Quality of Life and Clinical Features of Long-Term Survivors Surgically Treated for Pediatric Craniopharyngioma.

OBJECTIVE: Several studies have reported treatment methods and results for pediatric craniopharyngiomas; however, few have evaluated patients' quality of life (QOL) after long-term follow-up. To evaluate treatment options, we assessed the QOL of patients with pediatric craniopharyngioma approximately 19 years after surgery and analyzed factors affecting QOL. METHODS: Twenty-six survivors who underwent resection of craniopharyngiomas at <15 years of age enrolled in this study and their physical condition was assessed. QOL was assessed by a short-form health survey (SF-36 version 2) for patients older than 19 years of age or by Child Health Questionnaire Parent Form-50 for patients 18 years of age and younger. Patients were divided into good and fair QOL groups according to their physical and mental summary scores. Factors affecting the QOL of both groups were evaluated. RESULTS: Median follow-up time was 19.1 years (range, 2.8-44.1 years). Twenty-two (84.6%) patients were employed or in school; 14 (53.8%) had visual deficits. Panhypopituitarism was diagnosed in 22 of 26 (84.6%) subjects. SF-36 analysis indicated that patients had significantly lower scores for general and mental health. Visual deficits, obesity, and complications during follow-up significantly affected the fair QOL group long-term. Patients' basic characteristics, initial resection rates, times of operation or irradiation did not significantly affect long-term QOL. CONCLUSION: Long-term survivors lived independently but had a lower overall QOL. Not only monitor short-term results based on estimation of the initial resection or recurrence rate, it is important to preserve visual and hypothalamic function and monitor arising complications for extended periods to improve patients' long-term QOL.

13C MR imaging of methionine-rich gliomas at 4.7T: a pilot study.

We explored the feasibility of using carbon-13 ((13)C) magnetic resonance imaging ((13)C-MRI) to depict (13)C-labeled methionine-enriched gliomas at 4.7 tesla. We transplanted 2 types of glioma cells separately to 2 subcutaneous tissue sites on the backs of mice weighing 15 to 20 g. After confirming tumor growth, we used (13)C-MRI and (1)H-MRI to scan 4 mice that had been administered (13)C-labeled methionine and 2 control mice. (13)C-MRI of all 4 transplanted mice administered with (13)C-labeled methionine revealed 2 areas of hyperintensity that corresponded to the tumor sites on (1)H-MR images, but no such areas were visualized in transplanted controls. Our data suggest that (13)C-MRI can show the accumulation of (13)C-labeled tracer by gliomas.

Inhibition of eIF4E phosphorylation reduces cell growth and proliferation in primary central nervous system lymphoma cells.

The mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E) plays an important role in mRNA translation; its activity is implicated in cell growth and proliferation. In experimental models, eIF4E over-expression induces cellular transformation, tumorigenesis, and lymphomagenesis. The activity of eIF4E is regulated by the Akt/mTOR and MAPK/MAP kinase-interacting kinase-1 (MNK1) pathways. While investigating the participation of the MNK1/eIF4E signaling pathway in primary central nervous system lymphoma (PCNSL), we noted the over-expression of eIF4E and phosphorylated eIF4E (p-eIF4E) in specimens from PCNSL patients. Western blot analysis using B-cell lymphoma cell lines showed that eIF4E phosphorylation was serum-independent and was selectively inhibited by the MNK1 inhibitor. Furthermore, MNK1 inhibitor led to reduced cyclin D1 expression and caused inhibition of cell proliferation and cell death in human brain malignant lymphoma cell line (HKBML). Also, the growth of the subcutaneous HKBML xenografts in mice was inhibited by intraperitoneal administration of MNK1 inhibitor compared with mice treated with vehicle (P = 0.026). Our data suggest that in PCNSL cells eIF4E phosphorylation plays an important role in proliferation and our results identify inhibition of the MNK1/eIF4E pathway as a potential therapeutic target in patients with PCNSL.

Aberrant expression of serum amyloid A in head and neck squamous cell carcinoma.

Serum amyloid A (SAA) is an acute-phase reactant, the blood level of which is often elevated in response to some types of neoplasia. Here, we investigated expression of the gene SAA1 and the protein SAA in head and neck squamous cell carcinoma (HNSCC) and normal oral mucosal tissues as well as blood SAA levels in HNSCC patients. Also, we investigated the effects of inhibiting signal transducer and activator of transcription 3 (STAT3) signaling on SAA1 expression in the HNSCC cell line SAS. Serum SAA levels in HNSCC patients were significantly higher than those in healthy volunteers. In addition, real-time quantitative reverse transcription-polymerase chain reaction analysis revealed a significantly higher SAA1 expression level in HNSCC than in normal mucosa (P < 0.0001). Furthermore, Western blot and immunohistochemical analyzes revealed that high expression of SAA in carcinomas was detected predominantly in tumor cells, but not in normal mucosal tissues. An inhibitor of STAT3 activation, AG490, significantly reduced SAA1 expression in SAS cells. These data demonstrated that SAA was up-regulated in HNSCC through the Janus kinase-STAT3 pathway.

Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma.

PURPOSE: The biological effect of interleukin-6 (IL-6) signaling in oral squamous cell carcinoma (OSCC) and whether IL-6 receptor (IL-6R)-mediated signaling can be a therapeutic target for OSCC are unclear. The aim of this study was to investigate the effects of inhibition of IL-6R-mediated signaling on OSCC progression and to evaluate the availability of tocilizumab, a humanized antihuman IL-6R antibody, as a therapeutic agent for OSCC. EXPERIMENTAL DESIGN: We evaluated expression levels of IL-6 and IL-6R in 58 OSCC tissues and 4 OSCC cell lines by real-time quantitative reverse transcription-PCR and/or immunohistochemstry. We investigated the effects of tocilizumab on OSCC growth in vitro and in xenografts. Xenografts were analyzed by immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), Ki-67, and CD31, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was done. RESULTS: Expression levels of IL-6 at both mRNA and protein levels in OSCC tissues were significantly higher than those in normal mucosal tissues. In addition, OSCC cell lines expressed higher levels of both IL-6 and IL-6R mRNA than did HaCaT keratinocytes. Tocilizumab significantly reduced in vivo growth of SAS cells with a drastic reduction of STAT3 phosphorylation in tumor cells in mice. Inhibition of IL-6 signaling significantly decreased vascular endothelial growth factor mRNA expression in SAS, and microvessel density and vessel diameter in SAS tumors in tocilizumab-treated mice. CONCLUSIONS: Therapeutic approaches targeting IL-6R by tocilizumab may be effective for OSCC treatment by at least inhibiting angiogenesis.

Antitumor effect of humanized anti-interleukin-6 receptor antibody (tocilizumab) on glioma cell proliferation. Laboratory investigation.

OBJECT: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates diverse physiological functions, including cell proliferation and survival. Recent studies have shown that IL-6 expression is often elevated in response to several types of glioma. Although IL-6 is said to play an important role in glioma, the involvement of IL-6 signaling has been quite controversial. The aim of this study was to evaluate the involvement of IL-6 signaling in glioma and the inhibitory effect of IL-6 signaling on glioma tumor proliferation. METHODS: The expression of IL-6 receptors (IL-6Rs) was evaluated in glioma tissues by means of immunohistochemical analysis, and the involvement of IL-6 signaling in glioblastoma multiforme (GBM) U87MG cell proliferation was also determined. In addition, to examine the inhibitory effect of IL-6 signaling on glioma cell proliferation, the authors investigated the effects of tocilizumab, the humanized anti-human IL-6R antibody in U87MG cells. RESULTS: Increased immunoreactivity for IL-6R was predominantly found in the cytoplasm of endothelial cells in all GBM samples. Inhibition of IL-6 signaling by both IL-6- and IL-6R-specific small interfering RNA and AG490, a specific inhibitor of JAK2 phosphorylation, suppressed glioma cell proliferation. Furthermore, tocilizumab, a clinically developed humanized anti-human IL-6R antibody, exerted an antiproliferative effect on cells from the GBM cell line U87MG via the IL-6R-dependent JAK-STAT3 pathway. CONCLUSIONS: The IL-6 signaling pathway plays an important role in glioma cell proliferation, and tocilizumab exerts an antitumor effect in U87MG glioma cells. These results may bring new insight into the molecular pathogenesis of glioma and may lead to a new therapeutic intervention.

Endoscopic endonasal transsphenoidal approach through the bilateral nostrils for pituitary adenomas.

The endoscopic endonasal transsphenoidal approach through the bilateral nostrils was evaluated for the treatment of pituitary adenoma. The surgical approach is through the bilateral nostrils via minimal or wide dissection of the septal mucosa, depending on the degree of tumor extension. After anterior sphenoidotomy, the endoscope is fixed in one nostril and required instrumentation is inserted in either nostril. In addition, neuronavigation and real-time hormone monitoring are used. Tumor removal rate, endocrinological outcomes, and complications were retrospectively assessed in 194 patients with pituitary adenomas who underwent 213 procedures between December 2001 and March 2008. Greater than 95% resection was achieved in 74 of 131 nonfunctioning adenomas, and the removal rate was significantly higher during 2005-2008 compared to 2002-2004 (p < 0.05). Endocrinological remission was achieved in 20 of 26 growth hormone-secreting tumors of Knosp grades 0-2, 16 of 17 microprolactinomas, and 6 of 9 cases of pure Cushing's disease. Postoperative complications were cerebrospinal fluid leakage in 9 cases, visual worsening in 5, anterior pituitary insufficiency in 5, and permanent diabetes insipidus in 2. The bilateral endonasal approach provides a wide working area without the need for special instrumentation. By modifying mucosal dissection, the endoscopic approach provides flexibility and less invasiveness. The use of neuronavigation or intraoperative hormone monitoring leads to improved surgical results. The present study confirms that this approach is suitable for more extensive sellar tumors.

Complete response to temozolomide treatment in an elderly patient with recurrent primary central nervous system lymphoma--case report.

An 80-year-old woman presented with primary central nervous system (CNS) lymphoma manifesting as progressive disorientation and loss of activity. She received three cycles of high-dose methotrexate. The tumor shrank after two cycles and her mental status improved, but she suffered tumor recurrence. The second-line treatment consisted of four cycles of rituximab but the tumor enlarged. She was then treated with three cycles of temozolomide. Magnetic resonance imaging revealed no evidence of disease. Her mental status and performance status improved, and she suffered no toxicity. She is able to pursue her daily life without recurrence after 16 cycles of temozolomide. Temozolomide may be effective against relapsed primary CNS lymphoma without causing neurotoxicity in the elderly.

Sellar repair with resorbable polyglactin acid sheet and fibrin glue in endoscopic endonasal transsphenoidal surgery.

BACKGROUND: Cerebrospinal fluid leakage after transsphenoidal surgery represents a serious problem. Various methods to prevent postoperative CSF leakage are available, but immediate and tight dural closure is still difficult. The efficacy of a novel sellar repair was described. METHODS: The sellar repair using absorbable PGA sheet and fibrin glue was applied to 18 consecutive patients with sellar tumors that include 13 pituitary adenomas, 2 craniopharyngiomas, 2 Rathke's cleft cysts, and 1 meningioma within 135 patients who were treated with endoscopic endonasal transsphenoidal approach. The reaction speed and strength between PGA sheets and fibrin glue were examined in vitro. RESULTS: Polyglactin acid sheets were adhered to the rabbit skin with fibrin glue within 3 minutes and withstood a pressure of more than 220 mm Hg. Postoperative CSF leakage of the patients was not observed in any patients, and excellent adhesion of the PGA sheets to surrounding mucosa was estimated by endoscopic observation after the surgery. CONCLUSIONS: Repair of the sellar floor with PGA sheet and fibrin glue is a safe and effective method to prevent postoperative CSF leakage, which decreases the necessity for lumbar drainage after the operation.

Treatment of unruptured duplicated middle cerebral artery aneurysm: case report.

BACKGROUND: Duplication of the middle cerebral artery (DMCA) is an anomalous vessel arising from the internal carotid artery (ICA). The origin of the DMCA lies between the anterior choroidal artery and the distal end of the ICA. The association of cerebral aneurysm and DMCA is rare. CASE DESCRIPTION: In this 63-year-old woman, preoperative angiography and 3-dimensional computed tomography angiography revealed an aneurysm at the origin of the DMCA. The aneurysm was clipped and superficial temporal artery-DMCA anastomosis was performed. She was discharged with no neurologic deficits. Duplication of the middle cerebral artery can be divided into 2 types based on whether the site of separation from the ICA is at the top of the ICA (type A) or between the ICA top and the anterior choroidal artery (type B). The diameter of type A DMCA is comparable with that of the main middle cerebral artery trunk; in type B, it is smaller. In all 18 previously reported cases, the aneurysm was associated with type B DMCA. CONCLUSION: For appropriate treatment planning, it is necessary to determine the DMCA type and the anatomic relationship between the aneurysm and the DMCA. In patients with type B DMCA, the possibility of aneurysm formation should be considered.

Complete suppression of paroxysmal nonkinesigenic dyskinesia by globus pallidus internus pallidal stimulation.

Stereotactic functional surgery is being explored as potential therapies for medically intractable paroxysmal dyskinesias (PxD). We report on a 59-year-old man in whom stimulation of globus pallidus internus produced immediate and sustained relief of paroxysmal non-kinesigenic dyskinesia secondary to a rotator cuff tears on the left shoulder. Our finding strongly suggests that altered function of neuronal circuits of the basal ganglia underlies the manifestation of PxD.