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David N Louis

Publications and source records attributed to David N Louis.

71 records · Page 4Linked to original sources
PubMed2002

Transcript map of the 3.7-Mb D19S112-D19S246 candidate tumor suppressor region on the long arm of chromosome 19.

Allelic losses of the q13.3 region of chromosome 19 have been documented in malignant gliomas, neuroblastomas, and ovarian carcinomas, strongly suggesting the presence of a 19q13.3 tumor suppressor gene. Deletion mapping in tumors over the past decade has narrowed the candidate region considerably but has produced partially conflicting results, with some small candidate regions defined only by isolated tumors with deletions. Mutation and expression screening of genes from the most likely candidate regions has failed to identify the gene of interest, perhaps because of the conflicting deletion mapping data. The recently increased public availability of human genomic sequence, combined with improved bioinformatics capabilities, has now made it possible to map much larger candidate regions in considerable detail. We have manually generated a transcript map that spans most of the 19q13.3 tumor suppressor candidate region, from D19S219 to D19S246, with a resolution and quality superior to that of computer-generated maps. These results are presented in the hope that an improved map of the candidate region will facilitate further widespread screening and eventual identification of the gene or genes deleted in human gliomas, neuroblastomas, and ovarian cancers.

Chromosomes, Human, Pair 19↗
PubMed2002

Influence of unrecognized molecular heterogeneity on randomized clinical trials.

PURPOSE: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients' outcomes. PATIENTS AND METHODS: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase II studies. RESULTS: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase II trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders. CONCLUSION: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancer.

Bias↗
PubMed2002

DMBT1 polymorphisms: relationship to malignant glioma tumorigenesis.

The deleted in malignant brain tumors 1 (DMBT1) gene on 10q25-26 is a candidate tumor suppressor gene in malignant gliomas, but its role is controversial, e.g., some DMBT1 homozygous deletions reflect unmasking of constitutional deletion polymorphisms by 10q loss. To clarify the role of DMBT1 in gliomagenesis, we investigated three reported deletion hot spots. Homozygous deletions at DMBT1 repeat 2-4 to 2-7 were found in 10 of 73 gliomas with 10q loss, but all 10 deletions reflected unmasking of constitutional hemizygous deletions. Alleles bearing deletion 2-4/2-7 were not selected significantly for by 10q loss, with retention of only 10 of 16 deleted alleles. No homozygous deletion was detected at locus 74k in the 5' upstream region of DMBT1, and four tightly linked polymorphisms were found around this region; chromosome 10q loss randomly affected alleles with or without the variant sequences around locus 74k. Moreover, no significant selection pressure was detected for the haplotype with both deletion 2-4/2-7 and 5' polymorphisms. There was no segregation of deletion 2-4/2-7 in glioma patients compared with unrelated individuals from reference families but a suggestion of a difference in the distribution of the 5' polymorphisms between the reference individuals and glioma patients. Constitutional polymorphisms at DMBT1 repeat 2-9/2-10 appeared common in patients with both benign brain tumors and gliomas. A homozygote for both the 2-4/2-7 deletion and the 5' polymorphisms had a glioma arise at a typical age and without an apparent family cancer predisposition. These data suggest that DMBT1 polymorphisms are not likely primary targets of 10q loss in malignant gliomas and do not support a major role for DMBT1 in gliomagenesis.

Agglutinins↗
PubMed2002

Biocompatibility of lipid-protein-sugar particles containing bupivacaine in the epineurium.

Novel lipid-protein-sugar particles (LPSPs) are potentially biocompatible because they are composed of naturally occurring ingredients and their expected tissue dwell times are relatively short. In this research, we used histological sections to study tissue reaction to LPSPs (4.4-microm median diameter) when used for sciatic nerve block in the rat. As a reference, we compared LPSPs to 60-microm median diameter poly(lactic-co-glycolic) acid (PLGA) microspheres (110,000 MW PLGA, glycolic/lactic ratio 65:35). Four days after injection, both particle types produced acute inflammation within the confines of the injectate, inflammation in adjacent tissues, and myotoxicity. Bupivacaine-free particles did not display myotoxicity, and inflammation in adjacent tissues was reduced. At 2 weeks, inflammation from LPSPs had almost disappeared, whereas PLGA microspheres had a foreign-body giant cell reaction until at least 8 weeks after injection. In contrast, 3.6-microm median diameter, 20,000-MW PLGA microspheres produced a primarily histiocytic reaction 2 weeks after injection. In summary, the LPSPs and PLGA microspheres studied herein have excellent biocompatibility, but tissue reaction to the former is of much shorter duration. Myotoxicity and inflammation of surrounding tissue is largely attributed to bupivacaine. Foreign-body giant cells may be attributed to particle size rather than a specific reaction to PLGA.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2002

Prediction of central nervous system embryonal tumour outcome based on gene expression.

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

Adolescent↗
PubMed2002

Genetic signature of oligoastrocytomas correlates with tumor location and denotes distinct molecular subsets.

Oligoastrocytomas are heterogeneous tumors that have molecular features that overlap with either oligodendrogliomas or astrocytomas. Differences in the frequency of chromosomal losses of 1p and 19q in oligodendrogliomas are related to tumor location, with a low rate of allelic loss in tumors of the temporal and a high rate in tumors of the frontal, parietal, and occipital lobes. To test the possibility of regional molecular heterogeneity in oligoastrocytoma, we examined a series of 203 gliomas including 68 oligoastrocytomas and two control groups of 73 oligodendrogliomas and 62 astrocytomas for allelic losses of chromosomal arms 1p and 19q, and TP53 mutations, and compared these data with tumor localization. Common molecular alterations were found in oligodendrogliomas and oligoastrocytomas arising in extratemporal sites. In respect to the molecular parameters analyzed, temporal oligoastrocytomas were either indistinguishable from astrocytoma or similar to temporal oligodendrogliomas. Oligodendroglial neoplasms can thus be separated into three molecular subsets, two of which include lesions with the morphological features of oligodendrogliomas and oligoastrocytomas and one resembling temporal oligoastrocytoma. Molecular subclassification thus unifies previous findings about prognosis, behavior, response to therapy, genotype, and location in oligodendroglial tumors.

Astrocytoma↗
PubMed2002

Astrocyte inactivation of the pRb pathway predisposes mice to malignant astrocytoma development that is accelerated by PTEN mutation.

We have inactivated pRb, p107, and p130 in astrocytes by transgenic expression of T(121) (a truncated SV40 T antigen) under the GFAP promoter. Founder mice died perinatally with extensive expansion of neural precursor and anaplastic astrocyte populations. In astrocytes, aberrant proliferation and extensive apoptosis were induced. Using a conditional allele of T(121), early lethality was circumvented, and adult mice developed high-grade astrocytoma, in which regions of decreased apoptosis expressed activated Akt. Indeed, astrocytoma development was accelerated in a PTEN(+/-), but not p53(+/-), background. These studies establish a highly penetrant preclinical model for astrocytoma based on events observed in the human disease and further provide insight into the role of PTEN mutation in astrocytoma progression.

Aging↗
PubMed2002

Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis.

Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16(INK4a) and p19(ARF), but not of p53, p16(INK4a), or p19(ARF), enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf(-/-) neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16(INK4a) and p19(ARF) synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.

Animals↗
PubMed2002

Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma".

Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 "astrocytic" gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

The WHO classification of tumors of the nervous system.

The new World Health Organization (WHO) classification of nervous system tumors, published in 2000, emerged from a 1999 international consensus conference of neuropathologists. New entities include chordoid glioma of the third ventricle, cerebellar liponeurocytoma, atypical teratoid/rhabdoid tumor, and perineurioma. Several histological variants were added, including tanycytic ependymoma, large cell medulloblastoma, and rhabdoid meningioma. The WHO grading scheme was updated and, for meningiomas, extensively revised. In recognition of the emerging role of molecular diagnostic approaches to tumor classification, genetic profiles have been emphasized, as in the distinct subtypes of glioblastoma and the already clinically useful 1p and 19q markers for oligodendroglioma and 22q/INI1 for atypical teratoid/rhabdoid tumors. In accord with the new WHO Blue Book series, the actual classification is accompanied by extensive descriptions and illustrations of clinicopathological characteristics of each tumor type, including molecular genetic features, predictive factors, and separate chapters on inherited tumor syndromes. The 2000 WHO classification of nervous system tumors aims at being used and implemented by the neuro-oncology and biomedical research communities worldwide.

Humans↗
PubMed2002

Impact of genotype and morphology on the prognosis of glioblastoma.

The recognition of molecular subsets among glioblastomas has raised the question whether distinct mutations in glioblastoma-associated genes may serve as prognostic markers. The present study on glioblastomas (GBM) from 97 consecutively sampled adult patients is based on a clinical, histopathological, immunohistochemical, and molecular genetic analysis. Parameters assessed were age at diagnosis, survival, cell type, proliferation, necrosis, microvascular proliferation, sarcomatous growth, lymphocytic infiltration, thromboses, calcifications, GFAP expression, MIB-1 index, loss of heterozygosity (LOH) of the chromosomal arms 1p, 10p, 10q, 17p, 19q and structural alterations in the TP53, EGFR and PTEN genes. As in previous studies, younger age was significantly associated with better survival. Among the molecular parameters, TP53 mutations and LOH10q emerged as favorable and poor prognostic factors, respectively. TP53 mutations were a favorable prognostic factor independent of whether glioblastomas were primary or secondary. LOH1p or 19q, lesions suspected to be over-represented in long term survivors with malignant glioma, were not associated with better survival. However, the combination of LOH1p and LOH19q defined GBM patients with a significantly better survival. Notably, these patients did not exhibit morphological features reminiscent of oligodendroglioma. These findings indicate that genotyping of glioblastoma may provide clinical information of prognostic importance.

Adult↗
PubMed2002

Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors.

Twenty-five primary intracranial germ cell tumors (11 germinomas, 5 teratomas, 5 mixed teratomas-germinomas. 1 mixed choriocarcinoma-teratoma, 1 yolk sac tumor, 1 mixed yolk sac tumor-teratoma, and 1embryonal carcinoma; from 24 males and 1 female) were studied by fluorescence in situ hybridization with probes to the X and Y chromosomes, chromosome 12p, the CDKN2A/p16 gene, and chromosome 13q-loci previously noted to be altered in either intracranial or systemic germ cell tumors. An increased number of X chromosomes, typically 1 extra copy, was observed in 23 of 25 cases (92%), with methylation-sensitive PCR demonstrating that the additional X chromosomes were hypomethylated in 13 of 16 (81%) studied tumors. Five cases (20%) had increased copy numbers of 12p (including tumors with isochromosome 12p), and 3 (12%) had 13q loss. No tumors had CDKN2A/p16 deletion or mutation, and 16 of 25 (64%) were positive for p16 expression by immunohistochemistry. Genetic alterations such as isochromosome 12p, 13q loss and CDKN2A/p16 are therefore not common in intracranial germ cell tumors. However, gains of hypomethylated, active X chromosomes occur in nearly all intracranial germ cell tumors, regardless of histological subtype. Along with the observed male predominance of intracranial germ cell tumors and the predisposition in Klinefelter syndrome patients for these lesions, the data argue strongly that sex chromosome aberrations, rather than isochromosome 12p, are integral to intracranial germ cell tumorigenesis

Adolescent↗
PubMed2002

The use of frailty hazard models for unrecognized heterogeneity that interacts with treatment: considerations of efficiency and power.

Increasingly, genetic studies of tumors of the same histologic diagnosis are elucidating subtypes that are distinct with respect to clinical endpoints such as response to treatment and survival. This raises concerns about the efficiency of using the simple log-rank test for analysis of treatment effect on survival in studies of possibly heterogeneous tumors. Furthermore, such studies, designed under the assumption of homogeneity, may be severely underpowered. We derive analytic approximations for the asymptotic relative efficiency of the simple log-rank test relative to the optimally weighted log-rank test and for the power of the simple log-rank test when applied to subjects with unobserved heterogeneity, as reflected in a continuous frailty, that may interact with treatment. Numerical studies demonstrate that the simple log-rank test may be quite inefficient if the frailty interacts with treatment. Further, there may be a substantial loss of power in the presence of the frailty with or without an interaction with treatment.

Brain Neoplasms↗
PubMed2002

Novel PLA2G4C polymorphism as a molecular diagnostic assay for 19q loss in human gliomas.

PLA2G4C, encoding cytosolic phospholipase A2-gamma (cPLA2-gamma), is a 17-exon gene located on chromosome 19q13.3 within the putative glioma tumor suppressor gene region. Given the clinical importance of assessing 1p and 19q loss in human gliomas, the development of convenient and practical assays for detecting allelic loss is of considerable priority in neuro-oncology. We report a minisatellite polymorphism in the untranslated region of exon 1, with allelic variants that have one, two or three 27-bp repeats. The polymorphism is informative in 55.7% of a reference population, and accurately detects allelic loss of 19q in human gliomas. This novel marker offers distinct advantages for assessing 19q status in malignant gliomas. The relatively large size of the repeats allows detection of allelic variants with standard ethidium bromide-stained agarose gels and the PLA2G4C marker is the closest polymorphism to the smallest common deletion area in the putative glioma tumor suppressor gene region. These characteristics suggest that the PLA2G4C polymorphism will be a convenient and practical assay for clinical and research evaluation of 19q status in human gliomas.

Alleles↗
PubMed2002

In vivo 3-T MR spectroscopy in the distinction of recurrent glioma versus radiation effects: initial experience.

PURPOSE: To determine if 3-T magnetic resonance (MR) spectroscopy allows accurate distinction of recurrent tumor from radiation effects in patients with gliomas of grade II or higher. MATERIALS AND METHODS: This blinded prospective study included 14 patients who underwent in vivo 3-T MR spectroscopy prior to stereotactic biopsy. All patients received a previous diagnosis of glioma (grade II or higher) and high-dose radiation therapy (>54 Gy). Prior to MR spectroscopy, conventional MR imaging was performed at 1.5 T to identify a gadolinium-enhanced region within the irradiated volume. Diagnosis was assigned by means of histopathologic analysis of the biopsy samples. RESULTS: Sixteen of 17 biopsy locations could be classified as predominantly tumor or predominantly radiation effect on the basis of the ratio of choline at the biopsy site to normal creatine level by using a value greater than 1.3 as the criterion for tumor. The remaining case, classified as recurrent tumor on the basis of MR spectroscopy results, was diagnosed as predominantly radiation effect on the basis of histopathologic findings. Disease in this patient progressed to biopsy-proven recurrence within 3 months. Overall, the ratio of choline at the biopsy site to normal creatine level was significantly elevated (unpaired two-tailed Student t test, P <.002) in those biopsy samples composed predominantly of tumor (n = 9) compared with those containing predominantly radiation effects (n = 8). The ratio was not significantly different between the two histopathologic groups. CONCLUSION: In vivo 3-T MR spectroscopy has sufficient spatial resolution and chemical specificity to allow distinction of recurrent tumor from radiation effects in patients with treated gliomas.

Adult↗
PubMed2002

Massive growth of a meningioma into the brachial plexus and thoracic cavity after intraspinal and supraclavicular resection. Case report and review of the literature.

Extracranial meningiomas comprise approximately 2% of all meningiomas. Involvement of peripheral nerves by meningioma, either by a primary tumor or through secondary extension of an intraaxial lesion, is a much rarer entity; there have been only two reported primary brachial plexus meningiomas and one description of secondary involvement of the brachial plexus by extension of an intraaxial lesion. Although thoracic cavity meningiomas have been described in the literature, their pathogenesis is poorly understood. The authors present the case report of a 36-year-old man who was initially treated for a thoracic spinal meningioma that infiltrated the brachial plexus. After resection, progressive and massive growth with infiltration of the brachial plexus and pleural cavity occurred over a 5-year period despite radio- and chemotherapy. The case report is followed by a review of the literature of this rare entity.

Adult↗