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Michael K. Yoon, Andrew T. Parsa and Jonathan C. Horton

In children or young adults, the morphology of the skull can be altered by excessive drainage of CSF following placement of a ventriculoperitoneal (VP) shunt. In Sunken Eyes, Sagging Brain Syndrome, gradual enlargement of the orbital cavity occurs from low or negative intracranial pressure (ICP), leading to progressive bilateral enophthalmos. The authors report several heretofore unrecognized manifestations of this syndrome, which developed in a 29-year-old man with a history of VP shunt placement following a traumatic brain injury at the age of 9 years. Magnetic resonance imaging showed typical features of chronic intracranial hypotension, and lumbar puncture yielded an unrecordable subarachnoid opening pressure. The calvaria was twice its normal thickness, owing to contraction of the inner table. The paranasal sinuses were expanded, with aeration of the anterior clinoid processes, greater sphenoid wings, and temporal bones. The sella turcica showed a 50% reduction in cross-sectional area as compared with that in control subjects, resulting in partial extrusion of the pituitary gland. These new features broaden the spectrum of clinical findings associated with low ICP. Secondary installation of a valve to restore normal ICP is recommended to halt progression of these rare complications of VP shunt placement.

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Ian F. Parney, James S. Waldron and Andrew T. Parsa

Object

To date, glioma immunotherapy has been focused mostly on stimulating antitumor peripheral lymphocyte responses; however, some data suggest that microglia and/or macrophages (not lymphocytes) are the predominant inflammatory cells infiltrating gliomas. To study this hypothesis further, the authors analyzed inflammatory cell infiltrates in fresh human malignant glioma specimens and primary cultures.

Methods

Single-cell suspensions from fresh operative malignant glioma specimens, obtained by stereotactic localization, were analyzed for CD11b and CD45 by using flow cytometry. A comparison was made with peripheral blood mononuclear cells. In a subset of patients, a more detailed flow cytometry analysis of Class I and II major histocompatibility complex, B7-1, B7-2, CD11c, and CD14 expression was performed. Macrophage-like cells in primary glioma cultures were similarly assessed.

Results

Operative samples were obtained from 9 newly diagnosed malignant gliomas. The mean percent of CD45+/CD11b cells (lymphocytes) was 2.48% (range 0.65–5.50%); CD45dim/CD11b+ cells (microglia), 1.65% (range 0.37–3.92%); and CD45bright/CD11b+ (monocytes/macrophages), 6.25% (range 1.56–15.3%). More detailed fluorescence-activated cell sorting suggested that macrophage-like cells expressed Class I and II major histocompatibility complex, B7-2, and CD11c but not CD14 or B7-1. Primary human glioma cultures contained significant numbers of macrophage-like (CD45bright/CD11b+) cells, but these cells were lost with successive passages. These cells maintained the immunomarker profiles of macrophage-like cells from fresh specimens only if they were cultured in serum-free media.

Conclusions

The CD45+/CD11b+ cells are the predominant inflammatory cell infiltrating human gliomas. Of this type, the CD45bright/CD11b+ cells, a phenotype compatible with circulating macrophages in rodent models, and not microglia, are the most common. Their immunomarker profile is compatible with an immature antigen-presenting cell. They are present in primary glioma cultures but are lost in successive passages. Their role is enigmatic, and they may prove an important target for future glioma immunotherapy studies.

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Michael E. Sughrue, Michael W. McDermott and Andrew T. Parsa

Clinical approaches to the surgical management of optic chiasm compression stress quick action, as several case series have demonstrated minimal vision restoration following aggressive decompression in patients presenting more than 3 days after the onset of blindness. The authors here report the case of a 48-year-old woman who presented with near-complete binocular vision loss but regained visual function following surgical removal of a giant planum-tuberculum meningioma, which was performed 8 days after a documented loss in light perception. The interval between the patient's vision loss and successful vision-restoring decompressive surgery is the longest recorded to date in the literature. This case shows the importance of aggressive decompression of mass lesions despite extended intervals of optic nerve dysfunction.

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Eli T. Sayegh, Shayan Fakurnejad, Taemin Oh, Orin Bloch and Andrew T. Parsa

Patients who undergo craniotomy for brain tumor resection are prone to experiencing seizures, which can have debilitating medical, neurological, and psychosocial effects. A controversial issue in neurosurgery is the common practice of administering perioperative anticonvulsant prophylaxis to these patients despite a paucity of supporting data in the literature. The foreseeable benefits of this strategy must be balanced against potential adverse effects and interactions with critical medications such as chemotherapeutic agents and corticosteroids. Multiple disparate metaanalyses have been published on this topic but have not been applied into clinical practice, and, instead, personal preference frequently determines practice patterns in this area of management. Therefore, to select the current best available evidence to guide clinical decision making, the literature was evaluated to identify meta-analyses that investigated the efficacy and/or safety of anticonvulsant prophylaxis in this patient population. Six meta-analyses published between 1996 and 2011 were included in the present study. The Quality of Reporting of Meta-analyses and Oxman-Guyatt methodological quality assessment tools were used to score these meta-analyses, and the Jadad decision algorithm was applied to determine the highest-quality meta-analysis. According to this analysis, 2 metaanalyses were deemed to be the current best available evidence, both of which conclude that prophylactic treatment does not improve seizure control in these patients. Therefore, this management strategy should not be routinely used.

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Aaron J. Clark, Tene A. Cage, Derick Aranda, Andrew T. Parsa, Kurtis I. Auguste and Nalin Gupta

Object

Craniopharyngiomas are benign tumors but their close anatomical relationship with critical neurological, endocrine, and vascular structures makes gross-total resection (GTR) with minimal morbidity difficult to achieve. Currently, there is controversy regarding the extent, timing, and modality of treatment for pediatric craniopharyngioma.

Methods

The authors performed a systematic review of the published literature on pediatric craniopharyngioma to determine patterns of clinical practice and the reported outcomes of standard treatment strategies. This yielded 109 studies, which contained data describing extent of resection for a total of 531 patients. Differences in outcome were examined based upon extent of resection and choice of radiation treatment.

Results

Gross-total resection was associated with increased rates of new endocrine dysfunction (OR 5.4, p < 0.001), panhypopituitarism (OR 7.8, p = 0.006), and new neurological deficits (OR 9.9, p = 0.03) compared with biopsy procedures. Subtotal resection (STR) was not associated with an increased rate of new neurological deficits. Gross-total was associated with increased rates of diabetes insipidus (OR 7.7, p = 0.05) compared with the combination of STR and radiotherapy (RT). The addition of RT to STR was associated with increased rates of panhypopituitarism (OR 9.9, p = 0.01) but otherwise similar rates of morbidities.

Conclusions

Although subject to the limitations of a literature review, this report suggests that GTR is associated with increased rates of endocrinopathies compared with STR + RT, and this should be considered when planning goals of surgery.

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Seunggu J. Han, Isaac Yang, Tarik Tihan, Susan M. Chang and Andrew T. Parsa

Object

Although secondary gliosarcoma after treatment of primary glioblastoma multiforme has been described, little is known of these rare tumors. In this article the authors review the literature on secondary gliosarcoma, with attention to clinical course and pathological features.

Methods

A PubMed search of the key word intracranial “gliosarcoma” with and without “radiation” or “radiotherapy” in humans was performed. The 204 citations yielded were screened for relevancy to gliosarcomas that occur after treatment of previous intracranial neoplasms.

Results

A search of the literature yielded 24 relevant articles, combined for a total of only 12 cases of secondary gliosarcoma and 12 cases of radiation-induced gliosarcoma. Of the 12 cases of secondary gliosarcoma, all were previously treated with surgery and radiotherapy (mean dose 50.7 Gy), with a mean survival of 13 months since time of gliosarcoma diagnosis (range 6.9–19.4 months). In the cases of radiation-induced gliosarcoma, the mean dose of previous radiotherapy was 51.3 Gy (median 54 Gy, range 24–60 Gy), and the mean survival since gliosarcoma diagnosis was 6.7 months (median 6 months, range 2–10 months).

Conclusions

Secondary gliosarcoma and radiation-induced gliosarcoma are exceedingly rare. The literature on secondary gliosarcoma illustrates a more favorable survival than for primary gliosarcoma but remains limited regarding clinical and radiographic presentation, response to treatment, and pathogenesis. The results of the present review also support the notion that secondary gliosarcomas and radiation-induced gliosarcomas are distinct entities, with longer survival and shorter latency of gliosarcoma induction seen in the former. Efforts to elucidate the role of radiotherapy in the induction of gliosarcomas may yield new insights into therapeutic risks of cranial radiation and CNS tumor pathogenesis.

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William B. Feldman, Aaron J. Clark, Michael Safaee, Christopher P. Ames and Andrew T. Parsa

Object

Myxopapillary ependymomas (MPEs) are rare WHO Grade I tumors found in the conus medullaris, cauda equina, and filum terminale. Treatment generally consists of resection with or without adjuvant radiotherapy. Evidence-based guidelines for surgical management are lacking due to the rarity of this tumor.

Methods

An English-language PubMed search was performed using the key words “myxopapillary” and “ependymoma.” Reports describing fewer than 3 patients or those lacking data on the extent of resection or radiotherapy were excluded. A total of 28 articles describing 475 patients met the authors' inclusion criteria. Patients were grouped by extent of resection and whether or not they underwent adjuvant radiotherapy. Differences in recurrence rates were assessed by chi-square test.

Results

The overall recurrence rate was 15.5% in patients treated by gross-total resection (GTR) and 32.6% in patients treated by subtotal resection (STR), irrespective of whether they underwent adjuvant therapy (p < 0.001). Regardless of the extent of resection, adjuvant radiotherapy was not associated with a decrease in recurrence rates. The overall recurrence rate was 15.6% in patients who underwent GTR and radiotherapy compared with 15.9% in patients who underwent GTR alone (p = 0.58), and it was 29.3% in patients who underwent STR and radiotherapy compared with 35.1% in those who underwent STR alone (p = 0.53). The difference between recurrence rates for patients who underwent GTR alone versus STR and radiotherapy was statistically significant (p = 0.02). Subgroup analysis demonstrated significantly higher recurrence rates in pediatric patients compared with adults (40.5% vs 23.4%, respectively; p = 0.02). Even in the setting of GTR alone, recurrence rates were higher in pediatric patients (65% vs 7.6%; p < 0.001).

Conclusions

Gross-total resection alone is associated with decreased recurrence rates compared with STR with or without radiotherapy. The authors' results suggest that treatment goals should include attempted GTR whenever possible. The observation that children benefitted from radiation therapy to a greater extent than did adults suggests that biological differences between tumors in these patient populations warrants more rigorous scientific studies.

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Nader Sanai, Mei-Yin Polley, Michael W. McDermott, Andrew T. Parsa and Mitchel S. Berger

Object

The value of extent of resection (EOR) in improving survival in patients with glioblastoma multiforme (GBM) remains controversial. Specifically, it is unclear what proportion of contrast-enhancing tumor must be resected for a survival advantage and how much survival improves beyond this threshold. The authors attempt to define these values for the patient with newly diagnosed GBM in the modern neurosurgical era.

Methods

The authors identified 500 consecutive newly diagnosed patients with supratentorial GBM treated at the University of California, San Francisco between 1997 and 2009. Clinical, radiographic, and outcome parameters were measured for each case, including MR imaging–based volumetric tumor analysis.

Results

The patients had a median age of 60 years and presented with a median Karnofsky Performance Scale (KPS) score of 80. The mean clinical follow-up period was 15.3 months, and no patient was unaccounted for. All patients underwent resection followed by chemotherapy and radiation therapy. The median postoperative tumor volume was 2.3 cm3, equating to a 96% EOR. The median overall survival was 12.2 months. Using Cox proportional hazards analysis, age, KPS score, and EOR were predictive of survival (p < 0.0001). A significant survival advantage was seen with as little as 78% EOR, and stepwise improvement in survival was evident even in the 95%–100% EOR range. A recursive partitioning analysis validated these findings and provided additional risk stratification parameters related to age, EOR, and tumor burden.

Conclusions

For patients with newly diagnosed GBMs, aggressive EOR equates to improvement in overall survival, even at the highest levels of resection. Interestingly, subtotal resections as low as 78% also correspond to a survival benefit.

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Isaac Yang, Seunggu J. Han, Michael E. Sughrue, Tarik Tihan and Andrew T. Parsa

Object

The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.

Methods

Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm2). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen.

Results

Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma.

Conclusions

This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.