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Douglas C. Miller, Frederick F. Lang and Fred J. Epstein

Histopathological features that suggest the diagnosis of ganglioglioma require, in most cases, confirmation by special stains to distinguish these tumors from other gliomas. For this purpose, immunostaining for synaptophysin, which has previously been shown to selectively label the cell surface of neoplastic ganglion cells, was used to retrospectively examine glioma tumor specimens. Sixty-three cases of ganglioglioma were identified. The files of the Division of Neuropathology of New York University Medical Center contained 45 tumors that had been diagnosed as ganglioglioma, of which 42 were verified by synaptophysin; three cases were reclassified, two as astrocytomas and one as a gangliocytic paraganglioma. Thus, a tumor identified as ganglioglioma based on other criteria was likely to be a ganglioglioma. The other 21 cases of gangliogliomas were originally diagnosed as astrocytoma or mixed glioma, but were shown by synaptophysin staining to be gangliogliomas. In some cases the ultimate diagnosis was obtained after radical surgery provided relatively abundant amounts of tissue, thereby limiting sampling errors, in contrast to the biopsies from which the original diagnoses were made.

Histopathological review of these cases demonstrated that four features represent important clues to the correct diagnosis: 1) clusters of large cells potentially representing neurons (without such cells the tumor cannot be classified as a ganglioglioma); 2) no perineuronal clustering of the glial cells around the alleged neoplastic neurons; 3) fibrosis (desmoplasia); and 4) calcification. Binucleate neurons, previously suggested to be common in gangliogliomas, were not frequently found in this series, and lymphocytic infiltrates, while common, are so often found in other tumors that they gave no specific hint that any single neoplasm was a ganglioglioma. The glial elements were astrocytic in all cases, except that one tumor also had oligodendroglial and ependymal patterns. Four tumors also had small mature neurons, as seen in neurocytomas. Cells from one tumor were successfully grown in short-term tissue culture; the culture contained large dividing neurons with synaptophysin immunoreactivity as well as smaller dividing cells, demonstrating that the neuronal cells are a proliferating element in gangliogliomas.

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Central nervous system gangliogliomas

Part 2: Clinical outcome

Frederick F. Lang, Fred J. Epstein, Joseph Ransohoff, Jeffrey C. Allen, Jeffrey Wisoff, I. Richmond Abbott and Douglas C. Miller

The records of 58 patients with gangliogliomas surgically treated between January 1, 1980, and June 30, 1990, were retrospectively reviewed in order to determine long-term survival, event-free survival, and functional outcome resulting after radical resection and to assess the impact of histological grading on outcome. Tumors were located in the cerebral hemisphere in 19 cases, the spinal cord in 30, and the brain stem in nine. Forty-four patients had gross total resection and 14 had radical subtotal resection. Only six patients underwent postoperative irradiation or chemotherapy and, therefore, the outcome was generally related to surgery alone. Of the 58 gangliogliomas, 40 were classified as histological grade I, 16 were grade II, and two were grade III. The median follow-up period was 56 months. There were no operative deaths, and the operative morbidity rate was 5%, 37%, and 33% for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas, respectively. The 5-year actuarial survival rates for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas were 93%, 84%, and 73%, respectively (p = 0.7). The event-free survival rate at 5 years was 95% for cerebral hemisphere gangliogliomas and 36% for spinal cord gangliogliomas (p < 0.05); for brain-stem gangliogliomas the event-free survival rate at 3 years was 53% (p < 0.05). Neurological function at recent follow-up evaluation was stable or improved in 81% of patients. Multivariate analysis (Cox linear regression) revealed tumor location to be the only variable predictive of outcome, with spinal cord and brain-stem gangliogliomas having a 3.5- and 5-fold increased relative risk of recurrence, respectively, compared to cerebral hemisphere gangliogliomas. Histological grade was not predictive of outcome, although in each location there was a trend for higher-grade tumors to have a shorter time to recurrence. It is concluded that radical surgery leads to long-term survival of patients with gangliogliomas, regardless of location, and adjuvant therapy can probably be reserved for special cases.

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Frederick F. Lang, Douglas C. Miller, Maxim Koslow and Elizabeth W. Newcomb

✓ To characterize some of the genetic events underlying the development of glioblastoma multiforme, the authors analyzed 65 astrocytic tumors (seven pilocytic astrocytomas, eight astrocytomas, 16 anaplastic astrocytomas, and 34 glioblastomas multiforme) for loss of heterozygosity for chromosome 17p, loss of heterozygosity for chromosomes 10p and 10q, amplification of the epidermal growth factor receptor (EGFR) gene, and amplification of the oncogenes N-myc, c-myc, and N-ras using Southern blot analysis. Alterations of the p53 gene (positive immunostaining for p53 protein in tumors with or without p53 gene mutations) in these 65 tumors were analyzed previously. None of the 65 tumors showed amplification or rearrangement of N-myc, c-myc, or N-ras oncogenes.

The molecular analysis presented here demonstrates distinct variants of astrocytic tumors, with at least three genetic pathways leading to glioblastoma multiforme. One pathway was characterized by 43 astrocytomas with alterations in p53. Glioblastomas with p53 alterations may represent tumors that progress from lower-grade astrocytomas. This variant was more likely to show loss of chromosome 17p than tumors without p53 alterations (p < 0.04). Seventy-five percent of tumors with loss of one 17p allele demonstrated mutations in the p53 gene. Loss of chromosome 10 was associated with progression from anaplastic astrocytoma (13%) to glioblastoma (38%) (p < 0.04). Amplification of the EGFR gene was a rare (7%) but late event in tumor progression (p < 0.03). A second pathway was characterized by six astrocytomas without p53 alterations and may represent clinically de novo high-grade tumors. These tumors were more likely to show amplification of the EGFR gene (83%) than tumors with p53 alterations. Sixty percent of tumors with EGFR amplification also showed loss of chromosome 10; loss of chromosome 17p was infrequent in this variant. One or more alternative pathways were characterized by 16 astrocytomas without p53 alterations and with none of the genetic changes analyzed in this study. Glioblastomas are a heterogeneous group of tumors that may arise via multiple genetic pathways.

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Frederick F. Lang, W. K. Alfred Yung, Uma Raju, Floralyn Libunao, Nicholas H. A. Terry and Philip J. Tofilon

Object. The authors sought to determine whether combining p53 gene transfer with radiation therapy would enhance the therapeutic killing of p53 wild-type glioma cells. It has been shown in several reports that adenovirus-mediated delivery of the p53 gene into p53 mutant gliomas results in dramatic apoptosis, but has little effect on gliomas containing wild-type p53 alleles. Therefore, p53 gene therapy alone may not be a clinically effective treatment for gliomas because most gliomas are composed of both p53 mutant and wild-type cell populations. One potential approach to overcome this problem is to exploit the role p53 plays as an important determinant in the cellular response to ionizing radiation.

Methods. In vitro experiments were performed using the glioma cell line U87MG, which contains wild-type p53. Comparisons were made to the glioma cell line U251MG, which contains a mutant p53 allele. Monolayer cultures were infected with an adenovirus containing wild-type p53 (Ad5CMV-p53), a control vector (dl312), or Dulbecco's modified Eagle's medium (DMEM). Two days later, cultures were irradiated and colony-forming efficiency was determined. Transfection with p53 had only a minor effect on the plating efficiency of nonirradiated U87MG cells, reducing the plating efficiency from 0.23 ± 0.01 in DMEM to 0.22 ± 0.04 after addition of Ad5CMV-p53. However, p53 transfection significantly enhanced the radiosensitivity of these cells. The dose enhancement factor at a surviving fraction of 0.10 was 1.5, and the surviving fraction at 2 Gy was reduced from 0.61 in untransfected controls to 0.38 in p53-transfected cells. Transfection of the viral vector control (dl312) had no effect on U87MG radiosensitivity. In comparison, transfection of Ad5CMV-p53 into the p53 mutant cell line U251MG resulted in a significant decrease in the surviving fraction of these cells compared with controls, and no radiosensitization was detected.

To determine whether Ad5CMV-p53—mediated radiosensitization of U87MG cells involved an increase in the propensity of these cells to undergo apoptosis, flow cytometric analysis of terminal deoxynucleotidyl transferase-mediated biotinylated-deoxyuridinetriphosphate nick-end labeling—stained cells was performed. Whereas the amount of radiation-induced apoptosis in uninfected and dl312-infected control cells was relatively small (2.1 ± 0.05% and 3.7 ± 0.5%, respectively), the combination of Ad5CMV-p53 infection and radiation treatment significantly increased the apoptotic frequency (18.6 ± 1.4%).

To determine whether infection with Ad5CMV-p53 resulted in increased expression of functional exogenous p53 protein, Western blot analysis of p53 was performed on U87MG cells that were exposed to 9 Gy of radiation 2 days after exposure to Ad5CMV-p53, dl312, or DMEM. Infection with Ad5CMV-p53 alone increased p53 levels compared with DMEM- or dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in a further increase in p53 that reached a maximum at 2 hours postirradiation. To determine whether exogenous p53 provided by Ad5CMV-p53 had transactivating activity, U87MG cells were treated as described earlier and p21 messenger RNA levels were determined. Infection of U87MG cells with Ad5CMV-p53 only resulted in an increase in p21 compared with DMEM- and dl312-treated cells. Irradiation of Ad5CMV-p53—infected cells resulted in an additional time-dependent increase in p21 expression.

Conclusions. These data indicate that adenovirus-mediated delivery of p53 may enhance the radioresponse of brain tumor cells containing wild-type p53 and that this radiosensitization may involve converting from a clonogenic to the more sensitive apoptotic form of cell death. Although the mechanism underlying this enhanced apoptotic susceptibility is unknown, the Ad5CMV-p53—infected cells have a higher level of p53 protein, which increases further after irradiation, and this exogenous p53 is transcriptionally active. Thus, it is possible that the combination of Ad5CMV-p53 infection and radiation treatment increases p53 protein to a level that is sufficient to overcome at least partially the block in apoptosis existing in U87MG cells.

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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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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.

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Julie E. York, Garrett L. Walsh, Frederick F. Lang, Joe B. Putnam, Ian E. McCutcheon, Stephen G. Swisher, Ritsuko Komaki and Ziya L Gokaslan

Traditionally, superior sulcus tumors of the lung that involve the chest wall and spinal column have been considered to be unresectable, and historically, patients harboring these tumors have been treated with local radiation therapy with, at best, modest results. The value of gross-total resection remains unclear in this patient population; however, with the recent advances in surgical technique and spinal instrumentation, procedures involving more radical removal of such tumors are now possible. At The University of Texas M. D. Anderson Cancer Center, the authors have developed a new technique for resecting superior sulcus tumors that invade the chest wall and spinal column. They present a technical description of this procedure and results in nine patients in whom stage IIIb superior sulcus tumors extensively invaded the vertebral column. These patients underwent gross-total tumor resection via a combined approach that included posterolateral thoracotomy, apical lobectomy, chest wall resection, laminectomy, vertebrectomy, anterior spinal column reconstruction with methylmethacrylate, and placement of spinal instrumentation. There were six men and three women, with a mean age of 55 years (range 36–72 years). Histological examination revealed squamous cell carcinoma (three patients), adenocarcinoma (four patients), and large cell carcinoma (two patients). The mean postoperative follow-up period was 16 months. All patients are currently ambulatory or remained ambulatory until they died. Pain related to tumor invasion improved in four patients and remained unchanged in five. In three patients instrumentation failed and required revision. There was one case of cerebrospinal leak that was treated with lumbar drainage and one case of wound breakdown that required revision. Two patients experienced local tumor recurrence, and one patient developed a second primary lung tumor. The authors conclude that in selected patients, combined radical resection of superior sulcus tumors of the lung that involve the chest wall and spinal column may represent an acceptable treatment modality that can offer a potential cure while preserving neurological function and providing pain control.

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Julie E. York, Garrett L. Walsh, Frederick F. Lang, Joe B. Putnam, Ian E. McCutcheon, Stephen G. Swisher, Ritsuko Komaki and Ziya L Gokaslan

Object. Traditionally, superior sulcus tumors of the lung that involve the chest wall and spinal column have been considered to be unresectable, and historically, patients harboring these tumors have been treated with local radiation therapy with, at best, modest results. The value of gross-total resection remains unclear in this patient population; however, with the recent advances in surgical technique and spinal instrumentation, procedures involving more radical removal of such tumors are now possible. At The University of Texas M. D. Anderson Cancer Center, the authors have developed a new technique for resecting superior sulcus tumors that invade the chest wall and spinal column. They present a technical description of this procedure and results in nine patients in whom stage IIIb superior sulcus tumors extensively invaded the vertebral column.

Methods. These patients underwent gross-total tumor resection via a combined approach that included posterolateral thoracotomy, apical lobectomy, chest wall resection, laminectomy, vertebrectomy, anterior spinal column reconstruction with methylmethacrylate, and placement of spinal instrumentation. There were six men and three women, with a mean age of 55 years (range 36–72 years). Histological examination revealed squamous cell carcinoma (three patients), adenocarcinoma (four patients), and large cell carcinoma (two patients). The mean postoperative follow-up period was 16 months. All patients are currently ambulatory or remained ambulatory until they died. Pain related to tumor invasion improved in four patients and remained unchanged in five. In three patients instrumentation failed and required revision. There was one case of cerebrospinal fluid leakage that was treated with lumbar drainage and one case of wound breakdown that required revision. Two patients experienced local tumor recurrence, and one patient developed a second primary lung tumor.

Conclusions. The authors conclude that in selected patients, combined radical resection of superior sulcus tumors of the lung that involve the chest wall and spinal column may represent an acceptable treatment modality that can offer a potential cure while preserving neurological function and providing pain control.

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Sumeer Lal, Michel Lacroix, Philip Tofilon, Gregory N. Fuller, Raymond Sawaya and Frederick F. Lang

Object. To overcome the problems associated with using stereotactic techniques to establish intracranial xenografts in nude mice and to treat engrafted tumors with intratumoral therapies (such as gene or viral therapies), the authors developed an implantable guide-screw system. In this study, they describe the guide-screw system, its method of implantation, and their experience with establishing xenografts and delivering intratumoral therapy.

Methods. The system consists of a 2.6-mm guide screw with a central 0.5-mm diameter hole that accepts the 26-gauge needle of a Hamilton syringe. The screw is implanted into a small drill hole made 2.5 mm lateral and 1 mm anterior to the bregma. A stylet is used to cap the screw between treatments. Tumor cells or therapeutic agents are injected in a freehand fashion by using a Hamilton syringe and a 26-gauge needle fitted with a cuff to determine the depth of injection. To test this system, guide screws were successfully implanted in 44 (98%) of 45 nude mice. After 1 to 2 weeks of recovery, 38 mice were inoculated with U87MG cells and killed 5 days later. On histological studies in 37 (97%) of these animals, xenografts were evident within the caudate nucleus (mean diameter 2.5 mm). To determine whether injections into the center of an established xenograft could be reproducibly achieved with the guide-screw system, an adenovirus vector containing the β-galactosidase gene was injected 3 days after cell implantation in 15 of the mice. All of these animals demonstrated transduced cells within the tumor. To demonstrate that engrafted animals have a uniform survival time that is indicative of reproducible tumor growth, the survival of six mice was assessed after engraftment with U87MG cells. All six animals died within 28 to 35 days.

Conclusions. The guide-screw system allows a large number of animals to be rapidly and reproducibly engrafted and for intratumoral treatments to be accurately delivered into established xenografts.

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Daniel J. Miller, Frederick F. Lang, Garrett L. Walsh, Dima Abi-Said, David M. Wildrick and Ziya L. Gokaslan

Object. A unique method of anterior spinal reconstruction after decompressive surgery was used to prevent methylmethacrylate—dural contact in cancer patients who underwent corpectomy. The purpose of this study was to assess the efficacy and stability of polymethylmethacrylate (PMMA) anterior surgical constructs in conjunction with anterior cervical plate stabilization (ACPS) in these patients.

Methods. Approximately 700 patients underwent spinal surgery at The University of Texas M. D. Anderson Cancer Center over a 4-year period. The authors conducted a retrospective outcome study for 29 of these patients who underwent anterior cervical or upper thoracic tumor resections while in the supine position. These patients were all treated using the coaxial, double-lumen, PMMA technique for anterior spinal reconstruction with subsequent ACPS. No postoperative external orthoses were used. Twenty-seven patients (93%) harbored metastatic spinal lesions and two (7%) harbored primary tumors. At 1 month postsurgery, significant improvement was seen in spinal axial pain (p < 0.001), radiculopathy (p < 0.00 1), gait (p = 0.008), and Frankel grade (p = 0.002). A total of nine patients (31%) underwent combined anterior—posterior 360° stabilization. Twenty-one patients (72%) experienced no complications. Complications related to instrumentation failure occurred in only two patients (7%). There were no cases in which the patients' status worsened, and there were no neurological complications or infections. The median Kaplan—Meier survival estimate for patients with spinal metastases was 9.5 months. At the end of the study, 13 patients (45%) had died and 16 (55%) were alive. Postoperative magnetic resonance images consistently demonstrated that the dura and PMMA in all patients remained separated.

Conclusions. The anterior, coaxial, double-lumen, PMMA reconstruction technique provides a simple means of spinal cord protection in patients in the supine position while undergoing surgery and offers excellent results in cancer patients who have undergone cervical vertebrectomy.