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Ranjith Babu, Jordan M. Komisarow, Vijay J. Agarwal, Shervin Rahimpour, Akshita Iyer, Dylan Britt, Isaac O. Karikari, Peter M. Grossi, Steven Thomas, Allan H. Friedman and Cory Adamson

OBJECT

The prognosis of elderly patients with glioblastoma (GBM) is universally poor. Currently, few studies have examined postoperative outcomes and the effects of various modern therapies such as bevacizumab on survival in this patient population. In this study, the authors evaluated the effects of various factors on overall survival in a cohort of elderly patients with newly diagnosed GBM.

METHODS

A retrospective review was performed of elderly patients (≥ 65 years old) with newly diagnosed GBM treated between 2004 and 2010. Various characteristics were evaluated in univariate and multivariate stepwise models to examine their effects on complication risk and overall survival.

RESULTS

A total of 120 patients were included in the study. The median age was 71 years, and sex was distributed evenly. Patients had a median Karnofsky Performance Scale (KPS) score of 80 and a median of 2 neurological symptoms on presentation. The majority (53.3%) of the patients did not have any comorbidities. Tumors most frequently (43.3%) involved the temporal lobe, followed by the parietal (35.8%), frontal (32.5%), and occipital (15.8%) regions. The majority (57.5%) of the tumors involved eloquent structures. The median tumor size was 4.3 cm. Every patient underwent resection, and 63.3% underwent gross-total resection (GTR). The vast majority (97.3%) of the patients received the postoperative standard of care consisting of radiotherapy with concurrent temozolomide. The majority (59.3%) of patients received additional agents, most commonly consisting of bevacizumab (38.9%). The median survival for all patients was 12.0 months; 26.7% of patients experienced long-term (≥ 2-year) survival. The extent of resection was seen to significantly affect overall survival; patients who underwent GTR had a median survival of 14.1 months, whereas those who underwent subtotal resection had a survival of 9.6 months (p = 0.038). Examination of chemotherapeutic effects revealed that the use of bevacizumab compared with no bevacizumab (20.1 vs 7.9 months, respectively; p < 0.0001) and irinotecan compared with no irinotecan (18.0 vs 9.7 months, respectively; p = 0.027) significantly improved survival. Multivariate stepwise analysis revealed that older age (hazard ratio [HR] 1.06 [95% CI1.02–1.10]; p = 0.0077), a higher KPS score (HR 0.97 [95% CI 0.95–0.99]; p = 0.0082), and the use of bevacizumab (HR 0.51 [95% CI 0.31–0.83]; p = 0.0067) to be significantly associated with survival.

CONCLUSION

This study has demonstrated that GTR confers a modest survival benefit on elderly patients with GBM, suggesting that safe maximal resection is warranted. In addition, bevacizumab significantly increased the overall survival of these elderly patients with GBM; older age and preoperative KPS score also were significant prognostic factors. Although elderly patients with GBM have a poor prognosis, they may experience enhanced survival after the administration of the standard of care and the use of additional chemotherapeutics such as bevacizumab.

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Ranjith Babu, Steven Thomas, Matthew A. Hazzard, Allan H. Friedman, John H. Sampson, Cory Adamson, Ali R. Zomorodi, Michael M. Haglund, Chirag G. Patil, Maxwell Boakye and Shivanand P. Lad

Object

On July 1, 2003, the Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions for resident physicians due to concerns for patient and resident safety. Though duty-hour restrictions have increased resident quality of life, studies have shown mixed results with respect to patient outcomes. In this study, the authors have evaluated the effect of duty-hour restrictions on morbidity, mortality, length of stay, and charges in patients who underwent brain tumor and cerebrovascular procedures.

Methods

The Nationwide Inpatient Sample was used to evaluate the effect of duty-hour restrictions on complications, mortality, length of stay, and charges by comparing the pre-reform (2000–2002) and post-reform (2005–2008) periods. Outcomes were compared between nonteaching and teaching hospitals using a difference-in-differences (DID) method.

Results

A total of 90,648 patients were included in the analysis. The overall complication rate was 11.7%, with the rates not significantly differing between the pre– and post–duty hour eras (p = 0.26). Examination of hospital teaching status revealed that complication rates decreased in nonteaching hospitals (12.1% vs 10.4%, p = 0.0004) and remained stable in teaching institutions (11.8% vs 11.9%, p = 0.73) in the post-reform era. Multivariate analysis demonstrated a significantly higher complication risk in teaching institutions (OR 1.33 [95% CI 1.11–1.59], p = 0.0022), with no significant change in nonteaching hospitals (OR 1.11 [95% CI 0.91–1.37], p = 0.31). A DID analysis to compare the magnitude in change between teaching and nonteaching institutions revealed that teaching hospitals had a significantly greater increase in complications during the post-reform era than nonteaching hospitals (p = 0.040). The overall mortality rate was 3.0%, with a significant decrease occurring in the post-reform era in both nonteaching (5.0% vs 3.2%, p < 0.0001) and teaching (3.2% vs 2.3%, p < 0.0001) hospitals. DID analysis to compare the changes in mortality between groups did not reveal a significant difference (p = 0.40). The mean length of stay for all patients was 8.7 days, with hospital stay decreasing from 9.2 days to 8.3 days in the post-reform era (p < 0.0001). The DID analysis revealed a greater length of stay decrease in nonteaching hospitals than teaching institutions, which approached significance (p = 0.055). Patient charges significantly increased in the post-reform era for all patients, increasing from $70,900 to $96,100 (p < 0.0001). The DID analysis did not reveal a significant difference between the changes in charges between teaching and nonteaching hospitals (p = 0.17).

Conclusions

The implementation of duty-hour restrictions correlated with an increased risk of postoperative complications for patients undergoing brain tumor and cerebrovascular neurosurgical procedures. Duty-hour reform may therefore be associated with worse patient outcomes, contrary to its intended purpose. Due to the critical condition of many neurosurgical patients, this patient population is most sensitive and likely to be negatively affected by proposed future increased restrictions.

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Vijay Agarwal, Ranjith Babu, Jordan Grier, Owoicho Adogwa, Adam Back, Allan H. Friedman, Takanori Fukushima and Cory Adamson

Object

Tumors of the cerebellopontine angle (CPA) have always proven difficult for neurosurgeons to optimally manage. Studies investigating the natural history and treatment of vestibular schwannomas have dominated the literature in this regard. Distinguishing meningiomas from schwannomas in this location carries particular importance as each tumor type has certain prognostic and surgical considerations. In this study, the authors have characterized the outcomes of 34 patients surgically treated for CPA meningiomas and have investigated various factors that may affect postoperative neurological function.

Methods

The medical records of patients with CPA meningiomas who underwent surgery from 2005 to 2013 at the Duke University Health System were reviewed. Various patient, clinical, and tumor data were gathered from the medical records including patient demographics, pre- and postoperative neurological examinations, duration of symptoms, procedural details, tumor pathology and size, and treatment characteristics. Differences in continuous variables were then analyzed using the Student t-test while categorical variables were evaluated using the chi-square test.

Results

A total of 34 patients underwent surgical treatment for CPA meningiomas during the 8-year period. Jugular foramen invasion was seen in 17.6% of tumors, with nearly half (41.2%) extending into the internal acoustic canal. The most common presenting symptom was hearing loss (58.8%), followed by headache (52.9%) and facial numbness/pain (50.0%). The most common cranial nerve (CN) affected was CN X (11.8%), followed by CNs VI and VII (5.9%). Postoperatively, no patients experienced a decrease in hearing, with only 5.9% of patients experiencing facial nerve palsies. Patients with tumors larger than 3 cm had a significantly higher incidence of permanent CN deficits than those with smaller tumors (45.5% vs 5.9%, respectively; p = 0.011). Also, tumor extension into the jugular foramen was associated with the occurrence of lower CN deficits, none of which occurred in tumors without jugular foramen invasion. Internal acoustic canal tumor extension was not seen to be associated with postoperative complications or CN deficits.

Conclusions

Meningiomas of the CPA are challenging lesions to treat surgically. However, the risk of facial palsy and hearing loss is significantly lower when compared with vestibular schwannomas. Novel methods for preoperative differentiation are needed to appropriately counsel patients on surgical risks. Also, due to the significant potential for neurological deficits, further studies are needed to investigate the utility of radiotherapy for these lesions.

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Ranjith Babu, Jeffrey Hatef, Roger E. McLendon, Thomas J. Cummings, John H. Sampson, Allan H. Friedman and Cory Adamson

Object

Rhabdoid glioblastoma (GB) is an exceedingly rare tumor in which some of the tumor cells possess rhabdoid features such as eccentric nuclei, abundant eosinophilic cytoplasm, and pseudopapillary formations. These tumors are exceptionally aggressive, and leptomeningeal dissemination is common. In the 9 previously reported cases, the longest survival was only 9 months, with a median survival of 17.8 weeks. The authors report the clinicopathological characteristics of 4 cases of rhabdoid GB and demonstrate the utility of intensive temozolomide and adjuvant therapy in these tumors. The authors also review the literature to provide the most comprehensive understanding of these rare tumors to date.

Methods

A retrospective review was performed of patients treated for GB at the Duke University Medical Center between 2004 and 2012. One of two experienced neuropathologists identified 4 cases as being rhabdoid GBs. Immunohistochemistry and fluorescence in situ hybridization analyses were performed in all cases. Kaplan-Meier analysis was used to assess overall survival, with the log-rank test being used to evaluate differences between survival curves. An extensive review of the literature was also performed.

Results

The median age of patients with rhabdoid GB was 30 years. Clinical presentation varied with location, with headache being a presenting symptom in 90% of patients. All lesions were supratentorial, and 45.5% of the cases involved the temporal lobe. Leptomeningeal dissemination occurred in 63.6% of patients, with 1 patient having extracranial metastasis to the scalp and lungs. Fluorescence in situ hybridization revealed epidermal growth factor receptor gain or amplification in all study cases. The median survival in the authors' cohort was significantly higher than that of all previously reported cases (27.5 vs 4.5 months, p = 0.003). Postoperative treatment in the authors' cohort included radiotherapy with concurrent temozolomide, bevacizumab, interleukin 13, CCNU, and/or etoposide.

Conclusions

Enhanced survival in the authors' 4 patients suggests that the current standard of care for the treatment of GB may be beneficial in rhabdoid GB cases, with postoperative radiotherapy and concomitant temozolomide treatment followed by adjuvant therapy. Due to the rapid tumor dissemination associated with these lesions, aggressive and timely therapy is warranted, with frequent surveillance and/or continued therapy despite stable disease. Additionally, patients should undergo full craniospinal imaging to monitor the development of distant metastatic disease.

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Jong G. Park, Ranjith Babu, Peter G. Kranz, Roger E. McLendon and Cory Adamson

Intracranial dermoid cysts are rare congenital lesions that typically occur in the cisternal spaces. However, exceptionally rare cases of intraaxial involvement have been reported, with only 8 cases having been described in the literature. The authors report the first case of an intraaxial dermoid cyst located in the medulla and the first occurrence in an elderly patient. They also review the literature of the existing intraparenchymal cases and provide treatment guidelines. A 66-year-old man presented with slowly progressive dysphagia, left lower-extremity numbness, nausea, and hyperhidrosis. Neurological examination revealed decreased pinprick sensation of the left side of his face and body, and decreased vibratory sensation in his left lower extremity. Additionally, he had an unusual extraocular movement in which abduction of the eye resulted in closure of the contralateral eye. Magnetic resonance imaging revealed a nonenhancing cystic lesion centered in the medulla. The patient underwent a suboccipital craniotomy with laminectomy of C1–2 for excision of the cyst, with subtotal resection due to adherence of the cyst wall to the brainstem. At follow-up 7.5 years after surgery, the patient's neurological examination was stable. Magnetic resonance imaging did not reveal any progression or recurrence of the cyst. As the cyst wall is typically adherent to surrounding structures, resection is usually subtotal due to the risk of neurological deficits. As there have been no cases of progression after subtotal resection, gross-total resection is not warranted for the treatment of these lesions.

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Ranjith Babu, Jacob H. Bagley, Jong G. Park, Allan H. Friedman and Cory Adamson

Object

Low-grade astrocytomas are slow-growing, infiltrative gliomas that over time may progress into more malignant tumors. Various factors have been shown to affect the time to progression and overall survival including age, performance status, tumor size, and the extent of resection. However, more recently it has been suggested that histological subtypes (fibrillary, protoplasmic, and gemistocytic) may impact patient outcome. In this study the authors have performed a large comparative population-based analysis to examine the characteristics and survival of patients with the various subtypes of WHO Grade II astrocytomas.

Methods

Patients diagnosed with fibrillary, protoplasmic, and gemistocytic astrocytomas were identified through the Surveillance, Epidemiology, and End Results (SEER) database. The chi-square test and Student t-test were used to evaluate differences in patient and treatment characteristics between astrocytoma subtypes. Kaplan-Meier analysis was used to assess overall survival, and the log-rank test was used to evaluate the differences between survival curves. Univariate and multivariate analyses were also performed to determine the effect of various patient, tumor, and treatment variables on overall survival.

Results

A total of 500 cases were included in the analysis, consisting of 326 fibrillary (65.2%), 29 protoplasmic (5.8%), and 145 gemistocytic (29%) variants. Gemistocytic astrocytomas presented at a significantly older age than the fibrillary variant (46.8 vs 37.7 years, p < 0.0001), with protoplasmic and fibrillary subtypes having a similar age. Although protoplasmic and fibrillary variants underwent radiotherapy at similar rates, gemistocytic tumors more frequently received radiotherapy (p = 0.0001). Univariate analysis revealed older age, larger tumor size, and the use of radiotherapy to be poor prognostic factors, with resection being associated with improved survival. The gemistocytic subtype (hazard ratio [HR] 1.62 [95% CI 1.27–2.07], p = 0.0001) also resulted in significantly worse survival than fibrillary tumors. Bivariate analyses demonstrated that older age, the use of radiotherapy, and resection significantly influenced median survival. Tumor subtype also affected median survival; patients who harbored gemistocytic tumors experienced less than half the median survival of fibrillary and protoplasmic tumors (38 vs 82 months, p = 0.0003). Multivariate analysis revealed increasing age (HR 1.05 [95% CI 1.04–1.05], p < 0.0001), larger tumor size (HR 1.02 [95% CI 1.01–1.03], p = 0.0002), and the use of resection (HR 0.70 [95% CI 0.52–0.94], p = 0.018) to be independent predictors of survival. Examination of tumor subtype revealed that the gemistocytic variant (HR 1.30 [95% CI 0.98–1.74], p = 0.074) was associated with worse patient survival than fibrillary tumors, although this only approached significance. The protoplasmic subtype did not affect overall survival (p = 0.33).

Conclusions

Gemistocytic tumor histology was associated with worse survival than fibrillary and protoplasmic astrocytomas. As protoplasmic astrocytomas have a survival similar to fibrillary tumors, there may be limited utility to the identification of this rare variant. However, increased attention should be paid to the presence of gemistocytes in low-grade gliomas as this is associated with shorter time to progression, increased malignant transformation, and reduced overall survival.

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Ranjith Babu, Richa Sharma, Jacob H. Bagley, Jeffrey Hatef, Allan H. Friedman and Cory Adamson

Object

There are a variety of treatment options for the management of vestibular schwannomas (VSs), including microsurgical resection, radiotherapy, and observation. Although the choice of treatment is dependent on various patient factors, physician bias has been shown to significantly affect treatment choice for VS. In this study the authors describe the current epidemiology of VS and treatment trends in the US in the modern era. They also illustrate patient and tumor characteristics and elucidate their effect on tumor management.

Methods

Patients diagnosed with VS were identified through the Surveillance, Epidemiology, and End Results database, spanning the years 2004–2009. Age-adjusted incidence rates were calculated and adjusted using the 2000 US standard population. The chi-square and Student t-tests were used to evaluate differences between patient and tumor characteristics. Multivariate logistic regression was performed to determine the effects of various patient and tumor characteristics on the choice of tumor treatment.

Results

A total of 6225 patients with VSs treated between 2004 and 2009 were identified. The overall incidence rate was 1.2 per 100,000 population per year. The median age of patients with VS was 55 years, with the majority of patients being Caucasian (83.16%). Of all patients, 3053 (49.04%) received surgery only, with 1466 (23.55%) receiving radiotherapy alone. Both surgery and radiation were only used in 123 patients (1.98%), with 1504 patients not undergoing any treatment (24.16%). Increasing age correlated with decreased use of surgery (OR 0.95, 95% CI 0.95–0.96; p < 0.0001), whereas increasing tumor size was associated with the increased use of surgery (OR 1.04, 95% CI 1.04–1.05; p < 0.0001). Older age was associated with an increased likelihood of conservative management (OR 1.04, 95% CI 1.04–1.05; p < 0.0001). Racial disparities were also seen, with African American patients being significantly less likely to receive surgical treatment compared with Caucasians (OR 0.50, 95% CI 0.35–0.70; p < 0.0001), despite having larger tumors at diagnosis.

Conclusions

The incidence of vestibular schwannomas in the US is 1.2 per 100,000 population per year. Although many studies have demonstrated improved outcomes with the use of radiotherapy for small- to medium-sized VSs, surgery is still the most commonly used treatment modality for these tumors. Racial disparities also exist in the treatment of VSs, with African American patients being half as likely to receive surgery and nearly twice as likely to have their VSs managed conservatively despite presenting with larger tumors. Further studies are needed to elucidate the reasons for treatment disparities and investigate the nationwide trend of resection for the treatment of small VSs.

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Jacob H. Bagley, Ranjith Babu, Allan H. Friedman and Cory Adamson

Object

Low-grade gliomas (LGGs) are indolent tumors that have the potential to dedifferentiate into malignant high-grade tumors. Recent studies have demonstrated that cerebellar low-grade tumors have a better prognosis than supratentorial tumors, although no study has focused on the risk factors for poor prognosis in cerebellar LGGs in adults. The authors of the current study aimed to address both of these concerns by using a large cohort derived from a national cancer registry and a smaller cohort derived from their institution's experience.

Methods

Adults with diagnosed Grade I and Grade II gliomas of the cerebellum were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Multivariate Cox proportional hazard models were used to predict rates of survival, and the log-rank test was applied to evaluate differences in Kaplan-Meier survival curves. An institutional cohort was created by isolating all patients whose surgical pathology revealed an LGG of the cerebellum. Excluded from analysis were patients in whom a glioma was first diagnosed under the age of 18 years and those whose tumors could not be definitively determined to arise from the cerebellum.

Results

Data from the local cohort (11 patients) demonstrated that the most common presenting symptom was headache, which occurred in more than 70% of the cohort. Approximately half of the patients in this cohort had symptomatic improvement after treatment. Results from the SEER cohort (166 patients) revealed that adults with Grade I gliomas were slightly younger than those with Grade II tumors (p < 0.01), but no other demographic differences were observed. Patients with Grade I tumors were twice as likely to undergo gross-total resection (54% vs 21%), and those with Grade II gliomas were much more likely to receive postoperative radiation (3% vs 48%). Five-year survival was greater in the patients with Grade I gliomas than in those with Grade II lesions (91% vs 70%). Multivariate analysis revealed that an age ≥ 40 years (HR 7.30, 95% CI 3.55–15.0, p < 0.0001) and Grade II tumors (HR 2.76, 95% CI 1.12–6.84, p = 0.028) were risk factors for death, whereas female sex was protective (HR 0.28, 95% CI 0.14–0.59, p < 0.001). Log-rank tests revealed that a cerebellar location was protective (p < 0.0001), but this relationship was only true for Grade II tumors (p < 0.0001). Survival in patients with Grade I gliomas was not different based on the various lesion locations (p = 0.21).

Conclusions

Taken together, adults with cerebellar WHO Grade I and II astrocytomas have a much more favorable survival curve than those with similar supratentorial tumors. Research demonstrates that the primary driver of this phenomenon is the improved survival in patients with cerebellar Grade II gliomas.

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Ranjith Babu, Jacob H. Bagley, Chunhui Di, Allan H. Friedman and Cory Adamson

Intracerebral hemorrhage (ICH) is a subtype of stoke that may cause significant morbidity and mortality. Brain injury due to ICH initially occurs within the first few hours as a result of mass effect due to hematoma formation. However, there is increasing interest in the mechanisms of secondary brain injury as many patients continue to deteriorate clinically despite no signs of rehemorrhage or hematoma expansion. This continued insult after primary hemorrhage is believed to be mediated by the cytotoxic, excitotoxic, oxidative, and inflammatory effects of intraparenchymal blood. The main factors responsible for this injury are thrombin and erythrocyte contents such as hemoglobin. Therapies including thrombin inhibitors, N-methyl-D-aspartate antagonists, chelators to bind free iron, and antiinflammatory drugs are currently under investigation for reducing this secondary brain injury. This review will discuss the molecular mechanisms of brain injury as a result of intraparenchymal blood, potential targets for therapeutic intervention, and treatment strategies currently in development.