989 resultados para B-ALL


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La leucémie lymphoblastique aiguë (LLA) est responsable d’environ 25% de l’ensemble des cancers pédiatriques. Chez 85% des enfants diagnostiqués, la LLA entraîne une prolifération massive et incontrôlée de lymphocytes immatures de type précurseurs B dans la moelle osseuse (LLA pré-B). Des avancées intéressantes ont été faites au cours des trente dernières années et ont mené à une augmentation de l’efficacité des traitements thérapeutiques. Plus de 80% des enfants atteints de LLA seront guéris de cette maladie. Malheureusement, ces traitements manquent de spécificité à cause du manque de connaissances sur les mécanismes moléculaires impliqués durant l’initiation et le développement de la LLA pré-B pédiatrique. En d’autres termes, nous connaissons peu de chose sur l’étiologie de cette maladie. Plus de 25% des enfants atteints de la LLA pré-B présentent la translocation chromosomique t(12;21)(p13;q22) qui implique les gènes ETV6 et AML1. Celle-ci est formée in utero et mène à l’expression de la protéine chimère transcriptionnelle ETV6-AML1, dont la présence seule ne suffit pas au développement de la LLA pré-B. Ainsi, d’autres événements génétiques sont nécessaires au développement de cette leucémie. La délétion de l’allèle résiduel de ETV6 est un événement génétique fréquemment rencontré au moment du diagnostic de la LLA pré-B t(12;21)+. Cette délétion entraîne l’inactivation complète de ETV6 dans les lymphocytes pré-B leucémiques. ETV6 est un répresseur transcriptionnel de la famille Ets. Mon hypothèse de recherche est que ETV6 agit comme gène suppresseur de tumeur dans la LLA pré-B pédiatrique. L’inactivation de ETV6 causerait une dérégulation de l’expression de ses cibles transcriptionnelles et, par le fait même, favoriserait l’initiation et le déroulement de la leucémogenèse pédiatrique. Dans le cadre de mon projet, comme peu de cibles transcriptionnelles de ETV6 sont connues, j’ai effectué des expériences d’immunoprécipitation de la chromatine et des essais luciférases qui ont permis d’identifier six nouvelles cibles transcriptionnelles: TP53 (p53 et Δ133p53), SPHK1, IL-18, PTGER4 et LUM. J’ai démontré que la régulation transcriptionnelle médiée par ETV6 requiert la présence de ses deux domaines fonctionnels: PNT (interactions protéiques) et ETS (liaison à l’ADN). Ces domaines favorisent la reconnaissance d’un site EBS consensus dans une région située près du promoteur de base. Ce mécanisme peut dépendre du promoteur régulé par ETV6, mais également du contexte cellulaire. Des études fonctionnelles réalisées sur des lymphocytes pré-B leucémiques ont permis de mesurer l’impact de la dérégulation de l’expression des cibles transcriptionnelles de ETV6 sur trois voies biologiques: la prolifération cellulaire, l’apoptose induite par un stress génotoxique et la migration cellulaire dirigée par la voie de signalisation CXCL12/CXCR4. Ceci a permis de démontrer l’implication des gènes SPHK1, IL-18 et PTGER4 durant la leucémogenèse pédiatrique. Cette étude est une des premières à suggérer le rôle de ETV6 comme gène suppresseur de tumeur dans la LLA pré-B pédiatrique. Suite à l’inactivation du répresseur transcriptionnel ETV6, l’augmentation de l’expression de ses cibles transcriptionnelles favoriserait la prolifération et la survie des lymphocytes pré-B leucémiques dans la moelle osseuse. L’identification de nouveaux gènes impliqués dans le développement de la LLA pré-B pédiatrique ouvre la porte au développement de nouveaux traitements thérapeutiques qui pourront présenter une meilleure spécificité envers l’étiologie de la maladie.

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La leucémie aigüe lymphoblastique de précurseurs des cellules B (pré-B LAL) est le cancer le plus fréquent chez l’enfant. La transplantation de cellules souches hématopoïétiques (TCSH) est nécessaire dans environ 20 à 30 % des enfants ayant une pré-B LAL. Les rechutes après TCSH sont habituellement réfractaires aux thérapies actuelles, et par conséquent, il est important de développer et d’optimiser de nouvelles stratégies thérapeutiques. Dans cette étude, nous nous sommes intéressés aux cellules « cytokine-induced killer » (CIK). En effet, ces cellules ont été montrées comme hautement cytotoxique contre beaucoup de types de cancers. Cependant, leur activité cytotoxique contre les pré-B LAL n’est pas vraiment efficace. Par conséquent, nous avons étudié la possibilité de combiner l’immunothérapie des cellules CIK avec l’interféron alpha (IFN-α) afin d’optimiser l’activité lytique de ces cellules contre les cellules pré-B LAL. De plus, vu qu’il a été démontré que l’activité cytotoxique des cellules CIK provient de la fraction CD56+, plus particulièrement les cellules CD3+CD56+, nous avons décidé d’utiliser la fraction CD56+ (cellules CD56+) dans l’ensemble de nos expériences. Nous avons observé in vitro que les cellules CD56+ lysent mieux les lignées cellulaires pré-B LAL comparativement aux cellules CIK non purifiées. Aussi, leur activité cytotoxique peut être augmentée par le traitement avec l’IFN-α. Par ailleurs, nous avons démontré l’efficacité des cellules CD56+ traitées par l’IFN-α contre les lignées cellulaires pré- B LAL in vivo, dans le modèle de souris NOD/SCID/gamma c- (NSG). La survie des souris est significativement prolongée lorsqu’elles reçoivent les cellules pré-B LAL avec les cellules CD56+ traitées par l’IFN-α. Nous avons par la suite étudié le mécanisme d’action des cellules CD56+ contre les lignées cellulaires pré-B LAL. Nous avons observé que les cellules CD56+ provenant de sang de cordon sont plus efficaces que les cellules CD56+ provenant de sang I périphérique pour tuer les lignées cellulaires pré-B LAL. Nous avons également montré que les cellules CD56+ utilisent seulement la voie NKG2D ou bien les voies NKG2D et TRAIL selon la lignée cellulaire pré-B LAL cible et selon la provenance de la source des cellules CD56+. Par ailleurs, nous avons remarqué que les cellules CIK sont sensibles à l’apoptose par Fas, et que cette sensibilité influence leur activité cytotoxique contre les cellules tumorales. En conclusion, les cellules CD56+ sont cytotoxiques contre les lignées cellulaires pré-B LAL, et leur effet lytique est augmenté par l’IFN-α aussi bien in vitro qu’in vivo dans le modèle de souris NSG. Ces données précliniques sont encourageantes pour tester cette nouvelle approche d’immunothérapie dans le traitement contre la pré-B LAL.

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L’analyse des anomalies génomiques récurrentes est importante pour établir le diagnostic, le pronostic et pour orienter la thérapie des leucémies aiguës pédiatriques. L’objectif de notre étude est d’élaborer une stratégie optimale pour détecter les anomalies chromosomiques dans les leucémies aiguës lymphoblastiques (LAL) et myéloïdes (LAM) des enfants. Pour ce faire, nous avons caractérisé au caryotype, avec des panels d’hybridation in situ en fluorescence (FISH), par RT-PCR et par l’index d’ADN 253 leucémies de novo reçues au CHU Sainte-Justine entre 2005 et 2011 (186 LAL-B, 27 LAL-T et 40 LAM). Nous avons réussi à optimiser la détection des anomalies chromosomiques dans les trois types de leucémies, avec des fréquences de 93,5% dans les LAL-B (174/186), 66,7% dans les LAL-T (18/27) et 90% dans les LAM (36/40). Nos résultats suggèrent d’utiliser plusieurs tests génétiques concomitants afin d’optimiser la détection des anomalies génomiques dans les LAL et les LAM de novo pédiatriques.

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La leucémie aiguë lymphoblastique (LAL) est le cancer pédiatrique le plus fréquent. Plusieurs réarrangements chromosomiques ont été associés à cette maladie, dont la translocation t(12;21), qui est observée dans 25% des cas de LAL de type pré-B. Cette translocation engendre l’expression de la protéine de fusion ETV6-AML1. Toutefois, celle-ci n’est pas suffisante pour initier seule une leucémie, ce qui suggère que des mutations additionnelles sont nécessaires à la transformation oncogénique. Or, on observe que l’allèle non-réarrangé d’ETV6 est perdu dans 75% des cas de t(12;21). Cette délétion entraîne l’inactivation complète du facteur de transcription ETV6 et l’abolition de sa fonction biologique. Puisqu’ETV6 semble jouer un rôle de suppresseur de tumeurs, nous croyons que son inactivation favoriserait le développement de la leucémie via la dérégulation de ses gènes cibles. Ce projet visait donc à identifier de nouvelles cibles transcriptionnelles d’ETV6, afin d’élucider son implication dans la leucémie. Une expérience de RNA-Seq a permis d’identifier plus de 200 gènes dont l’expression est corrélée avec celle d’ETV6 dans des cellules souches hématopoïétiques CD34+. Parmi ceux-ci, plusieurs gènes sont impliqués dans la réponse immunitaire et inflammatoire, la migration cellulaire, l’homéostasie ionique et la signalisation intracellulaire. Nous avons également mis en place une approche d’immunoprécipitation de la chromatine afin d’identifier les régions auxquelles le facteur de transcription ETV6 peut se lier. À l’aide de cette méthode, nous avons démontré une interaction entre ETV6 et SLCO2B1, un gène dont l’expression est également co-régulée avec ETV6. Finalement, notre étude suggère qu’ETV6 contribuerait à la leucémogenèse en dérégulant l’expression de certains gènes ayant des propriétés oncogéniques.

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Introducción: El presente estudio pretende determinar la mortalidad y caracterizar morbilidad de este grupo de recién nacidos, para establecer planes de mejoramiento. Materiales y método: Estudio descriptivo retrospectivo de corte transversal. Se revisaron 158 historias clínicas de los recién nacidos prematuros menores de 1500 gramos hospitalizados en la unidad de cuidados intensivos neonatales del Hospital Universitario Departamental de Nariño durante el periodo 2011 al 2013. La información fue analizada estadísticamente. Resultados: Se encontró que de 5447 nacidos vivos el 2,9 % fueron menores de 1500 gramos. 52,5 % eran de género masculino, 63,9% nacieron por cesárea. El 23,4 % no recibió esteroides antenatales. La tasa de mortalidad para el periodo de estudio en este grupo de pacientes fue de 7.3 por mil nacidos vivos. El 100% de los recién nacidos de menos de 750 gr fallecieron. Mientras que no se registro ninguna sobrevida de menos de 24 semanas. Conclusiones: Podría establecerse este como límite de viabilidad el peso al nacer < 750 gr y menos de 24 semanas de gestación, en donde la muerte es prácticamente la regla, siempre teniendo en cuenta evaluar cuidadosamente cada caso particular. La morbilidad de los prematuros de muy bajo peso al nacer esta en los rangos reportados en la literatura.

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Objectives To evaluate the effectiveness of integrated motivational interviewing and cognitive behaviour therapy in addition to standard care for patients with psychosis and a co-morbid substance use problem. Design Two-centre, open, rater-blind randomised controlled trial Setting UK Secondary Care Participants 327 patients with clinical diagnoses of schizophrenia, schizophreniform or schizoaffective disorder and DSM-IV diagnoses of drug and/or alcohol dependence or abuse Interventions Participants were randomly allocated to integrated motivational interviewing and cognitive behaviour therapy or standard care. Therapy has two phases. Phase one – “motivation building” – concerns engaging the patient, then exploring and resolving ambivalence for change in substance use. Phase two –“Action” – supports and facilitates change using cognitive behavioural approaches. Up to 26 therapy sessions were delivered over one year. Main outcomes The primary outcome was death from any cause or admission to hospital in the 12 months after therapy. Secondary outcomes were frequency and amount of substance use (Timeline Followback), readiness to change, perceived negative consequences of use, psychotic symptom ratings, number and duration of relapses, global assessment of functioning and deliberate self harm, at 12 and 24 months, with additional Timeline Followback assessments at 6 and 18 months. Analysis was by intention-to-treat with robust treatment effect estimates. Results 327 participants were randomised. 326 (99.7%) were assessed on the primary outcome, 246 (75.2%) on main secondary outcomes at 24 months. Regarding the primary outcome, there was no beneficial treatment effect on hospital admissions/ death during follow-up, with 20.2% (33/163) of controls and 23.3% (38/163) of the therapy group deceased or admitted (adjusted odds-ratio 1.16; P= 0.579; 95% confidence interval 0.68 to 1.99). For secondary outcomes there was no treatment effect on frequency of substance use or perceived negative consequences, but a statistically significant effect of therapy on amount used per substance-using day (adjusted odds-ratios: (a) for main substance 1.50; P=0.016; 1.08 to 2.09, (b) all substances 1.48; P=0.017; 1.07 to 2.05). There was a statistically significant treatment effect on readiness to change use at 12 months (adjusted odds-ratio 2.05; P=0.004; 1.26 to 3.31), not maintained at 24 months. There were no treatment effects on assessed clinical outcomes. Conclusions Integrated motivational interviewing and cognitive behaviour therapy for people with psychosis and substance misuse does not improve outcome in terms of hospitalisation, symptom outcomes or functioning. It does result in a reduction in amount of substance use which is maintained over the year’s follow up. Trial registration Current Controlled Trials: ISRCTN14404480

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Background: This study tested the homeostatic model of subjective quality of life in a group of 47 short stay patients as they progressed through the stages of hospitalization for surgery.
Method: Participants completed a questionnaire measuring subjective quality of life, positive and negative affect, self-esteem, optimism and cognitive flexibility, the day prior to admission (T1), two days post-operation (T2) and one week after discharge (T3). Neuroticism and Extroversion were measured at Time 1.
Results: All variables remained stable across the three times, apart from positive affect, which dropped significantly post-operation but returned to its previous level post discharge.
Conclusion: Although the homeostatic model of subjective quality of life was supported at Time 1, the analyses raise doubts about the stability of personality. This finding is consistent with recent discussions of personality.

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Background: Heart Failure Management Programs (HFMPs) have proven to be cost-effective in minimising recurrent hospitalisations, morbidity and mortality. However, variability between the programs exists which could translate into variable health outcomes.
Objective: To survey the characteristics of HFMPs throughout Australia and to identify potential heterogeneity in their organisation and structure.
Method: Thirty-nine post-discharge HFMPs were identified from a systematic search of the Australian health-care system in 2002. A comprehensive 19-item questionnaire specifically examining characteristics of HFMPs was sent to co-ordinators of identified programs in early 2003.
Results: All participants responded with six institutions (15%) indicating that their HFMP had ceased operations due to a lack of funding. The survey revealed an uneven distribution of the 33 active HFMPs operating throughout Australia. Overall, 4450 post-discharge HF patients (median: 74; IQR: 24–147) were managed via these programs, representing only 11% of the potential caseload for an Australia-wide network of HFMPs. Heterogeneity of these programs existed in respect to the model of care applied within the program (70% applied a home-based program and 18% a specialist HF clinic) and applied interventions (30% of programs had no discharge criteria and 45% of programs prevented nurses administering/titrating medications). Sustained funding was available to only 52% of the active HFMPs.
Conclusion: Inequity of access to HFMPs in Australia is evident in relation to locality and high service demand, further complicated by inadequate funding. Heterogeneity between these programs is substantial. The development of national benchmarks for evidence-based HFMPs is required to address program variability and funding issues to realise their potential to improve health outcomes.


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Objective: Existing evidence suggests that family interventions can be effective in reducing relapse rates in schizophrenia and related conditions. Despite this, such interventions are not routinely delivered in Australian mental health services. The objective of the current study is to investigate the incremental cost-effectiveness ratios (ICERs) of introducing three types of family interventions, namely: behavioural family management (BFM); behavioural intervention for families (BIF); and multiple family groups (MFG) into current mental health services in Australia.

Method: The ICER of each of the family interventions is assessed from a health sector perspective, including the government, persons with schizophrenia and their families/carers using a standardized methodology. A two-stage approach is taken to the assessment of benefit. The first stage involves a quantitative analysis based on disability-adjusted life years (DALYs) averted. The second stage involves application of 'second filter' criteria (including equity, strength of evidence, feasibility and acceptability to stakeholders) to results. The robustness of results is tested using multivariate probabilistic sensitivity analysis.

Results: The most cost-effective intervention, in order of magnitude, is BIF (A$8000 per DALY averted), followed by MFG (A$21 000 per DALY averted) and lastly BFM (A$28 000 per DALY averted). The inclusion of time costs makes BFM more cost-effective than MFG. Variation of discount rate has no effect on conclusions.

Conclusions: All three interventions are considered 'value-for-money' within an Australian context. This conclusion needs to be tempered against the methodological challenge of converting clinical outcomes into a generic economic outcome measure (DALY). Issues surrounding the feasibility of routinely implementing such interventions need to be addressed.

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Background. Many studies have tended to explore individual characteristics that impact on nurses' decision-making, despite significant acknowledgement that context is a major determinant in decision-making. The few studies that have examined environmental influences have tended not to study real decisions in the dynamic and complex clinical environment.

Aims. To investigate environmental influences on nurses' real decisions in the critical care setting.

Method. Naturalistic observations and semi-structured interviews were conducted with 18 critical care nurses in private, public and rural hospitals. Observations and interviews were recorded, transcribed verbatim and coded for themes using content analysis.

Results. All clinical decisions were strongly influenced by the context in which the decision was made. Three main environmental influences were identified: the patient situation, resource availability and interpersonal relationships. Time and risk guided all clinical decisions. Nurses established the state of the situation, the time constraints on decisions and the level of risk involved for both patient and nurse.

Conclusions.
Decision-making is a manifestation of the landscape and although an increased understanding of the landscape is required, more important is the need to measure the impact of contextual variables on nurses' decision-making in order to improve health care outcomes.


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Objective To examine parent and adolescent agreement on physical, emotional, mental and social health and well-being in a representative population.
Methodology An epidemiological design was used to obtain parent–child/adolescent dyad data on comparable items and scales of a generic measure of health and well-being, the Child Health Questionnaire (parent/proxy report 50 item, self-report 80 item). Scale analysis included intraclass correlations (ICCs) to examine strength of parent–child associations and independent t-tests for differences between adolescents (with or without an illness). Where there were significant differences in scale scores, analysis of variance and two sample t-tests were used to examine the influence of social, demographic, health concern and school variables. Single items were examined for trends in response categories.
Results 2096 parent–adolescent dyads (adolescent mean age of 15.1 years, males 50%, maternal parent 83.2%, biological parent 93.5%). ICCs were strong. Overall, adolescents reported poorer emotional and social health, and clinically significant differences were observed for perceptions of general health (mean difference 8.1/100), frequency and amount of body pain (5.94/100), experience of mental health (5.14/100), and impact of health on family activities (12.43/100), which widen significantly for adolescents with illness. Social, health and school enjoyment and performance significantly widened parent–child differences.
Conclusions All adolescents were much less optimistic about their health and well-being than their parents, and were only in close agreement on aspects of health and well-being they rated highly. Adolescent reports are more likely to be sensitive to pain, mental health problems, health in general and the impact of their health on family activities.

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Objective: Antidepressant drugs and cognitive–behavioural therapy (CBT) are effective treatment options for depression and are recommended by clinical practice guidelines. As part of the Assessing Cost-effectiveness – Mental Health project we evaluate the available evidence on costs and benefits of CBT and drugs in the episodic and maintenance treatment of major depression.

Method: The cost-effectiveness is modelled from a health-care perspective as the cost per disability-adjusted life year. Interventions are targeted at people with major depression who currently seek care but receive non-evidence based treatment. Uncertainty in model inputs is tested using Monte Carlo simulation methods.

Results: All interventions for major depression examined have a favourable incremental cost-effectiveness ratio under Australian health service conditions. Bibliotherapy, group CBT, individual CBT by a psychologist on a public salary and tricyclic antidepressants (TCAs) are very cost-effective treatment options falling below $A10 000 per disability-adjusted life year (DALY) even when taking the upper limit of the uncertainty interval into account. Maintenance treatment with selective serotonin re-uptake inhibitors (SSRIs) is the most expensive option (ranging from $A17 000 to $A20 000 per DALY) but still well below $A50 000, which is considered the affordable threshold.

Conclusions: A range of cost-effective interventions for episodes of major depression exists and is currently underutilized. Maintenance treatment strategies are required to significantly reduce the burden of depression, but the cost of long-term drug treatment for the large number of depressed people is high if SSRIs are the drug of choice. Key policy issues with regard to expanded provision of CBT concern the availability of suitably trained providers and the funding mechanisms for therapy in primary care.

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Purpose. To examine associations among individual, social, and environmental barriers and children's walking or cycling to school.

Design. Exploratory cross-sectional study.

Setting. All eight capital cities in Australia.

Subjects. Parents (N = 720) of school-aged children (4-13 years; 27% response rate 49% parents of boys,).

Measures. Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for parental reporting of barriers to their children's walking or cycling to school, based on a computer-assisted telephone interview.

Results. Forty-one percent of children walked or cycled to school at least once per week. Multivariable analyses found inverse associations with individual ("child prefers to be driven" [OR = 0.4, 95% CI = 0.3-0.6], "no time in the mornings" [OR 0.5, 95% CI = 0.3-0.8]); social ("worry child will take risk" [OR = 0.6, 95% CI = 0.3-0.9], "no other children to walk with" [OR = 0.7, 95% CI = 0.4-0.99], "no adults to walk with" [OR = 0.6, 95% CI = 0.4-0.9]); and environmental barriers ("too far to walk" [OR = 0.1, 95% CI = 0.0- 0.1], "no direct route" [OR = 0.4, 95% CI = 0.2-0. 7]) and positive associations with "concern child may he injured in a road accident" (OR = 1.9, 95% CI = 1.1-3.1) and active commuting.

Conclusion.
Working with parents, schools, and local authorities to improve pedestrian, skills and environments may help to overcome barriers.

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Aims: The aim of this study was to explore the transition experiences of Australian women in resuming paid employment after an acute coronary syndrome (ACS) event. Background: Until recently cardiovascular research has focused predominantly on men but this is changing and research exploring women’s experiences of ACS has increased. Despite knowing that many women do not resume paid employment following an ACS event, little is known about the experience of those women who do, even though it is understood that returning to the previous level of employment after an ACS event is a positive outcome. Design: An exploratory qualitative approach underpinned by naturalistic inquiry was undertaken. Methods: A purposive sample of seven women who had experienced their first ACS event 12 months ago was selected. Each woman was interviewed using a semi–structured format and their interviews were transcribed verbatim. Thematic analysis of the transcript set and conceptual mapping were employed to formulate key themes. Findings: All women (mean age 52.6 years) resumed paid employment at various stages during their recovery, but reported similar transition processes. Three key themes representing this process were identified: primary motivation; influence through guidance and support; and resuming paid employment. Conclusions: Study findings revealed that these women required substantial support from family, friends and employers, with ongoing guidance from health professionals to return to paid work. The time frames for their return varied and some modified their roles within the workforce to enable them to return to paid work. However, formal cardiac rehabilitation did not appear to have a significant impact on these participants' decisions to return to work. They felt that more information about this decision may have been helpful if given at the time of cardiac rehabilitation.

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Purpose – This paper seeks to investigate the influence of Porter’s strategy types on the use of customer relationship management (CRM) techniques and traditional market research, against theoretical and empirical evidence that differences in strategy types may result in variation in favoured marketing information sources and procedure.

Design/methodology/approach – Depth interviews generated a series of scale items, which were combined with others derived from the literature in a questionnaire measuring strategy types, the roles of market research, and the characteristics of CRM systems. Responses were obtained from 240 senior marketing managers in Australia, and applied to the testing of five research propositions.

Findings –
ANOVA found no differences in CRM usage among the strategy types. Variation was widespread, however, in four roles of traditional market research: enhancing strategic decision making, increasing usability of existing data, presenting plans to senior management, and achieving productivity and political outcomes.

Research limitations/implications –
Future researchers using the Porter strategic types should separate “marketing differentiators” from “product differentiators” because they function and compete differently.

Practical implications –
All organisations can benefit from CRM systems, but “marketing differentiators” exhibit a relatively higher usage of traditional market research. This is likely to be because they compete by creating softer product differences, while others do so on harder characteristics such as price or product functionality.

Originality/value –
This is the first study to use the Porter types to explain differences between the roles and uses of market research and CRM within organisations.