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Susumu Nagasaka, Kenneth K. Tanabe, Janet M. Bruner, Hideyuki Saya, Raymond E. Sawaya and Richard S. Morrison

✓ The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase—polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.

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Ajay K. Bindal, Rajesh K. Bindal, Kenneth R. Hess, Almon Shiu, Samuel J. Hassenbusch, Wei Ming Shi and Raymond Sawaya

✓ Surgery and radiosurgery are effective treatment modalities for brain metastasis. To compare the results of these treatment modalities, the authors followed 31 patients treated by radiosurgery and 62 patients treated by surgery who were retrospectively matched. Patients were matched according to the following criteria: histological characteristics of the primary tumor, extent of systemic disease, preoperative Karnofsky Performance Scale score, time to brain metastasis, number of brain metastases, and patient age and sex. For patients treated by radiosurgery, the median size of the treated lesion was 1.96 cm3 (range 0.41–8.25 cm3) and the median dose was 20 Gy (range 12–22 Gy). The median survival was 7.5 months for patients treated by radiosurgery and 16.4 months for those treated by surgery; this difference was found to be statistically significant using both univariate (p = 0.0018) and multivariate (p = 0.0009) analyses. The difference in survival was due to a higher rate of mortality from brain metastasis in the radiosurgery group than in the surgery group (p < 0.0001) and not due to a difference in the rate of death from systemic disease (p = 0.28). Log-rank analysis showed that the higher mortality rate found in the radiosurgery group was due to a greater progression rate of the radiosurgically treated lesions (p = 0.0001) and not due to the development of new brain metastasis (p = 0.75).

On the basis of their data, the authors conclude that surgery is superior to radiosurgery in the treatment of brain metastasis. Patients who undergo surgical treatment survive longer and have a better local control. The data lead the authors to suggest that the indications for radiosurgery should be limited to surgically inaccessible metastatic tumors or patients in poor medical condition. Surgery should remain the treatment of choice whenever possible.

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Raymond Sawaya, Alan Rayford, Shinji Kono, K. Kian Ang, Yan Feng, L. Clifton Stephens and Jasti S. Rao

✓ The pathophysiology of radiation-induced damage to the central nervous system (CNS) is poorly understood. Preliminary data suggest that fibrinolytic inhibitors are involved in the development of necrosis. In this study, cervical spinal cord irradiation was studied in 90 rats by measuring plasminogen activator inhibitor (PAI)-1 on Days 2, 7, 30, 60, 90, 120, 130, or 145 after irradiation. Paralysis due to radiation necrosis developed in all animals kept alive for 140 to 150 days. Assay of PAI-1 was by Western blot, enzyme-linked immunosorbent assay (ELISA), and complex formation with 125I-labeled urokinase. No PAI-1 was detected in normal spinal cord tissue or in irradiated spinal cord up to Day 90. However, PAI-1 was detected at Day 120 and was marked by elevated ELISA levels at the time of paralysis. Western blot showed detectable PAI-1 (51 kD) at Day 120 and very significant levels at the time of paralysis. Complex formation with 125I-labeled urokinase was also detected at Day 120 with similar results. Immunohistochemical studies showed that PAI-1 was highly concentrated within and immediately adjacent to zones of necrosis at 145 days and was absent in normal tissue. This study adds considerable weight to the proposal that PAI-1 is closely associated with the pathogenesis of CNS radiation necrosis.

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George A. Younis, Raymond Sawaya, Franco DeMonte, Kenneth R. Hess, Steffen Albrecht and Janet M. Bruner

✓ A series of 25 patients with aggressive meningeal tumors was studied to determine the efficacy of various management options. The median age of the patients was 52 years, with a range of 13 to 73 years. A marked male preponderance (64%) was noted. Twenty of 25 patients experienced recurrence during a median follow-up time of 47 months. Survival and freedom from recurrence varied with histological diagnosis. Recurrence was noted sooner in patients who had received partial resections on first presentation of tumor than in those who had received total resections at first presentation. Survival time was also shorter for patients who underwent partial resections at first presentation than for patients who underwent total resections.

Patients' prognoses did not improve as a result of either chemotherapy or radiotherapy. Of six patients with extracranial metastases, the median time to metastasis was 102 months, with a 5-year metastasis-free rate of 85%. The most common sites of metastasis in these six patients were lung and bone. In each tumor type, histological features used in diagnosis and radiological features studied from computerized tomography and magnetic resonance imaging were evaluated, compared, and discussed. Of eight patients studied with an in vivo bromodeoxyuridine (BUdR) labeling index (LI), seven showed an LI of 1% or more. The authors support the incorporation of the BUdR LI into the diagnostic process to provide a better estimate of the potential for tumor recurrence.

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Ziya L. Gokaslan, Julie E. York, Garrett L. Walsh, Ian E. McCutcheon, Frederick F. Lang, Joe B. Putnam Jr., David M. Wildrick, Stephen G. Swisher, Dima Abi-Said and Raymond Sawaya

Anterior approaches to the spine for the treatment of spinal tumors have gained acceptance; however, in most published reports, patients with primary, metastatic, or chest wall tumors involving cervical, thoracic, or lumbar regions of the spine are combined. The purpose of this study was to provide a clear perspective of results that can be expected in patients who undergo anterior vertebral body resection, reconstruction, and stabilization for spinal metastases that are limited to the thoracic region.

Outcome is presented for 72 patients with metastatic spinal tumors who were treated by transthoracic vertebrectomy at The University of Texas M. D. Anderson Cancer Center. The predominant primary tumors included renal cancer in 19 patients, breast cancer in 10, melanoma or sarcoma in 10, and lung cancer in nine patients. The most common presenting symptoms were back pain, which occurred in 90% of patients, and lower-extremity weakness, which occurred in 64% of patients. All patients underwent transthoracic vertebrectomy, decompression, reconstruction with methylmethacrylate, and anterior fixation with locking plate and screw constructs. Supplemental posterior instrumentation was required in seven patients with disease involving the cervicothoracic or thoracolumbar junction, which was causing severe kyphosis. After surgery, pain improved in 60 of 65 patients. This improvement was found to be statistically significant (p < 0.001) based on visual analog scales and narcotic analgesic medication use. Thirty-five of the 46 patients who presented with neurological dysfunction improved significantly (p < 0.001) following the procedure. Thirty-three patients had weakness but could ambulate preoperatively. Seventeen of these 33 regained normal strength, 15 patients continued to have weakness, and one patient was neurologically worse postoperatively. Of the 13 preoperatively nonambulatory patients, 10 could walk after surgery and three were still unable to walk but showed improved motor function. Twenty-one patients had complications ranging from minor atelectasis to pulmonary embolism. The 30-day mortality rate was 3%. The 1-year survival rate for the entire study population was 62%.

These results suggest that transthoracic vertebrectomy and spinal stabilization can improve the quality of life considerably in cancer patients with spinal metastasis by restoring or preserving ambulation and by controlling intractable spinal pain with acceptable rates of morbidity and mortality.

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Akash J. Patel, Dima Suki, Mustafa Aziz Hatiboglu, Hiba Abouassi, Weiming Shi, David M. Wildrick, Frederick F. Lang and Raymond Sawaya

Object

Local recurrence (LR) of a resected brain metastasis occurs in up to 46% of patients. Postoperative whole-brain radiation therapy (WBRT) reduces that incidence. To isolate factors associated with the risk of LR after resection, the authors only studied patients who did not receive adjuvant radiotherapy.

Methods

The authors reviewed data from 570 cases involving patients who had undergone resection of a previously untreated single brain metastasis at The University of Texas M. D. Anderson Cancer Center between 1993 and 2006 without receiving postoperative WBRT. All tumors were measured preoperatively on MR images. The resection method (en bloc resection [EBR] or piecemeal resection [PMR]) was noted at the time of surgery. Predictors of LR were assessed using the Cox proportional hazards model.

Results

The median patient age was 58 years, 55% were male, and 88% had a Karnofsky Performance Scale Score ≥ 80. The most common primary cancers were those of the lung (28%), skin (melanoma, 21%), kidney (19%), and breast (11%). Piecemeal resection was performed in 201 patients (35%) and EBR in 369 (65%). Local recurrence developed in 84 patients (15%). The histological type of the primary cancer did not significantly predict LR; however, 7 of 22 patients with sarcoma developed LR (p = 0.16). The authors identified 2 variables that increased the risk of LR. Undergoing PMR carried a significantly higher LR risk than EBR (crude hazard ratio [HR] 1.7, 95% CI 1.1–2.6, p = 0.03). Tumors exceeding the median volume (9.7 cm3) had a significantly higher LR risk than those that were < 9.7 cm3 (crude HR 1.7; 95% CI 1.1–2.6; p = 0.02). In the multivariate analysis, small tumors removed by EBR had a significantly lower LR risk.

Conclusions

The LR risk of a single brain metastasis is influenced by biological factors (such as tumor volume) and treatments (such as the resection method). Early administration of postoperative WBRT may be particularly warranted when such negative tumor-related prognostic factors are noted or when treatment-related ones such as PMR are unavoidable.

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Adam S. Wu, Victoria T. Trinh, Dima Suki, Susan Graham, Arthur Forman, Jeffrey S. Weinberg, Ian E. McCutcheon, Sujit S. Prabhu, Amy B. Heimberger, Raymond Sawaya, Xuemei Wang, Wei Qiao, Kenneth R. Hess and Frederick F. Lang

Object

Seizures are a potentially devastating complication of resection of brain tumors. Consequently, many neurosurgeons administer prophylactic antiepileptic drugs (AEDs) in the perioperative period. However, it is currently unclear whether perioperative AEDs should be routinely administered to patients with brain tumors who have never had a seizure. Therefore, the authors conducted a prospective, randomized trial examining the use of phenytoin for postoperative seizure prophylaxis in patients undergoing resection for supratentorial brain metastases or gliomas.

Methods

Patients with brain tumors (metastases or gliomas) who did not have seizures and who were undergoing craniotomy for tumor resection were randomized to receive either phenytoin for 7 days after tumor resection (prophylaxis group) or no seizure prophylaxis (observation group). Phenytoin levels were monitored daily. Primary outcomes were seizures and adverse events. Using an estimated seizure incidence of 30% in the observation arm and 10% in the prophylaxis arm, a Type I error of 0.05 and a Type II error of 0.20, a target accrual of 142 patients (71 per arm) was planned.

Results

The trial was closed before completion of accrual because Bayesian predictive probability analyses performed by an independent data monitoring committee indicated a probability of 0.003 that at the end of the study prophylaxis would prove superior to observation and a probability of 0.997 that there would be insufficient evidence at the end of the trial to choose either arm as superior. At the time of trial closure, 123 patients (77 metastases and 46 gliomas) were randomized, with 62 receiving 7-day phenytoin (prophylaxis group) and 61 receiving no prophylaxis (observation group). The incidence of all seizures was 18% in the observation group and 24% in the prophylaxis group (p = 0.51). Importantly, the incidence of early seizures (< 30 days after surgery) was 8% in the observation group compared with 10% in the prophylaxis group (p = 1.0). Likewise, the incidence of clinically significant early seizures was 3% in the observation group and 2% in the prophylaxis group (p = 0.62). The prophylaxis group experienced significantly more adverse events (18% vs 0%, p < 0.01). Therapeutic phenytoin levels were maintained in 80% of patients.

Conclusions

The incidence of seizures after surgery for brain tumors is low (8% [95% CI 3%–18%]) even without prophylactic AEDs, and the incidence of clinically significant seizures is even lower (3%). In contrast, routine phenytoin administration is associated with significant drug-related morbidity. Although the lower-than-anticipated incidence of seizures in the control group significantly limited the power of the study, the low baseline rate of perioperative seizures in patients with brain tumors raises concerns about the routine use of prophylactic phenytoin in this patient population.

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Benjamin D. Fox, Hassan H. Amhaz, Akash J. Patel, Daniel H. Fulkerson, Dima Suki, Andrew Jea and Raymond E. Sawaya

Object

Medical student exposure to neurosurgery is limited. To improve the educational interactions between neurosurgeons and medical students as well as neurosurgical medical student rotations or clerkships (NSCs) we must first understand the current status.

Methods

Two questionnaires were sent, one to every neurosurgery course coordinator or director at each US neurosurgery residency program (99 questionnaires) and one to the associated parent medical school dean's office (91 questionnaires), to assess the current status of NSCs and the involvement of neurosurgeons at their respective institutions.

Results

We received responses from 86 (87%) of 99 neurosurgery course coordinators or directors and 64 (70%) of 91 medical school deans' offices. Most NSCs do not have didactic lectures (53 [62%] of 86 NSCs), provide their medical students with a syllabus or educational handouts (53 [62%] of 86), or have a recommended/required textbook (77 [90%] of 86). The most common method of evaluating students in NSCs is a subjective performance evaluation. Of 64 medical school deans, 38 (59%) felt that neurosurgery should not be a required rotation. Neurosurgical rotations or clerkships are primarily offered to students in their 4th year of medical school, which may be too late for appropriate timing of residency applications. Only 21 (33%) of 64 NSCs offer neurosurgery rotations to 3rd-year students.

Conclusions

There is significant room for improvement in the neurosurgeon-to–medical student interactions in both the NSCs and during the didactic years of medical school.

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Brian J. Williams, Dima Suki, Benjamin D. Fox, Christopher E. Pelloski, Marcos V. C. Maldaun, Raymond E. Sawaya, Frederick F. Lang and Ganesh Rao

Object

Stereotactic radiosurgery (SRS) is commonly used to treat brain metastases. Complications associated with this treatment are underreported. The authors reviewed a large series of patients who underwent SRS for brain metastases to identify complications and factors predicting their occurrence.

Methods

Prospectively collected clinical data from 273 patients undergoing SRS for 1 or 2 brain metastases at The University of Texas M. D. Anderson Cancer Center between June 1993 and December 2004 were reviewed. Patients who had received prior treatment for their tumor, including whole-brain radiation, SRS, or surgery, were excluded from the study. Data on adverse neurological and nonneurological outcomes following treatment were collected.

Results

Three hundred sixteen lesions were treated. Complications were associated with 127 (40%) of 316 treated lesions. New neurological complications were associated with 101 (32%) of 316 lesions. The onset of seizure was the most common complication, occurring in 41 (13%) of 316 SRS cases. On multivariate analysis, progressing primary cancer (hazard ratio [HR] = 2.4, 95% CI 1.6–3.6, p < 0.001), tumor location in eloquent cortex (HR = 2.3, 95% CI 1.6–3.4, p < 0.001), and lower (< 15 Gy) SRS dose (HR = 2.1, 95% CI 1.1–4.2, p = 0.04) were significantly associated with new complications. On multivariate analysis, a tumor location in the eloquent cortex (HR = 2.5, 95% CI 1.6–3.8, p < 0.001) and progressing primary cancer (HR = 1.6, 95% CI 1.1–2.5, p = 0.03) were significantly associated with new neurological complications.

Conclusions

The authors showed that new neurological and nonneurological complications were associated with 40% of SRS treatments for brain metastases. Patients with lesions in functional brain regions have a significantly increased risk of treatment-related complications.

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Ziya L. Gokaslan, Julie E. York, Garrett L. Walsh, Ian E. McCutcheon, Frederick F. Lang, Joe B. Putnam Jr., David M. Wildrick, Stephen G. Swisher, Dima Abi-Said and Raymond Sawaya

Object. Anterior approaches to the spine for the treatment of spinal tumors have gained acceptance; however, in most published reports, patients with primary, metastatic, or chest wall tumors involving cervical, thoracic, or lumbar regions of the spine are combined. The purpose of this study was to provide a clear perspective of results that can be expected in patients who undergo anterior vertebral body resection, reconstruction, and stabilization for spinal metastases that are limited to the thoracic region.

Methods. Outcome is presented for 72 patients with metastatic spinal tumors who were treated by transthoracic vertebrectomy at The University of Texas M. D. Anderson Cancer Center. The predominant primary tumors included renal cancer in 19 patients, breast cancer in 10, melanoma or sarcoma in 10, and lung cancer in nine patients. The most common presenting symptoms were back pain, which occurred in 90% of patients, and lower-extremity weakness, which occurred in 64% of patients. All patients underwent transthoracic vertebrectomy, decompression, reconstruction with methylmethacrylate, and anterior fixation with locking plate and screw constructs. Supplemental posterior instrumentation was required in seven patients with disease involving the cervicothoracic or thoracolumbar junction, which was causing severe kyphosis. After surgery, pain improved in 60 of 65 patients. This improvement was found to be statistically significant (p < 0.001) based on visual analog scales and narcotic analgesic medication use. Thirty-five of the 46 patients who presented with neurological dysfunction improved significantly (p < 0.001) following the procedure. Thirty-three patients had weakness but could ambulate preoperatively. Seventeen of these 33 regained normal strength, 15 patients continued to have weakness, and one patient was neurologically worse postoperatively. Of the 13 preoperatively nonambulatory patients, 10 could walk after surgery and three were still unable to walk but showed improved motor function. Twenty-one patients had complications ranging from minor atelectasis to pulmonary embolism. The 30-day mortality rate was 3%. The 1-year survival rate for the entire study population was 62%.

Conclusions. These results suggest that transthoracic vertebrectomy and spinal stabilization can improve the quality of life considerably in cancer patients with spinal metastasis by restoring or preserving ambulation and by controlling intractable spinal pain with acceptable rates of morbidity and mortality.