Sinonasal Complications of Combined Transseptal-transnasal and Bilateral Transnasal Approaches for Endoscopic Endonasal Transsphenoidal Pituitary Surgery.

BACKGROUND: The endoscopic combined transseptal-transnasal technique for pituitary adenoma excision is notable for enhanced postoperative functional outcomes. Our study compared the incidence of anterior nasal septal perforation and the resulting sinonasal complications between this method and the bilateral transnasal approach. METHODS: Utilizing a retrospective cohort from a preeminent tertiary referral center, we analyzed 141 cases of endoscopic endonasal transsphenoidal surgery performed between March 2018 and May 2023. Outcomes for the transseptal-transnasal group (n = 71) and the conventional bilateral transnasal group (n = 70) were compared. Nasal endoscopy and computed tomography were used to assess anterior nasal septal perforation. Functional outcomes were assessed preoperatively and at 6 months postoperatively using the Connecticut Chemosensory Clinical Research Center (CCCRC) test, Cross-Cultural Smell Identification Test (CCSIT), Sino-Nasal Outcome Test-22 (SNOT-22), and nasal obstruction symptom evaluation (NOSE) RESULTS: The transseptal-transnasal approach exhibited reduced rates of postoperative ear fullness (p < 0.001), along with fewer subjective complaints of smell/taste loss (p = 0.022) and thick nasal discharge (p = 0.008), compared to the conventional approach. However, objective smell test results were not significantly different between the two approaches (p = 0.243 and p = 0.454 for CCCRC and CCSIT, respectively). Additionally, although statistically insignificant, a higher incidence of anterior septal perforation was observed with the transseptal-transnasal approach (p = 0.067). CONCLUSION: For the surgical treatment of pituitary adenomas, the transseptal-transnasal approach offers several advantages over the bilateral transnasal method, particularly in reducing postoperative complications. However, this technique requires careful attention for preventing the occurrence of anterior septal perforation.

The Relationship between Seropositive Rheumatoid Arthritis and Congestive Heart Failure: A Nationwide Longitudinal Cohort Study in Korea.

Objectives: The aim of this nationwide longitudinal cohort study is to determine the risk of congestive heart failure (CHF) associated with a seropositive rheumatoid arthritis (RA) population in Korea. Methods: In this study, National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) data from 2002 to 2003 were used. The cohort was followed up with for 12 years until December of 2015. Seropositive RA was defined as a patient prescribed with a disease-modifying anti-rheumatic drug (DMARD) among patients with the International Classification of Diseases code M05 (seropositive RA). Patients who were diagnosed before 2004 were excluded. The seropositive RA group consisted of 2765 patients, and a total of 13,825 patients were in the control group. The Kaplan-Meier method was used to calculate the 12-year CHF incidence rate for each group. A Cox proportional hazards regression analysis was used to estimate the hazard ratio of CHF. Results: The hazard ratio of CHF in the seropositive RA group was 2.41 (95% confidence interval (CI): 1.40-4.14) after adjusting for age and sex. The adjusted hazard ratio of CHF in the seropositive RA group was 2.50 (95% CI: 1.45-4.30) after adjusting for age, sex, income, and comorbidities. In females aged ≥65 and aged <65, the incidence rates in the non-hypertension, non-diabetes mellitus, and non-dyslipidemia subgroups were significantly higher in the seropositive RA group than in the control group. Conclusions: This nationwide longitudinal cohort study shows an increased risk of CHF in patients with seropositive RA.

Clinicopathological analysis of non-functioning pituitary adenomas (PAs) according to the 2022 WHO classification.

PURPOSE: For asymptomatic non-functioning pituitary adenomas (NFPAs), conservative approaches such as observation are preferred. However, some NFPAs exhibit poor prognoses. Thus, the purpose of this study was to investigate clinicopathological characteristics of tumors for identifying those with unfavorable prognoses. METHODS: A total of 125 patients with NFPAs who underwent surgery between November 2017 and December 2022 at our institution were retrospectively analyzed. Clinical, radiological, and pathological data, including hormone profiles, tumor size, presence of cavernous sinus invasion, and Ki-67 index levels, were reviewed. High-risk PAs were identified according to 2022 WHO criteria. Statistical analyses including Kaplan-Meier survival analysis and Cox regression were performed to evaluate factors associated with tumor progression or recurrence. RESULTS: A high-risk group demonstrated a significantly higher rate of tumor progression/recurrence than a low-risk group (p-value = 0.004). In multivariate analysis, the high-risk group at the time of diagnosis remained as an independent prognostic factor for NFPAs (p-value = 0.0148). The high-risk group also had a higher percentage of younger patients (80.0% in the high-risk group vs. 62.2% in the low-risk group, p-value = 0.016) and female patients (91.4% vs. 34.4%, p< 0.001). The presence of cavernous sinus invasion and higher Ki-67 index levels were more commonly observed in the high-risk group, although these factors did not significantly impact the overall prognosis. CONCLUSION: Our findings indicate that patients with high-risk NFPAs have a more aggressive disease course and a higher rate of progression or recurrence. This high-risk group has higher prevalence of younger and female patients. They may benefit from closer monitoring and possibly more aggressive treatment approaches.

Delineation of three-dimensional tumor margins based on normalized absolute difference mapping via volumetric optical coherence tomography.

The extent of surgical resection is an important prognostic factor in the treatment of patients with glioblastoma. Optical coherence tomography (OCT) imaging is one of the adjunctive methods available to achieve the maximal surgical resection. In this study, the tumor margins were visualized with the OCT image obtained from a murine glioma model. A commercialized human glioblastoma cell line (U-87) was employed to develop the orthotopic murine glioma model. A swept-source OCT (SS-OCT) system of 1300 nm was used for three-dimensional imaging. Based on the OCT intensity signal, which was obtained via accumulation of each A-scan data, an en-face optical attenuation coefficient (OAC) map was drawn. Due to the limited working distance of the focused beam, OAC values decrease with depth, and using the OAC difference in the superficial area was chosen to outline the tumor boundary, presenting a challenge in analyzing the tumor margin along the depth direction. To overcome this and enable three-dimensional tumor margin detection, we converted the en-face OAC map into an en-face difference map with x- and y-directions and computed the normalized absolute difference (NAD) at each depth to construct a volumetric NAD map, which was compared with the corresponding H&E-stained image. The proposed method successfully revealed the tumor margin along the peripheral boundaries as well as the margin depth. We believe this method can serve as a useful adjunct in glioma surgery, with further studies necessary for real-world practical applications.

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.

Comprehensive Molecular Genetic Analysis in Glioma Patients by Next Generation Sequencing.

BACKGROUND: Glioma is caused by multiple genomic alterations. The evolving classification of gliomas emphasizes the significance of molecular testing. Next generation sequencing (NGS) offers the assessment of parallel combinations of multiple genetic alterations and identifying actionable mutations that guide treatment. This study comprehensively analyzed glioma patients using multi-gene NGS panels, providing powerful insights to inform diagnostic classification and targeted therapies. METHODS: We conducted a targeted panel-based NGS analysis on formalin-fixed and paraffin-embedded nucleic acids extracted from a total of 147 glioma patients. These samples underwent amplicon capture-based library preparation and sequenced using the Oncomine Comprehensive Assay platform. The resulting sequencing data were then analyzed using the bioinformatics tools. RESULTS: A total of 301 mutations, were found in 132 out of 147 tumors (89.8%). These mutations were in 68 different genes. In 62 tumor samples (42.2%), copy number variations (CNVs) with gene amplifications occurred in 25 genes. Moreover, 25 tumor samples (17.0%) showed gene fusions in 6 genes and intragenic deletion in a gene. Our analysis identified actionable targets in several genes, including 11 with mutations, 8 with CNVs, and 3 with gene fusions and intragenic deletion. These findings could impact FDA-approved therapies, NCCN guideline-based treatments, and clinical trials. CONCLUSION: We analyzed precisely diagnosing the classification of gliomas, detailing the frequency and co-occurrence of genetic alterations and identifying genetic alterations with potential therapeutic targets by NGS-based molecular analysis. The high-throughput NGS analysis is an efficient and powerful tool to comprehensively support molecular testing in neurooncology.

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.