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Robert J Weil

Publications and source records attributed to Robert J Weil.

At least 19 recordsLinked to original sources
PubMed2006

Comparative proteomic profiles of meningioma subtypes.

Meningiomas are classified into three groups (benign, atypical, and anaplastic) based on morphologic characteristics. Atypical meningiomas, which are WHO grade 2 tumors, and anaplastic meningiomas, which are WHO grade 3 tumors, exhibit an increased risk of recurrence and premature death compared with benign WHO grade 1 tumors. Although atypical and anaplastic meningiomas account for <10% of all of meningiomas, it can be difficult to distinguish them from benign meningiomas by morphologic criteria alone. We used selective tissue microdissection to examine 24 human meningiomas and did two-dimensional gel electrophoresis to determine protein expression patterns. Proteins expressed differentially by meningiomas of each WHO grade were identified and sequenced. Proteomic analysis revealed protein expression patterns unique to WHO grade 1, 2, and 3 meningiomas and identified 24 proteins that distinguish each subtype. Fifteen proteins showed significant changes in expression level between benign and atypical meningiomas, whereas nine distinguished atypical from anaplastic meningiomas. Differential protein expression was confirmed by Western blotting and immunohistochemistry. We established differential proteomic profiles that characterize and distinguish meningiomas of increasing grades. The proteins and proteomic profiles enhance understanding of the pathogenesis of meningiomas and have implications for diagnosis, prognosis, and treatment.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2006

Surgical remission of pituitary adenomas confined to the neurohypophysis in Cushing's disease.

CONTEXT: Partial or total removal of the pituitary cures 60-80% of patients with Cushing's disease (CD) in whom an adenoma cannot be identified at surgery. Many patients who fail complete or partial hypophysectomy are cured by sellar and parasellar irradiation. DESIGN/PATIENTS: As part of a series of prospective studies of CD, we identified 12 patients (34.5 +/- 19.9 yr; 11 females; four children) with tumors located completely within the neurohypophysis among 730 patients undergoing surgery for CD. SETTING: The study was conducted at a tertiary referral center at a clinical research hospital. RESULTS: All 12 patients had clinical and biochemically defined CD. Tumor was visible at surgery in 11 patients; all 12 tumors were positive for ACTH by immunohistochemistry. Two tumors were excised at repeat surgery because of persistent hypercortisolism within 14 d of negative exploration of the adenohypophysis. There were no long-term complications. At follow-up of 71.9 +/- 34.2 months (range, 30-138 months), all patients are in remission of CD. Adult patients have had significant improvement in weight and body mass indices, with restoration of normal menses in all women. In the four pediatric patients, height, weight, and body mass indices have been restored toward normal by surgical remission of CD. Hypopituitarism or long-term neurohypophysial dysfunction has not occurred. CONCLUSION: We report a new subset of patients with CD, ACTH-secreting adenomas that arise wholly within the posterior lobe of the pituitary gland. In cases of CD in which an adenoma is not identified in the adenohypophysis and in patients with persistent hypercortisolism after complete or partial excision of the anterior lobe, tumor within the neurohypophysis should be considered; selective adenomectomy of a neurohypophyseal, ACTH-secreting tumor can produce long-term remission.

Adenoma↗
PubMed2006

A novel method to detect functional microRNA targets.

MicroRNA (miRNA) molecules are non-coding RNAs, 19 to 24 nt in length that have been identified recently as important regulators of gene expression. Several computational methods have been developed to describe the target recognition mechanism by miRNA. We propose here a novel method to detect miRNA-mRNA complexes in eukaryotic cells. As a first step, we synthesize cDNA on an mRNA template using miRNAs as the endogenous cytoplasmic primer. This step extends miRNA and overcomes the problem of low complementary binding of miRNAs to their targets. Purified hybrid 3'-cDNA-miRNA-5' molecules are used in a second round of reverse transcription to anneal to target mRNA in a highly gene-specific manner. The 5'-end analysis of these cDNA molecules demonstrated that primers for cDNAs were "signatures" of miRNA molecules, and over-expression of their full-length mature miRNAs resulted in functional inhibition of target protein expression.

Base Sequence↗
PubMed2006

Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR.

Brain metastases (BM) from breast cancer are associated with significant morbidity and mortality. In the current study, we have examined a cohort of breast cancer patients who went on to develop BM for clinical-pathologic features and predictive markers that identify this high-risk subgroup of patients at the time of diagnosis. The primary tumors from 55 patients who developed BM were used to construct a tissue microarray. The clinical and pathologic features were recorded and the tissue microarray was stained for estrogen receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor by immunohistochemistry. This cohort of patients was compared against a group of 254 patients who remain free of metastases (67 mo mean follow-up), and another cohort of 40 patients who developed mixed visceral and bone metastatic disease without brain recurrence over a similar period of time. Breast cancer patients who went on to develop BM were more likely to be <50 years old (P<0.001), and the primary tumors were more likely to be estrogen receptor negative (P<0.001) and high grade (P=0.002). The primary tumors were also more likely to express cytokeratin 5/6 (P<0.001) and epidermal growth factor receptor (P=0.001), and to overexpress human epidermal growth factor receptor 2 (P=0.001). The data presented above suggest a profile for breast cancer patients at increased risk for developing BM. Predictive factors to help identify patients with metastatic breast cancer who are at an increased risk for developing central nervous system recurrence might allow for screening of this population for early detection and treatment or for the development of targeted strategies for prevention.

Brain Neoplasms↗
PubMed2006

35-year-old woman with progressive bilateral leg weakness.

A 35-year-old woman presented with one month's history of progressive bilateral leg weakness and altered sensation. There had been no pain. She had noted urinary frequency and constipation in the previous two weeks. On examination, the patient had diffuse lower extremity weakness (2-3/5), with a T6 sensory level to pain and temperature sensation. MRI demonstrated a T4-5 intradural mass ventral to the spinal cord, with an enhancing dural tail, consistent with meningioma. At surgery an intradural, extramedullary, firm, black neoplasm was encountered, which invaded the ventral dura and elevated and distorted the spinal cord. The mass was removed, leaving only microscopic invasion of the ventral dura. There was no bone invasion. Serial sections revealed a homogeneous black tumor without necrosis. H&E stained sections showed an occasionally fascicular tumor of melanocytes and small round blue tumor spindle cells with melanin pigmentation and 1-2 mitotic figures per 10 high-powered fields. The nuclei are generally oval-shaped and elongated, with prominent nucleoli. Necrosis, hemorrhage, and nuclear and cellular pleomorphism are not present and mitotic figures are rare. Immunohistochemical staining was positive for S-100 and HMB-45. MIB-1 labeling averaged 1-2%. A diagnosis of primary meningeal melanocytic tumor was made. Primary meningeal melanocytic tumors (PMMTs) are rare; fewer than 100 cases have been described. PMMTs of the CNS consist of a spectrum of tumors ranging from well-differentiated melanocytoma to its overtly malignant counterpart, melanoma. Intermediate grade melanocytomas (IMGs) are the least common variant, comprising about 10% of PMMTs reported. IGMS occur in the spinal leptomeninges and intracranially in approximately equal proportions. IGMs are more cellular than the well-differentiated variant, with 1-3 mitotic figures per 10 HPFs and MIB-1 labeling of <6%. By contrast, melanomas contain more mitotic figures (3-15 per 10 HPF) and MIB-1 labeling rates up to 15%. Once metastasis, including drop metastasis from pigmented medulloblastomas, have been excluded, the differential includes pigmented meningiomas and schwannomas (solitary or as part of Carney complex), as well as other pigmented CNS tumors such as ependymoma and pineoblastoma and systemic diseases such as lymphoma . . . For primary CNS melanocytic neoplasms, complete tumor resection is preferred, as it leads to cure of well-differentiated and intermediate-grade melanocytomas and most melanomas. Radiotherapy is recommended for incomplete resection of IMGs and melanomas; the recurrence potential of low-grade melanocytomas is less clear and watchful waiting may be employed, since recurrent tumors may be treated surgically prior to radiation. Two months after surgery, the patient had normal sensation and strength. She was given focused radiotherapy to the region of the ventral thecal sac to 40 cGy. At one year following surgery, the patient's neurological examination is normal and she remains free of residual disease by MR examination.

Adult↗
PubMed2006

Neuro-oncological applications of optical spectroscopy.

Advances in optics and molecular imaging have occurred rapidly in the past decade. One technique poised to take advantage of these developments is optical spectroscopy (OS). All optical spectroscopic techniques have in common tissue interrogation with light sources ranging from the ultraviolet (UV) to the infrared (IR) ranges of the spectrum, and collection of information on light reflected (reflectance spectroscopy) or light interactions with tissue and emergence at different wavelengths (fluorescence and Raman spectroscopy). OS can provide information regarding intrinsic tissue optical properties such as tissue structure, nuclear density, and the presence or absence of endogenous or exogenous fluorophores. Among other applications, this information has been used to distinguish tumor from normal brain tissues, to detect tumor margins in intrinsic, infiltrating gliomas, to identify radiation damage to tissues, and to assess tissue viability and predict the onset of apoptosis in vitro and in vivo. Potential applications of OS include detection of specific central nervous system (CNS) structures, such as brain nuclei, identification of cell types by the presence of specific neurotransmitters, and the detection of optically labeled cells or drugs during therapeutic interventions. All have potential utility in neuro-oncology, have been investigated in our laboratories, and will be the subject of this review.

Animals↗
PubMed2006

Intraoperative cortical surface characterization using laser range scanning: preliminary results.

OBJECTIVE: To present a novel methodology that uses a laser range scanner (LRS) capable of generating textured (intensity-encoded) surface descriptions of the brain surface for use with image-to-patient registration and improved cortical feature recognition during intraoperative neurosurgical navigation. METHODS: An LRS device was used to acquire cortical surface descriptions of eight patients undergoing neurosurgery for a variety of clinical presentations. Textured surface descriptions were generated from these intraoperative acquisitions for each patient. Corresponding textured surfaces were also generated from each patient's preoperative magnetic resonance tomograms. Each textured surface pair (LRS and magnetic resonance tomogram) was registered using only cortical surface information. Novel visualization of the combined surfaces allowed for registration assessment based on quantitative cortical feature alignment. RESULTS: Successful textured LRS surface acquisition and generation was performed on all eight patients. The data acquired by the LRS accurately presented the intraoperative surface of the cortex and the associated features within the surgical field-of-view. Registration results are presented as overlays of the intraoperative data with respect to the preoperative data and quantified by comparing mean distances between cortical features on the magnetic resonance tomogram and LRS surfaces after registration. The overlays demonstrated that accurate registration can be provided between the preoperative and intraoperative data and emphasized a potential enhancement to cortical feature recognition within the operating room environment. Using the best registration result from each clinical case, the mean feature alignment error is 1.7 +/- 0.8 mm over all cases. CONCLUSION: This study demonstrates clinical deployment of an LRS capable of generating textured surfaces of the surgical field of view. Data from the LRS was registered accurately to the corresponding preoperative data. Visual inspection of the registration results was provided by overlays that put the intraoperative data within the perspective of the whole brain's surface. These visuals can be used to more readily assess the fidelity of image-to-patient registration, as well as to enhance recognition of cortical features for assistance in comparing the neurotopography between magnetic resonance image volume and physical patient. In addition, the feature-rich data presented here provides considerable motivation for using LRS scanning to measure deformation during surgery.

Adult↗
PubMed2006

Concurrent lymphocytic hypophysitis and pituitary adenoma. Case report and review of the literature.

Lymphocytic hypophysitis (LyH) is an uncommon intrasellar lesion characterized by lymphocytic infiltration of the adenohypophysis. Evidence suggests that the cause is autoimmune, and the symptoms are usually related to either a mass effect or endocrine dysfunction. Lymphocytic hypophysitis has been described rarely in the setting of other simultaneous pathological processes that involve the pituitary and sella turcica, and is postulated to arise from an intrinsic inflammatory response. The authors report the case of a 43-year-old woman who presented with a 2-month history of galactorrhea and pseudohyperprolactinemia secondary to a 10-mm lesion within an enlarged pituitary gland. She was nulliparous and had no contributory medical history. Serial neuroimaging performed over a 2-year period demonstrated lesion growth, and visual deficits had developed; together these warranted surgical intervention. A transsphenoidal resection was performed. Microscopic and immunohistopathological examinations revealed a nonsecreting pituitary adenoma with concurrent lymphocytic adenohypophysitis. This is the first documented case of LyH in the setting of a null-cell pituitary adenoma. The authors review the related literature and outline potential mechanisms for the concurrent development of LyH and a pituitary adenoma.

Adenoma↗
PubMed2006

From tissue phenotype to proteotype: sensitive protein identification in microdissected tumor tissue.

Correlation of disease phenotype with protein profile (proteotype) is a significant challenge for biomedical research. The main obstacles have been the need to insure sufficient quantities of pure protein sample, the reproducibility of protein display, and rapid and accurate protein identification. We present a modified approach that combines enhanced detection sensitivity with tissue microdissection from frozen primary renal cancer tissues of different histological subtypes, followed by 2D gel analysis and protein identification with MALDI mass spectrometry. We obtained reliable and highly consistent results in phenotypically similar tumors of each individual subtype by performing strict morphological control of the analyzed tumor cells without physical or chemical alteration of the frozen tissue samples. By application of non-oxidizing silver staining, proteins were resolved and identified with high levels of specificity and sensitivity. This new combination of techniques allows not only for sensitive identification of specific protein patterns that correspond to a histological tumor phenotype, but also for identification of specific disease-associated protein targets.

Adenoma, Oxyphilic↗
PubMed2005

Individual adult human neurons display aneuploidy: detection by fluorescence in situ hybridization and single neuron PCR.

Neurons, once committed, exit the cell cycle and undergo maturation that promote specialized activity and are believed to operate upon a stable genome. We used fluorescence in situ hybridization, selective cell microdissection, and loss of heterozygosity analysis to assess degree of aneuploidy in patients with a neurodegenerative disease and in normal controls. We found that aneuploidy occurs in approximately 40% of mature, adult human neurons in health or disease and may be a physiological mechanism that maintains neuronal fate and function; it does not appear to be an unstable state. The fact that neuronal stem cells can be identified in adult humans and that somatic mosaicism may be found in neuronal precursor cells deserves further investigation before using adult neural stem cells to treat human disease.

Adult↗
PubMed2005

Proteomic-based prognosis of brain tumor patients using direct-tissue matrix-assisted laser desorption ionization mass spectrometry.

Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, non-subjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.

Biomarkers, Tumor↗
PubMed2005

Proteins and protein pattern differences between glioma cell lines and glioblastoma multiforme.

INTRODUCTION: Research into the pathogenesis, molecular signaling, and treatment of glioblastoma multiforme (GBM) has traditionally been conducted using cell lines derived from malignant gliomas. We compared protein expression patterns between solid primary GBMs and GBM cell lines to identify proteins whose expression may be altered in cell culture. METHODS: We cultured cell lines U87, U118, U251, and A172 and used tissue-selective microdissection of eight primary GBMs to obtain pure populations of tumor cells, which we studied using two-dimensional gel electrophoresis (2DGE) and examined using differential expression software. Select protein targets expressed differentially between GBM tumors and GBM cell lines were sequenced using tandem mass spectrometry. RESULTS: Analysis of the primary GBM tumor samples (n = 8) and the GBM cell lines revealed reproducibly similar proteomic patterns for each group, which distinguished tumors from the cell lines. Gels contained up to 500 proteins that were consistently identified in the pH 4 to 7 range. Comparison of proteins identified in the GBM tumors and in the cell lines showed approximately 160 proteins that were gained and 60 proteins that were lost on culture. Using normalized intensity patterns from the 2DGE images, ANOVA tests were done and statistically significant spots were identified. Seven proteins found in the cell lines were significantly increased when compared with the GBM tumors (P < 0.05), whereas 10 proteins were significantly decreased from cell lines compared with the GBM tumors. Proteins identified included transcription factors, tumor suppressor genes, cytoskeletal proteins, and cellular metabolic proteins. CONCLUSION: Global protein and proteomic differences were identified between primary GBM tumor samples and GBM cell lines. The proteins identified by 2DGE analysis elucidate some of the selection pressures of in vitro culture, help accentuate the advantages and limitations of cell culture, and may aid comprehension of gliomagenesis and enhance development of new therapeutics.

Brain Neoplasms↗
PubMed2005

Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.

Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.

Adrenal Gland Neoplasms↗
PubMed2005

Selective excision of metastatic brain tumors originating in the motor cortex with preservation of function.

PURPOSE: Brain metastases are common in patients with cancer and can cause considerable morbidity or death. Metastasis in eloquent areas of the brain, particularly the primary motor cortex, may present significant treatment challenges. PATIENTS AND METHODS: Seventeen consecutive patients with metastasis within the primary motor cortex underwent selective microsurgical tumor resection. Operative, hospital, neuroimaging, and follow-up information was reviewed. RESULTS: There were 10 women and seven men (mean age, 54.3 years) who underwent 17 operations for symptomatic brain metastases. Motor cortex was identified and tumor (mean volume, 10.2 cm(3)) was completely resected in all patients. Three patients had transient or reversible complications. Karnofsky performance scores improved in 16 of 17 patients at 4 weeks postoperatively, with a mean improvement of 1.8 grades compared with preoperative scores (P < .05). Overall survival of 16 patients with distant follow-up (> 6 months or until death) averaged 10.6 +/- 4.4 months, with nine of 16 (56%) assessable patients surviving 1 year or longer. Survival of these 16 patients, by recursive partitioning analysis (RPA), was 11.2, 13.3, and 6.7 months for RPA classes I, II, and III, respectively. The cause of death in 14 of 15 patients who have died was progressive systemic disease; in one patient it was a combination of systemic and distant CNS disease progression. There were no local CNS recurrences. CONCLUSION: Complete microsurgical resection of metastatic tumors in the primary motor cortex is feasible and efficacious, results in a sustained improvement in performance outcomes, and permits satisfactory long-term survival.

Adult↗