Biomedical subjects

Griffith R Harsh

Publications and source records attributed to Griffith R Harsh.

14 recordsLinked to original sources

PubMed2005

Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas.

PURPOSE: Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas. METHODS: We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells. RESULTS: We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022). CONCLUSION: Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.

Antineoplastic Agents, Alkylating↗

PubMed2005

Functional network analysis reveals extended gliomagenesis pathway maps and three novel MYC-interacting genes in human gliomas.

Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

Adult↗

PubMed2005

Characterization of the integrin alpha v beta3 in arteriovenous malformations and cavernous malformations.

BACKGROUND: Alpha V beta 3 (alphavbeta3) is an integrin specifically expressed on the endothelial cells of central nervous system (CNS) neoplasms. However, no data exist on the expression of alphavbeta3 in vascular malformations of the CNS. In this study, we investigate the expression of alphavbeta3 in arteriovenous malformations (AVMs) and cavernous malformations (CMs). METHOD: Frozen samples of AVMs from 12 patients and CMs from 5 patients were obtained intraoperatively. Once the final pathology had been confirmed, immunohistochemistry was performed using an antibody to the integrin alphavbeta3. The alphavbeta3 expression pattern was graded according to the percentage of positively staining vessels. RESULTS: Ten of 12 AVMs demonstrated alphavbeta3 immunopositivity. Six of these 10 AVMs had moderate or strong staining. Most notably, 5 of the 6 moderate or strongly staining AVMs came from patients 22 years of age or younger. Four of these 6 AVMs had previously been embolized. None of the cavernous malformations demonstrated alphavbeta3 immunopositivity. DISCUSSION: alphavbeta3 may contribute to the formation of AVMs in younger patients. alphavbeta3 may also provide a potential therapeutic target. The lack of alphavbeta3 expression in cavernous malformations, despite their high vascular densities, suggests that the pathophysiology of their formation differs from that of AVMs.

Adolescent↗

PubMed2005

High-resolution genome-wide mapping of genetic alterations in human glial brain tumors.

High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.

Brain Neoplasms↗

PubMed2005

Anterior skull base surgery.

This article focuses on selected key anatomic considerations in anterior skull base surgery, briefly reviews common pathologies of the paranasal sinuses, and provides an overview of surgical approaches, complications, and results.

Cranial Fossa, Anterior↗

PubMed2005

Amplification of whole tumor genomes and gene-by-gene mapping of genomic aberrations from limited sources of fresh-frozen and paraffin-embedded DNA.

Sufficient quantity of genomic DNA can be a bottleneck in genome-wide analysis of clinical tissue samples. DNA polymerase Phi29 can be used for the random-primed amplification of whole genomes, although the amplification may introduce bias in gene dosage. We have performed a detailed investigation of this technique in archival fresh-frozen and formalin-fixed/paraffin-embedded tumor DNA by using cDNA microarray-based comparative genomic hybridization. Phi29 amplified DNA from matched pairs of fresh-frozen and formalin-fixed/paraffin-embedded tumor samples with similar efficiency. The distortion in gene dosage representation in the amplified DNA was nonrandom and reproducibly involved distinct genomic loci. Regional amplification efficiency was significantly linked to regional GC content of the template genome. The biased gene representation in amplified tumor DNA could be effectively normalized by using amplified reference DNA. Our data suggest that genome-wide gene dosage alterations in clinical tumor samples can be reliably assessed from a few hundred tumor cells. Therefore, this amplification method should lend itself to high-throughput genetic analyses of limited sources of tumor, such as fine-needle biopsies, laser-microdissected tissue, and small paraffin-embedded specimens.

Chromosome Aberrations↗

PubMed2005

Concomitant ectatic posterior communicating artery and tentorial meningioma as a source of oculomotor palsy: case report.

OBJECTIVE AND IMPORTANCE: Although non-aneurysmal vascular compression of the oculomotor nerve is rare, it should be considered in the evaluation of unilateral oculomotor palsy. CLINICAL PRESENTATION: A 36-year-old non-diabetic man presented with two months of intermittent retro-orbital headache and third nerve paresis caused by compression of the oculomotor nerve between an ectatic, atherosclerotic posterior communicating artery (PComA) and a small tentorial meningioma. At operation, the subarachnoid portion of the nerve, prevented from migrating posteriorly and laterally by the meningioma, was grooved by the apex of the artery's loop. INTERVENTION: Microvascular decompression (MVD) of the artery loop from the nerve and resection of the meningioma were performed. Postoperatively, the patient's retro-orbital headache and oculomotor paresis, with the exception of mild anisocoria, resolved. Tumor infiltrating the posterior tentorium and lateral cavernous sinus was treated by Cyberknife radiosurgery five months later. One year after surgery, the patient had improvement in his headaches, full extra-ocular movements, and minimal residual anisocoria. CONCLUSION: Only one other report describes MVD of the third nerve from PComA compression. A review is presented of MVD carried out for similar cases of non-aneurysmal vascular compression of the oculomotor nerve. By analogy from cases in which an aneurysm is the compressing vascular structure, prompt surgical treatment is advocated. Complete evaluation of an isolated third nerve palsy should include MRI sequences designed to detect vascular compression of cranial nerves.

Adult↗

PubMed2004

Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: confounding effect of elevated rCBV of oligodendrogliomas [corrected].

BACKGROUND AND PURPOSE: The MR imaging characteristics of oligodendrogliomas and astrocytomas on spin-echo (SE), echo-planar relative cerebral blood volume (rCBV) maps, to our knowledge, have not previously been emphasized. We compared the specificity of SE rCBV mapping with that of conventional, contrast material-enhanced MR imaging in differentiating high- from low-grade glial tumors and in predicting survival of patients with these lesions. METHODS: Thirty consecutive adult patients with suspected gliomas underwent conventional and rCBV MR imaging. Representative maximal rCBV regions of interest were chosen from each lesion. Resultant values were normalized to those of corresponding, contralateral, uninvolved regions. These normalized CBV (nCBV) values were correlated with degree of contrast enhancement, histopathologic tumor grade, and survival. RESULTS: Twenty-two patients had astroctyomas and eight had oligodendrogliomas. With an nCBV cutoff ratio of 1.5, 13 of 13 high-grade astrocytomas were correctly categorized, three of which did not enhance. Seven of nine low-grade astrocytomas were correctly classified by their nCBV values, including one enhancing lesion. Of eight oligodendrogliomas, four of four high-grade and two of four low-grade tumors had elevated nCBV values; two low-grade oligodendrogliomas enhanced, one with nCBV greater than 1.5 and one with nCBV less than 1.5. In 19 patients with astrocytoma for whom survival data were available, correlation with survival was better for nCBV (mean survival 91 +/- 14 months for nCBV < 1.5 versus 24 +/- 27 months for nCBV > 1.5, P <.0001) than for enhancement (mean survival 61 +/- 35 months without enhancement versus 22 +/- 29 months with enhancement, P =.03). CONCLUSION: Elevated SE rCBV was a sensitive, but not specific, marker for high-grade histopathology: all high-grade tumors had nCBV foci values greater than 1.5. No tumor with nCBV region of interest less than 1.5 was high grade (100% predictive value for excluding high grade). Degree of nCBV elevation was a stronger predictor of both tumor grade and survival than was degree of enhancement. A significant proportion of low-grade glial neoplasms, most notably oligodendrogliomas, may display high rCBV foci not reflective of high-grade histopathology.

Adolescent↗

PubMed2003

Quality assurance of magnetic resonance spectroscopic imaging-derived metabolic data.

PURPOSE: Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy. METHODS AND MATERIALS: An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified. RESULTS: Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity. CONCLUSIONS: This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

Aspartic Acid↗

PubMed2003

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.

OBJECTIVE: We sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODS: Between November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5-35 mm), and the median tumor volume was 1.4 cm(3) (range, 0.1-15.9 cm(3)). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10-18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12-102.6 mo). RESULTS: The actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9-99.9%) and 93.6% (95% CI, 88.3-99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2-98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85-97.6%) and 89.4% (95% CI, 82-96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSION: Proton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.

Adult↗

PubMed2003

Synchronous subarachnoid drop metastases from a pituitary adenoma with multiple recurrences. Case report.

The authors report the case of a 49-year-old man with synchronous drop metastases from a multiply recurrent somatotroph pituitary adenoma. The metastatic lesions were found in the subarachnoid space of the cauda equina and foramen magnum 18 years after the initial diagnosis of the disease. Five transsphenoidal resections had previously failed to cure the sellar tumor. Two of these, performed 4 and 5 years before the patient's current presentation, had been complicated by cerebrospinal fluid rhinorrhea that necessitated lumbar drainage. Resections of the two subarachnoid lesions, separated by 14 months, removed pathologically aggressive pituitary adenomas. There were no signs of local recurrence or subarachnoid dissemination of disease during the postoperative follow-up periods, which lasted 18 and 4 months, respectively. Previous cases of subarachnoid spread of a pituitary adenoma have been associated with multiple intracranial metastases, multiple intraspinal metastases, or widely disseminated disease. This case demonstrates that subarachnoid metastasis of a pituitary adenoma, particularly when it follows multiple operations, is not invariably widely disseminated or associated with a very poor prognosis.

Acromegaly↗

PubMed2002

Proton beam stereotactic radiosurgery of vestibular schwannomas.

PURPOSE: The proton beam's Bragg peak permits highly conformal radiation of skull base tumors. This study, prompted by reports of transient (30% each) and permanent (10% each) facial and trigeminal neuropathy after stereotactic radiosurgery of vestibular schwannomas with marginal doses of 16-20 Gy, assessed whether proton beam radiosurgery using a marginal dose of only 12 Gy could control vestibular schwannomas while causing less neuropathy. METHODS AND MATERIALS: Sixty-eight patients (mean age 67 years) were treated between 1992 and 1998. The mean tumor volume was 2.49 cm(3). The dose to the tumor margin (70% isodose line) was 12 Gy. The prospectively specified follow-up consisted of neurologic evaluation and MRI at 6, 12, 24, and 36 months. RESULTS: After a mean clinical follow-up of 44 months and imaging follow-up of 34 months in 64 patients, 35 tumors (54.7%) were smaller and 25 (39.1%) were unchanged (tumor control rate 94%; actuarial control rate 94% at 2 years and 84% at 5 years). Three tumors enlarged: one shrank after repeated radiosurgery, one remained enlarged at the time of unrelated death, and one had not been imaged for 4 years in a patient who remained asymptomatic at last follow-up. Intratumoral hemorrhage into one stable tumor required craniotomy that proved successful. Thus, 97% of tumors required no additional treatment. Three patients (4.7%) underwent shunting for hydrocephalus evident as increased ataxia. Of 6 patients with functional hearing ipsilaterally, 1 improved, 1 was unchanged, and 4 progressively lost hearing. Cranial neuropathies were infrequent: persistent facial hypesthesia (2 new, 1 exacerbated; 4.7%); intermittent facial paresthesias (5 new, 1 exacerbated; 9.4%); persistent facial weakness (2 new, 1 exacerbated; 4.7%) requiring oculoplasty; transient partial facial weakness (5 new, 1 exacerbated; 9.4%), and synkinesis (5 new, 1 exacerbated; 9.4%). CONCLUSION: Proton beam stereotactic radiosurgery of vestibular schwannomas at the doses used in this study controls tumor growth with relatively few complications.

Adult↗

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

Dural marginal zone lymphoma with massive amyloid deposition: rare low-grade primary central nervous system B-cell lymphoma. Case report.

The authors report the case of a 63-year-old woman who presented with a primary dural extranodal marginal zone lymphoma (MZL) associated with massive kappa light chain amyloidosis of the meninges. Extranodal MZL is a low-grade B-cell lymphoma that may show variable degrees of plasmacytic differentiation. Like solitary plasmacytoma of soft tissue, which can also be associated with amyloid, extranodal MZL generally responds well to local therapy and has a good prognosis. It is important to distinguish these entities from high-grade primary central nervous system (CNS) B-cell lymphomas and more aggressive and/or widespread, potentially amyloidogenic conditions such as multiple myeloma, lympho-plasmacytoid lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma. To the authors' knowledge this is the first reported case of dural MZL associated with massive meningeal amyloid deposition. Extranodal MZL is a rare low-grade primary CNS B-cell lymphoma that may be associated with amyloidosis. It should be considered in the differential diagnosis of CNS lymphoproliferative lesions and CNS amyloidosis.

Amyloidosis↗