Dissertations / Theses on the topic 'Metastázy'

The ratio of companies and organizations in Norway with a number of employees between 5 and 9 and Internet access increased from 66% to 86% during a five year period from 2001 to 2006. This increased use of the Internet puts small companies in a vulnerable position considering information security. They are known to be remarkably less willing to pay for information security compared to companies with more employees and more revenue. There is no such thing as two identical organizations. Every single one has it's own assets, weaknesses, employees and fundamental strategies. This makes each company's requirement for ICT-systems and information security identical as well. One solution might be good for one company but not for others. The differences in organizational structure and mentality is important variables in the process of building a good and secure infrastructure for the organizations. The Australian Computer Crime Surveys presents four readiness to protect factors, they consist of: Technology, policies, training and standards. These factors are used as a template for this thesis. If companies focus on these four aspects of information security, and succeed in combining them in an optimal manner they are said to have security in depth. There is no use in investing great amounts of money on technology if these are not used in a justifiable manner. There might be several reasons for improper use of the technologies, among them; lack of knowledge, laziness and carelessness. The companies continuous inability to calculate their own risks of adverse events and their total losses experienced due to computer crime makes it difficult to perform investment analysis on information security. Smaller companies do often have very limited amount of money to spend in general, and therefore also on information security. The investment analysis model chosen therefore take the maximum amount of spend able money into account. The accuracy of the model presented relies in the companies ability to present trustworthy data, and use both willingness to pay calculations and cost/benefit-investments analysis methods, resulting in a more thorough presentation of an ALE/ROI method used in a proof of concept using estimated data based on surveys, professionals experiences and prices used by a Norwegian ICT-operations company.

Oralni karcinom je po učestalosti šesta najčešća maligna bolest u svetu čija incidenca varira u različitim geografskim područjima. Predstavlja 5% svih novootkrivenih malignih tumora godišnje i čini 14% svih malignih tumora glave i vrata. Pod oralnim karcinom podrazumevamo planocelularni karcinom obzirom na činjenicu da on čini preko 90% malignih tumora oralne lokalizacije, dok se u manjem procentu javljaju drugi tumori (maligni tumori malih pljuvačnih žlezda, limfomi, mezenhimni tumori). Oralni karcinom podrazumeva karcinome koji se javljaju u sledećim anatomskim regijama: sluznici prednje 2/3 jezika, poda usta, obraza, gingivi gornje i donje vilice, retromolarnom trouglu, kao i sluznici mekog i tvrdog nepca. Najčešća lokalizacija oralnog planocelularnog karcinoma je sluznica pokretnog dela jezika i poda usta. Oralni karcinom se češće javlja kod muškaraca (odnos muškarci:žene je 3:1) verovatno zbog većeg procenta rizičnog ponašanja kod muškaraca. Najčešće se javlja u šestoj i sedmoj deceniji života (medijana je 62 godine) iako se poslednjih godina sve češće javlja kod mlađih od 45 godina. Faktori rizika za oboljevanje su dobro poznati. Na prvom mestu se izdvaja pušenje duvana (značajna je dužina pušenja, da li pacijent puši lulu ili cigaretu, da li žvaće duvan, kao i dužina trajanja apstinencije). Smatra se da je smrtnost kod oralnog karcinoma direktno povezana sa brojem popušenih cigareta na dan. Preko 75% pacijenata sa oralnim karcinomom anamnestički daje podatak o prekomernoj upotrebi alkohola. Postoji sinergističko dejstvo alkohola i cigareta, dugotrajna ekspozicija ovim faktorima rizika dovodi do pojave “polja kancerizacije“, pojave genetske nestabilnosti i razvoja tumora. Kod oralnog planocelulranog karcinoma primećene su hromozomske abnormalnosti koje su rezultat oštećenja DNK i uključuju promene genetskog materijala na hromozomima.Jedna od najčešćih genetskih abnormalnosti kod oralnog planocelularnog karcinoma je mutacija r53 gena koji se nalazi na kratkom kraku hromozoma 17 i predstavlja tumor supresor gen. Planocelularni karcinom nije teško dijagnostikovati kada postane simptomatski. Pacijent se žali na bol, krvavljenje, otalgiju, otežano gutanje, smanjenje pokretljivosti jezika. Neretko je prvi simptom metastatski uvećan limfni čvor na vratu jer bolesnici ne primećuju ili ignorišu oralnu patologiju. Dijagnoza oralnog karcinoma se postavlja na osnovu detaljno uzete anamneze, kliničkog pregleda i patohistološke verifikacije. Oralni planocelularni karcinom se javlja u tri klinike forme: egzofitična, endofitična i infiltrativna. Zlatni standard za dijagnozu oralnog karcinoma je biopsija i patohistološka verifikacija, pri čemu se može primeniti „punch“ biopsija, inciziona biopsija ili eksciziona biopsija kod manjih promena. TNM „staging“ sistem AJCC (American Joint Committee on Cancer) se danas standardno koristi za klinički „staging“ oralnog karcinoma i bazira se na podacima dobijenim kliničkim pregledom i „imaging“ metodama. Sam „staging“ je bitan kako zbog komunikacije među lekarima koji učestvuju u lečenju bolesnika tako i zbog standardizacije prognoze. T stadijum označava veličinu primarnog tumora, N stadijum označava regionalnu nodalnu zahvaćenost dok M stadijum prikazuje prisustvo udaljenih metastaza. Terapija patohistološki dokazanog oralnog karcinoma zahteva multidisciplinarni pristup. Osnova terapije oralnog planocelularnog karcinoma je hirurško lečenje koje podrazumeva ablativno i rekonstruktivno hirurško lečenje. Osnovni princip ablativne hirurgije kod oralnog karcinoma je resekcija primarnog tumora sa najmanje 1cm negativnim hirurškim marginama. Pored ablacije tumora hirurško lečenje podrazumeva i uklanjanje regionalnih limfnih čvorova vrata. Cilj disekcije vrata je da se kod klinički evidentnih metastaza iste uklone (terapijska disekcija) ili da se uklone okultne metastaze koje su klinički neevidentne (elektivna disekcija). Oralni planocelularni karcinom spada u tumore sa visokom stopom smrtnosti, većom nego što je kod limfoma, laringealnog karcinoma, karcinoma testisa i endokrinih karcinoma. Stopa petogodišnjeg preživljavanja je direktno povezana sa veličinom tumora, prisustvom metastaza u regionalnim limfnim čvorovima i prisutvom udaljenih metastaza. Prosečno trogodišnje preživljavanje bolesnika sa oralnim karcinomom je 52% dok je prosečno petogodišnje preživljavanje oko 39% i ove stope se nisu mnogo menjale tokom godina bez obzira na nova saznanja i nove pristupe lečenju oralnog planocelulanog karcinoma. Ciljevi istraživanja su da se utvrdi da li postoji korelacija debljine OPK izmerene kompjuterizovanom tomografijom i svetlosnim mikroskopom, da li dubina invazije OPK i volume tumora mogu biti prediktivni faktor za razvoj regionalnih cervikalnih metastaza kod oralnog planocelularnog karcinoma. Istraživanje je uključilo 65 konsekutivnih bolesnika oba pola lečenih od oralnog karcinoma na Klinici za maksilofacijalnu hirurgiju Kliničkog centra Vojvodine. Dijagnoza oralnog karcinoma je postavljena na osnovu anamneze, kliničkog pregleda i biopsije. U sklopu TNM „staging“-a bolesnika načinjen je pregled glave i vrata i grudnog koša kompjuterizovanom tomografijom (CT) na osnovu kog smo dobili podatak o dimenzijama tumora. Na osnovu kliničkog nalaza i analize CT nalaza planiralo se operativno lečenje u skladu sa bolesnikovim TNM statusom. Postoperatativni patohistoški preparati je pregledan od strane istog patologa. Parametri koji će su određivani su sledeći: 1. Veličina tumora (2 dimenzije) izmerene na osnovu CT pregleda izražene u cm 2. Debljina tumora izmerena na osnovu CT pregleda izražena u cm 3. Veličina tumora (2 dijametra) na makroskopskom preparatu izražena u cm 4. Debljina tumora na mikroskopskom preparatu izmerena svetlosnim mikroskopom izražena u cm 5. Dubina invazije tumora na mikroskopskom preparatu izmerena svetlosnim mikroskopom izražena u mm 6. Volumen tumora koji se izračunavao prema formuli: VT=π/6 x maksimalni dijametar tumora A x minimalni dijametar tumora B x dubina invazije tumora i izražava se u cm³ 7. Broj metastatski izmenjenih limfnih čvorova u disekatu vrata 8. Ukupan broj patohistološki ispitanih limfnih čvorova u disekatu vrata Nakon prikupljanja planiranog materijala urađena je statistička obrada podataka. Statistička analiza podataka je uključila metode deskriptivne statistike (srednja vrednost, standardna devijacija, učestalost), kao i standardne parametrijske i neparametrijske testove za komparacije dve grupe (Studentov T test, Mann–Whitney U test, hikvadrat test). U fazi statističke analize međusobnih uticaja i povezanosti prikupljenih podataka korišćen je Pearsonov test korelacije. Sva testiranja sprovedena su na nivou statističke značajnosti p<0,05. REZULTATI: Istraživanje je obuhvatilo 65 bolesnika, od kojih je 82% bilo muškog pola prosečne starosti 59 godina. 83% bolesnika su se izjašnjavali kao pušači, dok je 69% bolesnika navelo da redovno koristi alkohol. Svim pacijentima je tokom hirurškog lečenja OPK rađena disekcija vrata i to najčeščće selektivna disekcija vrata (91%). Kod 30 bolesnika je utvrđeno postojanje cervikalnih regionalnih metastaza na operativnom preparatu te su bolesnici podeljeni u dve grupe: sa prisustvom i bez prisustva metastaza u limfnim čvorovima vrata. Utvrđeno je da se ove dve grupe statistički značajno razlikuju u dubini invazije tumora i volumenu tumora. Utvrđeno je takođe da postoji statistički značajna korelacija između debljine tumora izmerene CT pregledom i debljine tumora izmerene svetlosnim mikroskopom. Dokazano je da dubina invazije tumora veća od 7mm i zapremina tumora veća od 4cm³ predstavljaju prediktivni faktor za pojavu regionalnih cervikalnih metastaza. ZAKLjUČAK: Na osnovu istraživanja izvedeni su zaključci koji ukazuju na to da postoji statistički značajna korelacija između debljine tumora OPK izmerene CTpregledom i svetlosnim mikroskopom te se debljina tumora izmerena CT pregledom može koristiti za planiranje operativnog zahvata prilikom lečenja OPK. Dubina invazije tumora veća od 7mm i volumen tumora veći od 4 cm³ predstavljaju prediktivni faktor za pojavu nodalnih cervikalnih metastaza te su značajni za određivanje stadijuma bolesti.
Oral cancer is the sixth most common malignant disease in the world which incidence varies based on geographic area. It represents 5% of all newly discovered malignant tumors annually and constitutes 14 % of all malignant tumors of head and neck. Squamous cell carcinoma is considered to be a type of oral cancer because more than 90 % of malignant tumors that occur in oral cavity are squamous cell carcinomas while other tumors (malignant tumor of minor salivary gland, lymphoma, sarcoma) rarely occur. Oral cancer is the cancer found in the following anatomic regions: mucosa of front two-thirds of the tongue, the floor of the mouth, cheeks, upper and lower gingiva, retromolar trigone as well as  mucosa of soft and hard palates. Oral squamous cell carcinoma is most commonly localized in mucous membrane of the movable part of the tongue and floor of the mouth. Men are more affected than women (male to female ratio is 3:1) probably because of men’s riskier behavior. It is most commonly diagnosed in the sixth and seventh decade of life (the median is 62 years old) although it has been diagnosed in patents younger than 45 in recent years. Risk factors of oral squamous cell carcinoma are well known. The major factor is tobacco smoking (the period of smoking is significant, it is also important to consider whether a patient smokes a pipe or cigarette, whether he/she chews tobacco as well as the period of abstinence). The mortality rate is believed to be directly related to the number of cigarettes smoked a day. An excessive use of alcohol has been reported in over 75% of patients with oral cancer. There is a synergistic effect of alcohol and cigarette consumption and long-term exposure to these risk factors results in ‘field of cancerization’, genetic instability and tumor development. Chromosome abnormalities, which are caused by DNA damage and include the change in genetic material of chromosomes, have been reported in patients with oral squamous cell carcinoma. One of the most common genetic abnormalities in patients with oral squamous cell carcinoma is a mutation of р53 gene which is located on a short arm of chromosome 17 and represents a tumor suppressor gene. Oral squamous cell carcinoma is not difficult to diagnose when it becomes symptomatic. The patient complains of pain, bleeding, otalgia, swallowing difficulties, decreased tongue mobility. The first symptom is rarely metastatic lymph node on the neck because patients either do not notice or ignore oral pathology. The oral cancer is diagnosed based on the detailed anamnesis, physical examination and pathohistological verification. The oral squamous cell carcinoma occurs in three clinical forms: exophytic, endophytic and infiltrative form. The gold standard for diagnosis of oral cancer is biopsy and pathohistological verification. However, in case of smaller changes, punch biopsy, incisional and excisional biopsies can also be applied. ТNМ staging system of AJCC (American Joint Committee on Cancer) is nowadays used for clinical staging of oral cancer and it is based on the data acquired by clinical examination and imaging methods. Not only is the staging itself important for communication between the doctors involved in treatment, but it is also important for standardization of prognosis. Т describes the size of primary tumor, N describes regional nodal spread and М describes distant metastasis. The treatment of histopathologically proven oral cancer requires multidisciplinary approach. The main treatment of oral squamous cell carcinoma is surgical treatment which involves ablative and reconstructive surgical treatment. The basic principle of ablative surgery for oral cancer is the resection of primary tumor with at least 1 cm negative surgical margins. Apart from tumor ablation surgical treatment also involves removal of regional lymph nodes on the neck. The aim of neck dissection is to remove clinically evident metastasis (therapeutic dissection) or to remove occult metastasis that are not clinically evident (elective dissection). The oral squamous cell carcinoma is the cancer with high mortality rate. The mortality rate is higher than the mortality rate for lymphoma, laryngeal cancer, testicular cancer and endocrine cancer. The five-year survival rate is directly related to the size of the tumor, presence of metastasis in regional lymph nodes and distant metastasis. The average three-year survival rate of the patients with oral cancer is 52% and the average five-year survival rate is 39%. These rates have not changed a lot over the years regardless of new knowledge and approaches in treatment of oral squamous cell carcinoma. The aims of the study are to determine whether there is a correlation between the depth of invasion of oral squamous cell carcinoma determined by computed tomography and light microscope and whether the invasion depth of OSCC and tumor volume can be predictive factors of development of regional cervical metastases in case of oral squamous cell carcinoma. The study covered 65 consecutive patients of both sexes who received treatment for oral cancer at the Clinic for Maxillofacial Surgery of the Clinical Center of Vojvodina. The diagnosis of oral cancer was established based on the anamnesis, physical examination and biopsies. The TNM ‘staging’ of the cancer involved the examination of the patient’s head and thorax by computed tomography (CT) which enabled us to obtain reliable data about the tumor size. After obtaining clinical findings and CT results, the patients’ treatment was planned based on their TNM status. A postoperative histopathological examination was performed by the same pathologist and the following parameters were determined: 1. Tumor size (2 dimensions) measured by CT and expressed in cm 2. Tumor thickness measured by CT and expressed in cm 3. Tumor size (2 diameters) on microscopic device and expressed in cm 4. Tumor thickness on microscopic device measured by light microscope and expressed in cm 5. Depth of tumor invasion on microscopic device measured by light microscope and expressed in cm 6. Tumor volume calculated based on the following formula: VT=π/6 x maximum tumor diameter А x minimum tumor diameter B x depth of tumor invasion and expressed in cm³ 7. The number of metastatic lymph nodes in the neck dissection 8. Total number of pathohistologically tested lymph nodes in the neck dissection. Upon collecting the planned material, statistical analysis of all data was carried out. The statistical analysis included the methods of descriptive statistics (mean value, standard deviation, frequency) and standard parametric and nonparametric tests for comparison of two groups (Student’s T test, Whitney U test, chi-square test). The Pearson’s Test of Correlation was used in the phase of statistical analysis of interaction effects and correlation of obtained data. All tests were performed at the level of statistical significance of p<0.05. RESULTS: The study covered 65 patients, out of which 82% were male patients aged 59. 83% of patients said they smoked and 69% of patients stated that they consumed alcohol regularly. A neck dissection was performed in all patients during surgical treatment of OSCC and it was selective neck dissection (91%). Cervical regional metastasis was found in 30 patients so they were divided into two groups: the group of patients who had metastasis in the lymph nodes and the group of patients with no metastasis in lymph nodes of the neck. It was determined that there was a statistically significant difference in depth of invasion and tumor volume between these two groups. The statistically significant difference was also determined between the thickness of tumor measured by CT and thickness of tumor measured by light microscope. Moreover, the depth of invasion of tumor greater than 7mm and volume of tumor greater than 4cm³ were proven to represent a predictive factor of development of regional cervical metastasis. The study results show that there is a statistically significant correlation between the thickness of OSCC tumor measured by CT and the thickness measured by light microscope, so the thickness of tumor measured by CT can be used for planning the surgery during the treatment of OSCC. The depth of tumor invasion greater than 7 mm and tumor volume greater than 4 cm³ represent a predictive factor of development of cervical metastasis, which means that they are significant for determining the stage of disease.

Tumorsko pupljenje (TP) u karcinomu je morfološki 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 patohistološki odgovor na primenjeni hemioterapijski režim, prognostički i nezavisni negativni značaj TP , kao i korelacija TP i terapijskog odgovora histološke regresije kod R0 reseciranih sinhronih i metahronih jetrenih metastaza KRK, koji su primali polihemioterapije po protokolu Folfox 4, sa i bez VEGF inhibitora – bevacizumaba (AV).  Studija je prospektivno – retrospektivna i obuhvata 77 bolesnika oba pola, uzrasta preko 18 godina, sa patohistološki 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 histološki dokazan metastatski adenokarcinom kolorektuma sa R0 resekcijom i da su preoperativno dobijali HT sa biološkom terapijom ili bez nje. Bolesnike smo podelili u dve grupe: KRK – sinhrona metastatska bolest i KRK – metahrona metastatska bolest. Nakon selekcije bolesnika, rađena je mikroskopska analiza rutinskih histoloških i imunohistohemijskih preparata i određivana je gustina TP, histološka regresija prema mTRG bodovanju komparirala se sa radiološkim odgovorom po RECIST-u. Događaji od interesa u kliničkom toku bolesti jesu progresija nakon hirurškog zahvata jetrenih metastaza i ukupno preživljavanje u periodu od 24 meseca. Nema statistički značajne patohistološke razlike u učestalosti lošijeg terapijskog odgovora (mTRG 3 – 5) u odnosu na bolji terapijski odgovor (mTRG 1, 2) između bolesnika sa sinhronom i metahronom metastatskom bolešću 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 lošijeg histološkog odgovora na terapiju (mTRG 3 – 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, što se vidi u preživljavanju tokom dve godine.
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 – 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.

This thesis first describes theory of range of methods of textural and shape analysis. In several published articles some of the mentioned methods are used for automatic detection of lesion in spine in CT images. Some of these articles are shortly presented (in this thesis). Next part of the thesis includes description of various classifiers which are used for classification of feature vectors. Practical part of the thesis is a design and implementation of image data segmentation solution (metastatic lesions in vertebrae) with use of classification of feature vectors formed by texture and shape symptoms. The thesis also deals with the selection of significant features for segmentation. Segmentation algorithm is tested on medical data.

This diploma thesis is focused on time-development analysis of treated lesion in CT data. The theoretical part of the thesis deals with the anatomy, physiology, and pathophysiology of the spine and vertebral bodies. It further describes diagnostic and therapeutic options for the detection and treatment of spinal lesions. It contains an overview of the current state of usage of time-development analysis in oncology. The problems of the available databases are discussed and new databases are created for subsequent analysis. Futhermore, the methodology of time-development analysis according to the shape characterization and the size of the vertebral involvement is proposed. The proposed methodological approaches to feature extraction are applied to the created databases. Their choice and suitability is discussed, including their potential for possible usege in clinical practice of monitoring the development and derivation of characteristic dependences of features on the patient's prognosis.

The aim of the study is to analyse the learning process of the Dorze weaving in Ethiopia and its implications on Education for Sustainable Development, ESD. My two main questions are: 1. How do the Dorze understand their learning process in weaving? 2. What conclusions concerning education for sustainable development applied on textile handicraft can be drawn from the findings of my case study?   In order to answer these questions I have made a field study on the Dorze (the weavers) in Addis Ababa in Ethiopia for 10 weeks. The study has a socio-cultural and narrative approach and the method used are interviews, observations and review of documents. The result is presented in a “metastory” where I retell the stories and introduce the results of the study and that gives answers to question 1. UNESCO’s recommendations on ESD are used to analyse the findings and give the answer to question 2. The result shows that the learning process depends on the environment with its people, who have gathered knowledge of raw material and techniques for generations but the latter also needs to develop to meet new challenges. “Shiro Meda” is the centre of learning. To grow up in “Shiro Meda” it becomes natural to work with textile production, accept a special lifestyle with clear gender differences and a hierarchical structure. The educational model of spinning and twisting are “learning by doing”, whereas young boys start practising weaving under the leadership of an older teacher step by step.   From an ESD perspective the Dorze education is holistic, practical, individualized, and contains some problem solving even if the students are not participating in decisions on how they learn. The education is highly integrated in the daily life of the weaving community and is also relevant to the surrounding local community. Moreover the education transfers a historical legacy of cultural continuity, and has shown itself to be dynamic and adaptable to change. A weakness in this traditional knowledge system is the low profit the weavers are making and the set hierarchical and gender rules which need to be developed in order to be sustainable for future challenges. The final discussion highlights the relevance of my findings for a Swedish learning context.
2010ht4661

The aim of this work was the development of algorithms for detection segmentation and classification of difficult to define bone metastatic cancerous lesions from spinal CT image data. For this purpose, the patient database was created and annotated by medical experts. Successively, three methods were proposed and developed; the first of them is based on the reworking and combination of methods developed during the preceding project phase, the second method is a fast variant based on the fuzzy k-means cluster analysis, the third method uses modern machine learning algorithms, specifically deep learning of convolutional neural networks. Further, an approach that elaborates the results by a subsequent random forest based meta-analysis of detected lesion candidates was proposed. The achieved results were objectively evaluated and compared with results achieved by algorithms published by other authors. The evaluation was done by two objective methodologies, technical voxel-based and clinical object-based ones. The achieved results were subsequently evaluated and discussed.

UVOD: Maligni tumori reproduktivnih organa nalaze se među vodećim uzrocima obolevanja i umiranja od malignih bolesti žena, kako u svetu, tako i u Srbiji. Jedan od najvažnijih puteva širenja ovih bolesti je limfogeni, a konvencionalna radiološka dijagnostika limfnih čvorova kod ovih pacijentkinja je neprecizna. Funkcionalna radiološka dijagnostika, uključujući i magnentno rezonantnu sekvencu difuzionog kretanja (DWI) i iz nje izvedenu ADC mapu koja omogućava kvantitativnu analizu difuzionih osobina unutar limfnog čvora, daju obećavajuće rezultate u mogućnosti razlikovanja benignih od maligno izmenjenih limfnih čvorova male karlice i ingvinuma kod pacijentkinja obolelih od malignih tumora ženskih polnih organa. CILJ: Cilj studije je 1. utvrđivanje dijagnostičkih mogućnosti magnetnorezonantne sekvence difuzionog kretanja (DWI) u razlikovanju benignih od maligno izmenjenih limfnih čvorova male karlice i ingvinuma kod pacijentkinja obolelih od malignih tumora ženskih polnih organa, poređenjem preoperativno načinjenog magnetnorezonantnog pregleda i postoperativnog patohistološkog nalaza; 2. analiza povezanosti osobina metastatski izmenjenih limfnih čvorova na sekvenci difuzionog kretanja (DWI) i gradusa primarnog tumora, i 3. utvrđivanje uticaja tehničkih karakteristika sekvenci difuzinonog kretanja (DWI) na magnetnorezonantu procenu metastatske infiltracije karličnih i ingvinalnih limfnih čvorova i postoperativnog patohistološkog nalaza. MATERIJAL I METODE: Istraživanje je sprovedeno u periodu od 2013. do 2016.godine, kao prospektivna klinička studija u Centru za radiologiju, na Operativnom odeljenju Zavoda za ginekologiju, Klinike za ginekologiju i akušerstvo i u Zavodu za patologiju Kliničkog Centra Vojvodine u Novom Sadu. Studija je obuhvatila 80 pacijentkinja obolelih od malignih tumora vulve, vagine, grlića materice, tela materice i jajnika. Na osnovu lokalizacije malignog tumora sve ispitanice su razvrstane u 5 grupa: grupa A- 3 žene obolele od carcinoma vulve, grupa B- 1 žena obolela od karcinoma vagine, grupa C-32 pacijentkinje obolele od karcinoma grlića materice, grupa D- 30 pacijentkinja obolelih od malignih tumora tela materice i grupa E- 14 žena obolelih od malignih tumora jajnika. Procena stadijuma bolesti definitivno je izvršena posle operacije na osnovu histopatološkog pregleda kompletnog hirurškog materijala uključujući i pregled uklonjenih limfnih čvorova na osnovu aktuelne FIGO klasifikacije stadijuma bolesti zasebno za svaku pojedinačnu lokalizaciju malignog tumora. Svim pacijentkinjama je preoperativno načinjen magnetnorezonantni pregled male karlice na uređaju za magnetnu rezonancu 1.5 T General Electric Signa HDx u Centru za radiologiju, Kliničkog centra Vojvodine. Kod istih pacijentkinja naknadno je sprovedeno standardno hirurško lečenje po protokolu hirurškog lečenja za dato maligno ginekološko oboljenje sa karličnom i/ili ingvinalnom limfadenektomijom. Postoperativno je izvršena patohistološka analiza hirurški uklonjenog materijala i limfnih čvorova razdvojenih po anatomskim grupama u karlici i ingvinalnoj regiji. REZULTATI: Ukupno 2320 limfnih čvorova je mapirano i patohistološki pregledano kod 80 pacijenata. Metastaze u limfnim čvorovima patohistološki su verifikovane kod 28 pacijenata (35%). Kod ovih 28 (35%) pacijentkinja, 152 (27,28%) od ukupno 557 limfnih čvorova bilo je metastatski izmenjeno na patohistološkom pregledu. Metastaze u limfnim čvorovima utvrđene su kod 2 pacijentkinje (7,14%) sa karcinomom vulve, 11 (39,28%) sa karcinomom cerviksa, 9 (32,14%) sa tumorima tela materice, te 6 (21,42%) sa tumorima jajnika. Od 28 pacijentkinja kod kojih su utvrđeni pozitivni limfni čvorovi, 14 pacijentkinja (50%) imalo je dobro diferentovan primarni tumor, 8 (28,57%) srednje diferentovan, dok je 6 (21,42%) imalo loše diferentovan primarni tumor. Od ukupno 152 metastatski izmenjena limfna čvora u našoj studiji, 8 limfnih čvorova (5,26%) pripadalo je ingvinalnoj grupi od čega 5 (3,289%) površnoj ingvinalnoj, a 3 ( 1,97%) dubokoj ingvinalnoj grupi, 8 (5,26%) parametrijalnoj grupi, 48 (31,58%) opturatornoj grupi, 40 (26,31%) spoljašnjoj ilijačnoj grupi, 36 (23,684%) unutrašnjoj ilijačnoj grupi, dok je 12 (7,89%) pripadalo zajedničkoj ilijačnoj grupi karličnih limfnih čvorova. Kraći prečnik limfnog čvora nije pokazao značajnu razliku između metastatskih ( mean ± SD, 8,3 ± 5.4 mm, raspon , 4.5-30 mm ) i limfnih čvorova koji nisu bili metastatski izmenjeni ( 6,3 mm ± 1,5 , 4,5-9,6 mm ; P= 0,191 ). Izmerena ADC vrednost bila je značajno niža kod metastatski izmenjenih limfnih čvorova (mean ± SD , ADC: 0,8725 x 10-3 mm2/s ± 0,0125) nego kod limfnih čvorova koji nisu bili metastatski izmenjeni (mean ± SD, ADC: 1,116 x 10- 3 mm2/s ± 0,1848; P=0,001). Prosečne vrednosti ADC kod b =800 s/mm2 i b =1200 s/mm2 nisu se značajno razlikovale između metastaski izmenjenih limfnih čvorova (mean ± SD, ADC: 0,8575 ± 0,0125 x 10-3 mm2/s, ADC:0,8859 ± 0,0125 x 10-3 mm2/s) i limfnih čvorova koji nisu metastatski izmenjeni (mean ± SD, ADC:1,0345 ± 0,1222 x 10-3 mm2/s, ADC:1,1125 ± 1638 x 10-3 mm2/s; P =0,657 i P = 0,877). Ako se koristi vrednost ADC od 0,860 x 10- 3 mm2 / s kao kritična vrednost za razlikovanje metastatskih od limfnih čvorova koji nisu metastatski izmenjeni, senzitivnost DWI MR iznosila je 89%, specifičnost 85% i ukupna tačnost 86%. Pozitivna prediktivna vrednost (PPV) DWI MR u detekciji limfnih metastaza u karličnoj i ingvinalnoj regiji iznosila je 30%. Negativna prediktivna vrednost (NPV) testa iznosila je 99%. Pozitivna prediktivna vrednost (PPV) MR zasnovana na kriterijumu ADC vrednosti značajno je veća u odnosu na sve kriterijuma veličine (P < 0,001). Negativna prediktivna vrednost MR zasnovanoj na kriterijumima veličine limfnog čvora i na ACD vrednosti nisu se međusobno statistički značajno razlikovali (P<0,05). Performanse dijagnostičke metode (MR) bile su značajno bolje za minimalnu ADC vrednost od svih kriterijuma baziranih na veličini limfnih čvorova ( P=0.001 za minimalnu ADC vrednost u odnosu na sve druge kriterijume). MRI na osnovu definisanog modela koji kombinuje kriterijum ADC vrednosti sa kriterijumom veličine ima sledeće dijagnostičke performanse za diferencijaciju malignih od benignih limfnih čvorova: senzitivnost od 95%, specifičnost 92%, sveukupna tačnost od 92,5%, pozitivnu prediktivnu vrednost od 46% i negativnu prediktivnu vrednost od 99.6%. ZAKLJUČAK: Kriterijum veličine limfnog čvora nije dovoljno precizan pokazatelj metastatske invazije limfnih čvorova. Sekvenca difuzionog kretanja (DWI) uvek se mora analizirati zajedno sa ADC mapom i visoko rezolutivnim T1 i T2 otežanim magnetnorezonantnim sekvencama. Studijom je dokazan visok stepen povezanosti između preoperativnog određivanja metastaske infiltracije karličnih i ingvinalnih limfnih čvorova malignih tumora ženskih polnih organa primenom sekvence difuzionog kretanja (DWI) i postoperativnog patohistološkog nalaza. Uz graničnu ADC vrednost od 0,860 x 10-3 mm2/ s, senzitivnost MRI DWI u otkrivanju metastatskih limfnih čvorova iznosi 89%, a specifičnost 85%. Kombinacija ADC vrednosti i morfoloških karakteristika limfnih čvorova konvencionalnim magnentno rezonantnim pregledom je najprecizniji prediktor postojanja metastatske infiltracije karličnih i ingvinalnih limfnih čvorova kod pacijentkinja sa malignim tumorima ženskih polnih organa. Tehničke karakteristike sekvenci difuzionog kretanja (DWI) u smislu razlike u visokim b vrednostima ne utiču na magnentno rezonantnu procenu metastatske infiltracije karličnih i ingvinalnih limfnih čvorova kod pacijentkinja sa malignim tumorima ženskih polnih organa. Studijom nije utvrđena statistički značajna razlika između preoperativno utvrđenih ADC vrednosti metastatski izmenjenih limfnih čvorova i stepena histološke diferencijacije ovih tumora. Sekvenca difuzionog kretanja (DWI) je brza, jednostavna, neinvazivna metoda koja značajno doprinosi dijagnostičkim mogućnostima magnetne rezonance u razlikovanju benignih od malignih limfnih čvorova male karlice i ingvinuma.
INTRODUCTION: Malignant tumors of reproductive organs are among the leading causes of morbidity and mortality in women, both in Serbia and worldwide. Lymphatic spread is one of the most important pathways of tumor dissemination. However, conventional lymph node imaging in these patients is imprecise. Functional imaging, including diffusion-weighted magnetic resonance imaging (DWI MRI) and derived ADC map which allows quantitative analysis of diffusion parameters within a lymph node, provide promising results in discrimination benign from malignant pelvic and inguinal lymph nodes in patients with gynecological malignancies. AIM: Aim of the study was: 1. To assess diagnostic performances of DWI MRI in differentiation between benign and malignant pelvic and inguinal lymph nodes in patients with gynecological malignancies, by comparison of preoperative magnetic resonance and postoperative histopathological findings. 2. To analyze correlation between DWI characteristics of metastatic lymph nodes and grade of the primary tumor, and 3. To evaluate the influence of technical characteristics of DWI sequences on MR assessment of metastatic pelvic and inguinal lymph node and postoperative histopathological findings. MATERIAL and METHODS: The prospective clinical study was conducted in Center for Radiology, Surgery Department of Clinic for Gynecology and Obstetrics and Pathology Department of Clinical Center of Vojvodina from 2013 to 2016. It comprised 80 patients with malignant tumors of vulva, vagina, uterine cervix and body and ovaries. Based on the localization of the tumor, all patients were divided into 5 groups: group A-3 patients with vulvar cancer, group B- 1 patient with vaginal cancer, group C- 32 patients with cervical cancer, group D- 30 patients with uterine body tumors and group E- 14 patients with malignant ovarian tumors. Staging of the disease was performed after surgery based on histopathological examination of complete surgical specimen, including examination of removed lymph nodes, based on current FIGO classification separately for each primary tumor location. Preoperatively, all patients underwent MRI examination (1.5 T General Electric Signa HDx) at Center for Radiology, Clinical Center of Vojvodina. The same patients underwent standard surgical treatment according to the treatment protocol regarding the tumor type and stage, with complete pelvic and/or inguinal lymphadenectomy. Histopathological examination of surgically removed material and lymph nodes separated in pelvic and inguinal anatomic groups was performed after the surgery. RESULTS: The total of 2320 of lymph nodes were mapped and histopathologically examined in 80 patients included in the study. Metastases in lymph nodes were histopathologically confirmed in 28 patients (35%). In these 28(35%) patients, in 152 (27,28%) out of 557 lymph nodes histopathological examination confirmed metastases. Lymph node metastases were confirmed in 2 patients (7.14%) with vulvar cancer, 11 (39.28%) with cervical cancer, 9 (32.14%) with uterine body tumors and 6 (21.42%)patients with ovarian tumors. In 28 patients with positive lymph nodes, 14 patients (50%) had well differentiated primary tumor, 8 (28.57%) moderately differentiated, while 6 (21.42%) patients had poorly differentiated primary tumor. Out of 152 metastatic lymph nodes in our study, 8 lymph nodes (5.26%) were inguinal ( 5 (3.289%) superficial inguinal and 3 ( 1.97%) deep inguinal group), 8 (5.26%) were parametrial, 48 (31. 58%) obturatory, 40 (26.31%) external iliac, 36 (23.684%) internal iliac, while 12 (7. 89%) belonged to common iliac pelvic lymph nodes group. Shorter lymph node axis did not show significant difference between metastatic ( mean ± SD, 8.3 ± 5.4 mm, range , 4.5-30 mm ) and benign lymph nodes ( 6.3 mm ± 1.5 , 4.5-9.6 mm ; P= 0.191 ). Measured ADC values were significantly lower in metastatic (mean ± SD , ADC: 0.8725 x 10-3 mm2/s ± 0.0125) than benign lymph nodes (mean ± SD, ADC: 1.116 x 10-3 mm2/s ± 0.1848; P=0.001). Mean ADC values at b =800 s/mm2 and b =1200 s/mm2 did not differ significantly between metastatic (mean ± SD, ADC: 0.8575 ± 0.0125 x 10-3 mm2/s, ADC:0.8859 ± 0,0125 x 10-3 mm2/s) and benign lymph nodes (mean ± SD, ADC:1.0345 ± 0.1222 x 10-3 mm2/s, ADC:1.1125 ± 1638 x 10-3 mm2/s; P =0.657 i P = 0.877). If ADC value of 0.860 x 10- 3 mm2 / s is determined as a cut off value for discrimination of benign and malignant lymph nodes, DWI MRI sensitivity was 89%, specificity 85% and overall accuracy was 86%. Positive predictive value (PPV) of DWI MR in detection of pelvic and inguinal lymph node metastases was 30%. Negative predictive value (NPV) of the test was 99%. MRI PPV based on ADC value criteria was significantly higher compared to all size-based criteria (P < 0,001). MRI NPV based on size based and ADC values criteria did not differ significantly (P<0,05). Performances of diagnostic method (MRI) were significantly better for minimal ADC value compared to all lymph node size-based criteria ( P=0.001 for minimal ADC value compared to all other criteria). Combination of ADC value criteria and size-based criteria yields MRI the following diagnostic performances in discrimination between benign and malignant lymph nodes: sensitivity 95%, specificity 92%, overall accuracy 92.5%, positive predictive value 46% and negative predictive value 99.6%. CONCLUSION: Lymph node size is not sufficiently precise criteria for determination of metastatic lymph node involvement. DWI sequence always needs to be evaluated together with ADC map and high resolution T1W and T2W magnetic resonance sequences. The study shows high correlation between preoperative assessment of pelvic and inguinal lymph node metastases from gynecological malignancies using MRI DWI and postoperative histopathological findings. With a cut off ADC value of 0.860 x 10-3 mm2/ s, sensitivity of MRI DWI in metastatic lymph node detection is 89%, while specificity is 85%. Combination of ADC values and morphological lymph nodes characteristics assessed by conventional MRI is the most precise predictor of metastatic pelvic and inguinal lymph node invasion in patients with gynecological malignancies. Technical characteristics of DWI i.e. different high b-values do not influence MR assessment of metastatic pelvic and inguinal lymph node involvement in patients with gynecological malignancies. The study did not confirm statistically significant difference between preoperatively measured ADC valued of metastatic lymph nodes and histological grade of primary tumors. DWI MRI sequence is fast, simple, noninvasive method which aids significantly to MRI diagnostic performances in discrimination between benign and malignant pelvic and inguinal lymph nodes.

Fúze obrazu je dnes jednou z nejběžnějších avšak stále velmi diskutovanou oblastí v lékařském zobrazování a hraje důležitou roli ve všech oblastech lékařské péče jako je diagnóza, léčba a chirurgie. V této dizertační práci jsou představeny tři projekty, které jsou velmi úzce spojeny s oblastí fúze medicínských dat. První projekt pojednává o 3D CT subtrakční angiografii dolních končetin. V práci je využito kombinace kontrastních a nekontrastních dat pro získání kompletního cévního stromu. Druhý projekt se zabývá fúzí DTI a T1 váhovaných MRI dat mozku. Cílem tohoto projektu je zkombinovat stukturální a funkční informace, které umožňují zlepšit znalosti konektivity v mozkové tkáni. Třetí projekt se zabývá metastázemi v CT časových datech páteře. Tento projekt je zaměřen na studium vývoje metastáz uvnitř obratlů ve fúzované časové řadě snímků. Tato dizertační práce představuje novou metodologii pro klasifikaci těchto metastáz. Všechny projekty zmíněné v této dizertační práci byly řešeny v rámci pracovní skupiny zabývající se analýzou lékařských dat, kterou vedl pan Prof. Jiří Jan. Tato dizertační práce obsahuje registrační část prvního a klasifikační část třetího projektu. Druhý projekt je představen kompletně. Další část prvního a třetího projektu, obsahující specifické předzpracování dat, jsou obsaženy v disertační práci mého kolegy Ing. Romana Petera.

UVOD: Glavni problem u lečenju karcinoma dojke je kako na osnovu kliničke klasifikacije i morfoloških osobina tumora predvideti njegovo dalje ponašanje. Vrlo često ni kombinacija standardnih prognostičkih faktora ne daje odgovor o potrebi davanja adjuvantne hemioterapije. U cilju sprovođenja adekvatne dalje terapije karcinoma dojke i otkrivanja agresivnih tipova tumora, a nakon hirurškog lečenja, postoji stalna potreba za pronalaženjem novih pokazatelja pomoću kojih bi se identifikovale bolesnice koje imaju povećan rizik od razvoja relapsa bolesti. CILJEVI: Ciljevi su bili da se utvrdi prisustvo, lokalizacija i distribucija tumor infiltrišućih limfocita, kako ukupnih, tako i CD4+ i CD8+ T limfocita u tumoru dojke, njihova povezanost sa standardnim prognostičkim parametrima, kao i njihov prognostički značaj tj. razlike u nivou infiltracije limfocita u tumoru u odnosu na pojavu relapsa bolesti i dužinu preživljavanja. METOD: Istraživanjem je obuhvaćeno 120 bolesnica sa invazivnim duktalnim karcinomom, sa tumorom lokalizovanim samo u dojci, bez zahvatanja kože i grudnog mišića, sa veličinom tumora do 5 cm, bez udaljenih visceralnih i koštanih metastaza, koje su operisane u Institutu za onkologiju Vojvodine. U istraživanje su uključene bolesnice bez metastaza u limfnim čvorovima pazušne jame i bolesnice sa metastazama u limfnim čvorovima pazušne jame. Istraživanjem nisu obuhvaćene bolesnice koje su primale neoadjuvantnu (preoperativnu) hemioterapiju, kao ni bolesnice sa multifokalnim i multicentričnim tumorima. REZULTATI: Gust limfocitni infiltrat uočen je u 14% tumora dojke, umeren limfocitni infiltrat uočen je u 38%, a oskudan u 43% tumora dojke. Limfocitni infiltrat nije uočen u 5% tumora. Gust infiltrat CD4+ limfocita uočen je u 8% tumora dojke, umeren u 44%, a oskudan u 43% tumora dojke. CD4+ limfociti nisu uočeni u 5% tumora. Gust infiltrat CD8+ limfocita uočen je u 1% tumora dojke, umeren u 23%, a oskudan u 66% tumora dojke. CD8+ limfociti nisu uočeni u 10% tumora. Utvrđena je pozitivna povezanost između nivoa TIL-a i CD4+ limfocita i veličine tumora, histološkog stepena diferentovanosti tumora, prisustva metastaza u limfnim čvorovima pazušne jame, HER-2 statusa, tripl negativnog tumora i relapsa bolesti. Utvrđena je negativna povezanost između nivoa TIL-a i CD4+ limfocita i estrogen i progesteron receptora, kao i godina starosti. Utvrđena je pozitivna povezanost između nivoa CD8+ limfocita i histološkog gradusa tumora, kao i HER-2 statusa. Utvrđena je negativna povezanost između nivoa CD8+ limfocita i estrogen i progesteron receptora, kao i godina starosti. ZAKLJUČAK:Rezultati ovog istraživanja pokazuju povezanost tumor infiltrišućih limfocita i CD4+ limfocita sa brojnim negativnim prognostičkim faktorima, te kraćim vremenom slobodnog intervala bez bolesti, što sve ukazuje na to da su tumor infiltrišući limfociti kao i CD4+ limfociti loš prognostički faktor kod bolesnica sa rakom dojke.
INTRODUCTION: The main problem in the treatment of breast cancer that based on clinical classification and morphological characteristics of the tumor to predict its future behavior. Very often, not a combination of standard prognostic factors does not answer the need of giving adjuvant chemotherapy. In order to implement adequate further treatment of breast cancer and detection aggressive types of tumor, after surgical treatment, there is a constant need to find new indicators by which we can identify patients who have an increased risk of relapse. OBJECTIVES: The objectives were to determine the presence, localization and distribution of tumor infiltrating lymphocytes, in total, as well as CD4+ and CD8+ T lymphocytes in breast cancer, their correlation with standard prognostic parameters, as well as their prognostic value i.e. differences in the level of infiltration of lymphocytes in a tumor in relation to the occurrence of disease relapse and survival. METHOD: The study included 120 patients with invasive ductal carcinoma, tumor localized only in the breast without involvement of the skin and pectoral muscle, the size of tumors up to 5 cm without distant visceral and bone metastases, which are operated at the Institute of Oncology. The study included patients without metastases in axillary lymph nodes and patients with metastases in axillary lymph nodes. The research not covered by patients receiving neoadjuvant chemotherapy, or patients with multifocal and multicentric tumors. RESULTS: The high amount of lymphocytic infiltrate was observed in the 14% a breast tumor, a moderate amount of lymphocytic infiltrate was observed in 38%, and the low in 43% breast tumors. Lymphocytic infiltrate was not observed in 5% of the tumor. High CD4+ lymphocyte infiltration was observed in 8% of breast, moderate in 44%, and the low in 43% of breast tumors. CD4+ lymphocytes were not observed in 5% tumors. High infiltration of CD8+ lymphocytes was observed in 1% of breast, moderate in 23%, and the low 66% breast tumors. CD8+ lymphocytes have not been observed in 10% tumors. There is a positive correlation between the level of TIL and CD4+ lymphocytes and tumor size, histological grade of tumor differentiation, presence of metastases in axillary lymph nodes, HER-2 status, triple negative tumors and relapses of disease. There was a negative correlation between the level of TIL and CD4+ cell counts and estrogen and progesterone receptors, as well as age. There is a positive correlation between the level of CD8+ cells and histological grade of the tumor, and HER-2 status. There was a negative correlation between the level of CD8+ lymphocytes and estrogen and progesterone receptors, as well as age. CONCLUSION: The results of this study demonstrate the association between tumor infiltrating lymphocytes and CD4+ lymphocytes with a number of negative prognostic factors, and shorter free interval without the disease, all of which indicates that the tumor infiltrating lymphocytes and CD4+ lymphocytes bad prognostic factor in patients with breast cancer.

HER2 Gene-Protein Assay (GPA) је посебно погодан за истовремено процењивање експресије HER2 протеина и статуса амплификације HER2 гена на нивоу појединачних ћелија и њихово повезивање са ћелијском морфологијом. Циљ истраживања био је испитати да ли су постојећи критеријуми препоручени од стране ASCO/CAP довољни за дијагностиковање HER2 позитивности код пацијенткиња које показују интратуморску хетерогеност, како у примарним туморима тако и у метастазама у регионалне лимфне чворове, учесталост HER2 хетерогености у макрометастазама лоцираним у лимфним чворовима, те да ли постоји јасна корелација између хетерогености нађене у примарном тумору дојке и припадајућим метастазама у лимфним чворовима. Испитивање је обухватило 41 од планиране 51 пацијенткиње које су испуниле све критеријуме укључивања. Репрезентативни парафински блокови метастатских лимфних чворова одабрани су из архивираног материјала, обојени GPA методом и процењени у складу са критеријумима ASCO/CAP 2013. Анализирано је 120 ћелија у хистолошком резу сваког метастатског лимфног чвора. Статус HER2 се разликовао између примарног тумора и његових метастаза у 13,2% (5/38) случајева. Један случај HER2 позитивног примарног тумора имао је HER2 негативне метастазе, два додатна случаја са HER2 позитивним примарним тумором су имала метастазе са статусом граничне амплификације без прекомерне експресије HER2 протеина и два случаја са HER2 негативним примарним тумором су имала метастазе са статусом граничне амплификације без прекомерне експресије HER2 протеина. У 17.4% (4/23) случајева са HER2 не-амплификованим примарним тумором метастазе су постале граничне у статусу генске амплификације. Једна од четири метастазе HER2 негативног примарног тумора показала је мали фокус HER2 позитивних туморских ћелија (<3% тумора). Микрохетерогеност је анализирана у 108 лимфних чворова код 38 пацијенткиња и уочена у 22 лимфна чвора, тј. код четири пацијенткиње у свим анализираним лимфним чворовима, док је код једне пацијенткиње од 4 анализирана лимфна чвора микрохетерогеност потврђена у једном лимфном чвору. На основу добијених резултата може се закључити да постојећи критеријуми препоручени од стране ASCO/CAP применом прихваћених метода нису довољни за дијагностиковање HER2 позитивности код пацијенткиња које показују интратуморску и интертуморску хетерогеност како у примарним туморима тако и у метастазама, те да постоји статистички високо сигнификантан број макрометастаза лоцираних у лимфним чворовима које показују HER2 хетерогеност и позитивна корелација између хетерогености нађене у примарним туморима и припадајућим метастазама у лимфним чворовима.
HER2 Gene-Protein Assay (GPA) je posebno pogodan za istovremeno procenjivanje ekspresije HER2 proteina i statusa amplifikacije HER2 gena na nivou pojedinačnih ćelija i njihovo povezivanje sa ćelijskom morfologijom. Cilj istraživanja bio je ispitati da li su postojeći kriterijumi preporučeni od strane ASCO/CAP dovoljni za dijagnostikovanje HER2 pozitivnosti kod pacijentkinja koje pokazuju intratumorsku heterogenost, kako u primarnim tumorima tako i u metastazama u regionalne limfne čvorove, učestalost HER2 heterogenosti u makrometastazama lociranim u limfnim čvorovima, te da li postoji jasna korelacija između heterogenosti nađene u primarnom tumoru dojke i pripadajućim metastazama u limfnim čvorovima. Ispitivanje je obuhvatilo 41 od planirane 51 pacijentkinje koje su ispunile sve kriterijume uključivanja. Reprezentativni parafinski blokovi metastatskih limfnih čvorova odabrani su iz arhiviranog materijala, obojeni GPA metodom i procenjeni u skladu sa kriterijumima ASCO/CAP 2013. Analizirano je 120 ćelija u histološkom rezu svakog metastatskog limfnog čvora. Status HER2 se razlikovao između primarnog tumora i njegovih metastaza u 13,2% (5/38) slučajeva. Jedan slučaj HER2 pozitivnog primarnog tumora imao je HER2 negativne metastaze, dva dodatna slučaja sa HER2 pozitivnim primarnim tumorom su imala metastaze sa statusom granične amplifikacije bez prekomerne ekspresije HER2 proteina i dva slučaja sa HER2 negativnim primarnim tumorom su imala metastaze sa statusom granične amplifikacije bez prekomerne ekspresije HER2 proteina. U 17.4% (4/23) slučajeva sa HER2 ne-amplifikovanim primarnim tumorom metastaze su postale granične u statusu genske amplifikacije. Jedna od četiri metastaze HER2 negativnog primarnog tumora pokazala je mali fokus HER2 pozitivnih tumorskih ćelija (<3% tumora). Mikroheterogenost je analizirana u 108 limfnih čvorova kod 38 pacijentkinja i uočena u 22 limfna čvora, tj. kod četiri pacijentkinje u svim analiziranim limfnim čvorovima, dok je kod jedne pacijentkinje od 4 analizirana limfna čvora mikroheterogenost potvrđena u jednom limfnom čvoru. Na osnovu dobijenih rezultata može se zaključiti da postojeći kriterijumi preporučeni od strane ASCO/CAP primenom prihvaćenih metoda nisu dovoljni za dijagnostikovanje HER2 pozitivnosti kod pacijentkinja koje pokazuju intratumorsku i intertumorsku heterogenost kako u primarnim tumorima tako i u metastazama, te da postoji statistički visoko signifikantan broj makrometastaza lociranih u limfnim čvorovima koje pokazuju HER2 heterogenost i pozitivna korelacija između heterogenosti nađene u primarnim tumorima i pripadajućim metastazama u limfnim čvorovima.
HER2 Gene Protein Assay (GPA) is particularly convenient to simultaneously assess the expression of HER2 protein and the amplification status of the HER2 gene at individual cell level and to correlate them with cellular morphology. The aim of the study was to examine whether the existing criteria recommended by ASCO / CAP are sufficient for diagnosing HER2 positivity in patients showing intratumoral heterogeneity, both in primary tumors and in metastases in regional lymph nodes, the frequency of HER2 heterogeneity in macrometastases located in the lymph nodes, and whether there is a clear correlation between the heterogeneity found in the primary tumor of the breast and the associated metastases in the lymph nodes. The study included 41 of the planned 51 female patients which fulfilling all the inclusion criteria. Representative paraffin blocks of metastatic lymph nodes were selected from archived material, stained with the GPA and assessed in accordance with the ASCO/CAP 2013 criteria. We analyzed 120 cells per section of each metastatic lymph node. The HER2 status differed between the primary tumor and its metastases in 13.2% (5/38) of the cases. A single case of HER2 positive primary tumor had HER2 negative metastases, two additional cases with HER2 positive primary tumor had metastases with equivocal amplification status without protein overexpression and two cases with HER2 negative primary tumors had metastases with equivocal amplification status without protein overexpression. The HER2 status of the lymph node metastases within the same patient having at least two metastatic nodes showed only subtle variations. In 17.4% (4/23) of the cases with HER2 non-amplified primary tumor the metastases became equivocal in gene-amplification status. One out of the four metastases of a HER2 negative primary tumor showed a small focus of HER2 positive tumor cells (<3% of the tumor). Microheterogeneity was analyzed in 108 lymph nodes in 38 patients and observed in 22 lymph nodes, i.e. in four patients in all analyzed lymph nodes, while in one patient of 4 lymph node analyzed, microheterogeneity was confirmed in one lymph node. Based on the obtained results, it can be concluded that the existing criteria recommended by ASCO / CAP using the accepted methods are not sufficient to diagnose HER2 positivity in patients showing intratumoral and intertumoral heterogeneity both in primary tumors and in metastases, and that there is statistically significant number of macrometases located in the lymph nodes showing HER2 heterogeneity and a positive correlation between the heterogeneity found in primary tumors and associated metastases in the lymph nodes.

The aim of this thesis was to study the possibilities of influencing the metastasizing processes by means of proenzyme therapy. We accented the role of primary tumor excision. In the second part of the thesis we carried out our first screening experiments in the new area of cancer treatment based on tumour coupled PAMPs.

The CyberKnife is a device for frameless whole-body radiosurgery using image guided robotic technology and linear accelerator as a photon source. It was introduced in USA in 2001. First CyberKnife device in eastern ad middle Europe was installed in Faculty hospital Ostrava in 2010. So we were given a chance do use the most recent technology in treating oncological patients. Brain metastases are an important and frequently treated indication in modern radiosurgery. This non-invasive method offers good local control with minimum toxicity and repeability of the treatment. Biological aspect and dose delivery is equivalent to devices using framed stereotaxis and cobalt as radiation source (Gamma Knife). The difference is in technological performance. The ability of fraccionated therapy with CyberKnife enables radiotherapy of larger tumours. Patients treated with CyberKnife for metastatic brain disease are checked with repeated magnetic resonance imaging (MRI) to to figure out the growth of treated tumours and/or apperance of new lesions. In our prospective study we measure the volume of brain metastases on MRI with use of computer -assisted volumetry. We evaluate the predictive value of volumetric changes on MRI exams 6 weeks and 12 weeks post radiosurgery respectively. The aim was to identify high-risk...

Relevance of tumor infiltrating lymphocytes as a prognostic factors in patients with portal vein embolisation (PVE) and patients with PVE and administration of autologous stem cells Background: low future liver remnant volume (FLRV) is the cause of why 75% of patients with colorectal liver metastases (CLM) are primarily inoperable. Portal vein embolisation (PVE) helps to increase FLRV and so increase the operability. But PVE fails in almost 40 % of patients. Usage of stem cells (SCs) could be the way how to support the effect of PVE. Currently, there are studies of interactions of the immune system and malignancies. We do not know about papers focused on relations of the immune system and CLM in patients treated by PVE. There were not described interactions of ABC transporters and CLM at patients after PVE was performed too. Aims: the aim of this dissertation was to verify the effect of PVE and intraportal administration of SCs on the growth of FLRV and progression of the CLM. Other aims were to evaluate the tumor infiltrating lymphocytes, ABCC10 and ABCC11 transportes in patients treated by surgery for CLM after PVE and their clinical relevances. Methods: intraportal administration of SCs after PVE and their effect was explored in a group of 63 patients (43 patients with PVE alone, 20 in the group PVE with...

Tese de mestrado integrado em Medicina, apresentado á Faculdade de Medicina da Universidade de Coimbra
Introdução: O cancro da mama é, a nível mundial, o cancro mais comum na mulher e a segunda principal causa de morte por cancro, apresentando incidência crescente. Os marcadores tumorais, por apresentarem baixa sensibilidade e especificidade, têm aplicação clínica limitada. Raramente usados para rastreio ou diagnóstico precoce, a sua principal aplicabilidade é avaliar a resposta após a terapêutica, através de medições seriadas. No entanto, o doseamento de CA 15.3, marcador de eleição no cancro da mama, não é universalmente incluído no seguimento de doentes com cancro da mama. Objectivos: Evidenciar se existe alguma correlação entre determinado perfil imunohistoquímico de cancro da mama (expressão de receptores de estrogéneos e progesterona ou HER-2) e aumento do marcador tumoral aquando do desenvolvimento de metástases, bem como da evolução dos valores de CA 15.3, nesse período de metastização. Foi, ainda, correlacionado o local de metastização com o valor e a evolução do doseamento do marcador tumoral. Métodos: Foi feita análise retrospectiva de processos clínicos de doentes com cancro da mama acompanhadas no Serviço de Ginecologia dos Hospitais da Universidade de Coimbra, sendo incluídos os que apresentassem caracterização imunohistoquímica (IHQ) completa para os 2 receptores hormonais e HER-2, desenvolvimento de metástases e determinações seriadas de CA 15.3 no período de metastização. Resultados: O CA 15.3 positivou em 64,7% das doentes aquando da metastização, apresentando maior sensibilidade nos tumores com receptores hormonais negativos e HER-2 positivo. A relação entre cada perfil imunohistoquímico e os valores de CA 15.3 não foi estatisticamente significativa. Relativamente ao local das metástases, o CA 15.3 mostrou maior sensibilidade para detecção de metástases cerebrais (100%), ósseas (72,2%) e recorrências locorregionais (66,7%). A correlação entre local de metastização e a evolução do CA 15.3 não foi significativa. Conclusões: Não houve nenhum perfil IHQ específico que se correlacionasse com o aumento e evolução do CA 15.3. O CA 15.3 tem sensibilidade de detecção de metástases variável com a sua localização.
Introduction: Breast cancer is worldwide the most common cancer in women with increasing incidence and second leading cause of cancer death. Tumor markers have limited clinical application because they have low sensitivity and specificity. Rarely used for screening or early diagnosis, its main application is to evaluate the tumor, especially after therapy by serial measurements. However, the determination of CA 15.3, tumor marker of choice in breast cancer, is not universally included in the follow-up of patients with breast cancer. Objectives: To reveal if there is any correlation between specific immunohistochemical profile of breast cancer (expression of estrogen, progesterone and HER-2 receptors) and increased tumor marker during the development of metastases, as well as changes in its in this period. The authors also analyzed if the site of metastases is correlated with the value and amount of the tumor marker assay. Methods: We performed a retrospective analysis of clinical files of patients with breast cancer followed at the Department of Gynecology of the University Hospitals of Coimbra, and included those that presented a complete immunohistochemical characterization for hormone and HER-2 receptors , development of metastases and serial determinations of CA 15.3 during metastization. Results: CA 15.3 was positive in 64.7% of patients when metastized, showing greater sensitivity (72.7%) in hormone receptor-negative tumors and HER-2 positive. The relationship between each immunohistochemical profile and the values of CA 15.3 were not statistically significant. Regarding the site of metastases, the CA 15.3 showed a higher sensitivity for detecting bone metastases (72.2%) and locoregional recurrences (66.7%). The correlation between site of metastasis and the elevation of CA 15.3 was not significant. Conclusions: There was no correlation between the immunohistochemical profile and the increase of CA 15.3, neither with its changes. The sensitivity of CA 15.3 to detect metastases varies with their location.

In current days, examination of circulating tumor DNA (ctDNA) finds new use across different cancers. It is directed at tumor-derived short fragments of DNA present in peripheral blood of patiens (mainly in advanced stages). Due to its minimal invasivity, almost 100 % specificity and relatively high sensitivity in stage IV patients, this approch found its main potential clinical utility especially in early detection of disease relapse or progression after tumor resection (i.e. post-operative follow-up), prediction and monitoring of therapy response and estimation of prognosis. As a result of minute levels of ctDNA on a high background of other non-tumor DNA fragments present in plasma, a suitable method exhibiting highest sensitivity is the key for proper detection of this marker. The approach is predominantly based on initial identification of a mutation in tumor tissue and its subsequent detection in plasma. The present work is aimed at optimization of ctDNA isolation and method of its detection based on PCR amplification followed by heteroduplex analysis by denaturing capillary electrophoresis (DCE) to achieve highest sensitivity for detection of mutated fraction in plasma sample. I have applied the optimized protocol to examine ctDNA in three types of cancers, namely colorectal cancer (122...

Study of metastatic processes and response to chemotherapy in primary cultures obtained from colorectal carcinoma and lymph node metastases Colorectal carcinoma is one of the most common malignant diseases in the Czech Republic. Despite an implementation of primary population screening to detect premalignant lesions, the incidence and the mortality of the disease do not appear to decrease significantly. A significant percentage of patients still manifest with late (metastatic) stage of the disease. Isolation of primary cell cultures of colorectal carcinoma is a method in which a large number of tumour cells is obtained relatively rapidly under "in vitro" conditions. With a low number of passages the cells can retain most of the characteristics of the original cells "in vivo". Therefore, cell cultures are an ideal model for studying the efficacy of chemotherapeutics and chemoresistance, as well as markers involved in carcinogenesis and metastasis of colorectal carcinoma. Overall, samples from 60 patients with colon adenocarcinoma were obtained. Our intention was to take one sample from the primary tumour and another sample from the lymph node from each patient. From the primary tumours we successfully obtained 26 primocultures with a success rate of 45 % (26/58); from the collected lymph nodes we...

Title Complex preoperative brain tumor imaging Abstract The differentiation of glioblastoma, metastases and brain lymphoma using modern diagnostic imaging methods has a major impact on the strategy of further diagnostic examinations and treatment. In a group of 67 patients with glioblastoma and 31 with cerebral metastasis, the ability to differentiate them according to the evaluation of perfusion parameters changes in peritumoral white matter by T1 dynamic post-contrast magnetic resonance imaging was verified, with the positive predictive value in glioblastoma detection up to 91%. In a group of 36 brain lymphoma patients the importance of imaging submodalities and contribution of a complex magnetic resonance imaging protocol to detect lymphoma up to 80% were evaluated. Key words brain, glioblastoma, lymphoma, magnetic resonance imaging, neoplasm metastasis

Metastasizing is responsible for 90% of death in cancer patients. Metastatic tumour cells have several strategies that they use to invade surrounding tissues - they can migrate together or individually. When individual cells migrate, tumour cells adopt two different morphologies. They are either elongated and migrate using the proteolytically active mesenchymal mode, or they are rounded and migrate in the amoeboid mode. Metastatic tumour cells can switch between these modes, which complicates the development of effective migrastatics. In this work, we focused on the effect of inflammatory signalling on metastatic cell migration. We worked with cell lines of malignant human melanoma, which adopt a mixed morphology and show both amoeboid and mesenchymal phenotype during migration. Upon stimulation of melanoma human cells with interferon beta, a mesenchymal to amoeboid transition occurs. Interferon beta appears to induce amoeboid morphology by maintaining high levels of the ISGF3 complex, which is composed of the heterodimer of STAT 1 and STAT 2 proteins and the IRF9 protein. Upon blocking of Jak / Stat signalling pathway by negative regulators, human melanoma cells return to mesenchymal morphology. Key words - invasiveness, mesenchymal-ameboid transition, interferons, inflammation, migration, metastases

Fibroblasts are the principal cellular component of the connective tissue. They are a heterogeneous group of cells which contribute to the structure of connective tissue and wound healing by their ability to produce extracellular matrix (ECM). Fibroblasts and cells derived from them are involved in many pathological processes such as formation of malignant tumors and fibrosis. Tumor progression which finally leads to metastasis is a serious biomedical problem. There is a growing body of the recent evidence showing an important role of the tumor stroma and its interaction with cancer cells in cancer progression. Tumor stroma comprises mainly of myofibroblasts and their products, namely ECM, soluble factors, and enzymes. Myofibroblasts contribute more or less to all steps of cancer progression. Furthermore myofibroblasts play a key role in fibrosis, another serious human disease which is not efficiently treatable and which is associated with cancer progression. These facts made us to search for molecular means capable of eliminating the myofibroblastic phenotype. We succeeded to entirely dedifferentiate primary myofibroblasts by concomitant inhibition of TGFβ signaling and perturbation of MAPK signaling in a chick model that we have introduced. Malignant fibroblasts form sarcomas. ECM is the first...

The chorioallantoic membrane (CAM) of chicken embryos belongs to the in vivo model systems frequently used for the study of angiogenesis and cell invasiveness. Using CAM assay we have tested selected chicken sarcoma cell lines characterized by different angiogenic properties and different ability to form metastasis. In addition to CAM assay, several other methods have been used to characterize the phenotype of these cell lines. We have selected a few proteins which could significantly influence the angiogenic and metastatic properties of investigated cell lines. We have established cell lines stably overexpressing these genes and compared their phenotypes with parental cell lines. We have shown that genes encoding ISL1, ARNT2, PROM1, HOXA11 proteins participate, in our experimental model, in activation of programes controlling angiogenesis and cell invasion.

The regulation of transcription of tens of thousands of genes in a vertebrate organism is an enormously complex phenomenon which entails the participation of thousands of various regulatory proteins. The largest functional category of these regulators is accounted for by sequence-specific DNA-binding proteins known as transcription factors. Proteins of the EGR and Myb families of transcription factors are long-studied regulators of a variety of physiological processes including cellular proliferation and differentiation. The structural and physical aspects of their function have been well characterized. Their cell-type specific participation in complex gene-regulatory networks, on the other hand, is still incompletely understood and represents a major challenge in the respective research areas. Preliminary analysis of gene expression data from metastasizing PR9692 and non- metastasizing PR9692-E9 chicken sarcoma cell lines revealed that the transcription factor EGR1 is expressed at a higher level in metastasizing cells and can thus take part in the regulatory processes that underlie the differences between the two cell lines. Further investigation demonstrated that the introduction of exogenous EGR1 into PR9692-E9 cells restored their metastatic potential to a level indistinguishable from PR9692...

Metastasis is the main cause of death from solid cancer. The dissemination of cancer cells from a primary tumour is a very complex process that involves many steps and cells must overcome many obstacles to colonize distant organs. The tumour microenvironment influences the mode and the dynamics of invasion of cancer cells. Cancer cells have the ability to adapt to distinct environmental conditions in order to stay motile. Invasive cancer cells form membrane protrusions called invadopodia that are able to degrade extracellular matrix. The formation of invadopodia by cancer cells is interconnected to the production of matrix metalloproteases (MMPs). Metastasizing tumour cells use MMPs to break through extracellular matrix barriers and migrate in dense matrix. Both invadopodia formation and MMPs secretion is crucial for the degradation of the extracellular matrix. The most important is the membrane bound MMP-14 (MT1-MMP) and soluble MMP-2 and MMP-9. The invasive structures of tumour cells and the proteolytic enzymes in 2D environment is well described. However, a suitable model of localization and transport of MMPs and connection with invadopodia of tumour cells in 3D environment is still lacking. This diploma thesis focused on the extension of current knowledge of these key MMPs and on the...