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Daniel K. Fahim, Claudio E. Tatsui, Dima Suki, Joy Gumin, Frederick F. Lang and Laurence D. Rhines

Object

There is currently no reproducible animal model of human primary malignant bone tumors in the spine to permit laboratory investigation of the human disease. Therefore, the authors sought to adapt their previously developed orthotopic model of spinal metastasis to a model for primary malignant bone tumors of the spine.

Methods

A transperitoneal surgical approach was used to implant osteosarcoma (Krib-1) into the L-3 vertebral body of nude mice via a drill hole. Motor function was evaluated daily using the previously validated qualitative key milestones of tail dragging, dorsal stepping, hindlimb sweeping, and paralysis. A subset of these animals was euthanized upon reaching the various milestones, and the spines were removed, sectioned, and stained. The degree of spinal cord compression was correlated with the occurrence of milestones and assessed by a ratio between the neural elements divided by the area of the spinal canal. Another subset of animals received stably transfected Krib-1 cells with the luciferase gene, and bioluminescence was measured at 10, 20, and 30 days postimplantation.

Results

Osteosarcoma xenografts grew in all animals according to a reliable and reproducible time course; the mean time for development of behavioral milestones was noted in relation to the day of implantation (Day 1). Tail dragging (Milestone 1) occurred on Day 19.06 (95% CI 16.11–22.01), dorsal stepping (Milestone 2) occurred on Day 28.78 (95% CI 26.79–30.77), hindlimb sweeping (Milestone 3) occurred on Day 35.61 (95% CI 32.9–38.32), and paralysis of the hindlimb (Milestone 4) occurred on Day 41.78 (95% CI 39.31–44.25). These clinically observed milestones correlated with increasing compression of the spinal cord on histological sections. The authors observed a progressive increase in the local bioluminescence (in photons/cm2/sec) of the implanted level over time with a mean of 2.17 (range 0.0–8.61) at Day 10, mean 4.68 (range 1.17–8.52) at Day 20, and mean 5.54 (range 1.22–9.99) at Day 30.

Conclusions

The authors have developed the first orthotopic murine model of a primary malignant bone tumor in the spine, in which neurological decline reproducibly correlates with tumor progression as evidenced by pathological confirmation and noninvasive bioluminescence measurements. Although developed for osteosarcoma, this model can be expanded to study other types of primary malignant bone tumors in the spine. This model will potentially allow animal testing of targeted therapies against specific primary malignant tumor types.

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Daryl R. Fourney, Dima Abi-Said, Frederick F. Lang, Ian E. McCutcheon and Ziya L. Gokaslan

Object. Few reports are available on the use of pedicle screw fixation for cancer-related spinal instability. The authors present their experience with pedicle screw fixation in the management of malignant spinal column tumors.

Methods. Records for patients with malignant spinal tumors who underwent pedicle screw fixation at the authors' institution between September 1994 and December 1999 were retrospectively reviewed.

Results. Ninety-five patients with malignant spinal tumors underwent 100 surgeries involving pedicle screw fixation: metastatic spinal disease was present in 81 patients, and locally invasive tumors were demonstrated in 14 patients. Indications for surgery were pain (98%) and/or neurological dysfunction (80%). A posterior (48%) or a combined anterior—posterior (52%) approach was performed depending on the extent of tumor and the patient's condition. At the mean follow up of 8.2 months, 43 patients (45%) had died; median survival, as determined by Kaplan—Meier analysis, was 14.8 months. At 1 month postsurgery, self-reported pain had improved in 87% of cases (p < 0.001), which is a finding substantiated by reductions in analgesic use, and 29 (47%) of 62 patients with preoperative neurological impairments were functionally improved (p < 0.001). Postoperative complications were associated only with preoperative radiation therapy (p = 0.002) and with preexisting serious medical conditions (p = 0.04). In two patients asymptomatic violation of the lateral wall of the pedicle was revealed on postoperative radiography. The 30-day mortality rate was 1%.

Conclusions. For selected patients with malignant spinal tumors, pedicle screw fixation after tumor resection may provide considerable pain relief and restore or preserve ambulation with acceptable rates of morbidity and mortality.

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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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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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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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Adam S. Wu, Mariana E. Witgert, Frederick F. Lang, Lianchun Xiao, B. Nebiyou Bekele, Christina A. Meyers, David Ferson and Jeffrey S. Wefel

Object

Insular gliomas can be resected with acceptable rates of neurological morbidity, but little is known with regard to impairment of higher-order neurocognitive functions. The frequency and functional impact of neurocognitive deficits in patients with gliomas has until recently been underappreciated. The authors therefore examined neurocognitive function in patients with insular gliomas and compared the findings in this group to those in a matched control group of patients with gliomas in nearby brain regions.

Methods

Thirty-three patients with WHO Grade II or III insular gliomas participated in neuropsychological evaluations before and after resection. To establish whether the pattern of neurocognitive performance was different from that of other patients with tumors in neighboring areas, patients with insular tumors were matched with control patients for age, educational level, preoperative Karnofsky Performance Scale score, tumor side, grade, and volume. The control group comprised patients in whom gliomas had been resected from frontal, temporal, and parietal areas near the insula. Baseline pre- and postoperative neurocognitive test results were compared between and within groups.

Results

Preoperative neurocognitive impairment was common in both insular and control groups. Patients with insular tumors had significantly worse preoperative performance on naming tests. In both groups, postoperative decline occurred in most neurocognitive domains. There were no statistically significant differences between patients in the insular and control groups with regard to rates of postoperative decline on any test. However, there were trends suggesting differential cognitive performance postoperatively, because patients with insular tumors were more likely to experience greater decline in learning and memory. Neurological morbidity was similar to prior rates reported in the literature.

Conclusions

Few statistically significant differences in cognitive function were observed between patients in the insular and control groups at either the pre- or postoperative evaluation, although there was a trend for patients with insular tumors to exhibit greater postoperative decline in learning and memory. Although technically more challenging, surgery for insular region glioma appears feasible without profound neurological or cognitive morbidity for many patients.

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Wael Hassaneen, Dima Suki, Abhijit L. Salaskar, David M. Wildrick, Frederick F. Lang, Gregory N. Fuller and Raymond Sawaya

Object

The aim of this study was to review the outcome of patients undergoing surgery for treatment of lateral-ventricle metastases.

Methods

Imaging information and chart reviews of operative reports were used to conduct a retrospective analysis in 29 patients who underwent resection of lateral-ventricle metastases at the authors' institution between 1993 and 2007. Clinical and neurosurgical outcomes and recurrence rates were studied.

Results

The mean patient age was 56 years (range 20–69 years); 66% of patients were male. Single intraventricular metastases occurred in 69% of patients, and 55% of them had systemic metastases. The 30-day postoperative mortality rate was 7%. There was intracerebral tumor recurrence in 41% of patients, with 1 patient undergoing a second operation for this. The median postoperative survival duration for 28 patients (excluding 1 patient with preoperative leptomeningeal disease) was 11.7 months; the 3- and 5-year survival rates were 17 and 11%, respectively. Univariate analysis identified factors significantly influencing survival, including the preoperative Karnofsky Performance Scale (KPS) score (p = 0.02), the number of cerebral metastases (p = 0.02), the presence of primary renal cell carcinoma (RCC) (p = 0.02), and the resection method (en bloc vs piecemeal; p = 0.05). The presence of extracranial metastases did not significantly influence survival. Multivariate analysis showed that the preoperative KPS score (p = 0.002), the presence of primary RCC (p = 0.039), and the resection method (en bloc vs piecemeal; p = 0.008) correlated significantly with survival time.

Conclusions

Surgery is an important component in the management of intraventricular metastases. To the authors' knowledge, this is the first study focusing totally on resection of lateral-ventricle metastases. The authors found that patients with primary RCC, those with a favorable preoperative KPS score, and those who underwent en bloc resection had a better outcome than others.

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Frederick F. Lang, Nancy E. Olansen, Franco DeMonte, Ziya L. Gokaslan, Eric C. Holland, Christopher Kalhorn and Raymond Sawaya

Object. Surgical resection of tumors located in the insular region is challenging for neurosurgeons, and few have published their surgical results. The authors report their experience with intrinsic tumors of the insula, with an emphasis on an objective determination of the extent of resection and neurological complications and on an analysis of the anatomical characteristics that can lead to suboptimal outcomes.

Methods. Twenty-two patients who underwent surgical resection of intrinsic insular tumors were retrospectively identified. Eight tumors (36%) were purely insular, eight (36%) extended into the temporal pole, and six (27%) extended into the frontal operculum. A transsylvian surgical approach, combined with a frontal opercular resection or temporal lobectomy when necessary, was used in all cases. Five of 13 patients with tumors located in the dominant hemisphere underwent craniotomies while awake. The extent of tumor resection was determined using volumetric analyses. In 10 patients, more than 90% of the tumor was resected; in six patients, 75 to 90% was resected; and in six patients, less than 75% was resected. No patient died within 30 days after surgery. During the immediate postoperative period, the neurological conditions of 14 patients (64%) either improved or were unchanged, and in eight patients (36%) they worsened. Deficits included either motor or speech dysfunction. At the 3-month follow-up examination, only two patients (9%) displayed permanent deficits. Speech and motor dysfunction appeared to result most often from excessive opercular retraction and manipulation of the middle cerebral artery (MCA), interruption of the lateral lenticulostriate arteries (LLAs), interruption of the long perforating vessels of the second segment of the MCA (M2), or violation of the corona radiata at the superior aspect of the tumor. Specific methods used to avoid complications included widely splitting the sylvian fissure and identifying the bases of the periinsular sulci to define the superior and inferior resection planes, identifying early the most lateral LLA to define the medial resection plane, dissecting the MCA before tumor resection, removing the tumor subpially with preservation of all large perforating arteries arising from posterior M2 branches, and performing craniotomy with brain stimulation while the patient was awake.

Conclusions. A good understanding of the surgical anatomy and an awareness of potential pitfalls can help reduce neurological complications and maximize surgical resection of insular tumors.

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Marcos V. C. Maldaun, Dima Suki, Frederick F. Lang, Sujit Prabhu, Weiming Shi, Gregory N. Fuller, David M. Wildrick and Raymond Sawaya

Object. The goal of this study was to determine whether the presence of a large tumor cyst was associated with improved outcome in patients undergoing surgery for newly diagnosed glioblastomas multiforme (GBMs) by comparing these patients with a matched cohort of patients with noncystic GBMs in clinical features, tumor imaging characteristics, survival, and time to tumor recurrence after surgery.

Methods. A retrospective analysis was conducted in 22 patients by using imaging information and chart reviews of operative reports of GBMs with large cysts (≥ 50% of tumor volume) at The University of Texas M. D. Anderson Cancer Center between 1993 and 2002. Clinical and neurosurgical outcomes and recurrence rates were studied. A statistical comparison was made with a matching cohort of 22 patients with noncystic GBMs.

No significant differences in clinical variables were found between the cohort with cystic GBMs and the matched cohort with noncystic GBMs. To avoid bias in preoperative assessment of tumor volume, the tumor burden was compared in patients whose tumors had cysts (excluding the cystic mass) and in patients whose tumors did not contain cysts. There was no statistically significant difference between the two groups (p = 0.8). In patients with cystic GBMs the median survival time after surgery was 18.2 months (95% confidence interval [CI] 11.9–24.5 months) and at 2 years 43% of the patients were still alive. In comparison, in patients with noncystic GBMs, the median survival time was 14.3 months (95% CI 12.1–16.4 months) and only 16% of patients were alive at 2 years. The median time to tumor recurrence was 7.6 months (95% CI 0.01–18 months) in patients harboring cystic GBMs and 4.2 months (95% CI 1.8–6.6 months) in the matched cohort (log-rank test, p = 0.04). In the cystic GBM group, no recurrence was observed in 53% of patients at 6 months, 45% at 1 year, and 38% at 2 years after surgery, whereas the corresponding numbers for the noncystic group were 36, 14, and 9%, respectively.

Conclusions. The results indicate that patients harboring a GBM that contains a large cyst survive longer and have a longer time to recurrence than those who lack such a cyst. This is the first such observation in the literature.

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Daryl R. Fourney, Dima Abi-Said, Laurence D. Rhines, Garrett L. Walsh, Frederick F. Lang, Ian E. McCutcheon and Ziya L. Gokaslan

Object. Thoracic or lumbar spine malignant tumors involving both the anterior and posterior columns represent a complex surgical problem. The authors review the results of treating patients with these lesions in whom surgery was performed via a simultaneous anterior—posterior approach.

Methods. The hospital records of 26 patients who underwent surgery via simultaneous combined approach for thoracic and lumbar spinal tumors at our institution from July 1994 to March 2000 were reviewed. Surgery was performed with the patients in the lateral decubitus position for the procedure. The technical details are reported.

The mean survival determined by Kaplan—Meier analysis was 43.4 months for the 15 patients with primary malignant tumors and 22.5 months for the 11 patients with metastatic spinal disease. At 1 month after surgery, 23 (96%) of 24 patients who complained of pain preoperatively reported improvements (p < 0.001, Wilcoxon signed-rank test), and eight (62%) of 13 patients with preoperative neurological deficits were functionally improved (p = 0.01). There were nine major complications, five minor complications, and no deaths within 30 days of surgery. Two patients (8%) later underwent surgery for recurrent tumor.

Conclusions. The simultaneous anterior—posterior approach is a safe and feasible alternative for the exposure tumors of the thoracic and lumbar spine that involve both the anterior and posterior columns. Advantages of the approach include direct visualization of adjacent neurovascular structures, the ability to achieve complete resection of lesions involving all three columns simultaneously (optimizing hemostasis), and the ability to perform excellent dorsal and ventral stabilization in one operative session.