Search

Objective To analyze radiological characteristics, treatment strategy, and treatment outcomes of posterior fossa giant solid hemangioblastomas (GSHBs; ≥ 4 cm in maximum diameter). Methods We performed a retrospective study on 13 consecutive patients (9 male and 4 female patients [mean age 57.5 ± 13.3 years; range 24-76 years]) with GSHB who underwent surgical resection at a single institution between 2002 and 2018. The median follow-up was 33 months (range 12-120 months). For each patient, neuroimaging findings, operative record, and treatment outcome were reviewed. Results Seven tumors (53.8%) were located within cerebellar hemispheres, 4 (30.8%) in proximity to the brainstem, 1 (7.7%) within the cerebellar vermis, and 1 (7.7%) in the cerebellopontine angle. The mean maximum diameter was 4.8 ± 0.8 cm (range 4.0-6.7 cm). Gross total resection was achieved in 11 patients (84.6%), and near-total resection (NTR) in 2 patients (15.4%). Surgical complications occurred in 5 patients (38.5%); persistent neurological deficits occurred in 2 patients (15.4%). Estimated progression-free survival rates after surgery were 92.3%, 80.8%, and 80.8% at 1, 5, and 10 years, respectively, while the estimated 1-, 5- and 10-year overall survival rates were 100%, 90% and 90%, respectively. Conclusions GSHBs are surgically challenging. The current study shows that favorable outcome can be achieved for GSHBs in the cerebellar hemispheres and vermis. For those involving the brainstem, planned NTR or STR in a piecemeal fashion can be attempted if en bloc resection is judged to be infeasible, and further intervention can be considered as needed.

As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Glioblastoma (GBM) is the most malignant primary brain tumor in adults with substantial genomic alterations. The median survival is approximately 14.6 months, despite aggressive therapeutic intervention, which comprised of surgical resection, radiotherapy, and chemotherapy. Recent studies on cancer genomic have revealed crucial insights into dynamic molecular subgroups within GBM, which govern distinct clinical response and sensitivity of each individual to therapy. In the present study, we analyzed genomic composition of primary GBMs between two ethnic groups [IRCR (Institute of Refractory Cancer Research), and TCGA (The Cancer Genome Atlats)] to explore genomic and molecular features that constitute malignant behavior of glioblastoma based on distinct ethnicity. We identified enrichments of MAPK and p53 pathways in IRCR patients, while aberrant activation of Receptor Tyrosine Kinases (RTKs) were predominant in TCGA cohort. We also discovered differential clinical prognosis between two groups and explored essential features that present such diversity., Glioblastoma (GBM) is the most aggressive primary brain tumor. We analyzed recurrent somatic variants and molecular pathways that are enriched in different subpopulations.

The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E2 (PGE2), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients., How glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) interact to promote progression of glioblastoma multiforme (GBM) is currently unclear. Here, the authors demonstrate a role for the ARS2/MAGL signalling in regulating self-renewal and tumorigenicity of GSCs and M2-like TAM polarization.

Introduction The clinical benefit of stereotactic radiosurgery (SRS) in the treatment of malignant glioma remains controversial. We analyzed failure patterns of malignant gliomas following SRS to identify the clinical implications of SRS against these malignancies. Materials and methods We retrospectively reviewed 58 consecutive patients who received SRS with a gamma knife for their malignant glioma from January 2013 to December 2018. A total of 51 patients were available for analysis of failure patterns. Failure patterns were defined by the recurrent tumors’ spatial relation to SRS target as follows: in-field local recurrence, remote recurrence, and leptomeningeal seeding. If patients demonstrated several types of failure patterns simultaneously, we categorized them as a combined failure pattern. Results In-field local recurrence was found in 47.1% of patients. Other types of failure patterns were as follows: remote recurrence (19.6%), leptomeningeal seeding (13.7%), and combined failure pattern (19.6%). The majority of patients (52.9%) experienced disease progression beyond the radiation field of SRS, which implies limited efficacy of local therapy against these invasive tumors. The prognosis of patients differed according to failure pattern and patients with local recurrence had better survival outcomes compared to other types of disease progression (p-value = 0.0015, log-rank test). Conclusions This study illustrated that SRS could not improve survival of malignant gliomas significantly even when it had some effect within radiation field. Our findings support utilizing a multidisciplinary treatment strategy to improve the prognosis of malignant gliomas and suggest that SRS is one element of that treatment strategy.

PurposeWe investigated the efficacy of temozolomide during and after radiotherapy in Korean adults with anaplastic gliomas without 1p/19q co-deletion.Materials and MethodsThis was a randomized, open-label, phase 2 study and notably the first multicenter trial for Korean grade III glioma patients. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomized 1:1 to receive radiotherapy alone (60 Gy in 30 fractions of 2 Gy) (control group, n=44) or to receive radiotherapy with concurrent temozolomide (75 mg/m2/day) followed by adjuvant temozolomide (150-200 mg/m2/day for 5 days during six 28-day cycles) (treatment group, n=40). The primary end-point was 2-year progression-free survival (PFS). Seventy patients (83.3%) were available for the analysis of the isocitrate dehydrogenase 1 gene (IDH1) mutation status.ResultsThe two-year PFS was 42.2% in the treatment group and 37.2% in the control group. Overall survival (OS) did not reach to significant difference between the groups. In multivariable analysis, age was a significant risk factor for PFS (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.04 to 4.16). The IDH1 mutation was the only significant prognostic factor for PFS (HR, 0.28; 95% CI, 0.13 to 0.59) and OS (HR, 0.19; 95% CI, 0.07 to 0.50). Adverse events over grade 3 were seen in 16 patients (40.0%) in the treatment group and were reversible.ConclusionConcurrent and adjuvant temozolomide in Korean adults with newly diagnosed non-co- deleted anaplastic gliomas showed improved 2-year PFS. The survival benefit of this regimen needs further analysis with long-term follow-up at least more than 10 years.

Treatment options for patients with chemotherapy-refractory solid tumors are limited.We conducted an open-label, single-arm, single-center phase II trial to evaluate the efficacy and safety of gefitinib in patients with chemotherapy-refractory solid tumors and EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with patient-derived tumor cells (PDCs).EGFR amplification was detected by targeted sequencing. Sensitivity to an EGFR inhibitor was established in chemical screening using PDCs. Gefitinib (250 mg daily) was administered continuously in 28-day cycles until the occurrence of disease progression, unacceptable toxicity, or death due to any cause. The primary endpoint was the objective response rate (ORR).In total, 15 patients were assigned to the present study. The most common tumor type was glioblastoma multiforme (n = 9, 60%), followed by gastric cancer (n = 3, 20%), anal squamous cancer, rectal cancer, and sarcoma (each n = 1, 6.7%). Among 13 evaluable patients, one patient had a partial response and five had stable disease, with an ORR of 7.7% and a disease control rate of 46.1%. The median progression-free survival was 2.1 months (95% confidence interval [CI] 0.77-3.43). The most common adverse events were diarrhea (26.7%) and skin rash (26.7%).Gefitinib demonstrated modest anti-tumor activity and a manageable safety profile in chemotherapy-refractory solid tumors with EGFR amplification or sensitivity to an EGFR inhibitor identified through a drug-screening platform with PDCs. CLINICALTRIALS.NCT02447419.

Tumor treating fields (TTFields) are anti-mitotic, non-invasive loco-regional cancer therapy comprising low intensity, intermediate frequency alternating electric fields. TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report on Korean newly diagnosed GBM patients who participated in the EF-14 trial. Thirty-nine participants of the EF-14 trial were enrolled at 8 sites in South Korea. Patients (24 TTFields/TMZ; 14 TMZ alone) received: TTFields (200 kHz) for > 18 h/day; TMZ at 120–150 mg for 5 days per a 28 day cycle. Safety and efficacy were assessed. Patient baseline characteristics were balanced in the 2 arms and the mean age was 52.1 years, 66.7% were male with a mean KPS of 90. Safety incidence was comparable between the 2 arms. In the TTFields/TMZ arm, 30% suffered from skin irritation versus 52% in the entire study population. No TTFields-related serious adverse events were reported. The median progression-free survival (PFS) in the TTFields/TMZ arm was 6.2 months (95% CI 4.2–12.2) versus 4.2 (95% CI 1.9–11.2) with TMZ alone (p = 0.67). Median overall survival was 27.2 months (95% CI 21-NA) with TTFields/TMZ versus 15.2 months (95% CI 7.5–24.1; HR 0.27, p = 0.01) with TMZ alone. Median OS and 1- and 2-year survival rates were higher with TTFields/TMZ and similar to the entire EF-14 population. About 30% of patients reported skin irritation, a lower rate than seen in the entire EF-14 population. These results demonstrate the efficacy and safety of TTFields in Korean newly diagnosed glioblastoma patients. Clinicaltrials.gov Identifier: NCT00916409.

A late-onset treatment-related changes (TRCs), which represent radiographic radiation necrosis (RN), frequently occur after stereotactic radiosurgery (SRS) for brain metastases and often need surgical treatment. This study aimed to validate the true pathology and investigate clinical implication of surgically resected TRCs on advanced magnetic resonance imaging (MRI). Retrospective analyses of 86 patients who underwent surgical resection after radiosurgery of brain metastases were performed. Fifty-four patients displayed TRCs on preoperative MRI, comprising pure RN in 19 patients (TRC-RN group) and mixed viable tumor cells in 35 patients (TRC-PD group). Thirty-two patients revealed the consistent diagnosis of progressive disease in both MRI and histopathology (PD–PD group). The TRC-PD group showed larger prescription isodose volume (9.4 cm3) than the TRC-RN (4.06 cm3, p = 0.014) group and a shorter time interval from SRS to preoperative MRI diagnosis (median 4.07 months) than the PD–PD group (median 8.77 months, p = 0.004). Progression-free survival was significantly different among the three groups (p

Prediction of visual outcome after endoscopic endonasal tumor resection still remains a challenge. We investigated the prognostic value of the preoperative peripapillary retinal nerve fiber layer (pRNFL) using optical coherence tomography for visual outcome after endoscopic endonasal surgery (EES) for suprasellar tumors.We retrospectively analyzed 122 patients who underwent EES for sellar and suprasellar tumors between January 2016 and January 2018. We retrospectively analyzed the pre- and postoperative relationship between pRNFL thickness and visual outcome based on visual acuity (visual acuity score) and visual field (mean deviation [MD]).Preoperatively, 216 eyes (mean global pRNFL thickness, 94.3 ± 12.4 μm; 88.5%) were included in the normal pRNFL group (≥70 μm) and 28 eyes (mean global pRNFL thickness, 54.3 ± 11.0 μm; 11.5%) were included in the thin pRNFL group (70 μm). There was a very strong correlation between pre- and postoperative pRNFL thickness (r = 0.930). The thin pRNFL group showed a stronger correlation between pre- and postoperative MDs than the normal pRNFL group (r = 0.619 and r = 0.420, respectively; P0.01). Multivariate analyses identified pRNFL thickness as the only significant predictor of postoperative visual acuity (odds ratio [OR], 25.02; 95% confidence interval [CI], 7.68-81.50; P0.01) and visual field (OR, 39.46; 95% CI, 10.39-149.83; P0.01).Preoperative pRNFL thickness plays a prognostic value in postoperative visual outcome after EES for sellar and suprasellar tumors. Patients with pRNFL thickness ≥70 μm before surgery are more likely to improve visual outcome than those with thickness70 μm.

This study aimed to compare the surgical outcomes and morbidities of retrosigmoid and translabyrinthine approaches for large vestibular schwannoma (VS), with a focus on cerebellar injury and morbidities. Eighty-six consecutive patients with large VS, with a maximal extrameatal diameter > 3.0 cm, were reviewed between August 2010 and September 2018. The surgical outcomes, operating time, volume change of perioperative cerebellar edema, and inpatient rehabilitation related to cerebellar morbidities were compared between the two approaches. In total, 53 and 33 patients underwent the retrosigmoid and translabyrinthine approaches, respectively. The median follow-up time was 34.5 months. Surgical outcomes, including the extent of resection, tumor recurrence, and facial nerve preservation, showed no significant differences between the two groups. Patients who underwent the retrosigmoid approach showed a marginal trend for postoperative lower cranial nerve (LCN) dysfunction (P = 0.068). Although the approaching procedure time was longer in the translabyrinthine group, the tumor resection time was significantly longer in the retrosigmoid group (P = 0.001). The median change in the volume of the perioperative cerebellar edema was significantly larger in the retrosigmoid group (P < 0.001) and significantly related to the retrosigmoid approach, solid VS, and tumor resection time. Most cerebellar and LCN deficits were transient; however, the patients in the retrosigmoid group underwent inpatient rehabilitation more than those in the translabyrinthine group (P = 0.018). Both surgical approaches show equivalent surgical outcomes. Notably, the translabyrinthine approach for large VS has advantages in that it reduces cerebellar injury and related morbidities.

Stereotactic radiosurgery (SRS) is feasible for malignant glioma; however, delivering the optimal radiation dose with sufficient large-volume coverage is a major concern. We aimed to investigate the clinical efficacy and safety of fractionated SRS (fSRS) versus single-session SRS (sSRS) for malignant gliomas. We retrospectively reviewed 58 malignant glioma patients who underwent gamma knife SRS from January 2015 to December 2018. Forty-one underwent sSRS, and 17 underwent fSRS. Median dose for fSRS was 28 Gy (range 24–35 Gy), with a median dose of 6 Gy per fraction (range 5–7 Gy). Patients received 4 or 5 fractions on consecutive days. Median dose for sSRS was 18 Gy (range 11–25 Gy), with a median isodose of 50% (range 50–65%). Mean target volumes were 5.9 and 19.3 cc for sSRS and fSRS, respectively (p

The optimal interfraction intervals for fractionated radiosurgery has yet to be established. We investigated the outcome of fractionated gamma knife radiosurgery (FGKRS) for large brain metastases (BMs) according to different interfraction intervals. Between September 2016 and May 2018, a total of 45 patients who underwent FGKRS for BMs were enrolled in this study. They were divided into two groups (standard fractionation over 3 consecutive days with a 24-h interfraction interval versus prolonged fractionation over 4 or 5 days with an interfraction interval of at least 48-h). BMs with ≥ 2 cm in maximum diameter or ≥ 5 cm3 in volume were included in analysis. Among 52 BMs treated with 3-fraction GKRS, 25 (48.1%) were treated with standard fractionation scheme, and 27 (51.9%) with prolonged fractionation scheme. The median follow-up period was 10.5 months (range 5–25). Local tumor control rates of the standard group were 88.9% at 6 months and 77.8% at 12 months, whereas those of the prolonged group were 100% at 6 and 12 months (p = 0.023, log-rank test). In multivariate analysis, fractionation scheme (hazard ratio [HR] 0.294, 95% CI 0.099–0.873; p = 0.027) and tumor volume (HR 0.200, 95% CI 0.051–0.781; p = 0.021) were revealed as the only significant factors affecting the local tumor control after 3-fraction GKRS. Our preliminary tumor control results suggest a promising role of 3-fraction GKRS with an interfraction interval of at least 48-h. This fractionation regimen could be an effective and safe treatment option in the management of large BMs.

Purpose Targeted next-generation sequencing (NGS) panels for solid tumors have been useful in clinical framework for accurate tumor diagnosis and identifying essential molecular aberrations. However, most cancer panels have been designed to address a wide spectrum of pan-cancer models, lacking integral prognostic markers that are highly specific to gliomas. Materials and methods To address such challenges, we have developed a glioma-specific NGS panel, termed "GliomaSCAN," that is capable of capturing single nucleotide variations and insertion/deletion, copy number variation, and selected promoter mutations and structural variations that cover a subset of intron regions in 232 essential glioma-associated genes. We confirmed clinical concordance rate using pairwise comparison of the identified variants from whole exome sequencing (WES), immunohistochemical analysis, and fluorescence in situ hybridization. Results Our panel demonstrated high sensitivity in detecting potential genomic variants that were present in the standard materials. To ensure the accuracy of our targeted sequencing panel, we compared our targeted panel to WES. The comparison results demonstrated a high correlation. Furthermore, we evaluated clinical utility of our panel in 46 glioma patients to assess the detection capacity of potential actionable mutations. Thirty-two patients harbored at least one recurrent somatic mutation in clinically actionable gene. Conclusion We have established a glioma-specific cancer panel. GliomaSCAN highly excelled in capturing somatic variations in terms of both sensitivity and specificity and provided potential clinical implication in facilitating genome-based clinical trials. Our results could provide conceptual advance towards improving the response of genomically guided molecularly targeted therapy in glioma patients.

To find genetic markers associated with response to radiotherapy (RT) in glioblastoma (GB) patients.From Jan 2009 to Dec 2016, 161 patients with newly diagnosed IDH-wild type GB were treated with surgery and adjuvant concurrent chemoradiotherapy with the Stupp's regimen, and then genomic research proceeded with their surgical specimens. Among the 161 patients, 49 with clinically measurable disease on postoperative MRI were analyzed. The response evaluation to RT was based on Response Assessment in Neuro-Oncology (RANO) criteria. For genomic analyses to compare between patients with progression and non-progression, Fisher test for DNA mutations and copy number alterations and the Gene Set Enrichment Analysis (GSEA) were performed.RT responses were non-progressive and progressive disease (PD) in 22 (44.9%) and 27 patients (55.1%), respectively. After three months, seven of PD exhibited pseudoprogression. For true response adjusting pseudoprogression from PD, 1-year progression-free survival for true Non-Responders (tNR-group) and true Responders (tR-group) were 0% and 45.4% (p 0.001), and overall survival were 52.5% and 81.1% (p = 0.046), respectively. In genomic analyses, the tNR-group had more CDKN2A deletions (94.4% vs. 55.6%, p = 0.013), EGFR mutations (33.3% vs. 3.7%, p = 0.012) and less TP53 mutations (22.2% vs. 40.7%, p = 0.333) than the tR-group. In GSEA, immune-related gene sets were enriched in the tNR-group, and in contrast, some gene sets related with cell cycle were enriched in tR-groups.The RANO criteria were feasible for the short-term response evaluation from RT despite of pseudoprogression. Genomic differences such as CDKN2A deletion, EGFR mutation, and immune- or inflammation-related related gene sets enrichment were found to be potentially predictive markers of RT.

Hypermutagenesis refers to marked increase in the number of mutations due to continuous mutagenic process. Hypermutated tumors, have being found in several tumor types, are associated with inherited or acquired alterations in the DNA repair pathways. Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide(TMZ)‐induced mutagenesis. In our study, we have identified a rare subset of treatment‐naïve adult gliomas with de novo hypermutator phenotype and explored the evolution of spontaneous and treatment‐induced hypermutagenesis. We conducted Whole‐Exome Sequencing (WES), Whole‐Transcriptome Sequencing (WTS), and Single‐Cell Sequencing (SCS) of TMZ‐naïve and post‐TMZ‐treated hypermutated tumors to identify distinct clinical or genomic manifestations that contribute to the development of hypermutation in untreated adult gliomas. TMZ‐naïve hypermutated tumors were marked by absence of IDH1 somatic mutation and MGMT promoter (pMGMT) methylation, two genomic traits that were significantly associated with the TMZ‐induced hypermutagenic event in glioblastoma, and harbored inherited alterations in the mismatch repair (MMR) machinery. The immediate family members of the TMZ‐naive hypermutated glioma patients were also previous diagnosed with cancer development history, suggesting that germline dysfunction of the MMR pathway could potentially pose hereditary risk to genetic predisposition of carcinogenesis in gliomas. Lastly, both TMZ‐naïve and post‐TMZ‐treated hypermutated tumors exhibited a significant accumulation of neoantigen loads, suggesting immunotherapeutic alternatives. Our results present new and unique understanding of hypermutagenic process in adult gliomas and an important step towards clinical implication of immunotherapy in glioma treatment., What's new? Hypermutation has been observed in a subset of adult glioma patients as a direct result of temozolomide (TMZ)‐induced mutagenesis, leading to therapeutic resistance. Here, the authors identified a rare subset of pre‐treatment adult glioma patients with de novo hypermutator phenotype. TMZ‐naïve hypermutated tumors lacked somatic mutation of IDH1 and MGMT promoter methylation, and harbored both germline and somatic dysregulation of mismatch repair machinery encoding genes. Patients with TMZ‐naïve hypermutagenesis demonstrated high incidence of cancer‐development history in their immediate family members. Both TMZ‐naïve and post‐TMZ treated hypermutated tumors exhibited a significant accumulatin of neoantigen loads, pointing towards potential implementation of immunotherapy.

Objective The retroinfundibular and upper clival regions are challenging to access using the endoscopic endonasal approach because these regions are obstructed by the dorsum sellae and posterior clinoid processes. We evaluated the safety and clinical efficacy of endoscopic dorsum sellar resection (DSR) and identified the optimal indications for endoscopic DSR in patients with craniopharyngioma. Methods A retrospective study was conducted of patients who had undergone treatment with an endoscopic endonasal approach from January 2014 to January 2019. We identified a total of 50 patients who had undergone DSR. The indications for DSR included the following: 1) a tumor involving the upper clivus; 2) a tumor located behind the dorsum sellae; and 3) a tumor involving the interpeduncular or prepontine cistern. We evaluated the clinical outcomes, postoperative endocrinological status, and surgical morbidities. Results Of the 50 patients, 16 had been treated for craniopharyngioma, 30 for chordoma, 2 for pituitary adenoma, 1 for schwannoma, and 1 for chondrosarcoma. An extradural approach for DSR with posterior clinoidectomy was performed in 33 patients (66.0%) and an interdural transcavernous approach in 17 patients (34.0%). The overall gross total tumor resection rate was 92.0% (46 of 50 patients). Postoperatively, 28 of 33 patients (84.8%) with normal pituitary function preoperatively showed preservation of hormonal function postoperatively. Conclusions DSR with or without posterior clinoidectomy is a challenging procedure that requires considerable effort and advanced surgical techniques. However, it can be safely performed with accumulating experience and a thorough knowledge of the surrounding anatomical structures.

Background Intended subtotal resection (STR) followed by adjuvant gamma knife radiosurgery (GKRS) has emerged as an effective treatment option for facial nerve (FN) preservation in vestibular schwannomas (VSs). This study aimed to identify the optimal cut-off volume of residual VS to predict favorable outcomes in terms of both tumor control and FN preservation. Methods This retrospective study assessed the patients who underwent adjuvant GKRS for residual VS after microsurgery. A total of 68 patients who had been followed up for ≥ 24 months after GKRS were included. Tumor progression was defined as an increase in tumor volume (TV) of ≥ 20%. House-Brackmann grades I and II were considered to indicate good FN function. Results The median residual TV was 2.5 cm3 (range: 0.3–27.4). The median follow-up period after the first adjuvant GKRS was 64 months (range: 25.7–152.4). Eight (12%) patients showed tumor progression. In multivariate analyses, residual TV was associated with tumor progression (P = 0.003; hazard ratio [HR], 1.229; 95% confidence interval [CI], 1.075–1.405). A residual TV of 6.4 cm3 was identified as the cut-off volume for showing the greatest difference in progression-free survival (PFS). The 5-year PFS rates in the group with residual TVs of < 6.4 cm3 (54 patients) and that with residual TVs of ≥ 6.4 cm3 (14 patients) were 93.3% and 69.3%, respectively (P = 0.014). A good FN outcome was achieved in 57 (84%) patients. Residual TV was not associated with good FN function during the immediate postoperative period (P = 0.695; odds ratio [OR], 1.024; 95% CI, 0.908–1.156) or at the last follow-up (P = 0.755; OR, 0.980; 95% CI, 0.866–1.110). Conclusion In this study, residual TV was associated with tumor progression in VS after adjuvant GKRS following STR. As preservation of FN function is not correlated with the extent of resection, optimal volume reduction is imperative to achieve long-term tumor control. Our findings will help surgeons predict the prognosis of residual VS after FN-preserving surgery., Graphical Abstract

Intratumor spatial heterogeneity facilitates therapeutic resistance in glioblastoma (GBM). Nonetheless, understanding of GBM heterogeneity is largely limited to the surgically resectable tumor core lesion while the seeds for recurrence reside in the unresectable tumor edge. In this study, stratification of GBM to core and edge demonstrates clinically relevant surgical sequelae. We establish regionally derived models of GBM edge and core that retain their spatial identity in a cell autonomous manner. Upon xenotransplantation, edge-derived cells show a higher capacity for infiltrative growth, while core cells demonstrate core lesions with greater therapy resistance. Investigation of intercellular signaling between these two tumor populations uncovers the paracrine crosstalk from tumor core that promotes malignancy and therapy resistance of edge cells. These phenotypic alterations are initiated by HDAC1 in GBM core cells which subsequently affect edge cells by secreting the soluble form of CD109 protein. Our data reveal the role of intracellular communication between regionally different populations of GBM cells in tumor recurrence., Intratumoural spatial heterogeneity is crucial to enhance therapeutic resistance in glioblastoma. Here, the authors show a paracrine signaling mechanism where glioblastoma-initiating cells located in the tumour edge elevate their malignancy by interaction with core-located tumour cells.

Stereotactic radiosurgery such as Gamma Knife radiosurgery (GKRS) has been shown to have a good treatment effect for orbital cavernous venous malformation (CVM). However, radiation-induced retinopathy or optic neuropathy is a vision-threatening complication of orbital irradiation. Predicting the post-treatment visual outcome is critical. Clinical and radiological outcomes were investigated in 30 patients who underwent GKRS for orbital CVM between July 2005 and February 2020. Measurement of peripapillary retinal nerve fiber layer (pRNFL) thickness using optical coherence tomography (OCT) was obtained in 14 patients. The median clinical and radiological follow-up periods were 46.6 months (range, 15.9–105.8) and 27.5 months (range, 15.4–105.8), respectively. Twenty-eight patients underwent multisession (4 fractions) GKRS. The median cumulative marginal dose was 20 Gy (range, 16–24). Two patients underwent single-session GKRS. Marginal doses were 15 Gy and 10.5 Gy in each patient. The volume of CVM decreased in 29 (97%) patients. Visual acuity was improved in 6 (20%) patients and was stable in 22 (73%) patients. Visual field defect and exophthalmos were improved in all patients. Serial investigation of OCT showed no statistically significant difference in pRNFL thickness after GKRS. Patients with normal average pRNFL thickness showed better visual recovery than patients with thin average pRNFL thickness. GKRS is an effective and safe treatment option for orbital CVM. The pRNFL thickness before GKRS can be a prognostic indicator for visual recovery in orbital CVM after GKRS.

Objectives: Surgical resection of nonfunctioning pituitary adenoma (NFPA) invading the cavernous sinus (CS) remains a challenging and significant factor associated with incomplete resection. The residual tumor in CS is usually treated with adjuvant stereotactic radiosurgery (SRS), but there is little information concerning SRS as an initial treatment for CS-invading NFPA. In this study, we investigated the tumor control rate and clinical outcomes of the patients who received primary gamma knife radiosurgery (GKRS) for CS-invading NFPA. Methods: This was a single-institute retrospective analysis of 11 patients. CS invasion of tumor was categorized using the modified Knosp grading system. The median tumor volume and maximal diameter were 1.6 cm3 (range 0.4–6.5) and 17.2 mm (range 11.6–23.3), respectively. The median clinical follow-up period was 48.5 months (range 16.4–177.8). The median prescription dose at tumor margin was 15 Gy (range 11–25) and median prescription isodose was 50% (range 45–50). The maximum radiation dose to optic chiasm and optic nerve were 7.2 Gy (range 3.4–9.2) and 7.5 Gy (range 4.5–11.5), respectively. Results: Tumor control was achieved in all patients. The median tumor volume and maximal diameter at last follow-up were 0.4 cm3 (range 0.1–2.3) and 11.4 mm (range 4.7–19.5), respectively. The median volume reduction rate was 52% (range 33–88). Six patients showed downgrading of modified Knosp grade after GKRS. No patients developed GKRS-related complications such as hypopituitarism or visual disturbance. Conclusions: SRS may be an alternative primary treatment option for CS-invading NFPA if there is no urgent and absolute indication for surgery such as optic apparatus compression.

The optimal radiotherapy regimen in elderly patients with glioblastoma treated by chemoradiation needs to be addressed. We provide the results of a comparison between conventionally fractionated standard radiotherapy (CRT) and short-course radiotherapy (SRT) in those patients treated by temozolomide-based chemoradiation.Patients aged 65 years or older from the GBM-molRPA cohort were included. Patients who were planned for a ≥ 6-week or ≤ 4-week radiotherapy were regarded as being treated by CRT or SRT, respectively. The median RT dose in the CRT and SRT group was 60 Gy in 30 fractions and 45 Gy in 15 fractions, respectively.A total of 260 and 134 patients aged older than 65 and 70 years were identified, respectively. CRT- and SRT-based chemoradiation was applied for 192 (73.8%) and 68 (26.2%) patients, respectively. Compared to SRT, CRT significantly improved MS from 13.2 to 17.6 months and 13.3 to 16.4 months in patients older than 65 years (P 0.001) and 70 years (P = 0.002), respectively. Statistical significance remained after adjusting for age, performance status, surgical extent, and MGMT promoter methylation in both age groups. The benefit was clear in all subgroup analyses for patients with Karnofsky performance score 70-100, Karnofsky performance score ≤ 60, gross total resection, biopsy, methylated MGMT promoter, and unmethylated MGMT promoter (all P 0.05).CRT significantly improved survival compared to SRT in elderly glioblastoma patients treated with chemoradiation in selected patients amenable for chemoradiation. This study is hypothesis-generating and a prospective randomized trial is urgently warranted.

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ., Chemotherapy resistance in recurrent gliomas is a large hurdle for successful therapy. Here, the authors show that some recurrent gliomas harbour O-6-methylguanine-DNA methyltransferase (MGMT) genomic rearrangements, and in vitro and in vivo these contribute to temozolomide resistance.

OBJECTIVEThe authors conducted this retrospective study to investigate the clinical outcomes of intracranial solitary fibrous tumor (SFT) and hemangiopericytoma (HPC), defined according to the 2016 WHO classification of central nervous system (CNS) tumors.METHODSHistopathologically proven intracranial SFT and HPC cases treated in the period from June 1996 to September 2014 were retrospectively reviewed and analyzed. Two neuropathologists reviewed pathological slides and regraded the specimens according to the 2016 WHO classification. Factors associated with progression-free survival (PFS) and overall survival (OS) were statistically evaluated with uni- and multivariate analyses.RESULTSThe records of 47 patients—10 with SFT, 33 with HPC, and 4 with anaplastic HPC—were reviewed. A malignant transition from conventional SFT to WHO grade III SFT/HPC was observed in 2 cases, and 13 HPC cases were assigned grade III SFT/HPC. Mean and median follow-ups were 114.6 and 94.7 months, respectively (range 7.1–366.7 months). Gross-total resection (GTR) was significantly associated with longer PFS and OS (p = 0.012 for both), and adjuvant radiation therapy versus no such therapy led to significantly longer PFS (p = 0.018). Extracranial metastases to the liver, bone, lung, spine, and kidney occurred in 10 patients (21.3%). Grade III SFT/HPC was strongly correlated with the development of extracranial metastases (p = 0.031).CONCLUSIONSThe 2016 WHO classification of CNS tumors reflected the different types of pathological malignant progression and clinical outcomes better than prior classifications. Gross-total resection should be the primary treatment goal in patients with SFT/HPC, regardless of the pathological grade, and radiation can be administered as adjuvant therapy for patients with SFT/HPC that shows an aggressive phenotype or that is not treated with GTR.

In terms of response to fractionated radiotherapy, metastatic brain tumors of certain origins are considered radioresistant. To determine the influence of “radioresistant” histology on outcomes of brain metastases treated with radiosurgery. Between 2001 and 2017, 121 patients with brain metastases from renal cell carcinoma (RCC) and 2151 from non-small cell lung cancer (NSCLC) were reviewed. Eighty-seven pairs were derived using propensity score matching. Local progression-free survival (PFS), progression patterns, distant PFS, and overall survival were investigated. The median follow-up period was 13.7 months (range, 1.6–78.4 months). A total of 536 lesions were treated using gamma knife radiosurgery (GKS), with a median dose of 20 Gy (range, 12–28 Gy). The actuarial local PFS rates in the RCC group were 91% and 89% at 6 and 12 months, respectively, and did not differ from the NSCLC group (97% and 83% at 6 and 12 months, respectively). Continuous progression, without response to GKS, was noted in seven of the eight progressed RCCs. However, six of the seven progressed NSCLCs showed transient shrinkage before progression. The median distant PFS was 9.3 months (95% CI, 6.3–12.2) in the RCC group and 8.0 months (95% CI, 5.5–10.4) in the NSCLC group. The median overall survival was 16.1 months (95% CI, 11.3–20.8) and 14.9 months (95% CI, 11.9–17.8) in RCC and NSCLC groups, respectively. Histological differences had no effect on local control in the single high-dose range used for radiosurgery. However, changes in tumor volume during progression varied across tumor histology.

To determine the feasibility of using high dimensional computer-extracted features, known as radiomics features, in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma on multi-parametric MR imaging including diffusion-weighted imaging. Retrospective evaluation of data was approved by the local ethics committee and informed consent was waived. A total of 143 patients (two independent cohorts for discovery [n = 86; glioblastoma = 49, PCNSL = 37] and validation [n = 57; glioblastoma = 29, PCNSL = 28]) with newly diagnosed glioblastoma and PCNSL were subjected to radiomics analysis using the multi-parametric MRI (contrast-enhanced T1-weighted imaging, T2-weighted imaging, and diffusion-weighted imaging). Radiomics analyses were performed for two types of regions of interest (ROI) covering contrast-enhancing tumor and whole (enhancing or non-enhancing) tumor plus peritumoral edema. A total of 127 radiomics features were calculated. Feature selection was performed to identify the most discriminating features for every MR image in the discovery cohort. The identified features were used to calculate radiomics scores, which were later used in logistic regression to distinguish between PCNSL and glioblastoma. The classification model was further tested on the independent validation cohort. Fifteen features were selected as significant features in the discovery cohort. Using the identified features and calculated radiomics scores, the logistic regression-based classifier yielded an area under the curve (AUC) of 0.979, sensitivity of 0.938, and specificity of 0.944 in the discovery cohort to distinguish between glioblastoma and PCNSL. A similarly high rate of performance was observed in the validation cohort (AUC = 0.956). Radiomics features derived from multi-parametric MRI can be used to differentiate PCNSL from glioblastoma effectively.

Background Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features. Methods We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs. Results Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target. Conclusions Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients. Key points 1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.

Purpose Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression. Materials and methods We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3AmRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo. Results By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment. Conclusion In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.

Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

Objective Despite advances in endoscopic techniques, retrochiasmatic craniopharyngiomas (CPs) are difficult to remove completely, because the low-lying optic chiasm often provides an obstacle to an endoscopic endonasal approach. This study aimed to identify the endoscopic surgical outcomes of the retrochiasmatic CP and resolve the issues related to low-lying optic chiasm. Methods We reviewed 154 consecutive patients with CP who underwent endonasal endoscopic resection from February 2009 to April 2017 at 2 independent institutions. The topographic relationship of the tumor with the third ventricle, stalk, and optic chiasm and clinical outcomes were investigated. Results Retrochiasmatic CPs were found in 142 of 154 patients (92.2%). The median follow-up time was 25 months. Gross total resection and near-total resection were achieved in 113 patients (79.6%) and 21 patients (13.8%), respectively. Postoperative cerebrospinal fluid leaks were found in 16 patients (11.3%). Low-lying and high-lying chiasms were found in 44 patients (31.0%) and 98 patients (69.0%), respectively. Low-lying chiasm did not affect clinical outcomes including the extent of resection. Patients with low-lying chiasm showed a marginal trend for postoperative visual deterioration. The ventricular growth pattern representing the origin of the tumor and previous surgery were significantly associated with the position of the optic chiasm (P = 0.007 and 0.001, respectively). Conclusions An endoscopic endonasal approach is an effective surgical approach for retrochiasmatic CP, even in tumors with low-lying chiasm. However, a thorough and careful dissection is necessary to prevent visual deterioration.

This study was performed to determine the clinical significance of the Ki-67 labeling index (LI) for local control (LC) in patients with World Health Organization (WHO) grade II meningioma. We also tried to discern the effect of postoperative radiotherapy (PORT) on LC depending upon the Ki-67 LI value. The medical records and values of Ki-67 LIs were retrospectively reviewed for 50 patients who underwent surgical resection of intracranial WHO grade II meningiomas at Samsung Medical Center from May 2001 to December 2012. Forty-three patients (86%) were treated with immediate PORT. The median total radiation dose was 60 Gy (range, 54 to 60 Gy). The median follow-up was 47.4 months. The mean Ki-67 LI was 13% (range, 1% to 47%). Twelve patients (24.0%) showed local failure, and 8 patients (16.0%) experienced local failure even after PORT. The mean Ki-67 LI was 15% in patients with local failure (n=12) and 12% in patients without local failure (n=38). The 3-year actuarial LC was 80.5%. The 3-year overall survival was 89.5%. Ki-67 LI>13% and PORT were significant prognostic factors for LC (P=0.015 and 0.009, respectively). In patients with Ki-67 LI>13% (n=17), PORT (n=14) improved LC (P13%, PORT should be recommended to improve LC.

The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models.

We conducted this study to determine whether the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter was a prognostic marker for positive outcomes of gamma knife radiosurgery (GKS) for recurrent glioblastoma (GBM). We retrospectively examined 61 patients, who underwent GKS for local recurrent GBM between 2004 and 2015; in all patients, the methylation status of the MGMT promoter was identified via methylation-specific quantitative real-time polymerase chain reaction. All patients underwent surgical resection and were diagnosed histopathologically with GBM. Prognostic factors associated with progression-free survival (PFS) and overall survival (OS) were identified in univariate and multivariate analyses. Twenty-five (41%) had a methylated MGMT promoter, and 36 (59%) had an unmethylated MGMT promoter. The median age at GKS was 58 years. The median tumor volume at GKS was 7.0 cm3, and the median marginal dose was 16 Gy. The median follow-up period after GKS was 7.5 months. The median PFS time after GKS was 8.9 months (95% CI 4.3–13.5 months) in the methylated and 4.6 months (95% CI 3.7–5.5 months) in the unmethylated group (P = 0.016). The median OS time after GKS was 14.0 months (95% CI 9.3–18.7 months) in the methylated group and 9.0 months (95% CI 6.5–11.5 months) in the unmethylated group (P = 0.026). Methylation of the MGMT promoter correlated with better PFS and OS after GKS for recurrent GBM. Prospective comparative studies are required to determine whether MGMT methylation directly affects the efficiency of GKS.

Background Gynecologic malignancy is one of the leading causes of mortality in female adults worldwide. Comprehensive genomic analysis has revealed a list of molecular aberrations that are essential to tumorigenesis, progression, and metastasis of gynecologic tumors. However, targeting such alterations has frequently led to treatment failures due to underlying genomic complexity and simultaneous activation of various tumor cell survival pathway molecules. A compilation of molecular characterization of tumors with pharmacological drug response is the next step toward clinical application of patient-tailored treatment regimens. Results Toward this goal, we establish a library of 139 gynecologic tumors including epithelial ovarian cancers (EOCs), cervical, endometrial tumors, and uterine sarcomas that are genomically and/or pharmacologically annotated and explore dynamic pharmacogenomic associations against 37 molecularly targeted drugs. We discover lineage-specific drug sensitivities based on subcategorization of gynecologic tumors and identify TP53 mutation as a molecular determinant that elicits therapeutic response to poly (ADP-Ribose) polymerase (PARP) inhibitor. We further identify transcriptome expression of inhibitor of DNA biding 2 (ID2) as a potential predictive biomarker for treatment response to olaparib. Conclusions Together, our results demonstrate the potential utility of rapid drug screening combined with genomic profiling for precision treatment of gynecologic cancers.

Background We sought to describe corneal epithelial changes after using epidermal (EGFR) or fibroblast growth factor receptor (FGFR) inhibitors as chemotherapy and to clarify incidence and prognosis. Materials Retrospective chart review. Results Among 6871 patients and 17 EGFR or FGFR inhibitors, 1161 patients (16.9%) referred for ophthalmologic examination. In total, 1145 patients had disease-related or unrelated ocular complications. Among 16 patients with treatment-related ocular complications, three patients had treatment-related radiation retinopathy and one patient showed treatment-related corneal ulcer. Finally the authors identified that, in 12 patients, three EGFR inhibitors and two FGFR inhibitors caused corneal epithelial lesions. Vandetanib, Osimertinib, and ABT-414 caused vortex keratopathy in nine patients, while ASP-5878 and FPA-144 caused epithelial changes resembling corneal dysmaturation in three patients. The mean interval until symptoms appeared was 246 days with vandetanib, 196 days with osimertinib, 30 days with ABT-414, 55 days with ASP-5878, and 70 days with FPA-144. The mean of the lowest logarithm of minimal angle of resolution visual acuity results of the right and left eyes after chemotherapy were 0.338 and 0.413. The incidence rates of epithelial changes were 15.79% with vandetanib, 0.5% with osimertinib, 100% with ABT-414, 50.0% with ASP-5878, and 18.2% with FPA-144. After excluding deceased patients and those who were lost to follow-up or still undergoing treatment, we confirmed the reversibility of corneal lesions after the discontinuation of each agent. Seven patients showed full recovery of their vision and corneal epithelium, while three achieved a partial level of recovery. Although patients diagnosed with glioblastoma used prophylactic topical steroids before and during ABT-414 therapy, all developed vortex keratopathy. Conclusions EGFR and FGFR inhibitors are chemotherapy agents that could make corneal epithelial changes. Contrary to the low probability of ocular complication with old EGFR drugs, recently introduced EGFR and FGFR agents showed a high incidence of ocular complication with severe vision distortion. Doctors should forewarn patients planning chemotherapy with these agents that decreased visual acuity could develop due to corneal epithelial changes and also reassure them that the condition could be improved after the end of treatment without the use of steroid eye drops. Trial registration This study was approved by the institutional review board (IRB) of Samsung Medical Center (IRB no. 2019–04-027) and was conducted according to the principles expressed in the Declaration of Helsinki.

Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation.

Objective Although the endoscopic transpterygoid approach has been popularized, there are no studies about anatomy-specific morbidities of this approach. The objective of this study is to investigate the surgical morbidities associated with the endoscopic transpterygoid approach for resection of anatomic structures. Methods A retrospective analysis was carried out of prospectively collected data of patients who underwent the endoscopic transpterygoid approach for skull base tumor by a single ear nose and throat surgeon in a tertiary-care center from November 2013 to January 2019. Postoperative patient symptom prevalence associated with surgical findings and SNOT-22 (Sino-Nasal Outcome Test–22) score were included in the analysis. Results Thirty-seven consecutive patients were enrolled. The mean follow-up period was 12.4 months (range, 1–39 months). Twenty-six (70.3%) vidian nerves were sacrificed, but only 38.5% of those patients (10/26) reported mild dry eye symptoms. Fourteen nasolacrimal ducts (37.8%) were resected, with only 1 patient (7.1%) who had undergone previous radiation therapy reporting transient epiphora. SNOT-22 scores before and after surgery did not present statistical difference in inferior turbinate sacrifice group and preservation group. Conclusions Sacrifice of sinonasal structures such as the inferior turbinate or vidian nerve is sometimes inevitable for safe tumor resection with the endoscopic transpterygoid approach. Subjective symptoms were not apparent in most patients, despite the structural sacrifice.

Preoperative tumor-related edema of the optic tract (EOT) is often found along the white matter tract of the visual system. However, the relationship of EOT with visual function and outcome remains unclear. Therefore we aimed to elucidate whether the presence of EOT is associated with visual outcome in patients with sellar and suprasellar tumors.A total of 212 eyes of 106 patients who underwent endoscopic endonasal surgery for sellar and suprasellar tumors at our institution between March 2016 and August 2018 were included in this retrospective study. Data on patient characteristics, preoperative magnetic resonance imaging findings, and ophthalmologic evaluations were collected. Patients were assigned to 2 groups depending on preoperative magnetic resonance imaging findings (EOT group = 19 [17.9%], non-EOT group = 87 [82.1%]). Visual acuity, visual field (VF), global visual function score, VF index, VF mean deviation, and retinal nerve fiber layer thickness as determined by optical coherence tomography were compared between the groups before and after treatment.In the EOT group, 4 patients had pituitary adenoma, 8 had craniopharyngioma, and 7 had other pathologies. There was no significant difference of pathologies between the groups. Preoperatively, EOT group showed significantly lower values of global visual function score, VF index, mean deviation, and retinal nerve fiber layer thickness than did the non-EOT group (P0.001). Postoperatively, the EOT group showed worse visual outcomes than did the non-EOT group.This study reveals that EOT caused by sellar and suprasellar tumors is associated with worse visual function and poor improvement postoperatively.

Introduction Cerebrospinal fluid (CSF) leaks usually happen in the early postoperative period. However, delayed CSF leak can happen several years after treatment. The purpose of this study was to review the characteristics and clinical course of delayed CSF leak after treating skull base tumors. Methods We treated 9 patients with delayed CSF leak (occurring at least 3 months after treatment) between December 2015 and February 2018. Clinical data including initial treatment modality for skull base tumor, time between treatment and CSF rhinorrhea, and the result of endoscopic CSF repair were evaluated by retrospective chart review. Results Nine patients with delayed CSF leak were evaluated. The mean age was 42.3 ± 5.2 (mean ± SD) years. Six patients with pituitary adenomas, 1 with a Rathke cleft cyst, 1 with a meningioma, and 1 with an osteosarcoma were enrolled. Seven patients (78%) received radiation, and the mean radiation dose was 55.7 ± 2.6 Gy. The median time between the end of treatment for the skull base tumor and CSF rhinorrhea was 137.0 (interquartile range 24–145) months. Seven patients (78%) had meningitis at the time of operation. CSF rhinorrhea was treated with endoscopic reconstruction using a multilayer technique. Meningitis was improved without neurologic sequelae after reconstruction and antibiotic therapy. One patient had recurrence of CSF leak. Conclusion Patients with delayed CSF leak are more likely to have a history of radiation and to present with meningitis at diagnosis. Therefore, CSF rhinorrhea should always be suspected, even several years after treatment, if early symptoms of CSF leak develop in patients with a history of skull base tumor.

Glioblastoma multiforme (GBM), a deadly cancer, is the most lethal and common malignant brain tumor, and the leading cause of death in adult brain tumors. While genomic data continues to rocket, clinical application and translation to patient care are lagging behind. Big data now deposited in the TCGA network offers a window to generate novel clinical hypotheses. We hypothesized that a TCGA-derived gene-classifier can be applied across different gene profiling platforms and population groups. This gene-classifier validated three robust GBM-subtypes across six different platforms, among Caucasian, Korean and Chinese populations: Three Caucasian-predominant TCGA-cohorts (Affymetrix U133A = 548, Agilent Custom-Array = 588, RNA-seq = 168), and three Asian-cohorts (Affymetrix Human Gene 1.0ST-Array = 61, Illumina = 52, Agilent 4 × 44 K = 60). To understand subtype-relevance in patient therapy, we investigated retrospective TCGA patient clinical sets. Subtype-specific patient survival outcome was similarly poor and reflected the net result of a mixture of treatment regimens with/without surgical resection. As a proof-of-concept, in subtype-specific patient-derived orthotopic xenograft (PDOX) mice, Classical-subtype demonstrated no survival difference comparing radiation-therapy versus temozolomide monotherapies. Though preliminary, a PDOX model of Proneural/Neural-subtype demonstrated significantly improved survival with temozolomide compared to radiation-therapy. A larger scale study using this gene-classifier may be useful in clinical outcome prediction and patient selection for trials based on subtyping.

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.

Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P

Capmatinib is an oral, ATP‐competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose‐escalation results for capmatinib in advanced MET‐positive solid tumor patients and dose expansion in advanced non‐lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose‐limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, Ctrough >EC90 (90% inhibition of c‐MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose‐expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near‐complete immunohistochemically determined phospho‐MET inhibition (H‐score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high‐level MET GCN (GCN ≥6) and MET‐overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479)., MET dysregulation is an important newly established molecular driver of tumorigenesis in various cancers and is recognized as a negative prognostic factor. The findings of this study provide the recommended phase 2 dose (RP2D) of capmatinib and also safety and efficacy data in selected expansion cohorts treated at the RP2D.

Objective Crizotinib is a novel targeted anticancer agent for non–small cell lung cancer. In this study, we report our clinical outcomes from Gamma Knife radiosurgery (GKS) for brain metastasis (BM) under crizotinib treatment in non–small cell lung cancer patients. Methods We performed a retrospective review of 29 patients who underwent a total of 51 GKS procedures for BM while continuing on crizotinib. We compared 2 groups on the basis of the number of BMs: oligometastases (≤5) and polymetastases (>5). Results The actuarial 1- and 2-year overall survival rates from initial GKS were 73.5% and 42.6%, respectively. The estimated local progression-free survival (PFS) rates of the oligometastases group were 91.8% at 6 months and 84.2% at 12 months, whereas the local PFS rates of the polymetastases group at 6 and 12 months were 91.6% and 58.2%, respectively ( P = 0.153). The estimated distant PFS rates of the oligometastases group were 50.7% at 6 months and 20.3% at 12 months, whereas the distant PFS rates of the polymetastases group were 32.7% at 6 months and only 6.5% at 12 months ( P = 0.029). Conclusions GKS combined with crizotinib showed effective local tumor control and excellent outcome, especially in oligometastases. However, distant progression of BM during crizotinib after GKS occurred in most of the cases within a year. Thus brain surveillance after GKS is important for adequate and timely salvage treatment even when extracranial disease is well controlled by crizotinib.

// Doo-Sik Kong 1,* , Do-Hyun Nam 1,* , Shin-Hyuk Kang 2 , Jae Won Lee 3 , Jong-Hee Chang 4 , Jeong-Hoon Kim 5 , Young-Jin Lim 6 , Young-Cho Koh 7 , Yong-Gu Chung 2 , Jae-Min Kim 8 and Choong-Hyun Kim 8 1 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Department of Neurosurgery, College of Medicine, Korea University, Seoul, Korea 3 Department of Statistics, Korea University, Seoul, Korea 4 Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Korea 5 Department of Neurosurgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 6 Department of Neurosurgery, Kyunghee University Hospital, Seoul, Korea 7 Department of Neurosurgery, Konkuk University Medical Center, Seoul, Korea 8 Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea * These authors have contributed equally to this work Correspondence to: Choong Hyun Kim, email: // Keywords : immunotherapy, autologous cytokine-induced killer cell, glioblastoma Received : August 05, 2016 Accepted : September 23, 2016 Published : September 27, 2016 Abstract Purpose: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. Experimental design: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group). The efficacy endpoints were analyzed in the intention-to-treat set and in the per protocol set. Results: Between December 2008 and October 2012, a total of 180 patients were randomly assigned to the CIK immunotherapy ( n = 91) or control group ( n = 89 ). In the intention-to-treat analysis set, median PFS was 8.1 months (95% confidence interval (CI), 5.8 to 8.5 months) in the CIK immunotherapy group, as compared to 5.4 months (95% CI, 3.3 to 7.9 months) in the control group (one-sided log-rank, p = 0.0401). Overall survival did not differ significantly between two groups. Grade 3 or higher adverse events, health-related quality of life and performance status between two groups did not show a significant difference. Conclusions: The addition of CIK cells immunotherapy to standard chemoradiotherapy with TMZ improved PFS. However, the CIK immunotherapy group did not show evidence of a beneficial effect on overall survival.

PURPOSE The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample. MATERIALS AND METHODS A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively. RESULTS After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients, respectively. The methylation status of O6-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period. CONCLUSION Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

To discuss the appropriate treatment strategy for NF2-related vestibular schwannoma (VS) according to our experiences, we analyzed long-term clinical and radiological data focusing on NF2-related VS patients. Seventeen NF2-related VS patients were included. Based on their first management modality for VS, we classified these patients into the following four groups: microsurgery (MS), fractionated gamma knife radiosurgery (f-GKS), single session gamma knife radiosurgery (s-GKS), and conservative management (CM). Each patient was assessed for each separate ear. Changes of tumor volume and hearing status for 32 ears in 17 patients according to their first treatment modality were evaluated. The mean follow-up duration and tumor volume of the MS (4 ears, 4 patients), f-GKS (12 ears, 10 patients), s-GKS (8 ears, 7 patients), and CM (8 ears, 7 patients) groups were 3.9 years and 1.6 mL; 5.1 years and 11.1 mL; 8.4 years and 5.6 mL; and 6.1 years and 1.6 mL, respectively. Relatively lower local control rates were observed in the MS and the CM group (0 and 12.5 %, respectively). On the other hand, better local control rates for follow-up periods of 5.1 and 8.4 years were achieved in the f-GKS and the s-GKS groups (75 and 50 %, respectively). However, hearing preservation in all treatment modalities could not be achieved effectively. Long-term preservation of hearing in at least one serviceable ear as well as tumor control should be considered for each patient. Therefore, a proper treatment option should be selected at the appropriate time according to clinical characteristics of individual patients.

Objective Patients experience significant postoperative sinonasal symptoms for the first few months after endoscopic transnasal transsphenoidal approach (ETN-TSA) surgery. We modified this technique by bypassing the nasal mucosa and approaching through the septum bilaterally. In this study, we analyze whether these technical modifications, which we have termed the endoscopic modified transseptal transsphenoidal approach (EMTS-TSA), decrease postoperative sinonasal morbidity after endoscopic TSA. Methods We retrospectively reviewed a prospectively collected database. Patients who underwent endoscopic TSA from December 2012 to June 2014 were included. Thirty patients underwent ETN-TSA, and 51 underwent EMTS-TSA. Sino-Nasal Outcome Test-20, anterior skull base nasal inventory, and visual analog scale (VAS) for subjective olfaction were evaluated before and 1 and 3 months after surgery. Cross Cultural Smell Identification Test also was measured before and 3 months after surgery. Results There was a significant difference between the preoperative and 3-month VAS for olfaction in the ETN-TSA group (from 92.5 to 81.3; P = 0.002) but not the EMTS-TSA group (from 90.6 to 88.8; P = 0.403). There was no statistical difference in Sino-Nasal Outcome Test-20 or Cross-Cultural Smell Identification Test scores between 2 groups during follow-up. The EMTS-TSA group scored better than the ETN-TSA group in the anterior skull base nasal inventory subdomain ("nasal discharge," "urge to blow," and "trouble breading") 1 month postoperatively. Conclusions EMTS-TSA could preserve almost all nasal mucosa, including the septum and turbinates. EMTS-TSA may be useful for preserving early postoperative olfactory function and some sinonasal quality of life. We believe that EMTS-TSA is a good endoscopic pituitary surgery option.

The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR–GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.

The aim of this study was to compare sinonasal-related quality of life (QOL) in patients treated by extended or transsellar endoscopic skull base surgery.Prospective data analysis.Prospectively collected data from patients who underwent endoscopic skull base surgery between 2012 and 2017 were analyzed. Primary outcomes were preoperative Sino-Nasal Outcome Test-20 (SNOT-20) scores and then 1-month, 3-month, and 6-month follow-up. Comparative analysis was performed between the endoscopic transsellar approach (ETA) group (n = 647) and an extended endoscopic endonasal approach (EEEA) group (n = 120). In ETA group, the SNOT-20 score was compared between patients with a nasoseptal flap (NSF) (ETA-NSF) and without an NSF (ETA-no NSF).The mean total SNOT-20 score was significantly worse in the EEEA than ETA group at 1, 3, and 6 months postoperatively (P .05). Although there was no significant difference in total SNOT-20 score between the ETA-NSF and ETA-no NSF group at 3 and 6 months after surgery, the percentage of patients with significant change (≥0.8) in the SNOT-20 score was higher in the NSF used group at 1, 3, and 6 months postoperatively (22.92% vs. 13.51%, P = .029; 20.59% vs. 5.59%, P = .039; and 24.00% vs. 4.03%, P = .003, respectively). According to multivariate analysis conducted regarding factors that deteriorate sinonasal QOL at 6 months following surgery, only NSF usage is significantly associated with poor outcome (odds ratio: 4.371, P = .011) CONCLUSIONS: Sinonasal-related QOL was significantly worse in patients treated by the EEEA versus ETA. Use of an NSF is the only poor prognostic factor in sinonasal QOL after endoscopic skull base surgery.2b Laryngoscope, 129:1318-1324, 2019.