Bevacizumab Alone Versus Bevacizumab Plus Irinotecan in Patients With Recurrent Glioblastoma: A Nationwide Population-Based Study.

BACKGROUND: For treating recurrent glioblastoma, for which there is no established treatment, the antiangiogenic antibody, bevacizumab, is used alone or with irinotecan. This study was aimed at comparing the survival of patients with recurrent glioblastoma receiving bevacizumab monotherapy and those receiving bevacizumab plus irinotecan combination therapy (B+I) by using a nationwide population-based dataset. METHODS: Patients matching the International Classification of Diseases code C71.x were screened from the Health Insurance Review and Assessment Service database. From January 2008 to November 2021, patients who underwent surgery or biopsy and subsequent standard concurrent chemoradiation with temozolomide were included. Among them, those who received bevacizumab monotherapy or B+I were selected. Demographic characteristics, inpatient stay, prescription frequency, survival outcomes, and steroid prescription duration were compared between these two groups. RESULTS: Eight hundred and forty-six patients who underwent surgery or biopsy and received concurrent chemoradiotherapy with temozolomide were included. Of these, 450 and 396 received bevacizumab monotherapy and B+I, respectively. The corresponding median overall survival from the initial surgery was 22.60 months (95% confidence interval [CI], 20.50-24.21) and 20.44 months (95% CI, 18.55-22.60; P = 0.508, log-rank test). The B+I group had significantly more bevacizumab prescriptions (median 5 times; BEV group: median 3 times). Cox analysis, based on the postsurgery period, revealed that male sex (hazard ratio [HR], 1.28; P = 0.002), older age (HR, 1.01; P = 0.042), and undergoing biopsy instead of surgery (HR, 1.79; P < 0.0001) were significantly associated with decreased survival. Fewer radiotherapy cycles correlated with improved survival outcomes (HR, 0.63; P = 0.001). Cox analysis, conducted from the start of chemotherapy including bevacizumab, showed that male sex was the only variable significantly associated with decreased survival (HR, 1.18; P = 0.044). CONCLUSION: We found no significant difference in overall survival between the bevacizumab monotherapy and B+I groups. Considering the additional potential toxicity associated with irinotecan, bevacizumab monotherapy could be a suitable treatment option for treating recurrent glioblastoma.

Glymphatic system evaluation using diffusion tensor imaging in patients with traumatic brain injury.

PURPOSE: Glymphatic system dysfunction has been reported in animal models of traumatic brain injury (TBI). This study aimed to evaluate the activity of the human glymphatic system using the non-invasive Diffusion Tensor Image-Analysis aLong the Perivascular Space (DTI-ALPS) method in patients with TBI. METHODS: A total of 89 patients with TBI (June 2018 to May 2020) were retrospectively enrolled, and 34 healthy volunteers were included who had no previous medical or neurological disease. Magnetic resonance imaging (MRI) with DTI was performed, and the ALPS index was calculated to evaluate the glymphatic system's activity. Wilcoxon rank-sum test was used to compare the ALPS index between patients with TBI and healthy controls. ANOVA was done to compare the ALPS index among controls and patients with mild/moderate-to-severe TBI. Multivariate logistic regression analyses were used to identify independent clinical and radiological factors associated with the ALPS index. The correlation between Glasgow Coma Scale (GCS) score and the ALPS index was also assessed. RESULTS: The ALPS index was significantly lower in patients with TBI than in healthy controls (median, 1.317 vs. 1.456, P < 0.0001). There were significant differences in the ALPS index between healthy controls and patients with mild/moderate-to-severe TBI (ANOVA, P < 0.001). The presence of subarachnoid hemorrhage (P = 0.004) and diffuse axonal injury (P = 0.001) was correlated with a lower ALPS index in the multivariate analysis. There was a weak positive correlation between the ALPS index and GCS scores (r = 0.242, P = 0.023). CONCLUSIONS: The DTI-ALPS method is useful for evaluating glymphatic system impairment and quantifying its activity in patients with TBI.

A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres.

PURPOSE: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). METHODS: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. RESULTS: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). CONCLUSION: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.

Pedicled frontal periosteal rescue flap via eyebrow incision for skull base reconstruction (SevEN-002).

PURPOSE: Cerebrospinal fluid (CSF) leakage is one of the major complications after endoscopic endonasal surgery. The reconstructive nasoseptal flap is widely used to repair CSF leakage. However, it could not be utilized in all cases; thus, there was a need for an alternative. We developed a pericranial rescue flap that could cover both sellar and anterior skull base defects via the endonasal approach. A modified surgical technique that did not violate the frontal sinus and cause cosmetic problems was designed using the pericranial rescue flap. METHODS: We performed 12 cadaveric dissections to investigate the applicability of the lateral pericranial rescue flap. An incision was made, extending from the middle to the lateral part of the eyebrow. The pericranium layer was dissected away from the galea layer, from the supraorbital region towards the frontoparietal region. With endoscopic assistance, the periosteal flap was raised, the flap base was the pericranium layer at the eyebrow incision. After a burr-hole was made in the supraorbital bone, the pericranial flap was inserted via the intradural or extradural pathway. RESULTS: The mean size of the pericranial flap was 11.5 cm × 3.2 cm. It was large enough to cross the midline and cover the dural defects of the anterior skull base, including the sellar region. CONCLUSION: We demonstrated a modified endoscopic technique to repair the anterior skull base defects. This minimally invasive pericranial flap may resolve neurosurgical complications, such as CSF leakage.

Virtual dissection of the real brain: integration of photographic 3D models into virtual reality and its effect on neurosurgical resident education.

OBJECTIVE: Virtual reality (VR) is increasingly being used for education and surgical simulation in neurosurgery. So far, the 3D sources for VR simulation have been derived from medical images, which lack real color. The authors made photographic 3D models from dissected cadavers and integrated them into the VR platform. This study aimed to introduce a method of developing a photograph-integrated VR and to evaluate the educational effect of these models. METHODS: A silicone-injected cadaver head was prepared. A CT scan of the specimen was taken, and the soft tissue and skull were segmented to 3D objects. The cadaver was dissected layer by layer, and each layer was 3D scanned by a photogrammetric method. The objects were imported to a free VR application and layered. Using the head-mounted display and controllers, the various neurosurgical approaches were demonstrated to neurosurgical residents. After performing hands-on virtual surgery with photographic 3D models, a feedback survey was collected from 31 participants. RESULTS: Photographic 3D models were seamlessly integrated into the VR platform. Various skull base approaches were successfully performed with photograph-integrated VR. During virtual dissection, the landmark anatomical structures were identified based on their color and shape. Respondents rated a higher score for photographic 3D models than for conventional 3D models (4.3 ± 0.8 vs 3.2 ± 1.1, respectively; p = 0.001). They responded that performing virtual surgery with photographic 3D models would help to improve their surgical skills and to develop and study new surgical approaches. CONCLUSIONS: The authors introduced photographic 3D models to the virtual surgery platform for the first time. Integrating photographs with the 3D model and layering technique enhanced the educational effect of the 3D models. In the future, as computer technology advances, more realistic simulations will be possible.

Predicting survival using the 2016 World Health Organization classification for anaplastic glioma.

AIM: This study aimed to investigate the survival and prognostic factors for anaplastic glioma, and whether the updated 2016 WHO classification had superior ability to predict survival. MATERIALS AND METHODS: Between January 2001 and December 2013, 113 consecutive patients were diagnosed with anaplastic glioma based on the 2007 WHO classification. We re-classified their diagnoses in accordance with the 2016 WHO classification. The Kaplan-Meier method, multivariate Cox proportional regression analysis, and a time-dependent receiver operating characteristic curve were used for the analysis. RESULTS: The median overall survival was 48.4 months among all patients, and 21.5 months for the anaplastic astrocytoma, IDH wild-type (AAw) group. The median progression-free survival was 31.8 months among all patients and 16.4 in the AAw group. Age, MGMT promoter methylation status, deep tumor location, and resection extent were associated with overall survival and progression-free survival. CONCLUSION: We found that the 2016 WHO classification of central nervous system tumors had superior ability to predict survival in cases of anaplastic glioma, as compared to the 2007 WHO classification.

A Simple and Practical Scoring System for Radiosurgical Treatment in Patients with Brain Metastases.

BACKGROUND: The study aimed to investigate the prognostic factors for patients with brain metastases undergoing radiosurgical treatment and to introduce a simple and practical scoring system for the prediction of survival time. METHODS: We retrospectively analyzed data for 311 patients treated with Gamma Knife radiosurgery at a single institute. The mean age at time of treatment was 60 years (range 23-86 years), and the median Karnofsky performance status (KPS) score was 90 (range 60-100). Using a new prognostic index, the prognostic index for brain metastases (PIBM), the patients were categorized into 3 groups according to the primary tumor status and KPS score. We performed survival analysis and compared the prognostic ability of the PIBM with other published indices. RESULTS: During the median follow-up duration of 8.2 months (range 0.1-109 months), the median overall survival time was 9.1 months. Stable primary tumor status (hazard ratio [HR] 0.497, 95% confidence interval [CI] 0.321-0.769, p = 0.002) and KPS score ≥90 (HR 1.407, 95% CI 1.018-1.946, p = 0.039) significantly predicted longer overall survival. The PIBM showed the lowest Akaike information criterion value and the highest integrated area under the curve value compared with other prognostic indices. CONCLUSIONS: The PIBM may be a more accurate prognostic indicator than other published indices. Although this new and practical prognostic index requires further validation in larger cohort studies, we suggest that the PIBM could be useful to predict survival time and inform appropriate management of patients with brain metastases.

Biportal endoscopic transorbital approach: a quantitative anatomical study and clinical application.

BACKGROUND: We devised a biportal endoscopic transorbital approach (BiETOA) to gain surgical freedom by making a port for the endoscope and investigated the benefits and limitations of BiETOA. METHODS: A cylindrical port was designed and 3-D printed using biocompatible material. The port was inserted through a keyhole between the superolateral side of the orbital rim and the temporal muscle. An endoscope was inserted through the port, and other instruments were inserted through the conventional transorbital route. BiETOA was used to dissect eight cadaveric heads, and the angle of attack and surgical freedom were assessed. RESULTS: The mean maximal angle of attack was significantly different in BiETOA and endoscopic transorbital approach (ETOA) (P < 0.01) but not in BiETOA and ETOA lateral orbital rim (LOR) osteotomy (P = 0.207, P = 0.21). The mean surgical freedom was significantly different in BiETOA and ETOA (P < 0.01) and in BiETOA and ETOA LOR osteotomy (P < 0.01). In the clinical cases, tumors were removed successfully without any complications. CONCLUSIONS: BiETOA provided increased surgical freedom and better visibility of deep target lesion and resulted in good surgical and cosmetic outcomes.

Actinomycotic osteomyelitis of a long bone in an immunocompetent adult: a case report and literature review.

BACKGROUND: Actinomycosis is a rare, chronic granulomatous disease caused by Gram-positive anaerobic bacteria that colonize the oral cavity. Cervicofacial actinomycosis is the most frequent clinical presentation of actinomycosis, but hematogenous osteomyelitis at distant sites can occur in rare instance in immunocompromised or pediatric patients, only a few cases have been reported in healthy patients. Here we described a new case of distal femur osteomyelitis caused by Actinomyces in an adult patient who was immunocompetent and had no predisposing factors. CASE PRESENTATION: A woman aged 52 years with no history of trauma presented with severe pain, swelling, and increased local heat in the proximal area of the right knee 3 weeks after she first noticed discomfort. Magnetic resonance imaging showed persistent osteomyelitis of the distal metaphysis and diaphysis of the femur with a multifocal intraosseous abscess pocket. An incision and drainage of the abscess were conducted. The tissue culture, fungus culture, acid fast bacillus (AFB) culture, AFB smear, and tuberculosis polymerase chain reaction test results were negative. A pathologic examination confirmed the presence of actinomycosis. The patient was successfully treated with intravenous penicillin G for 8 weeks followed by oral amoxicillin-clavulanate for 6 weeks with repeated surgical debridement and drainage. After a 5-year follow up, the patient had no signs of recurring infection or complications and she had full range of movement in the affected knee. CONCLUSIONS: Although rare, actinomycotic osteomyelitis can occur in healthy people. Furthermore, actinomycotic osteomyelitis is easily misdiagnosed as tuberculosis in areas with a high prevalence of tuberculosis. To detect and identify the bacteria accurately, pathologic examination should be performed as well as culture tests, because the probability for culture confirmation of actinomycosis is quite low. The initial treatment is vital to a successful outcome without ostectomy or amputation.

Identifying candidates for gamma knife radiosurgery among elderly patients with brain metastases.

We investigated the outcomes of gamma knife radiosurgery (GKRS) for elderly patients (≥ 65 years) with brain metastases, and identified survival-associated factors. We retrospectively analyzed data from 115 patients treated with GKRS for 1-15 brain metastases. The median patient age was 72 years; most primary tumors were pulmonary (n = 83). The mean lesion volume was 2.1 ± 4.8 mL. A mean dose of 19.3 Gy was delivered to the mean 63.9% isodose line. The median overall survival (OS) was 5.3 months (95% confidence interval [CI] 3.5-7.1). During follow-up (median, 5.1 months), 91 patients died of primary cancer progression while 1 died of unknown causes. The 6- and 12-month local control rates were 94.9 and 88.1%, respectively. On multivariate analysis, female sex (p = 0.005, hazard ratio [HR] 0.533, 95% CI 0.343-0.827) and a controlled primary tumor (p < 0.001, HR 0.328, 95% CI 0.180-0.596) were significantly favorable prognostic factors. Of non-small cell lung cancer patients with EGFR mutations, 76.5% were women (p = 0.005). The median OS of EGFR-mutant and EGFR-wildtype patients were 19.1 and 4.7 months, respectively (p = 0.080). Brain metastases < 3 mL showed better local control rates after GKRS (p = 0.005). GKRS produces favorable outcomes in women with brain metastases who are ≥ 65 years and have controlled primary tumors. Such patients are therefore suitable candidates for GKRS.

Effectiveness of navigation-guided cyst aspiration before resection of large cystic brain tumors: a proof of concept for more radical surgery.

BACKGROUND: Resection of tumors close to the corticospinal tract (CST) carries a high risk of damage to the CST. For cystic tumors, aspirating the cyst before resection may reduce the risk of damage to vital structures. This study evaluated the effectiveness of cyst aspiration, by comparing the results before and after aspiration of diffusion tensor image (DTI) tractography. METHODS: This study enrolled 23 patients with large cystic brain tumors (>20 cm3) between 2012 and 2016. All underwent magnetic resonance imaging (MRI), including DTI tractography, followed by navigation-guided aspiration of the cyst and subsequent tumor resection via craniotomy. Distances between the tumor margin and CST before and after cyst aspiration, volume reduction, and postoperative outcomes were assessed. RESULTS: Median tumor volume decreased from 88 cm3 (range, 25-153) to 29 cm3 (range, 20-80) and distances between tumor margins and the CST increased from 5.7 mm (range, 0.6-22.0) to 14.8 mm (range, 0.6-41.4) after aspiration. Neurological symptoms of patients immediately improved after cyst aspiration. All patients, except for one with a secondary glioblastoma, underwent gross total resection of the tumor. No neurological deterioration was observed after tumor resection. CONCLUSIONS: Navigation-guided cyst aspiration followed by resection is a useful and safe procedure for brain tumors with large cystic components. Cyst aspiration resulted in expansion of the compressed brain tissue between the tumor margins and vital structures, making maximal safe resection possible.

Success of tumorsphere isolation from WHO grade IV gliomas does not correlate with the weight of fresh tumor specimens: an immunohistochemical characterization of tumorsphere differentiation.

BACKGROUND: A trend of stage-by-stage increase in tumorsphere (TS) formation from glioma samples has been reported. Despite this trend, not all surgical specimens give rise to TSs, even World Health Organization (WHO) grade IV gliomas. Furthermore, it has been reported that differences in overall survival of primary glioblastoma patients depends on the propensity of their tumors to form TSs. However, the weights of fresh specimens vary from one surgical isolate to the next. METHODS: Accordingly, we evaluated the relationship between the weights of surgical specimens in WHO grade IV gliomas with the capacity to isolate TSs. Thirty-five fresh WHO grade IV glioma specimens were separated into two groups, based on whether they were positive or negative for TS isolation, and the relationship between TS isolation and weight of surgical specimens was assessed. RESULTS: We observed no significant difference in the weights of surgical samples in the two groups, and found that the optimal weight of specimens for TSs isolation was 500 mg. CONCLUSION: Thus, contrary to our expectations, the ability to isolate TSs from WHO grade IV glioma specimens was not related to the weight of fresh specimens.

Pseudoprogression in glioblastoma patients: the impact of extent of resection.

Pseudoprogression (psPD) is a radiation-induced toxicity that has substantial neurological consequence in glioblastoma (GBM) patients. MGMT promoter methylation has been shown to be an important prognostic factor of psPD, but the significance of extent of resection (EOR) remains unclear. We performed a retrospective analysis on newly diagnosed GBM patients with assessable MGMT promoter status who underwent the Stupp protocol. EOR was grouped into gross total resection (GTR), subtotal resection (STR), partial resection (PR) and stereotactic biopsy. Contrast enhancing lesion enlargement was classified as psPD or non-psPD. Among a total of 101 patients, GTR, STR, PR and stereotactic biopsy was performed in 57 (56.4%), 34 (33.7%), 9 (8.9%) and 1 patient (1%), respectively. Follow-up imaging at the end of Stupp protocol classified 45 patients (44.6%) as psPD and 56 (55.4%) as non-psPD. psPD was observed in 24 (61.5%) of 39 patients with methylated MGMT promoter and 21 (33.9%) of 62 patients with unmethylated MGMT promoter (p < 0.01). psPD was documented in 17 (29.8%), 19 (55.9%), 8 (88.9%) and 1 (100%) patient with GTR, STR, PR and stereotactic biopsy (p < 0.01), respectively. On multivariate analysis MGMT promoter status (OR 3.36, 95% CI 1.36-8.34) and EOR (OR 4.12, 95% CI 1.71-9.91) were independent predictors of psPD. A Cox proportional hazards model showed that MGMT status (HR 2.51, p < 0.01) and EOR (HR 2.99, p < 0.01) significantly influenced survival. MGMT status and EOR have a significant impact on psPD. GTR can reduce the side effects of psPD and prolong survival.

Osteosynthesis versus endoprosthesis for the treatment of femoral neck fracture in Asian elderly patients.

BACKGROUND: The purpose of this study was to compare the clinical results between osteosynthesis and endoprosthesis for femoral neck fractures in asian elderly patients, and to analysis the factors that may affect the failure of osteosynthesis. METHODS: A retrospective review of 382 hips over 65-year old with femoral neck fracture was done. Within non-displaced fracture group, 81 cases (56.6 %) underwent internal fixation (IF) and with 62 cases (43.3 %) having bipolar hemiarthroplasty (BPHA). As for displaced fracture group, 60 cases (25.1 %) underwent internal fixation (IF) with 179 cases (74.8 %) having BPHA. Average follow-up period for the patients was 36.8 months. Analysis was conducted on complications depending on fracture types and osteoporosis, and clinical evaluation was done on gait capability by using Koval walking ability. RESULTS: In non-displaced group, BPHA group showed statistically significant lower percentage of complications compared to IF group, but re-operation rate and the degradations of Koval score were no significant differences. In displaced group, complication, re-operation rate and the degradations of Koval score of BPHA group were statistically better than those of IF group. Association between osteoporosis and non-union is no statistically significant. CONCLUSIONS: Endoprosthetic replacement could be a primary option for displaced femoral neck fracture in elderly asian patients. The choice of surgical treatment methods of non-displaced fracture in elderly asian patients should be determined carefully considering the age and the presence of osteoporosis.

Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study.

Purpose: This study aimed to investigate whether levetiracetam (LEV), the most used antiepileptic drug, influences survival in patients with glioblastoma (GBM), using a national database. Materials and Methods: This study used data from the Korea Health Insurance Review and Assessment database. Patients diagnosed with GBM between 2007-2018 treated with standard therapy were included. The study population was divided into long-term (≥60 days) and short-term (<30 days) LEV groups. A separate long-term valproic acid (VPA) group (≥60 days) was identified for comparison. Demographics, disease characteristics, and treatment parameters were collected. Kaplan-Meier method and Cox regression were used to compare survival outcomes between the groups. Results: Overall, 2,971 patients were included, with 1,319 and 1,652 in the short-term and long-term LEV groups, respectively. The median overall survival (OS) for the entire population was 19.15 months post-surgery. Kaplan-Meier analysis revealed a significantly longer median OS in the long-term LEV group versus the short-term LEV group. After adjusting for confounders, Cox proportional hazard analysis revealed an association of long-term LEV use with improved survival, which was also observed in a subgroup analysis of patients without preoperative seizure history. The long-term LEV group demonstrated longer median OS, compared with the long-term VPA group. Conclusion: Our nationwide population-based study found an association between long-term LEV use and improved survival in patients with GBM, regardless of preoperative seizure history. Prospective studies are needed to validate these findings and investigate the potential impact of LEV on the survival outcomes of patients with GBM.

Metastatic papillary renal cell carcinoma with portal vein tumor thrombosis confirmed on blind liver biopsy.

Portal vein tumor thrombosis (PVTT) is an uncommon condition in which tumor cells expand into the vessels, causing blood clot formation in the portal vein. PVTT is mainly associated with hepatocellular carcinoma, leading to an unfavorable prognosis; however, it can also develop in patients with other cancer types. Herein, we report a case of metastatic renal cell carcinoma diagnosed by a blind liver biopsy in a patient with dynamic computed tomography-confirmed portal vein thrombosis and cholangiopathy. This case illustrates the importance of systematic surveillance with routine laboratory tests and contrast-enhanced imaging studies on patients with cancer to detect potential liver infiltration of metastatic cancer.

Inhibitory effect of recombinant tyrosine­sulfated madanin­1, a thrombin inhibitor, on the behavior of MDA­MB­231 and SKOV3 cells in vitro.

Thrombin, which plays a crucial role in hemostasis, is also implicated in cancer progression. In the present study, the effects of the thrombin­targeting recombinant tyrosine­sulfated madanin­1 on cancer cell behavior and signaling pathways compared with madanin­1 wild­type (WT) were investigated. Recombinant madanin­1 2 sulfation (madanin­1 2S) and madanin­1 WT proteins were generated using Escherichia coli. SKOV3 and MDA­MB­231 cells were treated with purified recombinant proteins with or without thrombin stimulation. Migration and invasion of cells were analyzed by wound healing assay and Transwell assay, respectively. Thrombin markedly increased cell migration and invasion in both SKOV3 and MDA­MB­231 cells, which were significantly suppressed by madanin­1 2S (P<0.05). Madanin­1 2S also significantly suppressed thrombin­induced expression of phosphorylated (p)­Akt and p­extracellular signal­regulated kinase in both cell lines (P<0.05), whereas madanin­1 WT had no effect on the expression levels of these proteins in MDA­MB­231 cells. Furthermore, madanin­1 2S significantly reversed the effects of thrombin on E­cadherin, N­cadherin and vimentin expression in MDA­MB­231 cells (P<0.05), whereas madanin­1 WT did not show any effect. In conclusion, madanin­1 2S suppressed the migration and invasion of cancer cells more effectively than madanin­1 WT. It is hypothesized that inhibiting thrombin via the sulfated form of madanin­1 may be a potential candidate for enhanced cancer therapy; however, further in vivo validation is required.

Regulation of Hippo-YAP signaling axis by Isoalantolactone suppresses tumor progression in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a devastating malignancy characterized by aggressive tumor growth and limited treatment options. Dysregulation of the Hippo signaling pathway and its downstream effector, Yes-associated protein (YAP), has been implicated in CCA development and progression. In this study, we investigated the effects of Isoalantolactone (IALT) on CCA cells to elucidate its effect on YAP activity and its potential clinical significance. Our findings demonstrate that IALT exerts cytotoxic effects, induces apoptosis, and modulates YAP signaling in SNU478 cells. We further confirmed the involvement of the canonical Hippo pathway by generating LATS1/LATS2 knockout cells, highlighting the dependence of IALT-mediated apoptosis and YAP phosphorylation on the Hippo-LATS signaling axis. In addition, IALT suppressed cell growth and migration, partially dependent on YAP-TEAD activity. These results provide insights into the therapeutic potential of targeting YAP in CCA and provide a rationale for developing of YAP-targeted therapies for this challenging malignancy.

Supramaximal Resection for Glioblastoma: Redefining the Extent of Resection Criteria and Its Impact on Survival.

Glioblastomas (GBMs) are the most common and aggressive primary brain tumors, and despite advances in treatment, prognosis remains poor. The extent of resection has been widely recognized as a key factor affecting survival outcomes in GBM patients. The surgical principle of "maximal safe resection" has been widely applied to balance tumor removal and neurological function preservation. Historically, T1-contrast enhanced (T1CE) extent of resection has been the focus of research; however, the "supramaximal resection" concept has emerged, advocating for even greater tumor resection while maintaining neurological function. Recent studies have demonstrated potential survival benefits associated with resection beyond T1CE extent in GBMs. This review explores the developing consensus and newly established criteria for "supramaximal resection" in GBMs, with a focus on T2-extent of resection. Systematic reviews and meta-analyses on supramaximal resection are summarized, and the Response Assessment in Neuro-Oncology (RANO) resect group classification for extent of resection is introduced. The evolving understanding of the role of supramaximal resection in GBMs may lead to improved patient outcomes and more objective criteria for evaluating the extent of tumor resection.

Phospholipase C-γ as a Potential Therapeutic Target for Graves' Orbitopathy.

BACKGRUOUND: Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves' orbitopathy (GO). METHODS: The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1ß to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting. RESULTS: PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P<0.05). PLCG1 and PLCG2 mRNA expression was significantly increased (P<0.05) in IL-1ß, tumor necrosis factor-α, and a cluster of differentiation 40 ligand-stimulated GO fibroblasts. U73122 significantly inhibited the IL-1ß-induced expression of proinflammatory molecules, including IL-6, IL-8, monocyte chemoattractant protein-1, cyclooxygenase-2, and intercellular adhesion molecule-1 (ICAM-1), and phosphorylated protein kinase B (p-Akt) and p38 (p-p38) kinase in GO fibroblasts, whereas it inhibited IL-6, IL-8, and ICAM-1, and p-Akt and c-Jun N-terminal kinase (p-JNK) in normal fibroblasts (P<0.05). CONCLUSION: PLC-γ-inhibiting U73122 suppressed the production of proinflammatory cytokines and the phosphorylation of Akt and p38 kinase in GO fibroblasts. This study indicates the implications of PLC-γ in GO pathogenesis and its potential as a therapeutic target for GO.