Includes bibliographical references and index.

<p>Metotreksat kao antagonista folne kiseline ima &scaron;iroku upotrebu za lečenje brojnih maligniteta, primenjen u visokim dozama i u&nbsp; kombinciji&nbsp; sa leukovorinom. Iako&nbsp; je&nbsp; terapija&nbsp; visokim&nbsp; dozama&nbsp; metotreksata drastično pobolj&scaron;ala&nbsp; prognozu pacijenata sa malignitetom, te&scaron;ki neželjeni efekti terapije predstavljaju stalan klinički problem. Ciljevi istraživanja bili su određivanje serumske koncentracije metotreksata i izračunavanje farmakokinetičkih&nbsp; parametara&nbsp; metotreksata kod dece obolele od malignih&nbsp; bolesti&nbsp; koja su na terapiji visokim dozama metotreksata (2&nbsp; g/m² i&nbsp; 5&nbsp; g/m² ); ispitivanje postojanja uticaja primenjene doze metotreksata, demografskih i kliničkih karakteristika ispitanika&nbsp; na koncentracije i farmakokinetičke parametare. Ispitivano je prisustvo i stepen kliničkih i laboratorijskih znakova toksičnosti metotreksata, kao i uticaj primenjene&nbsp; doze&nbsp; metotreksata&nbsp; i demografskih karakteristika ispitanika&nbsp; na pojavu i stepen toksičnosti . U okviru retrospektivno - prospektivne&nbsp; studije&nbsp; ukjučeno&nbsp; je&nbsp; četrdeset&nbsp; i dva pedijatrijska&nbsp; pacijenta&nbsp; uzrasta od&nbsp; 0,75 do 17,75 godina (medijana 5,75&nbsp; godina). Svi pacijenti&nbsp; su lečeni&nbsp; u&nbsp; Službi&nbsp; za&nbsp; hematologiju i&nbsp; onkologiju&nbsp; Instituta&nbsp; za&nbsp; zdravstvenu za&scaron;titu dece i omladine Vojvodine (Novi Sad, Srbija) u periodu od juna 2004. godine do juna 2012. godine. Trideset i osam ispitanika&nbsp; je lečeno pod dijagnozom akutne limfoblastne leukemije&nbsp; prema dva&nbsp; uzastopna&nbsp; protokola ALL IC - BFM 2002 i ALL IC - BFM 2009 Internacionalne&nbsp; BFM studijske&nbsp; grupe &bdquo;I - BFM - SG&ldquo;&nbsp; (International Berlin -Frankfurt - M&uuml;nster Study Group) za proučavanje i lečenje dečje non-B akutne limfoblastne leukemije. Četvoro je&nbsp; imalo&nbsp; dijagnozu non - Hodgkin limfoma&nbsp; i bili su uključen i u&nbsp; protokol NHL - BFM&nbsp; 95. Istraživanje je obuhvatilo 113 ciklusa terapije metotreksatom (1&ndash; 4 ciklusa po pacijentu) sa 386 izmerenih serumskih koncentracija metotreksata. Raspon primenjenih doza metotreksata kretao se od 800 do 10.000 mg. Koncentracije metotreksata su merene 24, 36 i 42 sata nakon započinjanja infuzije metotreksata, a po potrebi i u dužim vremenskim intervalima. Za izračunavanje farmakokinetičkih parametara kori&scaron;ćen je dvokompartmanskih farmakokinetički&nbsp; model posle obustavljanja&nbsp; intravenske&nbsp; infuzije,&nbsp; gde&nbsp; postoje relacije&nbsp; za&nbsp; farmakokinetičke&nbsp; tačke. Podaci o kliničkim i laboratorijskim znacima toksičnosti metotreksata prikupljani su iz medicinske dokumentacije, a za stepenovanje toksičnosti kori&scaron;ćen je skor sistem - Common Terminology Criteria for&nbsp; Adverse&nbsp; Events (CTCAE), Version 4.0, U.S. Department&nbsp; of&nbsp; health&nbsp; and&nbsp; human services, National Institute of Health, National Cancer Institute. U cilju utvrđivanju uticaja karakteristika ispitanika, primenjene doze i prisustva produžene eliminacije na posmatrane parametre, vr&scaron;eno je poređenje tri grupe&nbsp; pacijenata (doza 2 g/m² bez produžene eliminacije, 5 g/m² bez produžene liminacije i 5 g/m² sa produženom eliminacijom metotreksata). Za celokupnu grupu ispitanika,&nbsp; medijane&nbsp; koncentracije metotreksta&nbsp; bile&nbsp; su 25,82 &mu;mol/l u 24. satu, 0,68 &mu;mol/l u 36. satu i 0,24 &mu;mol/l u 42. satu merenja. Najizraženija interindividualna varijabilnost u koncentracijama metotreksata bila je u 42. satu merenja, dok je&nbsp; intraindividualna varijabilnost bila najizraženija u 36. satu merenja. Medijana&nbsp; klirensa&nbsp;&nbsp; metotreksata&nbsp;&nbsp; bila&nbsp; je 8,32&nbsp;&nbsp; l/h. Farmakokinetički parametri&nbsp; redom bili su:&nbsp; medijana&nbsp; volumena&nbsp; centralnog&nbsp; kompartmana V₁ 28,47&nbsp; l, medijane konstanti k₁₀ 0,206, k₁₂ 0,0245, k₂₁ 0,1114. Najizraženiji uticaj primenjene doze na koncentracije metotreksata pokazan je u 24.&nbsp; satu&nbsp; merenja, dok uticaj doze na klirens&nbsp; metotreksata nije&nbsp; pokazan. Prisustvo produžene eliminacije metotreksata dovodi do smanjenih vrednosti konstanta k₁₀ i k₂₁. Nije pokazana statistički značajna&nbsp; interakcija ispitivanih demografskih karakteristika (uzrast, telesna povr&scaron;ina i pol)&nbsp; i koncentracija metotreksata, kao ni klirensa metotreksata. Pokazana je značajna interakcija između koncentracija metotreksata i nivoa laktat dehidrogenaze, kao i klirensa metotreksata i nivoa kreatinina i laktat dehidrogenaze. Većina ispoljenih&nbsp; toksičnosti bila je umerenog stepena (&lt;3 stepena). Najzastupljeniji klinički znak toksičnosti bio je oralni mukozitis, koji je bio većeg stepena u grupi sa većom primenjenom dozom metotreksata&nbsp; (5g/m²). Najzastupljeniji&nbsp; laboratorijski toksični efekti&nbsp; metotreksata bili su leukopenija i anemija. Najteži stepeni laboratorijskih znakova toksičnosti (leukopenija, anemija, porast&nbsp; AST,&nbsp; ALT i GGT) nalazili su se u grupi sa većom dozom&nbsp; (5 g/m²) i&nbsp; sa produženom eliminacijom metotreksata. Osnov&nbsp; za&nbsp; kliničko&nbsp; vođenje&nbsp; pacijenata&nbsp; na&nbsp; terapiji visokim dozama metotreksata je terapijsko praćenje leka (therapeutic drug monitoring &ndash; TDM) zbog velikih&nbsp; interindividualnih i intraindividualnih&nbsp; varijabilnosti&nbsp; u&nbsp; farmakokinetici&nbsp; leka. Rutinsko praćenje koncentracija metotreksata važno je za identifikaciju pacijenata sa povećanim rizikom od razvoja toksičnosti ,&nbsp; te&nbsp; je TDM&nbsp; standardna&nbsp; praksa&nbsp; za smernice spasavanja leukovorinom, naročito za pacijente za koje se zna da imaju smanjen&nbsp;&nbsp; klirens metotreksata ili druge rizike povezane sa prolongiranim citotoksičnim koncentracijama (bubrežna ili jetrena o&scaron;tećenja, kolekcije tečnosti u &ldquo;trećem prostoru&rdquo;, gastrointestinalna opstrukcija). Veliki&nbsp; broj&nbsp; istraživanja&nbsp; kod pedijatrijskih pacijenata pokazao je vezu između sistemskog izlaganja metotreksatu i&nbsp; efikasnosti&nbsp; i&nbsp; toksiĉnosti&nbsp; metotreksata. Ipak, ne postoji dovoljno&nbsp; informacija o farmakokinetici metotreksata kod dece obolele od akutne limfoblastne leukemije. Takođe, ova istraživanja nisu do sada sprovođena kod dece koja su lečena u na&scaron;oj sredini.</p> / <p>Methotrexate&nbsp; is&nbsp; an&nbsp; antifolate&nbsp; drug&nbsp; widely&nbsp; used&nbsp; for&nbsp; treatment&nbsp; of&nbsp; various malignant&nbsp; tumours.&nbsp; It&nbsp; is&nbsp; used&nbsp; at&nbsp; high&nbsp; doses&nbsp; and&nbsp; in&nbsp; combination&nbsp; with leucovorin rescue.&nbsp; Although&nbsp; high - dose&nbsp; MTX&nbsp; therapy&nbsp; dramatically&nbsp; improves&nbsp; the&nbsp; prognosis&nbsp; of patients with malignancies, severe adverse events are constant clinical concern. The&nbsp; aims&nbsp; of&nbsp; this&nbsp; stydy&nbsp; were&nbsp; to&nbsp; determine&nbsp; the&nbsp; serum&nbsp; concentration&nbsp; of&nbsp; methotrexate&nbsp; and&nbsp; to&nbsp; calculate&nbsp; the&nbsp; pharmacokinetic&nbsp; parameters&nbsp; of&nbsp; methotrexate&nbsp; in children&nbsp; suffering&nbsp; from&nbsp; malignant&nbsp; deseases&nbsp; who&nbsp; are&nbsp; treated&nbsp; with&nbsp; high&nbsp; doses&nbsp; of metotrexate&nbsp; (2&nbsp; g/m² i&nbsp; 5&nbsp; g/m² );&nbsp; furthermore,&nbsp; to&nbsp; investigate&nbsp; the&nbsp; effects&nbsp; of&nbsp; the&nbsp; applied doses of methotrexate, and demographic and clinical characteristics of the examinees on&nbsp;&nbsp; the&nbsp;&nbsp; concentration&nbsp;&nbsp; and&nbsp;&nbsp; pharmacokinetic&nbsp;&nbsp; parameters&nbsp;&nbsp; of&nbsp;&nbsp; the&nbsp;&nbsp; drug.&nbsp;&nbsp; The&nbsp;&nbsp; study investigated the&nbsp;&nbsp; presence&nbsp;&nbsp; and&nbsp;&nbsp; the&nbsp;&nbsp; degree&nbsp;&nbsp; of&nbsp;&nbsp; clinical&nbsp;&nbsp; and&nbsp;&nbsp; laboratory&nbsp;&nbsp; signs&nbsp;&nbsp; of metotrexate&nbsp; toxicity,&nbsp; as&nbsp; well&nbsp; as&nbsp; the&nbsp; effect&nbsp; of&nbsp; the&nbsp; applied&nbsp; doses,&nbsp; and&nbsp; demographic characteristics of the examinees on the appearance and the degree of toxicity. The retrospective - prospective study included 42&nbsp; pediatric patients aged from 0.75&nbsp; to&nbsp; 17.75&nbsp; years&nbsp; (median&nbsp; 5.75&nbsp; years).&nbsp; All&nbsp; patients&nbsp; were&nbsp; threated&nbsp; at&nbsp; the&nbsp; Children and Youth Health Care Institute of Vojvodina (Novi Sad, Serbia), Hemathology and Oncology&nbsp; Section,&nbsp; in&nbsp; the&nbsp; period&nbsp; from&nbsp; June&nbsp; 20 04&nbsp; to&nbsp; June&nbsp; 2012.&nbsp; 38&nbsp; examinees diagnosed as acute lymphoblastic leukemia were treated according to two subsequent protocols,&nbsp; ALL&nbsp; IC - BFM&nbsp; 2002&nbsp; and&nbsp; ALL&nbsp; IC - BFM&nbsp; 2009&nbsp; of&nbsp; the&nbsp; International&nbsp; BFM study&nbsp; group &bdquo;I - BFM - SG&ldquo; (International Berlin - Frankfurt - M&uuml;nster&nbsp; Study&nbsp; Group)&nbsp; for management&nbsp;&nbsp; of&nbsp;&nbsp; childhood&nbsp;&nbsp; non - B&nbsp;&nbsp; acute&nbsp;&nbsp; lymphoblastic&nbsp;&nbsp; leukemia.&nbsp;&nbsp; 4&nbsp;&nbsp; examinees diagnosed&nbsp; as&nbsp; non - Hodgkin&nbsp; lymphoma&nbsp; were&nbsp; treated&nbsp; according&nbsp; to&nbsp; the&nbsp; NHL - BFM&nbsp; 95 protocol. The study included 113 cycles of therapy with methotrexate (1-4 cycles per patient)&nbsp; with&nbsp; 3 86&nbsp; measured&nbsp; serum&nbsp; concentrations&nbsp; of&nbsp; methotrexate.&nbsp; The&nbsp; range&nbsp; of&nbsp; the applied doses was between 800 and 10,000 mg. The&nbsp; concentration&nbsp; of&nbsp; methotrexate&nbsp; was&nbsp; measured&nbsp; 24,&nbsp; 36&nbsp; and&nbsp; 42&nbsp; hours&nbsp; after the initiation of the methotrexate infusion, as well as in longer time intervals when needed.&nbsp; To&nbsp; calculate&nbsp; the&nbsp; pharmacokinetic&nbsp; parameters,&nbsp; the&nbsp; study&nbsp; applied&nbsp; the&nbsp; two - compartment&nbsp; pharmacokinetic&nbsp; model&nbsp; after&nbsp; the&nbsp; termination&nbsp; of&nbsp; intravenous&nbsp; infusion, when&nbsp; relations&nbsp; for&nbsp; pharmacokinetic&nbsp; points&nbsp; existed.&nbsp; Data&nbsp; on&nbsp; clinical&nbsp; and&nbsp; laboratory signs of methotrexate toxicity were collected&nbsp; from medical documentation, and the Common&nbsp; Terminology&nbsp; Criteria&nbsp; for&nbsp; Adverse&nbsp; Events&nbsp; (CTCAE),&nbsp; Version&nbsp; 4.0,&nbsp; U.S. Department&nbsp; of&nbsp; health&nbsp; and&nbsp; human&nbsp; services,&nbsp; National&nbsp; Institute&nbsp; of&nbsp; Health,&nbsp; National Cancer&nbsp; Institute, was&nbsp; used&nbsp; as&nbsp; the&nbsp; score&nbsp; system&nbsp; for&nbsp; toxicity&nbsp; ranking.&nbsp; In&nbsp; order&nbsp; to determine&nbsp; the&nbsp; effects&nbsp; of&nbsp; the examinees&rsquo;&nbsp; characteristics, applied&nbsp; doses&nbsp; and&nbsp; the presence&nbsp; of&nbsp; prolonged&nbsp; elimination on&nbsp; the&nbsp; parameters&nbsp; of&nbsp; interest,&nbsp; three&nbsp; groups&nbsp; of patients were&nbsp; compared (2 g/m² dose without prolonged elimination, 5 g/m² without prolonged elimination and 5 g/m² with prolonged elimination of methotrexate). In the&nbsp; entire&nbsp; group of&nbsp; examinees, the median&nbsp; concentration of methotrexate was&nbsp; 25.82 &mu;mol/l in the 24th hour, 0.68 &mu;mol/l in the 36th&nbsp; hour&nbsp; and 0.24 &mu;mol/l in the 42nd hour of&nbsp; observation. The largest inter - individual variability of methotrexate concentration&nbsp; was&nbsp; observed&nbsp; in&nbsp; the&nbsp; 24th&nbsp; hour&nbsp; while&nbsp; the&nbsp; largest&nbsp; intra - individual variability&nbsp; was&nbsp; recorded&nbsp; in&nbsp; the&nbsp; 36th&nbsp; hour&nbsp; of&nbsp; observation.&nbsp; The&nbsp; median&nbsp; clearance&nbsp; of methotrexate&nbsp; was&nbsp; 8.32l/h.&nbsp; Pharmacokinetic&nbsp; parameters&nbsp; were&nbsp; the&nbsp; following:&nbsp; median volume&nbsp; of&nbsp; the&nbsp; central&nbsp; compartment V₁ 28.47&nbsp; l,&nbsp; median&nbsp; constants k₁₀ 0,206, k₁₂ 0,0245, k₂₁ 0,1114, respectively. The&nbsp;&nbsp; strongest&nbsp;&nbsp; influence&nbsp;&nbsp; of&nbsp;&nbsp; the&nbsp;&nbsp; applied&nbsp;&nbsp; dose&nbsp;&nbsp; on&nbsp;&nbsp; the&nbsp;&nbsp; methotrexate concentration was recorded in the 24th hour of observation while no influence on the methotrexate&nbsp; clearance&nbsp; was&nbsp; found.&nbsp; The&nbsp; presence&nbsp; of&nbsp; prolonged&nbsp; elimination&nbsp; of methotrexate&nbsp;&nbsp; causes&nbsp;&nbsp; lower&nbsp; constants k₁₀ and&nbsp;&nbsp; k₂₁. There&nbsp;&nbsp; was&nbsp;&nbsp; no&nbsp;&nbsp; statistically significant&nbsp; interaction&nbsp; between&nbsp; the&nbsp; investigated&nbsp; demographic&nbsp; characteristics&nbsp; (age, body&nbsp; surface&nbsp; and&nbsp; gender)&nbsp; and&nbsp; the&nbsp; methotrexate&nbsp; concentration,&nbsp; nor&nbsp; between&nbsp; the demographic&nbsp;&nbsp; characteristics&nbsp;&nbsp; and&nbsp;&nbsp; the&nbsp;&nbsp; methotrexate&nbsp;&nbsp; clearance.&nbsp;&nbsp; A&nbsp;&nbsp; significant interaction was found between methotrexate concentration and lactat dehydrogenase level, as&nbsp;&nbsp; well&nbsp;&nbsp; as&nbsp;&nbsp; between&nbsp;&nbsp; methotrexate&nbsp;&nbsp; clearance&nbsp;&nbsp; and&nbsp;&nbsp; creatinine&nbsp;&nbsp; and&nbsp;&nbsp; lactate dehydrogenase level, respectively. Most of the observed toxicities were of moderate degree (&lt; 3 degrees). Oral mucositis&nbsp; was&nbsp; the&nbsp; most&nbsp; represented&nbsp; clinical&nbsp; sign&nbsp; of&nbsp; toxicity,&nbsp; and&nbsp; it&nbsp; was&nbsp; of&nbsp; higher degree&nbsp; in&nbsp; the&nbsp; group&nbsp; where&nbsp; the&nbsp; applied&nbsp; dose&nbsp; of&nbsp; methotrexate&nbsp; was&nbsp; higher&nbsp; (5&nbsp; g/m² ). Leucopenia&nbsp; and&nbsp; anemia&nbsp; were&nbsp; the&nbsp; most&nbsp; represented&nbsp; laboratory&nbsp; toxic&nbsp; effects.&nbsp; The most severe laboratory signs of toxicity&nbsp; (leucopenia, anemia, increase in AST, ALT and&nbsp; GGT&nbsp; activity)&nbsp; were&nbsp; observed&nbsp; in&nbsp; the&nbsp; group&nbsp; with&nbsp; the&nbsp; higher&nbsp; dose&nbsp; (5&nbsp; g/m² )&nbsp; and prolonged methotrexate elimination. Due to high inter- and&nbsp;&nbsp; intra-individual&nbsp;&nbsp;&nbsp; variability&nbsp; of&nbsp; the drug pharmacokinetics,&nbsp; the&nbsp; basis&nbsp; for&nbsp; the&nbsp; clinical&nbsp; care&nbsp; of&nbsp; patients&nbsp; on&nbsp; high&nbsp; methotrexate dosage&nbsp; therapy&nbsp; is&nbsp; therapeutic&nbsp; drug&nbsp; monitoring &ndash; TDM.&nbsp; Routine&nbsp; monitoring&nbsp; of methotrexate serum concentration is important for the identification of patients with a high&nbsp; risk&nbsp; of&nbsp; toxicity,&nbsp; and&nbsp; thus&nbsp; TDM&nbsp; is&nbsp; used&nbsp; as&nbsp; a&nbsp; standard&nbsp; procedure&nbsp; which&nbsp; provides guidelines&nbsp; for&nbsp; leucovorin&nbsp; rescue,&nbsp; particularly&nbsp; for&nbsp; patients&nbsp; with&nbsp; a&nbsp; lower&nbsp; methotrexate clearance or other risks associated with prolonged cytotoxic concent rations (kidney or liver&nbsp; damage,&nbsp; body&nbsp; fluid&nbsp; accumulation&nbsp; in&nbsp; the&nbsp; &ldquo;third&nbsp; space&rdquo;,&nbsp; gastrointestinal obstruction). Numerous studies involving pediatric patients have documented the link between&nbsp; a&nbsp; systemic&nbsp; methotrexate&nbsp; exposure&nbsp; on&nbsp; one&nbsp; hand,&nbsp; and&nbsp; the&nbsp; efficiency&nbsp; and toxicity of&nbsp; ethotrexate on the other hand. However, there is no sufficient data on the methotrexate&nbsp;&nbsp;&nbsp; pharmacokinetics&nbsp;&nbsp; in&nbsp;&nbsp; children&nbsp;&nbsp; suffering&nbsp;&nbsp; from&nbsp;&nbsp; acute&nbsp;&nbsp; lymphoblastic leukemia.&nbsp;&nbsp; Moreover,&nbsp;&nbsp; this&nbsp;&nbsp; type&nbsp;&nbsp; of&nbsp;&nbsp; research,&nbsp;&nbsp; involving&nbsp;&nbsp; children&nbsp;&nbsp; treated&nbsp;&nbsp; in&nbsp;&nbsp; the geographical region of this study, have not been conducted.</p>

<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>

A Leucemia Linfocítica Aguda na infância e adolescência é uma neoplasia de precursores linfóides de natureza heterogênea. Foi a primeira neoplasia disseminada a tornar-se curável pela quimioterapia. No Brasil os estudos cooperativos para o seu tratamento foram iniciados em 1980 com a criação do primeiro protocolo para o tratamento desta leucemia, denominado Grupo Brasileiro para o Tratamento da Leucemia na Infância. Na seqüência destes estudos foram observadas Sobrevidas Livre de Eventos de 50%, 58% e 70% nos protocolos 80, 82 e 85 respectivamente. Durante as décadas de 1980 e 1990, com a divulgação dos excelentes resultados alcançados com os regimes dos protocolos do grupo Berlin Frankfurt Münster, uma série de instituições em nosso País passou a adotá-los. Apesar de termos conhecimento dos dados referentes a evolução dos pacientes protocolados no GBTLI e dos demais estudos divulgados pelas instituições de origem, não tínhamos, porém, uma avaliação epidemiológica nem o conhecimento dos índices de sobrevivência alcançados no estado do Rio Grande do Sul. Neste trabalho foram avaliados 1472 pacientes com LLA, 833 (56,59%) do sexo masculino, 639 (43,41%) do sexo feminino, com idades entre zero e 20 anos, média de 7,40 anos (desvio padrão 5,14) e mediana de 5,70 anos (amplitude 0,06 a 20,76), no período de 1980 a 2008 provenientes deste Estado. Os dados foram colhidos individualmente dos prontuários dos pacientes admitidos nas principais instituições hospitalares que mantém assistência a pacientes pediátricos com neoplasias hematológicas. No presente estudo 487 pacientes (39,40%) foram registrados oficialmente nos protocolos do GBTLI; 678 (54,85%) receberam tratamento baseados nos regimes do grupo BFM e 71 (5,75%) por outros regimes incluindo os tratados segundo o protocolo UKALL. Os casos não foram, no entanto, protocolados e, na grande maioria não foram observados a totalidade dos itens exigidos para os pacientes registrados oficialmente. A sobrevida livre de eventos dos pacientes protocolados foi significativamente superior comparada aos não protocolados, 62,41% ± 2,43% e 53,86% ± 2,04% respectivamente, em cinco anos. De acordo com a faixa etária os pacientes que apresentavam idade de 15 a 19 anos tiveram um índice de SLE de 37,98% ± 4,72% em cinco anos, inferior quando comparado aos de zero a 4 anos e 5 a 9 anos respectivamente: 62,78% ± 2,28% e 62,43% ± 2,84%. Foi observada, na população estudada, uma SG de 63,73% ± 1,49% e SLE de 57,27% ± 1,57%, o que sugere uma discussão para implementar projetos com a finalidade de elevar estes índices de sobrevida. Epidemiologicamente a incidência da LLA com progenitores B seguiu o padrão observado em países desenvolvidos com um pico de freqüência absoluta entre as idades de 2 a 4 anos. Houve diferença significativa entre a população proveniente da região urbana ou rural sendo a SLE em cinco anos de 61,76% ± 1,76% e 49,81% ± 4,28% respectivamente. A SLE e a SG em lactentes e portadores de Síndrome de Down foi inferior aos resultados obtidos em instituições dos países desenvolvidos o que torna aconselhável uma revisão das condições para a assistência destes pacientes. Este estudo teve como finalidade principal retratar a situação passada e a atual do tratamento da LLA na infância e adolescência no Rio Grande do Sul e acumular dados aqui não interpretados e que poderão ser analisados posteriormente / Acute lymphocytic leukemia in childhood and adolescence is a neoplastic disease of lymphoid precursor of heterogeneous nature, being the first disseminated neoplasia to become curable through Chemotherapy. In Brazil, cooperative studies for the treatment of ALL started in 1980 with the creation of the first protocol by the Grupo Brasileiro para o Tratamento da Leucemia na Infância. According to these studies, Event Free Survival of 50%, 58% and 70% in the protocols of 1980, 1982 e 1985 respectively was observed. During the 80s and 90s many Brazilian institutions adopted the protocols motivated by the excellent results achieved by the Berlin Frankfurt Münster group. In spite of the knowledge provided by data related to the evolution of patients protocoled by the GBTLI and other studies published by medical institutions, there was not an epidemiologic evaluation or knowledge of survival indexes achieved in the state of Rio Grande do Sul. In this work, 1472 patients with ALL from the state of Rio Grande do Sul were evaluated. Among the subjects, 833 (56,59%) were male, 639 (43,41%) female, with age range between 0- 20 y average age of 7,40 (standard deviation 5,14) and median 5,70 years old (amplitude 0,06 to 20,76). Data was collected from the medical registers of patients with hematologic neoplasia in medical institutions, which offered pediatric assistance for ALL comprising the period between 1980 until 2008. In the present study, 487 patients (39,40%) were officially registered in the protocols of GBTLI; 678 (54,85%) received treatment based on the regime of the BFM group and 71 (5,75%) were treated according to other regimens (including the UKALL protocol). The cases, however, were not protocoled and, in most cases, the totality of items required for the patients registered officially were not observed. The EFS of the patients protocoled were significantly superior to those who were not protocoled (62,41% ± 2,43% and 53,86% ± 2,04% respectively) in five years. In respect to the age range, the patients which were between 15-20 years had an EFS index of 37,98% ± 4,72% in five years, which is inferior to the index of patients 0-4 years and 5-9 years: 62,78% ± 2,28% e 62,543± 2,84% respectively. An overall survival (OS) of 63,73% ± 1,49% and EFS of 57,27% ± 1,57% was observed in the population studied. These results indicate that a discussion for the implementation of projects, which can increase the indexes of cure, should be carried out. Epidemiologically, the incidence of ALL in B progenitors followed the pattern observed in developed countries with an absolute frequency peak in the age range of 2-4 years. The outcome was superior for patients coming from urban area in comparison to those from rural area. EFS and OS in infant and Down syndrome patients were inferior to the results obtained in developed countries, showing how important it is to review the conditions of the assistance provided to these patients. The objective of this work is to present the development of ALL treatment in childhood and adolescence in the state of Rio Grande do Sul, Brazil, from its beginning until the current days providing data, which can be analyzed and interpreted posteriorly

A Leucemia Linfocítica Aguda na infância e adolescência é uma neoplasia de precursores linfóides de natureza heterogênea. Foi a primeira neoplasia disseminada a tornar-se curável pela quimioterapia. No Brasil os estudos cooperativos para o seu tratamento foram iniciados em 1980 com a criação do primeiro protocolo para o tratamento desta leucemia, denominado Grupo Brasileiro para o Tratamento da Leucemia na Infância. Na seqüência destes estudos foram observadas Sobrevidas Livre de Eventos de 50%, 58% e 70% nos protocolos 80, 82 e 85 respectivamente. Durante as décadas de 1980 e 1990, com a divulgação dos excelentes resultados alcançados com os regimes dos protocolos do grupo Berlin Frankfurt Münster, uma série de instituições em nosso País passou a adotá-los. Apesar de termos conhecimento dos dados referentes a evolução dos pacientes protocolados no GBTLI e dos demais estudos divulgados pelas instituições de origem, não tínhamos, porém, uma avaliação epidemiológica nem o conhecimento dos índices de sobrevivência alcançados no estado do Rio Grande do Sul. Neste trabalho foram avaliados 1472 pacientes com LLA, 833 (56,59%) do sexo masculino, 639 (43,41%) do sexo feminino, com idades entre zero e 20 anos, média de 7,40 anos (desvio padrão 5,14) e mediana de 5,70 anos (amplitude 0,06 a 20,76), no período de 1980 a 2008 provenientes deste Estado. Os dados foram colhidos individualmente dos prontuários dos pacientes admitidos nas principais instituições hospitalares que mantém assistência a pacientes pediátricos com neoplasias hematológicas. No presente estudo 487 pacientes (39,40%) foram registrados oficialmente nos protocolos do GBTLI; 678 (54,85%) receberam tratamento baseados nos regimes do grupo BFM e 71 (5,75%) por outros regimes incluindo os tratados segundo o protocolo UKALL. Os casos não foram, no entanto, protocolados e, na grande maioria não foram observados a totalidade dos itens exigidos para os pacientes registrados oficialmente. A sobrevida livre de eventos dos pacientes protocolados foi significativamente superior comparada aos não protocolados, 62,41% ± 2,43% e 53,86% ± 2,04% respectivamente, em cinco anos. De acordo com a faixa etária os pacientes que apresentavam idade de 15 a 19 anos tiveram um índice de SLE de 37,98% ± 4,72% em cinco anos, inferior quando comparado aos de zero a 4 anos e 5 a 9 anos respectivamente: 62,78% ± 2,28% e 62,43% ± 2,84%. Foi observada, na população estudada, uma SG de 63,73% ± 1,49% e SLE de 57,27% ± 1,57%, o que sugere uma discussão para implementar projetos com a finalidade de elevar estes índices de sobrevida. Epidemiologicamente a incidência da LLA com progenitores B seguiu o padrão observado em países desenvolvidos com um pico de freqüência absoluta entre as idades de 2 a 4 anos. Houve diferença significativa entre a população proveniente da região urbana ou rural sendo a SLE em cinco anos de 61,76% ± 1,76% e 49,81% ± 4,28% respectivamente. A SLE e a SG em lactentes e portadores de Síndrome de Down foi inferior aos resultados obtidos em instituições dos países desenvolvidos o que torna aconselhável uma revisão das condições para a assistência destes pacientes. Este estudo teve como finalidade principal retratar a situação passada e a atual do tratamento da LLA na infância e adolescência no Rio Grande do Sul e acumular dados aqui não interpretados e que poderão ser analisados posteriormente / Acute lymphocytic leukemia in childhood and adolescence is a neoplastic disease of lymphoid precursor of heterogeneous nature, being the first disseminated neoplasia to become curable through Chemotherapy. In Brazil, cooperative studies for the treatment of ALL started in 1980 with the creation of the first protocol by the Grupo Brasileiro para o Tratamento da Leucemia na Infância. According to these studies, Event Free Survival of 50%, 58% and 70% in the protocols of 1980, 1982 e 1985 respectively was observed. During the 80s and 90s many Brazilian institutions adopted the protocols motivated by the excellent results achieved by the Berlin Frankfurt Münster group. In spite of the knowledge provided by data related to the evolution of patients protocoled by the GBTLI and other studies published by medical institutions, there was not an epidemiologic evaluation or knowledge of survival indexes achieved in the state of Rio Grande do Sul. In this work, 1472 patients with ALL from the state of Rio Grande do Sul were evaluated. Among the subjects, 833 (56,59%) were male, 639 (43,41%) female, with age range between 0- 20 y average age of 7,40 (standard deviation 5,14) and median 5,70 years old (amplitude 0,06 to 20,76). Data was collected from the medical registers of patients with hematologic neoplasia in medical institutions, which offered pediatric assistance for ALL comprising the period between 1980 until 2008. In the present study, 487 patients (39,40%) were officially registered in the protocols of GBTLI; 678 (54,85%) received treatment based on the regime of the BFM group and 71 (5,75%) were treated according to other regimens (including the UKALL protocol). The cases, however, were not protocoled and, in most cases, the totality of items required for the patients registered officially were not observed. The EFS of the patients protocoled were significantly superior to those who were not protocoled (62,41% ± 2,43% and 53,86% ± 2,04% respectively) in five years. In respect to the age range, the patients which were between 15-20 years had an EFS index of 37,98% ± 4,72% in five years, which is inferior to the index of patients 0-4 years and 5-9 years: 62,78% ± 2,28% e 62,543± 2,84% respectively. An overall survival (OS) of 63,73% ± 1,49% and EFS of 57,27% ± 1,57% was observed in the population studied. These results indicate that a discussion for the implementation of projects, which can increase the indexes of cure, should be carried out. Epidemiologically, the incidence of ALL in B progenitors followed the pattern observed in developed countries with an absolute frequency peak in the age range of 2-4 years. The outcome was superior for patients coming from urban area in comparison to those from rural area. EFS and OS in infant and Down syndrome patients were inferior to the results obtained in developed countries, showing how important it is to review the conditions of the assistance provided to these patients. The objective of this work is to present the development of ALL treatment in childhood and adolescence in the state of Rio Grande do Sul, Brazil, from its beginning until the current days providing data, which can be analyzed and interpreted posteriorly