ABSTRACT
BACKGROUND: Transsphenoidal surgery (TSS) is the main method to remove pituitary neuroendocrine tumor (PitNET), but large or multi-lobulated one is still challenging. OBJECTIVE: The less invasive simultaneous combined keyhole mini-transcranial approach and standard transsphenoidal approach was used to remove multi-lobulated or hourglass-shaped non-functioning PitNET to avoid the specific complications related to extended TSS. METHODS: Twenty-one patients of large multi-lobulated or hourglass-shaped PitNET (6 patients were recurrent cases after TSS or transcranial approach) were treated by this simultaneous combined approach. The supraorbital or midline keyhole approach was performed under the operating microscope so that the fine arteries feeding optic apparatus were dissected from the tumor capsule safely and securely and the suprasellar part of the tumor was removed in the extra-capsular fashion in combination with transsphenoidal approach. RESULTS: Visual function improved after the surgery in 14 (74â¯%) of 19 patients with preoperative disturbance of the visual fields. Four patients (19â¯%) developed postoperative deterioration of pituitary endocrine functions requiring permanent hormonal replacement. One patient (4.2â¯%) suffered cortical laminar necrosis without permanent disorders and another patient (4.2â¯%) suffered cerebrospinal fluid rhinorrhea but neither was permanent. Postoperative computed tomography detected no subarachnoid hemorrhage in any patient. Gross total removal was achieved in 15 patients (71â¯%). Five patients (24â¯%) with subtotal removal and one patient (4.2â¯%) with partial removal had lateral tumor extension with Knosp classification 3 or 4. CONCLUSION: The combined method is an effective treatment option to remove complex PitNET safely and securely with dissecting fine arteries on the tumor capsule.
ABSTRACT
In Japan, brain docking has enhanced the detection of unruptured intracranial aneurysms in healthy adults. At our institution, surgical clipping is the first-line treatment for unruptured intracranial aneurysms (UIA). In this study, the differences in neurological and radiological outcomes, as well as cognitive and psychological results, between standard clipping and keyhole clipping for these aneurysms detected via brain docking were evaluated. The study included 131 aneurysms detected via "brain dock." Of these, 65 were treated with keyhole clipping surgery (keyhole clipping group), and 66 were treated with standard clipping surgery (standard clipping group). Evaluations at 3 months included the National Institutes of Health Stroke Scale, modified Rankin Scale, Mini-Mental State Examination, Hasegawa's Dementia Scale-revised, Beck Depression Inventory, Hamilton Rating Scale for Depression, and radiological abnormalities. The mean operative time and postoperative hospitalization period were significantly shorter in the keyhole clipping group than in the standard clipping group (p < 0.001). Between the groups, no significant differences in postoperative neurological complications or radiological abnormalities were found. The keyhole clipping group demonstrated slightly but significantly better Beck Depression Inventory and Hamilton Rating Scale for Depression scores than the standard clipping group (Beck Depression Inventory, p = 0.046; Hamilton Rating Scale for Depression, p < 0.01). Both the Beck Depression Inventory and Hamilton Rating Scale for Depression scores at 3 months were significantly enhanced (p < 0.001) in the keyhole clipping group. These findings propose that keyhole clipping could be considered a new therapeutic option for small UIA detected via brain docking.
Subject(s)
Intracranial Aneurysm , Adult , Humans , Intracranial Aneurysm/diagnostic imaging , Intracranial Aneurysm/surgery , Japan , Neurosurgical Procedures/methods , Brain/surgery , Craniotomy/methods , Postoperative Complications/etiology , Treatment Outcome , Retrospective StudiesABSTRACT
Background: The pathophysiology of traumatic brain injury (TBI) is caused by the initial physical damage and by the subsequent biochemical damage (secondary brain injury). Oxidative stress is deeply involved in secondary brain injury, so molecular hydrogen therapy may be effective for TBI. Hydrogen gas shows the optimal effect at concentrations of 2% or higher, but can only be used up to 1.3% in the form of a gas cylinder mixed with oxygen gas, which may not be sufficiently effective. The partial pressure of hydrogen increases in proportion to the pressure, so hyperbaric hydrogen therapy (HBH2) is more effective than that at atmospheric pressure. Methods: A total of 120 mice were divided into three groups: TBI + non-treatment group (TBI group; n = 40), TBI + HBH2 group (n = 40), and non-TBI + non-treatment group (sham group; n = 40). The TBI and TBI + HBH2 groups were subjected to moderate cerebral contusion induced by controlled cortical impact. The TBI + HBH2 group received hyperbaric hydrogen therapy at 2 atmospheres for 90 minutes, at 30 minutes after TBI. Brain edema, neuronal cell loss in the injured hippocampus, neurological function, and cognitive function were evaluated. Results: The TBI + HBH2 group showed significantly less cerebral edema (p ⺠0.05). Residual hippocampal neurons were significantly more numerous in the TBI + HBH2 group on day 28 (p ⺠0.05). Neurological score and behavioral tests showed that the TBI + HBH2 group had significantly reduced hyperactivity on day 14 (p ⺠0.01). Conclusion: Hyperbaric hydrogen therapy may be effective for posttraumatic secondary brain injury.
Subject(s)
Brain Edema , Brain Injuries, Traumatic , Brain Injuries , Hyperbaric Oxygenation , Rats , Mice , Animals , Hydrogen/pharmacology , Hydrogen/therapeutic use , Rats, Sprague-Dawley , Brain Injuries/complications , Brain Injuries/therapy , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/therapy , Brain Edema/etiology , Brain Edema/therapy , BrainABSTRACT
OBJECTIVES: Patients sometimes present with high cervical internal carotid artery (ICA) stenosis. This study demonstrates the usefulness of the transstyloid approach to expose the distal ICA by dissection of the styloid diaphragm covering the distal cervical ICA for carotid endarterectomy (CEA). In particular, the possible exposure length achieved by this approach was investigated using cadaveric heads. METHODS: The procedure of the transstyloid diaphragm approach was confirmed in 10 cadaveric heads (20 sides). After the carotid triangle was opened, both the posterior belly of the digastric muscle (PBDM) and the stylohyoid muscle could be divided. Then, the carotid sheath was dissected, and the glossopharyngeal nerve was identified crossing over the distal ICA. The revealed length of the ICA was measured with or without dissection of both the PBDM and the stylohyoid muscle. The specimens were dissected under the surgical microscope. RESULTS: The transstyloid diaphragm approach was achieved successfully in all specimens. The revealed lengths of the ICA with and without dissection of the styloid diaphragm were 53.7 ± 5.9 mm and 38.8 ± 2.9 mm (mean ± standard deviation), respectively. Therefore, the revealed length of the distal ICA was 14.9 ± 4.5 mm greater using the transstyloid diaphragm approach compared to the regular CEA approach. CONCLUSIONS: More of the ICA can be revealed by dissection of both the PBDM and the stylohyoid muscle. The transstyloid diaphragm approach might be helpful to reveal the distal ICA in cases of high cervical ICA stenosis.
Subject(s)
Carotid Stenosis , Endarterectomy, Carotid , Plaque, Atherosclerotic , Humans , Endarterectomy, Carotid/methods , Diaphragm/surgery , Constriction, Pathologic , Carotid Stenosis/surgery , Cadaver , Carotid Artery, Internal/surgerySubject(s)
Meningeal Neoplasms , Meningioma , Humans , Meningioma/surgery , Cerebral Ventricles , Meningeal Neoplasms/surgery , Temporal LobeABSTRACT
Here, we investigated the detailed molecular oncogenic mechanisms of a novel receptor tyrosine kinase (RTK) fusion, KLC1-ROS1, with an adapter molecule, KLC1, and an RTK, ROS1, discovered in pediatric glioma, and we explored a novel therapeutic target for glioma that possesses oncogenic RTK fusion. When wild-type ROS1 and KLC1-ROS1 fusions were stably expressed in the human glioma cell lines A172 and U343MG, immunoblotting revealed that KLC1-ROS1 fusion specifically activated the JAK2-STAT3 pathway, a major RTK downstream signaling pathway, when compared with wild-type ROS1. Immunoprecipitation of the fractionated cell lysates revealed a more abundant association of the KLC1-ROS1 fusion with JAK2 than that observed for wild-type ROS1 in the cytosolic fraction. A mutagenesis study of the KLC1-ROS1 fusion protein demonstrated the fundamental roles of both the KLC1 and ROS1 domains in the constitutive activation of KLC1-ROS1 fusion. Additionally, in vitro assays demonstrated that KLC1-ROS1 fusion upregulated cell proliferation, invasion, and chemoresistance when compared to wild-type ROS1. Combination treatment with the chemotherapeutic agent temozolomide and an inhibitor of ROS1, JAK2, or a downstream target of STAT3, demonstrated antitumor effects against KLC1-ROS1 fusion-expressing glioma cells. Our results demonstrate that KLC1-ROS1 fusion exerts oncogenic activity through serum-independent constitutive activation, resulting in specific activation of the JAK-STAT pathway. Our data suggested that molecules other than RTKs may serve as novel therapeutic targets for RTK fusion in gliomas.
ABSTRACT
We evaluated the efficacy and safety of bevacizumab beyond progression (BBP) in Japanese patients with newly diagnosed glioblastoma and explored predictors of response to bevacizumab. This phase II study evaluated a protocol-defined primary therapy by radiotherapy with concurrent and adjuvant temozolomide plus bevacizumab, followed by bevacizumab monotherapy, and secondary therapy (BBP: bevacizumab upon progression). Ninety patients received the protocol-defined primary therapy (BBP group, n = 25). Median overall survival (mOS) and median progression-free survival (mPFS) were 25.0 and 14.9 months, respectively. In the BBP group, in which O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated tumors predominated, mOS and mPFS were 5.8 and 1.9 months from BBP initiation and 16.8 and 11.4 months from the initial diagnosis, respectively. The primary endpoint, the 2-year survival rate of the BBP group, was 27.0% and was unmet. No unexpected adverse events occurred. Expression profiling using RNA sequencing identified that Cluster 2, which was enriched with the genes involved in macrophage or microglia activation, was associated with longer OS and PFS independent of the MGMT methylation status. Cluster 2 was identified as a significantly favorable independent predictor for PFS, along with younger age and methylated MGMT. The novel expression classifier may predict the prognosis of glioblastoma patients treated with bevacizumab.
ABSTRACT
BACKGROUND: An entrapped temporal horn (ETH) is one of the critical complications after tumor removal in the lateral ventricle trigone that sometimes becomes life threatening. OBJECTIVE: We sought to develop a novel intraoperative method of prophylactic intraventricular piping (PIP) just after tumor removal to prevent ETH. METHODS: Three patients with meningiomas in the lateral ventricle trigone were treated by a novel intraoperative method of PIP just after tumor removal to prevent ETH. Silicone catheters normally used as ventricular drainage catheters were cut to 5- to 6-cm length and inserted into the tumor cavity to ensure communication between the temporal horn and the atrium or the body of the lateral ventricle through the piping straddling the trigone. RESULTS: None of our patients developed ETH during the follow-up period without complications caused by the tube placement. CONCLUSIONS: PIP might be beneficial to prevent ETH because constant osmotic pressure and constant cerebrospinal fluid pulse wave transmission are maintained between each compartment of the lateral ventricle.
Subject(s)
Meningeal Neoplasms , Meningioma , Humans , Meningioma/pathology , Lateral Ventricles/surgery , Lateral Ventricles/pathology , Neurosurgical Procedures , Temporal Lobe/pathology , Meningeal Neoplasms/pathologyABSTRACT
Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.
Subject(s)
Brain Neoplasms , Neoplasms, Germ Cell and Embryonal , Testicular Neoplasms , Adolescent , Alleles , Brain Neoplasms/genetics , Child , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Neoplasms, Germ Cell and Embryonal/genetics , Polymorphism, Single Nucleotide , Testicular Neoplasms/genetics , bcl-2 Homologous Antagonist-Killer Protein/geneticsABSTRACT
PURPOSE: Molecular targeted therapy using BRAF and/or MEK inhibitors has been applied to BRAFV600E-mutant high-grade gliomas (HGG); however, the therapeutic effect is limited by the emergence of drug resistance. EXPERIMENTAL DESIGN: We established multiple paired BRAFV600E-mutant HGG patient-derived xenograft models based on tissues collected prior to and at relapse after molecular targeted therapy. Using these models, we dissected treatment-resistant mechanisms for molecular targeted therapy and explored therapeutic targets to overcome resistance in BRAFV600E HGG models in vitro and in vivo. RESULTS: We found that, despite causing no major genetic and epigenetic changes, BRAF and/or MEK inhibitor treatment deregulated multiple negative feedback mechanisms, which led to the reactivation of the MAPK pathway through c-Raf and AKT signaling. This altered oncogenic signaling primarily mediated resistance to molecular targeted therapy in BRAFV600E-mutant HGG. To overcome this resistance mechanism, we performed a high-throughput drug screening to identify therapeutic agents that potently induce additive cytotoxicity with BRAF and MEK inhibitors. We discovered that HSP90 inhibition combined with BRAF/MEK inhibition coordinately deactivated the MAPK and AKT/mTOR pathways, and subsequently induced apoptosis via dephosphorylation of GSK3ß (Ser9) and inhibition of Bcl-2 family proteins. This mediated potent cytotoxicity in vitro and in vivo in refractory models with acquired resistance to molecular targeted therapy. CONCLUSIONS: The combination of an HSP90 inhibitor with BRAF or MEK inhibitors can overcome the limitations of the current therapeutic strategies for BRAFV600E-mutant HGG.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Brain Neoplasms , Glioma , HSP90 Heat-Shock Proteins , Melanoma , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Glioma/drug therapy , Glioma/genetics , Glioma/metabolism , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/genetics , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Molecular Targeted Therapy , Mutation , Neoplasm Recurrence, Local/drug therapy , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Meningioma is the most common intracranial tumor, with generally favorable patient prognosis. However, patients with malignant meningioma typically experience recurrence, undergo multiple surgical resections, and ultimately have a poor prognosis. Thus far, effective chemotherapy for malignant meningiomas has not been established. We recently reported the efficacy of eribulin (Halaven) for glioblastoma with a telomerase reverse transcriptase (TERT) promoter mutation. This study investigated the anti-tumor effect of eribulin against TERT promoter mutation-harboring human malignant meningioma cell lines in vitro and in vivo. Two meningioma cell lines, IOMM-Lee and HKBMM, were used in this study. The strong inhibition of cell proliferation by eribulin via cell cycle arrest was demonstrated through viability assay and flow cytometry. Apoptotic cell death in malignant meningioma cell lines was determined through vital dye assay and immunoblotting. Moreover, a wound healing assay revealed the suppression of tumor cell migration after eribulin exposure. Intraperitoneal administration of eribulin significantly prolonged the survival of orthotopic xenograft mouse models of both malignant meningioma cell lines implanted in the subdural space (P < .0001). Immunohistochemistry confirmed apoptosis in brain tumor tissue treated with eribulin. Overall, these results suggest that eribulin is a potential therapeutic agent for malignant meningiomas.
Subject(s)
Antineoplastic Agents/therapeutic use , Furans/therapeutic use , Ketones/therapeutic use , Meningeal Neoplasms/drug therapy , Meningioma/drug therapy , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Furans/pharmacology , Humans , Kaplan-Meier Estimate , Ketones/pharmacology , Meningeal Neoplasms/genetics , Meningeal Neoplasms/mortality , Meningeal Neoplasms/pathology , Meningioma/genetics , Meningioma/mortality , Meningioma/pathology , Mice , Mutation , Promoter Regions, Genetic , Telomerase/genetics , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Cotton patty is usually used to aspirate blood and cerebrospinal fluid to maintain a dry field. However, the cotton patty easily adheres to the vessels by capillary action, especially in combination with hemostat. Therefore, re-bleeding may be induced by removal of the cotton patty stuck to the vessel despite initial control of the bleeding. METHODS: We have developed a new cotton patty (Non-Stina X®, Hakujuji, Co., Ltd., Tokyo, Japan) which does not adhere to the vessels. The newly developed cotton patty is made of 100% cotton, with only the contact surface coated with polyurethane film which prevents capillary action. The coated side includes many holes to allow aspiration from both sides. RESULTS: The characteristics of four different surgical patties including our new patty which are available for surgical use in Japan were investigated. Transverse sections of four different surgical patties were investigated by light microscopy (magnification ×150). Our new cotton patty did not show any fluffing on the polyurethane-coated surface. However, other surgical patties showed some fluffing on their surfaces. The friction coefficients of four different surgical patties were investigated. Our new cotton patty had the lowest of the four neurosurgical patties. We confirmed the nonadherent characteristic using with hemostats of gelatinous sponge or fibrin glue-soaked oxidized cellulose cotton during hemostasis in neurosurgical procedures. The polyurethane-coated cotton patty could be removed easily from the hemostats without re-bleeding. CONCLUSIONS: The newly developed polyurethane-coated cotton patty is more effective for bleeding control from vessels with several types of hemostat due to the nonadherent characteristics.
ABSTRACT
Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Lomustine/therapeutic use , Nimustine/therapeutic use , Temozolomide/therapeutic use , Animals , Antineoplastic Agents/administration & dosage , Brain Neoplasms/metabolism , DNA Modification Methylases/metabolism , DNA Repair Enzymes/metabolism , Drug Resistance, Neoplasm/genetics , Female , Glioblastoma/metabolism , Histones/metabolism , Humans , Injections, Intraperitoneal , Lomustine/administration & dosage , Methylation , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Recurrence, Local/drug therapy , Nimustine/administration & dosage , Salvage Therapy/methods , Tumor Suppressor Proteins/metabolism , Xenograft Model Antitumor AssaysABSTRACT
Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.
ABSTRACT
Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second-generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase-dependent/-independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second-generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM.
Subject(s)
Anaplastic Lymphoma Kinase/genetics , Brain Neoplasms/drug therapy , Carbazoles/administration & dosage , Glioblastoma/drug therapy , Piperidines/administration & dosage , Pyrimidines/administration & dosage , STAT3 Transcription Factor/metabolism , Sulfones/administration & dosage , Administration, Oral , Anaplastic Lymphoma Kinase/metabolism , Animals , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Carbazoles/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Glioblastoma/genetics , Glioblastoma/metabolism , Humans , Mice , Piperidines/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Signal Transduction/drug effects , Sulfones/pharmacology , Temozolomide/pharmacology , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Rat ventral caudal artery (VCA, tail artery) cannulation for blood pressure monitoring and blood sampling is essential for maintaining consistent procedures in rat models. Double or triple insults are sometimes necessary, but repeated VCA cannulations have not been compared with repeated femoral artery cannulations. In addition, the collateral system for resistance to ischemia in the rat tail is unclear. Our present study revealed that repeated VCA cannulations on different days was a better technique than repeated femoral artery cannulations in terms of surgical time, postsurgical weight loss and ischemic complications. Furthermore, the lateral caudal arteries and the segmental anastomosing vessels were important for resistance to ischemic complications after VCA occlusion.
Subject(s)
Femoral Artery , Tail , Animals , Blood Pressure Determination , Catheterization , Feasibility Studies , Humans , RatsABSTRACT
To manage refractory and invasive glioblastomas (GBM)s, photodynamic therapy (PDT) using talaporfin sodium (NPe6) (NPe6-PDT) was recently approved in clinical practice. However, the molecular machineries regulating resistance against NPe6-PDT in GBMs and mechanisms underlying the changes in GBM phenotypes following NPe6-PDT remain unknown. Herein, we established an in vitro NPe6-mediated PDT model using human GBM cell lines. NPe6-PDT induced GBM cell death in a NPe6 dose-dependent manner. However, this NPe6-PDT-induced GBM cell death was not completely blocked by the pan-caspase inhibitor, suggesting NPe6-PDT induces both caspase-dependent and -independent cell death. Moreover, treatment with poly (ADP-ribose) polymerase inhibitor blocked NPe6-PDT-triggered caspase-independent GBM cell death. Next, it was also revealed resistance to re-NPe6-PDT of GBM cells and GBM stem cells survived following NPe6-PDT (NPe6-PDT-R cells), as well as migration and invasion of NPe6-PDT-R cells were enhanced. Immunoblotting of NPe6-PDT-R cells to assess the behavior of the proteins that are known to be stress-induced revealed that only ERK1/2 activation exhibited the same trend as migration. Importantly, treatment with the MEK1/2 inhibitor trametinib reversed resistance against re-NPe6-PDT and suppressed the enhanced migration and invasion of NPe6-PDT-R cells. Overall, enhanced ERK1/2 activation is suggested as a key regulator of elevated malignant phenotypes of GBM cells surviving NPe6-PDT and is therefore considered as a potential therapeutic target against GBM.
ABSTRACT
Molecular hydrogen (H2) protect neurons against reactive oxygen species and ameliorates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study investigated the effect of H2 on delayed brain injury (DBI) using the rat SAH + unilateral common carotid artery occlusion (UCCAO) model with the endovascular perforation method. 1.3% H2 gas (1.3% hydrogen premixed with 30% oxygen and balanced nitrogen) inhalation was performed on days 0 and 1, starting from anesthesia induction and continuing for 2 h on day 0, and starting from anesthesia induction and continuing for 30 min on day 1. EBI was assessed on the basis of brain edema, expression of S100 calcium-binding protein B (S100B), and phosphorylation of C-Jun N-terminal kinase on day 2, and neurological deficits on day 3. Reactive astrogliosis and severity of cerebral vasospasm (CV) were assessed on days 3 and 7. DBI was assessed on the basis of neurological deficits and neuronal cell death on day 7. EBI, reactive astrogliosis, and DBI were ameliorated in the H2 group compared with the control group. CV showed no significant improvement between the control and H2 groups. This study demonstrated that H2 gas inhalation ameliorated DBI by reducing EBI without improving CV in the rat SAH + UCCAO model.
Subject(s)
Brain Injuries/drug therapy , Brain Injuries/etiology , Hydrogen/administration & dosage , Hydrogen/therapeutic use , Subarachnoid Hemorrhage/complications , Administration, Inhalation , Animals , Blood Pressure , Brain/metabolism , Brain/pathology , Brain/physiopathology , Brain Edema/complications , Brain Edema/physiopathology , Brain Injuries/physiopathology , Cell Death , Cerebral Arteries/pathology , Cerebral Arteries/physiopathology , Cerebrovascular Circulation , Gliosis/complications , Gliosis/pathology , Gliosis/physiopathology , Intracranial Pressure , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Neurons/pathology , Phosphorylation , Rats, Sprague-Dawley , S100 Proteins/metabolism , Subarachnoid Hemorrhage/physiopathology , Time Factors , Vasospasm, Intracranial/pathology , Vasospasm, Intracranial/physiopathology , Water , Weight LossABSTRACT
Primary intracranial malignant melanoma(PIMM)is a rare neoplasm of the central nervous system, accounting for 1% of cases of malignant melanomas and 0.1% of cases of brain tumors. Here, we report a case of PIMM that was initially considered to be a traumatic brain contusion. A 44-year-old man was transferred to a local hospital because of general tonic convulsion after falling while riding a bike. CT showed an irregular high-density area in the left temporal pole, which was diagnosed as a traumatic contusion. MRI performed 3 months after the initial episode revealed an enlarged temporal lesion with surrounding edema, suggestive of a neoplasm. The MRI showed the lesion as mixed signal intensity, suggesting both solid and cystic components. Subtotal resection was performed, except for the tumor adhering to the peripheral middle cerebral arteries(MCAs). The definitive diagnosis was made based on pathological findings and no evidence of extracranial lesions. Gamma knife surgery was performed for the remnant tumor adjacent to MCAs. The radiologically positive tumor chronologically regressed, and the patient remained progression-free for 18 months. Radiological findings of PIMM vary but typically include high density on CT and hyperintensity on T1-weighted MRI. Close observation enabled early diagnosis based on the suspicion of a neoplasm according to atypical radiological findings. PIMM has a poor prognosis with an overall survival of 12.0 months without confirmative treatment. Gamma knife surgery might achieve suppression of this highly progressive tumor.
Subject(s)
Brain Contusion , Brain Neoplasms/surgery , Melanoma/surgery , Radiosurgery , Adult , Humans , Magnetic Resonance Imaging , MaleABSTRACT
OBJECTIVE: Clipping of paraclinoid aneurysm is still challenging because of poor visual morbidity. The extradural temporopolar approach was applied to clip paraclinoid aneurysms, with the expectation of reducing visual morbidity. Factors related to poor visual morbidity were evaluated, to assess the results for clipping of paraclinoid aneurysms. METHODS: A series of 40 unruptured paraclinoid aneurysms in 38 patients were clipped via extradural temporopolar approach. Preoperative and postoperative states of visual cognitive function and radiological outcomes were investigated. Aneurysms were classified into dorsal type or non-dorsal type, and small (<9 mm) or not-small (≥9 mm), respectively, to identify factors correlated with visual morbidity. RESULTS: Complete clipping rate was 90.0% without any recurrence (mean: 5.2 years). Visual morbidity was unexpectedly high at 28.9%, including 2.7% of blindness immediately after the operation, and 23.7% and 2.7% at the final examination (mean: 3.6 years). Multivariate analysis showed aneurysm size was significantly correlated with worse visual outcome. Visual morbidity was 13.3% and 11.1% for dorsal and the non-dorsal small aneurysms, respectively, and all these cases showed visual field defect limited to the nasal quadrant without decreased visual acuity. In contrast, the non-dorsal not-small aneurysms showed significantly worse visual morbidity (60%) with decreased visual acuity. CONCLUSIONS: Clipping via extradural temporopolar approach can achieve durable treatment for small unruptured paraclinoid aneurysms with acceptable visual morbidity. Visual morbidity of the not-small non-dorsal type, however, was poor. The indications for clipping of paraclinoid aneurysm should be limited to small aneurysms, especially the dorsal type in young patients.