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.

Long-term outcomes and potential predictive recurrence factors after endonasal endoscopic surgical treatment of symptomatic Rathke's cleft cysts.

Although patients with symptomatic Rathke's cleft cysts (RCCs) receive surgical treatment, recurrence sometimes occurs after surgery. However, the mechanism underlying recurrence remains unclear. We evaluated the outcomes of RCC decompression over a long-term follow-up period. We retrospectively reviewed the medical records of 35 patients with symptomatic RCC who underwent endonasal endoscopic surgery (EES) at our institution between 2008 and 2023. Patients' characteristics, intraoperative findings, and postoperative follow-up outcomes were evaluated. A univariate regression model was used to identify the predictors of recurrence. The median patient age was 48.0 years, and 74.2% of the patients were female. The mean follow-up duration was 94.7 ± 47.6 months. Cyst content recurrence was observed in 15 patients (42.8%). Five patients (14.2%) with symptomatic recurrence underwent reoperation. Postoperative vision improved in all 23 patients (100%); headaches improved in 20 patients (90.9%). A new hormonal deficit occurred in two patients (5.7%). Complications included intraoperative cerebrospinal fluid (CSF) leak in 10 patients (28.5%), postoperative CSF leak in two patients (5.7%), permanent diabetes insipidus in two patients (5.7%), and postoperative infection in three patients (8.5%). Univariate analyses revealed that the position of the anterior pituitary lobe (p = 0.019) and preoperative visual disturbances (p = 0.008) significantly affected recurrence after surgery. Although EES was efficient, the recurrence rate was relatively high over a long-term period. The anterior pituitary lobe position and preoperative visual disturbances were significantly associated with recurrence. The anterior-inferior position can predict a high risk of recurrence before surgery.

Intraoperative monitoring of trigeminal neuralgia: a technical note.

Trigeminal neuralgia causes excruciating pain in patients. Microvascular decompression is indicated for drug-resistant s trigeminal neuralgia. Unlike facial spasms, any part of the nerve can be the culprit, not only the root entry zone. Intraoperative monitoring does not yet exist for trigeminal neuralgia. We successfully used intermittent stimulation of the superior cerebellar artery during surgery and confirmed the disappearance of the trigeminal nerve motor branch reaction after the release of the compression. Intermittent direct stimulation of the culprit blood vessel using the motor branch of the trigeminal nerve may assist in intraoperative monitoring of decompression during trigeminal nerve vascular decompression surgery.

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.

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.

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.

[External Ocular Movement(EOM)Monitoring].

The intraoperative monitoring of extraocular motor nerves allows optimal skull base surgery by protecting the cranial nerves. For detecting cranial nerve function, several methods, such as external ocular movement monitoring with an electrooculogram(EOG), electromyogram(EMG), and piezoelectric device sensors, are present. While being valuable and useful, several problems related to its accurate monitoring persist when scanning from inside the tumor, which might be far from the cranial nerves. Here, we described three modalities, free-run EOG monitoring, trigger EMG monitoring, and piezoelectric sensor monitoring for monitoring external ocular movement. Improvement of these processes is essential for appropriately conducting these procedures during neurosurgical operations without harming the extraocular motor nerves.

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.

Diagnostic impact of monitoring transcranial motor-evoked potentials to prevent ischemic complications during endovascular treatment for intracranial aneurysms.

The present study aimed to determine the incidence of intraprocedural motor-evoked potential (MEP) changes and to correlate them with intraprocedural ischemic complications and postprocedural neurological deficits in patients after endovascular intracranial aneurysm treatment. This study analyzed data from 164 consecutive patients who underwent endovascular coil embolization to treat intracranial aneurysms under transcranial MEP monitoring. We analyzed associations between significant changes in MEP defined as > 50% decrease in amplitude, and intraprocedural complications as well as postoperative neurological deficits. Factors associated with postprocedural neurological deficits were also assessed. The treated aneurysms were predominantly located in the anterior circulation (71%). Fourteen (9%) were located at perforators or branches that supplied the pyramidal tract. Intraprocedural complications developed in eight (5%) patients, and four of eight (50%) patients occurred postprocedural neurological deficits. Significant intraprocedural MEP changes occurred during seven of eight endovascular procedures associated with intraprocedural complications and salvage procedures were performed immediately. Among these changes, four transient MEP changes, recovered within 10 min, were not associated with postprocedural neurological deficits, whereas three permanent MEP changes were associated with postprocedural neurological deficits and mRS ≥ 1 at discharge. Aneurysms located at perforators/branches supplying the pyramidal tract, and permanent intraprocedural MEP changes were associated with postprocedural neurological deficits. We conclude that intraprocedural transcranial MEP monitoring can reliably identify ischemic changes and can initiate prompt salvage procedures during endovascular aneurysm treatment.

Motor evoked potential monitoring can evaluate ischemic tolerance to carotid artery occlusion during surgery.

Balloon test occlusion (BTO) is a useful examination for evaluating ischemic tolerance to internal carotid artery (ICA) occlusion. The aim of this study was to investigate the relationships between intraoperative motor evoked potential (MEP) monitoring and the results of preoperative BTO. Between 2013 and 2017, 32 patients undergoing surgery under general anesthesia with intraoperative MEP monitoring, in whom preoperative BTO was performed, were identified. A receiver operator characteristic (ROC) analysis was performed to determine the appropriate cutoff value of MEP amplitude for BTO-positive. Furthermore, the accuracy of MEP monitoring for BTO-positive was compared with electroencephalogram (EEG) and somatosensory evoked potential (SEP) monitoring. Four of 32 (12.5%) patients were BTO-positive. The cutoff value of MEP amplitude for BTO-positive was a > 80% reduction from the baseline level, which showed sensitivity of 100% and specificity of 100%. Thus, the sensitivity and specificity for BTO-positive were significantly higher for MEP than for EEG (100% and 72.0%, p = 0.02) in 28 patients, but they were not significantly different compared with SEP (33.3% and 100%, p = 0.48) in 21 patients. MEP monitoring might be one of the alternatives for evaluating ischemic tolerance to ICA occlusion during surgery. The cutoff value of MEP amplitude was a > 80% reduction.

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.

Efficacy of the visual evoked potential monitoring in endoscopic transnasal transsphenoidal surgery as a real-time visual function.

BACKGROUND: Visual evoked potential (VEP) is used as a means of intraoperative visual function monitoring. It remains unclear, however, whether intraoperative VEP monitoring is a means of real-time visual function monitoring that has satisfactory effectiveness and sensitivity. To evaluate this, the relationships between VEP waveform changes in endoscopic transsphenoidal surgery and postoperative visual function were analyzed retrospectively. MATERIALS AND METHODS: Intraoperative VEP monitoring was carried out during 82 endoscopic transnasal transsphenoidal surgeries for 164 eyes at Nara Medical University Hospital, Nara, Japan under total intravenous anesthesia. Red light flash stimulation was provided to each eye independently. The VEP recording and postoperative visual function were then analyzed. RESULTS: In 160 of 164 eyes (98%), steady VEP monitoring was performed. Stable VEP was acquired from eyes with a corrected visual acuity >0.1. VEP was not recorded in four eyes that had a corrected visual acuity under 0.05. A transient VEP decrease was observed in 26 eyes, 8 of which had improved visual acuity and 18 of which had no change in visual acuity. A permanent gradual VEP decrease occurred in eight eyes; this finding did not correspond to a change in visual function. The visual acuity of the patients who underwent the transsphenoidal operation in our study did not worsen. CONCLUSION: Intraoperative monitoring of VEP predicts postoperative visual function, and a reversible change in VEP indicates that visual function will be preserved. Intraoperative VEP monitoring will be mandatory for surgeries harboring a risk of visual impairment.

Quantitative analysis of the trajectory of simulated basilar apex aneurysms through the internal carotid artery to assess the need for an orbitozygomatic approach.

BACKGROUND: The aim of this study was to identify the correlation between the location of the internal carotid artery (ICA) and the need for an orbitozygomatic approach (OZA) when approaching a basilar apex (BX) aneurysm. MATERIALS AND METHODS: By imaging the virtual trajectory to access the basilar artery (BA) through the ICA, the correlations among the height of the BX, the height and lateral breadth of the bifurcation of the ICA, and the need for removal of the orbital rim or zygomatic arch were investigated using three-dimensional computed tomography angiography (3DCTA) data of approximately 80 random samples not limited to BX aneurysms. Furthermore, the utility of 3D simulation to determine the need for the OZA was verified using data from five patients with BX aneurysms. RESULTS: The height of the bifurcation of the ICA was inversely correlated and the height of the BX was positively correlated with the need for the OZA (both p < 0.017). Among patients undergoing surgery, clipping was successfully performed without the OZA in two patients in whom the distance from the simulated skull point on the extended line from the BX through the bifurcation of the ICA was more than 4 cm from the zygoma and orbital rim. CONCLUSIONS: It is necessary to determine the spatial relationship between the basilar artery and the ICA to decide whether the OZA is needed for surgery. Correlations of the height of the ICA and BX with the need for the OZA were not very strong individually, though they were significant. Therefore, simulation using 3DCTA appears to be important for planning the surgical approach for the treatment of BX aneurysms.

Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo.

Nitrogen-containing bisphosphonates (N-BPs), which prevent bone resorption, exert direct and γδT cell (GDT)-mediated antitumor effects against several tumor cell types, including glioblastoma (GBM). However, limited information is available regarding the antitumor effects of N-BPs in GBM. Specifically, the antitumor effects of minodronate (MDA), a third-generation N-BP, in GBM are yet unclear. This study aimed to investigate the antitumor effects of MDA in GBM in vitro and in vivo. We performed growth inhibition and apoptosis detection assays using the GBM cell lines U87MG and U138MG. Apoptosis inhibition assays were also conducted. In vivo xenograft assays were performed in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic mice subcutaneously implanted with U87MG and U138MG cells. Growth inhibition and apoptosis detection assays demonstrated that MDA inhibited GBM cell growth via apoptosis, which was markedly enhanced by ex vivo expanded GDT. A pan-caspase inhibitor, z-VAD-fmk, inhibited MDA-induced U138MG apoptosis and MDA/GDT-induced U87MG and U138MG apoptosis. But z-VAD-fmk increased MDA-induced U87MG apoptosis. MDA/GDT-mediated apoptosis was blocked by the anti-T cell receptor (TCR) Vγ9, mevalonate pathway inhibitor, granzyme B inhibitor, and antitumor necrosis factor (TNF)-α. In vivo xenograft assays showed that combined intraperitoneal administration of MDA/GDT induced antitumor effects on unestablished U87MG-derived subcutaneous tumors. MDA exerted direct and GDT-mediated anti-GBM apoptotic effects in a caspase-dependent manner. GDT recognized MDA-exposed GBM cells via TCRVγ9 and induced apoptosis via granzyme B and TNF-α release. Because MDA elicited anti-GBM effects in synergy with GDT in vivo, a combination of MDA and ex vivo-generated GDT could be an effective treatment in patients with GBM.

Effects of Wnt-10b on proliferation and differentiation of murine melanoma cells.

In spite of the strong expression of Wnt-10b in melanomas, its role in melanoma cells has not been elucidated. In the present study, the biological effects of Wnt-10b on murine B16F10 (B16) melanoma cells were investigated using conditioned medium from Wnt-10b-producing COS cells (Wnt-CM). After 2 days of culture in the presence of Wnt-CM, proliferation of B16 melanoma cells was inhibited, whereas tyrosinase activity was increased. An in vitro wound healing assay demonstrated that migration of melanoma cells to the wound area was inhibited with the addition of Wnt-CM. Furthermore, evaluation of cellular senescence revealed prominent induction of SA-ß-gal-positive senescent cells in cultures with Wnt-CM. Finally, the growth of B16 melanoma cell aggregates in collagen 3D-gel cultures was markedly suppressed in the presence of Wnt-CM. These results suggest that Wnt-10b represses tumor cell properties, such as proliferation and migration of B16 melanoma cells, driving them toward a more differentiated state along a melanocyte lineage.

[A case of intraventricular isolated neurosarcoidosis diagnosed by neuroendoscopic biopsy].

A 76-year-old woman was admitted to our hospital because of dementia, nausea, and speech disturbances. Computed tomography(CT)of her brain showed hydrocephalus and an intra-ventricular mass with a left temporo-parieto-occipital low density area. She underwent emergency ventricular drainage. Thereafter, she was referred to our department: neurosurgery. Gadolinium-enhanced magnetic resonance imaging of the brain showed homonymous enhancement in the left lateral, third, and fourth ventricles. CT of her chest and abdomen showed no abnormal findings. Initially, we performed a neuro-endoscopic biopsy and made a histopathological diagnosis of noncaseating granuloma. However, because we did not detect pulmonary or ocular lesions, we eventually made a diagnosis of isolated neurosarcoidosis. She received a ventricular-peritoneal shunt and steroid pulse therapy, and recovered from all her symptoms. Neurosurgeons should be aware of the possibility of hydrocephalus mimicking an intraventricular tumor and caused by isolated neurosarcoidosis. In this article, we provide a case description and review of the literature.

[A Case of Symptomatic Cyst Formation after BCNU Wafer Implantation for Glioblastoma].

We report a case of a 56-year-old woman admitted to our hospital for status epilepticus. Three months before hospitalization, the patient underwent gross total removal of a glioblastoma with BCNU wafer implantation in the left parietal lobe. The cavity was subsequently lined with five BCNU wafers. After admission, magnetic resonance imaging(MRI)showed cyst formation accompanied by strong edema, with no recurrence of glioblastoma. She was initially administered antiepileptic drugs and glycerol with betamethasone, after which her seizures stopped but recurred one month later due to a decrease in betamethasone. The BCNU wafers were removed four months after the initial surgery, after which the seizures completely stopped. Histopathological examination of the cavity indicated the presence of inflamed tissue and no recurrence of glioblastoma. Neurosurgeons should be aware of the possibility of cyst formation after BCNU wafer implantation for malignant gliomas. In this manuscript, we provide a case presentation and a review of the literature.

Platelet inhibition by adjunctive cilostazol suppresses the frequency of cerebral ischemic lesions after carotid artery stenting in patients with carotid artery stenosis.

OBJECTIVE: Optimal platelet inhibition is an important therapeutic adjunct in patients with carotid artery stenosis undergoing carotid artery stenting (CAS). Clopidogrel resistance is associated with increased periprocedural thromboembolic complications from neurovascular stent placement procedures. The addition of cilostazol to dual antiplatelet therapy (DAT) has been reported to reduce platelet reactivity and to improve clinical outcomes after percutaneous coronary intervention. This study was undertaken to evaluate the impact of adjunctive cilostazol in patients with CAS. METHODS: Platelet function was assessed by light transmittance aggregometry using the VerifyNow assay. Sixty-four consecutive patients who underwent CAS received standard DAT, clopidogrel (75 mg daily), and aspirin (100 mg daily) more than 4 weeks before the procedure. From 2010 to 2011 (period I), 28 patients underwent CAS under standard DAT. From 2011 to 2013 (period II), 36 patients prospectively had preoperative assessment of platelet function, and 13 patients with clopidogrel resistance received adjunctive cilostazol (200 mg daily) in addition to standard DAT. The incidence of new ipsilateral ischemic lesions on diffusion-weighted imaging a day after CAS and ischemic or hemorrhagic events within 30 days was assessed. RESULTS: Clopidogrel resistance was indentified in 12 patients (43%) in period I and 13 patients (36%) in period II (P = .615). In period II, the addition of cilostazol significantly decreased P2Y12 reaction units and % inhibition (P = .006 and P = .005, respectively), and there was a significant difference in P2Y12 reaction units between the two periods. New ipsilateral ischemic lesions were significantly decreased in period II (2/36 patients) compared with period I (7/28 patients; P = .034); however, there was no significant difference in hemorrhagic and thromboembolic events between the two periods. CONCLUSIONS: Adjunctive cilostazol (triple antiplatelet therapy) in clopidogrel-resistant patients reduces the rate of clopidogrel resistance and suppresses new ischemic lesions without hemorrhagic complications, as compared with standard DAT. Antiplatelet management based on the evaluation of antiplatelet resistance would be required for prevention of perioperative thromboembolic complications in CAS.

Cytotoxic human peripheral blood-derived γδT cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma.

Glioblastoma (GBM) is a highly aggressive brain tumor for which novel therapeutic approaches, such as immunotherapy, are urgently needed. Zoledronate (ZOL), an inhibitor of osteoclastic activity, is known to stimulate peripheral blood-derived γδT cells and sensitize tumors to γδT cell-mediated killing. To investigate the feasibility of γδT cell-based immunotherapy for patients with GBM, we focused on the killing of GBM cell lines by γδT cells and the molecular mechanisms involved in these cell-cell interactions. Peripheral blood mononuclear cells were expanded in ZOL and interleukin (IL)-2 for 14 days, and γδT cells were enriched in the expanded cells by the immunomagnetic depletion of αßT cells. Gliomas are resistant to NK cells but susceptible to lymphokine-activated killer cells and some cytotoxic T lymphocytes. When the γδT cell-mediated killing of three GBM cell lines (U87MG, U138MG and A172 cells) and an NK-sensitive leukemia cell line (K562 cells) were tested, 32% U87MG, 15% U138MG, 1% A172, and 50% K562 cells were killed at an effector:target ratio of 5:1. The γδT cell-mediated killing of all three GBM cell lines was significantly enhanced by ZOL and this ZOL-enhanced killing was blocked by an anti-T cell receptor (TcR) antibody. These results indicated that TcR γδ is crucial for the recognition of ZOL-treated GBM cells by γδT cells. Since the low level killing of GBM cells by the γδT cells was enhanced by ZOL, γδT cell-targeting therapy in combination with ZOL treatment could be effective for patients with GBM.