Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the 'WIN' site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Medical Ethics and Artificial Intelligence in Neurosurgery-How Should We Prepare?

BACKGROUND: The development of artificial intelligence (AI) raises ethical concerns about its side effects on the attitudes and behaviors of clinicians and medical practitioners. The authors aim to understand the medical ethics of AI-based chatbots and to suggest coping strategies for an emerging landscape of increased access and potential ambiguity using AI. METHODS: This study examines the medical ethics of AI-based chatbots (Chat generative pretrained transformer [GPT], Bing Chat, and Google's Bard) using multiple-choice questions. ChatGPT and Bard correctly answered all questions (5/5), while Bing Chat correctly answered only 3 of 5 questions. ChatGPT explained answers simply. Bing Chat explained answers with references, and Bard provided additional explanations with details. RESULTS: AI has the potential to revolutionize medical fields by improving diagnosis accuracy, surgical planning, and treatment outcomes. By analyzing large amounts of data, AI can identify patterns and make predictions, aiding neurosurgeons in making informed decisions for increased patient wellbeing. As AI usage increases, the number of cases involving AI-entrusted judgments will rise, leading to the gradual emergence of ethical issues across interdisciplinary fields. The medical field will be no exception. CONCLUSIONS: This study suggests the need for safety measures to regulate medical ethics in the context of advancing AI. A system should be developed to verify and predict pertinent issues.

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.

Ribosome subunit attrition and activation of the p53-MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Structure-Based Discovery of Potent, Orally Bioavailable Benzoxazepinone-Based WD Repeat Domain 5 Inhibitors.

The chromatin-associated protein WDR5 (WD repeat domain 5) is an essential cofactor for MYC and a conserved regulator of ribosome protein gene transcription. It is also a high-profile target for anti-cancer drug discovery, with proposed utility against both solid and hematological malignancies. We have previously discovered potent dihydroisoquinolinone-based WDR5 WIN-site inhibitors with demonstrated efficacy and safety in animal models. In this study, we sought to optimize the bicyclic core to discover a novel series of WDR5 WIN-site inhibitors with improved potency and physicochemical properties. We identified the 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one core as an alternative scaffold for potent WDR5 inhibitors. Additionally, we used X-ray structural analysis to design partially saturated bicyclic P7 units. These benzoxazepinone-based inhibitors exhibited increased cellular potency and selectivity and favorable physicochemical properties compared to our best-in-class dihydroisoquinolinone-based counterparts. This study opens avenues to discover more advanced WDR5 WIN-site inhibitors and supports their development as novel anti-cancer therapeutics.

The Direction of Neurosurgery to Overcome the Living with COVID-19 Era : The Possibility of Telemedicine in Neurosurgery.

OBJECTIVE: Due to the implementation of vaccinations and the development of therapeutic agents, the coronavirus disease 2019 (COVID-19) pandemic that started at the end of 2019 has entered a new phase. As a result, neurosurgeons should reconsider the way they treat their patients. As the COVID-19 situation prolongs, the change in neurosurgical emergency patients according to the number of confirmed cases is no longer clear. Outpatient treatment by telephone was permitted according to government policy. In addition, visits to caregivers in the intensive care unit were limited. METHODS: The electronic medical records of patients who had been treated over the phone for a month (during April 2020, while the hospital was closing) were reviewed. Meanwhile, according to the limited visits to the intensive care unit, a video meeting was held with the caregivers. After the video meeting, satisfaction was evaluated using a questionnaire. RESULTS: During April 2020, 1021 patients received non-face-to-face care over the telephone. Among the patients, no critical medical problem occurred due to non-face-to-face care. From July 2021 to December 2021, 321 patients were admitted to the neurosurgical intensive care unit and 107 patients (33.3%) including their caregivers agreed to video visits. Twice a week, advance notice was given that access would be made through a mobile device and the nurse explained to caregivers how to use the mobile device. The time for the video meeting was approximately 20 minutes per patient. Based on the questionnaire, 81 respondents (75.7%) answered that they agreed, and 26 respondents (24.3%) answered that they strongly agreed that was easy to communicate through video meetings. Fifty-two (48.6%) agreed and 55 (51.4%) strongly agreed that they were easy to understand the doctor's explanation. For overall satisfaction with this video meeting, three respondents (2.8%) gave 4/5 points and 95 respondents (88.8%) gave 5/5 points, and nine (8.4%) gave 3/5 points. Their reason was that there was not enough time. CONCLUSION: In situations where patient visits are limited, video meetings through a mobile device can provide sufficient satisfaction to caregivers. Telemedicine will likely become common in the near future. Health care professionals should prepare and respond to these needs and changes. Therefore, establishing a system with institutional support is necessary.

Delayed Detection of a 5-Aminolevulinic Acid In Vivo: A Case of Metastatic Breast Cancer.

A 44-year-old female patient who had been diagnosed with breast cancer visited our oncology department. She had developed right-side weakness and mild dysarthria, and MRI revealed a 4-cm cystic-enhancing lesion in her left frontal lobe. Her surgery was postponed 48 hours after receiving 5-aminolevulinic acid (5-ALA), because a problem with thyroid function that had not been noticed before was discovered. The main lesion was enhanced on navigation and appeared to be a gross tumor; its 5-ALA uptake was very high. Specimens obtained from this location were histologically confirmed to contain tumor cells. The operation was completed, and removal of all enhancing lesions was confirmed by MRI within 24 hours postoperatively. The pathology report confirmed metastatic ductal carcinoma. The clinical efficacy of 5-ALA was confirmed even 48 hours after administration into a metastatic brain tumor from breast cancer.

From the perspective of pseudo-progression rather than treatment failure, how long should we wait before considering treatment failure if large cystic enlargement occurs after Gamma Knife radiosurgery for vestibular schwannoma?: insight into pseudoprogression based on two case reports.

Gamma knife radiosurgery (GKRS) has been accepted as a safe and effective treatment for vestibular schwannoma (VS). However, during follow-up, tumor expansion induced by irradiation can occur, and diagnosis of failure in radiosurgery for VS is still controversial. Tumor expansion with cystic enlargement causes some confusion regarding whether further treatment should be performed. We analyzed more than 10 years of clinical findings and imaging of patients with VS with cystic enlargement after GKRS. A 49-year-old male with hearing impairment was treated with GKRS (12 Gy; isodose, 50%) for a left VS with a preoperative tumor volume of 0.8 cc. The tumor size increased with cystic changes from the third year after GKRS, reaching a volume of 10.8 cc at 5 years after GKRS. At the 6th year of follow-up, the tumor volume started to decrease, up to 0.3 cc by the 14th year of follow-up. A 52-year-old female with hearing impairment and left facial numbness was treated with GKRS for a left VS (13 Gy; isodose, 50%). The preoperative tumor volume was 6.3 cc, which started to increase with cystic enlargement from the first year after GKRS, and reaching 18.2 cc by 5 years after GKRS. The tumor maintained a cystic pattern with slight changes in size, but no other neurologic symptoms developed during the follow-up period. After 6 years of GKRS, tumor regression was observed, eventually reaching a volume of 3.2 cc by the 13th year of follow-up. In both cases, persistent cystic enlargement in VS was observed at 5 years after GKRS, after which the tumors began to stabilize. After more than 10 years of GKRS, the tumor volume was less than that before GKRS. Enlargement with large cystic formation in the first 3-5 years after GKRS has been considered as treatment failure. However, our cases show that further treatment for cystic enlargement should be deferred for at least 10 years, especially in patients without neurological deterioration, as inadequate surgery can be prevented within that period.

Kaposiform hemangioendothelioma of skull base with dura invasion in a pediatric patient: a case report.

Kaposiform hemangioendothelioma is an extremely rare vascular tumor which shows aggressive local growth. We present a case of rapid growing vascular skull tumor with dura invasion in a pediatric patient with neurofibromatosis type 1. A 14-year-old male complained of headache and dizziness for 1 month after minor head trauma. Brain magnetic resonance imaging (MRI) revealed a 5-cm-sized tumor in the left frontotemporal bone with internal hemorrhage and cystic changes. The gross total resection of tumor was done. At the 7-month follow-up, brain MRI revealed a recurrent skull tumor with intracranial dura mass. He underwent second surgery, and the pathologic diagnosis was suggestive of Kaposiform hemangioendothelioma. For this vascular proliferative tumor, mTOR inhibitor was treated for 6 months, and there was the recurred nodular-enhancing mass along the sphenoid ridge. After additional 2 months of medication, the following MRI revealed a decreased nodular-enhancing mass.

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.

Analysis of stromal PDGFR-ß and α-SMA expression and their clinical relevance in brain metastases of breast cancer patients.

BACKGROUND: Breast cancer brain metastasis (BCBM) is a growing therapeutic challenge and clinical concern. Stromal cancer-associated fibroblasts (CAFs) are crucial factors in the modulation of tumorigeneses and metastases. Herein, we investigated the relationship between the expression of stromal CAF markers in metastatic sites, platelet-derived growth factor receptor-beta (PDGFR-ß), and alpha-smooth muscle actin (α-SMA) and the clinical and prognostic variables in BCBM patients. METHODS: Immunohistochemistry (IHC) of the stromal expression of PDGFR-ß and α-SMA was performed on 50 cases of surgically resected BCBM. The expression of the CAF markers was analyzed in the context of clinico-pathological characteristics. RESULTS: Expression of PDGFR-ß and α-SMA was lower in the triple-negative (TN) subtype than in other molecular subtypes (p = 0.073 and p = 0.016, respectively). And their expressions were related to a specific pattern of CAF distribution (PDGFR-ß, p = 0.009; α-SMA, p = 0.043) and BM solidity (p = 0.009 and p = 0.002, respectively). High PDGFR-ß expression was significantly related to longer recurrence-free survival (RFS) (p = 0.011). TN molecular subtype and PDGFR-ß expression were independent prognostic factors of recurrence-free survival (p = 0.029 and p = 0.030, respectively) and TN molecular subtype was an independent prognostic factor of overall survival (p < 0.001). CONCLUSIONS: Expression of PDGFR-ß in the stroma of BM was associated with RFS in BCBM patients, and the clinical implication was uniquely linked to the low expression of PDGFR-ß and α-SMA in the aggressive form of the TN subtype.

Structure-based discovery of potent WD repeat domain 5 inhibitors that demonstrate efficacy and safety in preclinical animal models.

WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P7 units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.

The long multi-epitope peptide vaccine combined with adjuvants improved the therapeutic effects in a glioblastoma mouse model.

Emerging data have suggested that single short peptides have limited success as a cancer vaccine; however, extending the short peptides into longer multi-epitope peptides overcame the immune tolerance and induced an immune response. Moreover, the combination of adjuvants such as lenalidomide and anti-programmed cell death protein 1 (PD1) with a peptide vaccine showed potential vaccine effects in previous studies. Therefore, the effects of a long multi-epitope peptide vaccine in combination with lenalidomide and anti-PD1 were analyzed in this study. Long multi-epitope peptides from two MHCI peptides (BIRC597-104 and EphA2682-689) and the pan-human leukocyte antigen-DR isotype (HLA-DR) binding epitope (PADRE) were synthesized. The therapeutic effects of long multi-epitope peptides in combination with lenalidomide and anti-PD1 were confirmed in the murine GL261 intracranial glioma model. Immune cells' distribution and responses to the long multi-epitope peptides in combination with these adjuvants were also estimated in the spleens, lymph nodes, and tumor tissues. The difference between long multi-epitope peptides and a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 was also clarified. As a result, long multi-epitope peptides combined with lenalidomide and anti-PD1 prolonged the survival of mice according to the suppression of tumor growth in an intracranial mouse model. While long multi-epitope peptides combined with these adjuvants enhanced the percentages of activated and memory effector CD8+ T cells, the increase in percentages of regulatory T cells (Tregs) was observed in a cocktail of multi-epitope peptides combined with lenalidomide and anti-PD1 group in the tumors. Long multi-epitope peptides combined with these adjuvants also enhanced the function of immune cells according to the enhanced pro-inflammatory cytokines and cytotoxicity against GL261 cells in ex vivo. In conclusion, long multi-epitope peptides composed of MHCI peptides, BIRC5 and EphA2, and the MHCII peptide, PADRE, in combination with lenalidomide and anti-PD1 has the potential to improve the therapeutic effects of a vaccine against GBM.

Effect of Choline Alphoscerate on the Survival of Glioblastoma Patients: A Retrospective, Single-Center Study.

Cognitive impairment often occurs in glioblastoma (GBM) patients due to the tumor itself and treatment side effects. Choline alphoscerate (L-alpha-glycerylphosphorylcholine, GPC) is frequently used to compensate for cognitive impairment in GBM patients. This study was conducted to determine whether GPC affects the overall survival (OS) and progression-free survival (PFS) of GBM patients. From 2011 to 2020, 187 isocitrate dehydrongenase (IDH)-wild-type GBM patients were analyzed. The patients were classified based on whether GPC was continuously used for at least 3 or 12 months (mos) after GBM diagnosis. Although GPC usage (≥3 mos) did not make significant differences in survival extension, median OS in the long-term GPC group (≥12 mos) was longer with statistical significance, compared to the control group (<12 mos) (38.3 vs. 24.0 mos, p = 0.004). In addition to younger age, supratentorial location, complete resection, and MGMT promoter methylation, long-term use of GPC (≥12 mos) was significantly associated with longer OS in multivariate analysis (p = 0.019, hazard ratio [HR] 0.532, 95% confidence interval [CI] 0.314−0.900). Despite the limitations of this study, long-term GPC use was possibly associated with prolonged survival in GBM patients. Multi-center prospective randomized studies with a large number of patients are needed to validate these findings.

Discovery of Potent Orally Bioavailable WD Repeat Domain 5 (WDR5) Inhibitors Using a Pharmacophore-Based Optimization.

WD repeat domain 5 (WDR5) is a nuclear scaffolding protein that forms many biologically important multiprotein complexes. The WIN site of WDR5 represents a promising pharmacological target in a variety of human cancers. Here, we describe the optimization of our initial WDR5 WIN-site inhibitor using a structure-guided pharmacophore-based convergent strategy to improve its druglike properties and pharmacokinetic profile. The core of the previous lead remained constant while a focused SAR effort on the three pharmacophore units was combined to generate a new in vivo lead series. Importantly, this new series of compounds has picomolar binding affinity, improved cellular antiproliferative activity and selectivity, and increased kinetic aqueous solubility. They also exhibit a desirable oral pharmacokinetic profile with manageable intravenous clearance and high oral bioavailability. Thus, these new leads are useful probes toward studying the effects of WDR5 inhibition.

Cadaver-Free Neurosurgical Simulation Using a 3-Dimensional Printer and Augmented Reality.

BACKGROUND: Training to become a neurosurgeon takes time and effort, with the training requirements continuing to increase. As such, more efficient educational tools are needed. OBJECTIVE: To evaluate the use of 3-dimensional (3D) printing and augmented reality (AR) systems within neurosurgical training programs. METHODS: The skull and its structures were segmented using normal computed tomography and MRI and printed with a 3D printer. Basic procedures (burr-hole trephination and other craniotomies) and advanced procedures of skull base approaches (anterior clinoidectomy, anterior petrosectomy, and mastoidectomy) were practiced with the printed model. Skull base approaches were practiced in an AR system. After the training program, a questionnaire was administered to the trainees about the effectiveness of the program. RESULTS: The basic procedure program was conducted four times with 22 trainees. Twenty trainees indicated that the present simulation program was important to their education (average of 4.9/5.0). When asked whether the model was similar to a human skull, the average score was 4.5 of 5 points. The advanced procedure program was conducted five times with 10 trainees. All 10 answered that the simulation program was a useful tool for training on skull base approaches (average of 5/5). All respondents answered that they would be able to perform the skull base approaches in patients after completing the training program (an average of 4.7/5). CONCLUSION: The simulation-based training program using 3D-printed anatomy with an AR system was demonstrated to be an important adjunct to training neurosurgery. It provides trainees a realistic environment to improve skills and performance during clinical practice.

What Clinicians Should Consider When Performing Oblique Lumbar Interbody Fusion in a Patient with Long Vertebral Body Osteophytes.

OBJECTIVE: Oblique lumbar interbody fusion (OLIF) is known as a minimally invasive technique for disc space augmentation. Motor weakness after OLIF has been known to occur in some cases. This study aimed to report the incidence and potential risk factors for motor weakness following OLIF. METHODS: We enrolled 36 patients and 57 segments who underwent OLIF. Computed tomography was performed before and after OLIF. Clinical data, including age, sex, presenting symptoms, bone mineral density, visual analog scale score, operating segments, and postoperative complications, were collected. We divided the patients into groups with and without neurologic deficit. The disc height was measured and compared between the 2 groups. We also divided the segments into groups with and without neurologic deficit. Foramen height and osteophyte length were measured and compared between the 2 groups. RESULTS: The neurologic deficit group included 3 patients (8%), whereas non-neurologic deficit group included 33 patients (92%). The neurologic deficit group included 5 segments (4%), whereas the non-neurologic deficit group included 109 segments (96%). The disc and foramen heights did not differ significantly between the groups with and without neurologic deficit; however, the osteophyte lengths were longer in the neurologic deficit group. CONCLUSIONS: In our study, vertebral osteophyte length was found to be a potential risk factor for motor weakness after OLIF. For patients with long osteophytes, additional laminectomy following OLIF or another surgical approach for direct decompression should be considered.

Application of fusion-fluorescence imaging using indocyanine green in endoscopic endonasal surgery.

OBJECTIVE: Indocyanine green (ICG) has been used in endoscopic surgery in the neurosurgical field, but it has been challenging to determine the associated efficiency due to limitations with visualization in the previous endoscopic system. A new endoscopic system was recently introduced; therefore, we summarize our experiences with the application and integration of the system. METHODS: From March to June 2021, a newly introduced endoscopic system was used in 10 patients. (8 pituitary adenomas, and 2 tuberculum sellae meningiomas) and 12.5 mg of ICG was injected for each study. RESULTS: Six pituitary adenomas, including one acromegaly, were well identified with ICG. However, two pituitary adenomas, presented with apoplexy and two meningiomas were not visualized with ICG. CONCLUSIONS: The ICG provides real-time information during endoscopic endonasal surgery. We suggest that the pituitary adenoma can be stained with an ICG using the fusion-fluorescence imaging endoscopic system. This approach will enhance the surgeon's ability to remove the tumor with preserve the normal gland more safely.

Comparative Analysis of COVID-19 Outbreak and Changes in Neurosurgical Emergency Patients.

OBJECTIVE: COVID-19 has spread worldwide since the first case was reported in Wuhan, China, in December 2019. Our institution is a regional trauma and emergency center in the northern Gyeonggi Province. The changing trend of patient care in the emergency room of this hospital likely reflects the overall trend of patients in the area. In the present study, whether changes in the surrounding social environment following the outbreak of COVID-19 changed the incidence of neurosurgical emergency patients and whether differences in practice existed were investigated. METHODS: The overall trend was analyzed from January 2020 which is before the outbreak of COVID-19 to September 2020. To remove bias due to seasonal variation, the previous 2 year's records during the same period were reviewed and compared. Confirmed COVID-19 patients in the northern Gyeonggi Province were identified using data released by the government. And patients who came to the emergency department with head trauma and stroke were identified. RESULTS: Based on the present study results, the total number of neurosurgery emergency patients decreased over the study period. In the trauma patient group, the number of patients not involved in traffic accidents significantly decreased compared with patients involved in traffic accidents. Among the stroke cases, the rate of ischemic stroke was lower than hemorrhagic stroke, although a statistically significant difference was not observed. Meanwhile, an increase in the risk of mortality associated with trauma or stroke cases was not observed during the COVID-19 outbreak compared with the same time period in the previous year. CONCLUSION: Due to the occurrence of COVID-19, non-essential activities have decreased and trauma cases not associated with traffic accidents appeared to decrease. Due to the decrease in overall activity, the number of stroke patients has also decreased. This trend is expected to continue even in the post-COVID-19 era, and accordingly, the results from the present study are relevant especially if the current situation continues.

Natural killer cell therapy potentially enhances the antitumor effects of bevacizumab plus irinotecan in a glioblastoma mouse model.

Various combination treatments have been considered to attain the effective therapy threshold by combining independent antitumor mechanisms against the heterogeneous characteristics of tumor cells in malignant brain tumors. In this study, the natural killer (NK) cells associated with bevacizumab (Bev) plus irinotecan (Iri) against glioblastoma multiforme (GBM) were investigated. For the experimental design, NK cells were expanded and activated by K562 cells expressing the OX40 ligand and membrane-bound IL-18 and IL-21. The effects of Bev and Iri on the proliferation and NK ligand expression of GBM cells were evaluated through MTT assay and flow cytometry. The cytotoxic effects of NK cells against Bev plus Iri-treated GBM cells were also predicted via the LDH assay in vitro. The therapeutic effect of different injected NK cell routes and numbers combined with the different doses of Bev and Iri was confirmed according to tumor size and survival in the subcutaneous (s.c) and intracranial (i.c) U87 xenograft NOD/SCID IL-12Rγnull mouse model. The presence of injected-NK cells in tumors was detected using flow cytometry and immunohistochemistry ex vivo. As a result, Iri was found to affect the proliferation and NK ligand expression of GBM cells, while Bev did not cause differences in these cellular processes. However, the administration of Bev modulated Iri efficacy in the i.c U87 mouse model. NK cells significantly enhanced the cytotoxic effects against Bev plus Iri-treated GBM cells in vitro. Although the intravenous (IV) injection of NK cells in combination with Bev plus Iri significantly reduced the tumor volume in the s.c U87 mouse model, only the direct intratumorally (IT) injection of NK cells in combination with Bev plus Iri elicited delayed tumor growth in the i.c U87 mouse model. Tumor-infiltrating NK cells were detected after IV injection of NK cells in both s.c and i.c U87 mouse models. In conclusion, the potential therapeutic effect of NK cells combined with Bev plus Iri against GBM cells was limited in this study. Accordingly, further research is required to improve the accessibility and strength of NK cell function in this combination treatment.