Nanomedicine for glioblastoma: Progress and future prospects.

Glioblastoma is the most aggressive form of brain tumor, accounting for the highest mortality and morbidity rates. Current treatment for patients with glioblastoma includes maximal safe tumor resection followed by radiation therapy with concomitant temozolomide (TMZ) chemotherapy. The addition of TMZ to the conformal radiation therapy has improved the median survival time only from 12 months to 16 months in patients with glioblastoma. Despite these aggressive treatment strategies, patients' prognosis remains poor. This therapeutic failure is primarily attributed to the blood-brain barrier (BBB) that restricts the transport of TMZ from reaching the tumor site. In recent years, nanomedicine has gained considerable attention among researchers and shown promising developments in clinical applications, including the diagnosis, prognosis, and treatment of glioblastoma tumors. This review sheds light on the morphological and physiological complexity of the BBB. It also explains the development of nanomedicine strategies to enhance the permeability of drug molecules across the BBB.

A rare case of sclerosing meningioma with immunohistochemical features.

To identify histological types of Meningiomas', immunohistochemically markers are used. We present Phosphohistone-H3 (PHH-3) staining for the first time. The patient's case notes were retrospectively reviewed. PHH-3 staining revealed sparse mitotically active cells. PHH-3 staining can be used to grade sclerosing meningioma.

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma.

Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be a "double-edged sword", and its effect on tumorigenesis varies with cell type. On the other hand, autophagy may play a significant role in the resistance mechanisms against various therapies. Therefore, it is of the utmost importance to gain insight into the molecular mechanisms deriving the autophagy-mediated therapeutic resistance and designing improved treatment strategies for glioblastoma. In this review, we discuss autophagy mechanisms, specifically its pro-survival and growth-suppressing mechanisms in glioblastomas. In addition, we try to shed some light on the autophagy-mediated activation of the cellular mechanisms supporting radioresistance and chemoresistance in glioblastoma. This review also highlights autophagy's involvement in glioma stem cell behavior, underlining its role as a potential molecular target for therapeutic interventions.

Neurosurgical management of patients with brain metastasis.

Brain metastasis is a serious complication in patients with systemic cancer. The main goal of the treatment in patients with brain metastasis is to control the disease in the brain, to prevent death from neurological disease and provide a satisfactory quality of life. Management of a patient with brain metastasis is important and sometimes demanding, and several factors such as tumor histology, status of primary disease, number of brain lesions, size of lesions, and performance status may influence the decision making process. We reviewed the neurosurgical treatment modalities in patients with metastatic brain tumor and suggested a treatment paradigm for different clinical conditions. The PubMed database was searched using combinations of search terms and synonyms for "management of brain metastasis," "stereotactic radiosurgery for brain metastasis," and "surgery for brain metastasis" between January 1, 1990, and January 1, 2018. This review would guide physicians to solve challenging problems in the treatment of patients with brain metastasis. In summary, local aggressive treatments such as surgical resection and stereotactic radiosurgery are reasonable in patients with limited intracranial disease, controlled primary disease, and high performance status. Besides, WBRT is still the standard treatment in patients with low performance score and leptomeningeal dissemination of cancer.

Gamma knife radiosurgery compared to whole brain radiation therapy enhances immunity via immunoregulatory molecules in patients with metastatic brain tumours.

Background: There is lack of data on the effect of stereotactic radiosurgery in modulation of the immune system for cancer patients with metastatic brain tumours. Therefore, we investigated the change in levels of immunoregulatory molecules after Gamma Knife radiosurgery (GKR) and whole brain radiation therapy (WBRT) in patients with brain metastases.Methods: Peripheral blood samples were collected from 15 patients who received GKR, nine patients who received WBRT for brain metastases and 10 healthy controls. Samples were obtained at three time points such as before, 1h after and 1 week after the index procedure for patients treated with GKR or WBRT. All patients' demographic data and radiosurgical parameters were retrospectively reviewed. We analyzed the change in the levels of T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death ligand-1 (PD-L1), and cytokines such as IL-2, IL-10, IFN-γ, TNF-α after GKR and WBRT using Enzyme-linked immunosorbent assays (ELISA).Results: Baseline level of IFN-γ was found to be lower and that of PD-L1 was higher in the GKR group compared to WBRT group and healthy controls (p < 0.05 and p < 0.01, respectively). Levels of IFN-γ and IL-2 were increased (p < 0.01 and p < 0.01, respectively), while CTLA-4 and PD-L1 were decreased (p = 0.05 and p = 0.01, respectively) after GKR compared to pre-GKR levels, while there was no change after WBRT.Conclusion: GKR regulates immunoregulatory molecules towards enhancing the immune system, while WBRT did not exert any effect. These findings suggested that treatment of metastatic brain lesion with GKR might stimulate a systemic immune response against the tumour.

Thymoquinone ameliorates delayed cerebral injury and cerebral vasospasm secondary to experimental subarachnoid haemorrhage.

AIM OF THE STUDY: Among subarachnoid haemorrhage (SAH) patients, delayed cerebral injury (DCI) and infarction are the most important causes of death and major disability. Cerebral vasospasm (cVS) and DCI remain the major cause of death and disability. Thymoquinone (TQ) is the substance most responsible for the biological activity of nigella sativa (NS) and is useful in the treatment of ischaemic and neurodegenerative diseases, oxidative stress, inflammatory events, cardiovascular and neurological diseases. We conducted an experimental study aimed to investigate the preventive and corrective effects of TQ. MATERIALS AND METHODS: 24 Sprague-Dawley rats were randomly divided into three groups. The first was the control group which was a sham surgery group. The second group was the SAH group where the double haemorrage SAH protocol was used to induce vasospasm. The third group was the SAH+TQ group, where cVS was induced by the SAH protocol and the animals received oral 2 cc thymoquinone solution for seven days at a dose of 10 mg/kg, after the induction of SAH. The rats were euthanised seven days after the first procedure. The degree of cerebral vasospasm was evaluated by measuring the basilar artery luminal area and arterial wall thickness. Apoptosis was measured by the western blot method at brainstem neural tissue. Oxidative stress was measured by the Erel Method. Endothelin-1 was measured with ELISA analysis at blood. Statistical analysis was performed. RESULTS: Endothelin-1 values were found to be statistically significantly lower in the control and SAH+TQ groups compared to the SAH group (P < 0.001). Mean lumen area values were significantly higher in the control and SAH+TQ groups than in the SAH group (P < 0.001). In the control and SAH+TQ groups, wall thickness values decreased significantly compared to the SAH group (P < 0.001). OSI values were significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001). Apoptosis was significantly lower in the control and SAH+TQ groups than in the SAH group (P < 0.001). CONCLUSION: Our results show that post-SAH TQ inhibits/improves DCI and cVS with positive effects on oxidative stress, apoptosis, ET-1, lumen area, and vessel wall thickness, probably due to its anti-ischaemic, antispasmodic, antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective effects.

Evaluating Critical Brain Radiation Doses in the Treatment of Multiple Brain Lesions with Gamma Knife Radiosurgery.

BACKGROUND: Treatment of patients with multiple brain metastases has shifted to stereotactic radiosurgery, withholding whole-brain (WB) radiation therapy. However, radiation toxicity to the brain is a concern when treating multiple brain lesions with single-fraction stereotactic radiosurgery. OBJECTIVE: The purpose of this study was to determine the changes in brain radiation doses when treating various numbers of targets and lesion volumes. METHODS: We simulated different treatment plans with different combinations of varying tumor volumes including 0.1, 0.5, 1, 2, and 5 cm3, and tumor numbers including 1, 3, 5, 10, 15, 20, and 25. Treatment planning was performed for all combinations in a computerized tomography of the head of a patient, using Leksell GammaPlan version 10.1.1 (Elekta AB, Stockholm, Sweden). Two different dosing strategies were used. In the lower-prescription dosing schedule, a marginal dose was given to the 50% isodose line, and 20 Gy were used when the number of lesions was less than 15 and 18 Gy were applied when the number of lesions was equal to or more than 15. In the higher-prescription dosing schedule, a marginal dose of 24 Gy was used for lesions of less than 5 cm3 and 20 Gy were applied for lesions equal to 5cm3. The mean WB dose, the WB integral dose, and the volume of brain receiving 12 Gy (V12 Gy) were calculated for each scenario. Also, the beam-on time of the Gamma Knife 4C unit was reported for all treatment scenarios. RESULTS: Regression analysis showed that the total tumor volume was a more significant predictor of V12 Gy than the number of lesions, and a linear correlation between the total tumor volume and V12 Gy was found. We also found that the total tumor volume was a more significant predictor of the mean WB dose and the WB integral dose compared to the number of lesions. CONCLUSION: Our results suggest that multiple small to mid-sized lesions could be safely treated with a single-fraction gamma knife.

Treatment of high numbers of brain metastases with Gamma Knife radiosurgery: a review.

Effectiveness of stereotactic radiosurgery (SRS) has been shown in patients with one to four brain metastases. Work has been done to evaluate the role of SRS alone treatment without whole-brain radiation therapy in patients with more than four metastases. A recent multiinstitutional JLGK 0901 prospective study revealed the class-2 evidence that SRS without whole-brain radiation therapy is an effective treatment for patients up to 10 metastatic lesions. Several retrospective studies exist to show the efficacy and safety of SRS for patients with even more than 10 lesions. However, patient selection is very critical for SRS alone treatment. The PubMed database was searched using combinations of search terms and synonyms for multiple brain metastases, Gamma Knife and SRS published between January 1, 2005 and January 1, 2015 in order to address the effectiveness of Gamma Knife for patients with multiple brain metastases. Good performance status, controlled primary disease, total treated tumor volume of 15 cm(3) or less have been found to be significant predictors for survival among patients with two or more brain lesions. The data suggest that SRS can be used and whole brain radiation therapy can be withheld in selected patients with multiple lesions to avoid acute or chronic adverse effects, especially neurocognitive decline, without causing survival disadvantage. In this review, we assessed the evidence for SRS treatment of patients with multiple brain metastases.

Hypofractionated Radiation Therapy Suppresses Radioresistance in U87 Human Glioma Cells by Inhibiting Yap1 and Hsp90 Proteins.

BACKGROUND: Radiotherapy plays a vital role in the management of high-grade gliomas. However, the radio resistance of glioma cells limits the effect of radiation and drives recurrence inside the irradiated tumor volume leading to poor outcomes for patients. METHODS: High-grade glioma cell radioresistance significantly contributes to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. An increasing body of evidence complies with the Yes Associated Protein 1 (Yap-1) and heat shock protein 90 (Hsp90) as biomarkers for radioresistance in glioma cells. A number of studies suggest the potential of radioresistance-associated factors as biomarkers and/ or novel therapeutic targets in glioma cells. Thus, it is essential for glioblastoma patients to identify robust druggable targets involved in radioresistance, optimizing irradiation protocol, and understanding their underlying molecular mechanisms. RESULTS: Therefore, in the present study, we hypothesized that hypofractionated Gamma Knife radiation therapy (HF-GKRT) could target Yap-1 and Hsp90 and downregulate the mechanism of radioresistance in high-grade glioma cells. CONCLUSION: For this purpose, expression levels of radioresistance markers Yap-1 and Hsp90 were evaluated after treatment with HF-GKRT, and this was compared with single fraction Gamma Knife radiation therapy (SF-GKRT) in U87MG primary human glioblastoma cell line model. This would help design a novel radiation therapy regimen for glioblastoma patients by reducing the risk of radioresistance.

Promising outcome of patients with recurrent glioblastoma after Gamma Knife-based hypofractionated radiotherapy.

BACKGROUND: The role of Gamma Knife radiosurgery (GKRS) in recurrent glioblastoma remains unclear. The purpose of this study is to evaluate the effects of GKRS in a group of patients with recurrent glioblastoma, focusing on survival and safety. METHODS: Patients undergoing GKRS for recurrent glioblastoma between September 2014 and April 2019 were included in this study. Relevant clinical and radiosurgical data, including GKRS-related complications, were recorded and analyzed. Overall survival (OS), local progression free survival (LPFS) and prognostic factors for outcome were thoroughly evaluated. RESULTS: Fifty-three patients were analyzed (24 female, 29 male). The median age was 50 years (range, 19-78 years). The median GKRS treatment volume was 35.01 cm3 (range, 2.38-115.57 cm3). Twenty patients (38%) were treated with single fraction GKRS, while 33 (62%) were treated with GKRS-based hypofractionated stereotactic radiotherapy (HSRT). The median prescription dose for single fraction GKRS, 3-fractions HSRT and 5-fractions HSRT were 16 Gy (range, 10-20 Gy), 27 Gy (range, 18-33 Gy) and 25 Gy (range, 25-30 Gy), respectively. The median LPFS and OS times were 8.1 months and 11.4 months after GKRS, respectively. HSRT and Bevacizumab were associated with improved LPFS, while HSRT alone was associated with longer OS. CONCLUSION: Our findings suggested that HRST would likely improve LPFS and OS in definite settings; the addition of Bevacizumab to GKRS was associated with increased rates of local control. No major complications were reported. Further prospective studies are warranted to confirm our findings.

Identification of Genetic Alterations in Rapid Progressive Glioblastoma by Use of Whole Exome Sequencing.

BACKGROUND: Glioblastoma poses an inevitable threat to patients despite aggressive therapy regimes. It displays a great level of molecular heterogeneity and numerous substitutions in several genes have been documented. Next-generation sequencing techniques have identified various molecular signatures that have led to a better understanding of the molecular pathogenesis of glioblastoma. In this limited study, we sought to identify genetic variants in a small number of rare patients with aggressive glioblastoma. METHODS: Five tumor tissue samples were isolated from four patients with rapidly growing glioblastoma. Genomic DNA was isolated and whole exome sequencing was used to study protein-coding regions. Generated FASTQ files were analyzed and variants were called for each sample. Variants were prioritized with different approaches and functional annotation was applied for the detrimental variants. RESULTS: A total of 49,780 somatic variants were identified in the five glioblastoma samples studied, with the majority as missense substitutions. The top ten genes with the highest number of substitutions were MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1. Notably, variant prioritization after annotation indicated that the MTCH2 (Chr11: 47647265 A>G) gene sequence change was putative deleterious in all of the aggressive tumor samples. CONCLUSION: The MTCH2 (Chr11: 47647265 A>G) gene substitution was identified as putative deleterious in highly aggressive glioblastomas, which merits further investigation. Moreover, a high tumor mutation burden was observed, with a signature of the highest substitutions in MUC3A, MUC4, MUC6, OR4C5, PDE4DIP, AHNAK2, OR4C3, ZNF806, TTN, and RP1L1 genes. The findings provide critical, initial data for the further rational design of genetic screening and diagnostic approaches against aggressive glioblastoma.

Gamma Knife Radiosurgery Modulates micro-RNA Levels in Patients with Brain Metastasis.

BACKGROUND: The relation between micro-RNA (miRNA) modulation and immune cell activity in high-dose radiation settings is not clearly understood. OBJECTIVE: To investigate the role of stereotactic radiosurgery (SRS) in (i) the regulation of tumorsuppressor and oncogenic miRNAs as well as (ii) its effect on specific immune cell subsets in patients with metastatic brain tumors (MBT). METHODS: 9 MBT patients who underwent gamma knife-based stereotactic radiosurgery (GKRS) and 8 healthy individuals were included. Serum samples were isolated at three-time intervals (before GKRS, 1 hour, and 1-month post-GKRS). Expressions of tumor-suppressor (miR-124) and oncogenic (miR-21, miR-181a, miR-23a, miR-125b, and miR-17) miRNAs were quantified by qPCR. The lymphocytic frequency (CD3+, CD4+, CD8+, CD56+, CD19+, and CD16+) was investigated by means of flow cytometry. RESULTS: The median age was 64 years (range: 50-73 years). The median prescription dose was 20Gy (range: 16Gy-24Gy), all delivered in a single fraction. The median overall survival and progression- free survival were 7.8 months (range: 1.7-14.9 months) and 6.7 months (range: 1.1-11.5 months), respectively. Compared to healthy controls, baseline levels of oncogenic miRNAs were significantly higher, while tumor-suppressing miRNA levels remained markedly lower in MBT patients prior to GKRS. Following GKRS, there was a reduction in the expression of miR-21, miR-17, and miR-181a; simultaneously, increased expression increased of miR-124 was observed. No significant difference in immune cell subsets was noted post GKRSIn a similar fashion. We noted no correlation between patient characteristics, radiosurgery data, miRNA expression, and immune cell frequency. CONCLUSION: For this specific population with MBT disease, our data suggest that stereotactic radiosurgery may modulate the expression of circulating tumor-suppressor and oncogenic miRNAs, ultimately enhancing key anti-tumoral responses. Further evaluation with larger cohorts is warranted.

The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models.

Melanoma is a common and deadly tumor that upon metastasis to the central nervous system (CNS) has median survival duration of less than 5 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of cyclophosphamide (CTX) against melanoma, including disease within the CNS. The mechanisms of efficacy were investigated by tumor- and immune-mediated cytotoxic assays, in vivo evaluation of the reduction of regulatory T cells (Tregs) and by determining intratumoral p-STAT3 expression by immunohistochemistry. Combinational therapy of WP1066, with both metronomic and cytotoxic dosing of CTX, was investigated in a model system of systemic and intracerebral melanoma in syngeneic mice. Inhibition of p-STAT3 by WP1066 was enhanced with CTX in a dose-dependent manner. However, in mice with intracerebral melanoma, the greatest therapeutic benefit was seen in animals treated with cytotoxic CTX dosing and WP1066, whose median survival time was 120 days, an increase of 375%, with 57% long-term survivors. This treatment efficacy correlated with p-STAT3 expression levels within the tumor microenvironment. The efficacy of the combination of cytotoxic dosing of CTX with WP1066 is attributed to the direct tumor cytotoxic effects of the agents and has the greatest therapeutic potential for the treatment of CNS melanoma.

Glioma cancer stem cells modulating the local tumor immune environment.

Glioma stem cells (GSCs) drive the resistance mechanism in glioma tumors and mediate the suppression of innate and adaptive immune responses. Here we investigate the expression of mesenchymal-epithelial transition factor (c-Met) and Fas receptor in GSCs and their role in potentiating the tumor-mediated immune suppression through modulation of tumor infiltrating lymphocyte (TIL) population. Tumor tissues were collected from 4 patients who underwent surgery for glioblastoma. GSCs were cultured as neurospheres and evaluated for the co-expression of CD133, c-Met and FasL through flow cytometry. TILs were isolated and evaluated for the lymphocyte subset frequencies including CD3 +, CD4 +, CD8 +, regulatory T cells (FOXP3 + CD25) and microglia (CD11b + CD45) using flow cytometry. Our findings revealed that a significant population of GSCs in all four samples expressed c-Met (89-99%) and FasL (73-97%). A significantly low microglia population was found in local immune cells ranging from 3 to 5%. We did not find a statistically significant correlation between expressions of c-Met + GSC and FasL + GSC with local and systemic immune cells. This may be regarded to the small sample size. The percent c-Met + and FasL + GSC population appeared to be related to percent cytotoxic T cells, regulatory T cells and microglia populations in glioblastoma patients. Further investigation is warranted in a larger sample size.

Investigation of cellular effects of thymoquinone on glioma cell.

Glioblastoma, as an invasive tumor, is one of the most common primary malignant brain tumors. Despite maximum aggressive treatment, patients with glioblastoma have a dismal prognosis. Thymoquinone (TQ) has been found to show anti-cancer effects on different types of cancer. There are a few in vitro studies on the effect of TQ on glial tumors. However, the molecular mechanism of TQ's anti-cancer effect has not been fully elucidated. In the present study, we aimed to investigate the genotoxic, apoptotic, and cytotoxic effects of TQ on C6 rat glioma cells. C6 glioma cells were analyzed after 24 h of exposure to different concentrations of TQ by the ATP cell viability assay for cytotoxicity, comet assay for genotoxicity, 2',7'dichlorodihydrofluorescein diacetate (H2DCF-DA) for intracellular reactive oxygen species (iROS) generation, 3.3'dihexyloxacarbocyanine iodide (DiOC6(3)) for mitochondrial membrane potential, GSH/GSSG-Glo Assay for glutathione level and Fura-2AM for intracellular calcium levels. Apoptosis induction was studied by acridine orange/ethidium bromide double staining, flow cytometry, and western blotting analyses. Caspase-3, Caspase-9, Bax, Bcl-2, and pSTAT3 protein levels were determined by the western blotting method. Cytotoxicity was enhanced by TQ in C6 glioma cells in a concentration-dependent manner. TQ also induced DNA damage, apoptosis, and increased iROS. Also, MMP and GSH levels were decreased by TQ. It inhibited pSTAT3, resulting in apoptosis induction through the regulation of anti-apoptotic and pro-apoptotic proteins. Our results suggest that TQ would be an effective treatment in glioma. Further studies should support these findings.

Targeting Glioblastoma: The Current State of Different Therapeutic Approaches.

BACKGROUND: Glioma is the primary cancer of the central nervous system in adults. Among gliomas, glioblastoma is the most deadly and aggressive form, with an average life span of 1 to 2 years. Despite implementing the rigorous standard care involving maximal surgical removal followed by concomitant radiation and chemotherapy, the patient prognosis remains poor. Due to the infiltrative nature of glioblastoma, chemo- and radio-resistance behavior of these tumors and lack of potent chemotherapeutic drugs, treatment of glioblastoma is still a big challenge. OBJECTIVE: The goal of the present review is to shed some light on the present state of novel strategies, including molecular therapies, immunotherapies, nanotechnology and combination therapies for patients with glioblastoma. METHODS: Peer-reviewed literature was retrieved via Embase, Ovid, PubMed and Google Scholar till the year 2020. CONCLUSION: Insufficient effect of chemotherapies for glioblastoma is more likely because of different drug resistance mechanisms and intrinsically complex pathological characteristics. Therefore, more advancement in various therapeutic approaches such as antitumor immune response, targeting growth regulatory and drug resistance pathways, enhancing drug delivery and drug carrier systems are required in order to establish an effective treatment approach for patients with glioblastoma.

The Effectiveness of Diffusion Tensor Imaging in Determining Radiological Response after Radiosurgery in Patients with Vestibular Schwannoma.

BACKGROUND: The effectiveness of Diffusion Tensor Imaging (DTI) in demonstrating functional changes in the tumor in determining the response to treatment after radiosurgery in patients with vestibular schwannoma (VS) is not clear yet. OBJECTIVE: The study aimed to determine the change in total tumor volume (TTV) in terms of radiological response in patients who had VS and were treated with radiosurgery and investigated the relationship between the TTV, follow-up times and DTI parameters. METHODS: Thirty-one patients were assessed using DTI and MRI. TTV, apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were calculated. Patients were divided into three groups: those who responded to the treatment (group 1) (n=11), those who did not (group 0) (n=9) and those who remained stable (group 2) (n=11). RESULTS: The mean duration of follow-up was 28.81±14 months. ADC values increased in patients with VS after radiosurgery (p=0.004). There was no statistical difference in the FA values. A significant reduction in TTV after radiosurgery was detected in group 1 (p=0.003). ADC values increased significantly after radiosurgery in group 2 (p=0.04). Although there were no significant differences, ADC values after radiosurgery increased in group 1 and group 0. CONCLUSIONS: ADC values continuously increase due to radiation damage in the period before the tumor volume shrinks after radiosurgery. We think that it is not appropriate to diagnose inadequate treatment or progression only when TTV is evaluated in terms of response to treatment in the early period after radiosurgery.

Evaluation of Brainstem Subcortical Auditory Pathways with Diffusion Tensor Imaging After Gamma Knife Radiosurgery in Intracanalicular Vestibular Schwannoma.

OBJECTIVE: To investigate changes in DTI (Diffusion Tensor Imaging) parameters in brainstem subcortical auditory pathways after Gamma Knife Radiosurgery (GKR) in patients with intracanalicular vestibular schwannoma (ICVS) and to analyze the relationship between tumor volume and ADC (apparent diffusion coefficient) and FA (fractional anisotropy) values. METHOD: Seventeen patients with ICVS were evaluated before and after GKR. ADC and FA values of the lateral lemniscus (LL) and inferior colliculus (IC) and tumor volume were calculated. Patients who responded to GKR were classified as Group 1 and those who did not respond adequately as Group 2. The relationship between ADC and FA values and changes in tumor volume were analyzed. RESULTS: Tumor volume significantly decreased after GKR. ADC values obtained from the tumor increased after GKR (p:0.002). There was no significant difference in LL and IC before and after GKR in terms of FA and ADC values (n:17). There was a positive correlation between response to treatment and contralateral LL ADC values after GKR (p=0.005, r:0.652). There was a negative correlation between contralateral IC FA values after GKR and response to treatment (p=0.017, r: -0.568). There was a significant difference between Groups 1 and 2 in regards to contralateral LL ADC (p=0.03) and IC FA values (p=0.017). CONCLUSION: Since the cochlear nerve and subcortical auditory pathways have low regeneration potential after nerve damage, ADC and FA changes in LL and IC may be explained with the presence of intracanalicular tumors prior to GKR. Since GKR does not cause additional damage to the subcortical auditory pathways at the brainstem level, we think that GKR is a noninvasive treatment method that can be used safely in patients with ICVS.