Central Nervous System Tumors In Adults Research Articles

RETROSPECTIVE ANALYSIS OF INTRACRANIAL AND INTRASPINAL SPACE OCCUPYING LESIONS AT A TERTIARY CARE CENTER- A FIVE YEAR STUDY

Background: Tumors of Central Nervous System constitute approximately 2% of all malignancies. Cancers of the central nervous system (CNS) are considered to be among the most notorious of all cancers. Low-grade cns tumors have been found over time to progress to high grade tumors. CNS is a common site for metastasis from other organs. Due to newer techniques used in radio diagnosis and stereotactic biopsies, more & more CNS tumors are being diagnosed & are being operated upon.
 Aims and objectives: The objective of this article is to provide an overview of intracranial and intraspinal space occupying lesions at a single tertiary care referral center. The aim was to study incidence of various lesions in light of the WHO classification of tumours of the central nervous system, 2016 and to study relevant statistics.
 Material and methods: A total of 124 cases were received between January,2007 & December, 2011 at Bharati Vidyapeeth Deemed University Medical College and Hospital, Pune. Intraoperative diagnosis was desired in 70 cases. The final diagnoses in all the cases were made on Hematoxylin and Eosin stained slides of routinely processed tissue.
 Results: Neoplastic lesions comprised 83.88 %, including metastatic tumors while 16.12 % were nonneoplastic. A wide range of histopathological spectrum of CNS tumors was observed and was classified according to WHO classification of CNS tumors, 2016. The primary CNS tumors were graded from Grade I to IV according to WHO grading system, 2016. Astrocytic tumors constituted the largest category with 33 cases and most of the astrocytomas were grade II at the time of diagnosis. Incidence was more in females than males and maximum number of lesions were seen in fifth and sixth decades of life.
 Conclusion: This study highlights the histological diversity of CNS tumors in both adults and children. The most common destructive but nonneoplastic lesions like, infections/abscesses, infarct and cysts can be diagnosed, by crush cytology and frozen section for the definitive management.

Documentation of Late-Effects Risks and Screening Recommendations for Adolescent and Young Adult Central Nervous System, Soft Tissue, or Bone Tumor Survivors Treated with Radiotherapy in British Columbia, Canada.

To assess the documentation of late-effects (LE) risks and screening recommendations in medical records of adolescent and young adult central nervous system (CNS), soft tissue, and bone tumor survivors. The medical records of all patients diagnosed with a CNS neoplasm, an arteriovenous malformation, a soft tissue, and bone tumor, at ages 15-39 years, treated between 1985 and 2010 with radiation therapy in the province of British Columbia, Canada, surviving >5 years, alive, and discharged to the community were assessed. The documentation of LE risks and screening recommendations were analyzed descriptively. In the medical records of 132 CNS tumor survivors and 94 soft tissue or bone tumor survivors, 15% and 13% included no documentation of LE risks, 21% and 22% included only nonspecific documentation, and 64% and 65% minimal documentation, respectively. Documentation of at least one specific LE risk increased significantly among CNS tumor patient charts (from 29% in 1980-1989, to 67% in 1990-1999, to 88% in 2000-2010, χ2 [2, N = 132] = 32.257, p < 0.000) and soft tissue or bone tumor patient charts (from 47% [1980-1989] to 56% [1990-1999] to 78% [2000-2010], χ2 [2, N = 94] = 6.702, p = 0.035). There was no documentation of a screening recommendation in 75% of CNS tumor patient charts and 91% of soft tissue and bone tumor charts. The documentation of LE risks and screening recommendations has been limited, highlighting the need to improve written communication with primary care providers.

Retrospective analysis of intracranial and intraspinal space-occupying lesions at a tertiary care center: A 5-Year study

Background: Incidence of central nervous system (CNS) tumors is 2% of all malignancies. Low-grade tumors progress to high-grade tumors. CNS is a common site for metastasis from other organs. Aims: The aim is to study the incidence of various lesions in light of the World Health Organization (WHO) classification of tumors of the CNS, 2016, and to study relevant statistics. Objectives: The objective of this study is to provide an overview of intracranial and intraspinal space-occupying lesions at a single tertiary care referral center. Materials and Methods: A total of 124 cases were studied. Intraoperative diagnosis was desired in 70 cases. The final diagnoses in all the cases were made by routine histopathology. Results: Neoplastic lesions comprised 83.88%, including metastatic tumors, while 16.12% were nonneoplastic. Classification and grading of CNS tumors was done according to the WHO, 2016. Astrocytic tumors constituted the largest category. Incidence was more in females than males and in the fifth and sixth decades of life. Conclusion: This study highlights histological diversity of CNS tumors in adults and children. The most common destructive but nonneoplastic lesions such as infections/abscesses, infarcts, and cysts can be diagnosed, by crush cytology and frozen section for the definitive management.

American Brain Tumor Association Adolescent and Young Adult Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012.

Brain and central nervous system (CNS) tumors found in adolescents and young adults (AYA) are a distinct group of tumors that pose challenges not only to treatment but also to reporting. Overall, cancer that occurs in this age group is biologically distinct from those that occur in both younger and older age groups1,2 posing significant challenges for clinicians. The most commonly diagnosed histologies in AYA vary from those in both children age (0-14 years), and older adults (40+ years).3,4 Prognosis and expected survival also varies between younger and older adults, with those who are diagnosed with brain and CNS tumors at younger ages having significantly longer survival. Despite this survival advantage, recent analyses have reported that while cancer survival has been improving overall, AYA have not experienced these same increases in survival and in some cases may have worse survival than those cancers diagnosed in persons over age 40 years.5 This report provides an in depth analyses of the epidemiology of brain and CNS tumors in adolescents and young adults in the United States (US), and is the first report to provide histology-specific statistics in this population for both malignant and non-malignant brain and other CNS tumors. In 2006, the National Institutes of Health, the National Cancer Institute (NCI) and the LiveStrong Young Adult Alliance conducted a Progress Review Group to investigate AYA Oncology entitled Research and care imperatives for adolescents and young adults with cancer: A Report of the Adolescent and Young Adult Oncology Progress Review Group. This group established the standard age range for the AYA group as 15-39 years. This is the age range used by the Surveillance Epidemiology and End Results (SEER) program of the NCI, as well as in the 2015 CBTRUS Statistical Report.3,6 Brain tumors and other CNS tumors are less common in AYA than in older adults, but they have a higher incidence than brain tumors in children (age 0-14 years).3 Non-malignant tumors are significantly more common in AYA than children (Average annual age adjusted incidence in age 15-39 years: 6.17 per 100,000; age 0-14 years: 0.79 per 100,000), while malignant tumors are slightly more common in those age 0-14 years (Average annual age adjusted incidence in 15-39 years old: 3.26 per 100,000; 0-14 years old: 3.73 per 100,000). While a rare cancer overall, brain and CNS tumors are among the most common cancers occurring in this age group (4.4% of all cancers in those age 15-39 years as compared to 32.4% in children age 0-14 years, and 2.2% of cancers in adults age 40+ years).3,4,7 Malignant brain and CNS tumors are the 11th most common cancer and the 3rd most common cause of cancer death7,8 in the AYA population. Incidence rates of brain tumors overall as well as specific histologies vary significantly by age. It is, therefore, important to provide an accurate statistical assessment of brain and other CNS tumors in the adolescent and young adult population to better understand their impact on the US population and to serve as a reference for afflicted individuals, for researchers investigating new therapies and for clinicians treating patients.

IMPS-18OVERCOMING TGFβ-MEDIATED SUPPRESSION OF NK CELL CYTOTOXICITY IN MEDULLOBLASTOMA

Medulloblastoma is the most common pediatric central nervous system (CNS) malignancy, with generally favorable outcomes depending on the molecular subtype. However, current therapies have significant long-term neurologic morbidities, and recurrent/relapsed disease portends a dismal prognosis. Therefore, novel, innovative, and safe therapies are needed. Immune cell therapy is an appealing, targeted approach, and NK cells have shown activity against some adult CNS tumors. However, NK cell adoptive cell therapy may be susceptible to the immunosuppressive effects of TGFβ, either produced by the tumor or the surrounding microenvironment. We have developed a robust expansion platform that yields NK cells in sufficient numbers and cyotoxic potency for therapy. We now seek to overcome TGFβ-mediated suppression to enhance NK cell cytotoxicity for CNS tumors. We show that expanded NK cells are highly cytotoxic against medulloblastoma cell lines, but have diminished cytotoxicity toward medulloblastoma in the presence of soluble TGFβ. The decrease in cytotoxicity correlates with a decrease in NKG2D expression on the expanded NK cells, as has been described for freshly-obtained peripheral blood NK cells. However, we also show that NK cells can be expanded in the presence of TGFβ without affecting their proliferative rate, and that the presence of TGFβ alters the CD16 and KIR expression profile, while maintaining NKG2D levels. Furthermore, NK cells that are expanded in the presence of TGFβ are resistant to the immunosuppressive effects of additional TGFβ. We are also exploring genetic and pharmacologic approaches to generating TGFβ-resistance. Understanding the mechanisms of NK cell immunosuppression by medulloblastoma may lead to a better understanding of the disease, and improved pre-clinical models and clinical trials of NK cell adoptive therapy for medulloblastoma and other pediatric CNS malignancies.

Progress in the application of molecular biomarkers in gliomas

Gliomas are a common adult central nervous system tumor, and glioblastoma (GBM), which has a poor prognosis, is the most lethal of all gliomas. The overall survival of GBM patients is only 12–14 months after diagnosis. With progress in the precision of personal medication, therapeutic options for various tumors have become gradually dependent on the molecular profiles of patients. GBM is one of the tumors in which treatment response relies largely on the molecular characteristics of the tumor. Therefore, awareness of the genetic background of each patient will help decision-making regarding the best treatment strategy to use. In this review, a novel molecular classification of gliomas based on recent findings of their genetic characteristics is introduced. Representative molecular markers, such as IDH1 mutation, 1p19q co-deletion, MGMT promoter methylation and EGFRvIII amplification, are described. Furthermore, the development of non-coding RNAs and omics studies of GBM are briefly discussed. Finally, a novel concept for non-invasive detection that could facilitate both diagnosis and treatment monitoring is presented. There is no doubt that the use of molecular profiling by biomarkers will indeed improve the overall survival and quality of life of GBM patients.

Radiotherapy for brain metastases: are we getting better?

Brain metastases are the most common malignant adult CNS tumor. The blood brain barrier (BBB) prevents many drugs from achieving therapeutic concentrations in the central nervous system (CNS), leaving the brain as a potential sanctuary site of disease and underscoring the importance of radiotherapy. Neurons, glial cells and vascular endothelium are prone to radiation-induced damage. Efforts have been made to reduce radiation-induced toxicity and increase efficacy (Stereotactic radio-surgery - SRS, advanced radiation-techniques that allow decreasing the dose to the hippocampi, while intensifying the radiation dose to large brain metastases or administering neuroprotective or radiation sensitizing agents during whole brain radiotherapy -WBRT in order to increase the therapeutic ratio). Surgery, radiotherapy and new pharmacological agents may become advantages for specific patient subgroups or in specific disease stages. Choosing how to treat brain metastases, must take into consideration patients and disease parameters (the primary tumor, age and performance status, systemic and brain tumor burden), and the potential risks and benefits of a treatment tool emphasising QOL considerations. Which modality to apply and when, is often a matter of local practice and treatment availability since level I evidence is lacking. The technology behind WBRT, FSR and SRS has substantially advanced over the previous decade, however only formal clinical trials will allow a definite answer to the question - are we getting better?

ED-07 * TRENDS IN CENTRAL NERVOUS SYSTEM TUMOR INCIDENCE RELATIVE TO OTHER COMMON CANCERS IN ADULTS, ADOLESCENTS, AND CHILDREN IN THE UNITED STATES, 2000-2010

SIGNIFICANCE: Time trends in cancer incidence rates (IR) measure the changing burden of cancer on a population over time. Overall IR of cancer in the US is declining, but trends in common cancers may obscure trends in rare cancers that contribute disproportionately to mortality and morbidity. We examined incidence time trends of the most common cancers in children, adolescents, and adults between 2000 and 2010 as compared to central nervous system tumors (CNST). METHODS: Data from the United States Cancer Statistics and the Central Brain Tumor Registry of the United States were used to analyze incidence trends by selected histologies and age. Age-adjusted IR per 100,000 population with 95% confidence intervals (95% CI) and Annual Percent Change (APC) with 95% CIs were calculated for CNST and selected common cancers overall, by age, gender, race/ethnicity, selected CNST histologies, and CNST malignancy status. RESULTS: In adults, there were significant decreases in malignant CNST (2008-2010: APC = -3.1), colon (2000-2010: APC = -3.1), breast (2000-2010: APC = -0.8), lung (2000-2010: APC = -1.1), and prostate cancer (2000-2010: APC = -2.4), but a significant increase in non-malignant CNST (2004-2010: APC = 2.7). In adolescents, there were significant increases in malignant CNST (2000-2008: APC = 1.0) and non-malignant CNST (2004-2010: APC = 3.9). In children, there were significant increases in malignant CNST (2000-2010: APC = 0.6), acute lymphocytic leukemia (2000-2010: APC = 1.0), and non-Hodgkin lymphoma (2000-2010: APC = 0.6). CONCLUSIONS: Between 2000 and 2010, there were significant decreases in malignant CNST and other common cancers in adults, significant increases in malignant CNST in adolescents, significant increases in malignant CNST and other common cancers in children, and significant increases in non-malignant CNST in adults and adolescents. Surveillance of IR trends is an important way to measure the changing public health and economic burden of cancer; histology-specific analyses are essential to measure the potential disproportionate impact of rare cancers.

Abstract PR12: Overcoming immune evasion in pediatric hematologic and solid tumor malignancies: A preclinical study using a humanized anti-CD47 antibody

Abstract CD47 is an anti-phagocytic cell surface protein mediating cancer cell evasion of phagocytosis by the innate immune system. Preclinical data suggest that CD47 is appears to be an indispensable means by which many cancer cells, including cancer stem cells, overcome intrinsic expression of their pro-phagocytic “eat me” signals. Blockade of CD47 with mAbs enables phagocytosis of cancer cells in vitro and in vivo. We have developed a novel humanized mAb (huCD47-Ab) that specifically binds CD47 and blocks it from interacting with its ligand, signal regulatory protein–α; (SIRPα), on phagocytic cells, resulting in the phagocytosis and elimination of cancer cells through their “eat me” signals. Normal cells generally do not express eat me signals, and are unaffected by CD47 blocking mAb. We observed expression of CD47 on aggressive pediatric tumors, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), Ewing's sarcoma, neuroblastoma, and several cancers of the central nervous system (CNS), including atypical tetroid rhabdoid tumor (ATRT), primitive neuroectodermal tumor (PNET), medulloblastoma (MB), and pediatric high-grade glioma (pHGG). In-vitro phagocytosis assays, of primary patient samples shows significant engulfment by human peripheral blood derived macrophages upon incubation with the HuCD47-Ab antibody as compared to control. Furthermore we observe potent anti-tumor efficacy and survival benefit in MB, pHGG, ATRT and PNET orthotopic xenografts models establishing the ability of the huCD47 antibody to across the blood brain barrier by the CD47 blocking antibody. Using a novel human neural stem cell/brain tumor co-engraftment orthotopic xenograft model we show specificity of the HuCD47 antibody to only tumor cells and not normal human cells. We further observe potent anti-tumor efficacy in non-CNS tumor (ALL, AML and Osteosarcoma) xenograft models as well. Furthermore we demonstrate that HuCD47-Ab can be administered safely to non-human primates at therapeutic serum levels. Pre-IND and IMPD meetings with the FDA in the US and the MHRA in the UK, have been held, and the clinical trials for adult patients with advanced stage malignancies will start in early 2014. After determining safety in these phase I trials, we initiate protocols for adult CNS tumors as part of expansion cohorts, and subsequently extend the trials to pediatric cancer patients, given manageable toxicity and signs of efficacy in the adult patients. This abstract is also presented as Poster A86. Citation Format: Siddhartha S. Mitra, Sharareh Gholamin, Jens-Peter Volkmer, Abdullah Feroze, Jie Liu, Achal Achrol, Lijuan Wang, Leanne Sayles, Michael Zhang, Kathleen Sakamoto, Michelle Monje-Deisseroth, Yoon-Jae Cho, Alejandro Sweet-Cordero, Ravi Majeti, Samuel Cheshier, Irving Weissman. Overcoming immune evasion in pediatric hematologic and solid tumor malignancies: A preclinical study using a humanized anti-CD47 antibody. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR12.

P17.69 * FOTEMUSTINE TRATMENT: WHAT ABOUT GLIOBLASTOMA PATIENTS' QUALITY OF LIFE?

Glioblastoma Multiforme (GBM) is the most common and aggressive type of adult primary central nervous system tumor. The median survival in GBM patients is about 14 months. The prognosis of GBM is poor and in addition there is a very high probability of recurrence. For most patients with newly diagnosed GBM, the gold standard first-line treatment is represented by postoperative radiotherapy plus temozolomide (TMZ). There is not yet a standard of care for treatment of recurrent GBM. Recent phase II studies have demonstrated the efficacy of fotemustine (FTM) in the treatment of recurrent gliomas. To the best of our knowledge, however, no studies have investigated the quality of life in GBM patients treated with FTM as second-line treatment. We therefore sought to assess the quality of life of recurrent glioblastoma patients treated with FTM standard schedule as proposed by Addeo et al. (a dose of 80 mg/sqm every 2 weeks for five consecutive administrations as the induction phase and every 4 weeks at 80 mg/sqm as the maintenance phase). We approached 54 recurrent glioblastoma patients treated with FTM. Of these 54 eligible patients, we excluded 4 patients because they were not willing to participate in the research study and 10 because they did not meet one of the inclusion criteria, i.e. Mini Mental State Examination ≥ 25. We evaluated overall patients' quality of life through various tools: European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC brain cancer module (QLQ-BN20), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory form Y (STAI-Y), Hospital Anxiety and Depression Scale (HADS), Psychological Distress Inventory (PDI). Of the total of 40 patients, 18 patients completed the battery of tests both at the beginning of therapy and 2 months after the start of therapy. We found that patients reported higher levels of distress at two months after the start of therapy (mean value = 22.4) as compared to those experienced at the beginning of the therapy (mean value = 24.5), t (17) = -2.59, p < .05). Although patients' anxiety and depression levels and their quality of life were not compromised, it is interesting to note that distress levels are formerly high at the beginning of the therapy and increase after two months. This finding underlines the necessity to taking into account patients' emotional distress in the first phase of second-line treatment in order to promote a better adjustment to a new condition of life in which patients have mainly to deal with the fact that they cannot be cured of their disease.

O8.10 * A MODEL FOR RESEARCH INITIATIVES FOR RARE CANCERS: THE COLLABORATIVE EPENDYMOMA RESEARCH NETWORK (CERN)

Ependymoma represents less than 5% of adult central nervous system (CNS) tumors and a higher percentage of pediatric CNS tumors, but it remains an orphan disease. The majority of the laboratory-based research and clinical trials have been conducted in the pediatric setting, a reflection of the relative incidence and funding opportunities. CERN, created in 2006, was designed to establish a collaborative effort between laboratory and clinical research and pediatric and adult investigators. The organization of CERN is based on integration and collaboration among five projects. Project 1 contains the clinical trials network encompassing both adult and pediatric centers. This group has completed 2 clinical trials with more underway. Project 2 is focused on molecular classification of human ependymoma tumor tissues and also contains the tumor repository which has now collected over 600 fully clinically annotated CNS ependymomas from adults and children. Project 3 is focused on drug discovery utilizing robust laboratory models of ependymoma to perform high throughput screening of drug libraries, then taking promising agents through extensive preclinical testing including monitoring of drug delivery to tumor using state of the art microdialysis. Project 4 contains the basic research efforts evaluating the molecular pathogenesis of ependymoma and has successfully translated these findings by generating the first mouse models of ependymoma that are employed in preclinical drug development in Project 3. Project 5 studies patient outcomes, including the incorporation of these measures in the clinical trials. This project also contains an online Ependymoma Outcomes survey, collecting data on the consequences of the disease and its treatment. These projects have been highly successful and collaborative. For example, the serial measurement of symptom burden (Project 5) has greatly contributed to the evaluation of treatment efficacy of a clinical trial (Project 1) and investigators from Project 2 are evaluating potential predictive markers from tumor tissue from the same clinical trial. Results from genomic and molecular discoveries generated by Project 4 were evaluated using the clinical material from the Tumor Registry (Project 2). Agents identified from the high throughput screening in Project 3 are being used to create novel clinical trials (Project 1). As a complimentary effort, CERN's community outreach efforts provide a major gateway to patients, families, caregivers and healthcare providers, contributing to greater awareness of ependymoma, and supporting clinical trial accrual in Project 1. In summary, CERN has successfully created a collaborative, multi-national integrated effort combining pediatric- and adult-focused investigators spanning from basic science to patient outcomes measures. This research paradigm may be an effective approach for other rare cancers.

Is CRX Protein a Useful Marker in Differential Diagnosis of Tumors of the Pineal Region?

The cone-rod homeobox (CRX) is a gene that belongs to the member of the orthodenticle homeobox (Otx) family, with important function in development and differentiation of retinal and pineal cells. Moreover, CRX appears to be specifically expressed in pineal tumors and retinoblastomas. We performed an immunohistochemical study on 91 pediatric and adult central nervous system tumors, plus 2 normal brain samples. Our results demonstrated that CRX is expressed not only in pineal parenchymal tumors and retinoblastoma, but also in a some medulloblastomas and supratentorial primitive neuroectodermal tumors. None of the glial tumors screened were positive for CRX. In conclusion, CRX could be useful in surgical neuropathology for the differential diagnosis of pineal region tumors, in particular to discriminate pineal tumors from glial tumors.

Assessment of expression of epidermal growth factor receptor and p53 in meningiomas

Meningiomas represent about 30% of primary adult central nervous system tumors. Though slow growing, they recur, causing significant morbidity and mortality. The objective of the following study is to grade meningiomas according to World Health Organization (WHO) 2007 criteria and to correlate the grade with degree of expression of epidermal growth factor receptor (EGFR) and p53. Meningiomas diagnosed in the year 2010 in the Department of Pathology of our institute, were included in the study. Clinical and radiological findings were noted from medical records. The histopathology slides were reviewed and the tumors were graded according to WHO 2007 criteria. Tissue microarrays (TMA) were prepared and immunohistochemical analysis with epithelial membrane antigen, Vimentin, Ki67, EGFR and p53 was performed on the TMA slides. A total of 79 meningiomas diagnosed during the study period included 30 male and 49 female patients with an age range of 10-75 years. There was a female preponderance with M:F ratio of 1:1.63. EGFR was found to be higher in grade I (82.93%) compared with grade II (35.71%) and grade III tumors (20%) with an overall positivity of 60.81%. Mean p53 indices were higher in grade III (50%) compared with grade II (39.29%) and grade I tumors (38.46%) with an overall positivity of 39.44%. Ki67 labeling index (LI) was significantly high in grade III (16.4%) compared with grade II (6.46%) and grade I tumors (3.13%). EGFR expression and Ki67 LI correlated with grade of meningioma P < 0.0001 and P < 0.0001 respectively which were statistically significant whereas p53 expression did not correlate (P - 0.90).

Molecular Cytogenetic Study of the NF2 Gene Deletion in Meningioma in Sudanese Patients.

Meningioma is the second most common adult central nervous system tumor. Mutations and/or deletions within the tumor suppressor gene neurofibromatosis type 2 (NF2) are associated with meningioma development and progression. We studied 29 meningioma samples by cytogenetic analysis and interphase fluorescence in situ hybridization (I-FISH) using a locus-specific probe for the NF2 gene region. We detected loss of the NF2 gene in all samples except for one. In 10 of the 29 samples, karyotypic analyses confirmed the I-FISH results and revealed additional numerical and/or structural rearrangements in nine of them. Our study confirmed: i) the limited role of banding cytogenetics in assessing chromosomal rearrangements in meningioma, as this tumor is hard to be grown in cell culture; ii) we could show that two-color I-FISH is well-suited for NF2-deletion screening. Our results were in accordance with those of comparable studies, even though the frequency of 97.0% of meningiomas with NF2 deletions is exceptionally high in the studied Sudanese patients.

Trends in mortality from tumors of the central nervous system in adults, Rio de Janeiro, 1980-2010

Background: Tumors of the Central Nervous System (CNS) are relatively rare in adults, but they present a high mortality rate: only half of the cases survive one year after diagnosis. Aims: To describe the mortality pattern from CNS tumors in adults in the city of Rio de Janeiro, Brazil, from 1980 to 2010. Methods: We conducted a descriptive study of deaths through the Consolidated Information System on Mortality. We calculated crude and adjusted mortality rates, as well as gender, age and tumor-specific mortality rates. For trend analysis, regression models were performed and the EAPC (Estimated Annual Percentage Change) was calculated. Results: In 1980, the mortality ratewas4.97/100,000 person-years, while in 2010the ratereached7.91/100,000 person-years. During the study period, most deaths were observed in white men, and occurred due to malignant tumors located in the encephalon. The standardized mortality rate for CNS tumors in adults over age 19 years increased 1% annually throughout the period. This increase was greater in women: 1.7% per year. Conclusions: The patterns of mortality from CNS tumors in the municipality of Rio de Janeiro are in accordance with global trends. Therefore, it is recommended to develop analytical studies to identify risk factors associated with these tumors, which may include genetic and environmental factors.

MiR-106a-5p Inhibits the Proliferation and Migration of Astrocytoma Cells and Promotes Apoptosis by Targeting FASTK

Astrocytomas are common malignant intracranial tumors that comprise the majority of adult primary central nervous system tumors. MicroRNAs (miRNAs) are small, non-coding RNAs (20–24 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In our previous studies, we found that the downregulation of miR-106a-5p in astrocytomas is associated with poor prognosis. However, its specific gene target(s) and underlying functional mechanism(s) in astrocytomas remain unclear. In this study, we used mRNA microarray experiments to measure global mRNA expression in the presence of increased or decreased miR-106a-5p levels. We then performed bioinformatics analysis based on multiple target prediction algorithms to obtain candidate target genes that were further validated by computational predictions, western blot analysis, quantitative real-time PCR, and the luciferase reporter assay. Fas-activated serine/threonine kinase (FASTK) was identified as a direct target of miR-106a-5p. In human astrocytomas, miR-106a-5p is downregulated and negatively associated with clinical staging, whereas FASTK is upregulated and positively associated with advanced clinical stages, at both the protein and mRNA levels. Furthermore, Kaplan-Meier analysis revealed that the reduced expression of miR-106a-5p or the increased expression of FASTK is significantly associated with poor survival outcome. These results further supported the finding that FASTK is a direct target gene of miR-106a-5p. Next, we explored the function of miR-106a-5p and FASTK during astrocytoma progression. Through gain-of-function and loss-of-function studies, we demonstrated that miR-106a-5p can significantly inhibit cell proliferation and migration and can promote cell apoptosis in vitro. The knockdown of FASTK induced similar effects on astrocytoma cells as those induced by the overexpression of miR-106a-5p. These observations suggest that miR-106a-5p functions as a tumor suppressor during the development of astrocytomas by targeting FASTK.

A Dosimetric Study of the Feasibility of Hippocampal and Hair Sparing Whole Brain Irradiation with Intensity Modulated Radiation Therapy (IMRT)

Hematogenous metastases are the most common adult central nervous system tumors. The standard treatment for these patients continues to include whole brain irradiation (WBI). Two major iatrogenic complications include hair loss and neurocognitive deficits including short-term memory loss. In the current study, we examined the feasibility of sparing the hippocampus and hair-bearing scalp using IMRT.

Current Signal Transduction Therapy for Brain Tumors Review Article

Primary central nervous system (CNS) tumors account for only 2% of all adult cancers and the annual incidence of primary malignant brain cancer was 7.3 per 100,000 person-years. Malignant gliomas are the most common primary CNS tumors in adults accounting for 78% of all primary malignant CNS tumors. Glial neoplasms represent about 40% of all primary CNS tumors, over three quarters being malignant. The median survival of patients with glioblastoma was 14.6 months after tereatment. Although recent basic and clinical research of malignant gliomas has improved, there is limitation of the outcome of the patients with malignant gliomas. Treatment strategy of tumor resection and radiotherapy for this tumor is still important and a recent advance in the use of concurrent chemo-radiation has improved survival in a large fraction of patients. New approaches using these signal transductional and gene researches are developing and may promise for further survival gains in the near future. Keywords: Signal transduction, brain tumors, target therapy, gene therapy

Detection of human herpesvirus-6 in adult central nervous system tumors: predominance of early and late viral antigens in glial tumors

The purpose is to determine the incidence of active and latent human herpesvirus-6 (HHV-6) infection in a large cohort of adult primary and recurrent CNS tumors. We screened a tissue microarray (TMA) containing more than 200 adult primary and recurrent CNS tumors with known clinical information for the presence of HHV-6 DNA by in situ hybridization (ISH) and protein by immunohistochemistry (IHC). One hundred six of 224 (47%) CNS tumors were positive for HHV-6 U57 Major Capsid Protein (MCP) gene by ISH compared to 0/25 non tumor control brain (P = 0.001). Fourteen of 30 (47%) tumors were HHV-6 MCP positive by nested PCR compared to 0/25 non-tumor brain controls (P = 0.001), revealing HHV-6 Variant A in 6 of 14 samples. HHV-6A/B early (p41) and late (gp116/64/54) antigens were detected by IHC in 66 of 277 (24%) (P = 0.003) and 84 of 282 (35%) (P = 0.002) tumors, respectively, suggesting active infection. HHV-6 p41 (P = 0.645) and gp116/64/54 (P = 0.198) antigen detection was independent of recurrent disease. Glial tumors were 3 times more positive by IHC compared to non glial tumors for both HHV-6 gp116/64/54 (P = 0.0002) and HHV-6 p41 (P = 0.004). Kaplan Meier survival analysis showed no effect of HHV-6 gp116/64/54 (P = 0.852) or HHV-6 p41 (P = 0.817) antigen detection on survival. HHV-6 early and late antigens are detected in adult primary and recurrent CNS tumors more frequently in glial tumors. We hypothesize that the glial-tropic features of HHV-6 may play an important modifying role in tumor biology that warrants further investigation.

Seasonal patterns of presentation in primary malignant brain tumors and metastases based on a retrospective neuropathologic database

AbstractSeasonal variation in the occurrence of several classes of cancer has been observed in the past. However, evidence for such trends in adult central nervous system tumors is scant. We have analyzed the monthly occurrence rates of glioblastomas as well as carcinomas metastatic to the brain in 6,154 neurosurgical patients in Toronto selected from the University Health Network neuropathologic database over a seven-year period (July 2001 to June 2008). The electronic repository was representative of the patient population in southern Ontario, and the case accession dates in the database reflected the onset patterns of the selected tumor groups. A modification to Nam's alternative method to the Roger test was developed to statistically quantify the differences. The results demonstrated significant cyclical occurrence rates of glioblastomas with seasonal peaks in March, June, September and December. Moreover, significant increases in the rates of carcinomas metastatic to the brain were found for January, April and August. Surprisingly, the monthly frequency for the two tumor groups resembled each other in peak/trough topology. Semiquantitative comparison of major histologic features between glioblastomas from a peak (March) and trough (November) month in the seven-year period was performed, revealing differences in the amount of perivascular lymphocytic inflammation. This novel observation may have profound implications for the understanding of the biology of adult central nervous system tumors.