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Recruitment by SDF-1α of CD34-positive cells involved in sciatic nerve regeneration

Laboratory investigation

Meei-Ling Sheu, Fu-Chou Cheng, Hong-Lin Su, Ying-Ju Chen, Chun-Jung Chen, Chih-Ming Chiang, Wen-Ta Chiu, Jason Sheehan, and Hung-Chuan Pan

Object

Increased integration of CD34+ cells in injured nerve significantly promotes nerve regeneration, but this effect can be counteracted by limited migration and short survival of CD34+ cells. SDF-1α and its receptor mediate the recruitment of CD34+ cells involved in the repair mechanism of several neurological diseases. In this study, the authors investigate the potentiation of CD34+ cell recruitment triggered by SDF-1α and the involvement of CD34+ cells in peripheral nerve regeneration.

Methods

Peripheral nerve injury was induced in 147 Sprague-Dawley rats by crushing the left sciatic nerve with a vessel clamp. The animals were allocated to 3 groups: Group 1, crush injury (controls); Group 2, crush injury and local application of SDF-1α recombinant proteins; and Group 3, crush injury and local application of SDF-1α antibody. Electrophysiological studies and assessment of regeneration markers were conducted at 4 weeks after injury; neurobehavioral studies were conducted at 1, 2, 3, and 4 weeks after injury. The expression of SDF-1α, accumulation of CD34+ cells, immune cells, and angiogenesis factors in injured nerves were evaluated at 1, 3, 7, 10, 14, 21, and 28 days after injury.

Results

Application of SDF-1α increased the migration of CD34+ cells in vitro, and this effect was dose dependent. Crush injury induced the expression of SDF-1α, with a peak of 10–14 days postinjury, and this increased expression of SDF-1α paralleled the deposition of CD34+ cells, expression of VEGF, and expression of neurofilament. These effects were further enhanced by the administration of SDF-1α recombinant protein and abolished by administration of SDF-1α antibody. Furthermore, these effects were consistent with improvement in measures of neurological function such as sciatic function index, electrophysiological parameters, muscle weight, and myelination of regenerative nerve.

Conclusions

Expression of SDF-1α facilitates recruitment of CD34+ cells in peripheral nerve injury. The increased deposition of CD34+ cells paralleled significant expression of angiogenesis factors and was consistent with improvement of neurological function. Utilization of SDF-1α for enhancing the recruitment of CD34+ cells involved in peripheral nerve regeneration may be considered as an alternative treatment strategy in peripheral nerve disorders.

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Editorial

Radiosurgery

Jason Sheehan

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A rare intraosseous arteriovenous malformation of the spine

Case report

Robert G. Louis Jr., Chun Po Yen, Carrie A. Mohila, James W. Mandell, and Jason Sheehan

The authors report the case of a patient with an intraosseous spinal arteriovenous malformation (AVM) presenting as an epidural mass lesion that was causing spinal cord compression. The 59-year-old woman had bilateral numbness, weakness, and hyperreflexia of both legs. Magnetic resonance imaging revealed intermediate T1 signal and hyperintense T2 signal involving the right transverse process, bilateral pedicles, and T-5 spinous process; the lesion's epidural extension was causing severe canal compromise and cord displacement. Coil embolization was performed, and the patient underwent resection, after which preoperative symptoms improved. Histopathological analysis revealed a benign vascular proliferation consistent with an intraosseous spinal AVM. On review of the literature, the authors found this case to be the second intraosseous spinal AVM, and the first in a patient whose clinical presentation was consistent with that of a mass lesion of the bone.

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Editorial: Brain dose with stereotactic radiosurgery

Jason Sheehan, Stanley Benedict, and David Schlesinger

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Editorial: Gamma Knife and meningiomas

Fredric B. Meyer

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Letter to the Editor: Temozolomide and pituitary adenoma

Dueng-Yuan Hueng, Hsin-I Ma, Huey-Kang Sytwu, and Ming-Ying Liu

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Editorial: Radiosurgery for breast cancer

Jason Sheehan

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Temozolomide-induced inhibition of pituitary adenoma cells

Laboratory investigation

Jason Sheehan, Jessica Rainey, James Nguyen, Ruthie Grimsdale, and Shaojie Han

Object

Aggressive pituitary adenomas frequently require multimodality treatment including pituitary-suppressive medications, microsurgery, and radiation therapy or radiosurgery. The effectiveness of temozolomide in terms of growth suppression and decreased hormonal production is evaluated.

Methods

Three pituitary adenoma cell lines—MMQ, GH3, and AtT20—were used. A dose escalation of temozolomide was performed for each cell line, and inhibition of cell proliferation was assessed using an MTT assay. Concentrations of temozolomide that produced statistically significant inhibition of cell proliferation for each cell type were identified. Extent of apoptosis for each selected temozolomide concentration was studied using TUNEL staining. The effect of temozolomide on prolactin secretion in MMQ and GH3 cells was also measured via ELISA.

Results

Significant inhibition of cell proliferation was noted for MMQ and GH3 cells at a concentration of 250 μM temozolomide. The AtT20 cells demonstrated statistically significant cell inhibition at a concentration of only 50 μM temozolomide (p < 0.05). Apoptosis significantly increased in all cell lines in as little as 24 hours of incubation at the respective temozolomide concentrations (p < 0.05). Prolactin secretion in the prolactin secreting MMQ and GH3 cell lines was inhibited by 250 μM temozolomide.

Conclusions

Temozolomide inhibits cell proliferation and induces apoptotic cell death in aggressive pituitary adenoma cells. A reduction in hormonal secretion in prolactinoma cells was also afforded by temozolomide. Temozolomide may prove useful in the multimodality management of aggressive pituitary adenomas.

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Gamma Knife surgery: the best is yet to come

Jason Sheehan

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Quality-of-life outcomes after Gamma Knife surgery for trigeminal neuralgia

Clinical article

Hung-Chuan Pan, Jason Sheehan, Chuan-Fu Huang, Meei-Ling Sheu, Dar-Yu Yang, and Wen-Ta Chiu

Object

Gamma Knife surgery (GKS) is an important part of the neurosurgical armamentarium for treatment of patients with trigeminal neuralgia (TN) and is regarded as the first-line treatment in patients with TN who have serious medical comorbidities. In this study, the authors investigated the efficacy of GKS on TN in patients with serious medical comorbidities.

Methods

Between May 2004 and September 2007, 52 severely ill patients who also had TN with Barrow Neurological Institute (BNI) facial pain scores of IV or V were entered into this study. The patients' medical records and imaging findings were reviewed by an anesthesiologist and neurosurgeons to determine whether GKS was a reasonable approach to palliate the patient's pain. All patients underwent GKS, in which a maximum dose of 80 Gy was targeted to the trigeminal nerve with or without plugging to keep the dose received by the brainstem at less than 16 Gy. After treatment, every patient had clinical follow-up every 1–3 months and filled out questionnaires designed to assess BNI facial pain and numbness scores, visual analog scale scores, and 36-Item Short Form Health Survey (SF-36) scores every 3 months until the end of the study. Statistical analysis was performed to find favorable prognostic factors related to pain relief and changes in quality of life.

Results

The median age of the patients was 71 years, and the male/female ratio was 30:22. The median follow-up period was 54 months (at least 2 years). All patients had a positive initial response to GKS, with BNI facial pain scores at least 1 point less than respective pre-GKS scores. Three patients (5.7%) obtained BNI facial pain Score I. Twenty-three patients (44.2%) experienced pain recurrence at a median follow-up of 33 months. One patient suffered from angina and required time in an intensive care unit; another patient had bleeding from a pin wound that required suturing. Alterations in BNI scores were highly correlated to visual analog scale scores (R2 = 0.978). In both univariate and multivariate analyses, a decreased BNI facial pain score at different time points was significantly (p < 0.05) related to younger patient age, no previous treatment, evidence of vessel compression on MR imaging, time of first GKS ≤ 24 months, physical function (SF-36), role limitation due to a physical problem (SF-36), role limitation due to an emotional problem (SF-36), mental health (SF-36), social functioning (SF-36), bodily pain (SF-36), and general health (SF-36), but was not related to vitality (SF-36). Five patients (9.6%) experienced facial numbness at a mean of 13.2 ± 3.1 months after GKS (4 patients with BNI facial numbness Score II and 1 with BNI facial numbness Score III). Post-GKS MR imaging changes, including focal contrast enhancement or T2-weighted signal alterations, were identified in 3 patients (5.7%).

Conclusions

Gamma Knife surgery produced significant pain relief in severely ill patients who had TN without causing appreciable morbidity. The effect of reduced pain significantly paralleled an improvement in SF-36 quality-of-life indices.