<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>

<p>Karcinom bronha najče&scaron;ći uzrok smrti među malignim bolesti u svetu. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Neodjuvantna terapija kod bolesnika sa lokalno uznapredovalim karcinomom pluća i zahvaćenim N2 limfnim čvorovima jedan je od modusa multimodalnog lečenja bolesnika sa nemikrocelularnim karcinomima pluća (NSCLC) u cilju pobolj&scaron;anja ishoda njihovog lečenja. Ovakav pristup podrazumeva prevođenje pacijenta iz vi&scaron;eg u niži stadijum bolesti - &bdquo;downstaging&rdquo;. Na taj način pacijent postaje potencijalno resektabilan u smislu daljeg hirur&scaron;kog lečenja koji bi mogao da obezebedi sveukupni onkolo&scaron;ki benefit. Osnovni ciljevi ove doktorske disertacije su bili: procena odgovora na neoadjuvantnu terapiju kod bolenika sa IIIA stadijumom nemikrocelularnog karcinoma bronha u odnosu na T faktor i N faktor, procena TNM klasifikacije pre i posle primenjene neoadjuvantne terapije kod bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha, određivanje stepena tumorske regresije patohistolo&scaron;kom analizom hirur&scaron;kog resekata nemikrocelularnog karcinoma bronha operisanih bolesnika nakon primenjene neoadjuvantne terapije, kao prognostički faktor za period bez bolesti i ukupnog preživljavanja i određivanje stepena regresije tumora u maligno izmenjenim limfnim čvorovima nakon primenjene neoadjuvantne terapije kod bolesnka sa IIIA stadijumom nemikrocelularnog karcinoma bronha, kao prognostički faktor za period bez bolesti i ukupnog preživljavanja.Rezultati su pokazali da neoadjuvantna terapija prema RECIST kriterijumima dovodi značajnog smanjenja veličine tumora, T faktora, kao i do znčajnog downstaging&ldquo;-a nodalnog statusa, N faktora, u terapiji bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha. Neoadjuvantna terapija prema RECIST kriterijumima dovodi značajnog smanjenja klinikog stadijuma bolesti, u terapiji bolesnika sa IIIA stadijumom nemikrocelularnog karcinoma bronha Nakon primenjene neoadjuvantne terapije nema značajne razlike u T faktoru koji je određen radiolo&scaron;ki prema RECIST kriterijumima (ycT) i patohistolo&scaron;ki (ypT) na hirur&scaron;kom materijalu. Nakon primenjene neoadjuvantne terapije prisutna je značajna razlika u N faktoru koji je određen radiolo&scaron;ki prema RECIST kriterijumima (ycN) i patohitolo&scaron;ki (ypN) na hirur&scaron;kom materijalu. Nakon primenjene neoadjuvantne terapije prisutna je značajna razlika u kliničkom stadijumu bolesti koji je određen radiolo&scaron;ki prema RECIST kriterijumima (yc) i patohitolo&scaron;ki (yp) na hirur&scaron;kom materijalu. Gradusi tumorske regresije su usko povezani sa procentom očuvanog tumorskog tkiva. Stepen tumorske regresije u resekatu primarnog tumora nije u korelaciji sa ukupnim preživljavanjem i procenom perioda bez bolesti kod pacijenata sa IIIA stadijumom nemikrocelularnog karcinoma bronha.</p> / <p>Lung cancer is the most common cause of death among malignant diseases in the world. In the twentieth century was a significant increase in both incidence and mortality of lung cancer in most countries. Median survival in all stages of the disease has improved significantly in recent years of the twentieth century, but not as we expected. In most cases, the disease is detected at an advanced stage, when the radical surgical treatment is considered impossible. Neoadjuvant therapy, in patients with locally advanced carcinoma of the lung, and with affected the lymph nodes N2, is one of the modes of multimodal treatment of patients with non-small cell lung cancer (NSCLC) in order to improve the outcome of their treatment. This involves translating the patient from a higher to a lower stage of the disease - &quot;downstaging&quot;. In this way the patient is considered for further surgical treatment that could provide him overall oncology benefit. Main objectives of this PhD dissertation are: evaluation of response to neoadjuvant therapy in stage IIIA NSCLC patients in relation to T factor and N factor; evaluation of TNM classification before and after use of neoadjuvant therapy in stage IIIA NSCLC patients; determination of degree of tumor regression with pathohistologic analysis of resection specimen of NSCLC obtained from patients after application of neoadjuvant therapy, as a prognostic factor for disease-free period and overall survival rate; and determination of degree of tumor regression in malignant lymph nodes after application of neoadjuvant therapy in stage IIIA NSCLC patients, as a prognostic factor for disease-free period and overall survival rate. Results have shown that neoadjuvant therapy according to RECIST criteria leads to significant reduction of tumor size, T factors, as well as significant downstaging of nodal status, N factor, in treatment of stage IIIA NSCLC patients. Furthermore, neoadjuvant therapy according to RECIST criteria leads to significant reduction of clinical stage of the disease in treatment of stage IIIA NSCLC patients. However, after neoadjuvant therapy is applied there is no significant difference in T factor determined radiologically according to RECIST criteria (ycT) and by pathohistologic analysis (ypT) of resected specimen. Neoadjuvant therapy leads to significant difference in N factor which is determined radiologically according to RECIST criteria (ycN) and by pathohistologic analysis (ypN) of resection specimen. After neoadjuvant therapy is applied there is significant difference in clinical stage of the disease determined radiologically according to RECIST criteria (yc) and by pathohistologic analysis (yp) of resection specimen. Tumor regression grading is closely linked to the percentage of preserved tumor tissue. Degree of tumor regression in surgical resection of primary tumor does not correlate to the overall survival rate and estimation of disease-free period in stage IIIA NSCLC patients.</p>

Orientador: Lair Zambon / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-21T10:28:19Z (GMT). No. of bitstreams: 1 PerroudJunior_MauricioWesley_D.pdf: 9913138 bytes, checksum: 5dd1ec64b004b6d50e2392e6383c9c98 (MD5) Previous issue date: 2012 / Resumo: Os resultados terapêuticos globais do carcinoma de pulmão não pequenas células em estádio avançado são bem limitados. A imunoterapia com células dendríticas foi desenvolvida como uma nova estratégia para o tratamento de câncer de pulmão. O objetivo deste estudo foi avaliar a viabilidade, segurança e respostas imunológicas em pacientes com carcinoma de pulmão não pequenas células tratados com vacina autóloga de células dendríticas maduras pulsadas com antígenos. Cinco pacientes HLA-A2 com carcinoma de pulmão não pequenas células inoperável (estádio III ou IV) foram selecionados para receber duas doses de 5 x 107 de células dendríticas administradas por vias subcutânea e intravenosa, duas vezes em intervalos de duas semanas. A segurança, tolerabilidade e respostas imunológica e tumoral à vacina foram avaliadas pela evolução clínica e laboratorial, ensaio de linfoproliferação e critérios de RECIST, respectivamente. A dose utilizada para a imunoterapia demonstrou ser segura e bem tolerada. O ensaio de linfoproliferação mostrou uma melhora na resposta imune específica após a imunização, com uma resposta significativa após a segunda dose (p = 0,001). Esta resposta não foi persistente e houve uma tendência à redução após duas semanas da segunda dose da vacina. Dois pacientes apresentaram uma sobrevida quase duas vezes maior que a média esperada e foram os únicos que expressaram os antígenos tumorais HER-2 e CEA Apesar do pequeno tamanho da amostra, os resultados sobre o tempo de sobrevida, resposta imune, segurança e tolerabilidade, combinado com os resultados de outros estudos, são animadores para a condução de um estudo clínico com doses múltiplas em pacientes com câncer de pulmão que foram submetidos a tratamento cirúrgico, seguindo as diretrizes do Cancer Vaccine Clinical Trial Working Group / Abstract: Overall therapeutic outcomes of advanced non-small-cell lung cancer (NSCLC) are poor. The dendritic cell (DC) immunotherapy has been developed as a new strategy for the treatment of lung cancer. The purpose of this study was to evaluate the feasibility, safety and immunologic responses in use in mature, antigen-pulsed autologous DC vaccine in NSCLC patients. Five HLA-A2 patients with inoperable stage III or IV NSCLC were selected to receive two doses of 5x107 DC cells administered subcutaneous and intravenously two times at two week intervals. The safety, tolerability and immunologic and tumor responses to the vaccine were evaluated by the clinical and laboratorial evolution, lymphoproliferation assay and RECIST's criteria, respectively. The dose of the vaccine has shown to be safe and well tolerated. The lymphoproliferation assay showed an improvement in the specific immune response after the immunization, with a significant response after the second dose (p = 0.001). This response was not long lasting and a tendency to reduction two weeks after the second dose of the vaccine was observed. Two patients had a survival almost twice greater than the expected average and were the only ones that expressed HER-2 and CEA together. Despite the small sample size, the results on the survival time, immune response, and safety and tolerability, combined with the results of other studies, are encouraging to the conduction of a large clinical trial with multiples doses in patients with early lung cancer who underwent surgical treatment, following the guidelines of the Cancer Vaccine Clinical Trial Working Group / Doutorado / Clinica Medica / Doutor em Ciências

<p>Karcinom bronha je danas u svetu najče&scaron;ći uzrok smrti povezanih sa malignim bolestima. U XX veku je registrovan značajan porast kako incidence, tako i mortaliteta karcinoma bronha u većini zemalja. Medijana&nbsp; preživljavanja u svim stadijumima bolesti se značajno pobolj&scaron;ala poslednjih godina XX veka, ali nedovoljno u odnosu na očekivano. U najvećem broju slučajeva, bolest se otkriva u uznapredovalom stadijumu, kada je radikalno hirur&scaron;ko lečenje kao optimalan vid lečenja nemoguće. Određivanje stadijuma bolesti (stejdžing) je najbitniji segment u evaluaciji svakog bolesnika s karcinomom bronha. Utvrđivanje zahvaćenosti medijastinalnih&nbsp; limfnih čvorova karcinomom je od posebne važnosti, jer je u velikom broju slučajeva upravo nodalni status faktor koji određuje svsishodnost primene hirur&scaron;kog lečenja, radioterapije i hemioterapije, a samim tim i jedan od bitnih faktora prognoze bolesnika sa nemikrocelularnim karcinomom bronha NSCLC. Bolesnici sa dokazanom zahvaćeno&scaron;ću N2 medijastinalnih limfnih čvorova se svrstavaju u IIIA stadijum NSCLC koji je potencijalno resektabilan, dok se bolesnici sa dokazanom zahvaćeno&scaron;ću N3 medijastinalnih limfnih čvorova svrstavaju u IIIB stadijum NSCLC, koji se smatra neresektabilnim. Cilj ove doktorske disertacije je bio da se utvrdi da li postoje prognostički značajni faktori za rezultat lečenja medijastinoskopski dokazanog N2 i N3 stadijuma NSCLC. Studija je bila nerandomizovana, delom retrospektivnog, a delom prospektivnog karaktera. U ispitivanje je uključeno 60 bolesnika lečenih u Institutu za plućne bolesti Vojvodine tokom&nbsp; 2006., 2007. i 2008. godine. Kod svih uključenih bolesnika medijastinoskopijom je dokazana propagacija NSCLC u medijastinalne limfne čvorove. U radu su analizirani sledeći faktori: pol, starost, ECOG performans status, pridružena hronična opstruktivna bolest pluća (HOBP), pridruženo kardiovaskularno oboljenje sa simtomatologijom klasifikovanom prema NYHA, T faktor, lokalizacija i broj medijastinoskopski dokazanih metastatski zahvaćenih limfnih čvorova, vrsta primenjenog&nbsp; lečenja (hemioradioterapija, hemioterapija, operacija), rezultat lečenja (odgovor na terapiju i preživljavanje). Univarijantnom analizom je utvrđeno da su kod bolesnika sa medijastinoskopski dokazanim N2 i N3 stadijumom NSCLC prognostički faktori koji su imali uticaj na lo&scaron;ije preživljavanje bili: ECOG PS 2 (p=0,00000), pridruženo kardivaskularno oboljenja sa simptomatologijom klase NYHA II (p=0,00113), zahvaćenost kontralateralnih medijastinalnih medijastinalnih limfnih čvorova (N3 stadijum) (p=0,000003), dok je uticaj zahvaćenosti vi&scaron;e pozicija ipsilateralnih medijastinalnih limfnih čvorova (multi station N2) bio na granici statističke značajnosti (p=0,05385). Utvrđeno je da bolesnici sa N2 i N3 stadijumom NSCLC lečeni hemioradioterapijom imaju bolju stopu odgovora na primenjenu terapiju u odnosu na bolesnike lečene samo hemioterapijom (p=0,03118), kao i da operativno lečenje primenjeno kod bolesnika koji su imali dobar odgovor na sprovedenu terapiju ima statistički značajan uticaj u vidu boljeg preživljavanja (p=0,00121). Univarijantnom analizom nije utvrđen značajan uticaj sledećih faktora na preživljavanje bolesnika sa N2 i N3 stadijomom NSCLC: pol, starost, pridružena HOBP, skvamozni tip NSCLC i T faktor. Multivarijantnom analizom su kao nezavisni prognostički faktori na preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC utvrđeni klinički N status (bolje preživljavanje ima N2 u odnosu na N3 stadijum) i sprovedena terapija (bolje preživljavanje ima hemioradioterapija u odnosu na hemioterapiju). Dobijeni rezultati navode nas na zaključak da su pozicija i broj zahvaćenih pozicija medijastinalnih limfnih čvorova, koji su utvrđeni medijastinoskopski, kao i sprovođenje multimodalnog lečenja ključni prognostički faktori za preživljavanje bolesnika sa N2 i N3 stadijumom NSCLC.</p> / <p>Lung&nbsp; cancer&nbsp; is&nbsp; the&nbsp; most&nbsp; common cause of cancer&nbsp; related mortality&nbsp; worldwide.&nbsp; Increase&nbsp; in&nbsp; both&nbsp; incidence&nbsp; and mortality&nbsp; of&nbsp; lung&nbsp; cancer&nbsp; was&nbsp; registered&nbsp; throughout&nbsp; 20th century. The median survival in every stage of lung cancer has been improved in last years of 20th century but it is still not satisfactory. In most cases, lung cancer is diagnosed in advanced&nbsp; stage&nbsp; when&nbsp; surgical&nbsp; treatment&nbsp; as&nbsp; the&nbsp; optimal approach&nbsp; is&nbsp; not&nbsp; possible. Staging&nbsp; is&nbsp; the&nbsp; most&nbsp; important element&nbsp; in&nbsp; the&nbsp; evaluation&nbsp; of&nbsp; every&nbsp; lung&nbsp; cancer&nbsp; patient. Mediastinal lymph node involvement is crucial, because in most of the cases nodal staging is factor which determines appropriate use of surgery, radiotherapy and chemotherapy and it is one of the important factors influencing prognosis of lung cancer patients. Patients with proven involvement of ipsilateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N2&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIA&nbsp; stage&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be potentially resectable, and patients with proven involvement of&nbsp; contralateral&nbsp; mediastinal&nbsp; lymph&nbsp; nodes&nbsp; (N3&nbsp; stage)&nbsp; are categorized&nbsp; in&nbsp; IIIB&nbsp; stage,&nbsp; which&nbsp; is&nbsp; considered&nbsp; to&nbsp; be nonresectable. The aim of this study was the determination of&nbsp; significant&nbsp; prognostic&nbsp; factors&nbsp; that&nbsp; have&nbsp; influence&nbsp; on treatment&nbsp; and&nbsp; survival&nbsp; of&nbsp; non-small&nbsp; cell&nbsp; lung&nbsp; cancer (NSCLC)&nbsp; patients&nbsp; in&nbsp; stage&nbsp; N2&nbsp; and&nbsp; N3.&nbsp; Study&nbsp; was nonrandomized,&nbsp;&nbsp; partially&nbsp;&nbsp; retrospective&nbsp;&nbsp; and&nbsp;&nbsp; partially prospective. It included 60 patients treated at the Institute for Pulmonary&nbsp; Diseases&nbsp; of&nbsp; Vojvodina&nbsp; during&nbsp; 2006,&nbsp; 2007&nbsp; and 2008. Cancer involvement of mediastinal lymph nodes was determined by mediastinoscopy in every patient. In study we analyzed following factors: gender, age, ECOG performance&nbsp;&nbsp; status,&nbsp;&nbsp; associated&nbsp;&nbsp; chronic&nbsp;&nbsp; obstructive pulmonary&nbsp; disease&nbsp; (COPD),&nbsp; associated&nbsp; cardiovascular disease with symptoms graded by NYHA classification, T status, position and number of involved mediastinal lymph nodes,&nbsp; applied&nbsp; treatment&nbsp; (surgery,&nbsp; chemoradiotherapy, chemotherapy alone), treatment result (response to treatment and&nbsp; survival).&nbsp; Prognostic&nbsp; factors&nbsp; for&nbsp; poorer&nbsp; survival&nbsp; on univariant analysis were ECOG PS 2 (p=0,0000), associated cardiovascular&nbsp;&nbsp; disease&nbsp;&nbsp; with&nbsp;&nbsp; symptoms&nbsp;&nbsp; NYHA&nbsp;&nbsp; II (p=0,00113)&nbsp; and&nbsp; involvement of&nbsp; contralateral&nbsp; mediastinal lymph nodes (N3 stage) (p=0,00003) while multi station N2 disease was borderline significant at level of p=0,05385. It was determined that patients treated with chemoradiotherapy achieved better response to treatment compared to patients treated&nbsp; with&nbsp; chemotherapy&nbsp; alone&nbsp; (p=0,03118).&nbsp; Univariant analyses&nbsp; did&nbsp; not&nbsp; confirm&nbsp; significance&nbsp; of&nbsp; gender,&nbsp; age, associate COPD, squamous cell lung cancer and T factor on survival. Multivariante&nbsp; analyses&nbsp; identified&nbsp; N&nbsp; status&nbsp; (better survival has N2 stage compared to N3 stage of NSCLC) and conducted treatment (better survival has&nbsp; chemoradiotherapy compared to chemotherapy alone) as independent prognostic factors.&nbsp; Our&nbsp; results&nbsp; suggest&nbsp; that&nbsp; position&nbsp; and&nbsp; number&nbsp; of cancer involved&nbsp; mediastinal lymph nodes position,&nbsp; proven by mediastinoscopy, as well as the conducted multimodality treatment are key prognostic factors which might influence the survival of patients with N2 and N3 stage of NSCLC.</p>

<p>Karcinomi pluća su najče&scaron;ći uzrok oboljevanja i umiranja od malignih tumora u Svetu. Neodjuvantna terapija kod bolesnika sa lokalno uznapredovalim (IIIA-IIIB) karcinomom pluća i zahvaćenim N2 limfnim čvorovima jedan je od modusa multimodalnog lečenja bolesnika sa nemikrocelularnim karcinomima pluća (NSCLC) u cilju pobolj&scaron;anja ishoda njihovog lečenja. Ovakav pristup podrazumeva prevođenje bolesnika iz vi&scaron;eg u niži stadijum bolesti - &bdquo;downstaging&rdquo;. Do danas nije utvrđena povezanost između pojedinih obrazaca tumorskog odgovora i vrste terapije. S obzirom na značaj kompletnog patolo&scaron;kog odgovora i tumorske regresije u prognozi ishoda lečenja, iznalaženje ove povezanosti je od značaja za dizajniranje budućih neoadjuvantnih trajala. Prilikom utvrđivnja histolo&scaron;ke slike tumorske regresije veoma je važno i merenje areje rezidualnog tumora (ART). Kako je veličina tumora jedan od prognostičkih faktora za bolesnike sa NSCLC koji nisu primali neoadjuvantnu terapiju tako je i merenje ART, za razliku od makroskopske veličine tumora, jedan od prognostičkih faktora za bolesnike sa NSCLC koji su primali neoadjuvantnu terapiju. Krajnji cilj neoadjuvantne terapije trebalo bi da bude resektabilnost i &bdquo;downstaging&rdquo; koji bi mogao da obezbedi u specifičnim kliničkim situacijama i sveukupni onkolo&scaron;ki benefit. Osnovni ciljevi ove doktorske disertacije su bili: da se objektivizira procena veličine ART u tumorskom tkivu pluća i limfnih čvorova; da se proceni povezanost povr&scaron;ine ART sa veličinom tumora na postoperativnom hirur&scaron;kom materijalu posle neoadjuvantne terapije; da se analizira i proceni povezanost histomorfolo&scaron;kih parametara kod tumorske regresije indukovane neoadjuvantnom terapijom i spontane tumorske regresije u tumorima pluća i limfnih čvorova na&nbsp; postoperativnom hirur&scaron;kom materijalu i u zavisnosti od histolo&scaron;kog tipa karcinoma; da se proceni povezanost kliničkog odgovora na neoadjuvantnu terapiju prema kriterijumima Svetske Zdravstvene Organizacije i histolo&scaron;kih parametara u tumorima pluća i limfnim čvorovima na postoperativnom hirur&scaron;kom materijalu nakon neoadjuvantne terapije; da se proceni povezanost patolo&scaron;kog ypTN sa kliničkim ycTN stadijumom bolesti i stepena tumorske regresije indukovane neoadjuvantnom terapijom i patolo&scaron;kog ypTN i da se proceni povezanosti između kliničke i patolo&scaron;ke zahvaćenosti N2 limfnih čvorova posle neoadjuvantne terapije. Merenje ukupne veličine očuvanih ART je najznačajniji objektivni parametar u proceni stepena tumorske regresije. Veličina rezidualnog tumora nije u korelaciji sa veličinom tumora posle neoadjuvantne terapije. Postoji signifikantna razlika u patohistolo&scaron;koj slici tumorske regresije indukovane neoadjuvantnom terapijom i spontane tumorske regresije. Ne postoji signifikantna razlika između histolo&scaron;kog tipa tumora i histolo&scaron;ke slike tumorske regresije. Ne postoji signifikantna povezanost između kliničkog odgovora i stepena tumorske regresije nakon neoadjuvantne terapije. Ne postoji korelacija između kliničkog i patolo&scaron;kog stadijuma bolesti posle neoadjuvantne terapije. Ne postoji korelacija između stepena tumorske regresije indukovane neoadjuvantnom terapijom i ypTN stadijuma bolesti. Ne postoji korelacija između kliničke i patolo&scaron;ke zahvaćenosti N2 limfnih čvorova posle neoadjuvantne terapije. Stepen regresije tumora i merenje ART posle neoadjuvantne terapije određen histopatolo&scaron;kom analizom reseciranog tumora je najobjektivniji kriterijum za procenu hemioterapijskog odgovora i predviđanja ishoda lečenja pacijenata.</p> / <p>Lung cancers are the most common cause of morbidity and mortality from malignant tumors in the World. The neodjuvant therapy in patients with locally advanced (IIIA-IIIB) lung cancer and affected N2 lymph nodes is one of the modes of multimodal treatment of patients with non-small cell lung cancer (NSCLC) in order to improve the outcome of their treatment. This involves converting patients from a higher to a lower stage of the disease - &quot;downstaging&quot;. There has been no significant connection between some forms of tumor response and types of therapy. Given the importance of complete pathological responses and tumor regression in the prediction of treatment outcomes, finding this relationship is of importance for the design of future neoadjuvant trails. In determining the histological tumor regression is very important measurement of area of residual tumor (ART). As the size of the tumor is one of the prognostic factors in patients with NSCLC who did not receive neoadjuvant therapy so the measurement of ART, as opposed to the macroscopic size of the tumor, one of the prognostic factors in patients with NSCLC, who had received neoadjuvant therapy. The ultimate goal of neoadjuvant therapy should be resectability and &quot;downstaging&quot; that could provide overall oncology benefit in specific clinical situations. The main objectives of this thesis were: to objectively estimate the size of ART in tumor tissue of lung and lymph nodes; to estimate the relation between the surface of ART with the size of the tumor on postoperative surgical material after neoadjuvant therapy; to analyze and estimate the relation between histomorphological parameters in tumor regression induced by neoadjuvant therapy and spontaneous tumor regression in tumors of the lung and lymph nodes in the postoperative surgical material and depending on the histological type of cancer; to estimate the relation between clinical response to neoadjuvant therapy according to criteria of the World Health Organization and histological parameters in lung tumors and lymph nodes in the postoperative surgical material after neoadjuvant therapy; to estimate the correlation of the pathological ypTN with clinical ycTN stage of the disease and the degree of tumor&nbsp; regression induced by neoadjuvant therapy and pathological ypTN and estimation of the relation between clinical and pathological involvement of N2 lymph nodes after neoadjuvant therapy. Measurement of the total size of the preserved ART is the most important objective parameter in the assessment of the grade of tumor regression. Size of residual tumor did not correlate with the size of the tumor after neoadjuvant therapy. There was a significant difference in the histological picture of tumor regression induced by neoadjuvant therapy and spontaneous tumor regression. There was no significant difference between the histologic type of tumor and histological tumor regression. There is no significant correlation between clinical response and the grade of tumor regression after neoadjuvant therapy. There is no correlation between clinical and pathological staging of the disease after neoadjuvant therapy. There is no correlation between the grade of tumor regression induced by neoadjuvant therapy and ypTN stage of the disease. There is no correlation between the clinical and the pathological involvement of the N2 lymph nodes to neoadjuvant therapy. The grade of tumor regression and measurement ART after neoadjuvant therapy determined by histopathological analysis of the resected tumor is the most objective criterion for evaluation of chemotherapeutic response and prediction of treatment outcome in patients.</p>

Deregulation of gene expression caused by genetic or epigenetic changes plays an important role in pathogenesis of cancer. The thesis is a commented collection of ten publications dealing with the molecular biology of tumours. The author has significantly contributed to all of them. All the articles contained in the thesis are linked to the topic of assessment of molecules involved in gene expression regulation (microRNAs) or DNA alterations that affect gene expression (promoter methylation, presence of a fusion gene). MicroRNAs are short single-stranded RNA molecules involved in posttranscriptional regulation of gene expression by triggering mRNA degradation or inhibiting translation. It is a basic mechanism with an impact on all cellular processes including the pathogenesis of various diseases. MicroRNAs can either act as oncogenes by decreasing the expression of tumour-suppressor genes or as tumour-suppressor genes by decreasing the expression of oncogenes. However, the network of microRNA - RNA interactions is much more complex. Our published results that are part of this thesis are focused on colorectal carcinoma (CRC), prostate cancer, head and neck squamous cell carcinoma (HNSCC), gastric cancer and non-small cell lung cancer (NSCLC). In patients with CRC, we demonstrated the prognostic...

Deregulation of gene expression caused by genetic or epigenetic changes plays an important role in pathogenesis of cancer. The thesis is a commented collection of ten publications dealing with the molecular biology of tumours. The author has significantly contributed to all of them. All the articles contained in the thesis are linked to the topic of assessment of molecules involved in gene expression regulation (microRNAs) or DNA alterations that affect gene expression (promoter methylation, presence of a fusion gene). MicroRNAs are short single-stranded RNA molecules involved in posttranscriptional regulation of gene expression by triggering mRNA degradation or inhibiting translation. It is a basic mechanism with an impact on all cellular processes including the pathogenesis of various diseases. MicroRNAs can either act as oncogenes by decreasing the expression of tumour-suppressor genes or as tumour-suppressor genes by decreasing the expression of oncogenes. However, the network of microRNA - RNA interactions is much more complex. Our published results that are part of this thesis are focused on colorectal carcinoma (CRC), prostate cancer, head and neck squamous cell carcinoma (HNSCC), gastric cancer and non-small cell lung cancer (NSCLC). In patients with CRC, we demonstrated the prognostic...