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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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Frederick F. Lang, Raymond Sawaya, Dima Suki, Ian E. McCutcheon and Kenneth R. Hess

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Joshua J. Chern, Andrew J. Tsung, William Humphries, Raymond Sawaya and Frederick F. Lang

Object

Intracranial hemorrhage (ICH) is a frequent complication found in leukemia patients with thrombocytopenia. At the University of Texas MD Anderson Cancer Center, when a leukemia patient is found to have ICH, a platelet transfusion is generally recommended until 50,000/μl is reached. The authors examine the feasibility and outcome of their intervention strategy in this study.

Methods

Records were reviewed from 76 consecutive leukemia patients with newly diagnosed ICH at the University of Texas MD Anderson Cancer Center from January 1, 2007, to December 31, 2009. Variables of interest included age, platelet count at presentation, leukemia subtype, history of trauma, Glasgow Coma Scale score at presentation, whether the 50,000/μl goal was reached after transfusion, and whether the patient was a transfusion responder (platelet count increase > 2000/μl/unit transfused). Outcome parameters were mortality rates at 72 hours and 30 days and imaging-documented hemorrhage progression.

Results

Thrombocytopenia was prevalent at the time of presentation (68 of 76 patients had platelet levels < 50,000/μl at presentation). Despite an aggressive transfusion protocol, only 24 patients reached the 50,000/μl target after an average of 16 units of transfusion. Death due to ICH occurred in 15 patients within the first 72 hours (mortality rate 19.7%). Death correlated with the presenting Glasgow Coma Scale score (p = 0.0075) but not with other transfusion-related parameters. A significant mortality rate was again observed after 30 days (32.7%). The 30-day mortality rate, however, was largely attributable to non-ICH related causes and correlated with patient age (p = 0.032) and whether the patient was a transfusion responder (p = 0.022). Reaching and maintaining a platelet count > 50,000/μl did not positively correlate with the 30-day mortality rate (p = 0.392 and 0.475, respectively).

Conclusions

Platelet transfusion in the setting of ICH in leukemia patients is undoubtedly necessary, but whether the transfusion threshold should be 50,000/μl remains unclear. Factors other than thrombocytopenia likely contribute to the overall poor prognosis.

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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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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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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.

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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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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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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.