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Scott L Pomeroy

Publications and source records attributed to Scott L Pomeroy.

At least 19 recordsLinked to original sources
PubMed2026

Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.

Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.

Animals↗
PubMed2007

Overlay analysis of the oligonucleotide array gene expression profiles and copy number abnormalities as determined by array comparative genomic hybridization in medulloblastomas.

Combined analysis of gene expression array data and array-based comparative genomic hybridization data have been used in a series of 26 pediatric brain tumors to define up- and downregulated genes that coincide with losses, gains, and amplifications involving specific chromosome regions. Frequent losses were defined in chromosome arms 3q, 6q, 8p, 10q, 16q, 17p, and gains were identified in chromosome 7, and chromosome arms 9p and 17q. Amplification of a 2p region was seen in only one tumor, which corresponded to increased expression of the MYCN and DDX1 genes. To facilitate the analysis of the two data sets, we have developed a custom overlay tool that defines genes that are underexpressed in regions of deletions and overexpressed in regions of gain, across the genome and specifically within regions showing recurrent involvement in medulloblastomas.

Cerebellar Neoplasms↗
PubMed2006

Medulloblastoma outcome is adversely associated with overexpression of EEF1D, RPL30, and RPS20 on the long arm of chromosome 8.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor of childhood. Improvements in clinical outcome require a better understanding of the genetic alterations to identify clinically significant biological factors and to stratify patients accordingly. In the present study, we applied cytogenetic characterization to guide the identification of biologically significant genes from gene expression microarray profiles of medulloblastoma. METHODS: We analyzed 71 primary medulloblastomas for chromosomal copy number aberrations (CNAs) using comparative genomic hybridization (CGH). Among 64 tumors that we previously analyzed by gene expression microarrays, 27 were included in our CGH series. We analyzed clinical outcome with respect to CNAs and microarray results. We filtered microarray data using specific CNAs to detect differentially expressed candidate genes associated with survival. RESULTS: The most frequent lesions detected in our series involved chromosome 17; loss of 16q, 10q, or 8p; and gain of 7q or 2p. Recurrent amplifications at 2p23-p24, 2q14, 7q34, and 12p13 were also observed. Gain of 8q is associated with worse overall survival (p = 0.0141), which is not entirely attributable to MYC amplification or overexpression. By applying CGH results to gene expression analysis of medulloblastoma, we identified three 8q-mapped genes that are associated with overall survival in the larger group of 64 patients (p < 0.05): eukaryotic translation elongation factor 1D (EEF1D), ribosomal protein L30 (RPL30), and ribosomal protein S20 (RPS20). CONCLUSION: The complementary use of CGH and expression profiles can facilitate the identification of clinically significant candidate genes involved in medulloblastoma growth. We demonstrate that gain of 8q and expression levels of three 8q-mapped candidate genes (EEF1D, RPL30, RPS20) are associated with adverse outcome in medulloblastoma.

Adolescent↗
PubMed2006

Molecular genetics of pediatric central nervous system tumors.

Recent advances in molecular biology have enhanced our understanding of the pathogenesis of brain tumors, particularly in children. The use of molecular diagnostic tools is quickly becoming a standard component in the diagnosis and classification of brain tumors in children, in addition to providing insight leading to treatment stratification and improved outcome prediction. All new protocols involving treatments for brain tumors in children include studies of biomarkers and biologic correlates as a means to identify new targets for therapeutics and possible intervention strategies.

Astrocytoma↗
PubMed2006

Everyday cognitive function after craniopharyngioma in childhood.

Despite clinical impressions that cognitive complaints are prominent in patients with a history of craniopharyngioma, formal neuropsychologic documentation is inconsistent. This study assessed everyday cognitive complaints and neuropsychologic test performance to evaluate the prevalence of problems and the relationship of these domains to one another in patients treated for craniopharyngioma in childhood or adolescence. Ten patients treated for craniopharyngioma completed measures of everyday cognitive function (Cognitive Failures Questionnaire, Rivermead Behavioural Memory Test) and a battery of standard neuropsychologic tests. The prevalence of problems was ascertained for each measure. Most patients demonstrated significant deficits in everyday memory (Cognitive Failures Questionnaire, 9/10 patients; Rivermead Behavioural Memory Test, 7/10 patients). Scores were within normal limits, however, for intelligence quotient, achievement, attention, verbal memory, and spatial working memory. Processing speed was slow (5/10 patients). Spatial working memory predicted Cognitive Failures Questionnaire (P < 0.07), as did somatic symptoms from the Beck Depression Inventory (P < 0.01), but these associations appeared independent. Adolescents and young adults with treated craniopharyngioma experience deficits in everyday cognitive functions, many involving memory, that are not easily detected by standard neuropsychologic testing. The extent of self-rated cognitive problems is related to spatial working memory and somatic concerns.

Activities of Daily Living↗
PubMed2006

Transverse myelitis after therapy for primitive neuroectodermal tumors.

Traditional therapy for malignant primitive neuroectodermal tumors in children includes surgery, multi-agent chemotherapy, and radiation. Given the poor prognosis with conventional therapy alone, newer treatment approaches have incorporated high-dose chemotherapy followed by autologous stem cell rescue. Treatment with chemotherapy and radiation is not without unanticipated and unwanted side effects. Specifically, radiation-induced damage to the central nervous system can occur, though the frequency is thought to be acceptably low. This report describes two cases of treatment-related transverse myelitis in patients who received induction chemotherapy and craniospinal irradiation followed by high-dose chemotherapy with autologous stem cell rescue. Other patients treated with a similar strategy but different sequence and timing of treatment did not experience symptoms of myelitis, suggesting that the specific timing of radiation in relationship to the chemotherapy may be of critical importance.

Adolescent↗
PubMed2005

Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation.

Snf5 (Ini1/Baf47/Smarcb1), a core member of the Swi/Snf chromatin remodeling complex, is a potent tumor suppressor whose mechanism of action is largely unknown. Biallelic loss of Snf5 leads to the onset of aggressive cancers in both humans and mice. We have developed an innovative and widely applicable analytical technique for cross-species validation of cancer models and show that the gene expression profiles of our Snf5 murine models closely resemble those of human Snf5-deficient rhabdoid tumors. We exploit this system to produce what we believe to be the first report documenting the effects on gene expression of inactivating a Swi/Snf subunit in normal mammalian cells and to identify the transcriptional pathways regulated by Snf5. We demonstrate that the tumor suppressor activity of Snf5 depends on its regulation of cell cycle progression; Snf5 inactivation leads to aberrant up-regulation of E2F targets and increased levels of p53 that are accompanied by apoptosis, polyploidy, and growth arrest. Further, conditional mouse models demonstrate that inactivation of p16Ink4a or Rb (retinoblastoma) does not accelerate tumor formation in Snf5 conditional mice, whereas mutation of p53 leads to a dramatic acceleration of tumor formation.

Animals↗
PubMed2005

Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

Cell Line, Tumor↗
PubMed2005

A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death.

Expression of the neurotrophin-3 receptor, tyrosine kinase C (TrkC), is associated with favorable prognosis in medulloblastoma patients. This may be due to increased tumor apoptosis induced by TrkC activation. Neurotrophin-3/TrkC-induced apoptosis is inhibited by the mitogen-activated protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059. In addition to extracellular signal-regulated kinase (ERK)-1/2, PD98059 also inhibits the more recently identified neurotrophin-responsive MAPK, ERK5 (big MAPK 1). In the present study, we investigate the contribution of ERK5 and its target myocyte enhancer factor 2 (MEF2) to neurotrophin-3/TrkC-induced medulloblastoma cell death. Neurotrophin-3 not only enhanced ERK5 phosphorylation but also significantly enhanced the transcriptional activity of MEF2, a specific target of ERK5. Overexpression of both ERK5 and MEF2 induced a statistically significant increase in cell death of neurotrophin-3-responsive and nonresponsive medulloblastoma cell lines (Daoy-trkC and Daoy) and primary cultures of patched heterozygous mouse medulloblastomas. Only those cells expressing MAP/ERK kinase 5 (MEK5) plus ERK5 or MEF2 constructs underwent apoptosis, indicating that overexpression of either is sufficient to induce medulloblastoma cell death. Expression of a dominant-negative MEF2 or small interfering RNA for the ERK5 activator, MEK5, significantly inhibited neurotrophin-3-induced cell death. The dominant-negative MEF2 construct also blocked MEK5/ERK5-induced cell death, supporting a role for MEF2 downstream of ERK5. Co-immunoprecipitation studies revealed direct interaction of phosphorylated ERK5 with MEF2 in response to neurotrophin-3. Our investigation of the mechanism of neurotrophin-3/TrkC-induced apoptosis has identified a novel role for both MEK5/ERK5 and MEF2 in cell death, suggesting that these molecules can be exploited to induce apoptosis in both TrkC-expressing and non-expressing medulloblastoma cells.

Animals↗
PubMed2005

Stereotactic radiotherapy for localized low-grade gliomas in children: final results of a prospective trial.

PURPOSE: To evaluate the efficacy of stereotactic radiotherapy (SRT) for small, localized, pediatric brain tumors and to determine the patterns of failure. METHODS AND MATERIALS: A total of 81 patients were enrolled in an institutional review board-approved prospective Dana-Farber Cancer Institute protocol between 1992 and 1998. Of the 81 patients, 50 had low-grade astrocytoma, 23 had residual or recurrent craniopharyngioma, 4 had posterior fossa ependymoma, and 4 had other histologic types. All patients underwent biopsy for diagnosis, with the exception of patients with neurofibromatosis and radiographic evidence of an optic system tumor. The neurocognitive outcome for all patients was also an endpoint of the study and will be reported separately. This report focused on the patients with low-grade gliomas only. Of the 50 patients, 26 were males and 24 females; the median age was 9 years (range, 2-26 years). The indications for treatment of patients with low-grade gliomas were progression during or after chemotherapy or progression after surgery alone. SRT was delivered using a dedicated 6-MV linear accelerator. Immobilization was accomplished with a removable head-frame. CT and MRI fusion was used for treatment planning. The target volume generally included the preoperative tumor plus a 2-mm margin for the planning target volume. The median collimator size was 47.25 mm (range, 30-60 mm). Three to nine arcs were used to deliver a mean total dose of 52.2 Gy in 1.8-Gy daily fractions. RESULTS: With a median follow-up of 6.9 years (range, 0.9-10.2 years), the progression-free survival rate was 82.5% at 5 years and 65% at 8 years. The overall survival was 97.8% at 5 years and 82% at 8 years. Six patients had local progression. Two of the patients with local progression had pathologic progression to anaplastic astrocytoma 3 and 7 years after initial SRT. Five patients, all with optic system/hypothalamic primary tumors, developed central nervous system dissemination 1.0-7.4 years after SRT. One patient developed a presumed radiation-induced primitive neuroectodermal tumor 6 years after initial treatment. Six patients died, three of dissemination, two of progression to higher grade tumors, and one of a secondary radiation-induced tumor. All 6 cases of local progression were within the primary tumor bed at the time of progression and had received the full prescription dose. No marginal failures occurred. CONCLUSION: Stereotactic radiotherapy provides excellent local control for children with small, localized low-grade glial tumors. Marginal failures have not been observed, supporting the use of limited margins to minimize late sequelae using stereotactic immobilization and planning techniques.

Adolescent↗
PubMed2005

Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor.

Atypical teratoid/rhabdoid tumors (AT/RT) are highly malignant lesions of childhood that carry a very poor prognosis. AT/RT can occur in the central nervous system (CNS AT/RT) and disease in this location carries an even worse prognosis with a median survival of 7 months. In spite of multiple treatment regimens consisting of maximal surgical resection (including second look surgery), radiation therapy (focal and craniospinal), and multi-agent intravenous, oral and intrathecal chemotherapy, with or without high-dose therapy and stem cell rescue, only seven long-term survivors of CNS AT/RT have been reported, all in patients with newly diagnosed disease. For this reason, many centers now direct such patients, particularly those under 5 years of age, or those with recurrent disease, towards comfort care rather than attempt curative therapy. We now report on four children, two with newly diagnosed CNS AT/RT and two with progressive disease after multi-agent chemotherapy who are long term survivors (median follow-up of 37 months) using a combination of surgery, radiation therapy, and intensive chemotherapy. The chemotherapy component was modified from the Intergroup Rhabdomyosarcoma Study Group (IRS III) parameningeal protocol as three of the seven reported survivors in the literature were treated using this type of therapy. Our four patients, when added to the three reported survivors in the literature using this approach, suggest that patients provided this aggressive therapy can significantly alter the course of their disease. More importantly, we report on the first two survivors after relapse with multi-agent intravenous and intrathecal chemotherapy treated with this modified regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

INI1 protein expression distinguishes atypical teratoid/rhabdoid tumor from choroid plexus carcinoma.

Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) and choroid plexus carcinoma (CPC) are rare, highly malignant tumors that predominantly arise in infants and young children. Overlapping clinical, histologic, ultrastructural, or immunophenotypic features may obscure the diagnosis in some cases. AT/RT is characterized by deletions and/or mutations of the INI1 tumor-suppressor gene on chromosome band 22q11.2. We have recently developed an INI1 immunohistochemical staining assay. Negative staining of tumor cells resulting from inactivation of the INI1 gene is a consistent feature of AT/RT. Mutations of INI1 in some CPCs have been reported. The purpose of the present study was to determine if immunohistochemical staining with an INI1 antibody would provide a sensitive means of distinguishing between CPC and AT/RT. We examined 28 tumors with a submitted diagnosis of CPC. Twenty-one CPCs showed retained expression of INI1 and seven tumors showed loss of INI1 expression. Cytogenetic, FISH, and/or INI1 mutation results were also available for 13 tumors. In three of the seven cases, monosomy 22 was the only cytogenetic abnormality, suggestive of AT/RT. However, monosomy 22 was also identified in 3 tumors with complex karyotypes that retained INI1 expression. The 7 tumors that were immunonegative for INI1 had features that were consistent with AT/RT. Immunostaining for INI1 protein is retained in the majority of CPC and is lost in AT/RT. This expression pattern seems to better define the 2 groups of tumors than does light or electron microscopy, routine immunohistochemistry, or cytogenetic analysis alone.

Adolescent↗
PubMed2005

Craniopharyngioma therapy: long-term effects on hypothalamic function.

BACKGROUND: Craniopharyngiomas are the most common intracranial tumor of extraneural origin in childhood. REVIEW SUMMARY: In this review, we discuss the presentation, diagnosis, and treatment of craniopharyngioma. As the survival prognosis of patients with craniopharyngioma is quite optimistic, long-term side effects of both the tumor and its treatment are now better appreciated. Aside from well-recognized hormonal deficiencies and visual deficits related to tumor location, patients are now acknowledged to experience pathologic obesity and deficits of higher cortical function, memory, and behavior. The combination of these deficits can have profoundly detrimental effects on quality of life. CONCLUSIONS: Careful attention to issues related to hormonal balance, visual field defects, cognitive function, and mood disorders is essential to optimize long-term outcome of patients with craniopharyngioma.

Craniopharyngioma↗
PubMed2005

Diencephalic syndrome: a cause of failure to thrive and a model of partial growth hormone resistance.

Diencephalic syndrome is a rare but potentially lethal cause of failure to thrive in infants and young children. The diencephalic syndrome includes clinical characteristics of severe emaciation, normal linear growth, and normal or precocious intellectual development in association with central nervous system tumors. Our group initially described a series of 9 patients with diencephalic syndrome and found a reduced prevalence of emesis, hyperalertness, or hyperactivity compared with previous reports. Also, the tumors were found to be larger, occur at a younger age, and behave more aggressively than similarly located tumors without diencephalic syndrome. We have been able to extend our follow-up of the original patients, as well as describe 2 additional cases. Because the mechanism of the growth and endocrinologic findings in diencephalic syndrome has not been explained, we report on these patients in light of current research on hypothalamic factors that affect growth and weight. This study emphasizes diencephalic syndrome as a model for additional study of growth hormone resistance and metabolic regulation of adiposity.

Astrocytoma↗
PubMed2004

Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers.

Identification of common mechanisms underlying organ development and primary tumor formation should yield new insights into tumor biology and facilitate the generation of relevant cancer models. We have developed a novel method to project the gene expression profiles of medulloblastomas (MBs)--human cerebellar tumors--onto a mouse cerebellar development sequence: postnatal days 1-60 (P1-P60). Genomically, human medulloblastomas were closest to mouse P1-P10 cerebella, and normal human cerebella were closest to mouse P30-P60 cerebella. Furthermore, metastatic MBs were highly associated with mouse P5 cerebella, suggesting that a clinically distinct subset of tumors is identifiable by molecular similarity to a precise developmental stage. Genewise, down- and up-regulated MB genes segregate to late and early stages of development, respectively. Comparable results for human lung cancer vis-a-vis the developing mouse lung suggest the generalizability of this multiscalar developmental perspective on tumor biology. Our findings indicate both a recapitulation of tissue-specific developmental programs in diverse solid tumors and the utility of tumor characterization on the developmental time axis for identifying novel aspects of clinical and biological behavior.

Animals↗
PubMed2004

Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas.

PURPOSE: Stratification of risk in patients with medulloblastoma remains a challenge. As clinical parameters have been proven insufficient for accurately defining disease risk, molecular markers have become the focus of interest. Outcome predictions on the basis of microarray gene expression profiles have been the most accurate to date. We ask in a multivariate model whether clinical parameters enhance survival predictions of gene expression profiles. PATIENTS AND METHODS: In a cohort of 55 young patients (whose medulloblastoma samples have been analyzed previously for gene expression profile), associations between clinical and gene expression variables and survival were assessed using Cox proportional hazards models. Available clinical variables included age, stage (ie, the presence of disseminated disease at diagnosis), sex, histologic subtype, treatment, and status. RESULTS: Univariate analysis demonstrated expression profiles to be the only significant clinical prognostic factor (P=.03). In multivariate analysis, gene expression profiles predicted outcome independent of other criteria. Clinical criteria did not significantly contribute additional information for outcome predictions, although an exploratory analysis noted a trend for decreased survival of patients with metastases at diagnosis but favorable gene expression profile. CONCLUSION: Gene expression profiling predicts medulloblastoma outcome independent of clinical variables. These results need to be validated in a larger prospective study.

Adolescent↗
PubMed2004

Neural development and the ontogeny of central nervous system tumors.

Recent evidence argues that the oncogenesis and growth of CNS tumors occurs through dysregulated molecular and cellular mechanisms of neural development. New insights have emerged that have had a significant impact on both research and treatment of these cancers.

Journal Article↗