Ashish H. Shah

The role of Gliadel wafers in the treatment of high-grade gliomas

Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Standard treatment includes surgery, radiation and chemotherapy. Prognosis is dismal with an average survival of approximately 1 year. Gliadel wafers are one treatment option, working as a source for local chemotherapy delivery. Their use is controversial with questionable survival benefit and potential side effects. We reviewed the literature in an effort to clarify their role in the treatment of high-grade gliomas. A systematic PubMed search was performed using the keywords ‘Gliadel’, ‘carmustine’ or ‘BCNU wafers’ in newly diagnosed high-grade glioma patients. Treatment regimen, and median survival were analyzed. Adverse event ratio was calculated by computing the number of adverse events in a study per patient receiving carmustine wafers. Nineteen studies with 795 patients were included in our review. Survival was 8.7–22.6 months with a mean overall survival (OS) of 16.2 months (control survival is approximately 14 months with surgery and adjuvant chemoradiotherapy). Adverse event ratio using Gliadel wafersin control group. Complication rate was 42.7%. Gliadel wafers may marginally increase survival and local control in newly diagnosed GBM patients but are associated with a high complication rate; therefore, we do not recommend using Gliadel wafers in patients with GBM. Further research may be warranted once a safer alternative to Gliadel wafers has been introduced.

The role of radiosurgery to the tumor bed after resection of brain metastases.

BACKGROUND Optimal postoperative management paradigm for brain metastases remains controversial. OBJECTIVE To conduct a systematic review of the literature to understand the role of postoperative stereotactic radiosurgery after resection of brain metastases. METHODS We performed a MEDLINE search of the literature to identify series of patients with brain metastases treated with stereotactic radiosurgery after surgical resection. Outcomes including overall survival, local control, distant intracranial failure, and salvage therapy use were recorded. Patient, tumor, and treatment factors were correlated with outcomes through the use of the Pearson correlation and 2-way Student t test as appropriate. RESULTS Fourteen studies involving 629 patients were included. Median survival for all studies was 14 months. Local control was correlated with the median volume treated with radiosurgery (r = -0.766, P < .05) and with the rate of gross total resection (r = .728, P < .03). Mean crude local control was 83%; 1-year local control was 85%. Distant intracranial failure occurred in 49% of cases, and salvage whole-brain radiation therapy was required in 29% of cases. Use of a radiosurgical margin did not lead to increased local control or overall survival. CONCLUSION Our systematic review supports the use of radiosurgery as a safe and effective strategy for adjuvant treatment of brain metastases, particularly when gross total resection has been achieved. With all limitations of comparisons between studies, no increase in local recurrence or decrease in overall survival compared with rates with adjuvant whole-brain radiation therapy was found.

Active immunotherapy using dendritic cells in the treatment of glioblastoma multiforme

OBJECTIVE Glioblastoma multiforme, the most common malignant brain tumor still has a dismal prognosis with conventional treatment. Therefore, it is necessary to explore new and/or adjuvant treatment options to improve patient outcomes. Active immunotherapy is a new area of research that may be a successful treatment option. The focus is on vaccines that consist of antigen presenting cells (APCs) loaded with tumor antigen. We have conducted a systematic review of prospective studies, case reports and clinical trials. The goal of this study was to examine the efficacy and safety in terms of complications, median overall survival (OS), progression free survival (PFS) and quality of life. METHODS A PubMed search was performed to include all relevant studies that reported the characteristics, outcomes and complications of patients with GBM treated with active immunotherapy using dendritic cells. Reported parameters were immune response, radiological findings, median PFS and median OS. Complications were categorized based on association with the craniotomy or with the vaccine itself. RESULTS A total of 21 studies with 403 patients were included in our review. Vaccination with dendritic cells (DCs) loaded with autologous tumor cells resulted in increased median OS in patients with recurrent GBM (71.6-138.0 wks) as well as those newly diagnosed (65.0-230.4 wks) compared to average survival of 58.4 wks. CONCLUSIONS Active immunotherapy, specifically with autologous DCs loaded with autologous tumor cells, seems to have the potential of increasing median OS and prolonged tumor PFS with minimal complications. Larger clinical trials are needed to show the potential benefits of active immunotherapy.

Awake craniotomy for brain tumor resection: The rule rather than the exception?

Objective: Awake craniotomy (AC) has seen an expanded role in brain tumor surgery over the past few decades. AC allows intraoperative cortical mapping and the continuous assessment of neurophysiological parameters, which are otherwise unattainable under general anesthesia (GA). The ability of AC to analyze eloquent brain areas makes it a powerful method for reducing the risks associated with tumor resection, especially in motor and language cortex. We present a review of the literature to examine the benefits and limits of using AC over GA. Methods: A literature search was performed using the Medline and PubMed databases from 1970 and 2012 that compared craniotomy for tumor resection under GA and AC. Data of interest included length of hospital stay, operating time, extent of resection, and neurological sequelae. Results: A total of 8 studies with 951 patients (411 utilizing AC and 540 utilizing GA) were included in this review. Our interpretation of the literature suggests that AC (4 d, n=110) results in a shorter hospital stay than GA (9 d, n=116). Mean extent of resection was slightly less under awake conditions (41%, n=321) versus GA (44%, n=444), and postoperative deficits were less frequent under awake conditions (7%, n=411) versus GA (23%, n=520). Surgery time was slightly less in the AC group (165 min, n=324) versus GA (168 min, n=477). Conclusions: Given the effectiveness of AC for resection of eloquent tumors, the data suggests an expanded role for AC in brain tumor surgery regardless of tumor location.

Epigenetic pathways and glioblastoma treatment

Glioblastoma multiforme (GBM) is the most common malignant adult brain tumor. Standard GBM treatment includes maximal safe surgical resection with combination radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. Alarmingly, patient survival at five-years is below 10%. This is in part due to the invasive behavior of the tumor and the resulting inability to resect greater than 98% of some tumors. In fact, recurrence after such treatment may be inevitable, even in cases where gross total resection is achieved. The Cancer Genome Atlas (TCGA) research network performed whole genome sequencing of GBM tumors and found that GBM recurrence is linked to epigenetic mechanisms and pathways. Central to these pathways are epigenetic enzymes, which have recently emerged as possible new drug targets for multiple cancers, including GBM. Here we review GBM treatment, and provide a systems approach to identifying epigenetic drivers of GBM tumor progression based on temporal modeling of putative GBM cells of origin. We also discuss advances in defining epigenetic mechanisms controlling GBM initiation and recurrence and the drug discovery considerations associated with targeting epigenetic enzymes for GBM treatment.

Predictors of Long-Term Survival in Patients With Glioblastoma Multiforme: Advancements From the Last Quarter Century

Over the last quarter century there has been significant progress toward identifying certain characteristics and patterns in GBM patients to predict survival times and outcomes. We sought to identify clinical predictors of survival in GBM patients from the past 24 years. We examined patient survival related to tumor locations, surgical treatment, postoperative course, radiotherapy, chemotherapy, patient age, GBM recurrence, imaging characteristics, serum, and molecular markers. We present predictors that may increase, decrease, or play no significant role in determining a GBM patients long-term survival or affect the quality of life.

Managing Intracranial Incidental Findings Suggestive of Low-Grade Glioma: Learning from Experience

NTRODUCTION Learning from experiencemay be one of themost important and pragmatic tools physicians possess today despite the uncertain nature of science. In today’s scientific world, hysicians constantly address the following question: How does ne deal with something he or she has not experienced or did not xpect? Will the physician be prone to failure regardless as Shaw uggests? Although these questions have confounded health care eams for years, they do have certain weight and relevance when onsidering current ethical and practical dilemmas of physicians anaging “unexpected” or incidental lesions. It is likely that very physician will encounter incidental lesions at some point in is or her career. As the overall number of incidental findings ncreases with the increasing frequency of radiographic scans, hese questions will soon begin to hold more importance and ravity. Specifically in the realm of neuroimaging, our experience with he “unexpected” has been insufficient. Today, there has yet to be consensus on the management of incidental findings found on agnetic resonance imaging (MRI), and different authors have eported various methods of managing these lesions (5). Some authors have suggested a uniform policy for handling incidental findings for all neuroimaging research, although research studies may not be the primary mode of discovery (1). Although most incidental findings on brain MRI are nonurgent (requiring no referral), approximately 1%–2% of these findings require routine or urgent referral to specialists (4). Of the referred patients, patients who present with MRI findings suggestive of low-grade gliomas (LGG) are even rarer with a reported incidence of 0.05% of the healthy population (6). Suspected incidental low-grade

The role of magnetic resonance-guided laser ablation in neurooncology

Abstract Introduction. The use of magnetic resonance-guided laser-induced thermal therapy (MR-LITT) as a minimally invasive method of treating intra-cranial pathology is a rapidly growing field. The use of MR-LITT in neurooncology has shown promising results; however, there has been no review to date of the current literature. Methods. A review of the published literature regarding MR-LITT in neurooncology was performed. Studies on PubMed were included if at least one patient with a cerebral tumour or radiation necrosis was treated using quantitative MR thermography-guided LITT, as well as if either safety or outcomes were discussed. Results. In treating recurrent Grade-III and -IV gliomas, we found improved median overall survival of 20.9 months from diagnosis of recurrence, which is comparable with that of 18.9 months for high-dose-rate brachytherapy and 24.4 months for repeated open surgery. Median progression-free survival (PFS) of recurrent glioma is noted to be 4.5 months. For metastatic lesions, we found a median overall survival (OS) to vary between 9.0 and 19.8 months with a PFS between 3.8 and 8.5 months. Current literature reports median OS in similar patients to lie between 7.0 and 28.6 months. Severe complication rates (with permanent deficits) are found to be between 12 and 16.7%, comparable with 11% found in literature for open surgery. Conclusions. The current literature shows that MR-LITT is safe and shows promising local tumour control rates. Larger randomised studies are warranted to further investigate this adjuvant therapy in the treatment of recurrent high-grade gliomas and metastases.

The role of whole-brain radiation therapy after stereotactic radiation surgery for brain metastases.

The benefit of whole-brain radiation therapy (WBRT) following stereotactic radiation surgery (SRS) for brain metastases is controversial. We conducted a systematic analysis of published literature to explore the outcome of brain metastases treated with SRS and WBRT versus SRS alone using PubMed and MEDLINE. Outcomes including survival, control, salvage therapy, and other quality of life measures were reported. Three randomized controlled trials involving 389 patients with 1 to 4 brain metastases were selected. In 2 of these trials (n = 190), the mean 1-year survival was 33.2% for SRS + WBRT and 38.7% for SRS alone (P = .5233); 1-year local control was 89% for SRS + WBRT and 71% for SRS alone (P < .001). Mean crude distant recurrence rate for SRS + WBRT was 36.6% and 54% for SRS alone (P < .001). Patients without WBRT were over 3 times more likely to require salvage therapy (P < .001). The addition of WBRT was associated with a decreased health-related quality of life assessment, mini mental status exam, and Hopkins Verbal Learning Test (P < .05). Five retrospective studies (n = 1122) were also included in a separate analysis and yielded findings that supported results from the randomized trials. Our systematic analysis demonstrates that adjuvant WBRT following SRS for the treatment of oligometastases in the brain is more effective at controlling local and distant recurrence than SRS alone, but there is no apparent benefit for survival or symptomology. The proven cognitive decline and neurotoxicity present with WBRT should be weighed against the benefit of local control. Prognosis of brain metastasis is poor regardless of current treatment and further exploration for alternative adjuvant treatment for SRS is warranted.

Dendritic cell vaccine for recurrent high-grade gliomas in pediatric and adult subjects: clinical trial protocol.

BACKGROUND Although there have been significant advances in understanding the basic pathogenesis of glioblastoma multiforme, the median survival of patients has changed little in the past 25 years. Recent studies have suggested that immune modulation through dendritic cell (DC) vaccines may stimulate the immune system against tumor antigens and potentially increase survival. OBJECTIVE To determine whether the use of adjuvant vaccination with autologous DCs (matured in situ after being loaded with tumor cell lysate derived from autologous refractory gliomas) is safe, feasible, and beneficial for adult and pediatric patients with recurrent high-grade gliomas. METHODS The study design is a single-center, nonrandomized, open phase I clinical trial. A total of 20 patients with malignant gliomas will be enrolled preoperatively over 2 years. Patients will be given adjuvant vaccination with autologous DCs loaded with tumor lysate after maximal safe surgical resection. EXPECTED OUTCOMES Using topical imiquimod before vaccination, it is anticipated that the immune response in vaccinated patients and potentially Overall survival will be greater than that demonstrated in the literature. We anticipate that there will be minimal side effects (minor dermatitis) associated with this treatment. DISCUSSION In the current trial, we assess immune response, safety, and survival using a novel vaccine protocol developed in Belgium that seems to markedly increase survival of certain subjects. Nevertheless, larger randomized clinical studies need to be performed to evaluate fully the efficacy of this therapy for both recurrent and newly diagnosed glioblastoma.