Meena Bhattacharjee

Cytogenetic analysis of 120 primary pediatric brain tumors and literature review

We report chromosome results from 108 pediatric central nervous system (CNS) tumors. From our data and those in the literature we found that (1) cerebellar and low-grade astrocytic tumors, including gangliogliomas, are most often karyotypically normal; (2) supratentorial tumors were more frequently high-grade tumors that demonstrated a complex karyotype. Chromosome abnormalities were similar to those described in adult astrocytic tumors, namely, +7, 9p abnormalities, and -10; (3) primitive neuroectodermal tumors (PNETs) were virtually always karyotypically abnormal with a high frequency of +7, -8, i(17q), and -22. PNETs with -22 may represent a subset of tumors; (4) typical choroid plexus papillomas showed a normal karyotype, atypical papillomas showed a hyperdiploid karyotype (with +7, +12, and +20), choroid plexus carcinomas showed a hyperhaploid karyotype; (5) a few ependymomas showed hyperdiploidy or hypertetraploidy; (6) germ cell tumors showed complicated karyotypes; (7) monosomy 22 or 22q abnormalities appear to be a recurring finding in the malignant rhabdoid tumors; and (8) meningiomas showed -22 or 22q abnormalities associated with a complex karyotype. In general, in pediatric CNS tumors the least differentiated neoplasms have the greatest number of cytogenetic abnormalities. However, our present morphologic criteria for tumor diagnosis do not always correlate with a consistent karyotype, and further study of pediatric brain tumor morphology, site, behavior, and karyotype is required.

Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation.

Germline mutations of the INI1 gene predispose children to the development of rhabdoid tumors. Reports of familial cases, however, are extremely rare.

Crosstalk between Medulloblastoma Cells and Endothelium Triggers a Strong Chemotactic Signal Recruiting T Lymphocytes to the Tumor Microenvironment

Cancer cells can live and grow if they succeed in creating a favorable niche that often includes elements from the immune system. While T lymphocytes play an important role in the host response to tumor growth, the mechanism of their trafficking to the tumor remains poorly understood. We show here that T lymphocytes consistently infiltrate the primary brain cancer, medulloblastoma. We demonstrate, both in vitro and in vivo, that these T lymphocytes are attracted to tumor deposits only after the tumor cells have interacted with tumor vascular endothelium. Macrophage Migration Inhibitory Factor (MIF)” is the key chemokine molecule secreted by tumor cells which induces the tumor vascular endothelial cells to secrete the potent T lymphocyte attractant “Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES).” This in turn creates a chemotactic gradient for RANTES-receptor bearing T lymphocytes. Manipulation of this pathway could have important therapeutic implications.

p53 protein in pediatric malignant astrocytomas: a study of 21 patients.

Malignant astrocytomas are uncommon brain tumors in children and it isknown that astrocytic tumors with similar degrees of histologic anaplasia often show different biologic behaviour. Their uncommonoccurrence has resulted in relatively few studies of the molecular biology and genetics of pediatric malignant astrocytomaswith somewhat conflicting results, in contrast with the many studies addressing astrocytomas in adults. p53 immunoreactivity has been usedto screen tissues for the abnormal presence of the p53 protein and abnormal immunoreactivity has been demonstratedin one-half to two-thirds of adult astrocytomas. We studied the frequency of p53 immunoreactivity and gene alteration in 21 childrenwith malignant astrocytomas (anaplastic astrocytomaand glioblastoma multiforme) and analysed the survival of patientswith p53 immunoreactive versus non-reactive tumors. Of the cases examined, 8 were anaplastic astrocytoma (AA) and 13 were glioblastomamultiforme (GM). We found that the overall frequencyof p53 immunoreactivity of 47% in this group of pediatric malignant astrocytomas is similar to that reported for adult astrocytomas. The median survival in both p53-positive and p53-negative groups of pediatric malignant astrocytomas wassimilar; however, the number of deaths in each group and the distributionof p53 scores is not statistically significant. Further studies to precisely identify p53 and other genetic mutations in pediatric gliomas are needed to understand their biology and the rationale for therapeutic options.

Early recurrence in standard-risk medulloblastoma patients with the common idic(17)(p11.2) rearrangement

Medulloblastoma is diagnosed histologically; treatment depends on staging and age of onset. Whereas clinical factors identify a standard- and a high-risk population, these findings cannot differentiate which standard-risk patients will relapse and die. Outcome is thought to be influenced by tumor subtype and molecular alterations. Poor prognosis has been associated with isochromosome (i)17q in some but not all studies. In most instances, molecular investigations document that i17q is not a true isochromosome but rather an isodicentric chromosome, idic(17)(p11.2), with rearrangement breakpoints mapping within the REPA/REPB region on 17p11.2. This study explores the clinical utility of testing for idic(17)(p11.2) rearrangements using an assay based on fluorescent in situ hybridization (FISH). This test was applied to 58 consecutive standard- and high-risk medulloblastomas with a 5-year minimum of clinical follow-up. The presence of i17q (ie, including cases not involving the common breakpoint), idic(17)(p11.2), and histologic subtype was correlated with clinical outcome. Overall survival (OS) and disease-free survival (DFS) were consistent with literature reports. Fourteen patients (25%) had i17q, with 10 (18%) involving the common isodicentric rearrangement. The presence of i17q was associated with a poor prognosis. OS and DFS were poor in all cases with anaplasia (4), unresectable disease (7), and metastases at presentation (10); however, patients with standard-risk tumors fared better. Of these 44 cases, tumors with idic(17)(p11.2) were associated with significantly worse patient outcomes and shorter mean DFS. FISH detection of idic(17)(p11.2) may be useful for risk stratification in standard-risk patients. The presence of this abnormal chromosome is associated with early recurrence of medulloblastoma.

A web page to teach neurology and neuropathology to medical students.

Sir: We describe a computer-based module developed to teach neurology and neuropathology to sophomore medical students, made available on both CD-ROM and the World Wide Web. Student reaction to the module was encouraging and exam scores also appeared to improve in the class that used this module. A medical student must gain a working knowledge of the intricacies of the nervous system and its pathology in a very limited amount of time. In the United States, neuropathology is usually taught during the second year of medical school, over about a 1±3 week period. In recent years there also has been increasing pressure to advance relevant clinical knowledge in the allied ®elds of neurology, neuropsychiatry and neuroradiology within the teaching of neuropathology. Successful teaching of neuropathology involves several factors. Obviously, the main goal is that students learn the material. There are many ways to establish how well this has been accomplished, such as class exams, preceptor evaluations and performance in subsequent clinical rotations in areas such as neurology, neurosurgery and neuroradiology. Standardized exams, such as the National Board of Medical Examiners (NBME) shelf exam, can provide a reasonable means of comparison [6]. Although instructors would like their students to perform well on exams, neuropathology also should be an enjoyable and stimulating experience for the students. How best to accomplish these goals in the teaching of neuropathology has been the subject of research and debate [1,2]. Case-based approaches are increasingly popular [5], as is the use of computer technology [4]. In previous studies we have investigated what students found useful in a web page to teach pathology and have found that students generally like computer-based teaching modules [3]. Students like web pages that provide images and material in a format that is easily organized for review. Student complaints often focused on pages that loaded slowly, or that required complicated or memory-hungry plug-ins. The principles learned from these earlier surveys were applied to construct a web page to teach neuropathology to second year medical students. The same material was provided on a CD-ROM and distributed free to the students during their neuropathology block. The success of this venture was measured in two ways: by examining student scores on the neuropathology portion of the NBME shelf exam; and by surveying student opinions of the course, the web page and the neuropathology computer module. A module was constructed to cover the following topics: congenital malformations; hydrocephalus; brain herniation; intracranial haemorrhage; cerebrovascular disorders and cerebral haemorrhage; degenerative, demyelinating, and neuromuscular diseases; infectious diseases of the nervous system; and tumours and phakomatoses of the nervous system. This module included digital images, case presentations and review questions. All material was written in simple Hypertext Markup Language (HTML). Images were stored as industry-standard formats (jpg; joint expert photographic ®les or gif; graphic interface ®les) so that any web browser could be used. Material was made available to students at the following web address: Http://www.tmc.tulane.edu/ student/2002/neuropathology/start_here.htm. Material was also provided on CD-ROM. Student performance in neuropathology was compared by examining performance in the neuropathology section of the NBME shelf exam for the class that had access to the neuropathology module (class of 2002) to the previous years class (class of 2001). In order to protect the integrity of the NBME exam, and to correct for variations in the comparative dif®culty of different questions on exams from different years, scores are reported as normalized to the national average rather than as raw scores (Figure 1). After the neuropathology block, students were asked to ®ll out a survey that included their overall opinion of the neuropathology CD-ROM (Figure 2) and their preferred media for accessing neuropathology material outside of class (Figure 3). Students were also encouraged to write comments about the neuropathology module in general. Con®dence intervals for percentages were calculated for extrapolation to an in®nite population using an alpha of 0.95. Comparisons between groups were made by student t-test. Neuropathology and Applied Neurobiology (2001), 27, 142±144

Vein of Galen aneurysmal malformations associated with high output cardiac failure: Report of three autopsy cases

Vein of Galen aneurysmal malformations (VGAMs) are rare congenital vascular, malformation. The malformation usually develops between the 6th to 11th wk of gestation. We report three autopsy cases, all prenatally diagnosed by ultrasound or fetal magnetic resonance imaging with VGAM with associated high-output cardiac failure. Prenatal fetal echocardiogram on two patients showed cardiomegaly, ventricular dilatation, pulmonary hypertension and reversed aortic flow. The cause of death in all the three patients was high-output cardiac failure due to VGAM. The autopsy findings confirmed feeding arteries from posterior cerebral arteries to VGAM in all patients. Other significant neuropathologic findings at autopsy were severe hydrocephalus, polymicrogyria, germinal matrix hemorrhage, periventricular leukomalacia, and microcalcification. The findings support that VGAM may be due to abnormal arterial venous communication and the most common cause of death in these patients is high-output cardiac failure. The presence of other associated brain abnormalities indicates a poor prognosis.