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Biomedical subjects

Andrew T Parsa

Publications and source records attributed to Andrew T Parsa.

At least 19 recordsLinked to original sources
PubMed2006

Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma.

Cancer immunoresistance and immune escape may play important roles in tumor progression and pose obstacles for immunotherapy. Expression of the immunosuppressive protein B7 homolog 1 (B7-H1), also known as programmed death ligand-1 (PD-L1), is increased in many pathological conditions, including cancer. Here we show that expression of the gene encoding B7-H1 increases post transcriptionally in human glioma after loss of phosphatase and tensin homolog (PTEN) and activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway. Tumor specimens from individuals with glioblastoma multiforme (GBM) had levels of B7-H1 protein that correlated with PTEN loss, and tumor-specific T cells lysed human glioma targets expressing wild-type PTEN more effectively than those expressing mutant PTEN. These data identify a previously unrecognized mechanism linking loss of the tumor suppressor PTEN with immunoresistance, mediated in part by B7-H1.

Analysis of Variance↗
PubMed2006

mTOR-independent translational control of the extrinsic cell death pathway by RalA.

Oncogenic potential is associated with translational regulation, and the prevailing view is that oncogenes use mTOR-dependent pathways to up-regulate the synthesis of proteins critical for transformation. In this study, we show that RalA, a key mediator of Ras transformation, is also linked to the translational machinery. At least part of this linkage, however, is independent of mTOR and acts through RalBP1 to suppress cdc42-mediated activation of S6 kinase and the translation of the antiapoptotic protein FLIP(S). This action, rather than contributing to transformation, opens a latent tumor-suppressive mechanism that can be activated by tumor necrosis factor-related apoptosis-inducing ligand. These results show that the translational machinery is linked to tumor suppression as well as cell-proliferative pathways and that the reestablishment of cell death pathways by activation of the Ral oncogenic program provides a means for selective therapeutic targeting of Ral-driven malignancies.

ATP-Binding Cassette Transporters↗
PubMed2006

Endoscopic third ventriculostomy.

Among patients with idopathic aqueductal stenosis or impedance of cerebrospinal fluid (CSF) flow in the posterior fossa due to tumour, endoscopic fenestration of the floor of the third ventricle creates an alternative route for CSF flow to the subarachnoid space via the prepeduncular cistern. By reestablishing CSF flow, this procedure dissipates any pressure gradient on midline structures. This may obviate the need for traditional CSF shunt diversion techniques in such settings. Currently, endoscopic third ventriculostomy is indicated in approximately 25% of patients with hydrocephalus and can be performed instead of shunt placement. Appropriate patients are those with aqueductal stenosis (10%), obstructive tumours (10%), and obstructive cysts (5%). Additional recent data suggest the favorability of third ventriculostomy over shunt implantation in additional patient cohorts. Operative technique is discussed.

Humans↗
PubMed2006

Serum IgE, tumor epidermal growth factor receptor expression, and inherited polymorphisms associated with glioma survival.

In population-based glioma patients, we examined survival in relation to potentially pertinent constitutive polymorphisms, serologic factors, and tumor genetic and protein alterations in epidermal growth factor receptor (EGFR), MDM2, and TP53. Subjects were newly diagnosed adults residing in the San Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to 1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects provided blood for serologic studies of IgE and IgG to four herpes viruses and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n = 471). We obtained 595 of 697 astrocytic tumors for marker studies. We determined treatments, vital status, and other factors using registry, interview, medical record, and active follow-up data. Cox regressions for survival were adjusted for age, gender, ethnicity, study series, resection versus biopsy only, radiation, and chemotherapy. Using a stringent P < 0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR), 0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1 deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients with elevated IgE had 9 months longer survival than those with normal or borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR expression in anaplastic astrocytoma was associated with nearly 3-fold poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and others' findings, we recommend further studies to (a) understand relationships of elevated IgE levels and other immunologic factors with improved glioblastoma survival potentially relevant to immunologic therapies and (b) determine which inherited ERCC1 variants or other variants in the 19q13.3 region influence survival. We also suggest that tumor EGFR expression be incorporated into clinical evaluation of anaplastic astrocytoma patients.

Astrocytoma↗
PubMed2006

Translational regulation of TRAIL sensitivity.

TNF-related apoptosis-inducing ligand (TRAIL) is a peptide that induces apoptosis to varying degrees in tumor cells. While TRAIL sensitivity in tumors has been linked to c-myc- and MEK/Erk-induced enhancement of caspase activation, our recent study identified a third input controlling TRAIL sensitivity, namely the Akt-mTOR pathway. We showed that instead of enhancing TRAIL sensitivity, Akt expression, acting through mTOR and the mTOR targets S6 kinase and eIF-4E, selectively enhances translation of the anti-apoptotic protein FLIP(S) and confers TRAIL resistance. In this perspective article we will discuss the linkage of the Akt-mTOR pathway to other regulators of TRAIL sensitivity, its importance in controlling a broader range of apoptotic events, its utility in predicting TRAIL responsiveness, and its potential manipulation for therapeutic benefit.

Apoptosis↗
PubMed2006

Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide.

We have shown that a COOH-terminal peptide of p53 (amino acids 361-382, p53p), linked to the truncated homeobox domain of Antennapedia (Ant) as a carrier for transduction, induced rapid apoptosis in human premalignant and malignant cell lines. Here, we report that human and rat glioma lines containing endogenous mutant p53 or wild-type (WT) p53 were induced into apoptosis by exposure to this peptide called p53p-Ant. The peptide was comparatively nontoxic to proliferating nonmalignant human and rat glial cell lines containing WT p53 and proliferating normal human peripheral marrow blood stem cells. Degree of sensitivity to the peptide correlated directly with the level of endogenous p53 expression and mutant p53 conformation. Apoptosis induction by p53p-Ant was quantitated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and Annexin V staining in human glioma cells in vitro and in a syngeneic orthotopic 9L glioma rat model using convection-enhanced delivery in vivo. The mechanism of cell death by this peptide was solely through the Fas extrinsic apoptotic pathway. p53p-Ant induced a 3-fold increase in extracellular membrane Fas expression in glioma cells but no significant increase in nonmalignant glial cells. These data suggest that p53 function for inducing Fas-mediated apoptosis in gliomas, which express sufficient quantities of endogenous mutant or WT p53, may be restored or activated, respectively, by a cell-permeable peptide derived from the p53 COOH-terminal regulatory domain (p53p-Ant). p53p-Ant may serve as a prototypic model for the development of new anticancer agents with unique selectivity for glioma cancer cells and it can be successfully delivered in vivo into a brain tumor by a convection-enhanced delivery system, which circumvents the blood-brain barrier.

Amino Acid Sequence↗
PubMed2006

Extended bifrontal craniotomy for midline anterior fossa meningiomas: minimization of retraction-related edema and surgical outcomes.

OBJECTIVE: Meningiomas of the anterior cranial base can be approached with a variety of techniques. The extended bifrontal approach is often thought to be associated with increased morbidity because of the need for extensive removal of the bone and longer surgical times. The authors have attempted to quantitate retraction-related edema occurring after surgery to determine whether the extra bone removal limits retraction and reduces the chance of brain injury. METHODS: Charts were reviewed for patients who underwent extended bifrontal craniotomies performed for meningiomas at the University of California, San Francisco, between 1997 and 2005. Magnetic resonance imaging scans obtained before and after surgery were reviewed for brain edema as indicated by fluid-attenuated inversion recovery/T2 abnormality and grouped into four categories: A, no edema; B, edema restricted to the gyrus rectus; C, edema beyond the gyrus rectus; and D, extensive bifrontal edema. RESULTS: Forty-five patients were identified. Fifty-four percent of patients had tumors with a diameter of more than 4 cm. Simpson Grade 2 or 3 resection was achieved in 82% of patients, and the average operative time was 12.3 hours. Vision outcome was favorable in 74% of patients. Extent of fluid-attenuated inversion recovery abnormality remained unchanged in 87.5%, with 91% of patients in categories A or B edema remaining in those categories after surgery. There were no infections and there were two cerebrospinal fluid leaks. CONCLUSION: The extended bifrontal approach is a safe surgical procedure with limited morbidity that the authors think: 1) prevents secondary brain injury from excessive retraction; 2) offers great flexibility of view for the surgeon; and 3) should be considered the preferred approach compared with the standard bifrontal craniotomy for large tumors of the anterior cranial base.

Adult↗
PubMed2006

Solitary fibrous tumor arising from Cranial Nerve VI in the prepontine cistern: case report and review of a tumor subpopulation mimicking schwannoma.

OBJECTIVE: The authors present a report of a solitary fibrous tumor (SFT) arising from the intradural component of the VIth cranial nerve as it travels through the prepontine cistern. SFTs of the central nervous system are extremely rare entities that clinically masquerade as dural-based lesions, such as meningiomas or hemangiopericytomas. Because of their infrequency and clinical similarity to other central nervous system (CNS) lesions, diagnosis is largely dependent on pathological features. In this study, the authors define a subpopulation of SFTs that seem to arise directly from nerve, rather than meninges, and clinically mimic the appearance of a schwannoma. CLINICAL PRESENTATION: The patient was a 29-year-old woman with a several-month history of progressive right arm and leg numbness and mild hemiparesis, with the development of diplopia 2 weeks before admission. Outside imaging revealed a 3.9-cm mass in the prepontine cistern with extension into Meckel's cave and the cavernous sinus, resulting in significant brainstem compression. INTERVENTION: The patient underwent preoperative angiography with embolization of feeding vessels off of the left meningohypophyseal trunk. The patient was then taken to the operating room by a combined neurosurgical and ear, nose, and throat team, where the patient underwent a retrolabyrinthine/subtemporal craniotomy for tumor resection. During resection of the prepontine component, the tumor was identified as originating from the left Cranial Nerve VI as it traversed through the prepontine cistern. Resection of the tumor component involving the cavernous sinus and Meckel's cave was deferred for follow-up treatment with intensity-modulated radiation therapy. Pathological examination revealed tissue consistent with the diagnosis of SFT. CONCLUSION: SFTs involving the CNS are rare entities that are almost always diagnosed after tissue is obtained because of their clinical and radiographic similarity to meningiomas. This patient had an SFT masquerading as a VIth cranial nerve schwannoma. Although the natural history of SFTs in the CNS is not completely understood, correct diagnosis is important, given the rate of recurrence found in the more common pleural-based SFT and examples of CNS SFTs with malignant features.

Abducens Nerve↗
PubMed2006

Defective receptor expression and dendritic cell differentiation of monocytes in glioblastomas.

OBJECTIVE: Better characterization of the changes that occur in the circulating monocytes of patients with glioblastoma has become more important recently as monocyte-derived dendritic cells are used as adjuvants in the development of glioma vaccines. This study seeks to develop understanding of the phenotypic changes that occur in circulating monocytes of patients with intracranial cancer and to assess the ability of these cells to differentiate into mature dendritic cells. METHODS: Monocyte expression levels of HLA-ABC, HLA-DR, CD86, ICAM-1, TNFRII, and GMCSFR were compared between three cohorts: patients with intracranial glioblastoma (n = 15), patients with intracranial metastases (n = 9), and a group of healthy controls (n = 10). Monocytes were then tested for their ability to differentiate into mature dentritic cells based on morphology, CD83 expression and high levels of co-stimulatory molecules. RESULTS: Comprehensive analysis of monocyte receptor expression demonstrated significantly reduced HLA-ABC, HLA-DR, CD86, ICAM-1, and TNFRII in patients with glioblastoma but not in patients with intracranial metastases compared with a group of healthy controls. GMCSFR expression was significantly reduced in both patients with glioblastoma and intracranial metastases. Additionally, the monocytes of patients with glioblastoma showed a reduced capacity to differentiate into mature dendritic cells as identified by CD83 expression, receptor expression, and morphology. CONCLUSION: Peripheral monocytes are phenotypically altered in the setting of glioblastoma and display a reduced functional capacity to differentiate into mature dendritic cells.

Adult↗
PubMed2006

Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme.

The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation and survival. Components of the mTOR pathway are activated in a variety of tumors, including glioblastoma multiforme (GBM), and we have found that one surprising consequence of mTOR pathway activation is resistance of GBMs to the proapoptotic effects of agents such as APO2L/TRAIL. mTOR inhibition has become feasible following the development of rapamycin and comparable analogs with improved pharmacological properties, including CCI-779, RAD001 and AP23573. Numerous studies have also demonstrated promising proapoptotic activity, with relatively mild side effects, using rapamycin analogs in vitro and in vivo in conjunction with APO2L/TRAIL. These studies suggest that mTOR inhibitors can be combined with APO2L/TRAIL as a potential tumor-selective therapy.

Antineoplastic Agents↗
PubMed2005

Prognostic significance of intracranial dissemination of glioblastoma multiforme in adults.

OBJECT: The clinical outcome and treatment of adult patients with disseminated intracranial glioblastoma multiforme (GBM) is unclear. The objective in the present study was to assess the prognostic significance of disseminated intracranial GBM in adults at presentation and at the time of tumor progression. METHODS: Clinical data from 1491 patients older than 17 years and harboring a GBM that had been diagnosed between 1988 and 1998 at the University of California at San Francisco neurooncology clinic were retrospectively reviewed. Dissemination of the GBM (126 patients) was determined based on Gd-enhanced magnetic resonance images. Classification of dissemination was as follows: Type I, single lesion with subependymal or subarachnoid spread; Type II, multifocal lesions without subependymal or subarachnoid spread; and Type III, multifocal lesions with subependymal or subarachnoid spread. Subgroups of patients were compared using Kaplan-Meier curves that depicted survival probability. The median postprogression survival (PPS), defined according to neuroimaging demonstrated dissemination, was 37 weeks for Type I (23 patients), 25 weeks for Type II (50 patients), and 10 weeks for Type III spread (19 patients). Patients with dissemination at first tumor progression (52 patients) overall had a shorter PPS than those in a control group with local progression, after adjusting for age, Kamofsky Performance Scale score, and time from tumor diagnosis to its progression (311 patients). When analyzed according to tumor dissemination type, PPS was significantly shorter in patients with Type II (33 patients, p < 0.01) and Type III spread (11 patients, p < 0.01) but not in those with Type I spread (eight patients, p = 0.18). CONCLUSIONS: Apparently, the presence of intracranial tumor dissemination on initial diagnosis does not in itself preclude aggressive treatment if a patient is otherwise well. A single focus of GBM that later demonstrates Type I dissemination on progression does not have a worse prognosis than a lesion that exhibits only local recurrence.

Adult↗
PubMed2005

Serial diffusion-weighted magnetic resonance imaging in cases of glioma: distinguishing tumor recurrence from postresection injury.

OBJECT: Diffusion-weighted magnetic resonance (MR) imaging is an invaluable tool in the diagnosis of acute stroke and other types of brain injury. Abnormalities in and around the resection cavity on diffusion-weighted imaging have been observed following surgery for infiltrating glioma. The purpose of this study was to investigate prospectively the incidence, time course, and ultimate outcome of these abnormalities. METHODS: Forty-four consecutive patients with newly diagnosed gliomas were prospectively observed using serial MR imaging including diffusion-weighted sequences. Clinical and surgical data were also collected. Immediately postoperatively neuroimaging identified 28 patients (64%) in whom areas of reduced diffusion appeared in or around the resection cavity (mean volume 8.2 +/- 1.5 cm3). Complete resolution of this reduced diffusion was demonstrated within 90 days in 24 patients (86%). On subsequent neuroimages these areas demonstrated Gd enhancement as early as postoperative Day 15 and as late as Day 198 and ultimately took on the appearance of encephalomalacia in 26 (93%) of 28 cases. Postoperative reduced diffusion was not predicted by the clinical or surgical parameters that were assessed. No clinical deficits were attributable to the reduced diffusion. CONCLUSIONS: An abnormality related to diffusion-weighted sequences on postoperative MR imaging can occur after resection of newly diagnosed gliomas. In this study the abnormality typically resolved and was replaced by contrast enhancement on follow-up imaging, ultimately demonstrating encephalomalacia on long-term follow up. Findings on neuroimaging during the period of enhancement could be confused with recurrent tumor and interpreted as early treatment failure. Based on the findings of this study the authors strongly suggest that the inclusion of diffusion-weighted sequences in postoperative MR imaging is essential, as is MR imaging immediately before radiation therapy to monitor disease progression. A new enhancement observed after glioma surgery should be interpreted in the context of the diffusion-weighted image obtained immediately postoperatively.

Adult↗
PubMed2005

Changes in transcranial motor evoked potentials during intramedullary spinal cord tumor resection correlate with postoperative motor function.

OBJECTIVE: Intraoperative monitoring of transcranial motor evoked potentials (TcMEPs) has been investigated recently as a means of preventing motor deficits associated with resection of intramedullary spinal cord tumors (IMSCTs). In this study, we hypothesized that changes in the intraoperative MEPs during tumor resection correlate with postoperative motor function deficits. METHODS: A retrospective record review was conducted for 28 patients who underwent resection of an IMSCT using myogenic or muscle-recorded TcMEPs during a 44-month period. Intraoperative MEP recordings and results from preoperative, immediate postoperative, and subsequent follow-up neurological examinations were analyzed. RESULTS: Of the 28 patients who underwent resection of an IMSCT using TcMEPs, MEP changes occurred in 13 patients (46%). Impaired motor conduction was detected by changes in pattern and duration of the MEP waveform morphology (polyphasic to biphasic in 9 patients and polyphasic to biphasic to loss of MEP response in 5 patients, 1 patient demonstrated both changes) and by an increase in voltage threshold (median, 175 V; range, 100-225 V; n = 22 extremities). Alterations in morphology and reduction in duration of the MEP response persisted despite significant increases in stimulation voltage. In 12 patients, reductions in the complexity and/or loss of the TcMEP waveform correlated with motor grade loss in the immediate postoperative period (P < 0.0001), at discharge (P < 0.001), and at follow-up (P < 0.001). The decrease in the duration of the response correlated with motor grade loss immediately after surgery (P < 0.001), at discharge (P < 0.0001), and at follow-up (P < 0.005). CONCLUSION: These results support the application of distal muscle-recorded TcMEPs to predict the occurrence and severity of postoperative motor deficits during resection of IMSCTs. Attention to such quantitative intraoperative monitoring data may help to minimize postoperative motor deficits by avoiding or correcting excessive spinal cord manipulation and modifying surgical technique during tumor resection.

Adult↗