31 research outputs found
Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up
No full textBackground: The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods.Methods: The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years.Results: In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients.Conclusions: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy
Molecular monitoring of response to imatinib (Glivec) in CML patients pretreated with interferon alpha. Low levels of residual disease are associated with continuous remission
No full textA significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL <0.1% as best molecular response are in continuous remission, while 6/13 patients (46%) with ratios >/=0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL &<0.1% are associated with continuous remission
Integrating cancer survivors' experiences into UK cancer registries: design and development of the ePOCS system (electronic Patient-reported Outcomes from Cancer Survivors).
No full textBACKGROUND: Understanding the psychosocial challenges of cancer survivorship, and identifying which patients experience ongoing difficulties, is a key priority. The ePOCS (electronic patient-reported outcomes from cancer survivors) project aims to develop and evaluate a cost-efficient, UK-scalable electronic system for collecting patient-reported outcome measures (PROMs), at regular post-diagnostic timepoints, and linking these with clinical data in cancer registries. METHODS: A multidisciplinary team developed the system using agile methods. Design entailed process mapping the system's constituent parts, data flows and involved human activities, and undertaking usability testing. Informatics specialists built new technical components, including a web-based questionnaire tool and tracking database, and established component-connecting data flows. Development challenges were overcome, including patient usability and data linkage and security. RESULTS: We have developed a system in which PROMs are completed online, using a secure questionnaire administration tool, accessed via a public-facing website, and the responses are linked and stored with clinical registry data. Patient monitoring and communications are semiautomated via a tracker database, and patient correspondence is primarily Email-based. The system is currently honed for clinician-led hospital-based patient recruitment. CONCLUSIONS: A feasibility test study is underway. Although there are possible challenges to sustaining and scaling up ePOCS, the system has potential to support UK epidemiological PROMs collection and clinical data linkage
Socio-economic inequality in small area use of elective total hip replacement in the English NHS in 1991 and 2001
No full textInternational evidence suggests that there are substantial socio-economic inequalities in the delivery of specialist health services, even in the UK and other high-income countries with publicly funded health systems (Goddard and Smith 2001, Dixon et al. 2003, Van Doorslaer, Koolman and Jones 2004, Van Doorslaer et al. 2000). Studies of total hip replacement in the English NHS have yielded particularly striking examples, given that hip replacement is such a common, effective and longestablished health technology. Administrative data show that people living in deprived areas are less likely to receive hip replacement (Chaturvedi and Ben-Shlomo 1995, Dixon et al. 2004) while survey data suggest they may be more likely to need it (Milner et al. 2004). However, previous studies have not examined change in inequality over time. This paper presents evidence on the change in socio-economic inequality in small area use of elective total hip replacement in the English NHS, comparing 1991 with 2001. This was a period of important large-scale health care reform in England, involving at least two significant reforms that might potentially have influenced socio-economic inequality in health care delivery: (1) the introduction and subsequent abolition of the Conservative “internal market” 1991-7, and (2) the introduction in 1995 of a revised NHS resource allocation formula designed to reduce geographical inequalities in health care delivery. Two datasets, for 1991 and 2001, were assembled from routine NHS data sources: Hospital Episode Statistics (HES) on hospital utilisation in England and the corresponding decennial National Censuses in 1991 and 2001. Both datasets contain information on over 8,000 electoral wards in England (over 95% of the total). To improve comparability, a common geography of frozen 1991 wards was adopted. The Townsend deprivation score was employed as an indicator of socio-economic status. Inequality was analysed in two ways. First, for comparability with previous small area studies of hip replacement, by using simple range measures based on indirectly age-sex standardised utilisation ratios (SURs) by deprivation quintile groups. Second, using concentration indices of deprivationrelated inequality in use based on indirectly age-sex standardised utilisation ratios for each individual small area. Each SUR is the observed use divided by the expected use, if each age and sex group in the study population had the same rates of use as the national population.
Total and methyl- mercury analysis of sea ice, seawater, snow, and brine samples collected during the SIPEX II voyage of the Aurora Australis, 2012
No full textProgress Code: completedStatement: When transferring melted core section IS7TM1D to a Teflon bottle, the sample was mixed with some of IS7TM1E (1:1 mixture, ~150 mL each), this sample is referred to as IS7TM1DE. Only had 75 mL of just IS7TM1E, and 150 mL of just IS7TM1D. IS7TM1D was run for both methyl and total mercury, but only had enough IS7TM1E to run for MeHg analysis.Sample collection:<br/>Seawater samples were taken from the trace metal rosette system from ten different depths. Seawater samples from just underneath the ice were collected at the trace metal site using a grab sample. Water samples were spiked with 1% v/v ultra pure HCl within 24 hours of collection and stored in double Ziploc bags at ambient temperature. Brine samples were collected from sac holes at the trace metal and main bio sites. Sea ice cores were collected from either the Main Bio sample site or the Trace Metal site using sampling protocol followed by each group. Ice cores were cut using a stainless steel saw, in 6 cm sections, and then placed in double Ziploc bags and stored at -20 degrees C in large, clean plastic bins. Snow samples were collected from undisturbed sites, upwind from the ship, close to the trace metal site. Samples were collected into acid-washed glass jars (SN0 samples), or into acid-washed buckets lined with sterile Ziploc bags (FSN or UFSN samples). Snow samples were allowed to melt overnight at 4 degrees C, then acidified with 1% v/v HCl. Snow, brine, seawater samples used for mercury analysis were kept in sterile PETG bottles (250 or 500 mL), or acid-washed Teflon, or acid-washed glass bottles or jars, and preserved with 1% v/v HCl. Snow, brine, and seawater samples kept for culturing work were preserved in falcon tubes in 20% v/v glycerol and stored at -80 degrees C. For a detailed record of samples taken and analysed, please refer to the sample inventory spreadsheet. <br/><br/>For mercury analysis, ice core sections were cut in half with a stainless steel trace metal hand saw and melted overnight at ambient temperature in acid-washed 500 mL glass jars. Half of the ice core sections were kept preserved at -20 degrees C for future analytical work. The melt (125-250 mL) was then transferred to acid-washed Teflon bottles and acidified with 1% v/v HCl and kept at ambient temperature. <br/><br/> <br/>Total and methylmercury analysis:<br/>Seawater, sea ice, snow, and brine samples were analysed for total and methyl- mercury at the Mercury Lab at the USGS Wisconsin Water Research Center in Middleton, Wisconsin in March 2013. Total mercury (HgT) analysis was performed using the Manual HgT procedure outlined on the USGS Mercury Lab's website (http://wi.water.usgs.gov/mercury-lab/analysis-methods.html), which is based on EPA Method 1631. Methylmercury (MeHG) analysis was performed per the Brooks-Rand "MERX" by ICPMS isotope dilution method (USGS Open-File Report 01-445, http://wi.water.usgs.gov/mercury-lab/analysis-methods.html). <br/><br/>Data files:<br/>Raw data for total mercury are saved as excel spreadsheets (YYYYMMDD_Analyst_HgT.xls), and the original logs of the chromatograms from the PeakNet software (MMDDYY.LOG). Raw data for methylmercury analysis are saved as excel files (YYYYMMDDAnalyst_MeHg Waters.xlsx), and the Chromera reports from the ICPMS
Atorvastatin as a stable treatment in bronchiectasis:a randomised controlled trial
No full textBackground: Bronchiectasis is characterised by chronic cough, sputum production, and recurrent chest infections. Pathogenesis is poorly understood, but excess neutrophilic airway inflammation is seen. Accumulating evidence suggests that statins have pleiotropic effects; therefore, these drugs could be a potential anti-inflammatory treatment for patients with bronchiectasis. We did a proof-of-concept randomised controlled trial to establish if atorvastatin could reduce cough in patients with bronchiectasis. Methods: Patients aged 18-79 years were recruited from a secondary-care clinic in Edinburgh, UK. Participants had clinically significant bronchiectasis (ie, cough and sputum production when clinically stable) confirmed by chest CT and two or more chest infections in the preceding year. Individuals were randomly allocated to receive either high-dose atorvastatin (80 mg) or a placebo, given orally once a day for 6 months. Sequence generation was done with a block randomisation of four. Random allocation was masked to study investigators and patients. The primary endpoint was reduction in cough from baseline to 6 months, measured by the Leicester Cough Questionnaire (LCQ) score, with a lower score indicating a more severe cough (minimum clinically important difference, 1·3 units). Analysis was done by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT01299181. Findings: Between June 23, 2011, and Jan 30, 2011, 82 patients were screened for inclusion in the study and 22 were excluded before randomisation. 30 individuals were assigned atorvastatin and 30 were allocated placebo. The change from baseline to 6 months in LCQ score differed between groups, with a mean change of 1·5 units in patients allocated atorvastatin versus -0·7 units in those assigned placebo (mean difference 2·2, 95% CI 0·5-3·9; p=0·01). 12 (40%) of 30 patients in the atorvastatin group improved by 1·3 units or more on the LCQ compared with five (17%) of 30 in the placebo group (difference 23%, 95% CI 1-45; p=0·04). Ten (33%) patients assigned atorvastatin had an adverse event versus three (10%) allocated placebo (difference 23%, 95% CI 3-43; p=0·02). No serious adverse events were recorded. Interpretation: 6 months of atorvastatin improved cough on a quality-of-life scale in patients with bronchiectasis. Multicentre studies are now needed to assess whether long-term statin treatment can reduce exacerbations. Funding: Chief Scientist's Office. © 2014 Mandal et al. Open Access article distributed under the terms of CC BY-NC-ND
The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching
No full textSignificance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc
Assessment and determinants of health care utilization among patients with musculoskeletal conditions undergoing outpatient rehabilitation in Germany
No full textThe overall objective of this doctoral thesis is to address some of the conditions necessary to routinely perform alongside economic evaluations of rehabilitation programs. The specific aims are to 1) present a standardized instrument to collect data about health care resource use, 2) identify major cost categories of direct medical costs to be used in comparative economic evaluations of subjects with musculoskeletal diseases and 3) identify determinants of direct medical costs among subjects with musculoskeletal diseases. This thesis is therefore subdivided into three parts. In the first part the development of a standardized instrument to collect health care resource use in the context of rehabilitation is described and lessons learned are discussed. In the next part major direct medical costs categories among patients with musculoskeletal conditions undergoing outpatient rehabilitation are identified. Lastly, the determinants of the direct medical costs as well as direct medical costs beyond the median incurred by chronic musculoskeletal patients are examined. Each of these parts contain a specific discussion section referring to its specific results
Disfunção cardíaca na sepse experimental avaliada em coração isolado e perfundido de camundongo
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia, Florianópolis, 2010A síndrome da resposta inflamatória sistêmica (SIRS), quando associada a uma infecção pode evoluir para sepse e choque séptico, que são importantes causas de morte nas UTIs. Em geral, a morte é causada por um colapso cardiovascular e hipotensão refratária, que aparecem logo no início da sepse. A disfunção vascular é mais estudada e compreendida que a disfunção cardíaca, contudo a última é reconhecida como um importante mediador da disfunção de múltiplos órgãos na sepse. O objetivo do presente trabalho foi caracterizar a disfunção cardíaca na sepse experimental induzida pela ligadura e perfuração do ceco (CLP) em camundongos, utilizando a metodologia de coração isolado e perfundido (preparação de Langendorff), e também, avaliar a participação do óxido nítrico nesse processo. Os parâmetros cardíacos avaliados foram: Tensão sistólica e diastólica, +dT/dt (velocidade de contração), -dT/dt (velocidade de relaxamento), AUC (área sob a curva), pressão de perfusão das coronárias e frequência cardíaca. Observamos que durante a sepse severa (índice de mortalidade de 100% quarenta e oito horas após a CLP) o perfil de atividade apresentado pelos corações sépticos, apesar de variado, mostra que a sepse causa importantes alterações na funcionalidade cardíaca. O parâmetro tensão sistólica, três horas após os animais serem submetidos à CLP, mostrou que 38% dos corações apresentaram valores superiores aos apresentados pelos corações controle (e por isso denominados de suprafuncionais), 12% apresentaram valores inferiores (subfuncionais) e 50% apresentaram valores semelhantes aos apresentados pelos corações controle (normofuncionais). Seis horas após a CLP o subgrupo suprafuncional correspondeu a apenas 21% do total de corações avaliados, enquanto o subgrupo subfuncional correspondeu a 29%. Doze horas após a CLP o subgrupo normofuncional foi o mais numeroso, correspondendo a 77% do total de corações avaliados. Por fim, vinte e quatro horas após a CLP houve um aumento substancial no número de corações subfuncionais, representando 40% dos corações avaliados. Perfil semelhante foi encontrado em relação aos parâmetros velocidade de contração, velocidade de relaxamento e AUC. Quando estimulados com isoprenalina para avaliação da capacidade contrátil e capacidade cronotrópica positiva, os corações dos animais submetidos à CLP vinte e quatro horas antes apresentaram importante redução no funcionamento das células auto-rítmicas do nodo sino-atrial, alterações no sistema de condução dos estímulos e ainda, o sistema contrátil destes corações encontrou-se parcialmente reduzido. Tanto os corações suprafuncionais avaliados três horas após a CLP quanto os corações suprafuncionais avaliados vinte e quatro horas após, apresentaram tensão sistólica superior à apresentada pelos corações controle em resposta à isoprenalina. A resposta cronotrópica e inotrópica positiva dos demais corações avaliados (subfuncionais três horas após a CLP, normofuncionais três e vinte e quatro horas após a CLP) foi semelhante à resposta apresentada pelos corações controle, sugerindo que a atividade beta-adrenérgica, atividade contrátil e o aspecto elétrico da frequência cardíaca estão preservados nestes corações. Observamos ainda que os níveis plasmáticos de NOx encontram-se elevados a partir de três horas após o procedimento cirúrgico, permanecendo assim até pelo menos quarenta e oito horas após a CLP. A infusão de um inibidor não-seletivo das enzimas NOS (L-NAME) não alterou a atividade basal dos corações controle e dos corações sépticos avaliados vinte e quatro horas após a CLP. Por outro lado, quando estimulados com isoprenalina, os corações controle infundidos com L-NAME apresentaram resposta cronotrópica e inotrópica positiva inferior à apresentada pelos corações controle que receberam apenas Krebs. Os corações sépticos que receberam L-NAME quando estimulados com isoprenalina apresentaram resposta concentração-dependente à isoprenalina, tanto no parâmetro tensão sistólica quanto no parâmetro frequência cardíaca, efeito este que não foi observado nos corações sépticos que receberam apenas Krebs. O substrato L-arginina não é um fator limitante para a produção de óxido nítrico, visto que não foram observadas diferenças em corações controle e corações sépticos avaliados vinte e quatro horas após a CLP e que tiveram arginina adicionada à solução de perfusão. Assim, nosso trabalho mostra que ocorrem importantes alterações cardíacas durante a sepse, as quais acometem tanto a maquinaria contrátil quanto as células auto-rítmicas, tendo início logo nas primeiras horas de instalação do quadro e perdurando até horários mais tardios. Demonstramos ainda, que o óxido nítrico parece estar envolvido nas alterações observadas
Feasibility test of a UK-scalable electronic system for regular collection of patient-reported outcome measures and linkage with clinical cancer registry data: The electronic Patient-reported Outcomes from Cancer Survivors (ePOCS) system
No full textAbstract Background Cancer survivors can face significant physical and psychosocial challenges; there is a need to identify and predict which survivors experience what sorts of difficulties. As highlighted in the UK National Cancer Survivorship Initiative, routine post-diagnostic collection of patient reported outcome measures (PROMs) is required; to be most informative, PROMs must be linked and analysed with patients' diagnostic and treatment information. We have designed and built a potentially cost-efficient UK-scalable electronic system for collecting PROMs via the internet, at regular post-diagnostic time-points, for linking these data with patients' clinical data in cancer registries, and for electronically managing the associated patient monitoring and communications; the electronic Patient-reported Outcomes from Cancer Survivors (ePOCS) system. This study aims to test the feasibility of the ePOCS system, by running it for 2 years in two Yorkshire NHS Trusts, and using the Northern and Yorkshire Cancer Registry and Information Service. Methods/Design Non-metastatic breast, colorectal and prostate cancer patients (largest survivor groups), within 6 months post-diagnosis, will be recruited from hospitals in the Yorkshire Cancer Network. Participants will be asked to complete PROMS, assessing a range of health-related quality-of-life outcomes, at three time-points up to 15 months post-diagnosis, and subsequently to provide opinion on the ePOCS system via a feedback questionnaire. Feasibility will be examined primarily in terms of patient recruitment and retention rates, the representativeness of participating patients, the quantity and quality of collected PROMs data, patients' feedback, the success and reliability of the underpinning informatics, and the system running costs. If sufficient data are generated during system testing, these will be analysed to assess the health-related quality-of-life outcomes reported by patients, and to explore if and how they relate to disease, treatment and/or individual differences characteristics. Discussion There is currently no system in the UK for collecting PROMs online and linking these with patients' clinical data in cancer registries. If feasible, ePOCS has potential to provide an affordable UK-scalable technical platform to facilitate and support longitudinal cohort research, and improve understanding of cancer survivors' experiences. Comprehensive understanding of survivorship difficulties is vital to inform the development and provision of supportive services and interventions.</p
