Endoscopic transorbital approach in children: surgical technique and early results.

OBJECTIVE: In this study, the authors aimed to describe the endoscopic transorbital approach (ETOA) in children. METHODS: Six pediatric patients (2 girls and 4 boys) underwent the ETOA for paramedian skull base lesions at a single institution between September 2016 and February 2023. RESULTS: The median age at the time of surgery was 7.5 (range 4-18) years. The median follow-up period was 33 (range 9-60) months. In this series, the ETOA level of difficulty included stage 1 (n = 2, 33.3%), stage 3 (n = 3, 50%), and stage 5 (n = 1, 16.7%). The ETOA was performed for tumor resection in 4 cases; the final pathology consisted of fibrous dysplasia, pilocytic astrocytoma, metastatic neuroblastoma, and choroid plexus papilloma. The procedure was also performed for repair of a petrous apex meningocele and for lateral orbital wall decompression of traumatic lateral rectus muscle entrapment. One patient experienced a transient cranial nerve III palsy after the procedure. There were no operative deaths in this series. CONCLUSIONS: In select cases, the ETOA can be considered a minimally invasive alternative for conventional skull base approaches in the armamentarium of pediatric skull base surgery. Further investigation and the accumulation of experience are warranted in the future to enhance the efficacy and applicability of the ETOA in pediatric patients.

Lateral Rectus Muscle Entrapment in Complex Orbital Fracture in a Child.

A 6-year-old boy presented with a lateral rectus muscle entrapment in a complex orbital fracture sustained during bicycle riding. He was diagnosed with a skull-base fracture with pneumocephalus and zygomatic and inferior orbital wall fractures at another hospital. The zygomatic fracture and pneumocephalus were treated conservatively. Although a detailed ocular motility examination could not be performed due to pain and inability to open the eyelid, the inferior wall fracture was surgically repaired. Postoperatively, persistent extraocular movement limitation prompted a referral to our clinic. Orbital CT imaging demonstrated a fracture at the greater wing of the sphenoid with a hypoattenuated area in the adjacent middle cranial fossa. Orbital MRI taken thereafter revealed lateral rectus and orbital fat prolapse into the middle cranial fossa, indicating entrapment of these structures through the lateral wall fracture. The incarcerated lateral rectus was released using an endoscopic transorbital approach via an upper lid crease, resulting in the recovery of extraocular movement.

Impact of boost sequence in concurrent chemo-radiotherapy on newly diagnosed IDH-wildtype glioblastoma multiforme.

BACKGROUND: The standard of care for glioblastoma multiforme (GBM) is maximal surgical resection followed by conventional fractionated concurrent chemoradiotherapy (CCRT) with a total dose of 60 Gy. However, there is currently no consensus on the optimal boost technique for CCRT in GBM. METHODS: We conducted a retrospective review of 398 patients treated with CCRT between 2016 and 2021, using data from two institutional databases. Patients were divided into two groups: those receiving sequential boost (SEB, N = 119) and those receiving simultaneous integrated boost (SIB, N = 279). The primary endpoint was overall survival (OS). To minimize differences between the SIB and SEB groups, we conducted propensity score matching (PSM) analysis. RESULTS: The median follow-up period was 18.6 months. Before PSM, SEB showed better OS compared to SIB (2-year, 55.6% vs. 44.5%, p = 0.014). However, after PSM, there was no significant difference between two groups (2-year, 55.6% vs. 51.5%, p = 0.300). The boost sequence was not associated with inferior OS before and after PSM (all p-values > 0.05). Additionally, the rates of symptomatic pseudo-progression were similar between the two groups (odds ratio: 1.75, p = 0.055). CONCLUSIONS: This study found no significant difference in OS between SEB and SIB for GBM patients treated with CCRT. Further research is needed to validate these findings and to determine the optimal boost techniques for this patient population.

Bevacizumab plus irinotecan with or without gamma knife radiosurgery after failure of concurrent chemo-radiotherapy for high-grade glioma.

INTRODUCTION: Concurrent chemo-radiotherapy (CCRT) with temozolomide (TMZ) is a standard first-line treatment for high-grade glioma. However, if CCRT with TMZ treatment fails, second-line treatment options have limited value. Bevacizumab plus irinotecan is the only available treatment option for such patients. The role of gamma knife radiosurgery (GKS) in patients with high-grade gliomas is not well-established. In this study, we evaluated the efficacy and safety of bevacizumab plus irinotecan with or without GKS in the treatment of high-grade glioma patients who progressed after initially being treated with CCRT with TMZ. METHODS: We collected clinical data of patients with biopsy-proven high-grade glioma (glioblastoma multiforme (GBM) or anaplastic astrocytoma) who were treated at Samsung Medical Center from January 2015 to December 2020, retrospectively. We evaluated the overall survival (OS), progression-free survival (PFS), and safety of bevacizumab plus irinotecan with or without GKS. RESULTS: In total, 203 patients were diagnosed with high-grade glioma, including GBM and anaplastic astrocytoma. The median OS was 8.73 months (95% confidence interval [CI]: 7.27-10.18), and the median PFS was 4.36 months (95% CI: 3.75-4.97). Sixty-eight (33.4%) patients underwent GKS prior to bevacizumab plus irinotecan treatment, which led to a significantly prolonged OS (10.13 months, 95% CI: 8.65-11.60 vs. 8.26 months, 95% CI: 7.01-9.51, p = 0.012). The most common adverse events of any grade were neutropenia (36.9%) and thrombocytopenia (22.6%). However, the incidence of adverse events in patients who underwent GKS prior to bevacizumab plus irinotecan was not different compared with those in patients who did not undergo GKS. CONCLUSIONS: Bevacizumab plus irinotecan was well-tolerated and moderately effective in patients with high-grade gliomas. The addition of GKS prior to bevacizumab plus irinotecan led to a significant OS benefit with a manageable safety profile. GKS prior to bevacizumab plus irinotecan can therefore be considered a potential treatment option for these patients.

Factors Influencing Patient Satisfaction after Microvascular Decompression for Hemifacial Spasm: A Focus on Residual Spasms.

INTRODUCTION: Patients with hemifacial spasm (HFS) experience improvement in symptoms after microvascular decompression (MVD); however, patient satisfaction is sometimes low. This study aimed to analyze the relationship between residual spasms and patient satisfaction, identify factors affecting satisfaction, and investigate the degree of improvement in spasms which result in patient satisfaction after surgery. METHODS: 297 patients who completed a questionnaire after MVD for HFS between March 2020 and June 2020 were included. Information on surgical outcomes and patient satisfaction was collected using the questionnaire, and their relationships were analyzed. RESULTS: Among the 297 patients, the mean residual spasm percentage and patient satisfaction score were negatively correlated with 14.0% and 8.8 points, respectively. In addition to residual spasms, discomfort caused by persistent spasms, psychological problem-solving, better social life, and interpersonal relationship improvement were associated with satisfaction. There was no significant association between the presence of complications and satisfaction. There was no significant difference in the satisfaction score at up to 30% residual spasm, and the patients with 0-30% residual spasm had a satisfaction score of 7 points or higher. CONCLUSION: Residual spasms and discomfort from residual spasms decreased patient satisfaction after MVD for HFS. It is then necessary to perform accurate surgical resolution to improve surgical outcomes and provide adequate management to reduce postoperative discomfort and anxiety, and ultimately to enhance satisfaction. Residual spasms of up to 30% compared with the preoperative severity can be considered a good outcome when evaluating surgical outcomes.

Functional and clinical outcomes after superior eyelid transorbital endoscopic approach for spheno-orbital meningiomas: illustrative case and literature review.

The pattern of growth of spheno-orbital meningiomas accounts for the main presenting symptoms, such as proptosis, eye motility deficit, visual impairment, diplopia. As these are benign tumors, the postoperative patient's quality of life is an important factor to consider during the preoperative planning. A detailed literature review of superior eyelid transorbital endoscopic approach for spheno-orbital meningiomas, including our own case, was made. A Medline search up to March 2022 in PubMed online electronic database was made using the following key phrases: "superior eyelid endoscopic transorbital approach spheno-orbital meningiomas," "superior eyelid endoscopic transorbital approach," "spheno-orbital meningiomas endoscopic approach." The inclusion criteria were surgical series, reviews, and case reports in English language, as well as papers written in other languages, but including the abstract in English. Cadaveric studies, multiportal combined approaches for SOM, were excluded. The literature review has disclosed five studies for a total of 65 patients, whose demographic, clinical, pathological, surgical, complications, and outcome data were analyzed. Functional and esthetic outcome data after superior eyelid transorbital approach are the following: improvement of proptosis (100%), of visual deficits (66.66%) and of ocular paresis (75%), with only 11 complications (4 trigeminal dysesthesia, 2 CSF leak, 2 wound complications, 1 upper eyelid necrosis, 1 hemorrhage of surgical field, 1 keratitis) reported, but at the expense of extent of resection (gross total resection 33.39%). Based on the outcome data, the superior eyelid transorbital endoscopic approach results in a suitable operative technique for selected spheno-orbital meningiomas.

Combined endoscopic endonasal and transorbital multiportal approach for complex skull base lesions involving multiple compartments.

PURPOSE: This study defines the specific areas that connect the surgical corridors of the endoscopic endonasal (EEA) and transorbital approach (TOA) to identify adequate clinical applications and perspectives of this combined multiportal approach. METHODS: Consecutive patients who underwent combined EEA and TOA procedures for various pathologies involving multiple compartments of the skull base were enrolled. RESULTS: A total of eight patients (2 chondrosarcomas, 2 meningiomas, 2 schwannomas, 1 glioma, and 1 traumatic optic neuropathy) were included between August 2016 and April 2021. The cavernous sinus (CS) was targeted as the connection area of the combined approach in four patients with tumors infiltrating the middle cranial fossa (MCF) and central skull base through the CS. For two patients with MCF tumors extending into the infratemporal fossa (ITF), the horizontal portion of the greater sphenoid wing and the foramen ovale were utilized as the connection area. In the remaining 2 patients, connection was achieved through the optic canal (OC). Gross total and near total resection was achieved in 5 patients with tumors, and circumferential removal of bone composing the OC was performed in one patient with traumatic compressive optic neuropathy. Postoperative complications included one cardiac arrest due to underlying cardiovascular disease and one case of oculomotor nerve palsy. CONCLUSIONS: The combined EEA and TOA procedure is a useful strategy for complex lesions involving multiple compartments of the skull base. Herein, we identified the specific areas connecting the two surgical approaches, allowing a common path for EEA and TOA procedures.

Learning curve and technical nuances of endoscopic skull base reconstruction with nasoseptal flap to control high-flow cerebrospinal fluid leakage: reconstruction after endoscopic skull base surgery other than pituitary surgery.

PURPOSE: Although reconstruction techniques after endoscopic skull base surgery have been improved, there are difficulties in reconstructing the skull base with a nasoseptal flap (NSF), especially in the case of high-flow cerebrospinal fluid (CSF) leak. The aim of this study was to analyze risk factors for the development of postoperative CSF leaks in terms of less experienced surgeon practices. METHODS: Retrospective review of medical records was performed for 125 patients who underwent endoscopic skull base surgery for intradural pathology with intraoperative high-flow CSF leakage between Oct 2012 and Apr 2017. Basic demographic data were collected, including body mass index (BMI), tumor pathology, comorbidities, and outcomes. To assess the learning curve effect, patients were divided into early cohort (n = 30) and late cohort (n = 95) groups. RESULTS: Overall postoperative CSF leakage was 10.4% (13/125) in this series. There were no significant risk factors for postoperative CSF leakage among the demographic data including BMI, comorbidities, or radiation history. Postoperative CSF leakage was most prevalent in the transclival approach than in other approaches, but the difference was not statistically significant (20.8%, p = 0.351). When dividing the results by timetable, the patients who underwent skull base reconstruction in the early cohort experienced more postoperative CSF leakage (23.3%, 7 cases out of 30) than in the late cohort (6.3%, 6 cases out of 95, p = 0.014). The learning curve was steeper in the early cohort (30 early cases 23.3%, 31-60 10%, 61-90 6.7%, 91-125 2.9%). CONCLUSIONS: To improve the success rate of endoscopic skull base reconstruction, surgeons have to keep the basic technical details in mind to reduce the learning curve.

Early hormonal recovery following endoscopic transsphenoidal surgery for silent non-functioning pituitary adenomas with hormone dysfunction.

PURPOSE: The role of transsphenoidal surgery in the recovery of preexisting hormone dysfunction from pituitary tumors remains controversial. This study aimed to investigate the incidence of hormone dysfunction among asymptomatic non-functioning pituitary adenomas and their recovery following endoscopic transsphenoidal surgery. METHODS: Eligibility criteria included age under 80 years, presence of a non-functioning pituitary adenoma compressing the normal gland resulting in deviation of the stalk, absence of visual symptoms, and availability for regular follow-up using MRI and pre- and post-operative endocrinological assessments. 182 patients with silent non-functioning pituitary adenomas were included in this study between March 2014 and December 2018. All patients underwent endoscopic transsphenoidal surgery and complete hormonal evaluation, with basal hormone assays and a combined pituitary function test before and after surgery until the end of last follow-up. RESULTS: Preoperative assessment of hormonal function revealed that 124 of 182 patients (68.1%) had at least a single hormone dysfunction preoperatively. Among these, 61 of 124 (49.2%) had a dysfunction in a single axis, and 63 (50.8%) had a hormone dysfunction in two or more axes. Overall, the median endocrinological follow-up duration was 15.0 months (6-57 months). At 1 month following surgery, 91 patients (73.4%) with hormone dysfunction experienced improvement in at least a single hormone axis. Prolactin was the most common hormone among those that recovered at the last follow up (92.8% improvement) followed by growth hormone (GH, 50.0%), thyroid stimulating hormone (TSH, 50.0%), gonadotropin (Gn, 46.9%), and adrenocorticotropic hormone (ACTH, 45.0%). Time to recovery varied from 1.1 months (for prolactin) to 2.2 months (for gonadotropin, and ACTH). In patients with preoperative deficiency in GH, and ACTH, postoperative transient diabetes insipidus was associated with poor recovery (GH: HR = 0.50, p = 0.048; ACTH: HR = 0.39, p = 0.023). CONCLUSIONS: Non-functioning pituitary adenomas with silent hormone dysfunction are often overlooked by clinicians and patients. We suggest that even silent hormone dysfunction in patients with non-functioning pituitary adenomas can be improved with effective surgical decompression and these tumors may be potential indications of endoscopic transsphenoidal surgery.

Orbital decompressive effect of endoscopic transorbital surgery for sphenoorbital meningioma.

PURPOSE: This study was aimed at evaluating the orbital decompressive effect of endoscopic transorbital approach (TOA) in the management of sphenoorbital meningioma involving the orbit. METHODS: Patients treated with TOA for this tumor from December 2016 to December 2019 were included, and the data were reviewed. Pre- and postoperative clinical and imaging findings were compared with a volumetric study. RESULTS: Eighteen patients (two men and 16 women) were included. Lateral wall hyperostosis (13 patients), extraconal tumor infiltration (18 patients), intraconal tumor infiltration (seven patients), and superior and lateral rectus encasement (nine patients) were found. Intraconal tumor infiltration in the posterior orbit affected compressive optic neuropathy (CON) more often than other tumor manifestations. The orbital soft tissue volume decreased to 91.18% ± 8.19% compared to that in the contralateral side preoperatively. The postoperative volume increased to 113.73% ± 12.92% compared to the preoperative volume. The average values of LogMAR visual acuity and visual field index score of ten patients with CON improved from 0.80 to 0.42 and 48.9 to 65.9%, respectively. All 17 patients with proptosis showed improvement after surgery. There were no significant complications associated with the surgery. Additional treatment, including gamma knife surgery, was applied to 12 cases for the remaining tumor. CONCLUSION: This minimally invasive surgical debulking procedure was successful in treating sphenoorbital meningioma without significant adverse events. Lateral orbital wall decompression and limited intraorbital tumor resection were effective for compressive orbitopathy from the tumor.

Association of Thyroid Hypofunction with Clinical Outcomes after Microvascular Decompression for Hemifacial Spasm.

INTRODUCTION: Data regarding the association between thyroid dysfunction and hemifacial spasm (HFS) are limited. We conducted a single-center, retrospective study to investigate the predictive value of thyroid dysfunction in patients with HFS after microvascular decompression (MVD). METHODS: Between July 2004 and January 2015, 156 patients who were tested for thyroid hormones after MVD for HFS were enrolled in the present study. We assessed their detailed history, clinical manifestations, serum thyroid hormone levels, and surgical outcomes. The patients were classified into low and high groups based on thyroid hormone concentrations, and clinical outcomes were evaluated in each group. RESULTS: In a total of 156 patients with a median follow-up period of 40.9 months, the improvement rate was 87.8%. The patients were classified into low (76, 48.7%) or high (80, 51.3%) groups based on serum thyroxine (T4) levels. There was a difference between the 2 groups in terms of postoperative outcomes following MVD (p = 0.020). There were no differences in the outcomes according to serum tri-iodothyronine (T3) levels as well as other factors associated with the outcomes. CONCLUSIONS: We found that decreased serum T4 levels are associated with poor postoperative outcomes among patients with HFS. Further studies are needed to examine the clinical benefit of thyroid hormone replacement therapy for patients with suboptimal T4 concentrations as well as active thyroid hormone screening for patients with HFS.

Comparison between retrosigmoid and translabyrinthine approaches for large vestibular schwannoma: focus on cerebellar injury and morbidities.

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 for orbital cavernous venous malformation: a single center's experience for 15 years.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Optimal Volume of the Residual Tumor to Predict Long-term Tumor Control Using Stereotactic Radiosurgery after Facial Nerve-preserving Surgery for Vestibular Schwannomas.

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.

Gamma Knife Radiosurgery as a Primary Treatment for Nonfunctioning Pituitary Adenoma Invading the Cavernous Sinus.

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.

Hypermutagenesis in untreated adult gliomas due to inherited mismatch mutations.

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.

Fractionated stereotactic radiosurgery for malignant gliomas: comparison with single session stereotactic radiosurgery.

PURPOSE: 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. METHODS: 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 < 0.001, two-sided t test). RESULTS: After SRS, median progression-free survival (PFS) was 4.5 and 4.6 months (p = 0.58), and median overall survival (OS) was 12.7 and 12.6 months for sSRS and fSRS (p = 0.41), respectively (log-rank test). The incidence of clinically significant radiation necrosis was 20.5% (8/39) and 18.8% (3/16) for sSRS and fSRS, respectively (p = 1, Fisher's exact test). CONCLUSION: fSRS for malignant glioma conferred local control and survival comparable with conventional sSRS. The radiation necrosis incidence was comparable between groups when a parallel biological effective dose was administered to the larger target volumes in the fSRS group. fSRS can be a better alternative to sSRS if re-irradiation is considered for large malignant gliomas.

Outcome of three-fraction gamma knife radiosurgery for brain metastases according to fractionation scheme: preliminary results.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Radiomics features to distinguish glioblastoma from primary central nervous system lymphoma on multi-parametric MRI.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Radiomics features derived from multi-parametric MRI can be used to differentiate PCNSL from glioblastoma effectively.