David M. Wildrick

Neurosurgical outcomes in a modern series of 400 craniotomies for treatment of parenchymal tumors

OBJECTIVE The goals were to critically review all complications resulting within 30 days after craniotomies performed for excision of intra-axial brain tumors relative to factors likely to affect complication rates and to assess the value of these data in predicting the risk of surgical morbidity, particularly for surgery in eloquent brain regions. METHODS Neurosurgical outcomes were studied for 327 patients who underwent 400 craniotomies for removal of intra-axial parenchymal brain neoplasms in a 21-month period. Tumors removed included gliomas (206 tumors) and metastases (194 tumors) located both supratentorially (358 tumors) and infratentorially (42 tumors). RESULTS The major complication incidence was 13%, and the operative mortality rate was 1.7%. The overall morbidity rate was 32%, but more types of complications were considered than in previous studies. The major neurological morbidity rate was 8.5%. Based on pre- versus postoperative (at 4 wk) Karnofsky Performance Scale scores, 9% of patients deteriorated neurologically, 32% improved, and 58% showed no change. The median postoperative hospital stay was 5 days. Tumors were defined as Grade I, II, or III based on their location relative to brain function, and this tumor functional grade was the most important variable affecting the incidence of any neurological deficit. Patients with tumors in eloquent (Grade III) or near-eloquent (Grade II) brain areas incurred more neurological deficits than did patients with tumors in noneloquent areas (Grade I). Neither repeat surgery for recurrent disease nor extent of surgical resection affected outcome significantly. Although most tumors in this study, including those in eloquent regions, were removed by gross total resection, this did not lead to more major neurological deficits. Regional complications (at the surgical sites) and systemic complications (medical) were more prevalent among older patients (age >60 yr) with lower preoperative Karnofsky Performance Scale scores (< or = 50) and posterior fossa masses. We showed how our data can be used to predict the total risk of surgical morbidity for a given patient, to facilitate patient counseling and surgical decision-making. CONCLUSION The finding that gross total resections could be performed in eloquent brain regions with an acceptable level of neurological impairment suggested that the mere presence of a tumor in eloquent brain does not automatically contraindicate surgery. Our results have practical risk-predictive value, and they should aid in the construction of subsequent outcome studies, because we have identified the key areas to monitor.

Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis.

OBJECTIVE Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient’s prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. METHODS On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. RESULTS One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. CONCLUSION A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.

Gastric Cancer and Metastasis to the Brain

Background: Metastasis of gastric carcinoma to the brain is very uncommon. At The University of Texas M. D. Anderson Cancer Center (M. D. Anderson), less than 1% of patients with primary gastric carcinoma are found to have brain metastases. Little has been published regarding the evaluation and treatment of these patients. The purpose of this study was to review our experience with gastric cancer metastatic to the brain and to describe the efficacy of the treatment used.Methods: Between 1957 and 1997, a total of 218,690 patients were seen for evaluation of malignant tumors at M. D. Anderson. Of these patients, 3320 (1.5%) had a diagnosis of gastric cancer; however, only 24 patients (0.7%) were found to have brain metastases on imaging studies or at autopsy. We performed a retrospective review of these 24 patients and divided them into three groups on the basis of the treatment they received.Results: Group 1 included patients who received steroids alone (16 mg of dexamethasone, daily). Group 2 patients received 3000 cGy of whole-brain radiation therapy (WBRT) delivered in 10 fractions in addition to steroids. Group 3 patients were managed with surgical resection, WBRT, and steroids. There were 18 male and 6 female patients, with a median age of 53 years. The most common presenting symptoms were weakness, difficulty with balance, and headache. Of the 19 patients diagnosed antemortem, 11 patients developed neurological symptoms after the primary diagnosis of gastric carcinoma, whereas 8 patients developed neurological symptoms before the diagnosis of gastric cancer. Forty-five percent of patients had a single brain metastasis, whereas 55% had multiple lesions. All patients had systemic disease, with bone, liver, and lung involvement seen in 46%, 42%, and 29%, respectively. Nineteen of 24 patients received treatment after diagnosis of brain metastases. Four patients received steroids only (group 1), 11 patients received WBRT and steroids (group 2), and 4 patients were treated with surgery, WBRT, and steroids (group 3). Median survival was approximately 2 months for patients in groups 1 and 2, whereas group 3 patients had a median survival of slightly greater than 1 year.Conclusions: Our results suggest that the overall prognosis of patients with brain metastases from gastric cancer is extremely poor (median survival, 9 weeks). WBRT, as an adjuvant to steroid treatment, was not effective in improving outcome in our series. In selected patients, most of whom were relatively young and had less advanced systemic disease, surgical resection followed by WBRT was associated with relatively long survival times (median survival, 54 weeks).

Volumetric measurement of brain tumors from MR imaging

Residual tumor volume has been considered important in predicting survival following brain surgery. The purpose of this study was to develop a procedure for quantifying pre- and postsurgical brain tumor volumes that is less subjective than the traditional qualitative grading scale still used by surgeons and radiologists to assess extent of resection (such as gross total, subtotal, and partial resection). Pre- and postsurgical magnetic resonance (MR) imaging brain scans on GE Medical System optical disks were transferred to a Macintosh personal computer using a Pioneer optical disk drive subsystem, and the MedVision 1.41 computer software program was used to analyze regions of interest (ROIs) within them for computation of the volume of tumor tissue therein. Because this procedure puts the original MRI (or CT scan) data file for a patient directly into the personal computer, it bypasses the need for scanning and digitizing MR (or CT scan) film images. Between June 1993 and May 1996, pre- and postsurgical volumetric measurements were made in more than 1,000 brain tumor resection cases and 49 radiosurgery cases. The average intra-observer error was estimated to be 1.8%. This method should facilitate the examination of the effects of various therapies on extent of brain tumor resection. The method is fast, is more precise than intraoperative visual assessment of tumor removal or qualitative comparison of pre- and postoperative scans, and it allows the computation of pre- and postsurgical (three-dimensional) volumes of even irregularly shaped tumors.

Intraoperative monitoring of spinal cord function using motor evoked potentials via transcutaneous epidural electrode during anterior cervical spinal surgery

Because false-positive results are not infrequent when monitoring somatosensory evoked potentials during surgery, monitoring of motor evoked potentials (MEPs) has been proposed and successfully used during the removal of spinal cord tumors. However, this often requires direct visual placement of an epidural electrode after a laminectomy. We evaluated the use of MEPs, recorded via a transcutaneously placed epidural electrode, to monitor motor pathway functional integrity during surgery on the anterior cervical spine. Sixteen patients underwent anterior cervical vertebral decompression and fusion for cervical myelopathy and/or radiculopathy. Before surgery, an epidural monitoring electrode was placed transcutaneously at the midthoracic level and was used to record MEPs after transcranial cortical electrical stimulation. Electrode placement was successful in all patients but one, and satisfactory baseline spinal MEPs were obtained except for one patient who had cerebral palsy with significant motor dysfunction. Patients showed no significant changes in spinal MEPs during surgery, and all had baseline or better motor function postoperatively. None had complications from epidural electrode placement or electrical stimulation. We conclude that motor pathways can be monitored safely during anterior cervical spinal surgery using spinal MEPs recorded via a transcutaneously placed epidural electrode, that MEP preservation during surgery correlates with good postoperative motor function, and that cerebral palsy patients may possess too few functional motor fibers to allow MEP recording.

Multiple craniotomies in the management of multifocal and multicentric glioblastoma

OBJECT Multiple craniotomies have been performed for resection of multiple brain metastases in the same surgical session with satisfactory outcomes, but the role of this procedure in the management of multifocal and multicentric glioblastomas is undetermined, although it is not the standard approach at most centers. METHODS The authors performed a retrospective analysis of data prospectively collected between 1993 and 2008 in 20 patients with multifocal or multicentric glioblastomas (Group A) who underwent resection of all lesions via multiple craniotomies during a single surgical session. Twenty patients who underwent resection of solitary glioblastoma (Group B) were selected to match Group A with respect to the preoperative Karnofsky Performance Scale (KPS) score, tumor functional grade, extent of resection, age at time of surgery, and year of surgery. Clinical and neurosurgical outcomes were evaluated. RESULTS In Group A, the median age was 52 years (range 32-78 years); 70% of patients were male; the median preoperative KPS score was 80 (range 50-100); and 9 patients had multicentric glioblastomas and 11 had multifocal glioblastomas. Aggressive resection of all lesions in Group A was achieved via multiple craniotomies in the same session, with a median extent of resection of 100%. Groups A and B were comparable with respect to all the matching variables as well as the amount of tumor necrosis, number of cysts, and the use of intraoperative navigation. The overall median survival duration was 9.7 months in Group A and 10.5 months in Group B (p = 0.34). Group A and Group B (single craniotomy) had complication rates of 30% and 35% and 30-day mortality rates of 5% (1 patient) and 0%, respectively. CONCLUSIONS Aggressive resection of all lesions in selected patients with multifocal or multicentric glioblastomas resulted in a survival duration comparable with that of patients undergoing surgery for a single lesion, without an associated increase in postoperative morbidity. This finding may indicate that conventional wisdom of a minimal role for surgical treatment in glioblastoma should at least be questioned.

Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery.

BACKGROUND:Treatment of tumors metastatic to the brainstem with stereotactic radiosurgery (SRS) has not been widely studied. OBJECTIVE:To identify the effects of SRS on patients with brainstem metastases by assessing duration of local progression-free survival (LPFS) and overall survival. METHODS:We retrospectively reviewed clinical data collected from 60 patients undergoing linear accelerator-based SRS for tumors metastatic to the brainstem between August 1994 and December 2007. The LPFS and overall survival were calculated with the Kaplan-Meier method. Prognostic factors were evaluated with the log-rank test and Cox proportional hazards model. RESULTS:The median age of patients was 61 years (range, 39-85 years); the median treated lesion volume was 1.0 mL (range, 0.1-8.7 mL); and the median SRS dose was 15 Gy (range, 8-18 Gy). The median overall survival interval after SRS was 4 months (95% confidence interval, 3.4-4.9 months); crude local tumor control was 76%; and median LPFS was 5.7 months (95% confidence interval, 3.0-8.4 months). Shorter overall survival was associated with a pretreatment tumor volume ≥4 mL (P < .001) and male sex (P = .03). Shorter LPFS was associated with a pretreatment tumor volume ≥4 mL (P = .008), a melanoma primary tumor (P = .002), and the presence of necrosis in pre-SRS magnetic resonance imaging (P = .04). A Basic Score for Brain Metastases of 2 to 3 vs 1 (P = .007) and a Score Index for Radiosurgery >5 (P = .003) were significantly associated with longer survival. Twelve patients (20%) developed SRS-related complications. CONCLUSION:Stereotactic radiosurgery provides noninvasive treatment and favorable local tumor control for patients with brainstem metastases.

Pineal cyst apoplexy: case report and review of the literature.

OBJECTIVE AND IMPORTANCE:Although most pineal cysts are clinically benign and asymptomatic, some can become symptomatic. Of the various symptomatic presentations, apoplexy is the rarest and most ill-defined. A comprehensive search of publications in the English language yielded 18 cases of pineal cyst apoplexy. We reviewed the literature to compare symptomatology and management strategies and their outcomes. CLINICAL PRESENTATION:A 29-year-old woman with a 1-month history of headaches presented with an acute worsening of her symptoms with a severe occipital headache and trouble focusing when reading. Her neurological examination was otherwise normal. Magnetic resonance imaging showed pineal cyst apoplexy and accompanying hydrocephalus. INTERVENTION:A left paramedian craniotomy with a transcallosal, transchoroidal approach using an intraoperative neuronavigation system was used to resect a pineal cyst. Postoperative imaging showed complete removal of the cyst and resolution of the hydrocephalus. Follow-up imaging at 12 months demonstrated no evidence of recurrence or any hydrocephalus. The patient has remained asymptomatic for 18 months. CONCLUSION:Pineal cyst apoplexy should always be considered when following a patient with a pineal cyst that becomes symptomatic. The most common symptom was severe headache of sudden onset or acute worsening. Other signs of hydrocephalus may or may not be present. Magnetic resonance imaging is essential to making a diagnosis. Although we believe that surgical resection is the most effective approach because it minimizes the risk for recurrence and complication, stereotactic aspiration has been used successfully to treat this condition.

Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors.

Matrix metalloproteinases (MMPs) have been implicated in the process of tumor invasion and metastasis formation. Thus, we determined the expression of MMPs in various primary and metastatic spinal tumors in order to assess the role of these enzymes in spinal invasion. MMP expression was examined by immuno-histochemical localization, and quantitative evaluation of MMP protein content was determined by enzyme-linked immunosorbant assay (ELISA) and Western blotting. MMP enzyme activity was determined by gelatin zymography. Lung carcinomas and melanomas metastatic to the spine were shown to have higher levels of MMP-9 activity than those of breast, thyroid, renal metastases and primary spinal tumors. Immunohistochemical analysis revealed similar difference in expression of MMP-9 in tissue samples. When the tissue samples were subjected to gelatin zymography for examination of MMP-2 and MMP-9 activity and to ELISA and Western blotting for quantitative estimation of protein content, the most striking results were obtained for lung carcinomas and melanomas relative to the other tumors. Lung carcinomas and melanomas metastatic to the spine had considerably higher levels of MMP-9 activity than those of primary spinal tumor or breast, thyroid, and renal carcinoma metastases. Within the metastatic tumor category, neoplasms that are known to be associated with the shortest overall survival rates and most aggressive behavior, such as lung carcinomas and melanomas, had the highest levels of MMP-2 and MMP-9 activity compared to those less aggressive metastatic tumors such as breast, renal cell, and thyroid carcinomas. Our results suggest that MMPs may contribute to the metastases to the spinal column, and overexpression of these enzymes may correlate with enhanced invasive properties of both primary and metastatic spinal tumors.© Kluwer Academic Publishers 1998

Characterization of the DiFi Rectal carcinoma cell line derived from a familial adenomatous polyposis patient

SummaryThe DiFi human colorectal cancer cell line was recently established from a familial adenomatous polyposis patient with extracolonic features characteristic of the Gardner syndrome. These cells have now been propagated for 150 passages in standard culture media and vessels without feeder layers or collagen coatings. They retain features of colonic epithelial cells such as surface microvilli, secretory vesicles, and desmosomes. Cytosol of DiFi cells contains a high level (502 U/mg protein) of the mucin CA 19-9. In addition, DiFi cells produce carcinoembryonic antigen, and induce tumors in athymic mice. Cytoskeleton analysis of DiFi cells by fluorescence microscopy showed a pronounced disorganization of actin cable structure. The isozyme genetic signature of DiFi cells is unique (0.01 probability of finding the same genetic signature in a different cell line), differs from that of HeLa cells, and has expressional features seen in other colorectal cell lines. The DiFi cell karyotype is tetraploid, contains many marker chromosomes, and shows numerous episomal particles. Two copies of chromosome 18 were absent, and only a single normal chromosome 17 was found. This parallels detection of allelic losses from DiFi cell DNA at loci on chromosomes 17p and 18 using molecular (cDNA) probes. DiFi cells clearly express transcripts for the c-myc proto-oncogene, the c-myb proto-oncogene, and thep53 tumor suppressor gene. Transforming growth factor beta inhibits DiFi cell growth in soft agar and suppresses c-myc expression in these cells. The value of this cell line in the study of genetic alterations in colorectal cancer is discussed.