Brain Tumors

Brain tumors comprise a spectrum of histological patterns. Their presentation and management depend on their location, size, and grade of lesions. This book is a collection of high-quality research work from global experts on brain tumors, including meningiomas, and their treatment

Morbidity in neurofibromatosis 1: Epidemiological perspectives on breast cancer and diabetes

Neurofibromatosis type 1 (NF1) is a dominantly inherited rare disorder caused by pathogenic variants of the NF1 tumor suppressor gene. The syndrome can be diagnosed based on its clinical manifestations, such as café-au-lait macules, skinfold freckling, and benign cutaneous neurofibroma tumors. NF1 affects several organ systems, yet it is best known as a tumor predisposition syndrome. In this thesis, a Finnish cohort of 1,476 individuals with NF1 was used to study the prevalence of NF1 and the risks for breast cancer and diabetes among individuals with NF1. For a more precise assessment of the risk for contralateral breast cancer in NF1, the Finnish NF1 cohort was analyzed together with four other European NF1 cohorts. Moreover, the effect of NF1 on the concentration of circulating free plasma DNA (cfDNA) was assessed in a small-scale clinical study. Breast cancer diagnoses of individuals with NF1 were obtained from the Finnish Cancer Registry. Diagnoses of diabetes were inferred from drug purchases and hospital visits and hospital stays. The characteristics of NF1-related breast cancer were also analyzed. The results demonstrate that the overall prevalence of NF1 may be as high as 1/2,052. NF1 is associated with increased mortality throughout the lifetime, and the age-specific prevalence of NF1 declines in older age groups. Women with NF1 face a marked risk for breast cancer, and the risk for being diagnosed with breast cancer is 7.8% by 50 years of age. The survival after NF1-related breast cancer is worse compared to breast cancer in the general population. Breast cancers diagnosed in individuals with NF1 also exhibit poor prognostic factors, such as hormone receptor negativity. Moreover, women with NF1 and breast cancer have a 16% risk for contralateral breast cancer within 20 years. In contrast, the risk for diabetes and type 2 diabetes, in particular, is decreased among individuals with NF1. The NF1 syndrome, as such, may not significantly alter plasma cfDNA concentration. The results highlight the need for identifying all individuals with NF1 in order to provide them surveillance for NF1-related complications, such as breast cancer. The findings demonstrate the role of the NF1 gene in the pathogenesis of two common diseases, namely breast cancer and diabetes. Sairastavuus tyypin 1 neurofibromatoosissa: epidemiologisia näkökulmia rintasyöpään ja diabetekseen Tyypin 1 neurofibromatoosi (NF1) on vallitsevasti periytyvä harvinaissairaus, joka aiheutuu muutoksista NF1-kasvunrajoitegeenissä. Sairaus voidaan diagnosoida kliinisten oireiden, kuten ihon maitokahviläiskien, taivealueiden kesakoiden ja hyvänlaatuisten neurofibrooma-ihokasvainten perusteella. NF1 vaikuttaa moniin elinjärjestelmiin, mutta parhaiten se tunnetaan kasvainalttiusoireyhtymänä. Tässä tutkimuksessa tarkasteltiin NF1:n yleisyyttä sekä potilaiden alttiutta sairastua rintasyöpään ja diabetekseen. Tutkimuksessa käytettiin 1476 henkilön suomalaista NF1-kohorttia. Vastakkaisen rinnan rintasyövän riskiä tutkittaessa hyödynnettiin tietoja myös neljästä muusta eurooppalaisesta NF1-kohortista. Lisäksi tarkasteltiin NF1:n vaikutusta plasman vapaiden nukleiinihappojen pitoisuuteen. NF1-potilaiden rintasyöpädiagnoosit haettiin Suomen Syöpärekisteristä. Diabetesdiagnoosit pääteltiin lääkeostotiedoista sekä sairaalakäynneistä ja -jaksoista. Lisäksi tarkasteltiin NF1:een liittyvän rintasyövän ominaisuuksia. Tulokset osoittavat, että NF1:n vallitsevuus on jopa 1/2052. NF1 aiheuttaa lisääntynyttä kuolleisuutta kaikissa ikäryhmissä, minkä vuoksi NF1:n vallitsevuus laskee vanhemmissa ikäryhmissä. NF1:een liittyy merkittävä rintasyöpäriski, ja NF1:tä sairastavilla naisilla on 7,8 %:n todennäköisyys sairastua rintasyöpään ennen 50 vuoden ikää. NF1 huonontaa rintasyövän ennustetta, ja NF1-naisten rintasyövät ovat usein hormonireseptorinegatiivisia. Lisäksi rintasyöpään sairastuneilla NF1- naisilla on 16 %:n riski sairastua vastakkaisen rinnan rintasyöpään 20 vuoden kuluessa. Sen sijaan erityisesti tyypin 2 diabeteksen riski on NF1:ssä pienempi kuin vertailuväestössä. NF1-sairaus itsessään ei vaikuta merkittävästi muuttavan plasman vapaiden nukleiinihappojen pitoisuutta. Tulokset korostavat tarvetta tunnistaa kaikki NF1:tä sairastavat henkilöt, jotta he pääsevät taudin edellyttämän seurannan piiriin. Tulosten perusteella NF1-geeni vaikuttaa kahden yleisen sairauden, rintasyövän ja diabeteksen, kehityksee

The role of the tumour microenvironment in arginine deprivation in malignant pleural mesothelioma

PhDApproximately 50% of all malignant pleural mesotheliomas (MPM) are deficient in argininosuccinate synthetase (ASS1), the rate-limiting enzyme in arginine biosynthesis, and are sensitive to arginine deprivation. This discovery in MPM has been translated into the clinic using the arginine depletor pegylated arginine deiminase (ADI-PEG20), which showed a halving in the risk of disease progression in a randomised phase II study. However, unstudied to date, stromal resistance to ADI-PEG20 may reduce its efficacy. Here, I studied the effect of macrophages, abundant in mesothelioma, on the tumour cytotoxicity of ADI-PEG20. A distinct pro-inflammatory cytokine gene expression signature involved in macrophage recruitment and activation was identified and validated in ADI-PEG20-treated ASS1 negative MPM cell lines. In vivo induction of pro-inflammatory cytokines was also seen in ADI-PEG20-treated patient plasma. Notably, in vitro co-culture experiments demonstrated a significant increase in ASS1 negative MPM cell viability upon co-culture with macrophages in the presence of ADI-PEG20. This was accompanied by a significant increase in ASS1 expression in co-cultured macrophages, with a corresponding increase in argininosuccinate lyase (ASL) expression in co-cultured tumour cells and a doubling in levels of the arginine precursor, argininosuccinate, in cell supernatant. The addition of argininosuccinate to tumour cell media rescued ASS1 negative MPM cells from ADI-PEG20 cytotoxicity, while the macrophage-mediated resistance to ADI-PEG20 was abrogated following ASL knockdown in MPM cells. Finally, xenograft studies demonstrated a significant reduction in tumour volume in mice treated with ADI-PEG20 in combination with macrophage depletion, compared with ADI-PEG20 alone. Collectively, the data indicate that as a result of metabolic ‘cross-talk’ between macrophages and ASS1 negative MPM cells, macrophages mediate MPM resistance to ADI-PEG20 via the provision of argininosuccinate. My studies provide a rationale for combining ADI-PEG20 with an inhibitor of macrophage recruitment in the treatment of ASS1-deficient mesothelioma.Medical Research Council (MRC), the British Lung Foundation (BLF), and the Mick Knighton Mesothelioma Research Fund (MKMRF)

Current strategies in targeted anticancer drug delivery systems to brain

Advanced Drug Delivery Systems in the Management of Cancer discusses recent developments in nanomedicine and nano-based drug delivery systems used in the treatment of cancers affecting the blood, lungs, brain, and kidneys. The research presented in this book includes international collaborations in the area of novel drug delivery for the treatment of cancer. Cancer therapy remains one of the greatest challenges in modern medicine, as successful treatment requires the elimination of malignant cells that are closely related to normal cells within the body. Advanced drug delivery systems are carriers for a wide range of pharmacotherapies used in many applications, including cancer treatment. The use of such carrier systems in cancer treatment is growing rapidly as they help overcome the limitations associated with conventional drug delivery systems. Some of the conventional limitations that these advanced drug delivery systems help overcome include nonspecific targeting, systemic toxicity, poor oral bioavailability, reduced efficacy, and low therapeutic index. This book begins with a brief introduction to cancer biology. This is followed by an overview of the current landscape in pharmacotherapy for the cancer management. The need for advanced drug delivery systems in oncology and cancer treatment is established, and the systems that can be used for several specific cancers are discussed. Several chapters of the book are devoted to discussing the latest technologies and advances in nanotechnology. These include practical solutions on how to design a more effective nanocarrier for the drugs used in cancer therapeutics. Each chapter is written with the goal of informing readers about the latest advancements in drug delivery system technologies while reinforcing understanding through various detailed tables, figures, and illustrations. Advanced Drug Delivery Systems in the Management of Cancer is a valuable resource for anyone working in the fields of cancer biology and drug delivery, whether in academia, research, or industry. The book will be especially useful for researchers in drug formulation and drug delivery as well as for biological and translational researchers working in the field of cancer

Evolution of the Molecular Biology of Brain Tumors and the Therapeutic Implications

A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years. In particular recent new avenues regarding the role of stem cells and microRNAs along with further understanding of the importance of angiogenesis, immunotherapy and explanations for the resistance of the tumors to chemotherapeutic agents and radiation therapy has been developed. It is hopeful that this new information will lead to efficacious treatment strategies for these tumors which remain a challenge. In this book a review of the latest information on these topics along with a variety of new therapeutic treatment strategies with an emphasis on molecular targeted therapies is provided