OBJECTIVE: Tumors involving Meckel’s cave remain extremely challenging because of the surrounding complex neurovascular structures and deep-seated location. The authors investigated a new minimal-access technique using the endoscopic transorbital approach (eTOA) through the superior eyelid crease to Meckel’s cave and middle cranial fossa lesions and reviewed the most useful surgical procedures and pitfalls of this approach.METHODS: Between September 2016 and January 2018, the authors performed eTOA in 9 patients with tumors involving Meckel’s cave and the middle cranial fossa. The lesions included trigeminal schwannoma in 4 patients, meningioma in 2 patients, metastatic brain tumor in 1 patient, chondrosarcoma in 1 patient, and dermoid cyst in 1 patient. In 7 of the 9 patients, eTOA alone was performed, while the other 2 patients underwent a combined eTOA and endoscopic endonasal approach or retrosigmoid craniotomy. Data including details of surgical techniques and clinical outcomes were recorded.RESULTS: Gross-total resection was performed in 7 of the 9 patients (77.8%). Four patients underwent extended eTOA (with lateral orbital rim osteotomy). Drilling of the trapezoid sphenoid floor, a middle fossa “peeling” technique, and full visualization of Meckel’s cave were applied to approach the lesions. Tumors were exposed and removed extradurally in 3 patients and intradurally in 6 patients. There was no postoperative CSF leak.CONCLUSIONS: The eTOA affords a direct route to access Meckel’s cave and middle cranial fossa lesions. With experience, this novel approach can be successfully applied to selected skull base lesions. To achieve successful removal of the tumor, emphasis should be placed on the importance of adequately removing the greater sphenoid wing and vertical crest. However, because of limited working space eTOA may not be an ideal approach for posterior fossa lesions.

Treatment of glioblastoma (GBM) remains a challenge using conventional chemotherapy, such as temozolomide (TMZ), and is often ineffective as a result of drug resistance. We have assessed a novel nitrone-based agent, OKN-007, and found it to be effective in decreasing tumor volumes and increasing survival in orthotopic GBM xenografts by decreasing cell proliferation and angiogenesis and increasing apoptosis. In this study, we assessed combining OKN-007 with TMZ in vivo in a human G55 GBM orthotopic xenograft model and in vitro in TMZ-resistant and TMZ-sensitive human GBM cell lines. For the in vivo studies, magnetic resonance imaging was used to assess tumor growth and vascular alterations. Percent animal survival was also determined. For the in vitro studies, cell growth, IC50 values, RNA-seq, RT-PCR, and ELISA were used to assess growth inhibition, possible mechanism-of actions (MOAs) associated with combined OKN-007 + TMZ versus TMZ alone, and gene and protein expression levels, respectively. Microarray analysis of OKN-007-treated rat F98 glioma tumors was also carried out to determine possible MOAs of OKN-007 in glioma-bearing animals either treated or not treated with OKN-007. OKN-007 seems to elicit its effect on GBM tumors via inhibition of tumorigenic TGF-β1, which affects the extracellular matrix. When combined with TMZ, OKN-007 significantly increases percent survival, decreases tumor volumes, and normalizes tumor blood vasculature in vivo compared to untreated tumors and seems to affect TMZ-resistant GBM cells possibly via IDO-1, SUMO2, and PFN1 in vitro. Combined OKN-007 + TMZ may be a potentially potent treatment strategy for GBM patients.

Glioblastoma multiforme (GBM) is clinically highly aggressive as a result of evolutionary dynamics induced by cross-talk between cancer cells and a heterogeneous group of immune cells in tumor microenvironment. The brain harbors limited numbers of immune cells with few lymphocytes and macrophages; thus, innate-like lymphocytes, such as γδ T cells, have important roles in antitumor immunity. Here, we characterized GBM-infiltrating γδ T cells, which may have roles in regulating the GBM tumor microenvironment and cancer cell gene expression. V(D)J repertoires of tumor-infiltrating and blood-circulating γδ T cells from four patients were analyzed by next-generation sequencing-based T-cell receptor (TCR) sequencing in addition to mutation and immune profiles in four GBM cases. In all tumor tissues, abundant innate and effector/memory lymphocytes were detected, accompanied by large numbers of tumor-associated macrophages and closely located tumor-infiltrating γδ T cells, which appear to have anti-tumor activity. The immune-related gene expression analysis using the TCGA database showed that the signature gene expression extent of γδ T cells were more associated with those of cytotoxic T and Th1 cells and M1 macrophages than those of Th2 cells and M2 macrophages. Although the most abundant γδ T cells were Vγ9Vδ2 T cells in both tumor tissues and blood, the repertoire of intratumoral Vγ9Vδ2 T cells was distinct from that of peripheral blood Vγ9Vδ2 T cells and was dominated by Vγ9Jγ2 sequences, not by canonical Vγ9JγP sequences that are mostly commonly found in blood γδ T cells. Collectively, unique GBM-specific TCR clonotypes were identified by comparing TCR repertoires of peripheral blood and intra-tumoral γδ T cells. These findings will be helpful for the elucidation of tumor-specific antigens and development of anticancer immunotherapies using tumor-infiltrating γδ T cells.