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Von Hippel-Lindau (VHL) syndrome is a rare neoplastic disorder characterized by central nervous system (CNS) and visceral tumors. We here present (68)Ga-labelled [1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid]-1-Nal3-Octreotide positron emission tomography computed tomography findings in a 52 year old female with VHL syndrome, demonstrating both CNS and visceral tumors.
Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.
Malignant gliomas are the most common and deadly brain tumors. Nevertheless, survival for patients with glioblastoma, the most aggressive glioma, although individually variable, has improved from an average of 10 months to 14 months after diagnosis in the last 5 years due to improvements in the standard of care. Radiotherapy has been of key importance to the treatment of these lesions for decades, and the ability to focus the beam and tailor it to the irregular contours of brain tumors and minimize the dose to nearby critical structures with intensity-modulated or image-guided techniques has improved greatly. Temozolomide, an alkylating agent with simple oral administration and a favorable toxicity profile, is used in conjunction with and after radiotherapy. Newer surgical techniques, such as fluorescence-guided resection and neuroendoscopic approaches, have become important in the management of malignant gliomas. Furthermore, new discoveries are being made in basic and translational research, which are likely to improve this situation further in the next 10 years. These include agents that block 1 or more of the disordered tumor proliferation signaling pathways, and that overcome resistance to already existing treatments. Targeted therapies such as antiangiogenic therapy with antivascular endothelial growth factor antibodies (bevacizumab) are finding their way into clinical practice. Large-scale research efforts are ongoing to provide a comprehensive understanding of all the genetic alterations and gene expression changes underlying glioma formation. These have already refined the classification of glioblastoma into 4 distinct molecular entities that may lead to different treatment regimens. The role of cancer stem-like cells is another area of active investigation. There is definite hope that by 2020, new cocktails of drugs will be available to target the key molecular pathways involved in gliomas and reduce their mortality and morbidity, a positive development for patients, their families, and medical professionals alike.
Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration.
The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide.
The fourth edition of the World Health Organization (WHO) classification of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a different age distribution, location, genetic profile or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic profiles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO ‘Blue Book', the classification is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classification is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the definition of brain tumours to the clinical oncology and cancer research communities world-wide
Now in its sixth edition, this highly-regarded book is designed as an introductory text on the principles of diagnosis, staging and treatment of tumours. The new edition: • Includes up-to-date information on the most recent techniques and therapies available • Emphasises the importance of multidisciplinary teamwork in the care of cancer patients • Highlights frequent dilemmas and difficulties encountered during cancer management • Features the important contributions of a new author Professor Daniel Hochhauser • Contains a brand-new two-colour design. As with previous editions, the first part of the book is devoted to the mechanisms of tumour development and cancer treatment. This is followed by a systematic account of the current management of individual major cancers. For each tumour there are details of the pathology, mode of spread, clinical presentation, staging and treatment with radiotherapy and chemotherapy. This accessible and practical resource will be invaluable to trainees in oncology, palliative care and general medicine, as well as specialist nurses, general practitioners, medical students, and professions allied to medicine. © 2005, 2003, 1998, 1995, reprinted 1987 & 1988, 1986 by R. Souhami and J. Tobias, 2010 J. Tobias and D. Hochhauser. All rights reserved.
It has been recently suggested that many types of cancer, including glioblastoma (GBM), contain functionally subsets of cells with stem-like properties named "cancer stem cells" (CSCs). These are characterized by chemotherapy resistance and considered one of the key determinants driving tumor relapse. Many studies demonstrated that Glioma stem cells (GSCs) reside in particular tumor niches, that are necessary to support their behavior. A hypoxic microenvironment has been reported to play a crucial role in controlling GSC molecular and phenotypic profile and in promoting the recruitment of vascular and stromal cells in order to sustain tumor growth. Recent advances in the field allow researches to generate models able to recapitulate, at least in part, the extreme heterogeneity found within GBM tumors. These models try to account for the presence of GSCs and more differentiated cells, the influence of different microenvironments enclosed within the mass, heterotypic interactions between GBM and stromal cells and genetic aberrations. Understanding the mechanism of action of the microenvironmental signals and the interplay between different cell types within the tumor mass, open new questions on how GSCs modulate GBM aggressiveness and response to therapy. The definition of these tumor features will allow to setup innovative multimodal therapies able to target GBM cells at multiple levels. Here, we will discuss the major advances in the study of GSC role in GBM and the therapeutic implications resulting from them, thus reporting the latest strategies applied to counteract and overcome GBM intrinsic resistance to therapy for a better management of patients.
Purpose of review:
Brain metastases are the most common neurologic complication related to systemic cancer. With continued improvements in systemic treatment, the incidence is expected to increase. This article reviews the clinical presentation, pathophysiology, prognostic factors, and treatment of metastatic brain tumors.
Recent findings:
Brain metastases from systemic cancer are up to 10 times more common than primary malignant brain tumors and are a significant burden in the management of patients with advanced cancer. Common presenting symptoms include headache, focal weakness or numbness, mental status change, and seizure. Management and treatment of metastatic brain tumors is complex and dependent on several factors, including age, performance status, number of metastases at presentation, and status of systemic disease. At the time of diagnosis, most patients have more than one brain metastasis, and treatment has traditionally consisted of whole-brain radiation therapy (WBRT). For those patients with single brain metastases, aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT has been shown to improve survival and neurologic outcomes compared with WBRT alone. In patients with a limited number of brain metastases, SRS alone is being increasingly explored as a treatment option that spares the upfront toxicity of WBRT. Currently, the role of chemotherapy is limited to experimental settings and salvage after radiation therapy.
Summary:
Patients with brain metastases have complex needs and require a multidisciplinary approach in order to optimize intracranial disease control while maximizing neurologic function and quality of life. Patients with multiple metastases, uncontrolled systemic disease, and poor functional status are typically treated with WBRT alone, whereas surgery and SRS may be used for additional local control in a subset of patients with fewer tumors and good functional status. The incorporation of neuropsychological outcomes, neurologic function, and quality of life as end points in future studies will offer further guidance for providing comprehensive care to patients with metastatic brain tumors.
A group of 86 patients with higher-grade glioma were investigated. Anaplastic astrocytoma (AA; WHO G III, n=29) showed bcl-2 expression in 48% of the cases, and immunohistochemical positivity was associated with a significantly shorter survival time (p=0.0068). In glioblastoma patients (GBM; WHO G IV, n=57), 51% of tumors were bcl-2 positive, but bcl-2 expression did not correlate significantly with survival (p=0.39). In a Cox proportional hazards regression model, bcl-2 positivity was confirmed as a negative prognostic parameter in AA, but not in GBM.
Almost without fail, one of the first questions a patient with a meningioma asks is, “What caused my tumor?” Many possible
etiologic factors have been proposed during the last century. Solid epidemiologic evidence for most of these factors has proven
fleeting. The availability and application of molecular biology techniques to investigate meningioma tumorigenesis, however,
has revealed many insights into how these tumors develop and progress on the cellular level. Not only will further understanding
of meningioma tumorigenesis answer the patient's “first” question, it may also lead to a better molecular classification to
complement the current morphologic classification of meningiomas (see Chapter 5) and, of course, hopefully lead to novel therapeutic
approaches to treat these tenacious tumors. Somewhat confounding efforts to elucidate the cause of meningioma is a lack of
universal agreement on the cell of origin for all meningiomas. Most meningiomas likely arise from mesodermal arachnoid cap
cells normally found at the apex of arachnoid granulations.1,2 Cleland, in 1846, is credited with first correlating these cells to meningioma formation.3 They are found adjacent to major venous sinuses where the majority of meningiomas occur, and the normal arachnoid cap cells
histologically resemble meningothelial meningiomas. However, meningiomas may occur at unusual sites such as choroid plexus,4,5 within bone,6,7 or, very rarely, outside the neural axis.8 For these tumors a different cell of origin may be possible, or they may arise from heterotopic meningothelial rests.
Li-Fraumeni syndrome (LFS) is a classic cancer predisposition disorder that is commonly associated with germline mutations of the p53 tumor suppressor gene. Examination of the wide spectrum of adult-onset and childhood cancers and the distribution of p53 mutations has led to a greater understanding of cancer genotype-phenotype correlations. However, the complex LFS phenotype is not readily explained by the simple identification of germline p53 mutations in affected individuals. Recent work has identified genetic events that modify the LFS phenotype. These include intragenic polymorphisms, mutations/polymorphisms of genes in the p53 regulatory pathway, as well as more global events such as aberrant copy number variation and telomere attrition. These genetic events may, in part, explain the breadth of tumor histiotypes within and across LFS families, the apparent accelerated age of onset within families, and the range of clinical outcomes among affected family members. This review will examine the clinical and genetic definitions of LFS and offer insight into how lessons learned from the study of this rare disorder may inform similar questions in other familial cancer syndromes.
Malignant brain tumours continue to be the cause of a disproportionate level of morbidity and mortality across a wide range of individuals. The most common variants in the adult and paediatric populations - malignant glioma and medulloblastoma, respectively - have been the subject of increasingly intensive research over the past two decades that has led to considerable advances in the understanding of their basic biology and pathogenesis. This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens.
Cancer stem cells (CSCs) have been identified in a growing number of hematopoietic and solid tissue malignancies and are typically recognized by virtue of the expression of cell surface markers. CD133, a stem cell marker, is now extensively used as a surface marker to identify and isolate brain tumor stem cells (BTSCs) in malignant brain tumors. However, CD133 as the marker to sort BTSCs suffered some controversies. In this review, we reviewed the rise of CD133, analyzed the efficiency of CD133 on identification and isolation of BTSCs, explained some controversial study results and summed up the role of CD133 and other effective CSCs markers in sorting CSCs in other tumors. We analyzed current limited reports and found that the expression of CD133 was correlated with poor clinical prognosis in brain tumors. Finally, we summarized the mechanisms of chemo- and radio- resistance of CD133+ brain tumor cell, especially emphasized that the aberrant activation of development pathways in BTSCs can be potential targets to BTSCs, and outlined current preclinical studies on killing BTSCs or sensitizing BTSCs to chemo- and radio-therapies.
Four types of cancer of the thyroid gland occur, each different in biological behaviour and in associated factors affecting prognosis. Knowledge of these differences makes it possible to determine appropriate treatment for each case and reduces the chance of undertreatment or overtreatment. Fortunately, most cancers of the thyroid gland are well differentiated and can be treated by conservative surgical measures; the results are low mortality, minimal morbidity, and good prognosis.
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