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Bowen Jiang, Harry Mushlin, Lei Zhang, Aaron W. James and Alan R. Cohen

Scalp and calvarial masses are common in children and the differential diagnosis is broad. The authors recently cared for a child with an unusual fibro-osseous lesion of the temporal bone that has previously not been described in the pediatric neurosurgery literature. A 10-year-old girl presented with a firm, slowly enlarging protuberant mass arising from the squamous suture of the temporal bone without intracranial extension. The mass was removed en bloc through a temporal craniectomy and cranioplasty was performed. The patient had a smooth postoperative course. Histological examination showed multiple oval osseous islands dispersed throughout a bland fibrous stroma. The pathological diagnosis was “Bullough’s bump,” a rare, benign fibro-osseous neoplasm first described in 1999, and only 8 reported cases appear in the literature. Here the authors report the first case of Bullough’s bump in a child.

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Harry Mushlin, Daina M. Brooks, Joshua Olexa, Bryan J. Ferrick, Stephen Carbine, Gerald M. Hayward II, Brandon S. Bucklen and Charles A. Sansur

OBJECTIVE

The sacroiliac joint (SIJ) is a known source of low-back pain. Randomized clinical trials support sacroiliac fusion over conservative management for SIJ dysfunction. Clinical studies suggest that SIJ degeneration occurs in the setting of lumbosacral fusions. However, there are few biomechanical studies to provide a good understanding of the effect of lumbosacral fusion on the SIJ. In the present study, researchers performed a biomechanical investigation to discern the effect of pelvic versus SIJ fixation on the SIJ in lumbosacral fusion.

METHODS

Seven fresh-frozen human cadaveric specimens were used. There was one intact specimen and six operative constructs: 1) posterior pedicle screws and rods from T10 to S1 (PS); 2) PS + bilateral iliac screw fixation (BIS); 3) PS + unilateral iliac screw fixation (UIS); 4) PS + UIS + 3 contralateral unilateral SIJ screws (UIS + 3SIJ); 5) PS + 3 unilateral SIJ screws (3SIJ); and 6) PS + 6 bilateral SIJ screws (6SIJ). A custom-built 6 degrees-of-freedom apparatus was used to simulate three bending modes: flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Range of motion (ROM) was recorded at L5–S1 and the SIJ.

RESULTS

All six operative constructs had significantly reduced ROM at L5–S1 in all three bending modes compared to that of the intact specimen (p < 0.05). In the FE mode, the BIS construct had a significant reduction in L5–S1 ROM as compared to the other five constructs (p < 0.05). SIJ ROM was greatest in the FE mode compared to LB and AR. Although the FE mode did not show any statistically significant differences in SIJ ROM across the constructs, there were appreciable differences. The PS construct had the highest SIJ ROM. The BIS construct reduced bilateral SIJ ROM by 44% in comparison to the PS construct. The BIS and 6SIJ constructs showed reductions in SIJ ROM nearly equal to those of the PS construct. UIS and 3SIJ showed an appreciable reduction in unfused SIJ ROM compared to PS.

CONCLUSIONS

This investigation demonstrated the effects of various fusion constructs using pelvic and sacroiliac fixation in lumbosacral fusion. This study adds biomechanical evidence of adjacent segment stress in the SIJ in fusion constructs extending to S1. Unilateral pelvic fixation, or SIJ fusion, led to an appreciable but nonsignificant reduction in the ROM of the unfused contralateral SIJ. Bilateral pelvic fixation showed the greatest significant reduction of movement at L5–S1 and was equivalent to bilateral sacroiliac fusion in reducing SIJ motion.

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Jie Lu, Zhengping Zhuang, Debbie K. Song, Gautam U. Mehta, Barbara Ikejiri, Harry Mushlin, Deric M. Park and Russell R. Lonser

Object

Nuclear receptor corepressor (N-CoR) forms a complex that maintains neural stem cells in an undifferentiated state through transcriptional repression. Recently, it has been shown that N-CoR is overexpressed in glioblastoma multiforme (GBM) tumor stem cells and has a putative role in maintaining these cells in an undifferentiated immortal state. To determine the effects of disruption of N-CoR complex function by serine/threonine protein phosphatase 2A (PP2A) inhibition on GBM tumor cell differentiation and proliferation, the authors developed and investigated a competitive small molecule inhibitor (LB1) of PP2A in GBM.

Methods

The authors investigated the effects of LB1 on GBM proliferation and molecular differentiation pathways using in vitro and in vivo studies.

Results

The LB1 inhibited PP2A, leading to increased levels of phosphorylated Akt kinase and decreased NCoR expression, as well as dose-dependent antiproliferative activity in cultured U87 and U251 malignant glioma cells (dose range 1–10 μM). Systemic LB1 treatment (1.5 mg/kg/day for 21 days) had significant tumor antiproliferative effects in mice harboring U87 glioma xenografts (73% mean reduction in tumor volume compared with controls; p < 0.001). Moreover, a reduction in PP2A expression and activity after LB1 treatment in vivo correlated with increased Akt phosphorylation, reduced nuclear N-CoR expression and N-CoR cytoplasmic translocation, and increased accumulation of acetylated core histones, which coincided with the appearance of glial fibrillary acidic protein–expressing tumor cells.

Conclusions

These findings indicate that PP2A inhibition effectively disrupts N-CoR complex function/expression and leads to cytoplasmic translocation of N-CoR with subsequent tumor cell differentiation and/or death. Therapeutic paradigms that target N-CoR function in the cancer stem cell component of malignant gliomas may have treatment utility.

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Jie Lu, Alexander Ksendzovsky, Chunzhang Yang, Gautam U. Mehta, Raymund L. Yong, Robert J. Weil, Deric M. Park, Harry M. Mushlin, Xueping Fang, Brian M. Balgley, Dae-Hee Lee, Cheng S. Lee, Russell R. Lonser and Zhengping Zhuang

Object

Tumor-initiating cells are uniquely resilient to current treatment modalities and play an important role in tumor resistance and recurrence. The lack of specific tumor-initiating cell markers to identify and target these cells presents a major obstacle to effective directed therapy.

Methods

To identify tumor-initiating cell markers in primary brain tumors, the authors compared the proteomes of glioma tumor-initiating cells to their differentiated progeny using a novel, nongel/shotgun-based, multidimensional liquid-chromatography protein separation technique. An in vivo xenograft model was used to demonstrate the tumorigenic and stem cell properties of these cells. Western blot and immunofluorescence analyses were used to confirm findings of upregulated ciliary neurotrophic factor receptor subunit–α (CNTFRα) in undifferentiated tumor-initiating cells and gliomas of increasing tumor grade. Sequencing of the CNTFRα coding regions was performed for mutation analysis. Finally, antibody-dependent cell-mediated cytotoxicity was used to establish the role of CNTFRα as a potential immunotherapeutic target.

Results

Ciliary neurotrophic factor receptor subunit–α expression was increased in tumor-initiating cells and was decreased in the cells' differentiated progeny, and expression levels increased with glioma grade. Mutations of CNTFRα are not common in gliomas. Functional studies using CNTF treatment in glioma tumor-initiating cells showed induction of differentiation through the CNTFRα pathway. Treatment with anti-CNTFRα antibody resulted in increased antibody-dependent cell-mediated cytotoxicity in CNTFRα expressing DAOY cells but not in cell lines that lack CNTFRα.

Conclusions

These data indicate that CNTFRα plays a role in the formation or maintenance of tumor-initiating cells in gliomas, is a marker that correlates with histological grade, may underlie treatment resistance in some cases, and is a potential therapeutic target.