the majority of patients with early breast cancer receive some form of systemic adjuvant therapy (chemo-, endocrine, and/or targeted therapy). Despite the increase in adjuvant therapy prescription, little progress has been made with respect to assisting oncologists to determine which breast cancer patients, particularly those deemed at “lower risk” of relapse, require chemotherapy or other systemic therapy and which women can safely be treated with loco-regional treatment alone. For these reasons, the identification of prognostic and predictive markers that will assist the clinician in selecting the most suitable form of medical therapy has become very high priority as well as a real challenge in translational research. <p>\ / Doctorat en Sciences biomédicales et pharmaceutiques / info:eu-repo/semantics/nonPublished

La galectine-3 (Gal-3), protéine de type lectine, de 29-35 kDa, étudiée comme marqueur d’aggressivité dans les gliomes, présente des caractéristiques biologiques importantes justifiant son étude dans le domaine du mélanome. En effet, la Gal-3 est une protéine qui peut se lier à la laminine, tout comme l’intégrine α6/β1 dont l’expression est réduite dans le mélanome. L’expression de cette intégrine peut d’ailleurs être modulée par la Gal-3 comme récemment montré dans des lignées cellulaires de cancer du sein (BT-549) et de glioblastome (U373).<p>Le mélanome, véritable problème de santé publique qui est susceptible d’atteindre 1 individu sur 75 dans nos contrées, reste un tumeur mal comprise avec des évolutions parfois incertaines, et des traitements dont l’efficacité est limitée. Le diagnostic histologique du mélanome lui-même peut parfois représenter une difficulté pour le clinicien et l’expert pathologiste ou dermatopathologiste. La couleur (hyperpigmentation d’un lésion pigmentée), dont l’évaluation d’ailleurs reste subjective à défaut de standardisation, ne peut à elle seule signer la malignité d’une lésion pigmentée. Globalement l’évolution d’un patient est prédite par l’indice de Breslow qui traduit en mm l’épaisseur de la tumeur. Si cet indice dépasse 1mm, le risque métastatique augmente, justifiant la réalisation de bilans extensifs de suivi. Ceci dit, certains mélanomes épais peuvent ne pas présenter de caractéristiques d’aggressivité, alors que des mélanomes fins sont parfois mortels. L’identification de marqueurs moléculaires est donc impérative, tant pour développer des stratégies thérapeutiques ciblées, que pour affiner le diagnostic et le pronostic d’un patient. <p>Après avoir mis en évidence par immunohistochimie une expression de Gal-3 par les mélanocytes, nous avons démontré une surexpression de cette protéine par les mélanocytes tumoraux. Nous avons démontré également sur des lésions primitives qu’à l’aggressivité mesurée selon l’indice de Breslow correspondait une diminution de cette surexpression. Cette observation a pu être confirmée par un modèle de greffe orthotopique chez la souris nude.<p>Nous nous somme intéressés par la suite à la détection de la protéine dans le sérum, et nous avons constaté, un taux élevé de Gal-3 dans le sérum de patients en stade métastatique avancé, ce taux élevé pouvant s’expliquer tant par la charge tumorale que par la présence d’une inflammation, d’ailleurs bien connue chez le patient cancéreux en stade avancé. Le rôle antiapoptotique de la Gal-3 nous a alors amené à préciser la valeur prédictive et pronostique de cette protéine. L’hypothèse d’une potentielle action bénéfique sur la réponse immunitaire des patients atteints de mélanome qui ont été vaccinés a été rejetée. La Gal-3 sérique s’est révélée comme facteur de mauvais pronostic chez les patients métastatiques, et une analyse multivariée avec la définition d’une valeur « cut-off » de 10 ng/ml a permis de montrer une valeur pronostique indépendante, supérieure à la S100B et à la CRP. <p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

ITC/USA 2010 Conference Proceedings / The Forty-Sixth Annual International Telemetering Conference and Technical Exhibition / October 25-28, 2010 / Town and Country Resort & Convention Center, San Diego, California / Providing normal telemetry behavior predictions prior to and post launch will help to stop surprise catastrophic satellite and spacecraft equipment failures. In-orbit spacecraft fail from surprise equipment failures that can result from not having normal telemetry behavior available for comparison with actual behavior catching satellite engineers by surprise. Some surprise equipment failures lead to the total loss of the satellite or spacecraft. Some recovery actions from a surprise equipment failure increase spacecraft risk and involve decisions requiring a level of experience far beyond the responsible engineers.

ITC/USA 2009 Conference Proceedings / The Forty-Fifth Annual International Telemetering Conference and Technical Exhibition / October 26-29, 2009 / Riviera Hotel & Convention Center, Las Vegas, Nevada / Providing normal telemetry behavior predictions prior to and post launch will help to stop surprise catastrophic satellite and spacecraft equipment failures. In-orbit spacecraft fail from surprise equipment failures that can result from not having normal telemetry behavior available for comparison with actual behavior catching satellite engineers by surprise. Some surprise equipment failures lead to the total loss of the satellite or spacecraft. Some recovery actions as a consequence of a surprise equipment failure are high risk and involve decisions requiring a level of experience far beyond the responsible engineers.

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published_or_final_version / abstract / Community Medicine / Doctoral / Doctor of Philosophy

Background: Patients older than 75 years with heart failure (HF) are at increased risk for mortality and hospital admissions. Echocardiography and brain natriuretic peptides (BNP, NTproBNP) are important diagnostic tools but sparsely evaluated in elderly PHC patients. Aims: Validate the clinical diagnosis of HF, investigate the types of HF and underlying cardiovascular disorders with focus on sex and age differences. Explore the sensitivity, specificity, negative and positive predictive values (NPV, PPV) of BNP and NT-proBNP in patients with systolic HF. Study the associations of HF or NTproBNP on all-cause and cardiovascular mortality. Study the prognostic value of different biomarkers and HF, on all-cause and cardiovascular hospitalizations. Methods: Patients with suspected HF were recruited from one selected PHC and registered on a prespecified record and referred for an echocardiographic examination and a final cardiologist consultation. Blood samples for natriuretic peptides were stored frozen at – 70° C. Death certificates were used to register all-cause mortality and cardiovascular mortality. To register hospitalisations, medical records were used and classification was defined according to ICD-10. Results The GPs identified 121 women and 49 men with suspected HF of whom 39% (51 women and 16 men) were above 80 years. Myocardial infarction (OR:4,3 CL: 1,8-10,6) hypertension (OR:3,4 CI:1,6-6,9) atrial fibrillation (OR:2,8 CL:1,0-7,9) predicted a confirmed diagnosis of HF. Confirmed HF was verified in 45% of the patients and was significantly more common in men than women (p=0,02). The best NPV was 88 % for NT-proBNP (200 ng/L) and 87 % for BNP (20 pg/ml). Age and male gender were independently associated with higher levels of NT-proBNP. During the 10-year follow up, 71 out of 144 patients died. In univariate Cox regression analysis, significant associations were found for overall HF (hazard ratio [HR]: 1.86; 95% confidence interval [CI]:1.15- 3.01), isolated systolic HF (HR:1.95; 95% CI:1.06-3.61), and combined (systolic and diastolic) HF (HR:3.28; 95% CI:1.74-6.14) with all-cause mortality, but not for isolated diastolic HF. In multivariable analysis, age (HR: 1.11; 95% CI: 1.06-1.17), kidney dysfunction (HR:1.91; 95% CI:1.11- 3.29), smoking (HR:3.70; 95% CI:2.02-6.77), and NTproBNP (HR:1.01; 95% CI:1.00-1.02), but not any type of HF, significantly predicted all-cause mortality. During ten years, 136 (80%) patients were hospitalised with 660 and 207 for all-cause and cardiovascular hospitalisations, respectively. Age (OR:1.1; 95% CI:1.01-1.15) and underlying heart disease (OR:3.5; 95% CI:1.00-11.89), significantly predicted all-cause hospitalisation. Overall HF (HR:1.8; 95% CI:1.06-2.94) significantly predicted time to first all-cause hospitalisations. For cardiovascular hospitalisations age (OR:1.1;95%CI:1.01-1.12), underlying heart disease (OR:3.4;95%CI:1.04-11.40) and NTproBNP ≥800 ng/L (OR:4,3;95%CI:1.5-12.50) were significant predictors. Conclusion: A confirmed diagnosis of HF was present in 45% of the patients. NPV was high, but not as high as in younger patients with HF. Patients with systolic HF had a higher mortality than patients with diastolic HF compared to patients with no HF. Patients with combined HF were at even higher risk for all-cause mortality and cardiovascular mortality. Age, kidney dysfunction, NTproBNP and smoking predicted mortality. Age and underlying heart diseases were predictors for all-cause hospitalisations and together with NTproBNP they also predicted cardiovascular hospitalisations.

Background Patients who experience a stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but little is known about temporal trends in unselected populations. Reports of low adherence to recommended treatments indicate a need for enhanced secondary preventive follow-up to achieve the full potential of evidence-based treatments. In addition, socioeconomic factors have been associated with poor health outcomes in a variety of contexts. Therefore, it is important to assess the implementation and results of secondary prevention in different socioeconomic groups. Aims The aims of this thesis were to assess temporal trends in ischemic stroke recurrence and evaluate the implementation and results of a nurse-led, telephone-based follow-up program to improve blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) levels after stroke/TIA. Methods In study I, we collected baseline data for unique patients with an ischemic stroke event between 1998 and 2009 (n=196 765) from the Swedish Stroke Register (Riksstroke). Recurrent ischemic stroke events within 1 year were collected from the Swedish National Inpatient Register (IPR) and the cumulative incidence was compared between four time periods using the Kaplan-Meier survival analysis and the logrank test. Implementation (study II) and 1-year results (study III-IV) for the secondary preventive follow-up were studied in the NAILED (Nurse-based Age-independent Intervention to Limit Evolution of Disease) study. Between 1 Jan 2010 and 31 Dec 2013, the baseline characteristics of consecutive patients admitted to Östersund Hospital for acute stroke or TIA were collected prospectively (n=1776). Consenting patients in a condition permitting telephone-based follow-up were randomized to nurse-led, telephone-based follow-up or follow-up according to usual care. Follow-up was cunducted at 1 and 12 months after discharge and the intervention included BP and LDL-C measurements, titration of medication, and lifestyle counseling. In study II, we analyzed factors associated with non-participation in the randomized phase of the NAILED study, including association with education level. In addition, we compared the 1-year prognosis in terms of cumulative survival between participants and non-participants. In study III, we compared differences in BP and LDL-C levels between the intervention and control groups during the first year of follow-up and, in study IV, in relation to level of education (low, ≤10 years; high, &gt;10 years). Results The cumulative 1-year incidence of recurrent ischemic stroke decreased from 15.0% to 12.0%. Among surviving stroke and TIA patients, 53.1% were included for randomization, 35.7% were excluded mainly due to physical or cognitive disability, and 11.2% declined participation in the randomized phase. A low level of education was independently associated with exclusion, as well as the patient’s decision to abstain from randomization. Excluded patients had a more than 12-times higher risk of death within 1 year than patients who were randomized. After 1 year of follow-up, the mean systolic BP, diastolic BP, and LDL-C levels were 3.3 mmHg (95% CI 0.3 to 6.3), 2.3 mmHg (95% CI 0.5 to 4.2), and 0.3 mmol/L (95% CI 0.1 to 0.4) lower in the intervention group than among controls. Among participants with values above the treatment goal at baseline, the differences in systolic BP and LDL-C levels were more pronounced (8.0 mmHg, 95% CI 4.0 to 12.1; 0.6 mmol/L, 95% CI 0.4 to 0.9). In the intervention group, participants with a low level of education achieved similar or larger improvements in BP and LDL-C than participants with a high level of education. In the control group, BP remained unaltered and the LDL-C levels increased among participants with a low level of education. Conclusion The 1-year risk of ischemic stroke recurrence decreased in Sweden between 1998 and 2010. Nurse-led, telephone-based secondary preventive follow-up is feasible in just over half of the survivors of acute stroke and TIA and achieve better than usual care in terms of BP and LDL-C levels, and equality in BP improvements across groups defined by education level. However, a large proportion of stroke survivors are in a general condition precluding this form of follow-up, and their prognosis in terms of 1-year survival is poor. Patients with a low education level are over-represented within this group and among patients declining randomization for secondary preventive follow-up.

Magnetic resonance imaging plays an important yet underutilized role in determining the natural history and prognosis of oral carcinoma. Depth of tumour invasion is an emergent factor in the oral cancer literature. However, problems exist with the definition of cut-points suitable for inclusion in TNM staging criteria. Statistical methodology represents a possible explanation but is underexplored. In this work, a review of the depth of invasion literature is conducted with emphasis on statistical technique. As well, statistical simulation is used to explore the implications of the of the minimum p-value method. The results demonstrate that the use of continuous variable categorization and multiple testing is widespread, and contributes to cut-point variability and false-positive tests. Depth, as a predictor of OCLNM and survival, must be questioned. The volume of tumour invasion is a promising prognostic factor that has not been fully investigated in the oral carcinoma literature. In this work, the volume of tumour invasion is measured on MRI and compared to thickness and maximum diameter in its capacity to predict 2-year all-cause, disease-related and disease-free survival, as well as occult cervical lymph node metastasis prediction. As part of a comprehensive approach, morphometric factors are incorporated into multifactor predictive models using regression, artificial neural networks and recursive partitioning. It is evident that MRI-based volume is superior all other linear measurements for both occult cervical lymph node metastasis and survival prediction. Artificial neural networks wee superior to all other techniques for survival prediction. There is a case for a unified artificial neural networks model for survival prediction that uses volume, midline invasion and N-stage to determine prognosis. This model can be used to determine individualized probabilities of 2-year survival. The lateral extrinsic muscles of the tongue lie just beneath the surface of the lateral tongue, yet their invasion is a criterion for T4 classification using the TNM staging system. In this work, the Visible Human Female is used to conduct an anatomic study of the extrinsic muscles of the tongue. Linear measurement is used to quantify the distance from the surface mucosa to the most superficial muscle fibres of the styloglossus and genioglossus. Further, the lateral extrinsic muscles are poorly demonstrated on MRI. An anatomic atlas of the tongue is fused with MRI images of oral carcinoma to demonstrate lateral muscle invasion. The results demonstrate that the styloglossus and hyoglossus lie very close to the surface of the lateral tongue, in some cases passing within 1 mm of the surface mucosa. These extrinsic muscles are readily invaded by even small tumours of the lateral tongue. Strict application of the TNM T4a criteria leads to unnecessary upstaging as these carcinomas do not warrant the prognosis and aggressive treatment of Stage IV disease. Extrinsic muscle invasion should be removed as a T4a criterion for the oral cavity. A separate category, T4a (oral tongue) specifying invasion of the genioglossus is also recommended. This work presented in this thesis is an original contribution to the field of oral cavity cancer research and has determined that there is capacity for improvement in current efforts to determine the natural history and prognosis of oral cavity squamous cell carcinoma. This thesis is the first to examine the role of statistical methodology in oral carcinoma depth of invasion cut-point variability. Further, this work presents an original approach to the prediction of regional metastasis and survival using advanced multivariate modeling techniques. No other work explored MRI-measured volume using the substantial sample size gathered in this thesis. Finally, this work is the first to demonstrate that lateral extrinsic muscle invasion is an unnecessary component of the T4a (oral cavity) classification criteria and should be reconsidered.