Yes / Despite being a preventable disease, pediatric HIV infection continues to be a public health concern due to the morbidity and mortality associated with the disease. Vertical transmission of HIV occurs when a mother living with HIV passes the virus to her baby during pregnancy, childbirth, or breastfeeding. Globally, the vertical transmission rate of HIV is 9% with sub-Saharan Africa accounting for 90% of these infections. In Kenya, the national vertical transmission rates of HIV stood at 11.5% by the end of 2018, with a target to reduce vertical transmission rates to below 5% and 2% in breastfeeding and non-breastfeeding infants respectively, by the end of 2021. To determine the prognostic factors influencing HIV-free survival among infants enrolled for HIV early infant diagnosis (EID) services in selected hospitals in Nairobi County, Kenya. A prospective cohort study design was adopted. HIV exposed infants were recruited at six weeks to determine HIV-free survival over 12 months follow up. Simple random sampling was used to select 166 infants and data were collected from the mothers using semi-structured interviewer-administered questionnaires. Log-rank tests were used to test for associations at the bi-variable level while Cox-proportional regression was used to analyze data at the multi-variable level, with the aid of STATA 14 software. Ethical approval was obtained from Kenya Medical Research Institute, Scientific Ethics Review Unit. The overall infant HIV incidence rate over one-year follow-up was 9 cases per 100 person-years (95% CI: 5.465-16.290). The failure event was defined as an infant with a positive PCR test during the study period with total failures being 13 (9.41%) over 12 months. Prognostic factors associated with poor infant HIV-free survival were young maternal age (18-24 years) and mothers with a recent HIV diagnosis of ≤ 2 years since a positive HIV diagnosis (HR 5.97 CI: 1.20, 29.58) and (HR 6.97 CI: 1.96, 24.76), respectively. Maternal prognostic factors associated with poor infant HIV-free survival were young maternal age (18-24 years) and recent maternal HIV diagnosis of ≤ 2 years since positive HIV diagnosis. The study recommended the development of an intervention package with more rigorous adherence counseling and close monitoring for young mothers, and mothers with recent HIV diagnoses.

ITC/USA 2011 Conference Proceedings / The Forty-Seventh Annual International Telemetering Conference and Technical Exhibition / October 24-27, 2011 / Bally's Las Vegas, Las Vegas, Nevada / The surprise failure of two NASA Space Shuttles and the premature failures of satellite subsystem equipment on NASA satellites are motivating NASA to adopt an engineering discipline that uses telemetry specifically developed for preventing surprise equipment failures. The NASA Orion spacecraft is an Apollo module-like capsule planned to replace the NASA Space Shuttle reusable launch vehicle for getting astronauts to space and return to the earth safely as well as a crew escape vehicle stored at the ISS. To do so, NASA is adopting a non-Markov reliability paradigm for measuring equipment life based on the prognostic and health management program on the Air Force F-35 Joint Strike Fighter. The decision is based on the results from the prognostic analysis completed on the Space Shuttle Challenger and Columbia that identified the information that was present but was ignored for a variety of reasons. The goal of a PHM is to produce equipment that will not fail prematurely. It includes using predictive algorithms to measure equipment usable life. Equipment with transient behavior caused from accelerated of parts will fail prematurely with 100% certainty. For many decades, it was believed that test equipment and software used to in testing and noise from communications equipment were the cause of most transient behavior. With the processing speed of today's processors, transient behavior is caused from at least one part suffering from accelerated aging. Transient behavior is illustrated in equipment telemetry in a prognostic analysis. Telemetry is equipment performance information and equipment performance has been used to increase reliability, but performance is unrelated to equipment remaining usable life and so equipment should be failing prematurely. A PHM requires equipment telemetry for analysis and so analog telemetry will be available from all Orion avionics equipment. Replacing equipment with a measured remaining usable life of less than one year will stop the premature and surprise equipment failures from occurring during future manned and unmanned space missions.

ITC/USA 2011 Conference Proceedings / The Forty-Seventh Annual International Telemetering Conference and Technical Exhibition / October 24-27, 2011 / Bally's Las Vegas, Las Vegas, Nevada / Launch vehicle equipment reliability is driven by infant mortality failures, which can be eliminated using a prognostic analysis prior, during and/or after the exhaustive and comprehensive dynamic environmental factory acceptance testing. Measuring and confirming equipment performance is completed to increase equipment reliability by identifying equipment that fails during test for repair/replacement. To move to the 100% reliability domain, equipment dynamic environmental factory testing should be followed by a prognostic analysis to measure equipment usable life and identify the equipment that will fail prematurely. During equipment testing, only equipment performance is measured and equipment performance is unrelated to equipment reliability making testing alone inadequate to produce equipment with 100% reliability. A prognostic analysis converts performance measurements into an invasive usable life measurement by sharing test data used to measure equipment performance. Performance data is converted to usable life data provides a time-to-failure (TTF) in minutes/hours/days/months for equipment that will fail within the first year of use, allowing the production of equipment with 100% reliability.

ITC/USA 2011 Conference Proceedings / The Forty-Seventh Annual International Telemetering Conference and Technical Exhibition / October 24-27, 2011 / Bally's Las Vegas, Las Vegas, Nevada / Satellite and launch vehicles continues to suffer from catastrophic infant mortality failures. NASA now requires satellite suppliers to provide on-orbit satellite delivery and a free satellite and launch vehicle in the event of a catastrophic infant mortality failure. A high infant mortality failure rate demonstrates that the factory acceptance test program alone is inadequate for producing 100% reliability space vehicle equipment. This inadequacy is caused from personnel only measuring equipment performance during ATP and performance is unrelated to reliability. Prognostic technology uses pro-active diagnostics, active reasoning and proprietary algorithms that illustrate deterministic data for prognosticians to identify piece-parts, components and assemblies that will fail within the first year of use allowing this equipment to be repaired or replaced while still on the ground. Prognostic technology prevents equipment failures and so is pro-active. Adding prognostic technology will identify all unreliable equipment prior to shipment to the launch pad producing 100% reliable equipment and will eliminate launch failures, launch pad delays, on-orbit infant mortalities, surprise in-orbit failures. Moving to the 100% reliable equipment extends on-orbit equipment usable life.

ITC/USA 2012 Conference Proceedings / The Forty-Eighth Annual International Telemetering Conference and Technical Exhibition / October 22-25, 2012 / Town and Country Resort & Convention Center, San Diego, California / The surprise failure of two NASA Space Shuttles and the premature failures of satellite subsystem equipment on NASA satellites are motivating NASA to adopt an engineering discipline specifically developed for preventing surprise equipment failures. The NASA Orion spacecraft is an Apollo module-like capsule planned to replace the NASA Space Shuttle reusable launch vehicle for getting astronauts to space and return to the earth safely as well as a crew escape vehicle stored at the ISS. To do so, NASA is adopting a non-Markov reliability paradigm for measuring equipment life based on the prognostic and health management program on the Air Force F-35 Joint Strike Fighter. The decision is based on the results from the prognostic analysis completed on the Space Shuttle Challenger and Columbia that identified the information that was present but was ignored for a variety of reasons prior to both accidents. The goal of a PHM is to produce equipment that will not fail prematurely and includes using predictive algorithms to measure equipment usable life. Equipment with transient behavior, missed by engineering analysis is caused from accelerated of parts will fail prematurely with 100% certainty. With the processing speed of today's processors, transient behavior is caused from at least one part suffering from accelerated aging. Transient behavior is illustrated in equipment telemetry in a prognostic analysis but not in an engineering analysis. Telemetry is equipment performance information and equipment performance has been used to increase reliability, but performance is unrelated to equipment remaining usable life and so equipment should be failing prematurely. A PHM requires equipment telemetry for analysis and so analog telemetry will be available from all Orion avionics equipment. Replacing equipment with a measured remaining usable life of less than one year will stop the premature and surprise equipment failures from occurring during future manned and unmanned space missions.

O avanço tecnológico nas unidades de terapia intensiva pediátricas (UTIPs) tornou-as aptas ao atendimento de casos de alta complexidade e elevado custo. Porém, a tecnologia disponível nem sempre tem conseguido melhorar a qualidade de atendimento aos pacientes e a própria capacidade de prolongar o tempo de vida torna-se um instrumento que potencializa a dor e o sofrimento. Sendo assim, tornou-se necessário caracterizar o estágio de gravidade da doença, que reflete a magnitude das comorbidades e distúrbios fisiológicos, no momento da internação. Esse procedimento pode ser realizado através dos escores prognósticos de mortalidade que quantificam a gravidade da doença, estimando a probabilidade de óbito de acordo com seu estágio clínico. Atualmente os escores prognósticos fazem parte das metodologias de controle de qualidade e de pesquisa. O Pediatric Risk of Mortality escore (PRISM) é um dos escores mais utilizados na unidade de terapia intensiva pediátrica (UTIP). O objetivo desse estudo foi avaliar a utilização do PRISM quanto a sua capacidade de discriminação entre sobreviventes e não-sobreviventes e determinar os fatores de prognóstico para óbito em uma UTIP terciária. Foi realizado um estudo retrospectivo na UTIP do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, que é considerada de nível de atendimento terciário. Foi anotado o valor do PRISM correspondente às primeiras 24 horas de internação; dados demográficos e da internação, para melhor caracterização da amostra. Foram incluídos 359 pacientes; as variáveis encontradas como fatores de prognóstico para óbito foram: presença de síndrome de disfunção de múltiplos órgãos e sistemas (SDMOS) à admissão, ventilação mecânica (VM), uso de fármacos vasoativos, infecção hospitalar, terapia nutricional parenteral (TNP) e duração da internação (p < 0,0001 para todas as variáveis). Cinquenta e quatro pacientes (15%) evoluíram a óbito; a mediana do PRISM foi significativamente maior nos pacientes que evoluíram para óbito (p= 0,0001). A curva ROC do PRISM mostrou um valor de 0.76 (IC 95% 0,690,83) e a calibração, calculada pelo teste qui-quadrado de Hosmer-Lemeshow, evidenciou x2 = 12,96 com p=0,11, sendo que para este teste é considerado significativamente estatístico um valor de p > 0,05. É importante a implantação de controle estrito de qualidade nas UTIPs para identificar grupos de risco para óbito e medir a eficácia do tratamento. Embora alguns autores já tenham enfatizado que o PRISM superestima a mortalidade e não seria apropriado em populações pediátricas específicas, esse estudo mostrou que o PRISM apresenta capacidade discriminatória adequada em diferenciar sobreviventes dos não-sobreviventes e constitui ferramenta útil para avaliar o prognóstico dos pacientes admitidos em UTIP terciária. / Technological advances in pediatric intensive care units (PICU) has made them suitable for the treatment of high complexity cases and high cost. However, the technology available has not always succeeded in improving the quality of patient care and their own ability to prolong the life becomes a tool that leverages the pain and suffering, sometimes prolonging the dying process. Thus, it became necessary to characterize the stage of disease severity, which reflects the magnitude of comorbidities and physiological disorders, at admission. These procedures can be performed by way of the mortality prognostic scores that quantify the severity of the disease, estimating the probability of death according to their clinical state. Nowadays the prognostic scores make part of the methodology of quality control and research. The Pediatric Risk of Mortality score (PRISM) is one of the main scores used in the PICU. The purpose of this study was to evaluate the use of PRISM for their ability to discriminate between survivors and non-survivors and to determine the prognostic factors for death in a tertiary PICU. Retrospective cohort study was conducted in the PICU of Instituto da Criança do Hospital das Clinicas of University São Paulo, which is considered a PICU of a tertiary care level. The PRISM scores (corresponding to the first 24 hours of hospitalization), demographic and hospitalization data were noted to better characterize the study population. We included 359 patients and the variables that were found to have prognostic factors for death were multiple organ dysfunction syndrome (MODS) on admission, mechanical ventilation (MV), use of vasoactive drugs, hospital-acquired infection, parenteral nutrition therapy (PNT) and longer period of hospitalization (p < 0,0001 for all variables). Fifty-four patients (15%) died; median PRISM score was significantly higher in patients who died (p= 0,0001). The ROC curve for PRISM yielded a value of 0.76 (CI 95% 0,690,83) and the calibration, calculated using the Hosmer-Lemeshow chi-square test, was shown x2 = 12,96 with p=0,11, being that for this test is considered a statistically significant p > 0.05 . It is imperative for PICU to implement strict quality controls to identify groups at greatest risk of death and to ensure the adequacy of treatment. Although some authors have shown that the PRISM score overestimates mortality and that it is not appropriate in specific pediatric populations, in this study PRISM showed satisfactory discriminatory performance in differentiating between survivors and non-survivors and constitutes a useful tool for the assessment of prognosis for pediatric patients admitted to a tertiary PICU.

Une maintenance efficace d’un dispositif industriel ne peut être basée que sur la fiabilité et l’exactitude de données physiques captées sur ledit dispositif, à des fins de surveillance. Dans certains cas, le monitoring de tels systèmes industriels ou de zones à surveiller ne peut pas être assuré à l’aide de capteurs individuels ou filaires, du fait par exemple de problèmes d’accès ou de milieux hostiles. Les Réseaux de Capteurs Sans Fil (RCSF) sont alors une alternative. En raison de la nature des communications dans ces réseaux, et des caractéristiques des appareils composants ces derniers, un RCSF est à fort risque de pannes au niveau des capteurs, et dans ce cas la perte de diverses données est probable - ce qui peut s’avérer problématique pour le monitoring du dispositif. Pour étudier la pertinence des RCSF pour le processus dit de PHM (Prognostic and Health Management, utilisé pour déterminer le plan de maintenance d’un dispositif à surveiller), et l’impact des diverses stratégies déployées dans ces premiers sur ces derniers, nous avons proposé un premier algorithme de diagnostic efficace et l’avons utilisé dans un RCSF simulé pour en mesurer la performance (ce simulateur étant un programme que nous avons développé). / Effective maintenance of an industrial device can only be based on the reliability and accuracy of physical data captured on said device for monitoring purposes. In some cases, monitoring of such industrial systems or areas to be monitored can not be ensured by individual or wire sensors, for example due to access problems or hostile environments. Wireless Sensor Networks (RCSF) are an alternative. Due to the nature of the communications in these networks, and the characteristics of the devices making up the latter, an RCSF is at high risk of failures at the sensors, and in this case the loss of various data is likely - problematic for the monitoring of the device. To study the relevance of the RCSF to the so-called Prognostic and Health Management (PHM) process used to determine the maintenance plan for a device to be monitored, and the impact of the various strategies deployed in the latter on the latter, proposed a first efficient diagnostic algorithm and used it in a simulated RCSF to measure its performance (this simulator being a program that we developed).

O avanço tecnológico nas unidades de terapia intensiva pediátricas (UTIPs) tornou-as aptas ao atendimento de casos de alta complexidade e elevado custo. Porém, a tecnologia disponível nem sempre tem conseguido melhorar a qualidade de atendimento aos pacientes e a própria capacidade de prolongar o tempo de vida torna-se um instrumento que potencializa a dor e o sofrimento. Sendo assim, tornou-se necessário caracterizar o estágio de gravidade da doença, que reflete a magnitude das comorbidades e distúrbios fisiológicos, no momento da internação. Esse procedimento pode ser realizado através dos escores prognósticos de mortalidade que quantificam a gravidade da doença, estimando a probabilidade de óbito de acordo com seu estágio clínico. Atualmente os escores prognósticos fazem parte das metodologias de controle de qualidade e de pesquisa. O Pediatric Risk of Mortality escore (PRISM) é um dos escores mais utilizados na unidade de terapia intensiva pediátrica (UTIP). O objetivo desse estudo foi avaliar a utilização do PRISM quanto a sua capacidade de discriminação entre sobreviventes e não-sobreviventes e determinar os fatores de prognóstico para óbito em uma UTIP terciária. Foi realizado um estudo retrospectivo na UTIP do Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, que é considerada de nível de atendimento terciário. Foi anotado o valor do PRISM correspondente às primeiras 24 horas de internação; dados demográficos e da internação, para melhor caracterização da amostra. Foram incluídos 359 pacientes; as variáveis encontradas como fatores de prognóstico para óbito foram: presença de síndrome de disfunção de múltiplos órgãos e sistemas (SDMOS) à admissão, ventilação mecânica (VM), uso de fármacos vasoativos, infecção hospitalar, terapia nutricional parenteral (TNP) e duração da internação (p < 0,0001 para todas as variáveis). Cinquenta e quatro pacientes (15%) evoluíram a óbito; a mediana do PRISM foi significativamente maior nos pacientes que evoluíram para óbito (p= 0,0001). A curva ROC do PRISM mostrou um valor de 0.76 (IC 95% 0,690,83) e a calibração, calculada pelo teste qui-quadrado de Hosmer-Lemeshow, evidenciou x2 = 12,96 com p=0,11, sendo que para este teste é considerado significativamente estatístico um valor de p > 0,05. É importante a implantação de controle estrito de qualidade nas UTIPs para identificar grupos de risco para óbito e medir a eficácia do tratamento. Embora alguns autores já tenham enfatizado que o PRISM superestima a mortalidade e não seria apropriado em populações pediátricas específicas, esse estudo mostrou que o PRISM apresenta capacidade discriminatória adequada em diferenciar sobreviventes dos não-sobreviventes e constitui ferramenta útil para avaliar o prognóstico dos pacientes admitidos em UTIP terciária. / Technological advances in pediatric intensive care units (PICU) has made them suitable for the treatment of high complexity cases and high cost. However, the technology available has not always succeeded in improving the quality of patient care and their own ability to prolong the life becomes a tool that leverages the pain and suffering, sometimes prolonging the dying process. Thus, it became necessary to characterize the stage of disease severity, which reflects the magnitude of comorbidities and physiological disorders, at admission. These procedures can be performed by way of the mortality prognostic scores that quantify the severity of the disease, estimating the probability of death according to their clinical state. Nowadays the prognostic scores make part of the methodology of quality control and research. The Pediatric Risk of Mortality score (PRISM) is one of the main scores used in the PICU. The purpose of this study was to evaluate the use of PRISM for their ability to discriminate between survivors and non-survivors and to determine the prognostic factors for death in a tertiary PICU. Retrospective cohort study was conducted in the PICU of Instituto da Criança do Hospital das Clinicas of University São Paulo, which is considered a PICU of a tertiary care level. The PRISM scores (corresponding to the first 24 hours of hospitalization), demographic and hospitalization data were noted to better characterize the study population. We included 359 patients and the variables that were found to have prognostic factors for death were multiple organ dysfunction syndrome (MODS) on admission, mechanical ventilation (MV), use of vasoactive drugs, hospital-acquired infection, parenteral nutrition therapy (PNT) and longer period of hospitalization (p < 0,0001 for all variables). Fifty-four patients (15%) died; median PRISM score was significantly higher in patients who died (p= 0,0001). The ROC curve for PRISM yielded a value of 0.76 (CI 95% 0,690,83) and the calibration, calculated using the Hosmer-Lemeshow chi-square test, was shown x2 = 12,96 with p=0,11, being that for this test is considered a statistically significant p > 0.05 . It is imperative for PICU to implement strict quality controls to identify groups at greatest risk of death and to ensure the adequacy of treatment. Although some authors have shown that the PRISM score overestimates mortality and that it is not appropriate in specific pediatric populations, in this study PRISM showed satisfactory discriminatory performance in differentiating between survivors and non-survivors and constitutes a useful tool for the assessment of prognosis for pediatric patients admitted to a tertiary PICU.

Despite improvements in therapy, the prognosis for non-small cell lung cancer (NSCLC) patients remains poor, and cure is only possible in localized tumors after surgical resection. A new generation of targeted cancer drugs has led to the expectation that lung cancer therapy can be significantly improved, but these drugs are today only an option in a small subset of NSCLC patients, and their effect is temporary. Therefore, the aim of this thesis was to characterize NSCLC in order to find new treatment targets and to evaluate biomarkers that further optimize therapy selection. In Paper I, the expression of the potential treatment targets claudin 6 and claudin 18.2 were evaluated based on immunohistochemical- and gene expression analysis. High ectopic protein and gene expression were demonstrated for both claudins in small subgroups of NSCLC. Clinical trials using humanized monoclonal antibodies against both proteins are ongoing in other cancer forms and may be extended to NSCLC. In Paper II, the prognostic impact of the inflammatory mediator cyclooxygenase 2 (COX-2) was evaluated. No prognostic significance was found in a meta-analysis incorporating gene expression data of 1337 NSCLC patients. Likewise, COX-2 protein expression in tumor cells was not associated with survival in two independent NSCLC cohorts. However, in one of the analyzed cohorts, higher COX-2 expression in the tumor stroma was associated with longer survival and may therefore be a subject for further investigation. In Paper III, tumor and stromal COX-2 protein expression was examined in patients treated with the COX-2 inhibitor celecoxib in order to evaluate if COX-2 expression is a predictive biomarker for benefit of celecoxib therapy. Celecoxib did not prolong overall survival neither in the whole cohort nor in patients stratified according to COX-2 expression in tumor or stromal cells. Noteworthy, a tendency towards longer survival was again demonstrated in patients with high COX-2 stromal expression. In Paper IV, the diagnostic methods for identification of ALK rearrangements were assessed in a large representative Swedish NSCLC population. Fluorescence in situ hybridization (FISH), as the diagnostic standard, was compared to two immunohistochemical assays. ALK gene expression levels were incorporated to supplement the molecular data. The frequency of ALK rearrangements was lower than previously reported. The different methods to detect the ALK fusion demonstrated overlapping results. However, the overlap was poor, so the methods cannot be regarded as interchangeable and should thereby be interpreted with caution when used in clinical diagnostics. In summary, this thesis applied an integrative translational approach to characterize potential new treatment targets and to evaluate the detection of existing predictive biomarkers in NSCLC.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Breast cancer is a heterogeneous disease characterised by marked inter-individual variability in presentation, prognosis and clinical outcome. The recognition that morphological assessment has limited utility in stratifying patients into prognostic subgroups led to clinico-pathological classification of tumour biology, based on receptor expression using immunohistochemical (IHC) techniques. This standard is currently complemented by the development of gene expression profiling methodology that led to the identification of intrinsic molecular subtypes, reflecting tumour genetics as the true driver of biological activity in breast cancer. The study was based on the hypothesis that molecular classification of breast carcinomas integrated with established clinico-pathological risk factors will improve current diagnostic and risk management algorithms used in clinical decision-making. A pathology-supported genetic testing strategy was used to evaluate microarray-based gene profiling against diagnostic pathology techniques as the current standard. Clinico-pathological factors including age, number of positive axillary nodes, tumour size, grade, proliferation index and hormone receptor status was documented for 141 breast cancer patients (143 tumours) referred for microarray-based gene expression profiling between 2007 and 2014. Subsets of patients were selected from the database based on the inclusion criteria defined for three phases in which the study was performed, in order to determine 1) the percentage of patients stratified as having a low as opposed to high risk of distant recurrence using the 70-gene MammaPrint profile within the inclusion criteria, 2) correlation of HER2 status as determined by IHC and fluorescence in situ hybridisation (FISH) with microarray-based mRNA readout (TargetPrint), and 3) the relationship between hormone receptor determination as reported by standard IHC and molecular subtyping using the 80-gene BluePrint profile. Similar distribution patterns for MammaPrint low- and high-risk profiles were obtained irrespective of whether fresh tumour biopsies or formalin-fixed paraffin embedded (FFPE) tissue was used. During the first phase of the study, 60% of the 106 tumour specimens analysed with MammaPrint were classified as low-risk and 40% as high-risk using a newly-developed MammaPrint pre-screen algorithm (MPA) aimed at cost-saving. In the second phase of the study, performed in 102 breast tumours, discordant or equivocal HER2 results were found in four cases. Reflex testing confirmed the TargetPrint results in discordant cases, achieving 100% concordance regardless of whether fresh tumour or FFPE tissue was used for microarray analysis. For the third phase of the study 74 HER2-negative tumour samples were selected for comparative analysis. Statistically significant positive correlations were found between protein expression (IHC score) and mRNA (TargetPrint) levels for estrogen receptor (ER) (R=0.53, p<0.0001) as well as progesterone receptor (PR) (R=0.62, p<0.0001), while combined ER/PR tumour status was reported concordantly in 82.4% of these tumours. BluePrint was essential for interpretation of these results used in treatment decision-making. The MPA developed in South Africa in 2009 was validated in this study as an appropriate strategy to prevent chemotherapy overtreatment in patients with early-stage breast cancer. The use of microarray-based analysis proved to be a reliable ancillary method of assessing HER2 status in breast cancer patients. Risk reclassification based on the TargetPrint results helped to avoid unnecessary high treatment costs in false-positive cases, in addition to providing potentially life-saving treatment to those for whom it was indicated. While neither IHC nor TargetPrint estimation of intrinsic subtype correlated independently with the molecular subtype as indicated by BluePrint profiling, the ability to distinguish between basal-like and luminal tumours was enhanced when the combined protein and mRNA values was considered. Genomic profiling provided information over and above that obtained from routine clinico-pathological assessments. This finding supports the relevance of a pathology-supported genetic testing approach to breast cancer management, whereby advanced genomic testing is combined with existing clinico-pathological risk stratification methods for improved patient management. / AFRIKAANSE OPSOMMING: Borskanker is „n heterogene siekte wat gekenmerk word deur merkbare inter-individuele variasie in kliniese beeld, prognose en uitkoms. Die beperkings van morfologiese klassifikasie vir identifikasie van prognostiese subgroepe het gelei tot klinies-patologiese tumor karakterisering op grond van reseptor uitdrukking deur gebruik van immunohistochemiese (IHC) toetse. Hierdie standaard word tans gekomplementeer deur ontwikkeling van geenuitdrukking tegnologie wat gelei het tot die identifikasie van intrinsieke molekulêre subtipes, wat die tumor genetika reflekteer as die ware drywer van biologiese aktiwiteit in borskanker. Die huidige studie is gebaseer op die hipotese dat integrasie van die molekulêre klassifikasie van borskanker met konvensionele risiko klassifikasie skemas huidige diagnostiese en behandelings algoritmes kan verbeter vir kliniese besluitneming. „n Patologie-gesteunde strategie is gebruik om mikroplaat-gebaseerde geen profilering te evalueer teen standaard patologie diagnotiese tegnieke. Kliniese-patologiese faktore insluitend ouderdom, aantal positiewe aksillêre limfnodes, tumor grootte, gradering, proliferasie indeks en hormoon reseptor status is gedokumenteer in 141 borskanker pasiente (143 tumore) wat verwys is vir mikroplaat-gebaseerde geenuitdrukking profilering tussen 2007 en 2014. Pasiënt subgroepe is geselekteer uit die databasis volgens die insluitingskriteria soos gedefiniëer in die drie fases waarvolgens hierdie studie uitgevoer is, om vas te stel 1) watter proporsie pasiënte geklassifiseer word as lae- of hoë-risiko vir latere herhaling van die borskanker deur gebruik van die 70-geen MammaPrint profile binne die insluitingskriteria, 2) hoe korreleer HER2 status soos vasgestel deur IHC en fluoreserende in situ hybridisasie (FISH) toetsing met mikroplaat-gebaseerde RNA lesings (TargetPrint), en 3) wat die verwantskap is tussen hormoon reseptor status soos deur standaard IHC gerapporteer en molekulëre klassifikasie volgens die 80-geen BluePrint profiel. Soortgelyke verdelingspatrone vir MammaPrint lae- teenoor hoe-risiko profiele is waargeneem ongeag of vars tumor biopsies of formalien-gefikseerde paraffin bevattende weefsel gebruik is. Tydens die eerste fase van die studie is 60% van die 106 tumore as lae-risiko en 40% as hoë-risiko geklassifiseer met toepassing van die nuwe MammaPrint Presifting Algoritme (MPA) wat ontwikkel is met die doel op kostebesparing. In die tweede fase van die studie waar 102 tumore ingesluit is, het die resultate van vier gevalle verskil van mekaar of was onbepaald ten opsigte van HER2 status. Refleks herevaluering het die TargetPrint resultate bevestig in alle nie-ooreenstemmende gevalle, en 100% ooreenstemming is bereik ongeag of vars tumor biopsies of formalien-gefikseerde paraffin bevattende weefsel gebruik is vir mikroplaat analise. In die derde fase van die studie is 74 HER2-negative tumore selekteer vir vergelykende analise. Statisties beduidende positiewe korrelasies is waargeneem tussen proteïen uitdrukking (IHC) en mRNA (TargetPrint) vlakke vir die estrogeen reseptor (ER) (R=0.53, p<0.0001) sowel as progesteroon reseptor (PR) (R=0.62, p<0.0001), terwyl gekombineerde ER/PR reseptor status ooreenstemming getoon het in 82.4% tumore. BluePrint was noodsaaklik vir die korrekte interpretasie van die resultate wat gebruik is in kliniese besluitneming vir behandeling van pasiënte. The MPA wat in Suid Africa ontwikkel is in 2009, is gedurende hierdie studie bevestig as n toepaslike strategie om onnodige handeling met chemoterapie te voorkom in pasiënte met vroeë stadium borskanker. Die gebruik van mikroplaat-gebaseerde analise is aangetoon as „n betroubare aanvullende metode om HER2 status te evalueer. Risiko herklassifikasie gebaseer op TargetPrint resultate het onnodige hoë behandelingskoste in vals-positiewe gevalle vermy, sowel as om die verskaffing van potensieël lewensreddende behandeling vir die toepaslike pasiënte te verseker. Genomiese profilering het inligting addisioneel tot dit wat met roetine klinies-patologies metodes verkry kan word verskaf. Hierdie bevinding ondersteun die relevansie van „n patologie-gesteunde genetiese toets benadering tot hantering van borskanker, waardeur genomiese toetsing gekombineer word met bestaande klinies-patologiese risiko stratifisering metodes om pasiënt behandeling te verbeter.