Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab.

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.

Infratentorial Pial Arteriovenous Fistula in the Elderly.

BACKGROUND: Intracranial pial arteriovenous fistulas (pAVFs) are rare vascular lesions, which may present with, but are distinct from arteriovenous malformation and dural arteriovenous fistula. They most often manifest during infancy or early childhood, but rarely in adulthood. METHODS: We report an exceptionally rare case of infratentorial pAVF in a 73-year-old man, who presented with progressive gait disturbance due to cerebellar edema resulting from arteriovenous shunts. RESULTS: The patient was successfully treated by endovascular flow reduction followed by surgical extirpation of the fistula. The diagnosis was confirmed by pathological findings. CONCLUSIONS: Pial arteriovenous fistula is rare, but can occur in the elderly. Combination of endovascular flow reduction and surgical disconnection yielded an excellent clinical outcome.

Effect of γ34.5 deletions on oncolytic herpes simplex virus activity in brain tumors.

The ICP34.5 protein of herpes simplex virus (HSV) is involved in many aspects of viral pathogenesis; promoting neurovirulence, inhibiting interferon-induced shutoff of protein synthesis, interacting with PCNA and TBK1, inhibiting dendritic cell (DC) maturation, and binding to Beclin 1 to interfere with autophagy. Because of its key role in neuropathogenicity, the γ34.5 gene is deleted in all oncolytic HSVs (oHSVs) currently in clinical trial for treating malignant gliomas. Unfortunately, deletion of γ34.5 attenuates virus replication in cancer cells, especially human glioblastoma stem cells (GSCs). To develop new oHSVs for use in the brain and that replicate in GSCs, we explored the effect of deleting the γ34.5 Beclin 1 binding domain (BBD). To ensure cancer selectivity and safety, we inactivated the ICP6 gene (UL39, large subunit of ribonucleotide reductase), constructing ICP6 mutants with different γ34.5 genotypes: Δ68HR-6, intact γ34.5; Δ68H-6, γ34.5 BBD deleted; and 1716-6, γ34.5 deleted. Multimutated Δ68H-6 exhibited minimal neuropathogenicity in HSV-1-susceptible mice, as opposed to Δ68H and Δ68HR-6. It replicated well in human glioma cell lines and GSCs, effectively killing cells in vitro and prolonging survival of mice bearing orthotopic brain tumors. In contrast, 1716 and 1716-6 barely replicated in GSCs. Infection of glioma cells with Δ68H-6 and 1716-6 induced autophagy and increased phosphorylation of eIF2α, while inhibition of autophagy, by Beclin 1 short hairpin RNA (shRNA) knockdown or pharmacological inhibition, had no effect on virus replication or phosphorylated eIF2α (p-eIF2α) levels. Thus, Δ68H-6 represents a new oHSV vector that is safe and effective against a variety of brain tumor models.

Impact of JSS-PCS on the In-Hospital Workflow and Outcomes of Reperfusion Therapy for Acute Ischemic Stroke: Cases of a Metropolitan Secondary Emergency Facility.

Objective: Protected code stroke has been widely introduced in the emergency medical system for acute stroke in the current coronavirus disease 2019 (COVID-19) pandemic. This study aims to confirm the effects of protected code stroke formulated by the Japan Stroke Society (JSS-PCS) on the quality and outcomes of reperfusion therapy for acute ischemic stroke (AIS), followed by evaluating its validity. Methods: The subjects were 109 consecutive patients with AIS who underwent reperfusion therapy between January 2016 and July 2021, excluding in-hospital onset cases. Patients were classified according to the treatment date into the pre-COVID-19 (n = 82) and the with-COVID-19 (n = 27) groups. JSS-PCS was applied to all patients in the latter group. Statistical comparisons were made between groups on time indicators for initial treatment (onset-to-door time, door-to-imaging time [DTI], door-to-needle time [DTN], door-to-puncture time [DTP], door-to-reperfusion time, and puncture-to-reperfusion time [PTR]). The time indicator transition over the entire period was also evaluated by subgroup analysis. Subsequently, the outcomes at discharge were statistically compared between the two periods, followed by a subgroup comparison. Finally, univariate and multivariate analyses examined whether the application of JSS-PCS affected clinical outcomes. Results: Slight delays were revealed in DTI, DTN, DTP, and PTR in the with-COVID-19 group with no statistical significance. The time indicators were delayed once entering the period of the COVID-19 pandemic and then shortened again. The outcomes at discharge tended to worsen slightly in the with-COVID-19 group with no significance. Subgroup analysis depicted a transient deterioration of outcomes early in the pandemic. Applying JSS-PCS did not significantly affect clinical outcomes in univariate and multivariate analyses. Conclusion: Regarding reperfusion therapy at our facility, the introduction and application of JSS-PCS during the COVID-19 pandemic significantly affected neither time indicators nor outcomes. Infection control should be a top priority in the first medical practice for AIS in today's world, where COVID-19 shows no signs of termination.

A case of embolic stroke imitating atherothrombotic brain infarction before massive hemorrhage from an infectious aneurysm caused by Streptococci.

Early detection followed by treatment with antibiotics in conjunction with direct or endovascular surgery is integral in the management of patients with intracranial infectious aneurysms. These aneurysms often manifest as massive intracranial hemorrhages, which severely deteriorate the outcome. It is very important to detect infectious aneurysms before they rupture. Although usually associated with infective endocarditis, these aneurysms can occur in a variety of clinical settings. We present a case of α-Streptococcus-provoked infectious aneurysm in a patient without infective endocarditis, initially presenting as atherothrombotic-like brain infarction, before massive intracranial hemorrhage. The present case alerts clinicians to keep in mind possible development of infectious aneurysms, even in patients who appear to be suffering from atherothrombotic stoke, especially in patients presenting with signs of infection.

Molecular investigation of brain tumors progressing during pregnancy or postpartum period: the association between tumor type, their receptors, and the timing of presentation.

OBJECTIVE: Brain tumors often become clinically evident during pregnancy; however, the mechanism has not been well elucidated. Purpose of this study is to investigate the influence of molecular genetic factors on the progression of brain tumors during pregnancy or the postpartum period. METHODS: Twelve cases of brain tumors that presented during pregnancy or postpartum period were included: five gliomas, three meningiomas, two vestibular schwannomas, and two chordomas. Tumor samples were investigated by metaphase comparative genomic hybridization and immunohistochemistry, for chromosomal copy number aberration (CNA) and receptor expression of sex hormones and growth factors. RESULTS: The results were correlated with the timing of tumor presentation in relation to the stage of pregnancy. EGFR, VEGFR-1/2, AR, and c-Myc were expressed in gliomas, PgR, ER, HER-2, VEGFR-1, EGF and VEGFR2 in meningiomas, VEGFR-1 in vestibular schwannomas, and EGFR, VEGFR-1/2, and c-Myc in chordomas. The CNAs of the tumors varied. Four of the five gliomas presented in the 2nd trimester, all three meningiomas in the 3rd trimester or postpartum period, and both of the two schwannomas in the late 2nd trimester. Expression of VEGFR-1/2 and EGFR was observed regardless of the timing of tumor presentation, whereas female hormone receptors and HER-2 were exclusively found in meningiomas. Interestingly, one anaplastic astrocytoma (IDH mut, non-codeleted) that progressed from precedent grade 2 tumor harbored amplification of the MYC locus. CONCLUSION: Progression of brain tumors during pregnancy is associated with various growth factors as well as sex hormones. The timing of presentation is likely dependent on molecular receptors specific to each tumor type.

Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer?

Despite aggressive treatments, including chemotherapy and radiotherapy, cancers often recur owing to resistance to conventional therapies. Oncolytic viruses such as oncolytic herpes simplex virus (oHSV) represent an exciting biological approach to cancer therapy. A range of viral mutations has been engineered into HSV to engender oncolytic activity. While oHSV as a single agent has been tested in a number of cancer clinical trials, preclinical studies have demonstrated enhanced efficacy when it is combined with cytotoxic anticancer drugs. Among the strategies that will be discussed in this article are combinations with standard-of-care chemotherapeutics, expression of prodrug-activating enzymes to enhance chemotherapy and small-molecule inhibitors. The combination of oHSV and chemotherapy can achieve much more efficient cancer cell killing than either single agent alone, often through synergistic interactions. This can be clinically important not just for improving efficacy but also for permitting lower and less toxic chemotherapeutic doses. The viral mutations in an oHSV vector often determine the favorability of its interactions with chemotherapy, just as different cancer cells, due to genetic alterations, vary in their response to chemotherapy. As chemotherapeutics are often the standard of care, combining them with an investigational new drug, such as oHSV, is clinically easier than combining multiple novel agents. As has become clear for most cancer therapies, multimodal treatments are usually more effective. In this article, we will discuss the recent progress of these combinatorial strategies between virotherapy and chemotherapy and future directions.

Spontaneous epidural hematoma due to skull metastasis of hepatocellular carcinoma.

Although "spontaneous" epidural hematomas are rare, they can occur in patients with metastatic skull tumors. We describe a case caused by skull metastasis of hepatocellular carcinoma (HCC), and review the relevant literature. In patients with HCC, potential skull metastasis should be kept in mind, since skull metastases from HCC seem to often cause devastating epidural hematoma.

High Cervical Spinal Cord Compression Associated with Anomaly of Bilateral Vertebral Arteries.

BACKGROUND: Anomalies of the vertebral arteries are rare and usually detected incidentally. However, very rarely, they can manifest with clinical symptoms. We describe such a symptomatic case of high cervical spinal cord compression associated with persistent C2 segmental arteries. CASE DESCRIPTION: A 67-year-old man presented with a 5-year history of worsening left-sided weakness and gait disturbance. Magnetic resonance imaging, 3-dimensional computed tomography, and digital subtraction angiography revealed anomalous courses of the vertebral arteries, which compressed the cervical spinal cord at the C1 level from both sides. Interestingly, the left vertebral artery had fenestration, which supposedly reflected that the intradural paramedian longitudinal axis had developmentally persisted until more distally on the left. Microvascular decompression was performed to transpose the offending vertebral arteries. With vascular tapes made of polyglycolic acid sheets and fascia, the vertebral arteries compressing the cervical spine were anchored to the dura mater of the vertebral arch. This maneuver effectively relieved the neurovascular conflict created by the bilateral anomalous vertebral arteries, and the patient's myelopathy improved after surgery. To our knowledge, this is the first report to clearly demonstrate this combination of vertebral artery anomalies causing clinical symptoms and its successful treatment by microvascular decompression. CONCLUSIONS: Transposition of the vertebral artery by anchoring to the dura mater of the vertebral arch could be an effective and safe option for these disease conditions.

Augmented therapeutic efficacy of an oncolytic herpes simplex virus type 1 mutant expressing ICP34.5 under the transcriptional control of musashi1 promoter in the treatment of malignant glioma.

Although second-generation replication-conditional herpes simplex virus type 1 (HSV-1) vectors defective for both ribonucleotide reductase (RR) and the virulence factor gamma(1)34.5 have been proven safe through a number of animal experiments and clinical trials, their therapeutic efficacy was also markedly reduced. To overcome this situation, we concentrated on the use of a tumor-specific promoter in this study, to express ICP34.5 selectively in malignant glioma cells. As a molecular marker for malignant glioma, we focused on the neural RNA-binding protein, Musashi1. On the basis of the results of defective vector dvM345, as reported previously, we created, via homologous recombination, a novel HSV-1 vector termed KeM34.5, which expresses ICP34.5 under the transcriptional control of the musashi1 gene promoter (P/musashi1). Cytotoxicity mediated by KeM34.5 was significantly enhanced in human glioma cell lines (U87MG, U87MG-E6, U251, and T98G), resulting in an approximately 2-log increase in viral yield, compared with its parental vector G207. This virus also showed much higher therapeutic efficacy in the in vivo glioma model, while maintaining the desirable neuroattenuated phenotype. These results suggest that oncolytic HSV-1 expressing ICP34.5 under the transcriptional control of the musashi1 gene promoter could be a promising therapeutic agent for the treatment of malignant glioma.

Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors.

Oncolytic viruses, such as the oncolytic herpes simplex virus (oHSV), are an exciting new therapeutic strategy for cancer as they are replication competent in tumor cells but not normal cells. In order to engender herpes simplex virus with oncolytic activity and make it safe for clinical application, mutations are engineered into the virus. Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Despite many advances in therapy, overall survival has not been substantially improved over the last several decades. A number of different oHSVs have been tested as monotherapy in early-phase clinical trials for GBM and have demonstrated safety and anecdotal evidence of efficacy. However, strategies to improve efficacy are likely to be necessary to successfully treat GBM. Cancer treatment usually involves multimodal approaches, so the standard of care for GBM includes surgery, radiotherapy and chemotherapy. In preclinical GBM models, combinations of oHSV with other types of therapy have exhibited markedly improved activity over individual treatments alone. In this review, we will discuss the various combination strategies that have been employed with oHSV, including chemotherapy, small-molecule inhibitors, antiangiogenic agents, radiotherapy and expression of therapeutic transgenes. Effective combinations, especially synergistic ones, are clinically important not just for improved efficacy but also to permit lower and less-toxic doses and potentially overcome resistance.

Conus medullaris-cauda arteriovenous malformation and Klippel-Trenaunay syndrome: what is the treatment goal?

A 29-year-old man with Klippel-Trenaunay syndrome (KTS) presented with a symptomatic conus medullaris-cauda arteriovenous malformation (AVM) manifesting as back and right limb pain, which abruptly worsened with the onset of right limb weakness and urinary retention. He was treated by multisession endovascular embolization resulting in improved neurological status. KTS is a sporadic disease with unknown etiology, but genetic susceptibility may lead to the over-expression of angiogenic factors and increased angiogenesis. KTS may be exceptionally associated with slow-flow spinal AVM, but there is no consensus about the optimal treatment for these symptomatic lesions. Embolization treatment may represent a safe option to minimize complications and possibly improve the neurological status in patients with spinal AVM associated with KTS, if one or both legs are already impaired by hypertrophy or other vascular malformations. Genetic analysis may reveal an underlying angiogenesis change, so closer follow up might be indicated in selected patients.

Clinical, histological, and genetic features of fourth ventricle ependymoma in the elderly. Case report.

A 71-year-old woman presented with a rare case of geriatric ependymoma originating from the fourth ventricle manifesting as progressive gait and memory disturbance. Imaging studies revealed an extraaxial mass in the fourth ventricle protruding into the right cerebellomedullary cistern, with concomitant obstructive hydrocephalus. Surgery achieved subtotal removal since the tumor tightly adhered to the right vestibular area of the fourth ventricular floor. The histological diagnosis was ependymoma, which was also confirmed by comparative genetic hybridization. Although she developed severe laryngeal edema and worsening of the hydrocephalus postoperatively which required additional treatment, she recovered with residual mild gait disturbance, and was transferred to a rehabilitation facility. Fourth ventricle ependymoma in the elderly is rare. Comparative genetic hybridization may be important in the diagnosis of geriatric ependymoma and in the choice for adjuvant therapy as well as in estimating the prognosis for patients with rare types of ependymoma.

Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells.

Glioblastoma (GBM), a fatal malignant brain tumor, contains abundant hypoxic regions that provide a "niche" to promote both the maintenance and enrichment of glioblastoma stem-like cells (GSCs) and confer resistance to chemo- and radiotherapy. Since GSCs, with an ability to resist conventional therapies, may be responsible for tumor recurrence, targeting GSCs located in such a hypoxic environment may be critical to improving the therapeutic outcome for GBM patients. Oncolytic viral therapies have been tested in the clinic as a promising therapeutic approach for GBM. In this study, we analyzed and compared the therapeutic effects of oncolytic herpes simplex virus (oHSV) type 1 G47Δ (γ34.5(-)ICP6(-)LacZ(+)α47(-)) in patient-derived GSCs under normoxia (21% oxygen) and hypoxia (1% oxygen). GSCs cultured in hypoxia showed an increased ability to form neurospheres and expressed higher levels of the putative stem cell marker CD133 compared with GSCs cultured in normoxia. G47Δ exhibited a comparable ability to infect, replicate, and kill GSCs in normoxia and hypoxia in vitro. Importantly, G47Δ could counteract hypoxia-mediated enhancement of the stem-like properties of GSCs, inhibiting their self-renewal and stem cell marker expression. Using orthotopic human GSC xenografts in mice, we demonstrated that intratumoral injection of G47ΔUs11fluc, a newly developed G47Δ derivative that expresses firefly luciferase driven by a true late viral promoter, led to an equivalent frequency of viral infection and replication in hypoxic and nonhypoxic tumor areas. These findings suggest that oHSV G47Δ represents a promising therapeutic strategy to target and kill GSCs, not only in normoxic areas of GBM but also within the hypoxic niche.

Oncolytic virus-mediated manipulation of DNA damage responses: synergy with chemotherapy in killing glioblastoma stem cells.

BACKGROUND: Although both the alkylating agent temozolomide (TMZ) and oncolytic viruses hold promise for treating glioblastoma, which remains uniformly lethal, the effectiveness of combining the two treatments and the mechanism of their interaction on cancer stem cells are unknown. METHODS: We investigated the efficacy of combining TMZ and the oncolytic herpes simplex virus (oHSV) G47Δ in killing glioblastoma stem cells (GSCs), using Chou-Talalay combination index analysis, immunocytochemistry and fluorescence microscopy, and neutral comet assay. The role of treatment-induced DNA double-strand breaks, activation of DNA damage responses, and virus replication in the cytotoxic interaction between G47Δ and TMZ was examined with a panel of pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of DNA repair pathways. Comparisons of cell survival and virus replication were performed using a two-sided t test (unpaired). The survival of athymic mice (n = 6-8 mice per group) bearing GSC-derived glioblastoma tumors treated with the combination of G47Δ and TMZ was analyzed by the Kaplan-Meier method and evaluated with a two-sided log-rank test. RESULTS: The combination of G47Δ and TMZ acted synergistically in killing GSCs but not neurons, with associated robust induction of DNA damage. Pharmacological and shRNA-mediated knockdown studies suggested that activated ataxia telangiectasia mutated (ATM) is a crucial mediator of synergy. Activated ATM relocalized to HSV DNA replication compartments where it likely enhanced oHSV replication and could not participate in repairing TMZ-induced DNA damage. Sensitivity to TMZ and synergy with G47Δ decreased with O(6)-methylguanine-DNA-methyltransferase (MGMT) expression and MSH6 knockdown. Combined G47Δ and TMZ treatment extended survival of mice bearing GSC-derived intracranial tumors, achieving long-term remission in four of eight mice (median survival = 228 days; G47Δ alone vs G47Δ + TMZ, hazard ratio of survival = 7.1, 95% confidence interval = 1.9 to 26.1, P = .003) at TMZ doses attainable in patients. CONCLUSIONS: The combination of G47Δ and TMZ acts synergistically in killing GSCs through oHSV-mediated manipulation of DNA damage responses. This strategy is highly efficacious in representative preclinical models and warrants clinical translation.

Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells.

The clinicopathological heterogeneity of glioblastoma (GBM) and the various genetic and phenotypic subtypes in GBM stem cells (GSCs) are well described. However, the relationship between GSCs and the corresponding primary tumor from which they were isolated is poorly understood. We have established GSC-enriched neurosphere cultures from 15 newly diagnosed GBM specimens and examined the relationship between the histopathological and genomic features of GSC-derived orthotopic xenografts and those of the respective patient tumors. GSC-initiated xenografts recapitulate the distinctive cytological hallmarks and diverse histological variants associated with the corresponding patient GBM, including giant cell and gemistocytic GBM, and primitive neuroectodermal tumor (PNET)-like components. This indicates that GSCs generate tumors that preserve patient-specific disease phenotypes. The majority of GSC-derived intracerebral xenografts (11 of 15) demonstrated a highly invasive behavior crossing the midline, whereas the remainder formed discrete nodular and vascular masses. In some cases, GSC invasiveness correlated with preoperative MRI, but not with the status of PI3-kinase/Akt pathways or O(6)-methylguanine methyltransferase expression. Genome-wide screening by array comparative genomic hybridization and fluorescence in situ hybridization revealed that GSCs harbor unique genetic copy number aberrations. GSCs acquiring amplifications of the myc family genes represent only a minority of tumor cells within the original patient tumors. Thus, GSCs are a genetically distinct subpopulation of neoplastic cells within a GBM. These studies highlight the value of GSCs for preclinical modeling of clinically relevant, patient-specific GBM and, thus, pave the way for testing novel anti-GSC/GBM agents for personalized therapy.

A novel oncolytic herpes simplex virus that synergizes with phosphoinositide 3-kinase/Akt pathway inhibitors to target glioblastoma stem cells.

PURPOSE: To develop a new oncolytic herpes simplex virus (oHSV) for glioblastoma (GBM) therapy that will be effective in glioblastoma stem cells (GSC), an important and untargeted component of GBM. One approach to enhance oHSV efficacy is by combination with other therapeutic modalities. EXPERIMENTAL DESIGN: MG18L, containing a U(S)3 deletion and an inactivating LacZ insertion in U(L)39, was constructed for the treatment of brain tumors. Safety was evaluated after intracerebral injection in HSV-susceptible mice. The efficacy of MG18L in human GSCs and glioma cell lines in vitro was compared with other oHSVs, alone or in combination with phosphoinositide-3-kinase (PI3K)/Akt inhibitors (LY294002, triciribine, GDC-0941, and BEZ235). Cytotoxic interactions between MG18L and PI3K/Akt inhibitors were determined using Chou-Talalay analysis. In vivo efficacy studies were conducted using a clinically relevant mouse model of GSC-derived GBM. RESULTS: MG18L was severely neuroattenuated in mice, replicated well in GSCs, and had anti-GBM activity in vivo. PI3K/Akt inhibitors displayed significant but variable antiproliferative activities in GSCs, whereas their combination with MG18L synergized in killing GSCs and glioma cell lines, but not human astrocytes, through enhanced induction of apoptosis. Importantly, synergy was independent of inhibitor sensitivity. In vivo, the combination of MG18L and LY294002 significantly prolonged survival of mice, as compared with either agent alone, achieving 50% long-term survival in GBM-bearing mice. CONCLUSIONS: This study establishes a novel therapeutic strategy: oHSV manipulation of critical oncogenic pathways to sensitize cancer cells to molecularly targeted drugs. MG18L is a promising agent for the treatment of GBM, being especially effective when combined with PI3K/Akt pathway-targeted agents.

Enhanced antitumor efficacy of low-dose Etoposide with oncolytic herpes simplex virus in human glioblastoma stem cell xenografts.

PURPOSE: Glioblastoma (GBM) inevitably recurs despite surgery, radiation, and chemotherapy. A subpopulation of tumor cells, GBM stem cells (GSC), has been implicated in this recurrence. The chemotherapeutic agent etoposide is generally reserved for treating recurrent tumors; however, its effectiveness is limited due to acute and cumulative toxicities to normal tissues. We investigate a novel combinatorial approach of low-dose etoposide with an oncolytic HSV to enhance antitumor activity and limit drug toxicity. EXPERIMENTAL DESIGN: In vitro, human GBM cell lines and GSCs were treated with etoposide alone, oncolytic herpes simplex virus (oHSV) G47Δ alone, or the combination. Cytotoxic interactions were analyzed using the Chou-Talalay method, and changes in caspase-dependent apoptosis and cell cycle were determined. In vivo, the most etoposide-resistant human GSC, BT74, was implanted intracranially and treated with either treatment alone or the combination. Analysis included effects on survival, therapy-associated adverse events, and histologic detection of apoptosis. RESULTS: GSCs varied in their sensitivity to etoposide by over 50-fold in vitro, whereas their sensitivity to G47Δ was similar. Combining G47Δ with low-dose etoposide was moderately synergistic in GSCs and GBM cell lines. This combination did not enhance virus replication, but significantly increased apoptosis. In vivo, the combination of a single cycle of low-dose etoposide with G47Δ significantly extended survival of mice-bearing etoposide-insensitive intracranial human GSC-derived tumors. CONCLUSIONS: The combination of low-dose etoposide with G47Δ increases survival of mice-bearing intracranial human GSC-derived tumors without adverse side effects. These results establish this as a promising combination strategy to treat resistant and recurrent GBM.

A case of 'lymphomatosis cerebri' diagnosed in an early phase and treated by whole brain radiation: case report and literature review.

'Lymphomatosis cerebri' (LC) is a term indicating a diffusely infiltrating form of primary central nervous system lymphoma (PCNSL) without evidence of a mass lesion. Not infrequently, diagnostic confusion is caused by its presentation on cranial magnetic resonance images (MRI), which is characterized by diffuse leukoencephalopathy without contrast enhancement. In this report, we describe a 53-year-old, immunocompetent man who had an insidiously progressive dementia and right weakness. On serial MRI in 4 months duration, diffuse white matter lesions without contrast enhancement gradually progressed, which was clinically consistent with his worsening condition. Biopsy specimen demonstrated nondestructive, diffusely infiltrating, large B-cell lymphoma, diagnosing LC. After the biopsy, corticosteroids were initiated, which dramatically alleviated his symptoms. Afterwards, he was treated by whole brain irradiation (total 36Gy) and discharged without noticeable deficits. Diagnosis of LC requires additional examinations generally not performed in the other white matter disorders. In suspected cases, biopsy should be performed to avoid deferring adequate cytostatic treatment.