bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving end of life care for people with dementia: a rapid participatory appraisal
Authors: Sampson Elizabeth , Mandal Uttara , Holman Amanda , Greenish Wendy , Dening Karen Harrison , Jones Louise 
Published: April 2012

ObjectivesPeople with dementia and their carers may experience poor end of life care, often having to navigate complex health and social care systems. The objectives of this study were to identify: (1) barriers for people with dementia and their carers in accessing good quality end of life care and (2) cost-effective ways of enabling improvements.MethodsRapid participatory appraisal gains information from different sources across a single locality. Participants were carers of people who had died of dementia, health and social care staff. Care pathways were modelled. Barriers identified from qualitative work were triangulated with detailed case audit and economic analysis. Results were presented to the stakeholder group who generated feasible solutions.ResultsNine cases were audited (predominantly white British male subjects, 64–84 years with advanced dementia). Six resided at home, one in a care home and two in continuing care wards. Five died in their place of residence and four in the acute hospital. Care costs over the 6 months before death were higher in care homes or continuing care (£37 029) than for those living at home (£19 854). Synthesis of qualitative and quantitative data generated areas for improvement: patient pathway, impact of acute hospitalisation, economic costs, advance care planning, impact on carers, skills and training of health and social care staff.ConclusionsThis method provided evidence for stimulating change in the health and social care system. Following the patient journey and identifying barriers to care allowed local context to be considered. Service providers generated solutions enabling ‘ownership’ of changes to service delivery.
Tumor Hypoxia Predicts Biochemical Failure following Radiotherapy for Clinically Localized Prostate Cancer
Authors: Milosevic Michael , Warde Padraig , Ménard Cynthia , Chung Peter , Toi Ants , Ishkanian Adrian , McLean Michael , Pintilie Melania , Sykes Jenna , Gospodarowicz Mary , Catton Charles , Hill Richard P. , Bristow Robert 
Published: April 2012

Abstract
Purpose: Tumor hypoxia is an important determinant of outcome in many human malignancies and is associated with treatment resistance and metastases. The aim of this study was to determine the effect of hypoxia in patients with prostate cancer treated with radiotherapy.
Experimental Design: Tumor hypoxia was measured in 247 patients with clinically localized prostate cancer before radiotherapy, with or without hormonal therapy. The median pO2 was 6.8 mm Hg and the median hypoxic percentage less than 10 mm Hg (HP10) was 63%. The median follow-up was 6.6 years.
Results: The 5-year biochemical relapse-free rate (bRFR) was 78%. Prostrate-specific antigen and Gleason score were both associated with biochemical relapse and formed a baseline clinical model. The effect of hypoxia was found to vary with the duration of patient follow-up. HP10, when added to the clinical model, was an independent predictor of early bRFR (P = 0.019). The relationship between hypoxia and early bRFR was more pronounced when the analysis was restricted to 142 patients with bulk tumor at the site of the oxygen measurements (P = 0.004). Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during follow-up (P = 0.043), again with the effect being greatest early after completing treatment.
Conclusions: This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It shows that hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland. Clin Cancer Res; 18(7); 2108–14. ©2012 AACR.
Metformin Use Is Associated with Better Survival of Diabetic Patients with Pancreatic Cancer
Authors: Sadeghi Navid , Abbruzzese James L. , Yeung Sai-Ching J. , Hassan Manal , Li Donghui 
Published: April 2012

Abstract
Purpose: Accumulating evidence suggests that metformin has antitumor activity. The aim of this study was to determine whether metformin use has a survival benefit in patients with pancreatic cancer.
Experimental Design: We conducted a retrospective study of patients with diabetes and pancreatic cancer treated at The University of Texas MD Anderson Cancer Center (Houston, TX). Information on diabetes history, including treatment modalities and clinical outcome of pancreatic cancer, was collected using personal interviews and medical record review. Survival analysis was carried out using a Kaplan–Meier plot, log-rank test, and Cox proportional hazards regression models.
Results: Among the 302 patients identified, there were no significant differences in demographic or major clinical characteristics between the patients who had received metformin (n = 117) and those who had not (n = 185). The 2-year survival rate was 30.1% for the metformin group and 15.4% for the non-metformin group (P = 0.004; χ2 test). The median overall survival time was 15.2 months for the metformin group, and 11.1 months for the non-metformin group (P = 0.004, log-rank test). Metformin users had a 32% lower risk of death; the HR (95% confidence interval) was 0.68 (0.52–0.89) in a univariate model (P = 0.004), 0.64 (0.48–0.86) after adjusting for other clinical predictors (P = 0.003), and 0.62 (0.44–0.87) after excluding insulin users (P = 0.006). Metformin use was significantly associated with longer survival in patients with nonmetastatic disease only.
Conclusions: Our finding that metformin use was associated with improved outcome of patients with diabetes and pancreatic cancer should be confirmed in independent studies. Future research should prospectively evaluate metformin as a supplemental therapy in this population. Clin Cancer Res; 18(10); 2905–12. ©2012 AACR.
Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors
Authors: Naing Aung , LoRusso Patricia , Fu Siqing , Hong David S. , Anderson Pete , Benjamin Robert S. , Ludwig Joseph , Chen Helen X. , Doyle Laurence A. , Kurzrock Razelle 
Published: April 2012

Abstract
Purpose: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R).
Experimental Design: Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months.
Results: Twenty patients [17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I–II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose.
Conclusion: Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors. Clin Cancer Res; 18(9); 2625–31. ©2012 AACR.
Metformin and Pancreatic Cancer: A Clue Requiring Investigation
Authors: Pollak Michael 
Published: April 2012

Abstract
Laboratory models show antineoplastic activity of metformin under certain conditions, and pharmacoepidemiologic studies have reported reduced cancer burden among diabetics taking metformin. Therefore, the hypothesis that metformin has antineoplastic activity is receiving increasing attention. However, gaps in knowledge must be addressed before metformin can be “repurposed” for oncologic indications. Clin Cancer Res; 18(10); 2723–5. ©2012 AACR.
Metformin Prevents Liver Tumorigenesis by Inhibiting Pathways Driving Hepatic Lipogenesis
Authors: Bhalla Kavita , Hwang Bor Jang , Dewi Ruby E. , Twaddel William , Goloubeva Olga G. , Wong Kwok-Kin , Saxena Neeraj K. , Biswal Shyam , Girnun Geoffrey D. 
Published: April 2012

Abstract
A number of factors have been identified that increase the risk of hepatocellular carcinoma (HCC). Recently it has become appreciated that type II diabetes increases the risk of developing HCC. This represents a patient population that can be identified and targeted for cancer prevention. The biguanide metformin is a first-line therapy for the treatment of type II diabetes in which it exerts its effects primarily on the liver. A role of metformin in HCC is suggested by studies linking metformin intake for control of diabetes with a reduced risk of HCC. Although a number of preclinical studies show the anticancer properties of metformin in a number of tissues, no studies have directly examined the effect of metformin on preventing carcinogenesis in the liver, one of its main sites of action. We show in these studies that metformin protected mice against chemically induced liver tumors. Interestingly, metformin did not increase AMPK activation, often shown to be a metformin target. Rather metformin decreased the expression of several lipogenic enzymes and lipogenesis. In addition, restoring lipogenic gene expression by ectopic expression of the lipogenic transcription factor SREBP1c rescues metformin-mediated growth inhibition. This mechanism of action suggests that metformin may also be useful for patients with other disorders associated with HCC in which increased lipid synthesis is observed. As a whole these studies show that metformin prevents HCC and that metformin should be evaluated as a preventive agent for HCC in readily identifiable at-risk patients. Cancer Prev Res; 5(4); 544–52. ©2012 AACR.
Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions
Authors: Vitale-Cross Lynn , Molinolo Alfredo A. , Martin Daniel , Younis Rania H. , Maruyama Takashi , Patel Vyomesh , Chen Wanjun , Schneider Abraham , Gutkind J. Silvio 
Published: April 2012

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mTOR complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type II diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and -independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression. Cancer Prev Res; 5(4); 562–73. ©2012 AACR.
Metformin and Hepatic Carcinogenesis
Authors: Pollak Michael , Gonzalez-Angulo Ana M. 
Published: April 2012

Abstract
Retrospective, hypothesis-generating population studies suggest that diabetics treated with metformin have a substantially reduced risk of several cancers, including hepatoma, relative to diabetics on other therapies. In this issue of the journal (beginning on page 544), Bhalla and colleagues contribute to the growing literature on metformin effects in experimental carcinogenesis models, showing reduced carcinogen-induced hepatoma in mice. The clinical need to develop novel prevention strategies for hepatoma is obvious, given an increasing prevalence and poor prognosis. The clues that metformin or related biguanides may have utility in this area justify accelerated laboratory research, as more data concerning mechanism, pharmacokinetics, and predictors of efficacy will help to optimize the design of clinical trials. Cancer Prev Res; 5(4); 500–2. ©2012 AACR.
Metformin Accelerates the Growth of BRAFV600E-Driven Melanoma by Upregulating VEGF-A
Authors: Martin Matthew J. , Hayward Robert , Viros Amaya , Marais Richard 
Published: April 2012

Abstract
The antidiabetic drug metformin has antitumor activity in a variety of cancers because it blocks cell growth by inhibiting TORC1. Here, we show that melanoma cells that are driven by oncogenic BRAF are resistant to the growth-inhibitory effects of metformin because RSK sustains TORC1 activity even when AMP-activated protein kinase (AMPK) is activated. We further show that AMPK targets the dual-specificity protein phosphatase DUSP6 for degradation and this increases ERK activity, which then upregulates the VEGF-A protein. Critically, this drives angiogenesis and accelerates the growth of BRAF-driven tumors in mice. Unexpectedly, however, when VEGF signaling is inhibited, instead of accelerating tumor growth, metformin inhibits tumor growth. Thus, we show that BRAF-driven melanoma cells are resistant to the antigrowth effects of AMPK and that AMPK mediates cell-autonomous and cell-nonautonomous effects that accelerate the growth of these cells in vivo.
Significance: Metformin inhibits the growth of most tumor cells, but BRAF-mutant melanoma cells are resistant to metformin in vitro, and metformin accelerates their growth in vivo. Unexpectedly, VEGF inhibitors and metformin synergize to suppress the growth of BRAF-mutant tumors, revealing a combination of drugs that may be effective in these patients. Cancer Discov; 2(4); 344–55. ©2012 AACR.
This article is highlighted in the In This Issue feature, 288
Differential Sensitivity of Glioma- versus Lung Cancer–Specific EGFR Mutations to EGFR Kinase Inhibitors
Authors: Vivanco Igor , Robins H. Ian , Rohle Daniel , Campos Carl , Grommes Christian , Nghiemphu Phioanh Leia , Kubek Sara , Oldrini Barbara , Chheda Milan G. , Yannuzzi Nicolas , Tao Hui , Zhu Shaojun , Iwanami Akio , Kuga Daisuke , Dang Julie , Pedraza Alicia , Brennan Cameron W. , Heguy Adriana , Liau Linda M. , Lieberman Frank , Yung W. K. Alfred , Gilbert Mark R. , Reardon David A. , Drappatz Jan , Wen Patrick Y. , Lamborn Kathleen R. , Chang Susan M. , Prados Michael D. , Fine Howard A. , Horvath Steve , Wu Nian , Lassman Andrew B. , DeAngelis Lisa M. , Yong William H. , Kuhn John G. , Mischel Paul S. , Mehta Minesh P. , Cloughesy Timothy F. , Mellinghoff Ingo K. 
Published: April 2012

Abstract
Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types.
Significance: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain. Cancer Discov; 2(5); 458–71. ©2012 AACR.
Read the Commentary on this article by Park and Lemmon, p. 398.
This article is highlighted in the In This Issue feature, p. 377.
Kinetics of Inhibitor Cycling Underlie Therapeutic Disparities between EGFR-Driven Lung and Brain Cancers
Authors: Barkovich Krister J. , Hariono Sujatmi , Garske Adam L. , Zhang Jie , Blair Jimmy A. , Fan Qi-Wen , Shokat Kevan M. , Nicolaides Theodore , Weiss William A. 
Published: April 2012

Abstract
Although mutational activation of the epidermal growth factor receptor (EGFR) features prominently in glioma and non–small cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in patients with NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles and quantified kinase-site occupancy by clinical inhibitors with the use of a novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase-site occupancy in glioma-derived EGFRvIII compared with NSCLC-derived EGFR mutants. Kinase-site occupancy correlated directly with cell-cycle arrest. EGFRvIII released erlotinib rapidly compared with wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly.
Significance: These data suggest that kinase-site occupancy is a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes the blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response. Cancer Discov; 2(5); 450–7. ©2012 AACR.
Read the Commentary on this article by Park and Lemmon, p. 398.
This article is highlighted in the In This Issue feature, p. 377.
Imaging Androgen Receptor Signaling with a Radiotracer Targeting Free Prostate-Specific Antigen
Authors: Ulmert David , Evans Michael J. , Holland Jason P. , Rice Samuel L. , Wongvipat John , Pettersson Kim , Abrahamsson Per-Anders , Scardino Peter T. , Larson Steven M. , Lilja Hans , Lewis Jason S. , Sawyers Charles L. 
Published: April 2012

Abstract
Despite intense efforts to develop radiotracers to detect cancers or monitor treatment response, few are widely used as a result of challenges with demonstrating clear clinical use. We reasoned that a radiotracer targeting a validated clinical biomarker could more clearly assess the advantages of imaging cancer. The virtues and shortcomings of measuring secreted prostate-specific antigen (PSA), an androgen receptor (AR) target gene, in patients with prostate cancer are well documented, making it a logical candidate for assessing whether a radiotracer can reveal new (and useful) information beyond that conferred by serum PSA. Therefore, we developed 89Zr-labeled 5A10, a novel radiotracer that targets “free” PSA. 89Zr–5A10 localizes in an AR-dependent manner in vivo to models of castration-resistant prostate cancer, a disease state in which serum PSA may not reflect clinical outcomes. Finally, we demonstrate that 89Zr–5A10 can detect osseous prostate cancer lesions, a context where bone scans fail to discriminate malignant and nonmalignant signals.
Significance: This report establishes that AR-dependent changes in PSA expression levels can be quantitatively measured at tumor lesions using a radiotracer that can be rapidly translated for human application and advances a new paradigm for radiotracer development that may more clearly highlight the unique virtues of an imaging biomarker. Cancer Discov; 2(4); 320–7. ©2012 AACR.
Read the Commentary on this article by Herschman and Czernin, p. 301
This article is highlighted in the In This Issue feature, p. 288
European Union Standards for Tuberculosis Care
Authors: Migliori G.B. , Zellweger J.P. , Abubakar I. , Ibraim E. , Caminero J.A. , De Vries G. , D'Ambrosio L. , Centis R. , Sotgiu G. , Menegale O. , Kliiman K. , Aksamit T. , Cirillo D.M. , Danilovits M. , Dara M. , Dheda K. , Dinh-Xuan A.T. , Kluge H. , Lange C. , Leimane V. , Loddenkemper R. , Nicod L.P. , Raviglione M.C. , Spanevello A. , Thomsen V.Ø. , Villar M. , Wanlin M. , Wedzicha J.A. , Zumla A. , Blasi F. , Huitric E. , Sandgren A. , Manissero D. 
Published: April 2012

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB).The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting.A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed.These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.