Role of the superior turbinate when performing endoscopic endonasal transsphenoidal approach.

BACKGROUND: This study examined the relationship between the superior turbinate and natural ostium of the sphenoid sinus, as seen during the endoscopic endonasal transsphenoidal approach (EETSA) for sellar lesions and described how to enter the sphenoethmoid cell safely for complete exposure of the sellar floor, including adjacent vital structures such as the prominence of the optic nerve and carotid artery. MATERIALS AND METHODS: This study retrospectively reviewed the medical records and operative findings of 154 patients, who underwent EETSA between February 2009 and February 2011. We evaluated the location of the natural ostium of the sphenoid sinus relative to the superior turbinate and revealed the clinical significance of the superior turbinate as a surgical guide to enter into the sphenoethmoid cell during EETSA. RESULTS: The natural ostium of the sphenoid sinus was located medially to the posteroinferior end of the superior turbinate in 151 (98%) patients. In 1 patient, the natural ostia of the sphenoid sinus were located lateral to the superior turbinate bilaterally. Sphenoethmoid cell was encountered in 53 (34%) patients. We could easily enter the sphenoethmoid cell at the point where the superior turbinate was attached to the anterior wall of the sphenoid sinus. CONCLUSIONS: The superior turbinate is a good surgical landmark for identifying the natural ostium of the sphenoid sinus and as a guide for the surgical entrance to the sphenoethmoid cell extending to the sphenoid sinus during EETSA.

The effects of mesenchymal stem cells injected via different routes on modified IL-12-mediated antitumor activity.

Owing to its tumor tropism and prolonged transgene expression, mesenchymal stem cell (MSC) has been considered as an ideal delivery vehicle for cancer gene therapies or therapeutic vaccines. In this study, we demonstrated that intratumoral (i.t.) injection of MSCs expressing modified interleukin-12 (MSCs/IL-12M) exhibited stronger tumor-specific T-cell responses and antitumor effects as well as more sustained expressions of IL-12 and interferon (IFN)-γ in both sera and tumor sites than did IL-12M-expressing adenovirus (rAd/IL-12M) in mice bearing both solid and metastatic tumors. Subcutaneous (s.c.) injection of MSCs/IL-12M at contralateral site of tumor exhibited similar levels of serum IL-12 and IFN-γ as i.t. injection, but much weaker antitumor effects in both B16F10 melanoma and TC-1 cervical cancer models than i.t. injection. Although intravenous (i.v.) injection elicited earlier peak serum levels of cytokines, it induced weaker tumor-specific T-cell responses and antitumor effects than i.t. injection, indicating that serum cytokine levels are not surrogate indicators of antitumor effects. Taken together, these results indicated that MSC is more efficient than adenovirus as a cytokine gene delivery vehicle and that i.t. injection of MSCs/IL-12M is the best approach to induce strong tumor-specific T-cell responses that correlate with anti-metastatic effects as well as inhibition of solid tumor growth, although MSCs themselves have an ability to migrate into the tumor site. In addition, MSCs/IL-12M embedded in Matrigel (MSCs/IL-12M/Matrigel) exhibited significant antitumor effects even in immunodeficient mice such as SCID and BNX mice lacking T, B and natural killer (NK) cells, but not in IFN-γ knockout mice. Our findings provide an optimal approach for designing an efficient clinical protocol of MSC-based cytokine gene therapy to induce strong tumor-specific T-cell responses and therapeutic anticancer efficacy.

Branched oligomerization of cell-permeable peptides markedly enhances the transduction efficiency of adenovirus into mesenchymal stem cells.

Cell-permeable peptides (CPPs) promote the transduction of nonpermissive cells by recombinant adenovirus (rAd) to improve the therapeutic efficacy of rAd. In this study, branched oligomerization of CPPs significantly enhanced the transduction of human mesenchymal stem cells (MSCs) by rAd in a CPP type-independent manner. In particular, tetrameric CPPs increased transduction efficiency at 3000-5000-fold lower concentrations than did monomeric CPPs. Although branched oligomerization of CPPs also increases cytotoxicity, optimal concentrations of tetrameric CPPs required for maximum transduction are at least 300-1000-fold lower than those causing 50% cytotoxicity. Furthermore, although only approximately 60% of MSCs were maximally transduced at 500 muM of monomeric CPPs, >95% of MSCs were transduced with 0.1 muM of tetrameric CPPs. Tetrameric CPPs also significantly increased the formation and net surface charge of CPP/rAd complexes, as well as the binding of rAd to cell membranes at a greater degree than did monomeric CPPs, followed by rapid internalization into MSCs. In a critical-size calvarial defect model, the inclusion of tetrameric CPPs in ex vivo transduction of rAd expressing bone morphogenetic protein 2 into MSCs promoted highly mineralized bone formation. In addition, MSCs that were transduced with rAd expressing brain-derived neurotrophic factor in the presence of tetrameric CPPs improved functional recovery in a spinal cord injury model. These results demonstrated the potential for tetrameric CPPs to provide an innovative tool for MSC-based gene therapy and for in vitro gene delivery to MSCs.

Surgical management of clinoidal meningiomas.

OBJECTIVE: Surgical outcome has been less than desirable in the management of patients with clinoidal meningiomas in the past, and little attention has been directed at improving their visual function. The purpose of this article is to advocate an available cranial base technique for removing these difficult tumors and to delineate the technique's advantages that aid in achieving an improved extent of tumor resection and enhancing the patients' overall outcome, particularly their visual outcome. METHODS: A retrospective analysis was performed on 15 consecutive patients with clinoidal meningiomas (including a patient with hemangiopericytoma) who underwent surgical resection at the Cleveland Clinic Foundation between June 1995 and January 2000. A cranial base technique consisting of extradural anterior clinoidectomy, coupled with optic canal unroofing and optic sheath opening, was used in 13 patients, and standard pterional craniotomy was used in 2. Eight of 15 patients had significant visual deficits preoperatively. All patients had thorough preoperative and postoperative ophthalmological evaluations. The follow-up period ranged from 6 to 60 months (mean, 37.2 mo). RESULTS: Total resection was achieved in 13 (86.7%) of the 15 patients in this series, and the majority of the patients with preoperative visual impairment experienced significant improvement (6 of 8 patients; 75%). CONCLUSION: In the majority of patients with clinoidal meningiomas, total resection may be achieved with minimal complications. For large tumors encasing the optic nerve and internal carotid artery, or for those tumors causing preoperative visual impairment, use of the cranial base technique delineated in this study may lead to significant improvement in the patients' visual and overall outcomes.

Molecular alterations in the neurofibromatosis type 2 gene and its protein rarely occurring in meningothelial meningiomas.

OBJECT: The neurofibromatosis Type 2 (NF2) gene is the only tumor suppressor gene that has been clearly implicated in the development of benign meningiomas. Interestingly, previous data obtained by the authors indicate that reduced NF2 protein expression seldom occurs in meningothelial meningiomas, the most common histological type of meningioma. The goal of the current study was to explore further the hypothesis of NF2 gene-independent tumorigenesis of meningothelial meningiomas. METHODS: The authors performed a mutational analysis of all 17 exons of the NF2 gene by using single-stranded conformational polymorphism (SSCP). In addition, expression levels of the NF2 protein and mu-calpain, a protease suggested to inactivate the NF2 protein, were determined by immunoblotting analysis of 27 meningiomas (20 meningothelial and seven nonmeningothelial). Mutations of the NF2 gene were found in only one (5%) of 20 meningothelial meningiomas and three (43%) of seven nonmeningothelial tumors (Fisher's exact test, p = 0.042). The levels of NF2 protein were severely reduced in six (28.5%) of 21 meningothelial meningiomas, in contrast to six (86%) of seven nonmeningothelial meningiomas (Fisher's exact test, p = 0.023). Activation of IL-calpain did not correlate with the status of NF2 protein expression in the meningiomas analyzed, demonstrating that mu-calpain activation does not account for the loss of NF2 protein in meningiomas with apparently normal NF2 genes. CONCLUSIONS: These results clearly demonstrate that NF2 gene mutations and decreased NF2 protein expression rarely occur in meningothelial meningiomas compared with other histological types of meningiomas. The clinical behavior of meningothelial meningiomas, however, is similar to that of other benign meningiomas. It is likely, therefore, that the tumorigenesis of meningothelial meningiomas is the result of deleterious alterations of genes that have final phenotypical effects similar to inactivation of the NF2 gene.

Unusual proximal migration of ventriculoperitoneal shunt into the heart.

Quite a number of cases of upward shunt migration have already been reported in the literature. In this paper, the intracardiac migration of a peritoneal shunt tube of a ventriculoperitoneal shunt system is reported. This is a rare complication of ventriculoperitoneal shunting and was diagnosed by a plain radiograph of the chest and a direct open heart surgery. To the author's knowledge this is the first reported case of migration of a peritoneal shunt tube into the heart. The authors postulate possible mechanisms and a physioanatomical explanation on the basis of the surgical findings.

Shunt-independent surgical treatment of middle cranial fossa arachnoid cysts in children.

The best operative intervention for children with arachnoid cysts remains the subject of controversy. Recent reports stress that craniotomy for cyst fenestration is associated with a low incidence of morbidity and mortality and may leave the child shunt-independent. Among a total of 66 intracranial arachnoid cysts operated on in the authors' department from 1985 to 1997, 44 cases (67%) were located in the middle cranial fossa. A higher incidence in the first decade of life (53 cases) and a marked male predominance (45 cases) were recognized. Headache, cranial deformities, symptoms of raised intracranial pressure, and seizures constituted the most frequent features of the clinical presentation. To determine which treatment provides the greatest benefit with the lowest incidence of complications, the records of the 44 patients with arachnoid cysts in the middle cranial fossa were reviewed. The mean age of these patients was 4.6 years (range 0-16 years). Different types of initial surgical procedures were performed. In 33 patients with middle cranial fossa arachnoid cysts (MCFAC) the initial surgery took the form of craniotomy with excision of the cyst walls and fenestration into the basal cisterns. Shunting procedures were performed in 9 patients: cysto-peritoneal shunts (CPS) were placed in 4 patients and ventriculo-peritoneal shunts (VPS), in 3 patients, and cyst excision was performed in addition to CPS in 2 patients. Excision of the cyst membrane alone without fenestration was performed in 2 patients. The initial treatment was successful in terms of reduced symptoms and decreased cyst size, with no additional treatment needed for the cyst, in 79% (26/33) of patients who had undergone excision of the cyst walls and fenestration into the basal cisterns, compared with 66% (6/9) of patients who had undergone shunting procedures. Cyst membrane excision was not successful in any of the patients who underwent this procedure alone. No significant difference in morbidity was noted between these different treatment options. On follow-up CT scan and MRI, cysts of types I and II (Galassi classification) exhibited a steady tendency to reduction or obliteration. These results confirm that radical excision of the outer and inner membranes of the cyst wall with fenestration into the basal cistern is a safe and effective shunt-independent procedure for MCFAC, especially for those of types I and II.

Tumors of the orbit. Pitfalls of the surgical approach in 37 children with orbital tumor.

The authors review their experience with 37 children with orbital tumors, summarizing their surgical techniques, the indications applied, and the pitfalls of each surgical approach. Tumors located in the retro-ocular or intraorbital space were surgically excised through a transcranial approach (28 cases), while for tumors in other sites lateral orbitotomy (5 cases), medial orbitotomy (1 case) and biopsy (3 cases) were performed. A transcranial approach was used for tumors with intracranial extension and for those located in the orbital apex and deep medial orbital compartment. Lateral orbitotomy was used for tumors located in the superior, temporal or inferior compartment of the orbit and those in the lateral apex. A medial orbitotomy was used for tumors located medial to the optic nerve. Outcomes of the surgical intervention varied, depending on the pathology, location and extent of the individual tumors. To obtain optimal exposure and minimize functional deficits, the pitfalls of surgical approaches to orbital tumors are discussed.

Experience with pineal region tumors.

The results are reported of a retrospective review of the presentation and outcome of 43 pineal region tumors treated from 1982 to 1996, including 20 identified tumors: 5 germinomas, 8 teratomas, 2 embryonal carcinomas, 1 endodermal sinus tumor, 2 pineocytomas and 2 pineoblastomas. Of the 43 tumors reviewed, 36 were located in the pineal region, 5 in the suprasellar, and 2 in both the pineal and suprasellar regions. Twenty patients underwent surgical resection: total in 6 and partial in 10, while only a biopsy was taken in 4 cases. Fifteen patients were managed on the basis of serum CSF tumor markers and radiation response. Twenty-three patients with germinomas received radiotherapy (RT) and had a 5-year survival rate of 87%. Fifteen patients with non-germinomatous germ cell tumors received RT and chemotherapy following direct surgery, and 5 died (mortality rate of 33.3%). The overall survival rate of the 43 patients with pineal tumors was 79.1% (34/43) and the death rate was 20.9% (9/43). It is now recognized that the wide variety of tumor types found in the pineal region necessitates different modes of treatment, and improved microsurgical and stereotactic surgical techniques have made mortality and morbidity rates acceptably low. Because the radiation response and CSF cytology are not enough to determine optimum treatment, a tissue diagnosis should be obtained in all patients.

Potentials and limitations of adenovirus-p53 gene therapy for brain tumors.

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.