Intratumoral IL-12 delivery via mesenchymal stem cells combined with PD-1 blockade leads to long-term antitumor immunity in a mouse glioblastoma model.

BACKGROUND: Although PD-1 blockade is effective for treating several types of cancer, the efficacy of this agent in glioblastoma is largely limited. To overcome non-responders and the immunosuppressive tumor microenvironment, combinational immunotherapeutic strategies with anti-PD-1 need to be considered. Here, we developed IL-12-secreting mesenchymal stem cells (MSC_IL-12) with glioblastoma tropism and evaluated the therapeutic effects of anti-PD-1, MSC_IL-12, and their combination against glioblastoma. METHODS: Therapeutic responses were evaluated using an immunocompetent mouse orthotopic model. Tumor-infiltrating lymphocytes (TILs) were analyzed using immunofluorescent imaging. Single-cell transcriptome was obtained from mouse brains after treatments. RESULTS: Anti-PD-1 and MSC_IL-12 showed complete tumor remission in 25.0% (4/16) and 23.1% (3/13) of glioblastoma-implanted mice, respectively, and their combination yielded synergistic antitumor efficacy indicated by 50.0% (6/12) of complete tumor remission. Analyses of TILs revealed that anti-PD-1 increased CD8+ T cells, while MSC_IL-12 led to infiltration of CD4+ T cells and NK cells. Both therapies reduced frequencies of Tregs. All these aspects observed in each monotherapy group were superimposed in the combination group. Notably, no tumor growth was observed upon rechallenge in cured mice, indicating long-term immunity against glioblastoma provoked by the therapies. Single-cell RNA-seq data confirmed these results and revealed that the combined treatment led to immune-favorable tumor microenvironment-CD4+, CD8+ T cells, effector memory T cells, and activated microglia were increased, whereas exhausted T cells, Tregs, and M2 polarized microglia were reduced. CONCLUSION: Anti-PD-1 and MSC_IL-12 monotherapies show long-term therapeutic responses, and their combination further enhances antitumor efficacy against glioblastoma via inducing immune-favorable tumor microenvironment.

Sinonasal Outcomes of the Combined Transseptal/Transnasal Approach with Unilateral Nasoseptal Rescue Flap in Endoscopic Endonasal Transsphenoidal Surgery: A Propensity Score Matching Analysis.

Objectives The authors applied surgical techniques acquired during the use of endoscopic combined transseptal/transnasal approach to reduce approach-related morbidity and improve sinonasal outcomes. Study Design This is a retrospective cohort study of a prospectively collected database. Setting The study setting involves a tertiary referral center. Participants A total of 86 patients who underwent endoscopic endonasal transsphenoidal surgery for newly diagnosed pituitary adenomas from April 2018 to March 2021 were included. Patients treated via the combined transseptal/transnasal approach served as the study group ( n = 18); those treated via the bilateral transnasal approach comprised the control group ( n = 68). From the control group, propensity score matching (PSM) analysis was further performed to account for potential confounders and selection bias. Main Outcome Measures Paired analysis was performed for pre- and 6-month-postoperative time points in study group, control group, and PSM control group. Olfactory function was evaluated by Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), and sinonasal outcomes were assessed by Sino-Nasal Outcome Test-22 (SNOT-22). Results In the study group, CCCRC ( p = 0.517) and CCSIT ( p = 0.497) did not show any significant difference before and after surgery. There was some improvement in the symptom score of SNOT-22, but it was not statistically significant ( p = 0.115). In the control group adjusted with PSM, a significant decrease in olfaction ( p = 0.047) was observed using CCCRC. The CCSIT score was also decreased but not significant ( p = 0.163). Also, there was no difference in the improvement of SNOT-22 ( p = 0.781). Conclusion Our new surgical method preserves olfactory function without compromising surgical outcomes.

From lymphopenia to restoration: IL-7 immunotherapy for lymphocyte recovery in glioblastoma.

Glioblastoma, the most prevalent malignant primary brain tumor, presents substantial treatment challenges because of its inherent aggressiveness and limited therapeutic options. Lymphopenia, defined as reduced peripheral blood lymphocyte count, commonly occurs as a consequence of the disease and its treatment. Recent studies have associated lymphopenia with a poor prognosis. Factors that contribute to lymphopenia include radiotherapy, chemotherapy, and the tumor itself. Patients who are female, older, using dexamethasone, or receiving higher doses of radiation therapy are particularly vulnerable to this condition. Several preclinical studies have explored the use of interleukin-7, a crucial cytokine for lymphocyte homeostasis, to restore lymphocyte counts and potentially rebuild the immune system to combat glioblastoma cells. With the development of recombinant interleukin-7 for prolonged activity in the body, various clinical trials are underway to explore this treatment in patients with glioblastoma. Our study provides a comprehensive summary of the incidence of lymphopenia, its potential biological background, and the associated clinical risk factors. Furthermore, we reviewed several clinical trials using IL-7 cytokine therapy in glioblastoma patients. We propose IL-7 as a promising immunotherapeutic strategy for glioblastoma treatment. We are optimistic that our study will enhance understanding of the complex interplay between lymphopenia and glioblastoma and will pave the way for the development of more effective treatment modalities.

Establishment of tumor microenvironment-preserving organoid model from patients with intracranial meningioma.

BACKGROUND: Although meningioma is the most common primary brain tumor, treatments rely on surgery and radiotherapy, and recurrent meningiomas have no standard therapeutic options due to a lack of clinically relevant research models. Current meningioma cell lines or organoids cannot reflect biological features of patient tumors since they undergo transformation along culture and consist of only tumor cells without microenvironment. We aim to establish patient-derived meningioma organoids (MNOs) preserving diverse cell types representative of the tumor microenvironment. METHODS: The biological features of MNOs were evaluated using WST, LDH, and collagen-based 3D invasion assays. Cellular identities in MNOs were confirmed by immunohistochemistry (IHC). Genetic alteration profiles of MNOs and their corresponding parental tumors were obtained by whole-exome sequencing. RESULTS: MNOs were established from four patients with meningioma (two grade 1 and two grade 2) at a 100% succession rate. Exclusion of enzymatic dissociation-reaggregation steps endowed MNOs with original histology and tumor microenvironment. In addition, we used a liquid media culture system instead of embedding samples into Matrigel, resulting in an easy-to-handle, cost-efficient, and time-saving system. MNOs maintained their functionality and morphology after long-term culture (> 9 wk) and repeated cryopreserving-recovery cycles. The similarities between MNOs and their corresponding parental tumors were confirmed by both IHC and whole-exome sequencing. As a representative application, we utilized MNOs in drug screening, and mifepristone, an antagonist of progesterone receptor, showed prominent antitumor efficacy with respect to viability, invasiveness, and protein expression. CONCLUSION: Taken together, our MNO model overcame limitations of previous meningioma models and showed superior resemblance to parental tumors. Thus, our model could facilitate translational research identifying and selecting drugs for meningioma in the era of precision medicine.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

PURPOSE: Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. METHODS: A total of 66 patients were divided into two groups: those treated with 30 Gy (2 Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30 Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6 Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50 Gy (range, 36.0-55.8 Gy). RESULTS: The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. CONCLUSION: Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Potential impact of high-density lipoprotein cholesterol in the postoperative outcomes of chronic subdural hematoma patients: multi-institutional study in Korea.

BACKGROUND: Chronic subdural hematoma (CSDH) is a common clinical situation in neurosurgical practice, but the optimal treatment option is controversial. This study aimed to evaluate the effect of cholesterol-lowering medications on and how they affected the prognoses of CSDH patients. METHODS: In this multi-institutional observational study performed in Korea, data from recently treated CSDH patients were gathered from 5 hospitals. A total of 462 patients were collected from March 2010 to June 2021. Patient clinical characteristics, history of underlying diseases and their treatments, radiologic features, and surgical outcomes were analyzed. RESULTS: Seventy-five patients experienced recurrences, and 62 had reoperations after the initial burr hole surgery. Among these, 15 patients with recurrences and 12 with reoperations were taking cholesterol-lowering medications. However, the use of medications did not significantly affect recurrence or reoperation rates (P = 0.350, P = 0.336, respectively). When analyzed by type of medication, no clinically relevant differences in total cholesterol (TC), triglyceride (TG), or low-density lipoprotein cholesterol (LDL-C) levels were identified. The combination of a statin drug and ezetimibe significantly elevated high-density lipoprotein cholesterol (HDL-C) levels (P = 0.004). TC, LDL-C, and TG levels did not significantly affect patient prognoses. However, HDL-C levels and recurrence (odds ratio (OR) = 0.96; 95% confidence interval (CI): 0.94-0.99; p = 0.010) were negatively correlated. An HDL-C level of 42.50 mg/dL was identified as the threshold for recurrence and reoperation. CONCLUSIONS: In this study, using cholesterol-lowering medications did not significantly impact the prognosis of patients who underwent surgical management for a chronic subdural hematoma. However, the findings showed that the higher the HDL-C level, the lower the probability of recurrence and reoperation.

Balancing Bleeding Risk and Thromboembolic Complications in Elderly Chronic Subdural Hematoma Patients Undergoing Burr Hole Trephination : A Multicenter Retrospective Cohort Study and Literature Review.

OBJECTIVE: Chronic subdural hematoma (CSDH) patients using antithrombotic agents (AT) at high risk for cardiovascular disease are increasing. The authors aimed to analyze the factors influencing outcome by targeting patients using AT and to establish a desirable treatment strategy. METHODS: A retrospective analysis was performed on data from 462 patients who underwent burr hole trephination (BHT) surgery for CSDH at five hospitals from March 2010 to June 2021. Outcomes included incidence of postoperative acute bleeding, recurrence rate, and morbidity or mortality rate. Patients were divided into the following four groups based on their history of AT use : no AT. Only antiplatelet agents (AP), only anticoagulants (AC), both of AP and AC. In addition, a concurrent literature review was conducted alongside our cohort study. RESULTS: Of 462 patients, 119 (119/462, 25.76%) were using AT. AP prescription did not significantly delay surgery (p=0.318), but AC prescription led to a significant increase in the time interval from admission to operation (p=0.048). After BHT, AP or AC intake significantly increased the period required for an in-dwelling drain (p=0.026 and p=0.037). The use of AC was significantly related to acute bleeding (p=0.044), while the use of AP was not (p=0.808). Use of AP or AC had no significant effect on CSDH recurrence (p=0.517 and p=1.000) or reoperation (p=0.924 and p=1.000). Morbidity was not statistically correlated with use of either AP or AC (p=0.795 and p=0.557, respectively), and there was no significant correlation with mortality for use of these medications (p=0.470 and p=1.000). CONCLUSION: Elderly CSDH patients may benefit from maintenance of AT therapy during BHT due to reduced thromboembolic risk. However, the use of AC necessitates individualized due to potential postoperative bleeding. Careful post-operative monitoring could mitigate prognosis and recurrence impacts.

Human gamma-delta (γδ) T cell therapy for glioblastoma: A novel alternative to overcome challenges of adoptive immune cell therapy.

Glioblastoma is the most common brain malignancy with devastating prognosis. Numerous clinical trials using various target therapeutic agents have failed and recent clinical trials using check point inhibitors also failed to provide survival benefits for glioblastoma patients. Adoptive T cell transfer is suggested as a novel therapeutic approach that has exhibited promise in preliminary clinical studies. However, the clinical outcomes are inconsistent, and there are several limitations of current adoptive T cell transfer strategies for glioblastoma treatment. As an alternative cell therapy, gamma-delta (γδ) T cells have been recently introduced for several cancers including glioblastoma. Since the leading role of γδ T cells is immune surveillance by recognizing a broad range of ligands including stress molecules, phosphoantigens, or lipid antigens, recent studies have suggested the potential benefits of γδ T cell transfer against glioblastomas. However, γδ T cells, as a small subset (1-5%) of T cells in human peripheral blood, are relatively unknown compared to conventional alpha-beta (αß) T cells. In this context, our study introduced γδ T cells as an alternative and novel option to overcome several challenges regarding immune cell therapy in glioblastoma treatment. We described the unique characteristics and advantages of γδ T cells compared to conventional αß T cells and summarize several recent preclinical studies using human gamma-delta T cell therapy for glioblastomas. Finally, we suggested future direction of human γδ T cell therapy for glioblastomas.

Polymorphisms of Killer Ig-like Receptors and the Risk of Glioblastoma.

PURPOSE: The immune responses of natural killer (NK) cells against cancer cells vary by patient. Killer Ig-like receptors (KIRs), which are some of the major receptors involved in regulating NK cell activity for killing cancer cells, have significant genetic variation. Numerous studies have suggested a potential association between the genetic variation of KIR genes and the risk of development or prognosis of various cancer types. However, an association between genetic variations of KIR genes and glioblastoma (GB) remains uncertain. We sought to evaluate the association of genetic variations of KIRs and their ligand genes with the risk of GB development in Koreans. METHODS: A case-control study was performed to identify the odds ratios (ORs) of KIR genes and Classes A, B, and, C of the human leukocyte antigen (HLA) for GB. The GB group was comprised of 77 patients with newly diagnosed IDH-wildtype GB at our institution, and the control group consisted of 200 healthy Korean volunteers. RESULTS: There was no significant difference in the frequency of KIR genes and KIR haplotypes between the GB and control groups. Genetic variations of KIR-2DL1, 3DL1, and 3DS1 with their ligand genes (HLA-C2, HLA-Bw4/6, and Bw4, respectively) had effects on the risk of GB in Korean patients. The frequency of KIR-2DL1 with HLA-C2 (OR 2.05, CI 1.19-3.52, p = 0.009), the frequency of KIR-3DL1 without HLA-Bw4 (80I) (OR 8.36, CI 4.06-17.18, p < 0.001), and the frequency of KIR-3DL1 with Bw6 (OR 4.54, CI 2.55-8.09, p < 0.001) in the GB group were higher than in the control group. In addition, the frequency of KIR-2DL1 without HLA-C2 (OR 0.44, CI 0.26-0.75, p = 0.003), the frequency of KIR-3DL1 with HLA-Bw4 (80T) (OR 0.13, CI 0.06-0.27, p < 0.001), the frequency of KIR-3DL1 without Bw6 (OR 0.27, CI 0.15-0.49, p < 0.001), and the frequency of KIR-3DS1 with Bw4 (80I) (OR 0.03, CI 0.00-0.50, p < 0.001) in the GB group were lower than in the control group. CONCLUSIONS: This study suggests that genetic variations of KIRs and their ligand genes may affect GB development in the Korean population. Further investigations are needed to demonstrate the different immune responses for GB cells according to genetic variations of KIR genes and their ligand genes.

The Korean Society for Neuro-Oncology (KSNO) Guideline for the Management of Brain Tumor Patients During the Crisis Period: A Consensus Recommendation Using the Delphi Method (Version 2023.1).

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, the need for appropriate treatment guidelines for patients with brain tumors was indispensable due to the lack and limitations of medical resources. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has undertaken efforts to develop a guideline that is tailored to the domestic situation and that can be used in similar crisis situations in the future. METHODS: The KSNO Guideline Working Group was composed of 22 multidisciplinary experts on neuro-oncology in Korea. In order to reach consensus among the experts, the Delphi method was used to build up the final recommendations. RESULTS: All participating experts completed the series of surveys, and the results of final survey were used to draft the current consensus recommendations. Priority levels of surgery and radiotherapy during crises were proposed using appropriate time window-based criteria for management outcome. The highest priority for surgery is assigned to patients who are life-threatening or have a risk of significant impact on a patient's prognosis unless immediate intervention is given within 24-48 hours. As for the radiotherapy, patients who are at risk of compromising their overall survival or neurological status within 4-6 weeks are assigned to the highest priority. Curative-intent chemotherapy has the highest priority, followed by neoadjuvant/adjuvant and palliative chemotherapy during a crisis period. Telemedicine should be actively considered as a management tool for brain tumor patients during the mass infection crises such as the COVID-19 pandemic. CONCLUSION: It is crucial that adequate medical care for patients with brain tumors is maintained and provided, even during times of crisis. This guideline will serve as a valuable resource, assisting in the delivery of treatment to brain tumor patients in the event of any future crisis.

The Korean Society for Neuro-Oncology (KSNO) Guideline for the Management of Brain Tumor Patients During the Crisis Period: A Consensus Survey About Specific Clinical Scenarios (Version 2023.1).

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, there was a shortage of medical resources and the need for proper treatment guidelines for brain tumor patients became more pressing. Thus, the Korean Society for Neuro-Oncology (KSNO), a multidisciplinary academic society, has undertaken efforts to develop a guideline that is tailored to the domestic situation and that can be used in similar crisis situations in the future. As part II of the guideline, this consensus survey is to suggest management options in specific clinical scenarios during the crisis period. METHODS: The KSNO Guideline Working Group consisted of 22 multidisciplinary experts on neuro-oncology in Korea. In order to confirm a consensus reached by the experts, opinions on 5 specific clinical scenarios about the management of brain tumor patients during the crisis period were devised and asked. To build-up the consensus process, Delphi method was employed. RESULTS: The summary of the final consensus from each scenario are as follows. For patients with newly diagnosed astrocytoma with isocitrate dehydrogenase (IDH)-mutant and oligodendroglioma with IDH-mutant/1p19q codeleted, observation was preferred for patients with low-risk, World Health Organization (WHO) grade 2, and Karnofsky Performance Scale (KPS) ≥60, while adjuvant radiotherapy alone was preferred for patients with high-risk, WHO grade 2, and KPS ≥60. For newly diagnosed patients with glioblastoma, the most preferred adjuvant treatment strategy after surgery was radiotherapy plus temozolomide except for patients aged ≥70 years with KPS of 60 and unmethylated MGMT promoters. In patients with symptomatic brain metastasis, the preferred treatment differed according to the number of brain metastasis and performance status. For patients with newly diagnosed atypical meningioma, adjuvant radiation was deferred in patients with older age, poor performance status, complete resection, or low mitotic count. CONCLUSION: It is imperative that proper medical care for brain tumor patients be sustained and provided, even during the crisis period. The findings of this consensus survey will be a useful reference in determining appropriate treatment options for brain tumor patients in the specific clinical scenarios covered by the survey during the future crisis.

A clinical evaluation of cystic features in patients with newly diagnosed glioblastoma with IDH-wildtype.

BACKGROUND: The prognostic significance of the presence of cystic features in patients with newly diagnosed glioblastoma (GB) is highly controversial. The purpose of this study was to determine whether cystic GB patients have a more favorable prognosis compared to non-cystic GB patients. METHODS: The records of all GB patients diagnosed between August 2008 and December 2020 at Seoul St. Mary's Hospital were reviewed retrospectively. Out of 254 GB patients, we excluded patients with a confirmed isocitrate dehydrogenase (IDH) mutation or an unknown IDH mutation status. A total of 145 patients met our eligibility criteria. RESULTS: Of the 145 patients we analyzed, 16 patients were classified as the cystic group, and 129 patients were classified into the non-cystic group. As there was a significant difference in the extent of resection between the two groups, 32 patients were matched according to propensity score matching. A Kaplan-Meier survival curve of the two groups indicated that the cystic group had better survival than the non-cystic group (28.6 months versus 18.8 months, respectively; p = 0.055). On multivariate analysis, the presence of cystic features (hazard ratio [HR]: 0.40, 95% confidence interval [CI]: 0.17-0.91, p = 0.029) was significantly related with a longer OS. Longer OS was also related with well-known prognostic factors, such as grossly total resection (HR: 0.05, CI: 0.01-0.31, respectively; p = 0.001) and lower European Cooperative Oncology Group (ECOG) score (HR: 3.67, CI: 1.56-9.02, respectively; p = 0.003). CONCLUSION: Our results suggest that the presence of cystic features could be an independent prognostic factor suggesting better survival in GB patients. Further larger and prospective studies to validate our findings are needed.

Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma.

PURPOSE: Addressing lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to increase total lymphocyte count (TLC), IL-7 therapy has been attempted in various cancers. Here, we describe the clinical results of treatment of recurrent glioblastoma (GBM) with a long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc). METHODS: This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Primary outcomes were safety profile and TLC. Secondary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: Among the 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. Mean TLC of the enrolled patients after the first rhIL-7-hyFc treatment increased significantly from 1131 cells/mm3 (330-2989) at baseline to 4356 cells/mm3 (661-22,661). Higher TLCs were maintained while rhIL-7-hyFc was repeatedly administered. Median OS and PFS were 378 days (107-864 days) and 231 days (55-726 days), respectively. CONCLUSION: Our study reports that IL-7 immunotherapy can restore and maintain TLC during treatment with various salvage chemotherapies in recurrent GBM patients without serious toxicity.

Human allogenic γδ T cells kill patient-derived glioblastoma cells expressing high levels of DNAM-1 ligands.

Adoptive transfer of γδ T cells is a novel immunotherapeutic approach to glioblastoma. Few recent studies have shown the efficacy of γδ T cells against glioblastoma, but no previous studies have identified the ligand-receptor interactions between γδ T cells and glioblastoma cells. Here, we identify those ligand-receptor interactions and provide a basis for using γδ T cells to treat glioblastoma. Vγ9Vδ2 T cells were generated from peripheral blood mononuclear cells of healthy donors using artificial antigen presenting cells. MICA, ULBP, PVR and Nectin-2 expression in 10 patient-derived glioblastoma (PDG) cells were analyzed. The in vitro cytokine secretion from the γδ T cells and their cytotoxicity toward the PDG cells were also analyzed. The in vivo anti-tumor effects were evaluated using a U87 orthotopic xenograft glioblastoma model. Expression of ligands and cytotoxicity of the γδ T cells varied among the PDG cells. IFN-γ and Granzyme B secretion levels were significantly higher when γδ Tcells were co-cultured with high-susceptible PDG cells than when they were co-cultured with low-susceptible PDG cells. Cytotoxicity correlated significantly with the expression levels of DNAM-1 ligands of the PDG cells. Blocking DNAM-1 resulted in a decrease in γδ T cell-mediated cytotoxicity and cytokine secretion. Intratumoral injection of γδ T cells showed anti-tumor effects in an orthotopic mouse model. Allogenic γδ T cells showed potent anti-tumor effects on glioblastoma in a DNAM-1 axis dependent manner. Our findings will facilitate the development of clinical strategies using γδ T cells for glioblastoma treatment.

Association between Temporal Muscle Thickness and Overall Survival in Non-Small Cell Lung Cancer Patients with Brain Metastasis.

Temporal muscle thickness (TMT) has recently been suggested as a novel biomarker of sarcopenia in head and neck malignancies. However, few studies have evaluated TMT as a prognostic marker in patients with brain metastasis. This study investigated the association of TMT with overall survival (OS) in non-small cell lung cancer (NSCLC) patients with brain metastasis. The records of all NSCLC patients with brain metastasis between 2009 and 2018 at St. Vincent's Hospital were reviewed retrospectively. A total of 221 patients met our eligibility criteria. In the group with TMT thicker than the median, OS was longer than the group with TMT thinner than the median (240 days versus 139 days, p = 0.014). In multivariate analysis, the thicker TMT group had longer survival (HR 0.73 CI 0.56−0.96, p = 0.024). Male (HR 1.58 CI 1.19−2.09, p = 0.002) and older age (≥65 years) (HR 2.05 CI 1.53−2.74, p < 0.001) also showed statistical significance. We also performed subgroup analysis in older patients (≥65 years). In this subgroup of 107 patients, the thicker TMT group also showed longer OS than the thinner TMT group (209 days versus 82 days, p = 0.009). Our findings suggest that TMT can be a useful biomarker for OS in NSCLC patients with brain metastasis.

Cytomegalovirus-Specific Immunotherapy for Glioblastoma Treatments.

Over the last two decades, numerous studies have investigated the presence of human cytomegalovirus (CMV) within glioblastoma or gliomas; however, the results are severely conflicting. While a few researchers have suggested the potential benefits of cytotoxic T lymphocyte or dendritic cell-based vaccines for recurrent or newly diagnosed glioblastoma patients, several studies did not at all agree with the existence of CMV in glioblastoma cells. In this review, we summarized the conflicting results and issues about the detection of CMV in glioblastoma or glioma patients. We also provided the clinical data of published and unpublished clinical trials using CMV-specific immunotherapy for glioblastomas.

Clinical feasibility of modified procarbazine and lomustine chemotherapy without vincristine as a salvage treatment for recurrent adult glioma.

Procarbazine, lomustine and vincristine (PCV) chemotherapy is considered a salvage option for adult glioma; however, its significant toxicities frequently lead to dose reduction or discontinuation in patients with recurrent glioma. The current study evaluated the safety and efficacy of modified procarbazine and lomustine (PC) chemotherapy that omits vincristine and reduces the lomustine dose compared with those of conventional PCV chemotherapy. Using electronic medical records, all patients with adult recurrent glioma who received PC or PCV chemotherapy between 2009 and 2020 at Seoul St. Mary's Hospital or St. Vincent's Hospital were examined retrospectively. A total of 59 patients met the eligibility criteria. Among them, 15 patients received modified PC chemotherapy (PC group) and 44 patients received PCV chemotherapy (PCV group). The PC group presented a significantly lower hematology toxicity (anemia, 6.7 vs. 45.5%, P=0.02; thrombocytopenia 20.0 vs. 70.4%, P<0.001). Additionally, the clinical impacts of PC chemotherapy, including delay of a cycle, dose reduction, discontinuation of drug(s) or total cessation of chemotherapy, were significantly less frequent compared with the PCV group (26.7 vs. 68.2%, P=0.012). The overall survival of the PC group was also significantly longer than that of PCV group (396 vs. 232 days, P=0.042), while there was no significant difference in progression-free survival between the two groups (284.5 vs. 131 days, P=0.077). The results suggested that modified PC chemotherapy may be an alternative chemotherapeutic regimen with tolerable toxicity and without loss of clinical efficacy in patients with recurrent adult glioma. Further prospective and larger studies are required to validate our findings.

Comparative analysis of safety and efficacy in subperiosteal versus subdural drainage after burr-hole trephination for chronic subdural hematoma.

PURPOSE: The treatment of choice for chronic subdural hematoma (CSDH) has been established as burr-hole trephination with drain insertion; however, controversy remains over the best place for the drainage catheter. In this study, we compare the safety and efficacy of a subperiosteal drain (SPD) with that of a subdural drain (SDD) after one burr-hole trephination for CSDH. METHODS: This retrospective and comparative study includes all CSDH patients treated with burr-hole trephination at our institution between January 2015 and December 2019. 59 patients were treated with SPD insertion (SPD group), and 203 patients were treated with SDD insertion (SDD group). RESULTS: The median hematoma thickness of the SPD group within 24 h after surgery was significantly thicker than that of the SDD group (9.5 mm vs. 7.5 mm, p = 0.003), but the midline shifting of the SPD group did not differ from that of the SDD group (3.8 mm vs. 3.5 mm, p = 0.280). The recurrence rate in the SPD group did not differ significantly from that in the SDD group (13.2% vs. 8.5%, p = 0.351). The frequency of bleeding events after surgery also did not differ significantly (5.1% vs. 3.5% p-value = 0.636). In contrast to surgery-related morbidities, medical morbidities such as pneumonia were significantly higher in the SDD group (4.4% vs. 0.0%, p = 0.044). The all-cause mortality rates during the perioperative period did not differ between the two groups (5.1% vs. 3.4%, p = 0.848). CONCLUSION: Our findings may suggest that burr-hole trephination with SPD insertion had better surgical feasibility and fewer perioperative complications than SDD insertion. The type of anesthesia seems to be related with fewer medical complications at perioperative period. Larger, randomized clinical trials focusing not only the drain type but anesthesia type, are needed to validate our findings.

HLA polymorphisms and risk of glioblastoma in Koreans.

PURPOSE: Immune responses for cancer cells can be altered according to genetic variation of human leukocyte antigen (HLA). Association of HLA polymorphism with risk of various cancer types is well known. However, the association between HLA and glioblastoma (GBM) remains uncertain. We sought to evaluate the association of HLA polymorphism with risk of GBM development in Koreans. MATERIALS AND METHODS: A case-control study was performed to identify the odds ratios (OR) of HLA class I and II genes for GBM. The control group consisted of 142 healthy Korean volunteers, and the GBM group was 80 patients with newly diagnosed GBM at our institution. HLA class I (-A, -B, and-C) and class II (-DR, -DQ, and-DP) genotyping was performed by high-resolution polymerase chain reaction (PCR)-sequence-based typing (PCR-SBT) methods. RESULTS: There were significantly decreased frequencies of HLA-A*26:02 (OR 0.22 CI 0.05-0.98), HLA-C*08:01 (OR 0.29 CI 0.10-0.87), and HLA-DRB1*08:03 (OR 0.32 CI 0.11-0.98), while there was significantly increased frequency of HLA-C*04:01 (OR 2.29 CI 1.05-4.97). In analysis of haplotypes, the frequency of DRB1*14:05-DQB1*05:03 was significantly decreased (OR 0.22 CI 0.05-0.98). CONCLUSION: This study suggests that genetic variations of HLA may affect GBM development in Koreans. Further investigations with larger sample sizes are needed to delineate any potential role of the HLA polymorphisms in the pathogenesis of GBM development.

Association between height and the risk of primary brain malignancy in adults: a nationwide population-based cohort study.

BACKGROUND: The association between height and the risk of developing primary brain malignancy remains unclear. We evaluated the association between height and risk of primary brain malignancy based on a nationwide population-based database of Koreans. METHODS: Using data from the Korean National Health Insurance System cohort, 6 833 744 people over 20 years of age that underwent regular national health examination were followed from January 2009 until the end of 2017. We documented 4771 cases of primary brain malignancy based on an ICD-10 code of C71 during the median follow-up period of 7.30 years and 49 877 983 person-years. RESULTS: When dividing the population into quartiles of height for each age group and sex, people within the highest height quartile had a significantly higher risk of brain malignancy, compared to those within the lowest height quartile (HR 1.21 CI 1.18-1.32) after adjusting for potential confounders. We also found that the risk of primary brain malignancy increased in proportion with the quartile increase in height. After analyzing subgroups based on older age (≥ 65) and sex, we found positive relationships between height and primary brain malignancy in all subgroups. CONCLUSIONS: This study is the first to suggest that height is associated with an increased risk of primary brain malignancy in the East-Asian population. Further prospective and larger studies with precise designs are needed to validate our findings.