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Jaime A. Quirarte, Vinodh A. Kumar, Ho-Ling Liu, Kyle R. Noll, Jeffrey S. Wefel and Frederick F. Lang

Supplementary motor area (SMA) syndrome is well known; however, the mechanism underlying recovery from language SMA syndrome is unclear. Herein the authors report the case of a right-handed woman with speech aphasia following resection of an oligodendroglioma located in the anterior aspect of the left superior frontal gyrus. The patient exhibited language SMA syndrome, and functional MRI (fMRI) findings 12 days postoperatively demonstrated a complete shift of blood oxygen level–dependent (BOLD) activation to the contralateral right language SMA/pre-SMA as well as coequal activation and an increased volume of activation in the left Broca’s area and the right Broca’s homolog. The authors provide, to the best of their knowledge, the first description of dynamic changes in task-based hemispheric language BOLD fMRI activations across the preoperative, immediate postoperative, and more distant postoperative settings associated with the development and subsequent complete resolution of the clinical language SMA syndrome.

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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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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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Jonathan G. Thomas, Brittany C. Parker Kerrigan, Anwar Hossain, Joy Gumin, Naoki Shinojima, Felix Nwajei, Ravesanker Ezhilarasan, Patrice Love, Erik P. Sulman and Frederick F. Lang

OBJECTIVE

Mesenchymal stem cells (MSCs) have been shown to localize to gliomas after intravascular delivery. Because these cells home to areas of tissue injury, the authors hypothesized that the administration of ionizing radiation (IR) to tumor would enhance the tropism of MSCs to gliomas. Additionally, they sought to identify which radiation-induced factors might attract MSCs.

METHODS

To assess the effect of IR on MSC migration in vitro, transwell assays using conditioned medium (CM) from an irradiated commercially available glioma cell line (U87) and from irradiated patient-derived glioma stem-like cells (GSCs; GSC7-2 and GSC11) were employed. For in vivo testing, green fluorescent protein (GFP)-labeled MSCs were injected into the carotid artery of nude mice harboring orthotopic U87, GSC7-2, or GSC17 xenografts that were treated with either 0 or 10 Gy of IR, and brain sections were quantitatively analyzed by immunofluorescence for GFP-positive cells. These GSCs were used because GSC7-2 is a weak attractor of MSCs at baseline, whereas GSC17 is a strong attractor. To determine the factors implicated in IR-induced tropism, CM from irradiated GSC7-2 and from GSC11 was assayed with a cytokine array and quantitative ELISA.

RESULTS

Transwell migration assays revealed statistically significant enhanced MSC migration to CM from irradiated U87, GSC7-2, and GSC11 compared with nonirradiated controls and in a dose-dependent manner. After their intravascular delivery into nude mice harboring orthotopic gliomas, MSCs engrafted more successfully in irradiated U87 (p = 0.036), compared with nonirradiated controls. IR also significantly increased the tropism of MSCs to GSC7-2 xenografts (p = 0.043), which are known to attract MSCs only poorly at baseline (weak-attractor GSCs). Ionizing radiation also increased the engraftment of MSCs in strong-attractor GSC17 xenografts, but these increases did not reach statistical significance. The chemokine CCL2 was released by GSC7-2 and GSC11 after irradiation in a dose-dependent manner and mediated in vitro transwell migration of MSCs. Immunohistochemistry revealed increased CCL2 in irradiated GSC7-2 gliomas near the site of MSC engraftment.

CONCLUSIONS

Administering IR to gliomas enhances MSC localization, particularly in GSCs that attract MSCs poorly at baseline. The chemokine CCL2 appears to play a crucial role in the IR-induced tropism of MSCs to gliomas.

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Markus M. Luedi, Sanjay K. Singh, Jennifer C. Mosley, Islam S. A. Hassan, Masumeh Hatami, Joy Gumin, Lukas Andereggen, Erik P. Sulman, Frederick F. Lang, Frank Stueber, Gregory N. Fuller, Rivka R. Colen and Pascal O. Zinn

OBJECTIVE

Dexamethasone, a known regulator of mesenchymal programming in glioblastoma (GBM), is routinely used to manage edema in GBM patients. Dexamethasone also activates the expression of genes, such as CEBPB, in GBM stem cells (GSCs). However, the drug’s impact on invasion, proliferation, and angiogenesis in GBM remains unclear. To determine whether dexamethasone induces invasion, proliferation, and angiogenesis in GBM, the authors investigated the drug’s impact in vitro, in vivo, and in clinical information derived from The Cancer Genome Atlas (TCGA) cohort.

METHODS

Expression profiles of patients from the TCGA cohort with mesenchymal GBM (n = 155) were compared with patients with proneural GBM by comparative marker selection. To obtain robust data, GSCs with IDH1 wild-type (GSC3) and with IDH1 mutant (GSC6) status were exposed to dexamethasone in vitro and in vivo and analyzed for invasion (Boyden chamber, human-specific nucleolin), proliferation (Ki-67), and angiogenesis (CD31). Ex vivo tumor cells from dexamethasone-treated and control mice were isolated by fluorescence activated cell sorting and profiled using Affymetrix chips for mRNA (HTA 2.0) and microRNAs (miRNA 4.0). A pathway analysis was performed to identify a dexamethasone-regulated gene signature, and its relationship with overall survival (OS) was assessed using Kaplan-Meier analysis in the entire GBM TCGA cohort (n = 520).

RESULTS

The mesenchymal subgroup, when compared with the proneural subgroup, had significant upregulation of a dexamethasone-regulated gene network, as well as canonical pathways of proliferation, invasion, and angiogenesis. Dexamethasone-treated GSC3 demonstrated a significant increase in invasion, both in vitro and in vivo, whereas GSC6 demonstrated a modest increase. Furthermore, dexamethasone treatment of both GSC3 and GSC6 lines resulted in significantly elevated cell proliferation and angiogenesis in vivo. Patients with mesenchymal GBM had significant upregulation of dexamethasone-regulated pathways when compared with patients with proneural GBM. A prognostic (p = 0.0007) 33-gene signature was derived from the ex vivo expression profile analyses and used to dichotomize the entire TCGA cohort by high (median OS 12.65 months) or low (median OS 14.91 months) dexamethasone signature.

CONCLUSIONS

The authors present evidence that furthers the understanding of the complex effects of dexamethasone on biological characteristics of GBM. The results suggest that the drug increases invasion, proliferation, and angiogenesis in human GSC-derived orthotopic tumors, potentially worsening GBM patients’ prognoses. The authors believe that careful investigation is needed to determine how to minimize these deleterious dexamethasone-associated side effects in GBM.