Background: A compilation of high quality systematic reviews (SRs) on lifestyle factors associated with adult glioma and meningioma was developed. Methods and Materials: Phase 1 consisted of a systematic overview of existing SRs. For Phase 2, high quality SRs were incorporated in an update. Moderate or low quality SRs which had not been considered in a high quality review were eligible for a de-novo synthesis. Results: Phase 1 resulted in seven moderate to low quality reviews. From this, in Phase 2, smoking, mobile phone and hair dye use were subjected to de-novo reviews. For smoking, it was suggestive that past smokers had an increased risk. For mobile phone use, there was no overall association, however it was suggestive that ipsilateral and high cumulative call time were associated with slight increased risk. No association was observed for personal hair dye use. Conclusions: Despite these null associations, rigorous SR methods were used providing confidence in conveying these results.

Prognostic factors come in a variety of forms and may be patient, tumour or environmental related. This thesis examines the interaction of prognostic factors for a variety of tumour types. It particularly focuses on single nucleotide polymorphisms (SNPs) of the vascular endothelial growth factor (VEGF) gene. The first section on meningiomas describes the frequency of sex steroid receptors in meningiomas. In this study, absence of progesterone receptors is associated with high tumour grade and male gender. Tumours that are progesterone receptor negative have an odds ratio for recurrence of 5.Choroid plexus carcinomas are aggressive malignant tumours generally occurring in young children. Gross total surgical resection has been shown to be a highly significant factor in tumour recurrence and survival. This study describes a treatment paradigm of neoadjuvant ICE chemotherapy in these children which decreases the vascularity and increase the chance of a complete removal. The operative blood loss with this regimen is reduced to 0.22 blood volumes from 1.11 blood volumes without neoadjuvant chemotherapy. The VEGF gene is highly polymorphic and SNPs of the region have previously been shown to influence VEGF protein expression. This study looks at cohorts of both adult gliomas and a variety of paediatric brain tumours; comparing them to controls. There are several associations described between the development of certain tumours and specific SNP genotypes. In addition to this, certain genotypes and haplotypes have an influence on survival of adult grade 2 astrocytomas and paediatric medulloblastomas and ependymomas. There are consistent themes to the prognostic genotypes throughout both the adult and the paediatric tumours.Prognostic factors come in a variety forms as described in this thesis. It is vital to understand the complex interaction between factors to best utilise them for the benefit of patients.

Philosophiae Doctor - PhD / Glioblastoma multiforme (GBM) remains the most malignant of all primary adult brain tumours. It is a highly invasive and vascularized neoplasm with limited treatment options and very low survival rate. GBM tumours are heterogeneous in nature with cellular hierarchy and at the apex of this hierarchy are the glioblastoma stem cells, known to promote tumourigenesis and resistance to chemotherapeutic agents and tumour recurrence. Currently, the standard care for GBM involves surgical resection, radiation, and chemotherapy treatment with temozolomide. Unfortunately, median survival after treatment is still daunting and tumour relapse is very frequent. Indeed, patients with recurrent glioblastoma have less than a year survival. To address this, novel therapies need to be developed with the early introduction of promising agents into clinical trials and subsequent approval for use. Importantly, for these novel therapies to be approved for GBM, they need to be safe, effective as well as being able to penetrate the blood-brain barrier (BBB). Due to the high cost and process time for the development of new drugs, existing approved drugs are currently being repurposed for new indications and this is gaining significance in clinical pharmacology as it allows rapid delivery of useful drugs from bench to bedside. Drugs of the antipsychotic class are well known to cross the BBB due to their neuroleptic action. To this end, the aim of this study was to identify and characterize the anti-cancer activities of novel phenothiazine-derivatives belonging to the antipsychotic class of drugs in glioblastoma. To achieve this, several novel phenothiazine-derivatives were initially screened for possible anti-cancer activity in the U87 and U251 malignant GBM cells. Two lead compounds, DS00326 and DS00329, were identified and their anti-cancer activities were determined in U87 and U251 cells as well as in primary patient-derived xenograft (PDX) glioblastoma cultures. DS00326 and DS00329 significantly inhibited glioblastoma cell viability, with minimal effects observed in the non-cancerous FG0 fibroblasts. The IC50 values of DS00326 and DS00329 for U251, U87 and PDX cells ranged from 1.61 to 12.53μM. Flow cytometry analyses showed that DS00326 and DS00329 treatment led to an increase in the G1 population of cells. Additionally, DS00326 and DS00329 induced double-strand DNA breaks, which lead to activation of the canonical DNA damage response pathway. Furthermore, DS00326 and DS00329 induced apoptosis as shown by morphological markers, flow cytometry with annexin V-FITC/propidium iodide staining, as well as western blotting with an antibody to detect levels of cleaved PARP. Interestingly, treatment with DS00326 and DS00329 also induced autophagy as evident by the increase of acidic vesicular organelles in cells following staining with acridine orange as well as an increase in levels of the autophagy marker LC3-II. Autophagy was seen as a pro-death pathway in the U87 and U251 cells as inhibition of autophagy led to a reversal of cytotoxicity and consequently increased cell survival. Moreover, it was demonstrated that DS00326 and DS00329 inhibited the PI3/Akt pathway while modulating the mitogen-activated protein kinases p38, ERK1/2 and JNK signalling pathways. Importantly DS00326 and DS00329 displayed anti-cancer stem cell activities by the inhibition of neurosphere formation and regulation of stem cell markers SOX2 and GFAP in PDX cells. Together, the findings from this study suggest that DS00326 and DS00329 may be effective in the treatment of glioblastoma and provide a strong rationale for further clinical studies exploiting phenothiazines and their derivatives as treatments for glioblastoma. / 2021-09-01

This thesis deals with a classification of glioma grade in high and low aggressive tumours and overall survival prediction based on magnetic resonance imaging. Data used in this work is from BRATS challenge 2019 and each set contains information from 4 weighting sequences of MRI. Thesis is implemented in PYTHON programming language and Jupyter Notebooks environment. Software PyRadiomics is used for calculation of image features. Goal of this work is to determine best tumour region and weighting sequence for calculation of image features and consequently select set of features that are the best ones for classification of tumour grade and survival prediction. Part of thesis is dedicated to survival prediction using set of statistical tests, specifically Cox regression

Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate Mgr. Dimitrios Vagiannis Supervisor RNDr. Jakub Hofman, Ph.D. Title of Doctoral Thesis Study on the role of pharmacokinetic mechanisms of drug resistance in new anticancer drugs with focus on solid tumors Cancer chemotherapy is an important tool for the cure of cancer. Although the development of new anticancer drugs has been rapidly progressing, the phenomenon of multidrug resistance (MDR) continues to be a key issue leading to therapy failure in oncological patients. MDR is based on pharmacodynamic as well as pharmacokinetic mechanisms. Pharmacokinetic MDR includes drug efflux transporters and biotransformation enzymes that decrease the amount of (active form of) a drug in tumors. While the MDR role of transporters has been well understood, the participation of drug metabolizing enzymes is still unclear. This thesis investigates the role of cytochromes P450 (CYPs) in cytostatic resistance. Furthermore, it focuses on the modulation of pharmacokinetic MDR using pharmacokinetic drug-drug interactions of new targeted antitumor drugs. Finally, it aims to confirm the in vitro findings in ex vivo patient-derived tumor explants. In our latest publication, we demonstrate the significant role of...

Sarcoid-like tumours have been reported in Cape mountain zebra (Equus zebra zebra) in two South African game parks recently. These tumours caused severe distress to the animals and also made them unsightly for tourists visiting the parks. The aim of this investigation was to identify and characterize the infectious agent considered to be involved in the aetiology of sarcoid in the Cape mountain zebra. Bovine papillomaviruses (BPV) -1 and -2 deoxyribonucleic acid (DNA) were detected by the polymerase chain reaction (PCR) in sarcoid tumour tissue, but not from blood specimens or unaffected skin. Differentiation between BPV-1 and -2 was made by using the restriction endonuclease BstXI on PCR products of the E5 open reading frame (ORF). A hybridization probe real-time assay was developed for the specific and sensitive detection and differentiation of BPV-1 and -2 DNA in blood, skin and sarcoid tumour samples. For the specific detection of BPV-1, an increase in fluorescence was detected at 640 nm and of BPV-2 at 705 nm. The test is extremely sensitive and able to detect 1.5 genome copies/reaction. The presence of BPV-1 and -2 DNA could be demonstrated in the blood of sarcoid-affected and -unaffected zebras even in the blood of zebras from parks where sarcoids have never been observed. The phylogenetic relationships of the papillomaviruses detected in tumours in the Cape mountain zebra in comparison with a broad selection of papillomavirus sequences available in GenBank were compiled. The papillomavirus sequences retrieved from the zebras were identified as variants of either BPV-1 or BPV-2. The age of the most recent common ancestor for BPV-1 variants is estimated to be 1.40 million years (Mya) and for BPV-2 variants, 0.55 Mya. The age of the most recent common ancestor of BPV-1 and BPV-2 is estimated to be 5.34 Mya. Certain major histocompatibility (MHC) haplotypes are associated with increased risk of sarcoid tumours in horses. The zebras in these parks may have become inbred for the MHC region with increased prevalence for a haplotype, conferring increased risk for sarcoid tumours. Therefore typing system was developed to determine whether or not a high prevalence of sarcoids among zebras is associated with a MHC haplotype. Single strand conformational polymorphism was used to assess the genetic variation in MHC class II genes. The use of DQB and DRB genes demonstrated that genetic variation and sarcoids in the zebras could not be attributed to a specific haplotype. The developed real-time PCR technique was also applied in the detection of cutaneous papillomavirus in two giraffes (Giraffa camelopardalis) which were manifesting cutaneous papillomatosis, in the Kruger National Park and in a fibropapilloma in a sable antelope (Hippotragus niger), on a game farm in the Kimberley district, South Africa. In conclusion, this was the first study to confirm the presence of BPV-1 and -2 DNA in the sarcoid tumours, healthy skin and blood of sarcoid-affected and healthy free-roaming zebras from sarcoidaffected parks. The presence of BPV-1 and -2 DNA in the blood of zebras from parks where sarcoids have not been previously observed was a significant finding. / Thesis (PhD)--University of Pretoria, 2010. / Veterinary Tropical Diseases / unrestricted

En neuro-oncologie pédiatrique, les études neurocognitives et neuropsychologiques sur les tumeurs hémisphériques (sus-tentorielles) sont plus rares que celles sur les tumeurs de la fosse postérieure (sous-tentorielles), bénignes (notamment l’astrocytome pilocytique du cervelet) ou malignes (en particulier, le médulloblastome qui est la tumeur maligne la plus fréquente chez l’enfant). A l’heure actuelle il n’existe pas, à notre connaissance, de séries publiées de cas d’enfants traités pour tumeur frontale, bénigne ou maligne et même les descriptions isolées d’un seul cas restent rares (Daigneault, S & al, 1997 ; Anderson, S.W, 2000). Il existe des séries de cas de tumeur frontale chez l’adulte (Roca & al, 2010 ; Yong-Gao & al, 2012). Il existe par contre une littérature importante porte sur le devenir et les séquelles des enfants traités pour une tumeur de la fosse postérieure. En effet, les progrès thérapeutiques ont amélioré les taux de survie, et plusieurs équipes ont examinés l’impact de différents facteurs (essentiellement mais pas exclusivement médicaux : topographie lésionnelle, âge d’apparition de la tumeur, nature des traitements et complications, etc., mais aussi niveau d’éducation des parents, etc.) sur les séquelles motrices et cognitives, le devenir et la qualité de vie de ces enfants et adolescents. Entre septembre 2010 et septembre 2011, 21 patients âgés entre 8 ans 3 mois et 27 ans 10 mois au moment de l’évaluation neuropsychologique ont été inclus dans cette étude. L’évaluation neuropsychologique, réalisée en deux temps, incluait des tests (tests papier-crayon et épreuves écologiques) évaluant l’efficience intellectuelle, des fonctions exécutives, d’attention, et de théorie de l’esprit. 44 patients contrôles ont été appariés en âge, sexe et NSC (niveau socio-économique) au groupe de patients. Au niveau statistique d’importantes différences sont relevées, notamment, dans les épreuves de reconnaissance d’expressions faciales émotionnelles. Il s’agit de la 1ère étude qui évalue les fonctions cognitives et affectives dans un groupe de patients ayant été traités dans l’enfance pour une tumeur frontale bénigne ou maligne. / Frontal lesions in children and adolescents have been mainly explored in traumatic brain injury (TBI). Other frontal lobe pathologies such as frontal lobe epilepsy (FLE), frontal focal lobe lesion, such as brain tumours or frontal focal lobe pathologies, can explain sequelae after frontal lobe pathologies. In the literature only two cases studies exist on benign frontal lobe tumour in children. To our knowledge there is no study group of frontal lobe tumours in children. Between September 2010 and September 2011, we observed 21 patients treated for benign/malign tumours. We examined 22 young patients aged between 8.3 years and 27.10 years old, all treated for benign or malign frontal tumour in Gustave Roussy’s Institute (in case of malign tumour) or Necker Enfants-Malades (in case of malign tumour). Treatment of this patients depended on benign or malign tumour. A total of 44 controls subjects were enrolled in study. All children and adolescents had neuropsychological tests, such as executive function tests (planning, mental flexibility, attention, working memory tasks) and measure or theory of mind tests such as face recognition test (TOM). All children were seen twice. Main differences are observed in facial recognition test between patients with malign and benign tumours and control subjects. IQ in not affected when tumours are benign, and most children obtain normal performances in executive tests. This is a first study with comprehensive neuropsychological assessment of children and adolescents with frontal lobe tumours. Findings have to be compared with classical studies of frontal lobe lesions in adults. Results suggest that many children treated for frontal lobe tumours do not present the classical dysexecutive syndrome and major behavioural changes as described in adults. However most of them present deficits in facial recognition of emotions and gesture imitations deficits.

Despite the remarkable success of adoptive T cell therapy in the treatment of melanoma and hematological malignancies, therapeutic capacity in a broad range of solid tumours is impaired due to immunosuppressive events that render tumour-specific T cells unable to persist and kill transformed cells. To address some of the limitations of ACT in solid tumours, our laboratory has developed a therapeutic modality utilizing oncolytic virus, which expresses a tumour-associated antigen, known as an oncolytic viral vaccine (OVV), in combination with tumour specific central memory T cells. With this therapeutic approach (ACT), we can achieve robust in vivo expansion of transferred cells resulting in the complete and durable tumour regression in multiple solid murine tumour models. However, we demonstrate that the curative potential is lost when the tumour stage and burden increase as expanded transferred cells differentiate to a dysfunctional state resulting in the progressive decline in the tumour-specific CD8+ T cell response. Thus, we believe that restoring the T cell response in late-stage tumours will lead to enhanced curative potential of ACT in late-stage tumours. We have previously shown that HDACi, MS-275, can enhance the therapeutic capacity of a T cell-based therapy in an aggressive brain tumour model. In addition, concomitant delivery of MS-275 with ACT ensures durable cures through immunomodulatory mechanisms. Strikingly, concomitant delivery of MS-275, a class 1 histone deacetylase inhibitor (HDACi), with ACT in late-stage tumours completely restores the transferred T cell response to similar levels observed in early-stage tumours resulting in the complete regression of advance-stage tumours. Furthermore, MS-275 enhanced the proliferative capacity and tumour-specific cytotoxic function of transferred cells, independently of tumour stage, type and mouse strain. Interestingly, we did not observe a complete reversal of T cell dysfunction, but rather observed that MS-275 conferred unique properties to T cells as the expression of some markers typically associated with T cell dysfunction was enhanced in addition to persistence and proliferation capacity. Moreover, concomitant delivery of MS-275 also restored the therapeutic capacity of endogenously primed tumour-specific CD8+ T cells expanded by an OVV in late-stage tumours, demonstrating the potential for general use for MS-275 in T cell-based therapies. Our data suggests the use of HDACi may potentiate T cell-based immunotherapies to overcome tumour-mediated T cell dysfunction in advanced stage solid tumours. / Thesis / Master of Science in Medical Sciences (MSMS)

<p>Breast cancer remains a major cause of cancer-related deaths among women despite several advances in the field due to metastasis with a 5-year survival rate of less than 30% for metastatic breast cancer. Dissemination of tumor cells to metastatic sites begins as early as the primary tumor is diagnosed at just 4mm in size. These cells remain dormant for extended periods of time evading immune surveillance and later turn into therapy resistant metastases resulting in the poor prognosis in breast cancer patients. Hence, there is a <b>critical need </b>to improve our understanding of the metastatic programs in breast cancer and its contributors to develop better therapy options.</p><p>One such contributor is alcohol which is listed as a carcinogen by the National Toxicology Program. Alcohol consumption is a risk factor for several cancers and increases the risk of breast cancer incidence in a dose dependent manner. We have observed in preliminary studies, that alcohol consumption causes increased neutrophil extracellular trap (NET) formation in the lungs and outgrowth of previously dormant cancer cells in mice. Further, NETs increase cancer cell seeding and play a role in metastasis. Hence, we hypothesized that alcohol consumption breaks cancer cell dormancy by activating neutrophils.</p><p>In this study, we have broken cancer cell dormancy and generated a novel cell line, Alcohol-D2.OR, by inducing outgrowth of the dormant D2.OR cells in mice through alcohol consumption. Reinjection of the Alcohol-D2.OR cells, into alcohol-naïve mice results in aggressive outgrowth of the cells suggesting these cells are modified on a genetic level. Indeed, RNA sequencing analysis of the gene expression in the cells showed that these cells have significantly modified gene expression as well as modified morphology and surface protein expression than the parental D2.OR cells. Importantly, from our analysis we have identified a tumor suppressor, SPINK5 which was significantly downregulated in the alcohol line. Further, SPINK5 expression in cancer cells suppressed neutrophil activity in-vitro. Knockdown of SPINK5 in the parental D2.OR line resulted in outgrowth of the cells in-vivo with increased lung NETs highlighting the importance of this gene for maintenance of dormancy by suppression of neutrophil activity.</p><p>Hence, we have successfully identified a gene responsible for dormancy maintenance, SPINK5 which will aid in not only therapeutic intervention but also in identification of breast cancer patients likely to progress to metastasis. Further, the newly established Alcohol-D2.OR cells provide a novel tool to study other initiators of metastasis in breast cancer.</p><p>A common side-effect of most chemotherapeutic treatments is neutropenia, reduced neutrophils in circulation increasing susceptibility to infections. Hence, GM-CSF is often administered to patients to mobilize bone marrow neutrophils. However, neutrophils have been increasingly shown to promote distant metastases. Circulating disseminated cancer cells (DCCs), which are present as early as primary diagnosis, have been shown to activate neutrophils resulting in the release of neutrophil extracellular traps (NETs). These NETs alter the lung architecture providing a suitable environment for the seeding and growth of DCCs promoting lung metastases. One key player in neutrophil activation is spleen tyrosine kinase (SYK), an intracellular non-receptor kinase which is activated by the engagement of b-integrin on the neutrophil surface.</p><p>Using a chemical genetics approach we are able to specifically inhibit SYK in the murine host. Using our transgenic model of specific SYK inhibition as well as the FDA approved SYK inhibitor, fostamatinib, we see similar results of decreased lung metastases compared to controls. We also observed decreased neutrophil viability in-vitro in the presence of fibronectin, an effect that was not seen on plastic highlighting the importance of integrin mediated activity of SYK. We also observe decreased neutrophil and macrophage infiltration into the lungs upon host-specific SYK inhibition. Overall, these findings suggest a paracrine effect of SYK in stromal cells that promotes favorable tumor microenvironment (TME) and its inhibition may be a useful therapeutic option to combat DCCs from forming metastases.</p><p>Hence, through this work we address two mechanisms of neutrophil-mediated breast cancer metastasis and that therapeutic intervention by rescuing SPINK5 expression in cancer cells or inhibition of SYK in the tumor microenvironment can suppress pulmonary metastasis in breast cancer.</p>

It is decidedly rare to come across evidence of primary or secondary malignant tumours in the archaeological record, both in the excavatory stage as well as the laboratory stage. However, the statistical absence of cancer in the archaeological record may not be representative of actual prevalence, geographical distribution, or severity. Despite the scarcity, there are some documented cases of suspected and hypothesised malignant skeletal neoplasms, of varying severity and disease progression. Some of these cases have been examined and put through a posthumous or presumptive diagnostic process, in which macroscopic analysis is followed by close microscopic examination, as well as the consideration and exclusion of differential diagnoses. This bachelor’s thesis will investigate 5 cases of such examination, with the help of three palaeopathological and paleo-oncological case studies. With an interdisciplinary approach encompassing contemporary medical science as well as palaeopathological osteoarchaeology, this thesis project will consider the clinical manifestations presented by the case studies in relation to their final hypothesised diagnosis. The results indicate that these individuals may have suffered from metastatic carcinoma with a soft tissue origin, a result which is significant to both contemporary medicine as well as osteoarchaeology. / Det är avgjort sällsynt att stöta på tecken på primära eller sekundära maligna tumörer i det arkeologiska förflutna, både i utgrävningsstadiet såväl som i laboratoriestadiet. Den statistiska frånvaron av cancer i det arkeologiska förflutna kanske inte är representativt för faktisk prevalens, geografisk spridning eller svårighetsgrad. Trots bristen finns det några dokumenterade fall av misstänkta och hypotetiska maligna skelettneoplasmer, av varierande svårighetsgrad och sjukdomsprogression. En del av dessa fall har undersökts och genomgått en postum eller presumtiv diagnostisk process, där makroskopisk analys följs av noggrann mikroskopisk undersökning, samt beaktande och uteslutning av differentialdiagnoser. Denna kandidatuppsats kommer att undersöka 5 fall av sådan undersökning, med hjälp av tre paleopatologiska och paleo-onkologiska fallstudier. Med ett tvärvetenskapligt tillvägagångssätt som omfattar samtida medicinsk vetenskap såväl som paleopatologisk osteoarkeologi kommer detta examensarbete att överväga de kliniska manifestationerna av fallstudierna i relation till deras slutgiltiga preliminära diagnos. Resultaten tyder på att dessa individer kan ha lidit av metastaserande karcinom med ursprung i mjukvävnad, ett resultat som är signifikant för såväl modern medicin som osteoarkeologi.