Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Background: Sputum is a non-invasive, economic investigation whereby bronchogenic carcinoma can be identified. Manual cytological screening is labour intensive, time-consuming and requires a continuous high level of alertness. Automation has recently been successfully introduced in gynaecological cytology. Since sputum samples are similar to cervical smears, the question arises as to whether they are also suitable for automated screening. Objective: This study presented with various objectives: 1) To test automated sputum screening using the BD FocalPoint™ Slide Profiler (FP) and compare with manual sputum screening. 2) To determine the sensitivity and specificity of sputum in identification of bronchogenic carcinoma. 3) To ascertain if any clinical, radiological or bronchoscopy findings would be predictors for bronchogenic carcinoma. 4) To determine the significance of adequacy. Method: Sputum samples were collected prospectively from patients attending the Division of Pulmonology at Tygerberg hospital for a transbronchial fine needle aspiration biopsy (TBNA) or a transthoracic fine needle aspiration biopsy (TTNA) for the period from 2010 to 2012. A pre-bronchoscopy sputum was collected and submitted for processing. Stained slides were put through the FP for automated screening. After slides were qualified, sputum slides were put back in the routine screening pool. Correlation was done using the TBNA/TTNA result as the standard to evaluate the sputum results. Results: 108 sputum samples were included in this study. Of the 84.3% malignant (n=91) and 15.7% benign (n=17) cases confirmed with a diagnostic procedure, sputum cytology had a sensitivity of 38.5% (35/91 malignant cases), and a specificity of 100% (17/17 benign cases). Automated screening had a better sensitivity of 94.3% (33/35 positive sputum cases), while manual screening showed a sensitivity of 74.3% (26/35 positive sputum cases) when compared to the final sputum result. Individual parameters with a significant association with positive sputum included the presence of an endobronchial tumour, partial airway obstruction / stenosis, round mass, spiculated mass (negative association), loss of weight (negative association) and squamous cell carcinoma as the histological subtype. Adequacy was not as significant as hypothesised since 85.3% of true positive sputum, but also 65.5% of false negative sputum, had large numbers of alveolar macrophages present. Conclusion: Sputum cytology remains an important part of the screening programme for bronchogenic carcinoma in the public health sector of South Africa. Results confirm that sputum cytology is very specific, and automated screening improves sensitivity. Automated screening proved to be more time efficient, resulting in 83.1% reduction (p<0.0001) in the screening time spent per case by a cytotechnologist. Results confirm that the quantity of alveolar macrophages is not directly proprtional to pathology representation. Positive sputum results did however improve with sputum adequacy, but had no significant association. Recommendations from this study include adopting automated sputum screening. / AFRIKAANSE OPSOMMING: Agtergrond: Die verkryging van ‘n sputummonster is ‘n nie-indringende, ekonomiese ondersoek waardeur bronguskarsinoom identifiseer kan word. Nie-geoutomatiseerde sitologiese ondersoek is arbeidsintensief, tydrowend en vereis ‘n deurlopende hoë vlak van konsentrasie en fokus. Outomatisering is onlangs suksesvol geïmplementeer in ginekologiese sitologie-ondersoeke. Aangesien sputummonsters soortgelyk aan servikale monsters is, het die vraag ontstaan of sputummonsters ook geskik sou wees vir geoutomatiseerde sifting. Doelwit: Hierdie studie het verskeie doelwitte gehad: 1) Om geoutomatiseerde sifting van sputummonsters te toets deur gebruik te maak van BD Focal Point ™ Slide Profiler (FP), en te vergelyk met nie-geoutomatiseerde sputum sifting. 2) Om die sensitiwiteit en spesifisiteit van sputum in die identifikasie van bronguskarsinoom te bepaal. 3) Om vas te stel of enige kliniese, radiologiese of brongoskopiese bevindings bronguskarsinoom sou kon voorspel. 4) Om die belang van ‘n verteenwoordigende monster te bepaal. Metode: ‘n Prospektiewe studie van die pasiënte wat die Divisie van Pulmonologie by Tygerberg Hospitaal vir transbrongiale nodale aspirasie (TBNA) of ‘n transtorakale aspirasie (TTNA) vanaf Julie 2010 tot Mei 2012 bygewoon het, is gedoen. ‘n Prebrongoskopiese sputum is geneem en gestuur vir prosessering. Die gekleurde skuifies is deur die FP gestuur vir geoutomatiseerde ondersoek. Indien die sputumskuifies gekwalifiseer het vir geoutomatiseerde sifting, is hulle in die groep vir ondersoek ingesluit. ‘n Korrelasiestudie, om die sputumresultate te evalueer, is uitgevoer deur die TBNA/TTNA bevindings as standaard te gebruik. Resultate: Vir hierdie studie is 108 sputummonsters ingesluit. Vanuit die 84.3% maligne (n=91) en 15.7% benigne (n=17) gevalle, bevestig deur ‘n diagnostiese prosedure, het sputumsitologie ‘n sensitiwiteit van 38.5% (35/91 maligne gevalle) en ‘n spesifisiteit van 100.0% (17/17 benigne gevalle), getoon. Geoutomatiseerde sifting het ‘n beter sensitiwiteit met 94.3% (33/35 maligne gevalle), terwyl nie-geoutomatiseerde (ondersoek) ‘n sensitiwiteit van 74.3% (26/35 maligne gevalle) wanneer met die finale resultaat vergelyk, gevind. Individuele parameters met ‘n betekenisvolle assosiasie het die teenwoordigheid van ‘n endobrongiale tumor, gedeeltelike lugwegobstruksie / stenose, ronde massa, ‘n spekuleerde massa (negatiewe assosiasie), gewigsverlies (negatiewe assosiasie) en plaveiselkarsinoom as die histologiese subtipe, ingesluit. Geskiktheid van die monster was nie so betekenisvol as wat in die hipotese gestel is nie: aangesien 85.3% van ware positief gediagnoseerde sputummonsters, maar ook 65.5% van die vals negatiewe sputummonsters, groot hoeveelhede alveolêre makrofae ingesluit het. Gevolgtrekking: Sputumsitologie bly steeds ‘n belangrike deel van die siftingsprogram vir bronguskarsinoom in die openbare gesondheidssektor in Suid-Afrika. Resultate van hierdie studie bevestig dat sputumsitologie baie spesifiek is en dat geoutomatiseerde sifting die sensitiwiteit verbeter. Ge-outomatiseerde sifting het bewys dat dit meer tydsbesparend is, met ‘n 83.1% vermindering (p<0.0001) in die siftingstyd wat deur een sitotegnoloog per geval bestee word. Resultate het bevestig dat die hoeveelheid alveolêre makrofae nie direk proporsioneel verwant is tot die patologie nie. Hoe meer verteenwoordigend die sputummonster was, hoe groter was die kanse om ‘n akkurate positiewe diagnose te maak. Die assosiasie van die geskiktheid van die sputummonster en die positiewe resultate het egter nie ‘n statisties betekenisvolle resultaat getoon nie. Aanbevelings vir hierdie studie sluit in die aanwending van geoutomatiseerde sputumondersoeke.

<p>UVOD: Savremenim dijagnostičkim i terapijskim dostignućima, kao i unapređenjem preventivnih mera produžen je životni vek ljudi. Starenje stanovni&scaron;tva je fenomen koji zahvata ceo svet. Povećanje broja starijeg stanovni&scaron;tva je udruženo sa porastom broja obolelih od karcinoma u ovoj starosnoj grupi, jer je starenje samo po sebi riziko faktor za nastanak karcinoma. Incidenca pojave karcinoma naglo raste od 50-te godine života sa vrhom u 80-toj godini života. U osoba starijih od 65 godina se dijagnostikuje 58% svih karcinoma, a 30% u starijih od 70 godina. Godine starosti nisu kontraindikaciija za sprovođenje hemioterapije kod starih bolesnika sa karcinomom. Starenje je povezano sa izmenjenom farmakodinamikom i farmakokinetikom antitumorskih lekova i povećanom osetljivo&scaron;ću normalnog tkiva na toksične komplikacije, te je odluka kliničara kod davanja hemioterapije ovoj starosnoj kategoriji bolesnika sa karcinomom uvek vrlo kompleksna i zahteva dobru procenu i odgovarajuću selekciju bolesnika za ovaj tretman. MATERIJAL I METODE: Doktorska disertacija obuhvata rezultate delom restrospektivnog, a delom prospektivnog opservacionog istraživanja sprovedenog u periodu 01.01.2011. do 31.12.2013.godine u Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici, u kojem je praćeno 152 bolesnika starosti 65 i vi&scaron;e godina kod kojih je dijagnostikovan nemikrocelularni karcinom bronha u uznapredovalom stadijumu bolesti, a koji su lečeni kombinovanim hemioterapijskim režimom na bazi platine. Kao prognostički faktori su uzeti: starosna dob bolesnika (grupa mlađih od 75 godina i starih 75 i vi&scaron;e godina), pol, navika pu&scaron;enja cigareta (pu&scaron;ač, nepu&scaron;ač, biv&scaron;i pu&scaron;ač), navika konzumiranja alkohola, performans status (prema ECOG-Eastern Cooperative Oncology Group skali) u momentu postavljanja dijagnoze, patohistolo&scaron;ki tip tumora (adenokarcinom, skvamozni karcinom, drugo), stadijum bolesti (IIIb, IV), veličina tumora (manje od 6 cm i 6 cm i vi&scaron;e), TNM status prema klasifikaciji tumora (7.revizija), parametri krvne slike (vrednosti leukocita, hemoglobina, trombocita), biohemijski parametri (vrednosti laktat-dehidrogenaze (LDH), alkalne fosfataze, aspartat- aminotransferaze (AST), alanin-aminotransferaze (ALT), kalijuma, natrijuma, bilirubina) na početku terapije, komorbiditeti u momentu postavljanja dijagnoze (broj komorbiditeta po sistemima, Charlson index), simptomi bolesti (ka&scaron;alj, hemoptizije, otežano disanje, bol u grudnom ko&scaron;u, promuklost, smetnje gutanja, sindrom gornje &scaron;uplje vene, bol u kostima, simptomi od strane centralnog nervnog sistema, povi&scaron;ena telesna temperatura), gubitak na telesnoj masi (vi&scaron;e od 5% u prethodnih 6 meseci), indeks telesne mase (&lt;18,5kg/m&sup2; pothranjen, 18,5-24,9kg/m&sup2; normalno uhranjen, 25-29,9kg/m&sup2; prekomerna telesna masa, ˃30kg/m&sup2; gojaznost). Svi potencijalni prognostički faktori su evaluirani univarijantnom analizom, a potom su svi faktori rizika za koje je utvrđena značajnost analizirani primenom multivarijantne logističke regresije, u cilju prepoznavanja nezavisnih prediktora za dvogodi&scaron;nje preživljavanje. Za otkrivanje nezavisnih prediktora preživljavanja na dve godine je primenjena binarna logistička regresiona analiza, a kao potencijalni prediktori su bile sledeće varijable: starost ispod 75 godina, pu&scaron;ačka navika, patohistolo&scaron;ki tip karcinoma, stadijum bolesti IV, T4 status, M1b status, prisustvo respiratornog komorbiditeta, otežano disanje, bol u grudima. Kumulativno preživljavanje je prikazano Kaplan-Meier-ovim krivama. Primenom multivarijantne Cox- regresione analize su dobijeni nezavisni prediktori kumulativnog preživljavanja. Iz dobijenih prognostičkih faktora koji se izdvajaju kao nezavisni prediktori za preživljavanje su kreirani matematički modeli za dvogodi&scaron;nje preživljavanje. CILJ ISTRAŽIVANJA: Utvrditi uticaj pojedinih prognostičkih faktora na dvogodi&scaron;nje preživljavanje ovih bolesnika i iz toga izvesti matematički model za stratifikaciju ovih bolesnika u odnosu na dvogodi&scaron;nje preživljavanje. REZULTATI: Analizom prognostičkih faktora je utvrđeno da grupa bolesnika starih 75 godina i vi&scaron;e ima ne&scaron;to duže dvogodi&scaron;nje preživljavanje od grupe bolesnika mlađih od 75 godina, ali bez statističke značajnosti, bolesnici sa tumorom veličine 6 cm i vi&scaron;e imaju kraće dvogodi&scaron;nje preživljavanje u odnosu na bolesnike sa tumorom manjim od 6 cm, bolesnici kod kojih je u momentu postavljanja dijagnoze T status tumora bio T4, a M status M1b imaju kraće dvogodi&scaron;nje preživljavanje, bolesnici kod kojih je na početku tretmana u laboratorijskim nalazima bila prisutna anemija i povi&scaron;ene vrednosti LDH imaju kraće dvogodi&scaron;nje preživljavanje, prisustvo vi&scaron;e komorbiditeta utiče na kraće preživljavanje, bolesnici sa gubitkom na telesnoj masi većim od 5% u periodu 6 meseci pre postavljanja dijagnoze bolesti imaju kraće dvogodi&scaron;nje preživljavanje. Kreirana su dva matematička modela (jedan za preživljavanje na 2 godine i jedan za kumulativno preživljavanje) za stratifikaciju gerijatrijskih bolesnika sa uznapredovalim stadijumom nemikrocelularnog karcinoma bronha lečenih hemioterapijom na bazi platine u odnosu na dvogodi&scaron;nje preživljavanje. ZAKLJUČAK: Dobijeni matematički modeli za preživljavanje gerijatrijskih bolesnika sa uznapredovalim stadijumom nemikrocelularnog karcinoma bronha lečenih hemioterapijom na bazi platine na jednostavan način stratifikuju bolesnike u odnosu na preterapijske prognostičke faktore za razliku od sveobuhvatne gerijatrijske procene koja je vremenski zahtevna procedura i zahteva obučen kadar.</p> / <p>INTRODUCTION: Nowadays life expectancy is prolonged due to modern diagnostic and therapy achievements, as well as promotion of preventive measurements. Aging of population is a phenomenon in the whole world. Increasing number of elderly population is accompanied with the increased number of diagnosed cancer in this age group, because the aging themselves is a risk factor for development of cancer. The appearance of cancer rapidly rises from the age of fifty with the peak at the age of eighty. 58% of cancer diagnoses are in the people older than sixty-five years and 30% in people older than seventy years. The age is not contraindication for chemotherapy treatment in older patient with cancer. The aging is associated with disturbed pharmacodynamics and pharmacokinetics of antitumor drugs and increased susceptibility of normal tissue for toxic complications, therefore clinical decision for introducing chemotherapy is very complex and requires good assessment and proper selection of the patients for this treatment. MATERIAL AND METHODS: This doctoral thesis includes results of partly retrospective and partly prospective observational research conducted in the period 01.01.2011. until 31.12.2013. at the Institute for pulmonary diseases of Vojvodina in Sremska Kamenica, which includes 152 lung cancer patients 65 and more years old with diagnosed non-small cell lung cancer in advanced stage treated with combined platinum based chemotherapy regimen. These prognostic factors are included: age of patients (group &lt;75 years, group &ge;75 years old), sex, smoking cessation (smoker, former smoker, non smoker), alcohol consuming habit, performance status (according to the ECOG-Eastern Cooperative Oncology Group scale) in the moment of confirmed diagnosis, pathohistological type of tumor (adenocarcinoma, squamous cell carcinoma, other), stage of disease (IIIb, IV), tumor size (&lt;6cm and &ge;6cm), TNM status according tumor classification (7th revision), blood count parameters (leucocyte, hemoglobin level, thrombocyte), biochemical parameters (lactate-dehydrogenase level (LDH), alkaline phosphatase level, aspartate aminotransferase level (AST), alanine aminotransferase level (ALT), potassium level, sodium level, bilirubin level) on the start of the chemotherapy, comorbidities at the moment of diagnosis (number of comorbid conditions, Charlson index), symptoms of the disease (cough, hemoptysis, dyspnea, chest pain, hoarseness, swallowing difficulties, caval venae compression symptoms, bone pain, central nervous symptoms, increased body temperature), weight loss (˃ 5% in the previous 6 months), body mass index (&lt;18,5kg/m&sup2; underweight 18,5-24,9kg/m&sup2; normal weight, 25-29,9kg/m&sup2; overweight , ˃30kg/m&sup2; obese). All potential prognostic factors were evaluated with univariante analysis, and after that all factors with confirmed significance were analysed with multivariante logistic regression, in order to identify independent predictors for 2-year survival. Binary logistic regression analysis was applied for identifying independent predictors for 2-years survival and those variables were analysed : age &lt;75 years, smoking cessation, pathohistological type of cancer, stage of disease IV, T4 status, M1b status, presence of respiratory comorbidity, dyspnea, chest pain. Cumulative survival of those patients was shown with Kaplan-Meier prognostic curves. Two mathematical model for 2-year survival was created from the factors confirmed as independent predictors for survival. AIM: This research objectives were to determine the influence of certain prognostic factors on 2-years survival of those patients and to create mathematical model for stratification of those patients related to 2-years survival. RESULTS: Univariante analysis confirmed that the group of patients older than 75 years and more have had better 2-year survival than group of patient younger than 75 year, but without the statistically significance, patients with tumor size &ge;6cm have had worst 2-year survival in comparison with patients with tumor size &lt;6cm, patients with tumor status T4 at the moment of diagnosis and M status M1b have had the shorter 2-year survival, patients with anemia and increased LDH level on the start of the chemotherapy treatment have had shorter 2-year survival, the presence of more comorbid conditions at the moment of diagnosis influence on shorter 2-year survival, patients with weight loss more than 5% in the previous 6 months have had shorter 2-year survival. Two mathematical models were created (one for 2-year survival and the other for the cumulative survival) for stratification of elderly patients with advanced staged non-small cell lung cancer treated with combined platinum based chemotherapy regimen related to 2-year survival. CONSLUSION: Created mathematical models for stratification of elderly patients with advanced staged non-small cell lung cancer treated with combined platinum based chemotherapy regimen more easily stratify patients compared to pretreatment prognostic factors as opposed to comprehensive geriatric assessment which is time-consuming procedure and requires trained personnel.</p>