Stenting for subclavian steal phenomenon to restore cerebral perfusion due to acute carotid occlusion following carotid endarterectomy: a case report.

BACKGROUND: Perioperative symptomatic carotid artery occlusion after carotid endarterectomy is a rare complication. In this study, we present a case of symptomatic acute carotid artery occlusion that occurred after carotid endarterectomy in a patient with coexistent subclavian artery steal phenomenon, which was successfully treated with subclavian artery stenting. CASE PRESENTATION: A 57-year-old East Asian female presented with stenosis in the left common carotid artery and left subclavian artery along with subclavian steal. The proximal segment of the left anterior cerebral artery was hypoplastic, and the posterior communicating arteries on both sides were well-developed. Left internal carotid artery stenosis progressed during the follow-up examination; therefore, left carotid endarterectomy was performed. On the following day, symptoms of cerebral perfusion deficiency appeared due to occlusion of the left carotid artery. The stenotic origin of the left common carotid artery and the suspected massive thrombus in the left carotid artery posed challenges to carotid revascularization. Therefore, left subclavian artery stenting for the subclavian steal phenomenon was determined to be the best option for restoring cerebral blood flow to the whole brain. Her symptoms improved after the procedure, and the postprocedural workup revealed improved cerebral blood flow. CONCLUSION: Subclavian artery stenting is safe and may be helpful in patients with cerebral perfusion deficiency caused by intractable acute carotid occlusion coexisting with the subclavian steal phenomenon. Revascularization of asymptomatic subclavian artery stenosis is generally not recommended. However, cerebral circulatory insufficiency as a comorbidity may be worth considering.

Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

Long-term efficacy and safety of perampanel as an add-on therapy in patients with epilepsy.

BACKGROUND: Perampanel (PER) is a newly developed amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist that has been globally approved for the treatment of both focal and generalized seizures. The efficacy and safety of PER have only been reported over short periods of treatment so far. This study aims to clarify the long-term efficacy and safety of PER as an add-on therapy. METHOD: This retrospective observational study investigated 176 epilepsy patients who received PER as add-on medical therapy in two Japanese epilepsy centers between June 2016 and July 2022. The adherence, seizure frequency, and plasma concentration of PER were evaluated at three time points: 6 months, 12 months, and 24 months or longer after the start of adjunctive PER treatment. RESULTS: 112 patients undergoing PER treatment were evaluated at 6 months, 86 were evaluated at 12 months, and 52 were evaluated at 24 months or longer. Overall, 42.9 % (48/112), 45.4 % (40/86), and 44.2 % (23/52) of the patients were seizure-free at 6, 12, and 24 months or longer, respectively. The rate of PER tolerance was 78.3 %, 69.9 %, and 54.7 % at 6, 12, and 24 months or longer, respectively. At the latest timepoint, the seizure-free group was taking a significantly lower dose of PER than the seizure-remnant group, and the number of anti-seizure medications (ASMs) was associated with seizure outcomes. In addition, the seizure-free rate was significantly higher in patients who received PER as a first add-on than in those who received it as a late add-on. No significant difference was found in the plasma concentration of PER between the seizure-free and seizure-remnant groups at 24 months or longer. Among the patients receiving PER at dose of 2 mg, however, the plasma concentrations were significantly higher in the seizure-free group than in the seizure-remnant group (282.7 ± 109.8 µg/ml vs 94.7 ± 54.9 µg/ml, p = 0.0024). CONCLUSION: This long-term retrospective observational study provides evidence of the efficacy and safety of PER over 2 years treatment period in Japan. Notably, patients who started on PER as the first add-on showed a better seizure outcome than those who received it as a late add-on over the long term. Measured plasma concentrations may provide valuable guidance for the management of patients. Higher plasma concentration at low dose PER may suggest the better seizure control.

Long-term prognosis of 452 moyamoya disease patients with and without revascularization under perfusion-based indications.

OBJECTIVES: To evaluate the long-term outcomes of patients treated under our perfusion-based strategy and assess whether conservative treatment without surgical treatment under our strategy is acceptable. MATERIALS AND METHODS: A total of 315 adult and 137 pediatric MMD patients (follow-up period ≥ 3 years from 2001 to 2020) were included. Follow-up events in each patient group (pediatric or adult, surgically treated or conservatively treated) were evaluated and compared to each other using a log-rank test. Risk factors for stroke and nonstroke events were also investigated using a multivariate Cox proportional hazard model. RESULTS: In adult-onset patients, the stroke event rates (person-year %) were not different between surgically treated patients and conservatively treated patients (2.00 % vs. 1.59 %, p = 0.558); however, conservative patients showed a higher stroke rate than surgically treated hemispheres (0.34 %; p = 0.025) and hemorrhagic stroke was the major type (18/26, 69.2 %). Hemorrhagic onset was associated with increased risk of stroke in adults (hazard ratio (95 % confidence interval) = 2.43 (1.10-5.36)). In pediatric-onset patients, no conservatively treated patients experienced stroke; however, nonstroke events occurred more frequently than in surgically treated hemispheres (4.86 % vs. 1.71 %, p = 0.020 for transient ischemic attack; and 7.91 % vs. 1.31 %, p < 0.001 for asymptomatic progression on magnetic resonance angiography). CONCLUSIONS: In adult patients, conservatively treated patients experienced stroke more frequently, especially hemorrhagic stroke. An additive strategy to prevent stroke in hemorrhagic-onset patients without hemodynamic disturbance seems to be needed. Pediatric patients with mild hemodynamic disturbance can be safely observed without initial surgical intervention, but close follow-up for disease progression is necessary.

Histone deacetylase inhibitors enhance oncolytic herpes simplex virus therapy for malignant meningioma.

Approximately 20% of meningiomas are not benign (higher grade) and tend to relapse after surgery and radiation therapy. Malignant (anaplastic) meningioma (MM) is a minor subset of high-grade meningioma that is lethal with no effective treatment options currently. Oncolytic herpes simplex virus (oHSV) is a powerful anti-cancer modality that induces both direct cell death and anti-tumor immunity, and has shown activity in preclinical models of MM. However, clinically meaningful efficacy will likely entail rational mechanistic combination approaches. We here show that epigenome modulator histone deacetylase inhibitors (HDACi) increase anti-cancer effects of oHSV in human MM models, IOMM-Lee (NF2 wild-type) and CH157 (NF2 mutant). Minimally toxic, sub-micromolar concentrations of pan-HDACi, Trichostatin A and Panobinostat, substantively increased the infectability and spread of oHSV G47Δ within MM cells in vitro, resulting in enhanced oHSV-mediated killing of target cells when infected at low multiplicity of infection (MOI). Transcriptomics analysis identified selective alteration of mRNA processing and splicing modules that might underlie the potent anti-MM effects of combining HDACi and oHSV. In vivo, HDACi treatment increased intratumoral oHSV replication and boosted the capacity of oHSV to control the growth of human MM xenografts. Thus, our work supports further translational development of the combination approach employing HDACi and oHSV for the treatment of MM.

Initial Management of Patients with Suspected Stroke in the SARS-CoV-2 Era: Effects on the Door-to-Picture Time.

Objective: To examine the effectiveness of a newly developed emergency room (ER) protocol to treat patients with stroke and control the spread of SARS-CoV-2 by evaluating the door-to-picture time. Methods: We retrospectively enrolled 126 patients who were transported to our ER by ambulance with suspected stroke between April 15 and October 31, 2020 (study group). A risk judgment system named the COVID level was introduced to classify the risk of infection as follows: level 0, no infection; I, infection unlikely; II, possible; III, probable; and IV, definite. Patients with COVID levels 0, I, or II and a Glasgow Coma Scale (GCS) score >10 were placed in a normal ER (nER) without atmospheric pressure control; the medical staff wore standard personal protective equipment (PPE) in such cases. Patients with COVID level II, III, or IV, and a GCS score of ≤10 were assigned to the negative pressure ER (NPER); the medical staff wore enhanced PPE for these cases. The validity of the protocol was assessed. The door-to-picture time of the study group was compared with that of 114 control patients who were transported with suspected stroke during the same period in 2019 (control group). The difference in the time for CT and MRI between the two groups was also compared. In the study group, the time spent in the nER and NPER was evaluated. Results: In all, 118 patients (93.7%) were classified as level I, 6 (4.8%) as level II, and 2 (1.6%) as level III. Only five patients (4.0%) were treated with NPER. Polymerase chain reaction tests were performed on 118 out of 126 patients (93.7%) and were negative. No significant differences were observed in age, sex, neurological severity, modalities of diagnostic imaging, and diagnosis compared with the control group. The median door-to-picture time was 18 (11-27.8) min in the study group and 15 (10-25) min in the control group (p = 0.08). No delay was found on CT (15 [10-21] vs. 14 [9-21] min, p = 0.24). In contrast, there was an 8-min delay for MRI (30 [21.8-50] vs. 22 [14-30] min, p = 0.01). The median door-to-picture time was 29 min longer in patients treated with NPER than in those treated with nER, although the difference was not significant due to the small number of patients (47 [27-57] vs. 18 [11-26] min, p = 0.07). Conclusion: Our protocol could optimize the use of medical resources with only a 3-min delay in the door-to-picture time in an area without explosive outbreak. Unfortunately, the effectiveness of the protocol in preventing infection could not be verified because of the low incidence of COVID-19. When developing and modifying an institutional protocol, recognizing the outbreak status surrounding each institution is important.

Modification of Extracellular Matrix Enhances Oncolytic Adenovirus Immunotherapy in Glioblastoma.

PURPOSE: Extracellular matrix (ECM) component hyaluronan (HA) facilitates malignant phenotypes of glioblastoma (GBM), however, whether HA impacts response to GBM immunotherapies is not known. Herein, we investigated whether degradation of HA enhances oncolytic virus immunotherapy for GBM. EXPERIMENTAL DESIGN: Presence of HA was examined in patient and murine GBM. Hyaluronidase-expressing oncolytic adenovirus, ICOVIR17, and its parental virus, ICOVIR15, without transgene, were tested to determine if they increased animal survival and modulated the immune tumor microenvironment (TME) in orthotopic GBM. HA regulation of NF-κB signaling was examined in virus-infected murine macrophages. We combined ICOVIR17 with PD-1 checkpoint blockade and assessed efficacy and determined mechanistic contributions of tumor-infiltrating myeloid and T cells. RESULTS: Treatment of murine orthotopic GBM with ICOVIR17 increased tumor-infiltrating CD8+ T cells and macrophages, and upregulated PD-L1 on GBM cells and macrophages, leading to prolonged animal survival, compared with control virus ICOVIR15. High molecular weight HA inhibits adenovirus-induced NF-κB signaling in macrophages in vitro, linking HA degradation to macrophage activation. Combining ICOVIR17 with anti-PD-1 antibody further extended the survival of GBM-bearing mice, achieving long-term remission in some animals. Mechanistically, CD4+ T cells, CD8+ T cells, and macrophages all contributed to the combination therapy that induced tumor-associated proinflammatory macrophages and tumor-specific T-cell cytotoxicity locally and systemically. CONCLUSIONS: Our studies are the first to show that immune modulatory ICOVIR17 has a dual role of mediating degradation of HA within GBM ECM and subsequently modifying the immune landscape of the TME, and offers a mechanistic combination immunotherapy with PD-L1/PD-1 blockade that remodels innate and adaptive immune cells.

Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRß represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the ability of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRß+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells.

Local Targeting of NAD+ Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma.

The aggressive primary brain tumor glioblastoma (GBM) is characterized by aberrant metabolism that fuels its malignant phenotype. Diverse genetic subtypes of malignant glioma are sensitive to selective inhibition of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT). However, the potential impact of NAD+ depletion on the brain tumor microenvironment has not been elaborated. In addition, systemic toxicity of NAMPT inhibition remains a significant concern. Here we show that microparticle-mediated intratumoral delivery of NAMPT inhibitor GMX1778 induces specific immunologic changes in the tumor microenvironment of murine GBM, characterized by upregulation of immune checkpoint PD-L1, recruitment of CD3+, CD4+, and CD8+ T cells, and reduction of M2-polarized immunosuppressive macrophages. NAD+ depletion and autophagy induced by NAMPT inhibitors mediated the upregulation of PD-L1 transcripts and cell surface protein levels in GBM cells. NAMPT inhibitor modulation of the tumor immune microenvironment was therefore combined with PD-1 checkpoint blockade in vivo, significantly increasing the survival of GBM-bearing animals. Thus, the therapeutic impacts of NAMPT inhibition extended beyond neoplastic cells, shaping surrounding immune effectors. Microparticle delivery and release of NAMPT inhibitor at the tumor site offers a safe and robust means to alter an immune tumor microenvironment that could potentiate checkpoint immunotherapy for glioblastoma. SIGNIFICANCE: Microparticle-mediated local inhibition of NAMPT modulates the tumor immune microenvironment and acts cooperatively with anti-PD-1 checkpoint blockade, offering a combination immunotherapy strategy for the treatment of GBM.

IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice.

The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.

Preclinical And Clinical Development Of Oncolytic Adenovirus For The Treatment Of Malignant Glioma.

Replication conditional oncolytic human adenovirus has long been considered a promising biological therapeutic to target high-grade gliomas (HGG), a group of essentially lethal primary brain cancer. The last decade has witnessed initiation and some completion of a number of Phase I and II clinical investigations of oncolytic adenovirus for HGG in the US and Europe. Results of these trials in patients are pivotal for not only federal approval but also filling an existing knowledge gap that primarily derives from the stark differences in permissivity to human adenovirus between humans and preclinical mouse models. DNX-2401 (Delta-24-RGD), the current mainstream oncolytic adenovirus with modifications in E1A and the fiber, has been shown to induce impressive objective response and long-term survival (>3 years) in a fraction of patients with recurrent HGG. Responders exhibited initial enlargement of the treated lesions for a few months post treatment, followed by shrinkage and near complete resolution. In accord with preclinical research, post-treatment specimens revealed virus-mediated alteration of the immune tumor microenvironment as evidenced by infiltration of CD8+ T cells and M1-polarized macrophages. These findings are encouraging and together with further information from ongoing studies have a potential to make oncolytic adenovirus a viable option for clinical management of HGG. This review deals with this timely topic; we will describe both preclinical and clinical development of oncolytic adenovirus therapy for HGG, summarize updated knowledge on clinical trials and discuss challenges that the field currently faces.

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma.

In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

A Monoclonal Antibody Against ß1 Integrin Inhibits Proliferation and Increases Survival in an Orthotopic Model of High-Grade Meningioma.

BACKGROUND: High-grade meningiomas (HGMs; World Health Organization [WHO] classification grade II and III) have high relapse rates and poor clinical outcomes despite surgery and radiation treatments. No effective medical therapy currently exists for HGMs, and developing novel therapeutic strategies depends on the identification of molecular drivers. In cancer, ß1 integrin enhances malignant characteristics, including proliferation, invasion, and drug resistance. OBJECTIVE: We conducted this study to investigate whether ß1 integrin could be a therapeutic target in HGMs. PATIENTS AND METHODS: Expression of ß1 integrin was examined in gene array datasets, with proteomics of clinical meningioma specimens, and in patient-derived HGM xenografts. Anti-tumor activity of OS2966, a first-in-class humanized antagonizing monoclonal antibody against ß1 integrin, was tested in vitro and in vivo using an orthotopic mouse model of patient-derived malignant meningioma. RESULTS: ß1 integrin was expressed in meningiomas of all WHO grades and two xenografts tested. In vitro, OS2966 suppressed the viability of NF2-deficient MN3 sphere cells and NF2-wild-type IOMM-Lee malignant meningioma cells only when plated on laminin-coated plastic. While OS2966 decreased phosphorylation of ERK1/2 in both MN3 cells and laminin-grown IOMM-Lee cells, OS2966 only affected the phosphorylation of FAK (Tyr397) in MN3, and of Akt (Ser473) in IOMM-Lee cells, respectively, indicating differential pathway inhibition. Systemic administration of OS2966 in mice bearing orthotopic MN3 HGMs inhibited HGM cell proliferation and significantly extended overall survival of the treated mice. CONCLUSIONS: ß1 Integrin may be a therapeutic target in HGMs, and further preclinical and clinical development of OS2966 for HGM therapy is warranted.

Genetically distinct glioma stem-like cell xenografts established from paired glioblastoma samples harvested before and after molecularly targeted therapy.

Intratumoural heterogeneity underlies tumour escape from molecularly targeted therapy in glioblastoma. A cell-based model preserving the evolving molecular profiles of a tumour during treatment is key to understanding the recurrence mechanisms and development of strategies to overcome resistance. In this study, we established a matched pair of glioblastoma stem-like cell (GSC) cultures from patient glioblastoma samples before and after epidermal growth factor receptor (EGFR)-targeted therapy. A patient with recurrent glioblastoma (MGG70R) harboring focal, high-level EGFR amplification received the irreversible EGFR tyrosine kinase inhibitor dacomitinib. The tumour that subsequently recurred (MGG70RR) showed diploid EGFR, suggesting inhibitor-mediated elimination of EGFR-amplified tumour cells and propagation of EGFR non-amplified cell subpopulations. The MGG70R-GSC line established from MGG70R formed xenografts retaining EGFR amplification and EGFR overexpression, while MGG70RR-GSC established from MGG70RR generated tumours that lacked EGFR amplification and EGFR overexpression. MGG70R-GSC-derived intracranial xenografts were more proliferative than MGG70RR-GSC xenografts, which had upregulated mesenchymal markers, mirroring the pathological observation in the corresponding patient tumours. In vitro MGG70R-GSC was more sensitive to EGFR inhibitors than MGG70RR-GSC. Thus, these molecularly distinct GSC lines recapitulated the subpopulation alteration that occurred during glioblastoma evasion of targeted therapy, and offer a valuable model facilitating therapeutic development for recurrent glioblastoma.

PLK1 Inhibition Targets Myc-Activated Malignant Glioma Cells Irrespective of Mismatch Repair Deficiency-Mediated Acquired Resistance to Temozolomide.

Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in up to 30% of recurrent high-grade gliomas, and represents a key molecular mechanism underlying the acquired resistance to the alkylating agent temozolomide (TMZ). To develop a therapeutic strategy that could be effective in these TMZ-refractory gliomas, we first screened 13 DNA damage response modulators for their ability to suppress viability of MSH6-inactivated, TMZ-resistant glioma cells. We identified a PLK1 selective inhibitor, Volasertib, as the most potent in inhibiting proliferation of glioblastoma cells. PLK1 inhibition induced mitotic catastrophe, G2-M cell-cycle arrest, and DNA damage, leading to caspase-mediated apoptosis in glioblastoma cells. Importantly, therapeutic effects of PLK1 inhibitors were not influenced by MSH6 knockdown, indicating that their action is independent of MMR status of the cells. Systemic treatment with Volasertib potently inhibited tumor growth in an MMR-deficient, TMZ-resistant glioblastoma xenograft model. Further in vitro testing in established and patient-derived cell line panels revealed an association of PLK1 inhibitor efficacy with cellular Myc expression status. We found that cells with deregulated Myc are vulnerable to PLK1 inhibition, as Myc overexpression sensitizes, whereas its silencing desensitizes, glioblastoma cells to PLK1 inhibitors. This discovery is clinically relevant as glioma progression post-TMZ treatment is frequently accompanied by MYC genomic amplification and/or pathway activation. In conclusion, PLK inhibitor represents a novel therapeutic option for recurrent gliomas, including those TMZ-resistant from MMR deficiency. Genomic MYC alteration may serve as a biomarker for PLK inhibitor sensitivity, as Myc-driven tumors demonstrated pronounced responses.

Syringomyelia due to Lumbar Spinal Fluid Drainage in the Acute Phase of Subarachnoid Hemorrhage: A Case Report.

Lumbar spinal fluid drainage is a common procedure for treating hydrocephalus and alleviating vasospasm by egesting blood in the subarachnoid cavity after subarachnoid hemorrhage. Despite being an effective and safe procedure, cerebrospinal fluid overdrainage might result in serious complications. Here we report the case of a 49-year-old man who suffered from tonsillar herniation with subsequent cervicothoracic syringomyelia in the acute phase of subarachnoid hemorrhage due to vertebral artery dissection. About 2 weeks after lumbar drainage was switched from external ventricular drainage initiated on the day of subarachnoid hemorrhage, the recovery from the disturbance of consciousness revealed tetraplegia, and magnetic resonance imaging demonstrated tonsillar herniation and syringomyelia. Removal of the spinal drain and resumption of external ventricular drainage resulted in the restoration of the herniated tonsils to the normal position and the complete disappearance of syringomyelia 11 days later. We should consider that spinal syringomyelia could develop as a complication of lumbar spinal fluid drainage in the acute phase of thick subarachnoid hemorrhage, particularly in the posterior cranial fossa.

Blockade of transforming growth factor-ß signaling enhances oncolytic herpes simplex virus efficacy in patient-derived recurrent glioblastoma models.

Despite the current standard of multimodal management, glioblastoma (GBM) inevitably recurs and effective therapy is not available for recurrent disease. A subset of tumor cells with stem-like properties, termed GBM stem-like cells (GSCs), are considered to play a role in tumor relapse. Although oncolytic herpes simplex virus (oHSV) is a promising therapeutic for GBM, its efficacy against recurrent GBM is incompletely characterized. Transforming growth factor beta (TGF-ß) plays vital roles in maintaining GSC stemness and GBM pathogenesis. We hypothesized that oHSV and TGF-ß inhibitors would synergistically exert antitumor effects for recurrent GBM. Here we established a panel of patient-derived recurrent tumor models from GBMs that relapsed after postsurgical radiation and chemotherapy, based on GSC-enriched tumor sphere cultures. These GSCs are resistant to the standard-of-care temozolomide but susceptible to oHSVs G47Δ and MG18L. Inhibition of TGF-ß receptor kinase with selective targeted small molecules reduced clonogenic sphere formation in all tested recurrent GSCs. The combination of oHSV and TGF-ßR inhibitor was synergistic in killing recurrent GSCs through, in part, an inhibitor-induced JNK-MAPK blockade and increase in oHSV replication. In vivo, systemic treatment with TGF-ßR inhibitor greatly enhanced the antitumor effects of single intratumoral oHSV injections, resulting in cures in 60% of mice bearing orthotopic recurrent GBM. These results reveal a novel synergistic interaction of oHSV therapy and TGF-ß signaling blockade, and warrant further investigations aimed at clinical translation of this combination strategy for GBM patients.

Origin, course and distribution of the nerves to the posterosuperior wall of the external acoustic meatus.

Patients with Ramsay Hunt syndrome have various clinical symptoms including vesicular rash of the external acoustic meatus and auricle. In addition to facial nerve paresis, neurological disturbances of various cranial nerves such as the acoustic nerve, glossopharyngeal nerve and vagus nerve are reported in patients of Ramsay Hunt syndrome. To understand the reasons for the clinical symptoms, we observed the nerve branches of the auricle and external acoustic meatus. We used 18 halves of 11 Japanese cadavers. All cadavers were fixed in 8% formalin and preserved in 30% ethanol. Dissection was performed under a stereomicroscope and the communication among the nerve branches was analyzed. Posterosuperior wall of the acoustic meatus was innervated by nerve branches that emerged from the tympanomastoid fissure in 17 specimens (17/18). These branches always crossed the facial canal and had more than one communicating branch with the facial nerve inside the canal (17/17) or in the petrous bone (1/17). These branches originated from the superior ganglion of the vagus. In the origin from the vagus nerve, some of these branches communicated with the glossopharyngeal nerve (3/17). In addition to these branches, the facial nerve, after originating from the stylomastoid foramen, bifurcated into two nerve branches in some specimens (7/17). Nerve branches around the external acoustic meatus and the auricle have various communications before reaching the central nervous system. The variety of communications could explain the varied symptoms of Ramsay Hunt syndrome.

Developmental processes and ectodermal contribution to the anal canal in mice.

The anorectal canal has two origins; the upper part is derived from endoderm and the lower part is derived from ectoderm. The process of ectodermal contribution to the canal remains unclear. To understand the development of this area, serial sagittal sections of mouse embryos were made every 12h from embryonic day 13.0 (E13.0) to E18.5. Three-dimensional (3-D) reconstructions were obtained from these sections. At the time of the disappearance of the cloacal membrane (E13.5), the endodermal lining reached the site of disintegrated membrane. Thus, the whole canal was of endodermal origin. The transitional zone between the dorsal end of the primary perineum and tail was thicker than other ectodermal epithelia. In this region, it changed from an acute to obtuse angle. After it straightened out and formed the canal, the secondary perineum appeared caudally. During these processes, the external sphincter appeared in the underlying mesenchyme of the thick ectoderm and functioned as a drawstring to form the ectodermal anal canal.