<p>Uvod: Hepatička osteodistrofija je termin koji obuhvata metaboličke bolesti kosti udružene sa hroničnim bolestima jetre. U alkoholnoj cirozi (AC) jetre postoji visoka zastupljenost deficijencije vitamina D proporcionalna stepenu disfunkcije jetre, ali njena uloga u patogenezi hepatičke osteodistrofije nije dovoljno obja&scaron;njena. Nivo 25(OH)D odražava status vitamina D. Kod AC jetre izmenjena je metabolička aktivnost kosti i suprimirano je formiranje kosti &scaron;to dovodi do smanjenja ko&scaron;tane mase. U centru interesovanja je postizanje optimalnog statusa vitamina D. Stavovi o suplementaciji vitaminom D kod AC jetre nisu jasno definisani. Cilj rada: Utvrditi nivo vitamina D, ispitati metaboličku aktivnost kosti i mineralnu gustinu kosti kod bolesnika sa AC jetre. Utvrditi efekte suplementacije sa 1000 IU vitamina D3 na dan tokom godinu dana u odnosu na metaboličku aktivnost kosti i mineralnu gustinu kosti kod ispitivanih bolesnika. Bolesnici i metode: Istraživanje je sprovedeno na Klinici za gastroenterologiju i hepatologiju Kliničkog centra Vojvodine u Novom Sadu kao prospektivna intervencijska studija sa primenom suplementacije sa 1000 IU vitamina D3 na dan kod bolesnika sa AC jetre. Grupu bolesnika koja je uključena u istraživanje (1) činilo je 70 bolesnika mu&scaron;kog pola sa dijagnozom AC jetre. Bolesnici su imali četiri pregleda (P), odnosno tačke studije: P1-uključivanje bolesnika i započinjanje suplementacije vitaminom D; P2, P3 i P4 posle tri, &scaron;est i dvanaest meseci suplementacije vitaminom D, redom. Prilikom svakog pregleda rađene su analize funkcije jetre, metabolizma kosti i statusa vitamina D. Na početku (P1) i na kraju istraživanja (P4) vr&scaron;eno je merenje mineralne gustine kosti (BMD) DXA metodom. Gubitak bolesnika od P1 do P4 bio je dvadeset, na različitim tačkama studije. Prvi deo istraživanja odnosi se na Grupu bolesnika koja je uključena u istraživanje (1) i zavr&scaron;ila prvi pregled (P1). Pedeset bolesnika je zavr&scaron;ilo kompletno istraživanje po predviđenom protokolu i oni se zbog realizacije svih pregleda i ponovljenih merenja posmatraju kao: Grupa bolesnika koja je zavr&scaron;ila istraživanje (2). Rezultati: (1): Kod bolesnika sa AC jetre utvrđena je deficijencija vitamina D, snižen nivo osteokalcina, normalni nivoi CrossLapsa, PTH, ukupnog i jonizovanog kalcijuma, fosfora i magnezijuma. Osteopeniju je imalo 42,65% a osteoporozu 14,71% ispitanika. Kod svih ispitanika najniži BMD izmeren je na vratu femura. (2): Suplementacija vitaminom D dovela je do značajnog porasta 25(OH)D. U odnosu na osteokalcin konstatovana je pozitivna razlika vrednosti P1/P4, iako je nivo ostao ispod donje granice normale. Kod nivoa CrossLapsa i PTH razlika P1/P4 je negativna, ali su nivoi u sva četiri merenja u okviru referentnih vrednosti. Na lumbalnoj kičmi do&scaron;lo je do pobolj&scaron;anja BMD za 0.87%, a pogor&scaron;anja su na vratu femura -1.87 % i kuku -1.65%. Konstatovano je i pobolj&scaron;anje funkcije jetre. Zaključci: Kod bolesnika sa AC jetre pobolj&scaron;anje statusa vitamina D dovodi do povećanja formiranja kosti i pobolj&scaron;anja ko&scaron;tane mase na lumbalnoj kičmi. Neophodno je određivanje statusa vitamina D kod svih bolesnika sa AC jetre i uvođenje suplementacije vitaminom D kod bolesnika koji imaju nivo 25(OH)D &lt; 80 nmol/l, uz tromesečne kontrole efekta. Kod postavljanja dijagnoze AC jetre potrebno je inicijalno određivanje BMD. Kod suplementacije vitaminom D nakon inicijalnog DXA pregleda sledeći se preporučuje nakon jedne do dve godine.</p> / <p>Introduction: The term Hepatic osteodystrophy defines a group of metabolic bone diseases associated with underlying chronic liver disease. Alcoholic liver cirrhosis (ALC) is characterized by high incidence of vitamin D deficiency that is proportional to the level of liver failure; however, its role in the pathogenesis of hepatic osteodystrophy has not yet been fully elucidated. The level of 25(OH)D best reflects the vitamin D status. ALC is characterized by changed bone metabolic activity and suppressed bone formation, resulting in the decrease in bone mass. The key topic of interest is the achievement of optimal vitamin D status. The attitude of health professionals towards vitamin D supplementation in alcoholic liver cirrhosis has not yet been clearly defined. The aim of the research: Determining of vitamin D levels, investigating the metabolic activity of the bone and bone mass in patients with alcoholic liver cirrhosis (ALC); Determining the effects of vitamin D3 supplementation at the dose 1000 IU/day during a one-year period in relation to metabolic activity of the bone and bone mineral density (BMD) in the investigated patient population. Patients and methods: The research was conducted at the Clinic for Gastroenterology and Hepatology of the Clinical Centre of Vojvodina in Novi Sad. The research was designed as a prospective interventional study implicating vitamin D3 supplementation at the dose 1000 IU/day to patients with ALC. The investigated patient population (1) encompassed 70 male patients diagnosed with ALC. The patients underwent four examinations (P), that is, research phases: P1 &ndash; inclusion of the patient into the study and introduction of vitamin D supplementation; P2, P3 and P4 after 3, 6 and 12 months of vitamin D supplementation treatment, respectively. Each examination included the analysis of liver function, bone metabolism and vitamin D status. At the beginning (P1) and at the end (P4) of the investigation period, bone mineral density (BMD) was measured by means of dual-energy x-ray absorptiometry (DXA) method. Twenty patients dropped out from the research at different stages throughout the investigation period (P1 to P4). The first part of the investigation pertains to the Group of patients who were included into the study (1) and completed the first examination (P1). Fifty patients have completed the entire research according to the foreseen protocol encompassing all examinations and repeated measurements. These patients are considered a Group of patients who completed the research (2) Results: (1): In ALC patients, vitamin D deficiency and decreased osteocalcin levels were established, as well as normal levels of CrossLaps, PTH, total and ionized calcium, phosphorus and magnesium. Osteopenia and osteoporosis were established in 42.65% and 14.71% of patients, respectively. The lowest BMD was measured in the femoral neck in all patients. (2): Vitamin D supplementation resulted in significant increase in 25(OH)D. Analysis of osteocalcin level revealed positive P1/P4 difference, even though the level remained below the lower normal limit. The levels of CrossLaps and PTH revealed negative P1/P4 difference; however, the levels determined at all four measurements were within the reference values. An improvement of BMD for 0.87% was established in lumbar spine, whereas a decrease was noticed in femoral neck (1.87%) and hip (1.65%). Furthermore, an improvement of liver function was established. Conclusions: Improvement of vitamin D status in ALC patients results in an increase of bone formation and improvement of body mass in lumbar spine. Determining the vitamin D status in all patients with ALC is of outmost importance, as well as the vitamin D supplementation of patients with levels of 25(OH)D &lt; 80 nmol/l along with the monitoring of treatment outcome at three-month intervals. Establishment of the diagnosis of alcoholic liver cirrhosis should encompass initial measurement of BMD. In case of vitamin D supplementation treatment, the initial DXA examination should be repeated after the period of one to two years.</p>

<p>S obzirom na visoku prevalencu metaboličkog sindroma (10-40% u svetskoj populaciji) i na činjenicu da prisustvo metaboličkog sindroma duplira rizik od nastanka aterosklerotske bolesti kardiovaskularnog sistema jasna je potreba za identifikacijom indivudualnih parametara koji doprinose njenom razvoju. Metabolički sindrom je klaster faktora rizika metaboličkog porekla koji je udružen sa povećanim rizikom za nastanak aterosklerotske bolesti kardiovaskularnog sistema i dijabetes melitusa tipa 2. Insulinska rezistencija, abdominalna gojaznost, aterogena dislipidemija, hipertenzija, proinflamatorno i protrombotično stanje su faktori koji su u osnovi metaboličkog sindroma a često su i praćeni nagomilavanjem masti u jetri. Cilj rada je bio da se utvrdi odnos između markera disfunkcije hepatocita (AST, ALT, GGT), serumskog nivoa inflamatornih biomarkera (broj leukocita, elektroforeza serumskih proteina, CRP, fibrinogen, TNF-&alpha;), biomarkera endotelne disfunkcije (ADMA i homocistein), kao i nivoa serumskih adipokina (leptin i adiponektin) i debljine intima-medija kompleksa (IMT) karotidne arterije kao pokazatelja prisustva aterosklerotskog procesa. Ispitivanje je dizajnirano kao studija preseka. U ispitivanje je uključeno 58 ispitanika oba pola sa karakteristikama metaboličkom sindroma (NCEP:ATP III kriterijumi). Odabir ispitanika je vr&scaron;en u Odeljenju za pravilnu ishranu i zdravstvenu bezbednost hrane, Instituta za javno zdravlje Vojvodine. Kontrolnu grupu su sačinjavale 30 klinički i biohemijski zdravih ispitanika nepu&scaron;ača koji su prema polnoj i dobnoj strukturi odgovarali ispitivanim grupama bolesnika. Iz ispitivanja su isključene osobe koje konzumiraju vi&scaron;e od 20g/dan alkohola, pu&scaron;ači, koji imaju dijagnostikovan virusni hepatitis B ili C ili pozitivan Hbs antigen, anti-Hbs antitela i anti-HCV antitela, osobe koje imaju verifikovana oboljenja kardiovaskularnog sistema, bubrega, CNS-a, infektivna, maligna i autoimuna oboljenja kao i druga oboljenja jetre i žučnih puteva, osobe koje su pod medikamentoznom terapijom koja može uticati na nivo serumskih biomarkera endotelne disfunckije, lipidni i lipoproteinski status, glikoregulaciju kao i menstruacioni ciklus. Sve laboratorijske analize su urađene u Centru za laboratorijsku medicinu, Kliničkog centra Vojvodine. Doppler ultrasonografski pregled karotidnih arterija i ultrazvuk abdomena i jetre je urađen u Centru za radiologiju Kliničkog centra Vojvodine. Signifikantna pozitivna korelacija niskog stepena je utvrđena između IMT zajedničke karotidne arterije i serumskih koncentracija GGT, hsCRP i leptina kao i odnosa neutrofili/limfociti. Prema prvom konstruisanom regresionom modelu u kojem je zavisna varijabla bila IMT preko 0,09 cm statistički značajan uticaj na predviđanje debljine IMT zajedničke karotidne arterije imaju hsCRP (Exp (B) 1,112 i glikemija (Exp (B) 1,973). Prema modelu neuronske mreže sa istom zavisnom varijablom najveću mogućnost predviđanja IMT imaju glikemija, AST i fibrinogen. Prema drugom konstruisanom regresionom modelu gde su zavisne varijable bile IMT zajedničke karotidne arterije preko 0,09 cm i prisutnost hepatične steatoze najveću mogućnost predviđanja imaju leptin Exp (B) 1,1022 i ALT Exp (B) 1,053. Prema modelu neuronske mreže sa istom zavisnom varijablom najveću mogućnost predviđanja IMT imaju ALT, ADMA i leptin.</p> / <p>Given the high prevalence of metabolic syndrome (10-40% in the world population) and the fact that the presence of metabolic syndrome doubles the risk of atherosclerotic disease of the cardiovascular system, there is a clear need to identify individual parameters that contribute to its development. Metabolic syndrome is a cluster of the risk factors of metabolic origin that is associated with an increased risk for the onset of atherosclerotic disease of the cardiovascular system and type 2 diabetes mellitus. Insulin resistance, abdominal obesity, atherogenic dyslipidemia, hypertension, proinflammatory and prothrombotic conditions are the factors at the base of the metabolic syndrome and are often accompanied by fat accumulation in the liver. The aim of this work was to determine the relation between markers of hepatic dysfunction (AST, ALT and GGT), serum levels of inflammatory biomarkers (white blood cell count, electrophoresis of serum proteins, CRP, fibrinogen, TNF-&alpha;), biomarkers of endothelial dysfunction (ADMA and homocysteine) as well as levels of serum adipokines (leptin and adiponectin) and intima-media thickness of carotid artery as indicators of atherosclerotic process in the patients with metabolic syndrome. Study was cross-sectional. It included 58 participants with metabolic syndrome (NCEP:ATP III criteria) as well as 30 clinically and biochemically healthy nonsmokers, age and gender matched controls. Participants were selected in the Department for Nutrition and Food Safety, Center of Hygiene and Human Ecology Institute of Public Health of Vojvodina. Patients that consumed alcohol more than 20g/day were excluded. Participants with positive HBsAg, anti-HBs-antibodies or anti- HCV antibodies were excluded also. Smokers were also excluded. Patients with cardiovascular diseases, renal diseases, infective, hepatic, malignant and autoimmune diseases were excluded from this study. Subjects which used drugs that could affect biomarker levels of endothelial dysfunction, lipid metabolism, glucose metabolism and menstrual cycle were also excluded. All laboratory analyzes were done in Centre for Laboratory Medicine, Clinical Centre of Vojvodina. Doppler ultrasonography of carotid arteries and ultrasound of abdomen and liver were done in Centre for Radiology, Clinical Centre of Vojvodina. Significant positive correlation of low degree was determined between IMT of common carotid artery and serum concentrations between GGT, hsCRP and leptin and relationship neutrophils/lymphocytes. According to the first constructed regression model where dependent variable was IMT of common carotid artery above 0.09 cm statistically significant influence on foreseeing IMT of common carotid artery have hsCRP (Exp (B) 1.112 and glycaemia (Exp (B) 1.973). According to the neuronal network with the same dependent variable greatest probability for foreseeing IMT have glycaemia, AST and fibrinogen. According to the second constructed regression model where dependent variable was IMT above 0.09 cm and present hepatic steatosis greatest probability for foreseeing IMT have leptin Exp (B) 1.1022 and ALT Exp (B) 1.053. According to the neuronal network with the same dependent variable greatest probability for foreseeing IMT have ALT, ADMA and leptin.</p>

<p>Raloksifen je predstavnik selektivnih modulatora estrogenih receptora koji se koristi u terapiji osteoporoze i invazivnog oblika raka dojke u postmenopauzi. Raloksifen se relativno dobro resorbuje iz gastrointestinalnog trakta, ali pri prvom prolasku kroz jetru podleže biotransformaciji u značajnom procentu, &scaron;to je uzrok njegove niske biolo&scaron;ke raspoloživosti. Bioraspoloživost kod ljudi iznosi 2%, a kod Wistar pacova 39%. Različite supstance se koriste da bi se pobolj&scaron;ala bioraspoloživost lekova. Žučne kiseline, kao &scaron;to je deoksiholna kiselina, omogućavaju bolji prolazak kroz biolo&scaron;ke membrane drugim supstancama, te mogu povećati bioraspoloživost lekova. Apigenin je &scaron;iroko rasprostranjeni flavonoid koji inhibi&scaron;e različite metaboličke puteve i na taj način može usporiti metabolizam i eliminaciju i povećati koncentraciju lekova u krvi. Ciljevi ovog istraživanja su bili da se ispita da li apigenin i natrijum-deoksiholat mogu povećati bioraspoloživost raloksifena, njihov uticaj na biohemijske parametre i parametre hemostaze, kao i da se ispita antioksidativni potencijal apigenina. Ispitan je i uticaj apigenina na akutno o&scaron;tećenje jetre usled primene toksične doze paracetamola. U istraživanju su kori&scaron;ćeni zdravi, beli pacovi mu&scaron;kog roda, soja Wistar. U ogledu su ukupno kori&scaron;ćene 84 eksperimentalne životinje. Sva ispitivanja na životinjama je odobrila Etička komisija Univerziteta u Novom Sadu. Raloksifen je primenjen intravenski i per os, dok su natrijum-deoksiholat i apigenin aplikovani peroralno. Uzorci krvi, urina i fecesa su kori&scaron;ćeni za određivanje farmakokinetskih parametara, dok su za određivanje biohemijskih, hemostatskih i parametara oksidativnog stresa kori&scaron;ćeni serum i uzorci jetre laboratorijskih životinja. Pretretman natrijum-deoksiholatom je doveo do smanjenja koncentracije raloksifena u krvi zbog olak&scaron;anog i brzog prodora raloksifena u periferne kompartmane. Time je značajno produženo poluvreme eliminacije i srednje vreme zadržavanja raloksifena i značajno je povećan volumen distribucije raloksifena. Apigenin je doveo do manjeg pada koncentracije raloksifena u prvim satima nakon intravenske primene raloksifena, dok su koncentracije raloksifena bile značajno vi&scaron;e nakon osmog časa od primene leka. Uticaj raloksifena na biohemijske parametre je bio značajno veći nakon intravenske nego nakon peroralne primene. Nakon intravenske primene raloksifena je značajno povećana aktivnost enzima jetre, ALP, ALT, AST i GGT, dok su pokazatelji funkcije bubrega, urea, mokraćna kiselina i kreatinin bili sniženi. U grupama koje su pretretirane natrijum-deoksiholatom i apigeninom vrednosti ovih parametara bile su niže u odnosu na grupu tretiranu samo raloksifenom. Statistički najznačajniji uticaj je imala primena trojne kombinacije, raloksifena, natrijum-deosiholata i apigenina, koja je dovela do značajnog pada aktivnosti enzima jetre, i u odnosu na grupu tretiranu raloksifenom i u odnosu na kontrolnu grupu. Kod životinja tretiranih kombinacijom apigenina i paracetamola pokazatelji toksičnosti su bili značajno niži, naročito vrednosti ALT i ALP, u odnosu na grupu koja je dobijala samo paracetamol. Hepatotoksičnost izazvana toksičnom dozom paracetamola je potvrđena i histopatolo&scaron;kim promenama na jetri, koje nisu primećene u grupi životinja tretiranih kombinacijom apigenina i paracetamola. Ispitivanjem je utvrđeno da apigenin može da spreči paracetamolom indukovano povećanje nivoa MDA, &scaron;to ukazuje da apigenin pozitivno utiče na očuvanje integriteta ćelije. Aktivnost enzima CAT i GR u homogenatima jetre je bila značajno povećana nakon primene toksične doze paracetamola u odnosu na kontrolnu grupu. Aktivnost enzima CAT i GR u grupi tretiranoj kombinacijom apigenina i paracetamola je bila približna vrednostima u kontrolnoj grupi. Na osnovu rezultata istraživanja može se zaključiti da natrijum-deoksiholat i apigenin značajno utiču na farmakokinetiku raloksifena. Primena natrijum-deoksiholata dovela je do pada koncentracije raloksifena u krvi, značajnog prelaska raloksifena iz krvi u periferne kompartmane i povećanja njegovog volumena distribucije, dok je apigenin značajno usporio metabolizam i eliminaciju raloksifena i doveo do njegovog produženog zadržavanja u krvi. Natrijum-deoksiholat i apigenin su pokazali pozitivan uticaj na biohemijske parametre, parametre hemostaze i smanjenje nivoa oksidativnog stresa. Kombinacija natrijum-deoksiholata i apigenina je pokazala sinergistički uticaj na navedene parametre, odnosno dovela je do značajnih promena u odnosu na pojedinačnu primenu ovih supstanci. Rezultati ispitivanja ukazuju na to da apigenin smanjuje stepen lipidne peroksidacije i da dovodi do značajnog povećanja enzimskih antioksidantnih mehanizama odbrane kod pacova kod kojih je hepatotoksičnost indukovana paracetamolom.</p> / <p>Raloxifene is selective estrogen receptor modulator used in treatment of osteoporosis and invasive breast cancer in postmenopausal women. Raloxifene is well absorbed from the gastrointestinal tract, but undergoes extensive first-pass metabolism, which results in very low bioavailability of raloxifene, 2% in humans, and 39% in Wistar rats. Various supstances are used for increasing bioavailability of other drugs. Bile acids, such as deoxycholic acid, promote transport of other supstances through biological membranes, and consequently, may increase their bioavailability. Apigenin is a widespread flavonoid, which inhibits different metabolic pathways. Thus, apigenin can slow down metabolism and elimination of drugs, and raise drug concentration in blood. Aims of this study were to investigate if apigenin and sodium deoxycholate could increase bioavailability of raloxifene, their influence on biochemical and hemostasis parameters, and to investigate antioxidative potential of apigenin. Furthermore, influence of apigenin on acute liver damage after toxic dose of paracetamol was examined. In vivo experiments were performed on 84 laboratory healthy male Wistar rats. All experiments were approved by Ethics Committee of University of Novi Sad. Raloxifene was applied intravenously and per os, while sodium deoxycholate and apigenin were given perorally. Blood, urine and feces samples were used for pharmacokinetic parameters measurement, whereas serum and liver samples were used for evaluation of biochemical, hemostasis and oxidative stress parameters. Pretreatment of sodium deoxycholate led to raloxifene blood concentration decrease due to easier penetration of raloxifene in peripher compartments. As a result, raloxifene half-life and mean residence time were significantly longer and volume of distribution was increased. Apigenin caused lower decrease in raloxifene concentration in first few hours after raloxifene intravenous application, while raloxifene concentrations after apigenin pretreatment were significantlny higher 8 hours after raloxifene application. Influence of raloxifene on biochemical parameters was more significant after intravenous than after per os application. Intravenous application of raloxifene led to increased activity of liver enzymes, ALP, ALT, AST and GGT, while parameters of kidney function, urea, uric acid and creatinine were decreased in comparison to the control group. In experimental groups pretreated with sodium deoxycholate and apigenin these parameters were lower than in the group treated only with raloxifene. Statistically the most significant effects were in the group treated with combination of raloxifene, sodium deoxycholate and apigenin, which caused significant decrease in activity of liver enzymes compared both with raloxifene and control group of animals. In experimental animals treated with combination of apigenin and paracetamol bioindicators of paracetamol toxicity were significantly lower, especially activity of ALT and ALP, in comparison to the group treated only with paracetamol. Hepatotoxicity induced by toxic dose of paracetamol was also confirmed by histopathological alterations in liver, which were not observed in the experimental group treated with combination of apigenin and paracetamol. In this study it was confirmed that apigenin could prevent paracetamol-induced MDA level increase, which suggests that apigenin have positive effects on cell integrity. Activity of CAT and GR in liver homogenates was significantly increased after toxic dose of paracetamol in comparison to the control group, while activity of these enzymes in the group treated with apigenin and paracetamol was similar to values in the control group. Results of this study showed that sodium deoxycholate and apigenin can significantly change pharmacokinetic parameters of raloxifene. Sodium deoxycholate caused signicant decrease in raloxifene blood concentration, extensive distribution from blood to peripheral compartments and increase of raloxifene volume of distribution. Apigenin inhibited metabolism and elimination of raloxifene and thus prolonged half-life and mean residence time of raloxifene. Sodium deoxycholate and apigenin showed positive effects on biochemical and hemostasis parameters and decreased the level oxidative stress. Combination of sodium deoxycholate and apigenin showed synergistic effects on these parameters in comparison to effects of separate application of sodium deoxycholate and apigenin. The result of our study indicates that apigenin inhibits the level of lipid peroxidation and significantly increase the enzyme antioxidant defence mehanisms in paracetamol induced hepatotoxicity in rats.</p>

<p>Tumorsko pupljenje (TP) u karcinomu je morfolo&scaron;ki fenomen koji predstavlja pojavu pojedinačnih ili malih grupa dediferentovanih tumorskih ćelija koje se na invazivnom frontu karcinoma odvajaju od glavne tumorske mase. Kod metastatskog kolorektalnog karcinoma (KRK) definitivno ne možemo odrediti pravi doprinos TP. Cilj je bio da se ispita terapijski patohistolo&scaron;ki odgovor na primenjeni hemioterapijski režim, prognostički i nezavisni negativni značaj TP , kao i korelacija TP i terapijskog odgovora histolo&scaron;ke regresije kod R0 reseciranih sinhronih i metahronih jetrenih metastaza KRK, koji su primali polihemioterapije po protokolu Folfox 4, sa i bez VEGF inhibitora &ndash; bevacizumaba (AV).&nbsp; Studija je prospektivno &ndash; retrospektivna i obuhvata 77 bolesnika oba pola, uzrasta preko 18 godina, sa patohistolo&scaron;ki verifikovanim jetrenim metastazama KRK, koji su operisani u Institutu za onkologiju Vojvodine u periodu od 1. maja 2007. do 1. juna 2017. godine. Od ukupno 120 bolesnika, njih 77 je ispunjavalo sledeće kriterijume: da je histolo&scaron;ki dokazan metastatski adenokarcinom kolorektuma sa R0 resekcijom i da su preoperativno dobijali HT sa biolo&scaron;kom terapijom ili bez nje. Bolesnike smo podelili u dve grupe: KRK &ndash; sinhrona metastatska bolest i KRK &ndash; metahrona metastatska bolest. Nakon selekcije bolesnika, rađena je mikroskopska analiza rutinskih histolo&scaron;kih i imunohistohemijskih preparata i određivana je gustina TP, histolo&scaron;ka regresija prema mTRG bodovanju komparirala se sa radiolo&scaron;kim odgovorom po RECIST-u. Događaji od interesa u kliničkom toku bolesti jesu progresija nakon hirur&scaron;kog zahvata jetrenih metastaza i ukupno preživljavanje u periodu od 24 meseca. Nema statistički značajne patohistolo&scaron;ke razlike u učestalosti lo&scaron;ijeg terapijskog odgovora (mTRG 3 &ndash; 5) u odnosu na bolji terapijski odgovor (mTRG 1, 2) između bolesnika sa sinhronom i metahronom metastatskom bole&scaron;ću KRK, koji su lečeni hemioterapijskim protokolom Folfox4: 13 (76,5%) vs. 13 (72,2%); p = 0,774. Kod bolesnika sa sinhronim metastazama KRK, lečenih hemioterapijskim protokolom Folfox 4, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine, i to kod bolesnika sa malom u odnosu na one sa velikom gustinom TP: 10 (90,9%) vs. 5 (55,6%); p = 0,049. Kod tih bolesnika, lečenih hemioterapijskim protokolom Folfox4/AV, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine, i to kod bolesnika sa malom u odnosu na one sa velikom gustinom TP: 9 (100%) vs. 6 (33,3%); p = 0,048. Kod bolesnika sa metahronim metastazama KRK lečenih hemioterapijskim protokolom Folfox4, sa i bez AV, nema statistički značajne razlike u učestalosti preživljavanja tokom dve godine u odnosu na gustinu TP. Kod bolesnika sa sinhronim i metahronim metastazama KRK nema statistički značajne razlike u učestalosti lo&scaron;ijeg histolo&scaron;kog odgovora na terapiju (mTRG 3 &ndash; 5) kod onih sa malom u odnosu na one sa velikom gustinom (TP): (8 (50%) vs. 15 (78,9%); p = 0,072 i TP: 8 (80%) vs. 13 (72,2%); p = 0,649). Kod bolesnika sa sinhronim metastazama KRK lečenih hemioterapijskim protokolom Folfox4, sa i bez AV, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine u odnosu na gustinu TP. Takođe, kod tih bolesnika velika gustina TP je nezavistan negativan faktor prognoze u odnosu na date terapijske režime, &scaron;to se vidi u preživljavanju tokom dve godine.</p> / <p>Tumor budding (TB) in cancer is a morphological phenomenon representing the appearance of single or small groups of dedifferentiated tumor cells that separate from the main tumor mass on the invasive front of cancer. In metastatic colorectal cancer (MCC), the true contribution of TB cannot be determined. The aim was to investigate the therapeutic pathohistological response to the applied chemotherapy, the prognostic and independent negative significance of TB, as well as the correlation of TB and the therapeutic response of histological regression in R0 resectable synchronous and metachronous liver metastases of MCC receiving polychemotherapy according to the Folfox 4 protocol, with and without VEGF inhibitors - bevacizumab (AV). The research was conducted as a prospective &ndash; retrospective study that included 77 patients of both sex, over 18 years of age, with pathohistologically verified MCC liver metastases, who underwent surgery at the Institute of Oncology of Vojvodina from 1st May 2007 until 1st June 2017. From 120 patients, 77 patients met the following criteria: they had histologically proven metastatic colorectal adenocarcinoma with R0 resection and also received preoperative chemotherapy with or without biological therapy. The patients were divided into two groups: MCC - synchronous metastatic disease and MCC - metachronous metastatic disease. After the patient selection, microscopic analysis of routine histological and immunohistochemical preparations was performed, the density of TB was determined, and the histological regression according to mTRG scoring was compared with a radiologic response according to the RECIST. The events of interest in the clinical course of the disease were the progression of hepatic metastases after surgery and overall survival during 24 months. There is no statistically significant pathohistological difference in the incidence of worse therapeutic response (mTRG 3 - 5) compared to the better therapeutic response (mTRG 1, 2) between patients with synchronous and metachronous MCC who were treated with the Folfox4 chemotherapy protocol: 13 (76.5%) vs. 13 (72.2%); p = 0.774. In patients with synchronous MCC metastases treated with the Folfox 4 chemotherapy protocol, there was a statistically significant difference in the survival rates during two years particularly in patients with low versus high TB density: 10 (90.9%) vs. 5 (55.6%); p = 0.049. In those patients who were treated with the Folfox4 / AV chemotherapy protocol, there was a statistically significant difference in survival rates during two years particularly in patients with low TB density in reference to those with high: 9 (100%) vs. 6 (33.3%); p = 0.048. In patients with metachronous MCC metastases who were treated with the Folfox4 chemotherapy protocol, with and without AV, there was no statistically significant difference in survival rate during two years when referring to the TB density. In patients with synchronous and metachronous metastases, MCC has no statistically significant difference in the incidence of worse histological response to therapy (mTRG 3 - 5) in patients with low TB density versus the ones with high density (TB): (8 (50%) vs. 15 (78.9%); p = 0.072 and TP: 8 (80%) vs. 13 (72.2%); p = 0.649). In patients with synchronous MCC metastases who were treated with the Folfox4 chemotherapy protocol, with and without AV, there is a statistically significant difference in survival rates during a two-year follow up when referring to the TB density. Also, the high density of TB is an independent negative prognostic factor in these patients in reference to the given therapeutic regimens, as seen in the two-year survival rate.</p>