Kyung Sub Moon

IDO Expression in Brain Tumors Increases the Recruitment of Regulatory T Cells and Negatively Impacts Survival

Purpose: Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4+FoxP3+GITR+ regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. Experimental Design: To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression, and long-term survival was determined. Results: Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Coincidently, both IDO-competent and deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared with IDO-competent brain tumors. Moreover, IDO deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO deficiency was lost in T-cell–deficient mice. Conclusions: These clinical and preclinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs that lead to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T-cell–mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and support the continued investigation of IDO–Treg interactions in the context of brain tumors. Clin Cancer Res; 18(22); 6110–21. ©2012 AACR.

The art of gene therapy for glioma: a review of the challenging road to the bedside

Glioblastoma multiforme (GBM) is a highly invasive brain tumour that is unvaryingly fatal in humans despite even aggressive therapeutic approaches such as surgical resection followed by chemotherapy and radiotherapy. Unconventional treatment options such as gene therapy provide an intriguing option for curbing glioma related deaths. To date, gene therapy has yielded encouraging results in preclinical animal models as well as promising safety profiles in phase I clinical trials, but has failed to demonstrate significant therapeutic efficacy in phase III clinical trials. The most widely studied antiglioma gene therapy strategies are suicide gene therapy, genetic immunotherapy and oncolytic virotherapy, and we have attributed the challenging transition of these modalities into the clinic to four major roadblocks: (1) anatomical features of the central nervous system, (2) the host immune system, (3) heterogeneity and invasiveness of GBM and (4) limitations in current GBM animal models. In this review, we discuss possible ways to jump these hurdles and develop new gene therapies that may be used alone or in synergy with other modalities to provide a powerful treatment option for patients with GBM.

Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma

Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-γ synthesis in CD8+ T cells (P<0.001), CD4+ T cells (P=0.009) and natural killer cells (P=0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P=0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P=0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P=0.041). Depletion of MDSCs with Gr1+ antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P=0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.

N-acetylcysteine amide augments the therapeutic effect of neural stem cell-based antiglioma oncolytic virotherapy

Current research has evaluated the intrinsic tumor-tropic properties of stem cell carriers for targeted anticancer therapy. Our laboratory has been extensively studying in the preclinical setting, the role of neural stem cells (NSCs) as delivery vehicles of CRAd-S-pk7, a gliomatropic oncolytic adenovirus (OV). However, the mediated toxicity of therapeutic payloads, such as oncolytic adenoviruses, toward cell carriers has significantly limited this targeted delivery approach. Following this rationale, in this study, we assessed the role of a novel antioxidant thiol, N-acetylcysteine amide (NACA), to prevent OV-mediated toxicity toward NSC carriers in an orthotropic glioma xenograft mouse model. Our results show that the combination of NACA and CRAd-S-pk7 not only increases the viability of these cell carriers by preventing reactive oxygen species (ROS)-induced apoptosis of NSCs, but also improves the production of viral progeny in HB1.F3.CD NSCs. In an intracranial xenograft mouse model, the combination treatment of NACA and NSCs loaded with CRAd-S-pk7 showed enhanced CRAd-S-pk7 production and distribution in malignant tissues, which improves the therapeutic efficacy of NSC-based targeted antiglioma oncolytic virotherapy. These data demonstrate that the combination of NACA and NSCs loaded with CRAd-S-pk7 may be a desirable strategy to improve the therapeutic efficacy of antiglioma oncolytic virotherapy.

Clinical utility of the inferior turbinate flaps in the reconstruction of the nasal septum and skull base.

Purpose The inferior turbinate flaps (ITFs) include the anterior pedicle inferior turbinate flap (APITF) and the posterior pedicle inferior turbinate flap (PPITF). The APITF has been used for the repair of the septal perforation, and the PPITF has been used for the reconstruction of the skull base. Because of the technical difficulties of endoscopic preparation of the ITF, clinical studies on endoscopic management with the ITFs have been sporadic. Methods We retrospectively reviewed 11 patients who underwent endoscopic reconstruction with the ITFs at our institutions from 2006 to 2010. The APITF had been used for the repair of the septal perforation and reconstruction of mucosal defect following excision of a septal tumor, and the PPITF had been used for the reconstruction of the skull base. Clinical data included characteristics of septal perforation and skull base defect, including defect size, types of the ITFs, repair techniques, and complications. Results Pathology included septal perforation (n = 4), pleomorphic adenoma (n = 2), ethmoid teratocarcinosarcoma (n = 1), and pituitary adenoma (n = 4). The 6 septal lesions were reconstructed with the APITF. The size of the septal mucosal defects ranged from 5 to 18 mm, and the success rate of APITF septal defect repair was 83.3% (5/6 patients). A patient with a tiny residual septal perforation was symptom-free. There was no full-thickness necrosis of the flap. Postoperatively, there was no excessive crusting or empty nose syndrome. The 5 skull base defects following endoscopic skull base surgery were repaired with the PPITF, where the nasoseptal flap was not available because of surgical loss of the nasal septum, operative injury to the posterior nasoseptal artery, or previous use of the nasoseptal flap. The sites of skull base reconstruction included the sellar floor (n = 3), clivus (n = 1), and posterior ethmoid (n = 1). Flap necrosis was noted in 2 patients who underwent surgery in the early period of this series, and the success rate of the PPITF was 60%. However, after acquisition of surgical skills, improved viability of the flap became evident. Conclusions Inferior turbinate flaps could be a feasible alternative in the repair of the nasal septum and skull base. Although endoscopic application of ITFs requires a considerable learning curve, increased familiarity with these flaps would improve flap survival and treatment outcome of reconstruction of the nasal septum and skull base.

Intra-Suprasellar Schwannoma Originating from the Diaphragma Sellae

A 49-year-old woman presented with headache, vomiting and visual disturbance. Neurological examination revealed bitemporal hemianopsia with poor visual acuity. Magnetic resonance imaging showed a bulky intra-suprasellar mass, which was isointense with brain parenchyma on T1-weighted images, and slightly hyperintense on T2-weighted images. After gadolinium administration, the mass was homogeneously enhanced. The mass was partially removed by the endonasal transsphenoidal approach and then the remnant mass was totally removed by the transcranial approach five months later. We found a yellowish mass which was attached to the diaphragm sellae in operation field. Histopathological examination of the tumor revealed the characteristic features of a schwannoma. We report an unusual case of an intra-suprasellar schwannoma resembling a non-functioning pituitary macroadenoma both clinically and radiologically.

Intractable Hiccup as the Presenting Symptom of Cavernous Hemangioma in the Medulla Oblongata: A Case Report and Literature Review

A case of intractable hiccup developed by cavernous hemangioma in the medulla oblongata is reported. There have been only five previously reported cases of medullary cavernoma that triggered intractable hiccup. The patient was a 28-year-old man who was presented with intractable hiccup for 15 days. It developed suddenly, then aggravated progressively and did not respond to any types of medication. On magnetic resonance images, a well-demarcated and non-enhancing mass with hemorrhagic changes was noted in the left medulla oblongata. Intraoperative findings showed that the lesion was fully embedded within the brain stem and pathology confirmed the diagnosis of cavernous hemangioma. The hiccup resolved completely after the operation. Based on the presumption that the medullary cavernoma may trigger intractable hiccup by displacing or compression the hiccup arc of the dorsolateral medulla, surgical excision can eliminate the symptoms, even in the case totally buried in brainstem.

Human U87 glioblastoma cells with stemness features display enhanced sensitivity to natural killer cell cytotoxicity through altered expression of NKG2D ligand

BackgroundGlioblastoma (GBM) is one of the most lethal tumors with a poor prognosis. Its inevitable recurrence is frequently explained by the presence of cancer stem cells. We aimed to show that human GBM cells with stemness features are more sensitive to natural killer (NK) cells than GBM cells without stemness characteristics.MethodsNatural killer cell cytotoxicity was measured using flow cytometry in neurosphere-forming U87 GBM cells cultured with neurobasal media (NBE condition) and compared with that in serum-cultured U87 GBM cells (serum condition). Cytotoxicity was examined after addition of blocking NKG2D monoclonal antibodies. The expression profile of NK ligands of NK cells were investigated by reverse transcription polymerase chain reaction and western blot analysis in the U87 GBM cells in both conditions.ResultsNBE U87 cells showed higher cytotoxicity to NK cells than serum U87 cells did (55 vs 35% at an effector to target cell ratio of 5:1). The increased cytotoxicity was diminished in NBE U87 cells by a larger gap than in serum U87 cells by adding NKG2D blocking antibodies. Of the NKG2D ligands, the expression of ULBP1 and ULBP3 was relatively increased in NBE U87 cells compared to serum U87 cells.ConclusionsU87 GBM cells with stemness features demonstrate increased cytotoxicity to NK cells in association with altered NKG2D ligand expression of NK cell activating receptor. Applying immune modulation to GBM treatment may be a promising adjuvant therapy in patients with intractable GBM.

Role of Craniofacial Resection for Malignant Tumors Involving the Anterior Skull Base: Surgical Experience in a Single Institution

Background Craniofacial resection (CFR) has been regarded as a standard treatment for various tumors involving the anterior skull base. The purpose of this study was to evaluate the results of CFR for the patients with anterior skull base malignancies in our hospital. Methods We retrospectively analyzed 17 patients with anterior skull base malignancies treated with CFR between 2001 and 2012. Mean follow-up duration was 41 months (range, 2-103 months). Results Intracranial involvement was found in 11 patients (65%) and orbital extension in 6 patients (35%). Classical bifrontal craniotomy was combined with endoscopic endonasal approach in 14 patients and external approach in 3 patients. Vascularized flap was used for reconstruction of the anterior fossa floor in 16 patients (94%). The most common pathological type was squamous cell carcinoma (6 patients). Gross total resection was achieved in all cases. Postoperative complications developed in 4 patients (24%) and included local wound problem and brain abscess. One patient with liver cirrhosis died from unexpected varix bleeding after the operation. Although postoperative treatment, such as radiotherapy or chemotherapy, was performed in 14 patients, local recurrence was seen in 6 patients. The mean overall survival time after the operation was 69.0 months (95% confidence interval: 47.5-90.5 months) with a 1-, 2-, and 5-year survival rate of 82.3%, 76.5%, and 64.7%, respectively. Postoperative radiotherapy was found to be the powerful prognostic factor for favorable survival. Conclusion Considering the higher local control rate and acceptable complication or mortality rate, CFR with adjuvant radiotherapy is a gold standard treatment option for malignant tumors involving anterior skull base, especially with extensive intracranial involvement.

Novel harvesting technique of the nasoseptal flap in large sphenoidotomy undergoing revision with transsphenoidal approach.

Objectives Blood supply to the nasoseptal flap (NSF) can be disrupted by large sphenoidotomies in an endonasal transsphenoidal approach (TSA). In such patients with recurrent sellar tumor, an NSF can be unavailable in the sellar reconstruction. Herein, we present a new harvesting method of the NSF in revision endonasal TSA, where injury to its vascular pedicle of the NSF by a large sphenoidotomy is highly suspected. Methods Data for patients with large sphenoidotomy who underwent revision endonasal TSA and NSF at Chonnam National University Hwasun Hospital were collected consecutively from January 2010 to July 2011. A retrospective review of these cases was performed. Results Seven patients with a previous large sphenoidotomy requiring revision TSA underwent a new modification technique of the NSF. Pathologies included 6 pituitary adenomas and 1 craniopharyngioma. All patients had intraoperative cerebrospinal fluid (CSF) leak, necessitating multilayered sellar reconstruction, including NSF. No patients had flap necrosis, and closure of CSF leak was possible in 6 of 7 patients. Delayed CSF leak in a patient was due to the migration of the flap over the defect, and no septal complications such as septal perforation and saddle nose were noted. Conclusions Our harvesting technique of the NSF in patients with recurrent sellar tumors is reliable for sellar reconstruction where the NSF may be unavailable because of previous large sphenoidotomy. This novel technique has an excellent success rate in flap viability and minimal additional endonasal morbidity.