Pre-treatment systemic inflammation response index and systemic immune inflammation in patients with primary central nerve system lymphoma as a useful prognostic indicator.

PURPOSE: The systemic inflammation response index (SIRI) and systemic immune-inflammation index (SII) are based on neutrophil, monocyte, platelet, and lymphocyte counts. The SIRI and SII are used to predict the survival of patients with malignant tumors. It is well known that the inflammatory immune response is closely related to cancer occurrence and progression. In the present study, we evaluated the potential prognostic significance of SIRI and SII in patients with primary central nervous system lymphoma (PCNSL). METHODS: Fifty-eight consecutive patients were enrolled in this study between November 2006 and May 2022. Among the 58 patients, 47 patients with sufficient blood test data and follow-up were analyzed. The patients with steroid intake at the time point of the blood test and higher C-reactive protein were excluded. RESULTS: The median follow-up and survival times were 31 and 36 months, respectively. The optimal cutoff SIRI value was based on the receiver operating characteristic curve (ROC) for overall survival (OS) and stratified patients into low (< 1.43 × 109/L, n = 22) and high (≥ 1.43 × 109/L, n = 25) SIRI groups. The optimal cutoff SII value based on the ROC for OS stratified patients into low (< 694.9, n = 28) and high (≥ 694.9, n = 19) SII groups. A low SIRI value was associated with longer OS (p = 0.006). Furthermore, a low SII value was associated with longer OS (p = 0.044). The prognostic factors associated with prolonged survival in univariate analysis using the Cox proportional hazard model were age < 65 years, low SIRI, and low SII. The multivariate analysis demonstrated that age < 65 years and low SIRI independently predicted longer OS. CONCLUSION: Simple, less expensive, and routinely ordered preoperative blood count assessments such as SIRI and SII predict the OS of patients with PCNSL. This study demonstrated that PCNSL is associated with pre-treatment systemic immune-inflammation states.

Characterization of HIF-1α Knockout Primary Human Natural Killer Cells Including Populations in Allogeneic Glioblastoma.

Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Natural killer cells (NK) are major innate effector cells with broad cytotoxicity against tumors. Accordingly, NK cells are ideal candidates for cancer immunotherapy, including glioblastoma (GBM). Hypoxia is a common feature of solid tumors, and tumor cells and normal cells adapt to the tumor microenvironment by upregulating the transcription factor hypoxia-inducible factor (HIF)-1α, which can be detrimental to anti-tumor effector immune cell function, including that of NK cells. We knocked out HIF-1α in human primary NK cells using clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9). Then, cellular characterizations were conducted in normoxic and hypoxic conditions. Electroporating two HIF-1α-targeting guide RNA-Cas9 protein complexes inhibited HIF-1α expression in expanded NK cells. HIF-1α knockout human NK cells, including populations in hypoxic conditions, enhanced the growth inhibition of allogeneic GBM cells and induced apoptosis in GBM-cell-derived spheroids. RNA-sequencing revealed that the cytotoxicity of HIF-1α knockout NK cells could be related to increased perforin and TNF expression. The results demonstrated that HIF-1α knockout human NK cells, including populations, enhanced cytotoxicity in an environment mimicking the hypoxic conditions of GBM. CRISPR-Cas9-mediated HIF-1α knockout NK cells, including populations, could be a promising immunotherapeutic alternative in patients with GBM.

Antitumor Effects of Intravenous Natural Killer Cell Infusion in an Orthotopic Glioblastoma Xenograft Murine Model and Gene Expression Profile Analysis.

Despite standard multimodality treatment, containing maximum safety resection, temozolomide, radiotherapy, and a tumor-treating field, patients with glioblastoma (GBM) present with a dismal prognosis. Natural killer cell (NKC)-based immunotherapy would play a critical role in GBM treatment. We have previously reported highly activated and ex vivo expanded NK cells derived from human peripheral blood, which exhibited anti-tumor effect against GBM cells. Here, we performed preclinical evaluation of the NK cells using an in vivo orthotopic xenograft model, the U87MG cell-derived brain tumor in NOD/Shi-scid, IL-2RɤKO (NOG) mouse. In the orthotopic xenograft model, the retro-orbital venous injection of NK cells prolonged overall survival of the NOG mouse, indirectly indicating the growth-inhibition effect of NK cells. In addition, we comprehensively summarized the differentially expressed genes, especially focusing on the expression of the NKC-activating receptors' ligands, inhibitory receptors' ligands, chemokines, and chemokine receptors, between murine brain tumor treated with NKCs and with no agents, by using microarray. Furthermore, we also performed differentially expressed gene analysis between an internal and external brain tumor in the orthotopic xenograft model. Our findings could provide pivotal information for the NK-cell-based immunotherapy for patients with GBM.

Natural Killer Cell-Based Immunotherapy against Glioblastoma.

Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults. Despite multimodality treatment involving surgical resection, radiation therapy, chemotherapy, and tumor-treating fields, the median overall survival (OS) after diagnosis is approximately 2 years and the 5-year OS is poor. Considering the poor prognosis, novel treatment strategies are needed, such as immunotherapies, which include chimeric antigen receptor T-cell therapy, immune checkpoint inhibitors, vaccine therapy, and oncolytic virus therapy. However, these therapies have not achieved satisfactory outcomes. One reason for this is that these therapies are mainly based on activating T cells and controlling GBM progression. Natural killer (NK) cell-based immunotherapy involves the new feature of recognizing GBM via differing mechanisms from that of T cell-based immunotherapy. In this review, we focused on NK cell-based immunotherapy as a novel GBM treatment strategy.

Therapeutic Anti-KIR Antibody of 1-7F9 Attenuates the Antitumor Effects of Expanded and Activated Human Primary Natural Killer Cells on In Vitro Glioblastoma-like Cells and Orthotopic Tumors Derived Therefrom.

Glioblastoma (GBM) is the leading malignant intracranial tumor, where prognosis for which has remained extremely poor for two decades. Immunotherapy has recently drawn attention as a cancer treatment, including for GBM. Natural killer (NK) cells are immune cells that attack cancer cells directly and produce antitumor immunity-related cytokines. The adoptive transfer of expanded and activated NK cells is expected to be a promising GBM immunotherapy. We previously established an efficient expansion method that produced highly purified, activated primary human NK cells, which we designated genuine induced NK cells (GiNKs). The GiNKs demonstrated antitumor effects in vitro and in vivo, which were less affected by blockade of the inhibitory checkpoint receptor programmed death 1 (PD-1). In the present study, we assessed the antitumor effects of GiNKs, both alone and combined with an antibody targeting killer Ig-like receptor 2DLs (KIR2DL1 and DL2/3, both inhibitory checkpoint receptors of NK cells) in vitro and in vivo with U87MG GBM-like cells and the T98G GBM cell line. Impedance-based real-time cell growth assays and apoptosis detection assays revealed that the GiNKs exhibited growth inhibitory effects on U87MG and T98G cells by inducing apoptosis. KIR2DL1 blockade attenuated the growth inhibition of the cell lines in vitro. The intracranial administration of GiNKs prolonged the overall survival of the U87MG-derived orthotopic xenograft brain tumor model. The KIR2DL1 blockade did not enhance the antitumor effects; rather, it attenuated it in the same manner as in the in vitro experiment. GiNK immunotherapy directly administered to the brain could be a promising immunotherapeutic alternative for patients with GBM. Furthermore, KIR2DL1 blockade appeared to require caution when used concomitantly with GiNKs.

Effect of remimazolam on the incidence of delirium after transcatheter aortic valve implantation under general anesthesia: a retrospective exploratory study.

PURPOSE: Delirium after transcatheter aortic valve implantation (TAVI) should be prevented because it is associated with worse patient outcomes. Perioperative administration of benzodiazepines is a risk factor for postoperative delirium; however, the association between remimazolam, a newer ultrashort-acting benzodiazepine for general anesthesia, and postoperative delirium remains unclear. This study aimed to evaluate whether remimazolam administration during TAVI under general anesthesia affected the incidence of postoperative delirium. METHODS: This single-center retrospective study recruited all adult patients who underwent transfemoral TAVI (TF-TAVI) under general anesthesia between March 2020 and May 2022. Patients were divided into the remimazolam (R) and propofol (P) groups according to the sedative used for anesthesia. In the R group, all patients received flumazenil after surgery. The primary endpoint was the incidence of delirium within 3 days after surgery. Factors associated with delirium after TF-TAVI were examined by multiple logistic regression analysis. RESULTS: Ninety-eight patients were included in the final analysis (R group, n = 40; P group, n = 58). The incidence of postoperative delirium was significantly lower in the R group than in the P group (8% vs. 26%, p = 0.032). Multiple logistic regression analysis revealed that remimazolam (odds ratio 0.17, 95% CI 0.04-0.80, p = 0.024) was independently associated with the incidence of postoperative delirium, even after adjustment for age, sex, preoperative cognitive function, history of stroke, and TF-TAVI approach. CONCLUSION: Remimazolam may benefit TF-TAVI in terms of postoperative delirium; however, its usefulness must be further evaluated in extensive prospective studies.

Capability of Human Dendritic Cells Pulsed with Autologous Induced Pluripotent Stem Cell Lysate to Induce Cytotoxic T Lymphocytes against HLA-A33-Matched Cancer Cells.

Irradiated murine induced-pluripotent stem cells (iPSCs) elicit the antitumor response in vivo. However, it is unclear whether human iPSCs would elicit antitumor effects. In the present study, we investigated the capability of human iPSC lysate (iPSL)-pulsed dendritic cells (DCs) (iPSL/DCs) to induce cancer-responsive cytotoxic T lymphocytes (CTLs) in vitro. iPSCs and DCs were induced from peripheral blood mononuclear cells isolated from a human leukocyte antigen (HLA)-A33 homozygous donor. The iPSL was pulsed with immature DCs, which were then stimulated to allow full maturation. The activated DCs were co-cultured with autologous CTLs and their responses to SW48 colorectal carcinoma cells (HLA-A32/A33), T47D breast cancer cells (HLA-A33/A33), and T98G glioblastoma cells (HLA-A02/A02) were tested with enzyme-linked immunospot (ELISPOT) assays. Comprehensive gene expression analysis revealed that the established iPSCs shared numerous tumor-associated antigens with the SW48 and T47D cells. Immunofluorescent analysis demonstrated that the fluorescent-labeled iPSL was captured by the immature DCs within 2 h. iPSL/DCs induced sufficient CTL numbers in 3 weeks for ELISPOT assays, which revealed that the induced CTLs responded to SW48 and T47D cells. Human iPSL/DCs induced cancer-responsive CTLs on HLA-A33-matched cancer cells in vitro and could be a promising universal cancer vaccine for treating and preventing cancer.

CRISPR-Cas9-Mediated TIM3 Knockout in Human Natural Killer Cells Enhances Growth Inhibitory Effects on Human Glioma Cells.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults. Natural Killer (NK) cells are potent cytotoxic effector cells against tumor cells inducing GBM cells; therefore, NK cell based- immunotherapy might be a promising target in GBM. T cell immunoglobulin mucin family member 3 (TIM3), a receptor expressed on NK cells, has been suggested as a marker of dysfunctional NK cells. We established TIM3 knockout in NK cells, using the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9). Electroporating of TIM3 exon 2- or exon 5-targeting guide RNA- Cas9 protein complexes (RNPs) inhibited TIM3 expression on NK cells with varying efficacy. T7 endonuclease I mutation detection assays showed that both RNPs disrupted the intended genome sites. The expression of other checkpoint receptors, i.e., programmed cell death 1 (PD1), Lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and TACTILE (CD96) were unchanged on the TIM3 knockout NK cells. Real time cell growth assays revealed that TIM3 knockout enhanced NK cell-mediated growth inhibition of GBM cells. These results demonstrated that TIM3 knockout enhanced human NK cell mediated cytotoxicity on GBM cells. Future, CRISPR-Cas9 mediated TIM3 knockout in NK cells may prove to be a promising immunotherapeutic alternative in patient with GBM.

Ex Vivo Expanded and Activated Natural Killer Cells Prolong the Overall Survival of Mice with Glioblastoma-like Cell-Derived Tumors.

Glioblastoma (GBM) is the leading malignant intracranial tumor and is associated with a poor prognosis. Highly purified, activated natural killer (NK) cells, designated as genuine induced NK cells (GiNKs), represent a promising immunotherapy for GBM. We evaluated the anti-tumor effect of GiNKs in association with the programmed death 1(PD-1)/PD-ligand 1 (PD-L1) immune checkpoint pathway. We determined the level of PD-1 expression, a receptor known to down-regulate the immune response against malignancy, on GiNKs. PD-L1 expression on glioma cell lines (GBM-like cell line U87MG, and GBM cell line T98G) was also determined. To evaluate the anti-tumor activity of GiNKs in vivo, we used a xenograft model of subcutaneously implanted U87MG cells in immunocompromised NOG mice. The GiNKs expressed very low levels of PD-1. Although PD-L1 was expressed on U87MG and T98G cells, the expression levels were highly variable. Our xenograft model revealed that the retro-orbital administration of GiNKs and interleukin-2 (IL-2) prolonged the survival of NOG mice bearing subcutaneous U87MG-derived tumors. PD-1 blocking antibodies did not have an additive effect with GiNKs for prolonging survival. GiNKs may represent a promising cell-based immunotherapy for patients with GBM and are minimally affected by the PD-1/PD-L1 immune evasion axis in GBM.

Arabidopsis SMN2/HEN2, Encoding DEAD-Box RNA Helicase, Governs Proper Expression of the Resistance Gene SMN1/RPS6 and Is Involved in Dwarf, Autoimmune Phenotypes of mekk1 and mpk4 Mutants.

In Arabidopsis thaliana, a mitogen-activated protein kinase pathway, MEKK1-MKK1/MKK2-MPK4, is important for basal resistance and disruption of this pathway results in dwarf, autoimmune phenotypes. To elucidate the complex mechanisms activated by the disruption of this pathway, we have previously developed a mutant screening system based on a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Here, we report that the second group of mutants, smn2, had defects in the SMN2 gene, encoding a DEAD-box RNA helicase. SMN2 is identical to HEN2, whose function is vital for the nuclear RNA exosome because it provides non-ribosomal RNA specificity for RNA turnover, RNA quality control and RNA processing. Aberrant SMN1/RPS6 transcripts were detected in smn2 and hen2 mutants. Disease resistance against Pseudomonas syringae pv. tomato DC3000 (hopA1), which is conferred by SMN1/RPS6, was decreased in smn2 mutants, suggesting a functional connection between SMN1/RPS6 and SMN2/HEN2. We produced double mutants mekk1smn2 and mpk4smn2 to determine whether the smn2 mutations suppress the dwarf, autoimmune phenotypes of the mekk1 and mpk4 mutants, as the smn1 mutations do. As expected, the mekk1 and mpk4 phenotypes were suppressed by the smn2 mutations. These results suggested that SMN2 is involved in the proper function of SMN1/RPS6. The Gene Ontology enrichment analysis using RNA-seq data showed that defense genes were downregulated in smn2, suggesting a positive contribution of SMN2 to the genome-wide expression of defense genes. In conclusion, this study provides novel insight into plant immunity via SMN2/HEN2, an essential component of the nuclear RNA exosome.

Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6.

Mitogen-activated protein kinase (MAPK) pathways have a pivotal role in innate immunity signaling in plants. In Arabidopsis, the MAPK pathway that consists of MEKK1, MKK1/MKK2 and MPK4 is involved in pattern-triggered immunity signaling upstream of defense gene expression. This pathway is partly guarded by SUMM2, a nucleotide-binding domain leucine-rich repeat (NLR) protein, which is activated by disruption of the MAPK pathway. To identify other components required for the guard mechanism, here we developed a new mutant screening system utilizing a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Mutants with suppression of the dwarf, autoimmune phenotypes were identified, and one locus responsible for the phenotype was designated as suppressor of MEKK1N overexpression-induced dwarf 1 (SMN1). MutMap analysis revealed that SMN1 encodes the Toll/Interleukin-1 receptor (TIR)-class NLR protein RPS6, a previously identified resistant protein against bacterial pathogen Pseudomonas syringae pv. tomato expressing the HopA1 effector. Importantly, mutations in SMN1/RPS6 also partially suppressed the dwarf, autoimmune phenotypes of mekk1 and mpk4 plants. Our results suggest that the two structurally distinct NLR proteins, SMN1/RPS6 and SUMM2, monitor integrity of the MEKK1-MKK1/MKK2-MPK4 pathway.

Vertebral artery stump syndrome associated with a bihemispheric posterior inferior cerebellar artery.

Background: Vertebral artery (VA) stump syndrome (VASS) is an embolic source for cerebral infarction (CI) in the posterior circulation after VA occlusion. Case Description: A 63-year-old patient with a history of hypertension presented to our emergent department with dizziness, vomiting, and gait disturbance. Head magnetic resonance imaging (MRI) showed acute CIs in the bilateral cerebellar hemispheres and the vermis. Magnetic resonance angiography revealed patency of the VA and basilar artery. Left subclavian artery digital subtraction angiography (DSA) revealed severe left VA orifice stenosis and collateral flow from the deep cervical artery into the left V2 segment. Right VA angiography showed retrograde flow to the left V4 segment, branching bihemispheric posterior inferior cerebellar artery (PICA), and to-and-flow appearance in the proximal PICA segment and VA. VASS was diagnosed, and conservative treatment with aspirin was administered. Worsened nausea and gait disturbance had developed during hospitalization. MRI revealed an enlarged posterior circulation CI. Follow-up DSA revealed proximal to-and-flow appearance translocation to the proximal V4 segment and poor PICA flow. We performed proximal V4 segment parent artery occlusion (PAO) by endovascular therapy. No recurrence of symptoms or CI was observed. The patient was discharged on day 32 of hospitalization with 1 on the modified Rankin scale. Conclusion: We reported a rare case of VASS involving bihemispheric PICA. No CI recurrence was observed after performing PAO of the proximal V4 segment. When treating acute cases of bilateral cerebellar CI due to VASS, the contribution of PICA variations should be considered.

Combined endovascular therapy and surgery for central giant cell granuloma in the temporal bone: A case report.

Background: Central giant cell granuloma (CGCG) is an uncommon, benign intraosseous lesion that most frequently occurs in the mandible and maxilla. Case Description: A 31-year-old female with a medical history of Kawasaki disease presented to our hospital complaining of a clogged right ear. Head computed tomography revealed a mass in the squamous part of the right temporal bone, with osteolytic changes and invasion of the external auditory canal, middle ear, temporomandibular joint, and mastoid air cells. Enhanced magnetic resonance imaging (MRI) showed a strong signal in the intraosseous lesion. Digital subtraction angiography revealed tumor staining from multiple feeders, including the middle meningeal, posterior deep temporal, and posterior auricular arteries. Preoperative feeder embolization using a detachable coil and Embosphere Microspheres were performed for the middle meningeal artery under general anesthesia. After the endovascular treatment, we operated on the temporal bone lesion. Postoperative enhanced MRI showed subtotal resection and residual tumor near the external auditory canal, which was left in place to prevent opening the external auditory canal. The histopathological examination showed proliferation of mononuclear cells intermingled with osteoclast-like multinucleated giant cells. A diagnosis of CGCG was made. The postoperative course was uncomplicated, and the patient was discharged on day 10 of hospitalization. Conclusion: We reported a rare case of CGCG in the temporal bone, managed by endovascular therapy and surgical resection. This combination therapy resulted in subtotal resection, preserving surrounding normal structures, such as the external auditory canal and tympanic cavity.

A case of spontaneous direct vertebral artery - External vertebral venous plexus fistula in the upper cervical portion.

Background: Spontaneous direct vertebral artery-external vertebral venous plexus (VA-EVVP) fistula is a rare disease that presents in patients with neurofibromatosis type 1 (NF-1) or trauma. Case Description: An 82-year-old female patient with no neurological deficits or trauma presented to our hospital with right hemianopsia. Head magnetic resonance imaging (MRI) revealed left occipital cerebral infarction and magnetic resonance angiography demonstrated high signal intensity in the left transverse sinus (TS). The attending doctor diagnosed an old infarction on the left occipital lobe and dural arteriovenous fistula (AVF) in the TS. After 3 years after the first diagnosis, her new attending doctor re-checked the MRI and performed digital subtraction angiography (DSA). The DSA examination revealed a single-hole AVF between the vertebral artery and external vertebral plexus at the C2 level, which was diagnosed as upper cervical VA-EVVP. The patient presented with tinnitus due to a high-flow VA-EVVP fistula, so we performed coil embolization of the fistula under general anesthesia using a double-catheter technique and achieved subtotal embolization, which diminished the intracranial reflux. The 6-month follow-up DSA image revealed complete obliteration of the AVF. Conclusion: We report a rare case of upper cervical VA-EVVP fistula in a patient with no history of trauma and relevant medical conditions. Coil embolization of the fistula was performed using a combination of balloon-assisted and double-catheter techniques. Although the patient showed residual shunt flow after the intervention, follow-up DSA revealed complete obliteration. These findings should provide novel insights for the treatment strategy against VA-EVVP fistula.

Preoperative Blood Counts Predict Overall Survival in Patients Undergoing Surgical Removal of Brain Metastasis.

OBJECTIVE: The prognosis for patients with cancer with brain metastasis (BM) requiring surgical removal is quite limited. Preoperative prognostic factors can provide meaningful information to surgeons, oncologists, and patients. This study evaluated the preoperative blood counts in patients with BM who were treated with surgical removal. METHODS: Between January 2011 and November 2021, 221 consecutive surgeries were conducted on 198 patients with BM. Among the 198 patients, 188 patients with sufficient blood test data and follow-up were analyzed in this study. The tumors originated from the lungs (n = 102, 54.3%), colon (n = 26, 13.3%), breast (n = 13, 6.9%), kidney (n = 8, 4.3%), stomach (n = 6, 3.2%), and others (n = 33, 17.6%). The blood test data included neutrophils, lymphocytes, monocytes, eosinophils, basophils, red blood cell count, hemoglobin, and albumin. RESULTS: The median follow-up and median survival times were both 11 months (range: 0-139 months). Higher neutrophil-lymphocyte ratio ≥ 3.17, platelet-lymphocyte ratio ≥112.7, systemic immune-inflammation index ≥594.4, systemic inflammation response index ≥1.25 were unfavorable predictors of prognosis for the patients treated with surgical removal for BM (P < 0.001). Furthermore, lower lymphocyte-monocyte ratio < 2.33 and prognostic nutritional index < 48.5 were unfavorable predictors. CONCLUSIONS: Simple, less expensive, routinely ordered preoperative blood count assessments, such as the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and prognostic nutritional index, can predict the overall survival of patients treated with surgical removal for BM.

Effect of Intraoperative Ventricular Opening on Recurrence Patterns Following Bis-Chloroethyl-Nitrosourea Wafer Implantation for Newly Diagnosed Glioblastoma.

Objective: To evaluate the effect of ventricular opening (VO) on recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with bis-chloroethyl-nitrosourea (BCNU) wafer implantation. Methods: This single-center retrospective study included 40 patients with newly diagnosed GBM who received BCNU wafer implantation after tumor resection between March 2013 and February 2022. The patients were categorized into two groups based on whether VO occurred during the GBM resection. While 18 patients had VO, 22 did not have VO. In cases with VO, the ventricular wall defect is closed with gelatin or oxidized regenerated cellulose and fibrin glue before BCNU wafer implantation. Recurrence patterns-classified as local, diffuse, distant, or multifocal-and time to recurrence were compared between patients with and without VO. Results: The median follow-up period for the entire cohort was 32.2 months (interquartile range, 16.7-38 months). Median survival time was comparable between patients with VO and patients without VO (38 vs. 26 months, p=0.53). Recurrence occurred in 31/40 patients (77.5%) in entire cohort. The incidence of recurrence was comparable between patients with VO and patients without VO (14 [77.8%] vs. 17 [77.3%], p=1.0). No significant differences were seen between the two groups in time to recurrence (p=0.59) or recurrence patterns (p=0.35). Conclusion: Ventricular opening during surgery with BCNU wafer implantation does not seem to influence the recurrence patterns. Ventricular opening does not induce distant recurrence if appropriate ventricular closure is performed.

Bulk RNA sequencing reveals the comprehensive genetic characteristics of human cord blood-derived natural killer cells.

Introduction: Innate immune cells are important in tumor immunotherapy. Natural killer cells (NKCs) are also categorized as innate immune cells and can control tumor growth and metastatic spread. Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. NKC-based immunotherapy is a promising treatment strategy against GBM. We previously reported a feeder-free expansion system that yielded large-scale highly purified and cytotoxic NKCs derived from human cord blood (CB). In the present study, we performed comprehensive genomic analyses of NKCs generated from human CB (CBNKCs) as compared those from human peripheral blood (PB) (PBNKCs). Methods: Frozen T cell-free CB mononuclear cells were cultured with recombinant human interleukin (rhIL)-18 and rhIL-2 in anti-NKp46 and anti-CD16 antibody immobilization settings. After 14-day expansion, the total RNA of the CBNKCs or PBNKCs was extracted and transcriptomic analyses was performed to determine their similarities and differences. We also examined CBNKC and PBNKC activity against a GBM cell line. Results: Differential expression gene analysis revealed that some NK activating and inhibitory receptors were significantly downregulated in the CBNKCs compared to PBNKCs. Furthermore, genes related to anti-apoptosis and proliferation were upregulated in the CBNKCs. Enrichment analysis determined that the gene sets related to immune response and cytokines were enriched in the CBNKCs. Gene set enrichment analysis demonstrated that the immune response pathway was upregulated in the CBNKCs. Cytotoxic assays using impedance-based cell analyzer revealed that the CBNKCs enhanced NKC-mediated cytotoxicity on GBM cells as compared to the PBNKCs. Conclusions: We demonstrated the characteristics of human CBNKCs. Cell-based therapy using the CBNKCs is promising for treating GBM.

Clinical Results and Hematologic Predictors of Linear Accelerator-Based Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Brain Metastasis in Patients Aged 75 Years or Older: A Retrospective Study.

OBJECTIVE: This study aimed to evaluate prognostic factors including pre-radiosurgical blood count in elderly patients (EPs) with brain metastasis (BM) who were treated using linear accelerator (LINAC)-based stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (fSRT) with a micro-multileaf collimator. METHODS: Between January 2011 and November 2021, 101 consecutive EPs with BM were treated by LINAC-based SRS or fSRT using LINAC with a micro-multileaf collimator. EPs were defined as patients aged ≥75 years. RESULTS: The tumors originated from the lungs (n = 90; 89.1%), colon (n = 2; 2.0%), and others (n = 9; 8.8%) in these EPs. The median pretreatment Karnofsky Performance Status was 80 (range, 40-100). The median follow-up time was 10 months (range, 0-76), as was the median survival. The 6-month, 1-year, and 2-year survival in the EP group was 58.3%, 43.2%, and 28.5%, respectively. Freedom from local failure at 6 months and 1 and 2 years was 97%, 95%, and 91.5%, respectively. Freedom from distant failure at 6 months and 1 and 2 years in EPs was 70.6%, 59.4%, and 54.2%, respectively. A high neutrophil/lymphocyte ratio >5.33 was an unfavorable predictor of prognosis for EPs with BMs treated with SRS and fSRT (P < 0.001). In the EPs, the prognostic factors associated with prolonged survival in the Cox proportional hazards model were being female and a good pretreatment Karnofsky Performance Status. CONCLUSIONS: The findings of our study highlight the efficacy of LINAC-based SRS and fSRT with a micro-multileaf collimator in the treatment of EPs with BMs. Neutrophil/lymphocyte ratio can be an important factor in treatment decisions for EPs with BMs.

Management of Combined Cardiac Surgery Using Cardiopulmonary Bypass With Acute Normovolemic Hemodilution in a Jehovah's Witness: A Case Report.

Combined cardiac surgery under cardiopulmonary bypass (CPB) has a high risk of requiring blood transfusion. Performing this surgery on Jehovah's Witnesses (JWs) is challenging as they strictly refuse allogeneic blood transfusions due to their religious beliefs. A 73-year-old female JW patient underwent combined surgery involving coronary artery bypass grafting and mitral valvuloplasty under CPB. Preoperative hematopoiesis maintained the hemoglobin (Hb) level at >12 g/dL preoperatively; the Hb level was maintained at >7 g/dL during CPB for effective acute normovolemic hemodilution (ANH). Compared with the values obtained immediately after CPB weaning, the Hb level and coagulation functions (measured using viscoelastic tests) improved after autologous transfusion at the end of the surgery. When cardiac surgery under CPB is performed on JWs, ANH can be useful for maintaining postoperative Hb levels and coagulation factors. Sufficient preoperative hematopoiesis and determination of an appropriate volume for intraoperative ANH may be important for effective ANH.