In this thesis the two disciplines of Statistics and Artificial Neural Networks are combined into an integrated study of a data set of a weather modification Experiment. An extensive literature study on artificial neural network methodology has revealed the strongly interdisciplinary nature of the research and the applications in this field. An artificial neural networks are becoming increasingly popular with data analysts, statisticians are becoming more involved in the field. A recursive algoritlun is developed to optimize the number of hidden nodes in a feedforward artificial neural network to demonstrate how existing statistical techniques such as nonlinear regression and the likelihood-ratio test can be applied in innovative ways to develop and refine neural network methodology. This pruning algorithm is an original contribution to the field of artificial neural network methodology that simplifies the process of architecture selection, thereby reducing the number of training sessions that is needed to find a model that fits the data adequately. [n addition, a statistical model to classify weather modification data is developed using both a feedforward multilayer perceptron artificial neural network and a discriminant analysis. The two models are compared and the effectiveness of applying an artificial neural network model to a relatively small data set assessed. The formulation of the problem, the approach that has been followed to solve it and the novel modelling application all combine to make an original contribution to the interdisciplinary fields of Statistics and Artificial Neural Networks as well as to the discipline of meteorology. / Mathematical Sciences / D. Phil. (Statistics)

<p>Увод: Туморска лимфангиогенеза је подручје активног истраживања у циљу проналаска параметара који би омогућили прецизније предвиђање понашања меланома него што то омогућавају традиционални хистолошки и клинички параметри. Иако су импресивна открића о улози лимфангиогенезе у промовисању метастазирања меланома коже, ипак су остала отворена бројна питања и још увек нису усаглашене препоруке које би биле примењиване у дијагностици и терапији. Циљ истраживања је био испитати да ли параметри лимфангиогенезе и Шилдсов индекс имају значај за прогнозу код пацијената са меланомом коже. Материјал и методе: У истраживање је укључено 100 пацијената са меланомом коже (52 без метастаза и 48 са метастазама у лимфним чворовима). За приказ ендотела лимфних судова исечци тумора су бојени имунохистохемијском методом са D2-40 антителима. Квантитативни параметри лимфангиогенезе &ndash; густина и површина лимфних судова добијени су компјутерском морфометријском анализом. За детекцију инвазије лимфних судова туморским ћелијама меланома урађено је дупло бојење D2-40 и S-100 антигена. Имунохистохемијски је испитана експресија васкуларног ендотелног фактора раста (VEGF)-C и VEGF-D у туморским ћелијама, макрофагима и фибробластима меланома. Шилдсов индекс је рачунат као логаритам производа дебљине меланома, квадриране перитуморске густине лимфних судова (ГЛС) и броја 2 за присутну лимфатичну инвазију. Резултати: Параметри који су статистички значајно доприносили појави метастаза меланома у лимфним чворовима, на униваријантној анализи, били су интратуморска ГЛС, перитуморска ГЛС, експресија VEGF-C и VEGF-D у туморским ћелијама, дебљина тумора, улцерација, дубља инвазија по Кларку, нодуларни тип меланома и мушки пол. Мултиваријантна анализа је показала да су значајни независни прогностички фактори за настанак метастаза позитивна експресија VEGF-C у туморским ћелијама, повећана дебљина тумора, повећана интратуморска ГЛС и перитуморска ГЛС. Као најјачи предиктор појаве метастаза показала се позитивна експресија VEGF-C у туморским ћелијама. Пацијенти са &lt;20% VEGF-C позитивних туморских ћелија имали су 20 пута већи ризик за развој метастаза него пацијенти са негативном експресијом. Параметри са утицајем на меланом-специфично преживљавање на униваријантној анализи су били интратуморска ГЛС, перитуморска ГЛС, експресија VEGF-C и VEGF-D у туморским ћелијама, док је мултиваријантна анализа издвојила повећану интратуморску и перитуморску ГЛС као независне факторе ризика за смртни исход. Интратуморска и перитуморска површина лимфних судова, лимфатична инвазија и експресија VEGF-C и VEGF-D у макрофагима и фибробластима нису биле значајно повезане са појавом метастаза нити са краћим меланом-специфичним преживљавањем. Ниједан параметар лимфангиогенезе није био значајно повезан са краћим преживљавањем без рецидива болести. Анализа оперативне карактеристичне криве (ROC) је показала да је Шилдсов индекс веома добар параметар за процену настанка метастаза, са сензитивношћу 81,3% и специфичношћу 75%. Већа површина испод ROC криве код Шилдсовог индекса (0,857) у поређењу са површином код других параметара, указује да је индекс најтачнији прогностички параметар за настанак метастаза, затим следи интратуморска ГЛС (површина 0,795), перитуморска ГЛС (површина 0,772), дебљина меланома (површина 0,762) и American Joint Committee on Cancer систем класификације (површина 0,752). Закључак: Истраживање туморске лимфангиогенезе идентификује нове параметре као значајније предикторе исхода болести од дебљине тумора, улцерације и осталих клиничко-патолошких параметара. Помоћу интратуморске и перитуморске ГЛС, експресије VEGF-C и VEGF-D у туморским ћелијама, као и прорачуна Шилдс индекса, може се предвидети метастатски капацитет меланома. Рутинска патохистолошка анализа меланома требало би да укључи квантитативну анализу мреже лимфних судова и семиквантитативну евалуацију експресије VEGF-C и VEGF-D у туморским ћелијама.</p> / <p>Uvod: Tumorska limfangiogeneza je područje aktivnog istraživanja u cilju pronalaska parametara koji bi omogućili preciznije predviđanje ponašanja melanoma nego što to omogućavaju tradicionalni histološki i klinički parametri. Iako su impresivna otkrića o ulozi limfangiogeneze u promovisanju metastaziranja melanoma kože, ipak su ostala otvorena brojna pitanja i još uvek nisu usaglašene preporuke koje bi bile primenjivane u dijagnostici i terapiji. Cilj istraživanja je bio ispitati da li parametri limfangiogeneze i Šildsov indeks imaju značaj za prognozu kod pacijenata sa melanomom kože. Materijal i metode: U istraživanje je uključeno 100 pacijenata sa melanomom kože (52 bez metastaza i 48 sa metastazama u limfnim čvorovima). Za prikaz endotela limfnih sudova isečci tumora su bojeni imunohistohemijskom metodom sa D2-40 antitelima. Kvantitativni parametri limfangiogeneze &ndash; gustina i površina limfnih sudova dobijeni su kompjuterskom morfometrijskom analizom. Za detekciju invazije limfnih sudova tumorskim ćelijama melanoma urađeno je duplo bojenje D2-40 i S-100 antigena. Imunohistohemijski je ispitana ekspresija vaskularnog endotelnog faktora rasta (VEGF)-C i VEGF-D u tumorskim ćelijama, makrofagima i fibroblastima melanoma. Šildsov indeks je računat kao logaritam proizvoda debljine melanoma, kvadrirane peritumorske gustine limfnih sudova (GLS) i broja 2 za prisutnu limfatičnu invaziju. Rezultati: Parametri koji su statistički značajno doprinosili pojavi metastaza melanoma u limfnim čvorovima, na univarijantnoj analizi, bili su intratumorska GLS, peritumorska GLS, ekspresija VEGF-C i VEGF-D u tumorskim ćelijama, debljina tumora, ulceracija, dublja invazija po Klarku, nodularni tip melanoma i muški pol. Multivarijantna analiza je pokazala da su značajni nezavisni prognostički faktori za nastanak metastaza pozitivna ekspresija VEGF-C u tumorskim ćelijama, povećana debljina tumora, povećana intratumorska GLS i peritumorska GLS. Kao najjači prediktor pojave metastaza pokazala se pozitivna ekspresija VEGF-C u tumorskim ćelijama. Pacijenti sa &lt;20% VEGF-C pozitivnih tumorskih ćelija imali su 20 puta veći rizik za razvoj metastaza nego pacijenti sa negativnom ekspresijom. Parametri sa uticajem na melanom-specifično preživljavanje na univarijantnoj analizi su bili intratumorska GLS, peritumorska GLS, ekspresija VEGF-C i VEGF-D u tumorskim ćelijama, dok je multivarijantna analiza izdvojila povećanu intratumorsku i peritumorsku GLS kao nezavisne faktore rizika za smrtni ishod. Intratumorska i peritumorska površina limfnih sudova, limfatična invazija i ekspresija VEGF-C i VEGF-D u makrofagima i fibroblastima nisu bile značajno povezane sa pojavom metastaza niti sa kraćim melanom-specifičnim preživljavanjem. Nijedan parametar limfangiogeneze nije bio značajno povezan sa kraćim preživljavanjem bez recidiva bolesti. Analiza operativne karakteristične krive (ROC) je pokazala da je Šildsov indeks veoma dobar parametar za procenu nastanka metastaza, sa senzitivnošću 81,3% i specifičnošću 75%. Veća površina ispod ROC krive kod Šildsovog indeksa (0,857) u poređenju sa površinom kod drugih parametara, ukazuje da je indeks najtačniji prognostički parametar za nastanak metastaza, zatim sledi intratumorska GLS (površina 0,795), peritumorska GLS (površina 0,772), debljina melanoma (površina 0,762) i American Joint Committee on Cancer sistem klasifikacije (površina 0,752). Zaključak: Istraživanje tumorske limfangiogeneze identifikuje nove parametre kao značajnije prediktore ishoda bolesti od debljine tumora, ulceracije i ostalih kliničko-patoloških parametara. Pomoću intratumorske i peritumorske GLS, ekspresije VEGF-C i VEGF-D u tumorskim ćelijama, kao i proračuna Šilds indeksa, može se predvideti metastatski kapacitet melanoma. Rutinska patohistološka analiza melanoma trebalo bi da uključi kvantitativnu analizu mreže limfnih sudova i semikvantitativnu evaluaciju ekspresije VEGF-C i VEGF-D u tumorskim ćelijama.</p> / <p>Introduction: Tumor lymphangiogenesis is a field of active research with the aim of finding parameters which would enable the more precise prediction of melanoma behavior in comparison to the prediction of traditional histological and clinical parameters. Although scientific findings about the role of lymphangiogenesis in developing cutaneous melanoma are impressive, there are unresolved questions and recommendations to be applied in diagnostics and therapy, which are still not in compliance. The aim of this research is to examine if parameters of lymphangiogenesis and the Shields Index are important for the prognosis in patients with cutaneous melanoma. Material and methods: The research included a hundred patients with cutaneous melanoma (52 without metastasis and 48 with metastasis of lymphatic nodes). To present endothelial lymphatic vessels, specimens were stained by an immunohistochemical method with D2-40 antibodies. Quantitative parameters of lymphangiogenesis &ndash; lymphatic vessel density (LVD) and area (LVA) were calculated by computer-assisted morphometric analysis. In order to detect the invasion of lymphatic vessels by melanoma tumor cells, a double staining of D2-40 and S-100 antigens was performed. The expression of vascular endothelial growth factor (VEGF)-C and VEGF-D was tested by an immunohistochemical method in tumor cells, macrophages and fibroblasts melanoma. The Shields Index was calculated as a logarithm by multiplying the melanoma thickness, square of peritumoral LVD and the number 2 for present lymphatic invasion. Results:Parameters that statistically had a significant contribution to the emergence of melanoma metastases in lymph nodes, during the univariate analysis, were intratumoral LVD, peritumoral LVD, VEGF-C and VEGF-D expression in tumor cells, tumor thickness, ulceration, deeper Clarkꞌs level of invasion, nodular type of melanoma and a male sex. The multivariate analysis showed that positive expression of VEGF-C in tumor cells, tumor thickness, increased intratumoral LVD and peritumoral LVD are significant independent prognostic factors. The most important predictor of metastases is a positive expression of VEGF-C in tumor cells. Patients with &lt;20% VEGF-C positive tumor cells were 20 times more at risk of developing metastases than patients with a negative expression. Parameters that influence melanoma-specific survival at the univariate analysis were intratumoral LVD, peritumoral LVD, VEGF-C and VEGF-D expression in tumor cells, while the multivariate analysis singled out an increased intratumoral and peritumoral LVD as independent factors of the death risk. Intratumoral and peritumoral LVA, lymphatic invasion and VEGF-C and VEGF-D expression in macrophages and fibroblasts were not significantly correlated either with the emergence of metastases or with melanoma-specific survival. Non-parameter of lymphangiogenesis was significantly related with shorter disease-free survival. The analysis of receiver operator characteristic (ROC) curve showed that the Shields Index is a very good parameter for the estimation of the appearance of metastases, with the sensitivity of 81.3% and specificity of 75%. A bigger area under the ROC curve with the Shields Index (0.857) in comparison to the area in other parameters shows that the index is the most accurate prognostic parameter for an emergence of metastases, followed by intratumoral LVD (area 0.795), peritumoral LVD (area 0.772), the thickness of melanoma (area 0.762), and the American Joint Committee on Cancer classification system (area 0.752). Conclusion: The research of tumor lymphangiogenesis identifies new parameters as significant predictors of the disease outcome more so than the parameters like tumor thickness, ulceration, and other clinical-pathological parameters. By intratumoral and peritumoral LVD, VEGF-C and VEGF-D expression in tumor cells, as well as by the calculation of Shields Index, metastatic capacity of melanoma can be predicted. A routine pathohistological analysis of melanoma should include quantitative analysis of the lymphatic vessels network and semiquantitative evaluation of VEGF-C and VEGF-D expression in tumor cells.</p>

<p>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 &scaron;irenja ovih bolesti je limfogeni, a konvencionalna radiolo&scaron;ka dijagnostika limfnih čvorova kod ovih pacijentkinja je neprecizna. Funkcionalna radiolo&scaron;ka 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 patohistolo&scaron;kog 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 patohistolo&scaron;kog 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 aku&scaron;erstvo 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 izvr&scaron;ena posle operacije na osnovu histopatolo&scaron;kog pregleda kompletnog hirur&scaron;kog 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 hirur&scaron;ko lečenje po protokolu hirur&scaron;kog lečenja za dato maligno ginekolo&scaron;ko oboljenje sa karličnom i/ili ingvinalnom limfadenektomijom. Postoperativno je izvr&scaron;ena patohistolo&scaron;ka analiza hirur&scaron;ki uklonjenog materijala i limfnih čvorova razdvojenih po anatomskim grupama u karlici i ingvinalnoj regiji. REZULTATI: Ukupno 2320 limfnih čvorova je mapirano i patohistolo&scaron;ki pregledano kod 80 pacijenata. Metastaze u limfnim čvorovima patohistolo&scaron;ki su verifikovane kod 28 pacijenata (35%). Kod ovih 28 (35%) pacijentkinja, 152 (27,28%) od ukupno 557 limfnih čvorova bilo je metastatski izmenjeno na patohistolo&scaron;kom 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 lo&scaron;e diferentovan primarni tumor. Od ukupno 152 metastatski izmenjena limfna čvora u na&scaron;oj studiji, 8 limfnih čvorova (5,26%) pripadalo je ingvinalnoj grupi od čega 5 (3,289%) povr&scaron;noj ingvinalnoj, a 3 ( 1,97%) dubokoj ingvinalnoj grupi, 8 (5,26%) parametrijalnoj grupi, 48 (31,58%) opturatornoj grupi, 40 (26,31%) spolja&scaron;njoj ilijačnoj grupi, 36 (23,684%) unutra&scaron;njoj 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 &plusmn; SD, 8,3 &plusmn; 5.4 mm, raspon , 4.5-30 mm ) i limfnih čvorova koji nisu bili metastatski izmenjeni ( 6,3 mm &plusmn; 1,5 , 4,5-9,6 mm ; P= 0,191 ). Izmerena ADC vrednost bila je značajno niža kod metastatski izmenjenih limfnih čvorova (mean &plusmn; SD , ADC: 0,8725 x 10-3 mm2/s &plusmn; 0,0125) nego kod limfnih čvorova koji nisu bili metastatski izmenjeni (mean &plusmn; SD, ADC: 1,116 x 10- 3 mm2/s &plusmn; 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 &plusmn; SD, ADC: 0,8575 &plusmn; 0,0125 x 10-3 mm2/s, ADC:0,8859 &plusmn; 0,0125 x 10-3 mm2/s) i limfnih čvorova koji nisu metastatski izmenjeni (mean &plusmn; SD, ADC:1,0345 &plusmn; 0,1222 x 10-3 mm2/s, ADC:1,1125 &plusmn; 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 &lt; 0,001). Negativna prediktivna vrednost MR zasnovanoj na kriterijumima veličine limfnog čvora i na ACD vrednosti nisu se međusobno statistički značajno razlikovali (P&lt;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 patohistolo&scaron;kog 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 morfolo&scaron;kih 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 histolo&scaron;ke 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.</p> / <p>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 &plusmn; SD, 8.3 &plusmn; 5.4 mm, range , 4.5-30 mm ) and benign lymph nodes ( 6.3 mm &plusmn; 1.5 , 4.5-9.6 mm ; P= 0.191 ). Measured ADC values were significantly lower in metastatic (mean &plusmn; SD , ADC: 0.8725 x 10-3 mm2/s &plusmn; 0.0125) than benign lymph nodes (mean &plusmn; SD, ADC: 1.116 x 10-3 mm2/s &plusmn; 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 &plusmn; SD, ADC: 0.8575 &plusmn; 0.0125 x 10-3 mm2/s, ADC:0.8859 &plusmn; 0,0125 x 10-3 mm2/s) and benign lymph nodes (mean &plusmn; SD, ADC:1.0345 &plusmn; 0.1222 x 10-3 mm2/s, ADC:1.1125 &plusmn; 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 &lt; 0,001). MRI NPV based on size based and ADC values criteria did not differ significantly (P&lt;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.</p>

The emergency departments in Region Östergötland use pen and paper to a large extent when recording emergency care procedures and measurements. During treatment the patient should be the main focus. Because of this, recording of measurements done could be delayed or in worst case forgotten during stressful situations. The proposal of this project is the development of a prototype that tries to make the administrative work a passive procedure rather than an active one. The system developed uses a Raspberry Pi, along with Node-Red, which connects predefined patient data and medical records, with the clinical staff tending the patient. All these connections are initiated by mainly using RFID technology. The conclusion made with the developed system is that it should unload the staff with the recording of data and that it helps make a data logging a more passive work than today’s used methods. Along with a process that is easier to operate, the time spent on administrative work could be reduced with the proposed system.

Introdução: O adenocarcinoma gástrico é uma doença de elevada incidência e alta mortalidade. A gastrectomia com linfadenectomia é tratamento potencialmente curativo, promovendo controle loco-regional da doença e fornecendo material para análise histopatológica. Para o adequado estadiamento dos pacientes é recomendado que pelo menos 16 linfonodos sejam examinados pela patologia, entretanto, espera-se maior sobrevida quando >= 30 linfonodos são avaliados, mesmo em pacientes com tumores precoces. A justificativa para este achado é o sub-estadiamento de pacientes com poucos linfonodos examinados. Linfonodos pequenos são particularmente difíceis de serem encontrados, mas podem conter metástases e impactar negativamente na sobrevida. Visando facilitar sua identificação, soluções clareadoras de gordura foram propostas, entretanto não há evidência clara de seu benefício clínico. Objetivos: Comparar as soluções de Carnoy e de formalina neutra tamponada em relação ao número absoluto de linfonodos encontrados na peça cirúrgica de pacientes submetidos a gastrectomia. Averiguar se linfonodos retirados cirurgicamente são perdidos com a fixação em formalina e, caso isso ocorra, se este fato é relevante para o estadiamento. Observar se o protocolo de pesquisa influenciou o número de linfonodos encontrados. Métodos: Cinquenta produtos de gastrectomia subtotal com linfadenectomia D2 por adenocarcinoma gástrico foram randomizados para fixação em Carnoy ou formalina com posterior dissecção da peça em busca de linfonodos. Após a dissecção do grupo Formalina, a gordura residual a ser desprezada foi imersa em Carnoy e reavaliada posteriormente. Os dados de 25 gastrectomias D2 operadas previamente ao estudo também foram avaliados. Resultados: A média de linfonodos encontrados nos grupos Carnoy e Formalina foi de 50,4 e 34,8; respectivamente (p < 0,001). Na gordura residual foram encontrados linfonodos em todos os casos (média 16,9 linfonodos), elevando a média do grupo Formalina para 51,7 (valor similar ao do grupo Carnoy, p=0,809). Com exceção de 1 linfonodo de 7mm, todos os demais encontrados na gordura residual mediram <= 3mm. Treze linfonodos metastáticos passaram despercebidos com a fixação em formalina e a revisão da gordura residual determinou a mudança de estadiamento de 2 (8%) pacientes. Os linfonodos encontrados no Carnoy possuíam tamanho significativamente menor quando comparados aos do grupo Formalina (p=0,01). A média de linfonodos encontrados no grupo retrospectivo foi similar ao do grupo Formalina prospectivo (p=0,802). Conclusões: Quando comparada à formalina, a solução de Carnoy permite encontrar número maior de linfonodos no espécime cirúrgico de gastrectomias com linfadenectomia. Linfonodos milimétricos foram perdidos após a fixação em formalina, estes foram identificados com o Carnoy e são clinicamente relevantes, pois podem conter metástases modificando assim, o estádio clínico e prognóstico do paciente. A implementação de protocolo de pesquisa não influenciou o número de linfonodos encontrados neste estudo / Background: Gastric adenocarcinoma is a frequent disease with high mortality ratio. Gastrectomy with lymphadenectomy is potentially curative, allows local control of the disease and provides material for TNM classification. While pathology examination of at least 16 lymph nodes is recommended following surgery, longer survival rates are expected when >=30 lymph nodes are examined, even for early gastric cancer. The understaging of patients with less examined lymph nodes justifies this findings. Small lymph nodes are particularly difficult to identify and fat clearing solutions have been proposed to improve this, but there is no evidence of their clinical benefit. Objectives: Compare Carnoy\'s solution (CS) and formalin in terms of the total number of examined lymph nodes following gastrectomy. Verify if surgically retrieved lymph nodes are lost with the formalin fixation and if this fact is clinically significant. Observe if a research protocol influences the number of examined lymph nodes. Methods: Fifty specimens of gastrectomy with D2 lymphadenectomy were randomized for fixation in CS or formalin with posterior dissection in search for lymph nodes. In the Formalin group, the residual fat to be discarded was immersed in CS and dissected again. Data from 25 D2 gastrectomies performed previously the present study were retrospectively analyzed. Results: The medium number of examined lymph nodes was 50.4 and 34.8 for CS and formalin, respectively (p < 0.001). Lost lymph nodes were found in all cases in the Residual Fat group (medium 16.9), this increased the Formalin group average to 51.7 (which is similar to the CS group, p=0.809). With one exception (7mm), all other examined lymph nodes in the Residual Fat group measured <= 3mm. Thirteen lymph nodes from this group were metastatic, this determined the upstaging of 2 (8%) patients. Lymph nodes from the CS group were smaller than those found in the formalin group (p=0.01). The medium number of retrieved lymph nodes in the retrospective group was similar to the formalin group (p=0.802). Conclusions: When compared to formalin, Carnoy\'s solution increases lymph node detection following gastrectomy with lymphadenectomy. CS identifies small lymph nodes lost with formalin fixation and that are clinically significant, since they may contain metastasis, modifying the TNM classification. No influence of the research protocol over the number of examined lymph nodes was observed in the present study.

Le travail que nous développons dans le cadre de cette thèse s'articule autour des problèmes de recherche de structure de recouvrement de graphes sous contrainte sur le degré des sommets. Comme l'arbre de recouvrement couvre les sommets d'un graphe connexe avec un minimum de liens, il est généralement proposé comme solution à ce type de problèmes. Cependant, pour certaines applications telles que le routage dans les réseaux optiques, les solutions ne sont pas nécessairement des sous-graphes. Nous supposons dans cette thèse que la contrainte sur le degré est due à une capacité limitée instantanée des sommets et que la seule exigence sur le recouvrement est sa connexité. Dans ce cas, la solution peut être différente d'un arbre. Nous reformulons ces problèmes de recouvrement en nous appuyant sur une extension du concept d'arbre appelée hiérarchie de recouvrement. Notre objectif principal est de démontrer son intérêt vis-à-vis de l'arbre en termes de faisabilité et de coût du recouvrement. Nous considérons deux types de contraintes sur le degré : des bornes sur le degré des sommets ou une borne sur le nombre de sommets de branchement et cherchons dans les deux cas un recouvrement de coût minimum. Nous illustrons aussi l'applicabilité des hiérarchies en étudiant un problème prenant davantage en compte la réalité du routage optique. Pour ces différents problèmes NP-difficiles, nous montrons, tant sur le coût des solutions optimales que sur la garantie de performance des solutions approchées, l'intérêt des hiérarchies de recouvrement. Ce constat se voit conforté par des expérimentations sur des graphes aléatoires. / The work conducted in this thesis is focused on the minimum spanning problems in graphs under constraints on the vertex degrees. As the spanning tree covers the vertices of a connected graph with a minimum number of links, it is generally proposed as a solution for this kind of problems. However, for some applications such as the routing in optical networks, the solution is not necessarily a sub-graph. In this thesis, we assume that the degree constraints are due to a limited instantaneous capacity of the vertices and that the only pertinent requirement on the spanning structure is its connectivity. In that case, the solution may be different from a tree. We propose the reformulation of this kind of spanning problems. To find the optimal coverage of the vertices, an extension of the tree concept called hierarchy is proposed. Our main purpose is to show its interest regarding the tree in term of feasibility and costs of the coverage. Thus, we take into account two types of degree constraints: either an upper bound on the degree of vertices and an upper bound on the number of branching vertices. We search a minimum cost spanning hierarchy in both cases. Besides, we also illustrate the applicability of hierarchies by studying a problem that takes more into account the reality of the optical routing. For all those NP-hard problems, we show the interest of the spanning hierarchy for both costs of optimal solutions and performance guarantee of approximate solutions. These results are confirmed by several experimentations on random graphs.

A crescente demanda de tráfego em redes de acesso pressiona a melhor utilização das redes backbone, que são utilizadas para transporte de grandes taxas de dados em diversos domínios (Sistemas Autônomos, SAs). Com o aumento destas redes, aumenta-se a complexidade de topologia das interligações entre domínios. Desta maneira, roteamento de tráfego e pontos de interconexão de SAs (nós de borda) são questões importantes para o desempenho destas redes, que são operadas por diversos provedores que podem utilizar protocolos de comunicação distintos. Neste sentido, o roteamento interdomínio apresenta desafios como a publicação ou não de informações de parâmetros de rede de SAs e como tratar esta questão de maneira globalizada, com novos protocolos e suas especificações. Em termos de pontos de interconexão de SAs, a especificação dos locais onde enlaces inter-redes são conectados aos domínios são importantes para seu desempenho, já que são responsáveis por toda troca de tráfego entre redes distintas. O trabalho considera redes ópticas opacas e translúcidas em cenário multidomínio com bandas multigranulares. Neste cenário é estudado um algoritmo de roteamento multidomínio. No trabalho também é feito um planejamento, especificando em quais nós serão conectados enlaces interdomínio. A principal contribuição deste trabalho é o estudo de planejamento de enlaces interdomínio, com a proposta de um método para escolha de nós de borda (sistematização), com objetivo de diminuir a probabilidade de bloqueio interdomínio. A sistematização é baseada em estudos de resultados de algoritmo genético desenvolvido para o mesmo propósito e sua utilização diminui em até 42% o bloqueio interdomínio. Um algoritmo de alocação de banda também foi desenvolvido para redes multidomínio, que considera parâmetros da camada de rede e óptica para o cálculo de peso de enlaces para encontrar caminhos ópticos entre nós fonte e destino. Os resultados mostram diminuição de até 35% no bloqueio interdomínio com a modificação feita em algoritmo proposto na literatura. / The huge demand for traffic in last mile networks push the better utilization of backbone networks, which are used to transport large data rates in several domains (Autonomous Systems, ASs). With this growth, the topology complexity of interdomain links increases. Then, traffic routing and interconnection points of ASs (border nodes) are relevant questions for the performance of these networks, which are managed by several providers that can use distinct communications protocols. Thus, the interdomain routing presents challenges such as the decision on publishing or not the network´s parameters from ASs and how to deal with this issue in a global way, with new protocols and its specifications. For interconnection points between ASs, the points where interdomain links are connected are important for their performances, since they are responsible for all traffic exchange between distinct networks. This work considers opaque and translucent optical networks in a multidomain scenario with multigranular data rates. In this scenario a multidomain routing algorithm is studied and a network planning is developed, specifying the nodes where interdomain links are connected. The main contribution of this work is the planning of interdomain links, with the proposal of a method for border nodes selection (systematization), with the objective of decreasing the interdomain blocking probability. The systematization is based on the results from a genetic algorithm developed for the same purpose and its utilization decrease up to 42% of the interdomain blocking. A bandwidth allocation algorithm was also created for multidomain scenarios, that considers parameters from network and optical layer for the link weight calculation in order to find optimal paths. The results show a decreasing of up to 35% for interdomain blocking with a contribution based on literature\'s work.

Nous étudions dans cette thèse des problèmes d’optimisation avec applications dans les réseaux optiques. Les problèmes étudiés sont liés à la tolérance aux pannes et à l’utilisation efficace des ressources. Les résultats obtenus portent principalement sur la complexité de calcul de ces problèmes. La première partie de cette thèse est consacrée aux problèmes de trouver des chemins et des chemins disjoints. La recherche d’un chemin est essentielle dans tout type de réseaux afin d’y établir des connexions et la recherche de chemins disjoints est souvent utilisée pour garantir un certain niveau de protection contre les pannes dans les réseaux. Nous étudions ces problèmes dans des contextes différents. Nous traitons d’abord les problèmes de trouver un chemin et des chemins lien ou nœud- disjoints dans des réseaux avec nœuds asymétriques, c’est-à-dire des nœuds avec restrictions sur leur connectivité interne. Ensuite, nous considérons les réseaux avec des groupes de liens partageant un risque (SRLG) en étoile : ensembles de liens qui peuvent tomber en panne en même temps suite à un événement local. Dans ce type de réseaux, nous examinons le problème de recherche des chemins SRLG-disjoints. La deuxième partie de cette thèse est consacrée au problème de routage et d’allocation de spectre (RSA) dans les réseaux optiques élastiques (EONs). Les EONs sont proposés comme la nouvelle génération des réseaux optiques et ils visent une utilisation plus efficace et flexible des ressources optiques. Le problème RSA est central dans les EONs. Il concerne l’allocation de ressources aux requêtes sous plusieurs contraintes. / We study in this thesis optimization problems with application in optical networks. The problems we consider are related to fault-tolerance and efficient resource allocation and the results we obtain are mainly related to the computational complexity of these problems. The first part of this thesis is devoted to finding paths and disjoint paths. Finding a path is crucial in all types of networks in order to set up connections and finding disjoint paths is a common approach used to provide some degree of protection against failures in networks. We study these problems under different settings. We first focus on finding paths and node or link-disjoint paths in networks with asymmetric nodes, which are nodes with restrictions on their internal connectivity. Afterwards, we consider networks with star Shared Risk Link Groups (SRLGs) which are groups of links that might fail simultaneously due to a localized event. In these networks, we investigate the problem of finding SRLG-disjoint paths. The second part of this thesis focuses on the problem of Routing and Spectrum Assignment (RSA) in Elastic Optical Networks (EONs). EONs are proposed as the new generation of optical networks and they aim at an efficient and flexible use of the optical resources. RSA is the key problem in EONs and it deals with allocating resources to requests under multiple constraints. We first study the static version of RSA in tree networks. Afterwards, we examine a dynamic version of RSA in which a non-disruptive spectrum defragmentation technique is used. Finally, we present in the appendix another problem that has been studied during this thesis.

<p>Colorectal cancer is one of the most common malignancies in Sweden, with more than 5000 new cases annually. Median age at time of diagnosis is approximately 75 years. Owing to the ageing population, the incidence of colorectal cancer is increasing. The improvement in surgical technique and the introduction of adjuvant radio- and chemotherapy increased the 5-year survival rate from approximately 30-40% in the early 1960s to almost 60% in the late 1990s. The cost of public health care has risen considerably, and case-costing systems are increasingly demanded. Linked to clinical guidelines and quality registers, such control systems form a proper basis for quality assurance projects and improvement. The aim of this thesis is to describe the efficiency and cost effectiveness of colorectal cancer treatment in a defined Swedish population. Emergency surgery for colon cancer, constituting 25% of the cases, increased both mortality and cost. Among emergency cases there was not only an increase in postoperative mortality but also a stage specific decrease in long-term survival rate. Correct staging is decisive for further treatment of patients after colon cancer surgery and influences long-term survival. The number of lymph nodes examined varied between different pathology departments and could be used as a quality measurement. The proportion of tumour stage III increased the more nodes examined. A prognostic estimation of stage III cases that is less sensitive to the number of nodes examined is proposed. A case-control study aimed at identifying risk factors for anastomotic leakage after rectal cancer surgery confirmed previously known risk factors but failed to identify further steps during the perioperative course that were amenable to improvement. This research has confirmed that population-based quality and case-costing registers, linked to clinical guidelines, constitute a proper source for projects of quality improvement and decisions about distribution of resources in health care.</p>

This dissertation analyses the consequences of seemingly placeless processes like the European integration and the increasing economic globalisation on Brussels and the people living there. The study shows that Brussels has become one of our time's most important international political capitals and a leading business node in Europe. European institutions, international organisations, headquarters and subsidiaries of transnational corporations are increasingly locating themselves in Brussels. Simultaneously there has been an influx of transnational professionals working in the international sector. This research shows that with the internationalisation of Brussels there has been concomitant economic restructuring with the emergence of an advanced service economy. The labour market has become polarised between those who have jobs and those who do not. Brussels has also experienced a spatial and socio-economic polarisation along ethnic lines. The thesis explores the connections between these changes and Brussels' international role. Drawing on the world / global city thesis of Saskia Sassen and John Friedmann, a theoretical framework is developed to analyse this. One of the important results of this study is that the world / global city thesis needs to be complemented with a thorough analysis of the place: the political and historical context, and also the role of the local agents, to enable an explanation of the observed development. The interplay between global and local processes needs to be clarified. It is also argued that to properly understand cities with an international role like Brussels, we need to know why international agents locate there. Michael Storper's concepts of 'economic reflexivity' and 'territorial specificities' are used to analyse the rise of Brussels into a reflexive world city - a city vibrating with specific knowledge, produced through inter alia social interaction and critical reflection, that some transnational agents find extremely vital to tap into.