

    Saleem, Azeem; Matthews, Julian C; Ranson, Malcolm R; Callies, S; André, V; Lahn, M; Dickinson, C; Prenant, Christian; Brown, Gavin; McMahon, Adam; et al. (2011)
    Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.
  • Prediction of post-treatment trismus in head and neck cancer patients.

    Lee, Rana; Slevin, Nicholas J; Musgrove, Brian; Swindell, Ric; Molassiotis, Alexander; Christie Hospital NHS Trust, Manchester M20 4BX, UK. (2011-07-25)
    Our aim was to establish the incidence of trismus over time, together with risk factors (including quality of life (QoL)) for the prediction of trismus after treatment in patients with cancer of the head and neck. It was a longitudinal study of 152 patients accepted for primary operation who attended the head and neck cancer clinic of a tertiary referral cancer centre in the United Kingdom. A total of 87 patients was studied prospectively. Our results showed that 41/87 (47%) of patients presented with trismus, 57/80 (71%) had postoperative trismus, and 41/52 (79%) had trismus 6 months after operation or radiotherapy (trismus defined as a maximum mouth opening of ≤35mm). Men and those who drank a lot of alcohol were less likely to have trismus after treatment. QoL variables showed that pain, eating, chewing, taste, saliva, social functioning, social contact, and dry mouth were significantly more impaired in the trismus group than among those without trismus. Postoperative differences in QoL between the two groups highlighted problems with social function and role-playing, fatigue, activity, recreation, and overall reduction in QoL. Women, and those who do not drink alcohol, are at particularly high risk of developing trismus, and, to prevent it and treat it, patients may benefit from multidisciplinary management at an early stage during treatment.
  • Balancing the efficacy and toxicity of chemotherapy in colorectal cancer.

    Braun, Michael S; Seymour, M T; Consultant, Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2011-01)
    As the therapeutic options for the treatment of colorectal cancer have expanded over the past 20 years, so has the complexity of decision making. The goals of treatment in the palliative, adjuvant and neoadjuvant settings vary and it is not only the efficacy of drugs that influence treatment decisions. Age, performance status, the presence of significant comorbidities and the different treatment regimens and strategies provide medical oncologists with an array of options to attempt to maximize patients' quality of life and longevity.
  • SCOTCERV: a phase II trial of docetaxel and gemcitabine as second line chemotherapy in cervical cancer.

    Symonds, R P; Davidson, Susan E; Chan, S; Reed, N S; McMahon, T; Rai, D; Harden, S; Paul, J; University of Leicester, Department of Cancer Studies & Molecular Medicine, Leicester, UK. (2011-10)
    The aim of the study was to determine the response rate and response duration of cervical cancer previously treated by cisplatin (with or without radiation) to a combination of docetaxel and gemcitabine. Secondary endpoints were assessment of toxicity and quality of life (QoL) of patients receiving the treatment.
  • Fulvestrant revisited: efficacy and safety of the 500-mg dose.

    Howell, Anthony; Sapunar, F; CRUK Department of Medical Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road, Manchester, UK. (2011-08)
    Postmenopausal women with hormone receptor-positive advanced breast cancer are candidates for endocrine therapy. As the disease will eventually progress in most patients, it is important to investigate agents with novel modes of action to reduce the likelihood of treatment cross-resistance. Fulvestrant is an estrogen receptor antagonist with no known agonist effects that has been shown to be as effective as anastrozole following failure on tamoxifen, at the approved dose of 250 mg/mo. However, pharmacokinetic modelling and evidence of clinical efficacy in early trials, together with the favorable tolerability profile of fulvestrant 250 mg, led to suggestions that increasing the fulvestrant dose would lead to an improved benefit-risk profile. This review describes the rationale behind the development of a 500 mg/mo higher dose of fulvestrant and details relevant clinical trials, including the pivotal phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study. CONFIRM demonstrated a significant improvement in progression-free survival for fulvestrant 500 mg versus 250 mg in postmenopausal patients who had progressed on previous endocrine therapy. Here, we present and discuss a pooled safety analysis of CONFIRM and three further clinical studies demonstrating fulvestrant 500 mg to be well-tolerated with no evidence of dose-related adverse events. Overall, these data indicate an improved benefit-risk profile for fulvestrant 500 mg versus 250 mg following failure on prior endocrine therapy, and suggest that fulvestrant 500 mg may be considered in future as initial endocrine treatment for advanced breast cancer.
  • Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers.

    Harrington, K J; Billingham, L J; Brunner, T B; Burnet, N G; Chan, C S; Hoskin, P; Mackay, Ranald I; Maughan, T S; Macdougall, J; McKenna, W G; et al. (2011-08-23)
  • Development of an advanced database for clinical trials integrated with an electronic patient record system.

    Newsham, A C; Johnston, C; Hall, G; Leahy, Michael G; Smith, A B; Vikram, A; Donnelly, A M; Velikova, G; Selby, P J; Fisher, S E; et al. (2011-08)
    Secondary use of patient databases is essential in healthcare if clinical trials are to progress efficiently to planned time and target and imperative if the planned UK expansion of research and development (R&D) at point of care is to be achieved. Integration of effective databases primarily designed to facilitate patient care with R&D requirements is needed but represents a complex challenge. We present a system that achieves an integrated approach with online management of complex datasets for clinical trials within care records using a specific study as an example to show functionality in practice; illustrating how this system provides an ideal resource to meet the needs of both clinicians and researchers.

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