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Sameer Agnihotri, Kenneth D. Aldape and Gelareh Zadeh

Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low-grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1–mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival.

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Yuri M. Andrade-Souza, Gelareh Zadeh, Meera Ramani, Daryl Scora, May N. Tsao and Michael L. Schwartz

Object. The aim of this study was to validate the radiosurgery-based arteriovenous malformation (AVM) score and the modified Spetzler—Martin grading system to predict radiosurgical outcome.

Methods. One hundred thirty-six patients with brain AVMs were randomly selected. These patients had undergone a linear accelerator radiosurgical procedure at a single center between 1989 and 2000. Patients were divided into four groups according to an AVM score, which was calculated from the lesion volume, lesion location, and patient age (Group 1, AVM score < 1; Group 2, AVM score 1–1.49; Group 3, AVM score 1.5–2; and Group 4, AVM score > 2). Patients with a Spetzler—Martin Grade III AVM were divided into Grades IIIA (lesion > 3 cm) and IIIB (lesion < 3 cm). Sixty-two female (45.6%) and 74 male (54.4%) patients with a median age of 37.5 years (mean 37.5 years, range 5–77 years) were followed up for a median of 40 months. The median tumor margin dose was 15 Gy (mean 17.23 Gy, range 15–25 Gy). The proportions of excellent outcomes according to the AVM score were as follows: 91.7% for Group 1, 74.1% for Group 2, 60% for Group 3, and 33.3% for Group 4 (chi-square test, degrees of freedom (df) = 3, p < 0.001). Based on the modified Spetzler—Martin system, Grade I lesions had 88.9% excellent results; Grade II, 69.6%; Grade IIIB, 61.5%; and Grades IIIA and IV, 44.8% (chi-square test, df = 3, p = 0.047).

Conclusions. The radiosurgery-based AVM score can be used accurately to predict excellent results following a single radiosurgical treatment for AVM. The modified Spetzler—Martin system can also predict radiosurgical results for AVMs, thus making it possible to use this system while deciding between surgery and radiosurgery.

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Mitchel S. Berger, Jeffrey N. Bruce, Thomas C. Chen and Gelareh Zadeh

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Kathleen Joy Khu, Francesco Doglietto, Ivan Radovanovic, Faisal Taleb, Daniel Mendelsohn, Gelareh Zadeh and Mark Bernstein

Object

Routine and nonselective use of awake and outpatient craniotomy for supratentorial tumors has been shown to be safe and effective from a medical standpoint. In this study the authors aim was to explore patients' perceptions about awake and outpatient craniotomy.

Methods

Qualitative research methodology was used. Two semistructured, open-ended interviews were conducted with 27 participants, who were ambulatory adult patients who underwent craniotomy for brain tumor excision between October 2008 and April 2009. The participants were each assigned to one of the following categories: 1) awake outpatient; 2) awake inpatient; 3) outpatient under general anesthesia; and 4) inpatient under general anesthesia. Interviews were audiotaped and transcribed, and the data were subjected to thematic analysis.

Results

The following 6 overarching themes emerged from the data: 1) patients had a positive experience with awake craniotomy; 2) patient satisfaction with outpatient surgery was high; 3) patients understood the rationale behind awake surgery; 4) patients were surprised that brain surgery can be done on an outpatient basis; 5) trust in one's surgeon was important; and 6) patients were more concerned about the disease than the procedure.

Conclusions

The results reflected positively on the patients' awake and outpatient surgery experience, but there were some areas that require improvement, specifically perioperative pain control and postoperative care. These insights on patients' perspectives can lead to better delivery of care, and ultimately, improved health outcomes.

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Kyle Juraschka, Osaama H. Khan, Bruno L. Godoy, Eric Monsalves, Alexandra Kilian, Boris Krischek, Aisha Ghare, Allan Vescan, Fred Gentili and Gelareh Zadeh

Object

While the use of endoscopic approaches has become increasingly accepted in the resection of pituitary adenomas, limited evidence exists regarding the success of this technique for patients with large and giant pituitary adenomas. This study reviews the outcomes of a large cohort of patients with large and giant pituitary adenomas who underwent endoscopic endonasal transsphenoidal surgery at the authors' institution and focuses on identifying factors that can predict extent of resection and hence aid in developing guidelines and indications for the use of endoscopic endonasal transsphenoidal surgery versus open craniotomy approaches to large and giant pituitary adenomas.

Methods

The authors reviewed 487 patients who underwent endoscopic endonasal transsphenoidal resection of sellar masses. From this group, 73 consecutive patients with large and giant pituitary adenomas (defined as maximum diameter ≥ 3 cm and tumor volume ≥ 10 cm3) who underwent endoscopic endonasal transsphenoidal surgery between January 1, 2006, and June 6, 2012, were included in the study. Clinical presentation, radiological studies, laboratory investigations, tumor pathology data, clinical outcomes, extent of resection measured by volumetric analysis, and complications were analyzed.

Results

The mean preoperative tumor diameter in this series was 4.1 cm and the volume was 18 cm3. The average resection rate was 82.9%, corresponding with a mean residual volume of 3 cm3. Gross-total resection was achieved in 16 patients (24%), near-total in 11 (17%), subtotal in 24 (36%), and partial in 15 (23%). Seventy-three percent of patients experienced improvement in visual acuity, while 24% were unchanged. Visual fields were improved in 61.8% and unchanged in 5.5%. Overall, 27 patients (37%) experienced a total of 32 complications. The most common complications were sinusitis (14%) and CSF leak (10%). Six patients underwent subsequent radiation therapy because of aggressive tumor histopathology. No deaths occurred in this cohort of patients. Statistically significant predictors of extent of resection included highest Knosp grade (p = 0.001), preoperative tumor volume (p = 0.025), preoperative maximum tumor diameter (p = 0.002), hemorrhagic component (p = 0.027), posterior extension (p = 0.001), and sphenoid sinus invasion (p = 0.005).

Conclusions

Endoscopic endonasal transsphenoidal surgery is an effective treatment method for patients with large and giant pituitary adenomas, which results in high (> 80%) rates of resection and improvement in visual function. It is not associated with high rates of major complications and is safe when performed by experienced surgeons. The preoperative Knosp grade, tumor volume, tumor diameter, hemorrhagic components on MRI, posterior extension, and sphenoid sinus invasion may allow a prediction of extent of resection and in these patients a staged operation may be required to maximize extent of resection.

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Daipayan Guha, Benjamin Davidson, Mustafa Nadi, Naif M. Alotaibi, Michael G. Fehlings, Fred Gentili, Taufik A. Valiante, Charles H. Tator, Michael Tymianski, Abhijit Guha and Gelareh Zadeh

OBJECTIVE

A surgical series of 201 benign and malignant peripheral nerve sheath tumors (PNSTs) was assessed to characterize the anatomical and clinical presentation of tumors and identify predictors of neurological outcome, recurrence, and extent of resection.

METHODS

All surgically treated PNSTs from the Division of Neurosurgery at Toronto Western Hospital from 1993 to 2010 were reviewed retrospectively. Data were collected on patient demographics, clinical presentation, surgical technique, extent of resection, postoperative neurological outcomes, and recurrence.

RESULTS

One hundred seventy-five patients with 201 tumors had adequate follow-up for analysis. There were 182 benign and 19 malignant PNSTs. Of the benign lesions, 133 were schwannomas, 21 of which were associated with a diagnosis of schwannomatosis. There were 49 neurofibromas, and 26 were associated with neurofibromatosis Type 1 (NF1). Patients presenting with schwannomas were significantly older than those with neurofibromas. Schwannomas were more readily resected than neurofibromas, with the extent of resection of the former influenced by tumor location. Patients with benign PNSTs typically presented with a painful mass and less frequently with motor deficits. The likelihood of worsened postoperative motor function was decreased in patients with fully resected tumors or preoperative deficits. Recurrence of schwannomas and neurofibromas were seen more frequently in patients diagnosed with NF3 and NF1, respectively. Subtotal resection was associated with the increased recurrence of all benign lesions.

CONCLUSIONS

Outcomes following resection of benign PNSTs depend on tumor histopathology, tumor location, and genetic predisposition syndrome. Gross-total resection should be attempted for benign lesions where possible. The management of malignant PNSTs remains challenging, requiring a multimodal approach.

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Roberto Jose Diaz, Roberto Rey Dios, Eyas M. Hattab, Kelly Burrell, Patricia Rakopoulos, Nesrin Sabha, Cynthia Hawkins, Gelareh Zadeh, James T. Rutka and Aaron A. Cohen-Gadol

OBJECT

Intravenous fluorescein sodium has been used during resection of high-grade gliomas to help the surgeon visualize tumor margins. Several studies have reported improved rates of gross-total resection (GTR) using high doses of fluorescein sodium under white light. The recent introduction of a fluorescein-specific camera that allows for high-quality intraoperative imaging and use of very low dose fluorescein has drawn new attention to this fluorophore. However, the ability of fluorescein to specifically stain glioma cells is not yet well understood.

METHODS

The authors designed an in vitro model to assess fluorescein uptake in normal human astrocytes and U251 malignant glioma cells. An in vivo experiment was also subsequently designed to study fluorescein uptake by intracranial U87 malignant glioma xenografts in male nonobese diabetic/severe combined immunodeficient mice. A genetically induced mouse glioma model was used to adjust for the possible confounding effect of an inflammatory response in the xenograft model. To assess the intraoperative application of this technology, the authors prospectively enrolled 12 patients who underwent fluorescein-guided resection of their high-grade gliomas using low-dose intravenous fluorescein and a microscope-integrated fluorescence module. Intraoperative fluorescent and nonfluorescent specimens at the tumor margins were randomly analyzed for histopathological correlation.

RESULTS

The in vitro and in vivo models suggest that fluorescein demarcation of glioma-invaded brain is the result of distribution of fluorescein into the extracellular space, most likely as a result of an abnormal blood-brain barrier. Glioblastoma tumor cell–specific uptake of fluorescein was not observed, and tumor cells appeared to mostly exclude fluorescein. For the 12 patients who underwent resection of their high-grade gliomas, the histopathological analysis of the resected specimens at the tumor margin confirmed the intraoperative fluorescent findings. Fluorescein fluorescence was highly specific (up to 90.9%) while its sensitivity was 82.2%. False negatives occurred due to lack of fluorescence in areas of diffuse, low-density cellular infiltration. Margins of contrast enhancement based on intraoperative MRI–guided StealthStation neuronavigation correlated well with fluorescent tumor margins. GTR of the contrast-enhancing area as guided by the fluorescent signal was achieved in 100% of cases based on postoperative MRI.

CONCLUSIONS

Fluorescein sodium does not appear to selectively accumulate in astrocytoma cells but in extracellular tumor cell-rich locations, suggesting that fluorescein is a marker for areas of compromised blood-brain barrier within high-grade astrocytoma. Fluorescein fluorescence appears to correlate intraoperatively with the areas of MR enhancement, thus representing a practical tool to help the surgeon achieve GTR of the enhancing tumor regions.

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Sameer Agnihotri, Isabel Gugel, Marc Remke, Antje Bornemann, Georgios Pantazis, Stephen C. Mack, David Shih, Sanjay K. Singh, Nesrin Sabha, Michael D. Taylor, Marcos Tatagiba, Gelareh Zadeh and Boris Krischek

Object

Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown.

Methods

In this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway.

Results

The authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2–associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their geneexpression study and evaluated this pathway for therapeutic targeting. Testing the compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death.

Conclusions

These findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strategy.