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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.

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Showing 11 to 16 of 16 (0.042 seconds)

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11

Ispitivanje 8-hidroksi-2-deoksiguanozina, produkata lipidne peroksidacije i aktivnosti antioksidativnih enzima kod prekanceroznih lezija i u karcinomu grlića materice / Analysis of 8-hydroxy-2-deoxyguanosine, lipid peroxidation products and activity of antioxidative enzymes in precancerous lesions and in cervical cancer

Jelić Marija 21 June 2019 (has links)
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Accent 2"/> <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 2"/> <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 2"/> <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 2"/> <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 2"/> <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 2"/> <w:LsdException Locked="false" Priority="67" Name="Medium Grid 1 Accent 2"/> <w:LsdException Locked="false" Priority="68" Name="Medium Grid 2 Accent 2"/> <w:LsdException Locked="false" Priority="69" Name="Medium Grid 3 Accent 2"/> <w:LsdException Locked="false" Priority="70" Name="Dark List Accent 2"/> <w:LsdException Locked="false" Priority="71" Name="Colorful Shading Accent 2"/> <w:LsdException Locked="false" Priority="72" Name="Colorful List Accent 2"/> <w:LsdException Locked="false" Priority="73" Name="Colorful Grid Accent 2"/> <w:LsdException Locked="false" Priority="60" Name="Light 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Name="Colorful Grid Accent 3"/> <w:LsdException Locked="false" Priority="60" Name="Light Shading Accent 4"/> <w:LsdException Locked="false" Priority="61" Name="Light List Accent 4"/> <w:LsdException Locked="false" Priority="62" Name="Light Grid Accent 4"/> <w:LsdException Locked="false" Priority="63" Name="Medium Shading 1 Accent 4"/> <w:LsdException Locked="false" Priority="64" Name="Medium Shading 2 Accent 4"/> <w:LsdException Locked="false" Priority="65" Name="Medium List 1 Accent 4"/> <w:LsdException Locked="false" Priority="66" Name="Medium List 2 Accent 4"/ / <p>Free radicals are produced in our body under physiological conditions. Although in very low concentrations, they can show some toxic effects. While trying to bind electrons, in the chemical reaction of oxidation, they rapidly and unpredictably bind to adjacent molecules- proteins, lipids, carbohydrates and nucleic acids from which the structural elements of the cell are made, triggering the internal pathway of apoptosis. Antioxidants are substances that prevent or significantly reduce the oxidation of biomolecules. Oxidative stress is a condition that occurs when the production of free radicals exceeds the capacity of antioxidant enzymes to neutralize them. The antioxidant enzymes include: superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione-S-transferase (GST). Lipid Peroxidation (LP) is the process of oxidation of polyunsaturated fatty acids by free radicals. Malondialdehyde is a biochemical marker by which it is possible to measure the degree of oxidative damage of cell membranes. The oxidative modification of DNA leads to a change in DNA structure that results in genetic damage. The most commonly used marker of oxidative stress is urinary 8-hydroxy-2-deoxiguanosine (8-OHdG). The damage to proteins, lipids and DNA is an important basis for many diseases such as atherosclerosis, neurodegenerative diseases, diabetes, obesity, aging, retinopathy, chronic inflammatory disease and cancer. Starting from the hypothesis that these biomolecules are different at different stages of the disease, they could represent a prognostic marker of the progression of the disease. The aim of the study was to examine whether there were differences between the control group (healthy women), the patients with precancerous lesions on the cervix (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) and the patient with locally advanced cervical cancer (IIa - IV) in the indicators of DNA damage (determining the value of 8-OHdG), indicators of oxidative stress (by determining the lipid peroxidation intensity (TBARS)), indicators of antioxidant defense (by determining the activity of antioxidative enzymes of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase GPx), glutathione reductase (GR), and glutathione-S-transferase (GST)). In addition, the aim of the study was to compare the values of 8- OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx, GR) within the group of patients with early stage cervical cancer divided into two subgroups- with low and high risk in relation to the relapse of the disease. The research was performed at the Clinic for operative oncology, Department of Gynecology at the Institute of Oncology of Vojvodina, Medical Faculty in Novi Sad, Department of Pharmacy and the Institute for Health Care of Novi Sad in the period from 2013 to 2017. Samples of blood and urine of the patients were collected, prepared adequately and stored at -80 &deg; until the analysis. The activity of the antioxidant enzymes as well as the lipid peroxidation were determined by spectrophotometric methods, and the concentration of 8-OHdG was determined by gas chromatography with mass detection. The approval of the Ethical Committee of the Institute for Oncology of Vojvodina was obtained before conducting the research. It has been shown that there are statistically significant differences between the control group (healthy women), patient with precancerous cervical lesions (HSIL), the patients with early stage cervical cancer (FIGO Ia-Ib) compared to a group of patients with locally advanced cervical cancer (IIa-IV) in indicators of damage to DNA (concentration of 8-OHdG), indicators of oxidative stress (lipid peroxidation (TBARS)), indicators of antioxidant defense (activities of antioxidant enzymes SOD, CAT and GST). There was no difference between the groups in activity of glutathione peroxidase enzyme (GPx) and glutathione reductase (GR). There were no differences in the concentration of 8-OHdG, lipid peroxidation products (TBARS) and the activity of antioxidant enzymes (SOD, CAT, GST, GPx and GR) within the group of patients with locally restricted cervical cancer divided into two subgroups with low and high risk in relation on relapses of the disease. CAT and GST activities were the best predictors of disease recurrence among defined groups. Based on the activities of these two oxidative enzymes, the separation of the group of patients who did not experience disease recurrence after a follow-up period from the other two groups in which recurrence of the disease occurred was possible. Based on the obtained results it is concluded that it is possible to use the studied biomarkers as diagnostic markers in patients with cervical cancer. These biomolecules can help in the patient&#39;s classification into certain groups according to the stage of the disease, and consequently the more efficient choice of appropriate treatment. In addition, CAT and GST enzyme activity have been shown to be predictors of disease recurrence in defined patient groups.</p>
12

Análise e comparação da expressão imunoistoquímica de marcadores moleculares (ERCC1, Bcl-2, Lin28a e Ki67) potencialmente preditores de resposta à quimioterapia em carcinomas neuroendócrinos extra-pulmonares e carcinoma de pequenas células de pulmão / Evaluation of biomarkers (ERCC1, BCL-2, Lin28a e Ki67) potencially predictive of response and prognosis in patients with high-grade extrapulmonary neuroendocrine carcinomas or small cell lung cancer treated with platin-based chemotherapy

Juliana Florinda de Mendonça Rêgo 21 November 2016 (has links)
INTRODUÇÃO: O carcinoma de pulmão de pequenas células (CPPC) e o carcinoma neuroendócrino (CNE) extra-pulmonar apresentam características histopatológicas e tratamentos similares, porém os desfechos encontrados nos dois grupos podem ser diferentes. Avaliamos a expressão de alguns biomarcadores e a associação destes com taxa de resposta (TR) à quimioterapia baseada em platina e sobrevida global (SG) nos dois grupos. METODOS: Realizamos estudo retrospectivo de pacientes com CPPC e CNE extra-pulmonares tratados com quimioterapia baseada em platina. Todas as amostras tumorais foram revisadas pelo mesmo patologista (R.S.S.M.) e analisadas quanto a expressão imunoistoquímica de Ki-67, ERCC1, Bcl-2 e Lin28a, a qual foi determinada através do H-escore (calculado multiplicando o produto da intensidade da coloração - 0 a 3 - com a porcentagem de células positivas - 0 a 100 -, podendo variar de 0 a 300 - positivo quando >= 200). Os biomarcadores foram analisados tanto como variáveis contínuas quanto categóricas e a TR foi determinada por RECIST 1.1. A associação entre a expressão de cada biomarcador e a TR foi avaliada através do teste de qui-quadrado ou teste exato de Fisher para variáveis categóricas e regressão logística simples para variáveis contínuas. Sobrevida global foi estimada por Kaplan-Meier e as curvas foram comparadas por log-rank. O modelo de regressão de cox foi utilizado para avaliar associação entre SG e a expressão de biomarcadores como variável contínua. RESULTADOS: Entre Julho de 2006 e Julho de 2014, 142 pacientes foram identificados: N=82 (57,7%) com CPPC e N=60 (42,3%) com CNE extra-pulmonar. As características clínicas eram semelhantes em ambos os grupos. Mediana de ki67 foi de 60% (7-100) no CPPC e de 50% (20-95%) no segundo grupo (p=0,858). Com uma mediana de 5 ciclos por paciente (N=123 elegíveis para análise de TR), a TR foi de 86,8% no CPPC, enquanto nos com CNE extra-pulmonar, foi de 44,6% (p < 0.001). A mediana de SG (N=132 elegíveis para análise da SG) foi similar entre os grupos (10,3 meses em CPPC e 11,1 meses em CNE extra-pulmonar; p=0,069). Não houve diferença no padrão de expressão do ERCC1 (p=0,277) e do Lin28a (p=0,051) entre os grupos. Bcl2 foi expresso em 38 pacientes (46,3%) com CPPC e em 17 pacientes (28,3%) com CNE extra-pulmonar (p=0,030). Apenas no grupo com CNE extra-pulmonar, a alta expressão do Bcl2 foi associada com pior prognóstico (8,0 meses vs 14,7 meses; p=0,025). A expressão dos demais marcadores em CNE extra-pulmonar e dos quatro em CPPC não apresentou influência sobre a SG, não havendo também associação entre estes e a taxa de resposta à quimioterapia. Dentre os pacientes com CNE extra-pulmonar, não houve diferença na SG ou na TR entre os pacientes com carcinoma bem diferenciado (N=13;) e com carcinoma pouco diferenciado (N=47). CONCLUSÃO: Apesar do CPPC e do CNE extra-pulmonar serem tratados de forma semelhante, nesta coorte a taxa de resposta entre os grupos foi significativamente diferente. Quando comparado com CPPC, os pacientes com CNE extra-pulmonar apresentam uma menor responsividade à quimioterapia baseada em platina, mas com tendência a maior SG. Dentre os CNE extra-pulmonares, a alta expressão de Bcl-2 foi associada a pior prognóstico. Os demais biomarcadores não apresentaram papel preditor de resposta ou prognóstico / INTRODUCTION: Small cell lung cancer (SCLC) and high-grade extrapulmonary neuroendocrine carcinomas (EPNEC) share similar histopathological features and treatment, but outcomes may differ. We evaluated the expression of biomarkers and their association with response rate (RR) to platin-based chemotherapy and overall survival (OS) in these entities. METHODS: We conducted a retrospective analysis of patients with advanced EPNEC and SCLC treated with platinum-based chemotherapy. A single pathologist (R.S.S.M.) revised all samples. Paraffin-embedded tumor samples were tested for Ki-67, ERCC1, Bcl-2 and Lin28a expression by immunohistochemistry (IHC). Final IHC score (H-score) was calculated multiplying the intensity of staining by grading (0-300, with >= 200 considered positive). Biomarkers were analyzed as both categorical and continuous variables. RR was determined by RECIST 1.1. Associations between each biomarkers expression and RR were assessed using Chi-square or Fisher\'s exact test for categorical variables and univariate logistic regression for continuous variables. OS was estimated by the Kaplan-Meier method and curves were compared by log-rank. Cox regression analysis was used to evaluate any association between biomarkers expression (continuous variables) and OS. RESULTS: From July 2006 to July 2014, 142 patients were identified: N=82 (57,7%) with SCLC and N=60 (42,3%) with EPNEC. Baseline clinical characteristics were similar. Median Ki67 was 60% (7-100) among SCLC patients and 50% (20-95%) in EPNEC (p=0,858). With a median of 5 cycles per patient in both groups (N=123 evaluable patients), the RR was significantly higher in the SCLC group (86,8% vs 44.6%; p < 0.001). Median OS (N=132 evaluable patients) was similar between the groups (10.3 months in SCLC and 11.1 months in EPNEC; p=0,069). In the EPNEC group, there wasn\'t any difference in OS or RR between the patients with welldifferentiated (N=13) and poorly differentiated carcinoma (N=47). ERCC1 (p=0.277) and Lin28a (p=0.051) were similarly expressed between the groups. Bcl2 was expressed in 38 SCLC patients (46.3%) and in 17 EPNEC patients (28.3%; p=0.030). Only in the EPNEC group, Bcl2 high expression was associated with worse survival (8.0 months vs 14.7 months; p = 0.025). RR to chemotherapy was not influenced by the expression of the ERCC1, Lin28a, Bcl-2, Ki-67 in either EPNEC or SCLC groups. CONCLUSION: Even though SCLC and EPNEC are treated similarly, in this cohort, the rate response differed significantly. When compared with SCLC, patients with EPNEC apparently had tumors less responsive to platin-based chemotherapy, but tended to live longer. In EPNEC treated with platin, high expression of Bcl2 was associated with poor prognosis. We could not identify additional predictive or prognostic biomarkers
Bcl-2
Biomarcadores tumorais
Carcinoma neuroendócrino
ERCC1
Estudos retrospectivos
Ki67
Lin28a
Prognóstico
Sobrevida
Bcl-2
ERCC1
Ki67, Retrospective studies
Lin28a
Neuroendocrine carcinoma
Prognosis
Survivorship
13

Prognostički značaj gustine tumorskih pupoljaka i citoplazmatskih pseudofragmenata u tumorskom tkivu karcinoma kolona kod bolesnika u stadijumu II / Prognostic significance of density of tumor buds and cytoplasmic pseudofragments in stage II colonic carcinoma

Šolajić Nenad 15 September 2016 (has links)
<p>UVOD: Karcinom kolona (KK) je velik javnozdravstveni problem usled visoke incidence i stope mortaliteta. Kod KK je stadijum bolesti najvažniji pojedinačni nezavisni faktor prognoze. U prisustvu nepovoljnih prognostičkih parametara, u koje spadaju visok histolo&scaron;ki gradus, ileus, limfo-vaskularna i perineuralna invazija, nakon potencijalno kurativne operacije se kod pacijenata u stadijumu II indikuje primena adjuvantne hemioterapije koja ima pozitivan uticaj na ukupno preživljavanje i na produženje perioda bez bolesti. Međutim, relapsi bolesti nastaju kod nekih bolesnika bez negativnih prognostičkih faktora, &scaron;to ukazuje na moguće postojanje drugih tkivnih faktora lo&scaron;e prognoze. U novije vreme se sve veća pažnja posvećuje fenomenu tumorskog pupljenja koje predstavlja pojavu tumorskih pupoljaka (TP), odnosno oligocelularnih grupa tumorskih ćelija koje se na invazivnom frontu tumora odvajaju od glavne tumorske mase. Ove tumorske ćelije poprimaju fenotip mezenhimnih ćelija i stiču sposobnost ameboidnog kretanja kroz ekstracelularni matriks, uz pomoć citoplazmatskih podija koje se na dvodimenzionalnim histolo&scaron;kim rezovima vizualizuju kao citoplazmatski pseudofragmenti (CPF). Značaj gustine TP i CPF je jo&scaron; uvek nedovoljno ispitan, ali postoje indicije da se radi o moćnom prediktoru biolo&scaron;kog pona&scaron;anja tumora. CILJ: Cilj je bio da se ispita zavisnost dužine perioda bez relapsa, veličine primarnog tumora, gustine peritumorske limfocitne infiltracije i konfiguracije tumorske margine od gustine TP i CPF kod bolesnika sa KK u stadijumu II. METODOLOGIJA: Istraživanjem je obuhvaćeno 114 bolesnika operisanih od KK u stadijumu II na Institutu za onkologiju Vojvodine, bez nepovoljnih prognostičkih faktora i bez indikacija za primenu adjuvantne hemioterapije. Mikroskopskom analizom rutinskih histolo&scaron;kih i imunohistohemijskih preparata utvrđivana je gustina TP i CPF, koja je zatim korelirana sa vremenom pojave relapsa, veličinom primarnog tumora, gustinom peritumorske limfocitne infiltracije i konfiguracijom tumorske margine. REZULTATI: Velika gustina TP i/ili CPF nađena je kod 45 tumora (39,5%). U ovoj grupi se relaps dogodio kod 26 bolesnika (57,8%). U grupi bolesnika sa malom gustinom TP/CPF relaps je registrovan u 4 slučaja (5,8%). Poređenje krivih preživljavanja pokazalo je da je verovatnoća relapsa značajno veća ako se u tumoru nalazi velika gustina TP/CPF (p&lt;0,0001). Tumori sa velikom gustinom TP/CPF su imali najveći prečnik koji je varirao u rasponu od 25 do 100 mm, dok su tumori sa malom gustinom TP/CPF bili najvećeg prečnika od 20 do 110 mm (p=0,6744). Intenzitet peritumorskog limfoidnog odgovora je bio velik kod 13 tumora sa velikom gustinom TP/CPF (28,9%) i kod 17 tumora sa malom gustinom TP/CPF (24,6%), p=0,7747. Konfiguracija tumorske margine je bila infiltrativna u svim tumorima sa velikom gustinom TP/CPF, kao i kod 42 tumora sa malom gustinom TP/CPF (60,9%). ZAKLJUČAK: Velika gustina TP/CPF je nezavisan tkivni indikator lo&scaron;e prognoze kod bolesnika sa KK u stadijumu II, koji je ne korelira ni sa veličinom primarnog tumora ni sa intenzitetom peritumorskog limfoidnog odgovora. Velika gustina TP/CPF nije kompatibilna sa ekspanzivnom konfiguracijom tumorske margine, ali infiltrativna konfiguracija tumorske margine nije prediktor velike gustine TP/CPF.</p> / <p>INTRODUCTION: Colonic carcinoma (CC) is a serious public health problem due to its high incidence and mortality rate. Stage is the single most important independent prognosticator in patients with CC. In the presence of indicators of poor prognosis, including high histologic grade, ileus, lympho-vascular invasion and perineural invasion, there is a need for adjuvant chemotherapy after a potentially curative operation in patients with stage II CC, because the therapy improves both overall survival and disease-free survival. However, some patients with no documented poor prognostic factors suffer recurrences, which indicates that there may be some other tissue features that confer poor prognosis. In the recent publications there is an increasing interest in the phenomenon of tumor budding, a term assigned to the presence of small groups of discohesive tumor cells at the invasive front of the tumor &ndash; tumor buds (TB&#39;s). These cells acquire mesenchymal phenotype and gain the ability to migrate through the extracellular matrix by means of cytoplasmic extrusions which are visible on the two-dimensional immunohistologic sections and are called cytoplasmic pseudofragments (CPF&#39;s). Significance of density of TB&#39;s and CPF&#39;s is still to be evaluated, but the pool of evidence suggests that this is a powerful predictor of biologic behaviour of CC. AIM: The aim of this study was to determine the influence of density of TB&#39;s and CPF&#39;s on the risk of recurrence in patients with stage II CC. This research also attempted to establish whether there is a correlation between the density of TB&#39;s and CPF&#39;s and several other morphologic features such as tumor diameter, peritumoral lymphocytic response and the configuration of the tumor margin. METHODS: 114 patients with stage II CC were enrolled in the study. All the patients received surgery at the Institute of Oncology in Sremska Kamenica and no patient had indication for adjuvant chemotherapy. Microscopic analysis of routine histologic and immunohistochemical slides was performed to establish the density of TB&#39;s and CPF&#39;s, to estimate the intensity of the peritumoral lymphocytic response and to determine the configuration of the tumor margin. RESULTS: High density of TB&#39;s and/or CPF&#39;s was found in 45 tumors (39.5%). In this group recurrence occured in 26 patients (57.8%). In the group of patients with low density of TB/CPF in the tumor tissue 4 patients relapsed (5.8%). Comparison of survival curves showed that the probability of recurrence was significantly greater if the density of TB/CPF&#39;s was high (p&lt;0.0001). Tumors with high density of TB/CPF&#39;s ranged from 25 to 100 mm in greatest diameter, while those with low density measured from 20 to 110 mm (p=0.6744). Intensity of peritumoral lymphocytic response was high in 13 tumors with high density of TB/CPF&#39;s (28.9%) and in 17 tumors with low density of TB/CPF&#39;s (24.6%), p=0.7747. All tumors with high density of TB/CPF&#39;s and 42 tumors with low density of TB/CPF&#39;s (60.9%) had infiltrative configuration of tumor margin. CONCLUSION: High density of TB/CPF&#39;s is an independent indicator of poor prognosis in patients with stage II CC and it correlates neither with tumor diameter nor with intensity of peritumoral lymphocytic response. High density of TB/CPF&#39;s is not compatible with the expansive configuration of tumor margin, but the infiltrative configuration of tumor margin is not a predictor of high density of TB/CPF&#39;s.</p>
14

Učestalost i prognostički značaj genskih alteracija u tumorskim ćelijama i njihova povezanost sa kliničko-patološkim karakteristikama bolesnika sa ranim stadijumom adenokarcinoma bronha / Frequency and prognostic value of gene alterations in tumor cells and their correlation with clinicopathological characteristics of patients with early stage lung adenocarcinoma

Stojšić Vladimir 27 April 2018 (has links)
<p>Napredak na polju molekularne biologije omogućio je identifikaciju molekularnih markera za karcinom bronha sa vrednim prognostičkim i prediktivnim značajem i njihova uloga kod uznapredovalog, metastatskog oblika bolesti je u velikoj meri istražena, dok kod ranih stadijuma bolesti jo&scaron; uvek nije sasvim jasna. Cilj ovog istraživnja bio je da se utvrdi učestalost najče&scaron;ćih genskih alteracija u tumorskim ćelijama bolesnika sa ranim stadijumom adenokarcinoma bronha, da se utvrdi pojedinačna zavisnost ispitivanih genskih alteracija u tumorskim ćelijama sa određenim kliničko-patolo&scaron;kim karakteristikama i da se utvrdi potencijalni prognostički značaj pojedinačne genske alteracije u tumorskim ćelijama na vreme preživljavanja bez povratka bolesti i ukupno vreme preživljavanja. Istraživanje je obuhvatilo 161 bolesnika sa adenokarcinomom bronha, stadijuma bolesti od I do IIIA, kod kojih je sprovedena radikalna hirur&scaron;ka resekcija u Institutu za plućne bolesti Vojvodine u periodu izmedju 2007 i 2014 godine. U tumorskim uzorcima fiksiranim u parafinu odredjivane su mutacije EGFR, KRAS i PIK3CA gena, ALK i ROS1 rearanžman i PD1 i PD-L1 ekspresija. Kliničkopatolo&scaron;ke karakteristike su preuzete iz registra za karcinom bronha Instituta za plućne bolesti Vojvodine. Ukupno preživljavanje je računato od dana operacije do dana smrti, a preživljavanje bez povratka bolesti je računato od dana operacije do momenta ponovne pojave bolesti. Od 161 testiranog tumorskog uzorka, prisustvo mutacija detektovano je kod 96 uzoraka (59.6%). Prisustvo mutacije KRAS gena detektovano je kod 69 (42.9%), mutacije EGFR gena kod 10 (6.2%), a mutacije PIK3CA gena kod 7 (4.3%) tumorskih uzoraka. ALK rearanžman je detektovan kod 3 (1.9%), a ROS1 rearanžman kod 7 (4.3%) tumorskih uzoraka. PD-1 ekspresija detektovana je u 71 tumorskom uzorku (45%), dok je PD-L1 ekspresija detektovana u 59 tumorskih uzoraka (36.6%). PD-1 ekspresija nije bila značajno povezana ni sa jednim od klinčko-patolo&scaron;kih karakteristika (uključujući KRAS, EGFR, ALK, ROS1 i PI3KCA status). PD-L1 ekspresija je bila značajno povezana sa tipom hirurgije (P = 0.01) i sa prisustvom KRAS mutacije (P = 0.02). Mutacioni status u domenu KRAS gena je bio značajno povezan sa godinama starosti (P = 0.004), polom (P = 0.006) i pu&scaron;ačkim statusom (P = 0.004). Mutacioni status u domenu EGFR gena je bio značajno povezan sa pu&scaron;enjem (P &lt; 0.001) i sa godinama starosti (P = 0.013). Mutacioni statusi u domenu gena za ALK, ROS1 i PI3KCA nisu bili značajno povezani ni sa jednom od ispitivanih kliničko-patolo&scaron;kih karakteristika. Prisustvo PD-1 ekspresije je bilo značajno povezano sa preživljavanjem bez povratka bolesti (P = 0.03) i ukupnim preživljavanjem (P = 0.01). PD-L1 ekspresija, KRAS, EGFR, ALK, ROS1 i PIK3CA mutacioni status nisu bili značajno opvezani sa preživljavanjem bez povratka bolesti i ukupnim preživljavanjem. Najče&scaron;će detektovane genske alteracije su mutacije u domenu KRAS i EGFR gena. Prisustvo KRAS mutacije je značajno povezano sa godinama starosti ispitanika, polom i pu&scaron;ačkim statusom dok je prisustvo EGFR mutacije značajno povezano sa godinama starosti ispitanika i pu&scaron;ačkim statusom. Prisustvo PD-L1 ekspresije je značajno povezano sa vrstom hirur&scaron;kog lečenja i sa prisustvom KRAS mutacija. Jedino prisustvo PD-1 ekspresije u tumorskim ćelijama predstavlja nezavistan prognostički faktor za preživljavanje bez povratka bolesti i ukupno preživljavanje bolesnika sa ranim stadijumom adenokarcinoma bronha.</p> / <p>Advances in the field of molecular biology gave us insight into biomarkers for lung cancer with great prognostic and predictive value and their role in advanced stage disease is well known while in early stage disease is yet to be proven. The aim of this study was to determine the frequencies of the most common gene alterations in patients with early stage lung adenocarcinoma, to determine the relationship between gene alterations in tumor cells and clinicopathologial characteristics and to determine prognostic value of each gene alteration regarding overall survival and disease free survival. One hundred sixty-one patients diagnosed with lung adenocarcinoma clinical stage I-IIIA who underwent radical surgical resection at the Institute for Pulmonary Diseases of Vojvodina between 2007 and 2014 were included in this study. Mutations in EGFR, KRAS and PIK3CA gene, ALK and ROS1 rearrangement and PD-1 and PD-L1 expression were determined in representative formalin-fixed, paraffin-embedded (FFPE) tumor block from each patient. Clinical data were extracted from the institutional lung cancer registry of the Institute for Pulmonary Diseases. Overall survival was calculated as time from the day of surgery to the day of death. Disease free survival was calculated as time from the day of surgery to the day of disease relapse. Among 161 tested tumor tissue, presence of mutation was found in 96 (59.6%) of them. There were 69 (42.9%) mutations in KRAS gene, 10 (6.2%) in EGFR gene and 7 (4.3%) in PIK3CA gene. ALK and ROS1 rearrangement were present in 3 (1.9%) and 7 (4.3%), respectively. PD-1 expression was determined in 71 (45.0%) tumor sample while PD-L1 expression was determined in 59 (36.6%). PD-1 expression was not correlated with any of the clinicopathologial characteristics (including KRAS, EGFR, ALK, ROS1 and PIK3CA mutational status). PD-L1 expression correlated with type of surgery (P = 0.01) and KRAS positivity (P = 0.02). KRAS mutation status correlated with age (P = 0.004), sex (P = 0.006) and smoking status (P = 0.004). EGFR status correlated with smoking status (P &lt; 0.001) and age (P = 0.013). ALK, ROS1 and PIK3CA status were not correlated with any of the clinicopathologial characteristics. PD-1expression was significantly associated with disease free survival (P = 0.03) and overall survival (P = 0.01). PD-L1 expression, KRAS, EGFR, ALK, ROS1 and PIK3CA status were not associated with disease free survival and overall survival. The most frequent gene alteration are mutations in KRAS and EGFR gene. Presence of KRAS mutation is in correlation with patients age, sex and smoking status while presence of EGFR mutation is in correlation with patients age and smoking status. PD-L1 expression is in correlation with type of surgery and KRAS mutational status. Only presence of PD-1 expression represent an independent prognostic factor for disease free survival and overall survival.</p>
15

Klinička vrednost određivanja Ki-67 proliferativnog indeksa u karcinomima dojke sa pozitivnim hormonskim receptorima / Clinical value of determination of Ki-67 proliferative index in carcinomas with positive hormone receptors

Lakić Tanja 22 November 2018 (has links)
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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--><b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Uvod: </span></b><span style="font-size:11.0pt;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;color:black;mso-ansi-language:EN-US;mso-fareast-language:EN-US;mso-bidi-language:AR-SA">Karcinom dojke je heterogena bolest koju karakteri&scaron;u različita morfologija, imunohisto-hemijski profil, klinički tok i terapijski odgovor. Ki-67 proliferativni indeks je jedan od markera sa prognostičkim i prediktivnim značajem, čije metodolo&scaron;ko određivanje i analiza jo&scaron; uvek nisu standardizovani. <b>Cilj: </b>Utvrditi graničnu (&ldquo;cut-off&rdquo;) prognostičku vrednost Ki-67 indeksa, kao i povezanost vrednosti Ki-67 u ranom luminalnom karcinomu dojke sa prognostičkim i prediktivnim parametrima karcinoma dojke, kao &scaron;to su životna dob bolesnica, veličina tumora, histolo&scaron;ki gradus (HG) i nivo tumorske ekspresije receptora estrogena (ER) i progesterona (PR). Takođe, cilj istraživanja je i utvrđivanje značajnosti razlike u vrednosti Ki-67 proliferativnog indeksa u odnosu na pojavu lokalnog recidiva, udaljenih metastaza i dužinu preživljavanja u toku petogodi&scaron;njeg perioda praćenja pacijentkinja. <b>Metode: </b>Retrospektivno je analizirano 120 patohistolo&scaron;kih izve&scaron;taja bolesnica kojima je u periodu od 01.01.2009. godine do 31.12.2011. godine na Institutu za onkologiju Vojvodine imunohistohemijskom analizom dokazan luminalni karcinom dojke (pozitivan ER i PR, negativan HER2), bez metastaza u aksilarnim limfnim čvorovima. <b>Rezultati: </b>Metodama deskriptivne statistike prosečna starost pacijentkinja je iznosila 57,42&plusmn;10,17 godina; prosečna veličina tumora 17,98&plusmn;6,97mm; recidiv je registrovan kod 8 (6,7%) pacijentkinja uz prosečan vremenski period do pojave recidiva od 49&plusmn;20,23 meseci. Vrednost &ldquo;cut off&rdquo; indeksa Ki-67 od prognostičkog značaja za vremenski period bez recidiva je iznosio 20,75%. Nije dokazana signifikantna veza između vrednosti Ki-67 i godina starosti pacijentkinja (p=0,401, odnosno p=0,293), kao i jačine ekspresije ER (p=1,00, p=0,957) i PR (p=0,273, p=0,189). Ustanovljena je signifikantna povezanost Ki-67 postoji sa veličinom (p=0,035, p=0,20) i HG tumora (p=0,041, p=0,20). Prosečan period praćenja bolesnica iznosio je 72,92&plusmn;8,38 meseci; nije registrovana pojava udaljenih metastaza, kao ni smrtni ishod. U odnosu na pojavu lokalnog recidiva, Kaplan-Majerovom analizom i Koksovom regresionom analizom proliferativni indeks Ki-67 se pokazao kao signifikantan prediktor za procenu ponovnog javljanja bolesti, lokalnog recidiva (Log rank (df = 1) = 2,73; p=0,045). Takođe je ustanovljeno da je statistički značajan prediktor za procenu recidiva bolesti i starosna dob bolesnica (Log rank (df = 1) = 6,885; p=0,009). Intenzitet pozitivnosti ER i PR, veličina tumora i histolo&scaron;ki gradus se nisu pokazali kao prediktori za pojavu recidiva luminalnih karcinoma dojke (p &gt; 0,05). <b>Zaključak: </b>Zbog heterogene prirode oboljenja, kori&scaron;ćenjem standardnih histopatolo&scaron;kih faktora i biomarkera te&scaron;ko je predvideti tok i ishod karcinoma dojke. Ki-67 je proliferativni marker, čija visoka vrednost korelira sa faktorima lo&scaron;e prognoze.</span></p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Tanja Lakic</o:Author> <o:Version>12.00</o:Version> </o:DocumentProperties></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> <w:DontGrowAutofit/> <w:SplitPgBreakAndParaMark/> <w:DontVertAlignCellWithSp/> <w:DontBreakConstrainedForcedTables/> 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Normal";mso-tstyle-rowband-size:0;mso-tstyle-colband-size:0;mso-style-noshow:yes;mso-style-priority:99;mso-style-qformat:yes;mso-style-parent:"";mso-padding-alt:0cm 5.4pt 0cm 5.4pt;mso-para-margin-top:0cm;mso-para-margin-right:0cm;mso-para-margin-bottom:10.0pt;mso-para-margin-left:0cm;line-height:115%;mso-pagination:widow-orphan;font-size:11.0pt;font-family:"Calibri","sans-serif";mso-ascii-font-family:Calibri;mso-ascii-theme-font:minor-latin;mso-hansi-font-family:Calibri;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;}</style><![endif]--></p><p class="Default"><b><span style="font-size:11.0pt">Introduction: </span></b><span style="font-size:11.0pt">Breast cancer is a heterogeneous disease characterized by different morphology, immunohistochemical profile, clinical course and response to applied therapy. Ki-67 proliferative index is one of the prognostic and predictive factors, whose methodological determination and analysis are still unstandardized. <b>Objective: </b>Determination of cut-off value for Ki-67 index, its corelation in luminal breast carcinoma with patient&#39;s age, tumor size, histological grade (HG) and expression of estrogen (ER) and progesterone (PR). Also, the aim of the study was to determine the significance of the difference in the value of the Ki-67 proliferative index in relation to the occurrence of local relapse, distant metastases and survival rates during the five-year follow-up period of the patient. <b>Methods: </b>Retrospectively, we analysed 120 pathohistological reports of patients who were treated in the period from 01.01.2009 until 31.12.2011 at the Oncology Institute of Vojvodina, and to whom immunohistochemically was proven luminal breast cancer (positive ER and PR, negative HER2), without axillary lymph node metastases. </span><b><span style="font-size:11.0pt">Results: </span></b><span style="font-size:11.0pt">The average patient&rsquo;s age was 57.42&plusmn;10.17 years; average tumor size 17.98&plusmn;6.97mm; recurrence was registered in 8 (6.7%) patients with average recurrence time of 49&plusmn;20.23 months. &quot;Cut off&quot; Ki-67 value of prognostic significance for period without recurrence was 20.75%. Test didn&rsquo;t show significant relationship between Ki-67 and patient&rsquo;s age (p=0.401 and p=0.293), as well as the strength of expression ER (p=1.00, p=0.957) and PR (p=0.273, p=0.189). Significant correlation was present for Ki-67 with size (p=0.035, p=0.20) and tumor&rsquo;s HG (p=0.041, p=0.20). The average follow-up period for patients was 72.92&plusmn;8.38 months; there was no registered occurrence of distant metastases or fatal outcome. In relation to the occurrence of local relapse, Kaplan-Meier analysis and Cox regression analysis, the proliferative index Ki-67 proved to be a significant predictor for the assessment of recurrence of the disease, local relapse (Log rank (df = 1) = 2.73; p = 0.045). Also, it was founded that a statistically significant predictor for assessing the recurrence of the disease is the age of the patients (Log rank (df = 1) = 6.885; p = 0.009). The intensity of ER and PR expression, tumor size and histological grade have not been shown to be predictors of the recurrence of luminal breast carcinoma (p&gt; 0.05). </span><b><span style="font-size:11.0pt">Conclusion: </span></b><span style="font-size:11.0pt">Breast carcinoma is heterogeneous disease, so it is difficult to predict its course and outcome using standard histopathological factors and biomarkers. Ki-67 is proliferative marker whose high value correlates with factors of bad prognosis. </span></p>
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Клинички значај идентификације туморских матичних ћелија у ткиву аденокарцинома колона / Klinički značaj identifikacije tumorskih matičnih ćelija u tkivu adenokarcinoma kolona / Clinical impact of colon cancer stem cells identificaton in adenocarcinoma tumour tissue

Kresoja Ignjatović Milana 22 December 2020 (has links)
<p>Karcinom debelog creva predstavlja treći uzrok smrnosti od maligniteta kod mu&scaron;karaca i drugi kod žena. Postoji osnovana sumnja da kancerske matične ćelije (KMĆ) imaju veliki značaj u karcinogenezi, invazivnosti, &scaron;irenju i rezistenciji na hemioterapiju primarnog tumora. Njihova identifikacija u primatnom kolorektalnom karcinomu (KRK) putem markera kancerskih matičnih ćelija bi selektovala visokorizičnu grupu bolesnika, omogućila ciljano delovanje na ove ćelije i veću &scaron;ansu za izlečenje. Cilj ovog istraživanja je bio utvrđivanje uticaja prisustva kancerskih matičnih ćelija u primarnom tumoru obolelih od karcinoma kolona na pojavu relapsa bolesti, dužino preživljavanja bez bolesti i sveukupno preživljavanje.&nbsp; Istraživanje je sprovedeno kao prospektivno&minus;retrospektivna randomizovana analitička studija na Klinici za operativnu onkologiju i Službi za patolo&scaron;ko &ndash; anatomsku i laboratorijsku dijagnostiku Instituta za onkologiju Vojvodine u Sremskoj Kamenici u periodu od 2016-2019. godine. U studiju su uključeno 112 bolesnica operisanih na Institutu za onkologiju Vojvodine u periodu od 2007-2012. godine sa patohistolo&scaron;ki potvrđenom dijagnozom primarnog, nemetastatskog (stadijumi I, II i III) KRK. Bolesnici su randomizovani u odnosu na pojavu recidiva bolesti i prisustvo metastaza u regionalnim limfnim čvorovima u odnosu 1:1. Uzorci tumorskog tkiva dobijeni hirur&scaron;kom resekcijom su nakon standardne patohistolo&scaron;ke obrade tretirani primenom monoklonskih antitela na CD44, CD166 i &alpha;-Lgr5. Određivani su prisustvo, intezitet i lokalizacija kancerskih matičnih ćelija (KMĆ) u primarnom tumoru i njihov uticaj na pojavu relapsa bolesti, dužinu preživljavanja bez bolesti i sveukupno preživljavanje u grupi svih bolesnika a potom bolesnika podeljenih prema stadijumu bolesti. Bolesnici u prvom i drugom stadijumu bolesti koji su imali relaps su imali statistički značajno veće prisustvo CD44+ KMĆ u primarnom tumoru. Kod ovih bolesnika je prisutan kraći period preživljavanja bez bolesti kao i kraće sveukupno preživljavanje. Takođe, uočen je statistički značajan uticaj koekspresije CD44/CD166 u KMĆ na pojavu relapsa bolesti, dužinu preživljavanja bez bolesti i sveukupno preživljavanje kod bolesnika u prvom i drugom stadijumu bolesti. Nije uočena statistička značajnost prisustva KMĆ u primarnom tumoru na pojavu relapsa bolesti, dužinu preživljavanja bez bolesti i sveukupno preživljavanje kod bolesnika u trećem stadijumu bolesti. Prisustvo CD166 i &alpha;-Lgr5 obojenih KMĆ nije pokazalo statističku značajnost u pogledu pojave relapsa bolesti, dužine preživljavanja bez bolesti i sveukupnog preživljavanja, kako u grupi svih bolesnika tako i prilikom podele bolesnika na stadijume bolesti.</p> / <p>Colon cancer is the third most common case of death of malignancy in the world. There is justified theory that cancer stemm cells have significant impact on colon cancer tumorogenesis, invasiviness, spread and resistancy on chemotherapy. Identification of colon cancer stem cells in primary tumor by various biological markers would lead to identification of high risk group of patients, target therapy of colon cancer an higher chance to cure. Aim of this study was to determine wether presence of colon cancer stem cells in primary tumour have impact on recurrence, disease free survival (DFS) and overall survival (OS) in patients with colorectal cancer. An randomized, analytical prospective-retrospective study was performed on Clinic for Operative Oncology and Department for Anatomical Pathology of Oncology Institute of Vojvodina in Sremska Kamenica in period of 2016&minus;2019. Study included 112 patient with patohistological proven, non metastatic colon adenocarcinoma who were operated on Oncology Institute of Vojvodina in period of 2007-2012. Patients were randomized by recurrence and presence of metastatic lymph nodes by 1:1 ratio. After standard patohistological preparation, tumour specimens were stained for monoclonal CD44, CD166 and &alpha;-Lgr5 antibody. Presence, intensity of expression and localization of colon cancer stem cells were observed and their impact on relapse, disease free survival and overall survival in group of all patients as well as in groups divided by stages of the disease. We demonstrate that patients in Stage I and II of the disease who experience disease recurrence have statistically significant higher expression of CD44+ in primary tumor specimen. They also have shorter DFS and OS. Coexpression of CD44/CD166 antibody also have strong negative impact on recurrence, disease free survival and overall survival in Stage I and II patients. There is no correlation between presence of colon cancer stem cells and recurrence nor presence of colon cancer stem cells had impact on disease free survival and overall survival. Presence of CD166 and &alpha;-Lgr5 expression did not show significant impact on recurrence nor disease free survival and overall survival as in group of all patients as well in group of patients divided by stages of the disease. High expression of CD44+ and coexpression of CD44/CD166+ colon cancer stem cell markers in primary tumor specimen correlates with higher chance for disease recurrence and also leads to shorter DFS and OS.</p>

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