Leksell Frame-Based Stereotactic Biopsy for Infratentorial Tumor : Practical Tips and Considerations.

The Leksell frame-based transcerebellar approach was proposed with the arc support frame attached upside down to the Z coordinate. This study presented practical tips and considerations for obtaining adequate tissue samples for deep-seated cerebellar lesions or lower brainstem lesions specifically those accessible via the cerebellar peduncle. For practical insights, the Leksell coordinate frame G was fixed to prevent the anterior screw implantation within the temporalis muscle, to avoid interference with the magnetic resonance (MR)-adapter, and taking into account the magnetic field of MR in close proximity to the tentorium. After mounting of indicator box, the MR imaging evaluation should cover both the indicator box and the infratentorial region that deviated from it. The coordinates [X, Y, Za, Arc0, Ringa0] obtained from Leksell SurgiPlan® software (Elekta, Stockholm, Sweden) with arc 00 located on the patient's right side were converted to [X, Y, Zb=360-Za, Arc0, Ringb0=Ringa0-1800]. The operation was performed in the prone position under general anesthesia in four patients with deep cerebellar (n=3) and brainstem (n=1) tumors. The biopsy results showed two cases of diffuse large B-cell lymphoma, one metastatic braintumor and one glioblastoma. One patient required frame repositioning as a complication. Drawing upon the methodology outlined in existing literature, we anticipate that imparting supplementary expertise could render the stereotactic biopsy of infratentorial tumors more consistent and manageable for the practitioner, thereby facilitating adequate tissue samples and minimizing patient complications.

Two-Day Fraction Gamma Knife Radiosurgery for Large Brain Metastasis.

Objective: We investigated how treating large brain metastasis (LBM) using two-day fraction gamma knife radiosurgery (GKRS) affects tumor control and patient survival. A prescription dose of 10.3 Gy was applied for two consecutive days, with a biologically effective dose (BED) equivalent to a tumor single-fraction dose of 16.05 Gy and a brain single-fraction dose of 15.12 Gy. Methods: Between November 2017 and December 2021, 42 patients (mean age: 68.3 years, range: 50-84 years, male: 29 [69.1%], female: 13 [30.9%]) with 44 tumors underwent two-day fraction GKRS to treat large volume brain metastasis. The main cancer types were non-small cell lung cancer (NSCLC, N=16), small cell lung cancer (SCLC, N=7), colorectal cancer (N=7), breast cancer (N=3), gastric cancer (N=2), and other cancers (N=7). Twenty-one (50.0%) patients had a single LBM, nineteen (46.3%) had a single LBM and other metastasi(e)s, and two had two (4.7%) large brain metastases. At the time of the two-day fraction GKRS, the tumors had a mean volume of 23.1 cc (range: 12.5-67.4). on each day, radiation was administered at a dose of 10.3 Gy, mainly using a 50% isodose-line. Results: We obtained clinical and magnetic resonance imaging (MRI) follow-up data for 34 patients (81%) with 35 tumors, who had undergone two-day fraction GKRS. These patients did not experience acute or late radiation-induced complications during follow-up. The median and mean progression-free survival (PFS) periods were 188 and 194 days, respectively. The local control rates at 6, 9, and 12 months were 77%, 40%, and 34%, respectively. The prognostic factors related to PFS were prior radiotherapy (P = 0.019) and lung cancer origin (P = 0.041). Other factors such as tumor volumes, each isodose volumes, and peri-GKRS systemic treatment were not significantly related to PFS. The overall survival period of the 44 patients following repeat SRS ranged from 15-878 days (median: 263±38 days, mean: 174±43) after the two-day fraction GKRS. Eight patients (18.2%) were still alive. Conclusion: Considering the unsatisfactory tumor control, a higher prescription dose should be needed in this procedure as a salvage management. Moreover, in the treatment for LBM with fractionated SRS, using different isodoses and prescription doses at the treatment planning for LBMs should be important. However, this report might be a basic reference with the same fraction number and prescription dose in the treatment for LBMs with frame-based SRS.

Synergistic Antitumor Effect of Combined Radiotherapy and Engineered Salmonella typhimurium in an Intracranial Sarcoma Mouse Model.

Intracranial sarcoma is an uncommon aggressive cancer with a poor prognosis and a high recurrence rate. Although postoperative adjuvant radiotherapy (RT) is the most recommended treatment strategy, it does not significantly improve survival rates. In this study, we used an attenuated Salmonella typhimurium strain engineered to secrete Vibrio vulnificus flagellin B (SLpFlaB) as an immunotherapy to assist with the antitumor effects of RT on intracranial sarcoma. In vitro, the expression of γH2AX and cleaved caspase-3 was analyzed by Western blot. In vivo detection of SLpFlaB colonization time in tumors was measured using an in vivo imaging system (IVIS). Tumor growth delay and elimination were demonstrated in an intracranial mouse model, and the distribution of macrophages, M1 macrophages, and CD8+ cells after treatment was measured using FACS analysis. Our findings in vitro suggest that combination therapy increases S-180 radiosensitivity, the expression of DNA double-strand breaks, and programmed cell death. In vivo, combination treatment causes intracranial sarcoma to be eliminated without tumor recurrence and redistribution of immune cells in the brain, with data showing the enhanced migration and infiltration of CD8+ T cells and macrophages, and an increased proportion of M1 macrophage polarization. Compared to RT alone, the combination therapy enhanced the radiosensitivity of S-180 cells, promoted the recruitment of immune cells at the tumor site, and prevented tumor recurrence. This combination therapy may provide a new strategy for treating intracranial sarcomas.

Distinct Specialized Center of Excellence, the Story of Hwasun Neurosurgery at Chonnam National University Hwasun Hospital.

The paper provides a comprehensive overview of the growth and development of Hwasun Neurosurgery at Chonnam National University Hwasun Hospital over the past 18 years. As the first brain tumor center in Korea when it was established in April 2004, Hwasun Neurosurgery has since become one of the leading institutions in brain tumor education and research in the country. Its impressive clinical and basic research capabilities, dedication to professional education, and numerous academic achievements have all contributed to its reputation as a top-tier institution. We hope this will become a useful guide for other brain tumor centers or educational institutions by sharing the story of Hwasun Neurosurgery.

Synergistic Effects of Radiotherapy With JNK Inhibitor-Incorporated Nanoparticle in an Intracranial Lewis Lung Carcinoma Mouse Models.

BACKGROUND: Radiosurgery has been recognized as a reasonable treatment for metastatic brain tumors. Increasing the radiosensitivity and synergistic effects are possible ways to improve the therapeutic efficacy of specific regions of tumors. c-Jun-N-terminal kinase (JNK) signaling regulates H2AX phosphorylation to repair radiation-induced DNA breakage. We previously showed that blocking JNK signaling influenced radiosensitivity in vitro and in an in vivo mouse tumor model. Drugs can be incorporated into nanoparticles to produce a slow-release effect. This study assessed JNK radiosensitivity following the slow release of the JNK inhibitor SP600125 from a poly (DL-lactide-co-glycolide) (LGEsese) block copolymer in a brain tumor model. MATERIALS AND METHODS: A LGEsese block copolymer was synthesized to fabricate SP600125-incorporated nanoparticles by nanoprecipitation and dialysis methods. The chemical structure of the LGEsese block copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The physicochemical and morphological properties were observed by transmission electron microscopy (TEM) imaging and measured with particle size analyzer. The blood-brain barrier (BBB) permeability to the JNK inhibitor was estimated by BBBflammaTM 440-dye-labeled SP600125. The effects of the JNK inhibitor were investigated using SP600125-incorporated nanoparticles and by optical bioluminescence, magnetic resonance imaging (MRI), and a survival assay in a mouse brain tumor model for Lewis lung cancer (LLC)-Fluc cells. DNA damage was estimated by histone γ H2AX expression and apoptosis was assessed by the immunohistochemical examination of cleaved caspase 3. RESULTS: The SP600125-incorporated nanoparticles of the LGEsese block copolymer were spherical and released SP600125 continuously for 24h. The use of BBBflammaTM 440-dye-labeled SP600125 demonstrated the ability of SP600125 to cross the BBB. The blockade of JNK signaling with SP600125-incorporated nanoparticles significantly delayed mouse brain tumor growth and prolonged mouse survival after radiotherapy. γ H2AX, which mediates DNA repair protein, was reduced and the apoptotic protein cleaved-caspase 3 was increased by the combination of radiation and SP600125-incorporated nanoparticles.

Flagellin synergistically enhances anti-tumor effect of EGFRvIII peptide in a glioblastoma-bearing mouse brain tumor model.

BACKGROUND: Glioblastoma (GBM) is the most aggressive type of brain tumor with heterogeneity and strong invasive ability. Treatment of GBM has not improved significantly despite the progress of immunotherapy and classical therapy. Epidermal growth factor receptor variant III (EGFRvIII), one of GBM-associated mutants, is regarded as an ideal therapeutic target in EGFRvIII-expressed GBM patients because it is a tumor-specific receptor expressed only in tumors. Flagellin B (FlaB) originated from Vibrio vulnificus, is known as a strong adjuvant that enhances innate and adaptive immunity in various vaccine models. This study investigated whether FlaB synergistically could enhance the anti-tumor effect of EGFRvIII peptide (PEGFRvIII). METHODS: EGFRvIII-GL261/Fluc cells were used for glioblastoma-bearing mouse brain model. Cell-bearing mice were inoculated with PBS, FlaB alone, PEGFRvIII alone, and PEGFRvIII plus FlaB. Tumor growth based on MRI and the survival rate was investigated. T cell population was examined by flow cytometry analysis. Both cleaved caspase-3 and CD8 + lymphocytes were shown by immunohistochemistry (IHC) staining. RESULTS: The PEGFRvIII plus FlaB group showed delayed tumor growth and increased survival rate when compared to other treatment groups. As evidence of apoptosis, cleaved caspase-3 expression and DNA disruption were more increased in the PEGFRvIII plus FlaB group than in other groups. In addition, the PEGFRvIII plus FlaB group showed more increased CD8 + T cells and decreased Treg cells than other treatment groups in the brain. CONCLUSIONS: FlaB can enhance the anti-tumor effect of PEGFRvIII by increasing CD8 + T cell response in a mouse brain GBM model.

The Tumor Control According to Radiation Dose of Gamma Knife Radiosurgery for Small and Medium-Sized Brain Metastases from Non-Small Cell Lung Cancer.

OBJECTIVE: The effectiveness of gamma knife radiosurgery (GKR) in the treatment of brain metastases is well established. The aim of this study was to evaluate the efficacy and safety of maximizing the radiation dose in GKR and the factors influencing tumor control in cases of small and medium-sized brain metastases from non-small cell lung cancer (NSCLC). METHODS: We analyzed 230 metastatic brain tumors less than 5 mL in volume in 146 patients with NSCLC who underwent GKR. The patients had no previous radiation therapy for brain metastases. The pathologies of the tumors were adenocarcinoma (n=207), squamous cell carcinoma (n=18), and others (n=5). The radiation doses were classified as 18, 20, 22, and 24 Gy, and based on the tumor volume, the tumors were categorized as follows : small-sized (less than 1 mL) and medium-sized (1-3 and 3-5 mL). The progression-free survival (PFS) of the individual 230 tumors and 146 brain metastases was evaluated after GKR depending on the pathology, Eastern Cooperative Oncology Group (ECOG) performance score (PS), tumor volume, radiation dose, and anti-cancer regimens. The radiotoxicity after GKR was also evaluated. RESULTS: After GKR, the restricted mean PFS of individual 230 tumors at 24 months was 15.6 months (14.0-17.1). In small-sized tumors, as the dose of radiation increased, the tumor control rates tended to increase (p=0.072). In medium-sized tumors, there was no statistically difference in PFS with an increase of radiation dose (p=0.783). On univariate analyses, a statistically significant increase in PFS was associated with adenocarcinomas (p=0.001), tumors with ECOG PS 0 (p=0.005), small-sized tumors (p=0.003), radiation dose of 24 Gy (p=0.014), synchronous lesions (p=0.002), and targeted therapy (p=0.004). On multivariate analyses, an improved PFS was seen with targeted therapy (hazard ratio, 0.356; 95% confidence interval, 0.150-0.842; p=0.019). After GKR, the restricted mean PFS of brain at 24 months was 9.8 months (8.5-11.1) in 146 patients, and the pattern of recurrence was mostly distant within the brain (66.4%). The small and medium-sized tumors treated with GKR showed radiotoxicitiy in five out of 230 tumors (2.2%), which were controlled with medical treatment. CONCLUSION: The small-sized tumors were effectively controlled without symptomatic radiation necrosis as the radiation dose was increased up to 24 Gy. The medium-sized tumors showed potential for symptomatic radiation necrosis without signifcant tumor control rate, when greater than 18 Gy. GKR combined targeted therapy improved the tumor control of GKR-treated tumors.

Treatment Outcome of Gamma Knife Radiosurgery for Petroclival Meningiomas: Retrospective Analysis of a Single Institution Experience.

BACKGROUND: Although Gamma Knife radiosurgery (GKRS) has been widely used for intracranial meningiomas as an alternative or adjuvant treatment, guidelines have not been established for the selection of patients with petroclival meningioma (PCM) for GKRS. In this study, we reported the factors related to tumor progression and postoperative complications in PCM patients treated by GKRS, with a review of the literatures. METHODS: Between 2004 and 2019, 64 patients (52 patients for alternative and 12 patients for adjuvant treatment) with PCM underwent GKRS in our institution. The clinical and radiological factors were retrospectively analyzed. The mean radiologic follow-up duration was 58.4 months (range, 6-164 months). The mean tumor volume and diameter before GKRS were 13.4 cm³ and 2.9 cm, respectively. The median marginal dose was 12 Gy (range, 10-14 Gy) with a 50% median isodose line. Fractionation was used in 19 cases (29%, two fractionations in 5 cases & three fractionations in 14 cases). RESULTS: Progression was noted in 7 cases (10.9%) and the progression-free survival rates were 91.1% at 5 years and 69.6% at 10 years. Although large in volume, moderate to severe peritumoral edema and male gender were somewhat related to progression, they did not reach statistical significance. Ten patients (15.6%) developed complications after GKRS. The most common complication was cranial nerve deficit (n=8), followed by hemiparesis, cognitive dysfunction, and hydrocephalus. Large size (maximal diameter ≥5 cm) [hazard ratio (HR) 0.091, 95% confidence interval (CI) 0.014-0.608; p=0.013] and multiplicity (HR 0.102, 95% CI 0.018-0.573; p=0.009) were independent factors for developing complications after GKRS. CONCLUSION: GKRS can be considered an effective and safe treatment for large-volume PCM. However, for patients with large size or multiple masses, the treatment method should be determined with caution because the probability of complications after GKRS may increase.

What Clinicians Should Consider to Determine a More Beneficial Treatment Strategy for Small to Medium Sized Vestibular Schwannoma With Serviceable Hearing: A Single Surgeon's Long-term Outcome of Microsurgery and Gamma Knife Radiosurgery.

OBJECTIVE: The number of small to medium sized vestibular schwannoma (VS) patients presenting with serviceable hearing has steadily increased. There are various treatment strategies for small to medium sized VS, including microsurgery (MS), gamma knife radiosurgery (GKS), and serial observations using magnetic resonance imaging. In this study, we presented the long-term outcomes of patients with small to medium sized VS with serviceable hearing. We also evaluated the potential prognostic factors for hearing preservation and discussed appropriate treatment strategies. METHODS: A retrospective review of 504 cases of all VS patients who underwent MS or GKS between 1993 and July 2019 was conducted. Surgical resection was performed on 267 patients using the retro-sigmoid approach and 55 (20.6%) of them were small to medium sized VS. GKS was performed on 237 patients and 175 (73.8%) of them were small to medium sized VS. Small to medium sized VS was defined as less than 25 mm in the greatest dimension. After applying the inclusion and exclusion criteria, 51 patients with small to medium sized VS with serviceable hearing were enrolled in this study and underwent either MS (n = 21) or GKS (n = 30). To define the clinical characteristics of the patients, clinical data at the time of treatment, age, sex, presenting symptoms, tumor location type, preoperative hearing status, posttreatment related complications, recurrence, and hearing loss progression-free survival data were collected. RESULTS: In the MS group, the hearing preservation rate was 71.4% and the tumor control rate was 100%. In the GKS group, the tumor control rate was 93.3% and two patients experienced recurrence at a median interval of 41.5 months. Kaplan-Meier curves showed that the hearing progression-free survival rates at 1-, 3-, and 5-years following GKS were 80, 66.7, and 53.3%, respectively. The MS group had a higher hearing preservation rate at 5 years (71.4 versus 53.3%), but the difference did not reach statistical significance (p = 0.173). Hearing preservation was statistically significant when the preoperative hearing status was class A in the GKS group (p = 0.016), but it was not statistically significant in the MS group (p = 0.777). In the MS group, medial type VS had a higher hearing preservation rate (80%) than the lateral fundal extended type VS (63.6%), and this difference was almost close to statistical significance (p = 0.058). The GKS group had a higher occurrence of postoperative tinnitus (23.3%) than the MS group (9.5%). CONCLUSION: MS was more suitable for patients who are younger, have good physical status, good preoperative hearing status including AAO-HNS class B, and medial type VS. GKS was more suitable for patients who are elderly, have poor physical status, preoperative AAO-HNS class A hearing.

The Application of Magnetic Resonance Imaging-Deformed 11C-Methionine-Positron Emission Tomography Images in Stereotactic Radiosurgery.

BACKGROUND: Although 11C-methionine positron emission tomography (MET-PET) images can be fused with magnetic resonance (MR) images using planning software for gamma knife radiosurgery (GKR), the stereotactic information has limited value in patients with recurrent malignant brain tumor due to the difference in imaging protocols between MET-PET and MR images. The aim of this study was to evaluate the clinical application of MR imaging (MRI)-deformed MET-PET images in GKR using a deformable registration tool. METHODS: We examined the enhanced MR stereotactic images, MET-PET and MRI-deformed MET-PET images without stereotactic information for 12 newly developed metastatic brain tumors. MET-PET and MRI-deformed MET-PET images were co-registered with the MR stereotactic images using radiosurgery planning software. Visual analysis was performed to determine whether the MET-PET and MR images matched better after using the deformable registration tool. In addition, the matching volume between MR and MET-PET images was compared before and after applying this tool. The matching volume was calculated as the metabolic tumor volume on the MET-PET images, including the MR-enhanced volume. The matching percentage was calculated as the matching volume divided by the MR-enhanced volume, multiplied by 100. RESULTS: Visual analysis revealed that the MRI-deformed MET-PET images provided the same axial plane as that of the MR images, with the same window level, enabling easy identification of the tumor with the radiosurgery planning software. The mean matching percentage of the MET-PET/MR fusion images was 61.1% (range 24.7-94.7) and that of the MRI-deformed MET-PET/MR fusion images was 63.4% (range 20.8-94.3). No significant difference was found in the matching percentage between the two types of fusion images (p = 0.754). CONCLUSIONS: The MRI-deformed MET-PET images enable utilization of the functional information when planning a treatment in GKR without significant volume change.

Hyaluronic Acid-Conjugated with Hyperbranched Chlorin e6 Using Disulfide Linkage and Its Nanophotosensitizer for Enhanced Photodynamic Therapy of Cancer Cells.

The main purpose of this study is to synthesize novel types of nanophotosensitizers that are based on hyperbranched chlorin e6 (Ce6) via disulfide linkages. Moreover, hyperbranched Ce6 was conjugated with hyaluronic acid (HA) for CD44-receptor mediated delivery and redox-sensitive photodynamic therapy (PDT) against cancer cells. Hyperbranched Ce6 was considered to make novel types of macromolecular photosensitizer since most of the previous studies regarding nanophotosensizers are concerned with simple conjugation between monomeric units of photosensitizer and polymer materials. Hyperbranched Ce6 was synthesized by conjugation of Ce6 each other while using disulfide linkage. To synthesize Ce6 tetramer, carboxyl groups of Ce6 were conjugated with cystamine and three equivalents of Ce6 were then conjugated again with the end of amine groups of Ce6-cystamine. To synthesize Ce6 decamer as a hyperbranched Ce6, six equivalents of Ce6 was conjugated with the end of Ce6 tetramer via cystamine linkage. Furthermore, HA-cystamine was attached with Ce6 tetramer or Ce6 decamer to synthesize HA-Ce6 tetramer (Ce6tetraHA) or HA-Ce6 decamer (Ce6decaHA) conjugates. Ce6tetraHA and Ce6decaHA nanophotosensitizers showed small diameters of less than 200 nm. The addition of dithiothreitol (DTT) and hyaluronidase (HAse) induced a faster Ce6 release rate in vitro drug release study, which indicated that Ce6tetraHA nanophotosensitizers possess redox-sensitive and HAse-sensitive release properties. Ce6tetraHA nanophotosensitizers showed higher intracellular Ce6 accumulation, higher ROS generation, and higher PDT efficacy than that of Ce6 alone. Ce6tetraHA nanophotosensitizers responded to the CD44 receptor of cancer cell surface, i.e., the pre-treatment of HA blocked CD44 receptor of U87MG or HCT116 cells and then inhibited delivery of nanophotosensitizers in vitro cell culture study. Furthermore, in vivo tumorxenograft study showed that fluorescence intensity in the tumor tissues was stronger than those of other organs, while CD44 receptor blocking by HA pretreatment induced a decrease of fluorescence intensity in tumor tissues when compared to liver. These results indicated that Ce6tetraHA nanophotosensitizers delivered to tumors by redox-sensitive and CD44-sensitive manner.

Quantitative Feasibility Evaluation of 11C-Methionine Positron Emission Tomography Images in Gamma Knife Radiosurgery : Phantom-Based Study and Clinical Application.

OBJECTIVE: The functional information of 11C-methionine positron emission tomography (MET-PET) images can be applied for Gamma knife radiosurgery (GKR) and its image quality may affect defining the tumor. This study conducted the phantom-based evaluation for geometric accuracy and functional characteristic of diagnostic MET-PET image co-registered with stereotactic image in Leksell GammaPlan® (LGP) and also investigated clinical application of these images in metastatic brain tumors. METHODS: Two types of cylindrical acrylic phantoms fabricated in-house were used for this study : the phantom with an array-shaped axial rod insert and the phantom with different sized tube indicators. The phantoms were mounted on the stereotactic frame and scanned using computed tomography (CT), magnetic resonance imaging (MRI), and PET system. Three-dimensional coordinate values on co-registered MET-PET images were compared with those on stereotactic CT image in LGP. MET uptake values of different sized indicators inside phantom were evaluated. We also evaluated the CT and MRI co-registered stereotactic MET-PET images with MR-enhancing volume and PET-metabolic tumor volume (MTV) in 14 metastatic brain tumors. RESULTS: Imaging distortion of MET-PET was maintained stable at less than approximately 3% on mean value. There was no statistical difference in the geometric accuracy according to co-registered reference stereotactic images. In functional characteristic study for MET-PET image, the indicator on the lateral side of the phantom exhibited higher uptake than that on the medial side. This effect decreased as the size of the object increased. In 14 metastatic tumors, the median matching percentage between MR-enhancing volume and PET-MTV was 36.8% on PET/MR fusion images and 39.9% on PET/CT fusion images. CONCLUSION: The geometric accuracy of the diagnostic MET-PET co-registered with stereotactic MR in LGP is acceptable on phantom-based study. However, the MET-PET images could the limitations in providing exact stereotactic information in clinical study.

Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models.

BACKGROUND: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models. METHODS: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models. RESULTS: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone. CONCLUSION: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.

Repeat Stereotactic Radiosurgery for Recurred Metastatic Brain Tumors.

OBJECTIVE: We investigated the outcomes of repeat stereotactic radiosurgery (SRS) for metastatic brain tumors that locally recurred despite previous SRS, focusing on the tumor control. METHODS: A total of 114 patients with 176 locally recurring metastatic brain tumors underwent repeat SRS after previous SRS. The mean age was 59.4 years (range, 33 to 85), and there were 68 male and 46 female patients. The primary cancer types were non-small cell lung cancer (n=67), small cell lung cancer (n=12), gastrointestinal tract cancer (n=15), breast cancer (n=10), and others (n=10). The number of patients with a single recurring metastasis was 95 (79.8%), and another 19 had multiple recurrences. At the time of the repeat SRS, the mean volume of the locally recurring tumors was 5.94 mL (range, 0.42 to 29.94). We prescribed a mean margin dose of 17.04 Gy (range, 12 to 24) to the isodose line at the tumor border primarily using a 50% isodose line. RESULTS: After the repeat SRS, we obtained clinical and magnetic resonance imaging follow-up data for 84 patients (73.7%) with a total of 108 tumors. The tumor control rate was 53.5% (58 of the 108), and the median and mean progression-free survival (PFS) periods were 246 and 383 days, respectively. The prognostic factors that were significantly related to better tumor control were prescription radiation dose of 16 Gy (p=0.000) and tumor volume less than both 4 mL (p=0.001) and 10 mL at the repeat SRS (p=0.008). The overall survival (OS) periods for all 114 patients after repeat SRS varied from 1 to 56 months, and median and mean OS periods were 229 and 404 days after the repeat SRS, respectively. The main cause of death was systemic problems including pulmonary dysfunction (n=58, 51%), and the identified direct or suspected brain-related death rate was around 20%. CONCLUSION: The tumor control following repeat SRS for locally recurring metastatic brain tumors after a previous SRS is relatively lower than that for primary SRS. However, both low tumor volume and high prescription radiation dose were significantly related to the tumor control following repeat SRS for these tumors after previous SRS, which is a general understanding of primary SRS for metastatic brain tumors.

Genetically-engineered Salmonella typhimurium expressing TIMP-2 as a therapeutic intervention in an orthotopic glioma mouse model.

Glioma is one of the most devastating and refractory cancers. The main factors underlying therapeutic failure include extremely invasive characteristics and lack of effective methods for drug delivery. Attenuated Salmonella strains presented a high concentration of tumor targets in various types of cancer models, suggesting a role as potential vectors for drug delivery. In this study, we genetically engineered an attenuated strain of Salmonella as an anti-invasive vector for the targeted delivery and expression of tissue inhibitor of metalloproteinases 2 (TIMP-2) in an orthotopic nude mouse model of glioma. The bioluminescence signals related to tumor size significantly declined in the TIMP-2-expressing Salmonella (SLpTIMP-2)-treated group compared with the control group. Compared with the control group with a survival rate of an average of 33 days, the SLpTIMP-2 group showed an extended survival rate by nearly 60% and lasted an average period of 53 days with TIMP-2 induction. These results indicated the promising therapeutic potential of S. typhimurium for targeted delivery and secretion of TIMP-2 in glioma.

Efficacy of Gamma Knife Radiosurgery for Recurrent High-Grade Gliomas with Limited Tumor Volume.

OBJECTIVE: This study aims to determine whether gamma knife radiosurgery (GKR) improves survival in patients with recurrent highgrade gliomas. METHODS: Twenty nine patients with recurrent high-grade glioma underwent 38 GKR. The male-to-female ratio was 10 : 19, and the median age was 53.8 years (range, 20-75). GKR was performed in 11 cases of recurrent anaplastic oligodendrogliomas, five anaplastic astrocytomas, and 22 glioblastomas. The median prescription dose was 16 Gy (range, 10-24), and the median target volume was 7.0 mL (range, 1.1-15.7). Of the 29 patients, 13 (44.8%) received concurrent chemotherapy. We retrospectively analyzed the progression-free survival (PFS) and overall survival (OS) after GKR depending on the Eastern Cooperative Oncology Group (ECOG) performance status (PS), pathology, concurrent chemotherapy, radiation dose, and target tumor volume. RESULTS: Starting from when the patients underwent GKR, the median PFS and OS were 5.0 months (range, 1.1-28.1) and 13.0 months (range, 1.1-75.1), respectively. On univariate analysis, the median PFS was significantly long in patients with anaplastic oligodendroglioma, ECOG PS 1, and target tumor volume less than 10 mL (p<0.05). Meanwhile, on multivariate analysis, patients with ECOG PS 1 and target tumor volume less than 10 mL showed improved PFS (p=0.043 and p=0.007, respectively). The median OS was significantly increased in patients with ECOG PS 1 and tumor volume less than 10 mL on univariate and multivariate analyses (p<0.05). CONCLUSION: GKR could be an additional treatment option in recurrent high-grade glioma, particularly in patients with good PS and limited tumor volume.

Optimization of diagnostic performance for differentiation of recurrence from radiation necrosis in patients with metastatic brain tumors using tumor volume-corrected 11C-methionine uptake.

BACKGROUND: Tumor to normal tissue ratio (T/N ratio) on 11C-methionine (11C-MET) positron emission tomography/computed tomography (PET/CT) is affected by variable factors. We investigated whether T/N ratio cutoff values corrected according to metabolic tumor volume (MTV) could improve the diagnostic performance of 11C-MET PET/CT for diagnosis of recurrence in patients with metastatic brain tumor. Forty-eight patients with metastatic brain tumors underwent 11C-MET PET/CT for differential diagnosis between recurrence and radiation necrosis after gamma knife radiosurgery (GKR). Both T/N ratio and MTV were estimated in each lesion on 11C-MET PET/CT. The lesions were classified into three groups based on MTV criteria (≤ 0.5 cm3; > 0.5, ≤ 4.0 cm3; and > 4.0 cm3). The optimal cutoff values of the T/N ratio from receiver operating characteristic (ROC) curve were determined in each group (MTV-corrected) as well as total lesions (non-corrected). Finally, diagnostic performance of 11C-MET PET/CT was compared with the MTV-corrected cutoff values. RESULTS: Among 77 lesions, 51 were diagnosed with recurrence. The mean T/N ratio was 2.25 (± 1.12) for recurrent lesions and 1.44 (± 0.22) for radiation necrosis (P < 0.001). T/N ratio of 1.61 (non-corrected) provided the best sensitivity, specificity, and diagnostic accuracy (70.6, 80.8, and 74.0%, respectively). Using the MTV criteria, optimal cutoff values of the T/N ratios in each group were 1.23 (MTV ≤ 0.5 cm3), 1.54 (0.5 cm3 < MTV ≤ 4.0 cm3), and 1.85 (MTV > 4.0 cm3). In small-sized lesions (MTV ≤ 0.5 cm3), MTV-corrected cutoff values (1.23) could maintain favorable diagnostic performance with sensitivity, specificity, and diagnostic accuracy (70.0, 80.0, and 73.3%, respectively), compared to non-corrected cutoff values. CONCLUSIONS: MTV-corrected cutoff values of T/N ratio could maintain the diagnostic performance of 11C-MET PET/CT in small sized, metastatic brain tumors. We expect our results to contribute to reproducible and standardized interpretation of 11C-MET PET/CT.

Prognostic value of post-treatment metabolic tumor volume from 11C-methionine PET/CT in recurrent malignant glioma.

We investigated the diagnostic and prognostic significance of metabolic parameters from 11C-methionine (MET) positron emission tomography (PET) in patients with malignant glioma. The MET-PET was examined in 42 patients who had been previously treated with adjuvant treatment for malignant glioma. Both ratios of maximal MET uptake of the tumors to those of the contralateral normal gray matter (T/N ratio) and metabolic tumor volume (MTV) were estimated in each lesion. The diagnostic performance for recurrence was investigated in all enrolled patients. A definitive diagnosis was done with pathologic confirmation or clinical follow-up. Among recurrent patients, we evaluated the prognostic value of metabolic parameters (T/N ratio and MTV) as well as clinical factors. Among 42 patients, 35 patients were revealed with recurrence. Both T/N ratios (p = 0.009) and MTV (p = 0.001) exhibited statistical significance to differentiate between recurrence and post-treatment radiation effect. A T/N ratio of 1.43 provided the best sensitivity and specificity for recurrence (91.4 and 100 %, respectively), and a MTV of 6.72 cm3 provided the best sensitivity and specificity (77.1 % and 100 %, respectively). To evaluate the prognostic impact, different cutoffs of MTV were examined in patients with recurrent tumor and a threshold of 60 cm3 was determined as a best cutoff value to separate the patients in two prognostic groups. Univariate analysis revealed improved overall survival (OS) for patients with Karnofsky performance scale (KPS) score ≥70 (p < 0.001) or MTV <60 cm3 (p = 0.049). Multivariate analysis showed that patients with KPS score ≥70 (p < 0.001; hazard ratio = 0.104; 95 % CI, 0.029-0.371) or MTV < 60 cm3 (p = 0.031; hazard ratio = 0.288; 95 % CI, 0.093-0.895) were significantly associated with a longer OS. However, T/N ratio was not correlated with patients' outcome. Metabolic parameters had the diagnostic value to differentiate recurrence from post-treatment radiation effect. Compared with T/N ratio, MTV was an independent significant prognostic factor with KPS score in patients with recurrent tumor. Our study had a potential to manage these patients according to prognostic information using MET-PET.

PDIA6 regulation of ADAM17 shedding activity and EGFR-mediated migration and invasion of glioblastoma cells.

OBJECTIVE In patients with glioblastoma, local invasion of tumor cells causes recurrence and shortens survival. The goal of this study was to determine whether protein disulfide isomerase (PDI) A6 regulates migration and invasion of glioblastoma cells and the associated factors. METHODS U87MG cells were treated with either PDIA6 or ADAM17 small interfering RNA (siRNA) fragments or with both types of siRNA fragments, and expression was confirmed by reverse transcription-polymerase chain reaction and Western blot. Migration and invasion were assessed using a wound-healing assay, a Matrigel assay, and an organotypic culture system. After the U87MG cells were treated with siRNAs and epidermal growth factor receptor (EGFR) inhibitors, the expression of matrix metalloproteinase-2 (MMP-2), membrane Type 1-matrix metalloproteinase (MT1-MMP), integrin, phosphorylated focal adhesion kinase (pFAK), and phosphorylated EGFR (pEGFR) was detected by Western blotting and zymography. RESULTS U87MG cell migration and invasion increased significantly after inhibition of PDIA6. The MMP-2 activation ratio and ADAM17 activity (as a sheddase of the proligand) increased, and expression of pEGFR, pFAK, integrin α5ß3, and MT1-MMP was induced, compared with control levels. Furthermore, heparin-binding epidermal growth factor (EGFR signaling ligand) was highly expressed in PDIA6-knockdown cells. After siPDIA6-transfected U87MG cells were treated with EGFR signaling inhibitors, expression of pFAK, MMP-2, and MT1-MMP decreased and invasion decreased significantly. Simultaneous double-knockdown of PDIA6 and ADAM17 reduced pEGFR and pFAK expression, compared with control levels. CONCLUSIONS The authors propose that inhibiting PDIA6 could transduce EGFR signaling by activating and inducing ADAM17 during migration and invasion of U87MG glioblastoma cells. The results of this study suggest that PDIA6 is an important component of EGFR-mediated migration and invasion of U87MG cells. This is the first report of the effects of PDIA6 on migration and invasion in glioblastoma.

Is Fractionated Gamma Knife Radiosurgery a Safe and Effective Treatment Approach for Large-Volume (>10 cm3) Intracranial Meningiomas?

BACKGROUND: Even with great advances in surgery and improved clinical outcome, morbidity and mortality are still high for large-volume intracranial meningiomas (MNGs). Recently, Gamma Knife radiosurgery (GKS) has proven to be a safe and effective treatment for many patients with intracranial MNGs. However, single-session GKS may increase the risk of radiation-induced toxicity for large MNGs. Recently, fractionated GKS (FGKS) has been performed for an increasing number of patients with surgically high-risk and large intracranial tumors. In this study, we report our results on the efficacy and safety of FGKS for large MNGs. METHODS: The authors performed a retrospective review of 70 patients who underwent GKS for large-volume (>10 cm3) intracranial MNGs between 2004 and 2015, with a minimum follow-up of 12 months. The authors classified these patients into 2 groups of single-session GKS, FGKS. The patients were followed by clinical examination and serial imaging with magnetic resonance imaging. RESULTS: In the single-session GKS group (42 patients), the median tumor volume was 15.2 cm3 (range 10.3-48.3 cm3); the median prescription dose was 12 Gy (range 8-14 Gy), and the median follow-up duration was 57.8 months (range 14.5-128.4 months). In the FGKS group (28 patients), the median tumor volume was 21 cm3 (range 10.2-54.7 cm3), and the median prescription was 7.5 Gy in 2 fractions (range 5-8 Gy), 6 Gy in 3 fractions (range 5-6.5 Gy), and 4.5 Gy in 4 fractions. The median follow-up duration for the FGKS group was 50 months (range 12.5-90.6 months). The overall 5-year tumor control rate was 92.9% in the FGKS group and 88.1% in the single-session GKS group. Fourteen (33.3%) symptomatic complications after single-session GKS were noted, including 5 cases of hemiparesis, 4 of seizure, 3 of peritumoral edema, and 2 of hydrocephalus. Two (7.1%) symptomatic complications after FGKS were noted, including 2 cases of hemiparesis. The FGKS group had higher progression-free survival (PFS) rate at 5 years (92.9% vs. 88.1%), but the differences did not reach statistical significance (P = 0.389). The patients in the FGKS group, however, experienced a lower complication rate compared with patients with a single-session GKS group (P = 0.017, hazard ratio, 5.7:1). CONCLUSION: When the large-volume (>10 cm3) intracranial MNGs are expected to have high morbidity after microsurgery and for patients that have a poor medical status for surgery, FGKS can be considered an alternative with good tumor control and lower complications rates compared with single-session GKS (P = 0.017).