<p>Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. </p><p>HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G>C)) was identified and the 434GG genotype correlated to NS histology and high ESR.</p><p>The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. </p><p>Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome.</p><p>In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.</p>

Hodgkin lymphoma (HL) is characterised histologically by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells surrounded by benign cells, and clinically by a relatively good prognosis. The treatment, however, leads to a risk of serious side effects. Knowledge about the biology of the disease, particularly the interaction between the HRS cells and the surrounding cells, is essential in order to improve diagnosis and treatment. HL patients with abundant eosinophils in the tumours have a poor prognosis, therefore the eosinophil derived protein eosinophil cationic protein (ECP) was studied. Serum-ECP (S-ECP) was elevated in most HL patients. It correlated to number of tumour eosinophils, nodular sclerosis (NS) histology, and the negative prognostic factors high erythrocyte sedimentation rate (ESR) and blood leukocyte count (WBC). A polymorphism in the ECP gene (434(G&gt;C)) was identified and the 434GG genotype correlated to NS histology and high ESR. The poor prognosis in patients with abundant eosinophils in the tumours has been proposed to depend on HRS cell stimulation by the eosinophils via a CD30 ligand (CD30L)-CD30 interaction. However, CD30L mRNA and protein were detected in mast cells and the predominant CD30L expressing cell in HL is the mast cell. Mast cells were shown to stimulate HRS cell lines via CD30L-CD30 interaction. The number of mast cells in HL tumours correlated to worse relapse-free survival, NS histology, high WBC, and low blood haemoglobin. Survival in patients with early and intermediate stage HL, diagnosed between 1985 and 1992, was generally favourable and comparatively limited treatment was sufficient to produce acceptable results for most stages. The majority of relapses could be salvaged. Patients treated with a short course of chemotherapy and radiotherapy had an excellent outcome. In conclusion prognosis is favourable in early and intermediate stages and there are possibilities for further improvements based on the fact that mast cells and eosinophils affect the biology and prognosis of HL.

3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...

Proteomics is a set of analytical methods which enable qualitative and quantitative characterization of the proteome. Expression proteomics quantitatively compares proteomes of cells, tissues, body fluids or other biological materials to find differencies in protein expression and, based on these differencies, to describe the biological processes occuring in investigated organisms. An initial material for expression proteomic studies are complex mixtures containing thousands of proteins, which are analyzed using separation (electrophoretic and chromatographic) methods, and identified, possibly quantified using mass spectrometry. The aim of this Thesis is to demonstrate the application of the tools of expression proteomics in solving diverse challenges in biomedicine. We employed various proteomic approaches and tools for studying molecular mechanisms of human diseases using pacient biological samples, or a model organism and a cell culture. We were conducting three different research projects, namely: A quest for potencial molecular targets for selective elimination of TRAIL-resistant mantle cell lymphoma cells; Investigation of molecular mechanisms of heart failure using a rat model of the disease induced by volume overload; and Searching for diagnostically usable serum biomarkers of ovarian...

Kaposi's sarcoma-associated herpesvirus (KSHV) is a DNA tumor virus that has been associated with all epidemiological forms of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). Like other herpesviruses, KSHV undergoes two phases of life cycle (latent and lytic replication). During latency, the viral genome persists as a circular episome in the nucleus of the host cell and only a few viral genes are expressed, namely LANA (latency- associated nuclear antigen), Kaposin, vFLIP (viral FLICE inhibitory protein), vCyclin, and vIRF3/LANA2 (viral interferon regulatory factor 3). These viral genes are responsible for regulation of host cell proliferation, prevention of apoptosis, facilitation of immune evasion, and maintenance of the extrachromosomal viral genome during cell divisions. vIRF3 is a multifunctional nuclear protein that is constitutively expressed in KSHV positive PEL cells and Castleman's disease tumors, which expression causes dramatic changes of critical host pathways that are involved in the regulation of apoptosis, cell cycle, antiviral immunity, and tumorigenesis. In our study, we have demonstrated and elucidated predicted mechanism, by which vIRF3 enhances transcription activity of c-Myc. Moreover, we have clarified the previously unappreciated...

Proteomics is a set of analytical methods which enable qualitative and quantitative characterization of the proteome. Expression proteomics quantitatively compares proteomes of cells, tissues, body fluids or other biological materials to find differencies in protein expression and, based on these differencies, to describe the biological processes occuring in investigated organisms. An initial material for expression proteomic studies are complex mixtures containing thousands of proteins, which are analyzed using separation (electrophoretic and chromatographic) methods, and identified, possibly quantified using mass spectrometry. The aim of this Thesis is to demonstrate the application of the tools of expression proteomics in solving diverse challenges in biomedicine. We employed various proteomic approaches and tools for studying molecular mechanisms of human diseases using pacient biological samples, or a model organism and a cell culture. We were conducting three different research projects, namely: A quest for potencial molecular targets for selective elimination of TRAIL-resistant mantle cell lymphoma cells; Investigation of molecular mechanisms of heart failure using a rat model of the disease induced by volume overload; and Searching for diagnostically usable serum biomarkers of ovarian...

3 Abstract The doctor thesis is composed of two major studies, both of them focused on the mantle cell lymphoma (MCL). The first part deals with the verification of the prognostic influence of Mantle Cell Lymphoma International Prognostic Index (MIPI) and of the proliferative activity in 235 patients with MCL diagnosed in 1996-2008 in the Czech Republic. This population study was performed in the collaboration with the Czech Lymphoma Study Group. The clinical data of patients were completed in April 2012. The diagnosis of MCL was confirmed by our central histopathologic examination of pretherapeutic histological samples. The median overall survival (OS) was 47 months, median progression free survival (PFS) was 22 months. We demonstrated the influence of proliferative activity, MIPI and of the therapy type (intensive/non-intensive) on OS and PFS in univariate and multivariate analysis. Using univariate analysis we showed the prognostic influence of aggressive/other cytomorphological variants of MCL, nodal/extranodal localization of primary sample and also of the variants of MIPI - s-MIPI, MIPIb and a completely new variant of MIPI - combined MIPI. The prognostic influence of growth pattern and of the results of immunohistochemical reaction with CD23, CD5 and cyclin D1 antibodies were not confirmed. The other...

Bakgrund: Diffust storcelligt B-cellslymfom (DLBCL) är en högmalign cancersjukdom som drabbar B-lymfocyterna, en typ av vita blodkroppar. Incidensen i Sverige är omkring 600 fall per år. Utan effektiv behandling sker sjukdomsprogressionen med ett snabbt förlopp. Under de senaste två årtiondena har behandlingarna som använts i första och andra linjen kunnat bota 60–70% av patienterna med DLBCL. För patienterna som inte svarat på standardbehandlingarna är prognosen mycket allvarlig. YESCARTA är ett nytt genterapiläkemedel som består av patientens egna T-celler modifierade med en chimär antigen receptor (CAR). När CAR T-cellen binder till B-lymfocyter frisätts inflammatoriska mediatorer som orsakar celldöd av både normala och tumöromvandlade B-lymfocyter. Syfte: Hur påverkar behandling med YESCARTA den totala överlevnaden (OS), responsfrekvensen (ORR), progressionsfri överlevnad (PFS), händelsefri överlevnad (EFS), responsduration (DOR), samt komplett och partiell respons (CR &amp; PR) hos patienter med diffust storcelligt B-cellslymfom (DLBCL)? Detta arbete syftar till att systematiskt sammanställa och utvärdera befintlig vetenskaplig litteratur om YESCARTA för att besvara denna frågeställning. Metod: Litteratursökningen utfördes i PubMed. Samtliga MeSH-termer för läkemedlet YESCARTA konsoliderades och filter för observation- och kliniska studier applicerades. Sökningen genererade 34 artiklar, varav 10 kunde inkluderas. Exklusion skedde huvudsakligen av studier som undersökt annat än den terapeutiska effekten av YESCARTA. Resultat: Majoriteten av studierna var av typen fas II. En fas III-studie med varianter i uppföljningstid och undergruppsanalys inkluderades. YESCARTA förefaller vara överlägsen standardbehandling i alla utfallsmått. Resultatet är mest robust för ORR, EFS och PFS. Cirka fyra av fem patienter kan förväntas uppnå remission efter behandling med YESCARTA. Effektfördelen av YESCARTA i OS och DOR är osäker med avseende på statistisk signifikans. Slutsats: För särskilt utvalda patienter med DLBCL är YESCARTA ett effektivt behandlingsalternativ.

Identification and localization of FDG-avid lymphoma lesions in PET-CT image volumes is of high importance for the diagnosis and monitoring of treatment progress in lymphoma patients. This process is tedious, time-consuming, and error-prone, due to large image volumes and the heterogeneity of lesions. Thus, a fully automatic method for lymphoma detection is desirable. The AutoPET challenge dataset contains 145 full-body FDG-PET-CT images of lymphoma patients with pixel-level segmentation of lesions. The Retina U-Net utilizes semantic segmentation maps for object detection through simultaneous segmentation and detection. More recently, transformer-based methods became increasingly popular due to their good performance. Here, TransRUnet is proposed, a 2D deep neural network capable of segmentation and object detection, combining the Retina U-Net with a Feature Pyramid Transformer. Firstly, a Retina U-Net was trained as a Baseline on 2D axial slices of 116 patient volumes from the AutoPET dataset, achieving an mAP of 0.377 and a DSC of 0.737 on the 29 test patients. Secondly, the TransRUnet was trained on the same patients, achieving an mAP and DSC of 0.285 and 0.732, respectively. Performance comparison based on mAP and DSC did not show significant differences (p = 0.596 and p = 0.940, for mAP and DSC, respectively) between the Retina U-Net and the TransRUnet. Furthermore, a substantial difference in FROC between the two models could not be observed. The ground truth data should be preprocessed to reduce noise in the training data or a 3D generalization of the TransRUnet should be used to improve the detection performance. / Att i PET-CT-bildvolymer identifiera och lokalisera lymfomlesioner med hög FDG-aviditet är av stor betydelse för diagnos och övervakning av behandlingseffekt hos lymfompatienter. Denna process är omständlig, tidskrävande och felbenägen på grund av stora bildvolymer och heterogeniteten hos lesionerna. Därför är det önskvärt med en helautomatisk metod för lymfomdetektion. AutoPET Challenge-datasetet innehåller 145 FDG-PET-CT-bilder av lymfom-patienter med segmentering av lesioner på pixelnivå. Retina U-Net använder semantiska segmenteringskartor för objektsdetektering genom samtidig segmentering och detektering. På senare tid har transformatorbaserade metoder blivit alltmer populära på grund av sina goda prestanda. Här föreslås TransRUnet, ett djupgående neuralt 2D-nätverk som kan segmentera och upptäcka objekt och som kombinerar Retina U-Net med en Feature Pyramid Transformer. I första steget tränades ett Retina U-Net som baslinje på 2D axialskivor av 116 patientvolymer från AutoPET-dataset, och uppnådde en mAP på 0,377 och en DSC på 0,737 på de 29 testpatienterna. I nästa steg tränades TransRUnet på samma patienter och uppnådde en mAP och DSC på 0,285 respektive 0,732. Jämförelse av prestanda baserat på mAP och DSC visade inga signifikanta skillnader (p = 0,596 och p = 0,940 för mAP respektive DSC) mellan Retina U-Net och TransRUnet. Dessutom kunde ingen väsentlig skillnad i FROC mellan de två modellerna observeras. Ground truth-data bör förbehandlas för att minska bruset i träningsdata eller också bör en 3D-generalisering av TransRUnet användas för att förbättra detektionsprestanda.