Yong-Kil Hong

A New Hope in Immunotherapy for Malignant Gliomas: Adoptive T Cell Transfer Therapy

Immunotherapy emerged as a promising therapeutic approach to highly incurable malignant gliomas due to tumor-specific cytotoxicity, minimal side effect, and a durable antitumor effect by memory T cells. But, antitumor activities of endogenously activated T cells induced by immunotherapy such as vaccination are not sufficient to control tumors because tumor-specific antigens may be self-antigens and tumors have immune evasion mechanisms to avoid immune surveillance system of host. Although recent clinical results from vaccine strategy for malignant gliomas are encouraging, these trials have some limitations, particularly their failure to expand tumor antigen-specific T cells reproducibly and effectively. An alternative strategy to overcome these limitations is adoptive T cell transfer therapy, in which tumor-specific T cells are expanded ex vivo rapidly and then transferred to patients. Moreover, enhanced biologic functions of T cells generated by genetic engineering and modified immunosuppressive microenvironment of host by homeostatic T cell expansion and/or elimination of immunosuppressive cells and molecules can induce more potent antitumor T cell responses and make this strategy hold promise in promoting a patient response for malignant glioma treatment. Here we will review the past and current progresses and discuss a new hope in adoptive T cell therapy for malignant gliomas.

PD-L1 Expression and Combined Status of PD-L1/PD-1–Positive Tumor Infiltrating Mononuclear Cell Density Predict Prognosis in Glioblastoma Patients

Background Programmed death ligand 1 (PD-L1) in tumor cells is known to promote immune escape of cancer by interacting with programmed cell death 1 (PD-1) in tumor infiltrating immune cells. Immunotherapy targeting these molecules is emerging as a new strategy for the treatment of glioblastoma (GBM). Understanding the relationship between the PD-L1/PD-1 axis and prognosis in GBM patients may be helpful to predict the effects of immunotherapy. Methods PD-L1 expression and PD-1–positive tumor infiltrating mononuclear cell (PD-1+tumor infiltrating mononuclear cell [TIMC]) density were evaluated using tissue microarray containing 54 GBM cases by immunohistochemical analysis; the associations with patient clinical outcomes were evaluated. Results PD-L1 expression and high PD-1+TIMC density were observed in 31.5% and 50% of GBM cases, respectively. High expression of PD-L1 in tumor cells was an independent and significant predictive factor for worse overall survival (OS; hazard ratio, 4.958; p = .007) but was not a significant factor in disease-free survival (DFS). PD-1+TIMC density was not correlated with OS or DFS. When patients were classified based on PD-1 expression and PD-1+TIMC density, patients with PD-L1+/PD-1+TIMC low status had the shortest OS (13 months, p = .009) and DFS (7 months, p = .053). Conclusions PD-L1 expression in GBM was an independent prognostic factor for poor OS. In addition, combined status of PD-L1 expression and PD-1+TIMC density also predicted patient outcomes, suggesting that the therapeutic role of the PD-1/PD-L1 axis should be considered in the context of GBM immunity.

Differentially expressed gene products in glioblastoma cells suppressed for tumorigenicity.

The loss of large segments or an entire copy of chromosome 10 is the most common genetic alteration in human glioblastomas. To address the biological and molecular consequences of this chromosomal alteration, we transferred a human chromosome 10 into a glioma cell clone devoid of an intact copy. The hybrid cells exhibited an altered cellular morphology, a decreased saturation density, and a suppression of both anchorage-independent growth and tumor formation in nude mice. The hybrids also expressed the recently identified candidate tumor suppressor gene MMAC1/PTEN. To further identify gene products that may be involved in glioma progression, a subtractive hybridization was performed between the human glioblastoma cells and the phenotypically suppressed hybrid cells to identify differentially expressed gene products. Sixty-one clones were identified, with nine clones being preferentially expressed in the hybrid cells. Four cDNA clones represented markers of differentiation in glial cells. Two cDNA clones shared homology with platelet derived growth factor-alpha and the insulin receptor, respectively, both genes previously implicated in glioma progression. A novel gene product that was expressed predominantly in the brain, but which did not map to chromosome 10, was also identified. This clone contained an element that was also present in three additional clones, two of which also exhibited differential expression. Consequently, the presence of a functional copy of chromosome 10 in the glioma cells results in differential expression of a number of gene products, including novel genes as well as those associated with glial cell differentiation.

Endoscopic Endonasal Transsphenoidal Approach From the Surgeon Point of View

Objective: In February 2009, the authors’ center formed a team of neurosurgeons, otolaryngologists, endocrinologists, and radiologists to perform pituitary surgery using the endoscopic endonasal transsphenoidal approach (EETSA). This paper reviews the authors’ experience with the technique, pathological outcomes, hormone profiles, and postoperative complications. Methods: Between February 2009 and December 2015, 535 patients underwent the EETSA with 2-nostrils/4-hands surgery. All of the patients had preoperative neurophthalmological and endocrinological assessments and neuroimaging. Patients were followed for at least 6 months with otolaryngological evaluations. Results: The most common pathology treated was pituitary adenomas, with 390 (72.9%) patients. Of these, 287 (73.6%) were nonfunctioning adenomas. As the surgical method, the conventional 2-nostrils/4-hands technique was performed in 77 patients (14.4%), a right conventional nasoseptal flap and left modified nasoseptal rescue flap technique was used in 135 patients (25.2%), and bilateral modified nasoseptal rescue flaps were used in 323 patients (60.4%). Postoperative complications occurred in 46 patients (8.6%). The most common complications were vascular injury or hematoma (10 patients, 1.9%), and the most common postoperative sinonasal complaints were hyposmia or anosmia. Olfactory function was significantly decreased according to the Connecticut Chemosensory Clinical Research Center test (P <0.001) and Cross-Cultural Smell Identification Test scores (P <0.001) evaluated 6 months postoperatively. Conclusions: Skull-base tumor surgery via an EETSA with a team approach was performed for various extended tumors. It is important to consider postoperative sinonasal dysfunction, such as hyposmia or anosmia, and to have this followed by an otolaryngologist.

Invagination of the Sphenoid Sinus Mucosa after Endoscopic Endonasal Transsphenoidal Approach and Its Significance

Objective To describe the clinical features of invagination of the sphenoid sinus mucosa (ISM) and compare them with other similar cases using a visual analog scale (VAS) to assess the various nasal symptoms and to discuss its clinical significance and means of prevention. Study Design Retrospective chart review at a tertiary referral center. Methods Between 2010 and 2015, 8 patients who had undergone EETSA surgery displayed postoperative ISM. The comparison group consisted of 147 patients who underwent the same surgical procedures and were diagnosed with the same diseases. Pre- or postoperative paranasal sinus computed tomography (PNS CT) and VAS were performed and subsequently analyzed. Results The clinical features of ISM of the sphenoid sinus showed sellar floor invagination and regenerated inverted ingrowing sphenoid mucosa on endoscopic imaging. PNS CT also showed a bony defect and invaginated air densities at the sellar turcica. Pre- and postoperative VAS scores revealed that the ISM group had much less of an improvement in headaches after surgery than that of the comparison group (p = 0.049). Conclusion ISM may occur because of a change in pressure, sphenoid mucosal status, or arachnoid membrane status. Moreover, ISM is related to improvements in headaches. Therefore, EETSA patients should avoid activities that cause rapid pressure changes during the healing process. In addition, sellar reconstruction that is resistant to physical pressure changes should be mandated despite the absence of an intraoperative CSF leak.

How to Expose the Entire Sella Floor With Minimal Manipulation During an Endoscopic Endonasal Transsphenoidal Approach

Objective: A method of opening the posterior ethmoid air cells with minimal manipulation is important for adequate exposure of the sella floor and minimal nasal morbidity. Methods: Between February 2009 and August 2016, 373 patients with skull-base tumors underwent surgery via endoscopic endonasal transsphenoidal approach with the 2-nostrils/4-hands technique using this technique. Results: A linear incision was made laterally toward one-third of the superior turbinate along the superior border of the sphenoid sinus ostium. Then, the superior turbinate mucosa was fully elevated to expose the superior turbinate bone. This allowed us to expose the entire sella floor and adjacent vital structures, such as the optic and carotid protuberances, medial and lateral opticocarotid recesses, planum sphenoidale, and clivus, leaving the superior turbinate and surrounding nasal mucosa intact. Conclusion: This technique could improve the manipulability of surgical instruments and increase the accessibility of the parasellar region. This approach better conserves the nasal mucosa, posterior ethmoid, and superior and supreme turbinates and more efficiently exposes skull-base tumors than traditional methods with pathology of the anterior cranial fossa and parasellar region. This technique also prevents the drilling procedure from damaging the surrounding nasal mucosa, including the exfoliated and laterally preserved posterior sphenoid mucosa.

Prognostic Significance of High Ki-67 Index and Histogenetic Subclassification in Primary Central Nervous System Lymphoma.

In diffuse large B-cell lymphoma (DLBCL), the germinal center B-cell (GCB) subtype is associated with a better prognosis compared with the nongerminal center B-cell-like (non-GCB) subtype. However, validity of this immunohistochemical subgrouping in primary DLBCL of the central nervous system is unclear. A total 45 cases of primary central nervous system lymphoma (PCNS)/DLBCL were selected, and immunohistochemistries for CD10, Bcl-6, MUM1, and Ki-67 were performed. Each of the cases was subclassified as either GCB or non-GCB based on its immunoprofile. Among clinical and immunologic markers, patients under 70 years of age and who had methotrexate chemotherapy showed a significantly better overall survival (OS). High Ki-67 (ie, a Ki-67 index ≥90%) was an independent prognostic factor for a poor OS in the whole cohort and in the patients with non-GCB subtype tumors (P=0.017, HR=4.267, 95% CI, 1.3-14.0; P=0.031, HR=3.752, 95% CI, 1.3-12.5). Tumors were dominantly non-GCB subtype (41/45, 91.1%); only 4 (8.9%) were GCB subtype. The 2-year OS rates for these groups were 73% and 100%. There was, however, no statistically significant difference between these groups for OS and progression-free survival. The subclassification of PCNS/DLBCL into GCB and non-GCB subtypes did not seem to have a prognostic value. In non-GCB subtype PCNSL patients, high Ki-67 index was an adverse independent prognostic marker that could be used to stratify patients for more suitable management.