Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted-prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy.

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted is known for their relative chemosensitivity and indolent clinical course among diffuse gliomas of adult type. Based on the data from phase 3 clinical trials, the standard of post-surgical care for those tumors is considered to be initial chemoradiotherapy regardless of histopathological grade, particularly with PCV. However, partly due to its renewed definition in late years, prognostic factors in patients with those tumors are not well established. Moreover, the survival rate declines over 15 years, with only a 37% OS rate at 20 years for grade 3 tumors, even with the current standard of care. Given that most of this disease occurs in young or middle-aged adults, further improvements in treatment and management are necessary. Here, we discuss prognostic factors, standard of care and chemotherapy, and future perspectives with neoadjuvant strategy in those tumors.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma.

PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.

[Meningioma].

Meningioma is considered as a single type by the World Health Organization 2021 classification, encompassing 15 subtypes. These classifications are primarily based on histological attributes. However, recent advancements in understanding driver gene mutations and molecular prognostic markers are of particular importance for comprehending the clinical behavior of these tumors. Meningiomas are stratified molecularly, predominantly based on the presence of NF2 mutation. Over 50% are associated with mutations in the NF2 gene and/or monosomy of chromosome 22, whereas the remaining are associated with gene mutations in either of AKT1, SMO, KLF4, TRAF7, or the other less common ones. Importantly, these driver gene mutations are mutually exclusive and significantly associated with tumor location, histological subtype, and grading. The majority of higher-grade meningiomas is associated with multiple chromosomal aberrations, including the loss of 1p, 6q, and 14q, along with NF2 mutations. Homozygous deletion of CDKN2A/CDKN2B genes or TERT promoter mutations serves as a predictor of poor prognosis. Notably, these molecular markers are now incorporated into the criteria for anaplastic meningioma. The amalgamation of molecular insights with clinical and histological parameters, alongside patient prognosis, holds significant utility in the management of patients with meningiomas. It is anticipated to pave the way for treatments founded on molecular-clinical associations.

Clinical, histopathological and molecular risk factors for recurrence of pilocytic astrocytomas: brainstem/spinal location, nestin expression and gain of 7q and 19 are associated with early tumor recurrence.

Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C.

BACKGROUND: The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. METHODS: An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ±â€…10 Gy boost (arm A) or WBRT ±â€…boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS). RESULTS: Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95-4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. CONCLUSIONS: This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.

The role of optimal cut-off diagnosis in 11C-methionine PET for differentiation of intracranial brain tumor from non-neoplastic lesions before treatment.

PURPOSE: Amino acid positron emission tomography (PET) may provide additional information to computed tomography and magnetic resonance imaging for detecting the pretreatment diagnosis of intracranial lesions. The purpose of this study was to investigate the role of cutoff values of 11C-METPET, an amino acid PET tracer, in the differentiation of pretreatment brain tumors from non-neoplastic lesions. METHODS: This retrospective cohort study analyzed 101 pretreatment patients with a definitive diagnosis out of a total of 425 consecutive 11C-METPET imaging studies. The standardized uptake values (SUV) and the ratios of lesion to contralateral normal frontal-lobe gray matter uptake (L/N ratios) were measured. Cutoff values for the differential diagnosis of brain tumors from non-neoplastic lesions were determined using receiver operating characteristics curve (ROC) analysis. RESULTS: Based on the ROC analyses, the cutoffs were 3.33 for maximum SUV, 2.54 for mean SUV, 2.33 for peak SUV, 2.04 for Lmax/Nmean, and 2.23 for Lmax/Nmax. The sensitivity and specificity of these cutoffs were 69.2% and 82.6%, respectively, for maximum SUV, 64.1% and 91.3% for mean SUV, 69.2% and 91.3% for peak SUV, 70.5% and 91.3% for Lmax/Nmax and 75.6% and 82.6% for Lmax/Nmean. CONCLUSION: In differentiating intracranial brain tumor from non-neoplastic lesion with 11C-METPET, the use of optimal cutoff values indicates the high specificity, which means that positive result indicates the high likelihood of brain tumor. Considering the high specificity of 11C-METPET, more invasive examinations such as biopsy may be considered in positive cases.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors.

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Impact of Neoadjuvant Bevacizumab on Neuroradiographic Response and Histological Findings Related to Tumor Stemness and the Hypoxic Tumor Microenvironment in Glioblastoma: Paired Comparison Between Newly Diagnosed and Recurrent Glioblastomas.

Background: Previously, we reported that bevacizumab (Bev) produces histological and neuroradiographic alterations including changes in tumor oxygenation, induction of an immunosupportive tumor microenvironment, and inhibition of stemness. To confirm how those effects vary during Bev therapy, paired samples from the same patients with newly diagnosed glioblastoma (GBM) who received preoperative neoadjuvant Bev (neoBev) were investigated with immunohistochemistry before and after recurrence. Methods: Eighteen samples from nine patients with newly diagnosed GBM who received preoperative neoBev followed by surgery and chemoradiotherapy and then autopsy or salvage surgery after recurrence were investigated. The expression of carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1 alpha (HIF-1α), nestin, and Forkhead box M1 (FOXM1) was evaluated with immunohistochemistry.For comparison between neoBev and recurrent tumors, we divided the present cohort into two groups based on neuroradiographic response: good and poor responders (GR and PR, respectively) to Bev were defined by the tumor regression rate on T1-weighted images with gadolinium enhancement (T1Gd) and fluid-attenuated inversion recovery images. Patterns of recurrence after Bev therapy were classified as cT1 flare-up and T2-diffuse/T2-circumscribed. Furthermore, we explored the possibility of utilizing FOXM1 as a biomarker of survival in this cohort. Results: A characteristic "pseudo-papillary"-like structure containing round-shaped tumor cells clustered adjacent to blood vessels surrounded by spindle-shaped tumor cells was seen only in recurrent tumors. Tumor cells at the outer part of the "pseudo-papillary" structure were CA9-positive (CA9+)/HIF-1α+, whereas cells at the inner part of this structure were CA9-/HIF-1α+ and nestin+/FOXM1+. CA9 and HIF-1α expression was lower in T1Gd-GR and decreased in the "T2-circumscribed/T2-diffuse" pattern compared with the "T1 flare-up" pattern, suggesting that tumor oxygenation was frequently observed in T1Gd-GR in initial tumors and in the "T2-circumscribed/T2-diffuse" pattern in recurrent tumors. FOXM1 low-expression tumors tended to have a better prognosis than that of FOXM1 high-expression tumors. Conclusion: A "pseudo-papillary" structure was seen in recurrent GBM after anti-vascular endothelial growth factor therapy. Bev may contribute to tumor oxygenation, leading to inhibition of stemness and correlation with a neuroimaging response during Bev therapy. FOXM1 may play a role as a biomarker of survival during Bev therapy.

[Glioblastoma That Does Not Improve with Standard Treatment: Standard and Personalized Treatment Making The Most of Limited Modalities].

The standard treatment for glioblastoma is maximal surgical resection followed by postoperative temozolomide administration combined with radiation therapy. Although treatment outcomes have improved in recent years, glioblastoma remains a fatal malignant brain tumor. In addition to standard treatment, it is important to understand the characteristics of additional therapies or limited therapeutic modalities, such as bevacizumab, photodynamic therapy, BCNU wafers, tumor treating fields, and genomic medicine. Furthermore, combination therapy should be applied, depending on the individual patient's condition, to treat this intractable disease.

The oligodendroglial histological features are not independently predictive of patient prognosis in lower-grade gliomas.

The relevance of oligodendroglial histological features to patient prognoses is controversial. 93 LrGGs resected for about 2 decades were re-assessed based on WHO2007 with special interest to pure oligodendroglial diagnosis (oligodendroglioma or anaplastic oligodendroglioma) and presence of CFO features. Those histological features, patients OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q-based molecular groups. There was significant association between 1p19q status with the oligodendroglial histological diagnosis as well as presence of CFO in the entire cohort. The oligodendroglial diagnosis was associated with longer OS in IDHmut/codel group; however, this association was not significant in the multivariate analyses. In IDHmut/noncodel and IDH-wildtype groups, the oligodendroglial diagnosis was not associated with patient OS. Presence of CFO was not associated with patient OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any molecular groups. The oligodendroglial histological features are not independently predictive of either patient prognosis or chemotherapeutic response in LrGGs, leaving the possibility of marginal favorable association only in IDHmut/codel tumors.

Histopathological investigation of the 1p/19q-codeleted gliomas resected following alkylating agent chemotherapy.

PURPOSE: Lower grade gliomas with 1p/19q codeletion are often responsive to chemotherapy, and several of these have been treated using upfront chemotherapy and subsequent resection following tumor volume decrease. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in 1p/19-codeleted gliomas. METHODS: Fourteen 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin-eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry for Ki-67/MIB-1, CD68 as a pan-macrophage/monocyte marker, CD163 as a presumed marker of M2 polarity, and nestin and CD133 as markers of GSCs. RESULTS: The most frequent histological findings following chemotherapy included a sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 index decreased and the number of CD68 + cells increased after chemotherapy. The increasing rate of CD68 + cells in the post-/pre-chemotherapy specimens was inversely correlated with patient prognosis but not tumor response. The number of CD163 + cells, M2/M1 + M2 ratio, and the ratio of GSCs to total tumor cells increased after chemotherapy, and those in the post-chemotherapy specimens were negatively correlated with patient prognosis. There was a correlation between the M2/M1 + M2 ratio and the ratio of GSCs in both pre- and post-chemotherapy specimens. CONCLUSION: GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in 1p/19q-codeleted gliomas.

Determining the extent of tumor resection at surgical planning with 18F-fluciclovine PET/CT in patients with suspected glioma: multicenter phase III trials.

OBJECTIVE: Glioma is the most common type of central nervous system tumor reported worldwide. Current imaging technologies have limitations in the diagnosis and assessment of glioma. The present study aimed to confirm the diagnostic efficacy and safety of anti-1-amino-3-[18F]fluorocyclobutane carboxylic acid (18F-fluciclovine; anti-[18F]FACBC) as a radiotracer for patients undergoing combined positron emission tomography and computed tomography (PET/CT) for suspected glioma. METHODS: Combined data from two multicenter, open-label phase III clinical trials were evaluated for this study. The two trials enrolled patients with suspected high- or low-grade glioma on the basis of clinical symptoms, clinical course, and magnetic resonance imaging findings, and who were scheduled for tumor resection surgery. Patients fasted for ≥ 4 h and received 2 mL of 18F-fluciclovine (radioactivity dose 78.3-297.0 MBq), followed by a 10-min PET scan 10-50 min after injection. The primary efficacy endpoint was the positive predictive value (PPV) of the gadolinium contrast-enhanced T1-weighted image negative [Gd (-)] and 18F-fluciclovine PET-positive [PET ( +)] area of the scans, using the histopathological diagnosis of the tissue sampled from that area as the standard of truth. All adverse events reported during the study were recorded for safety analysis. RESULTS: A total of 45 patients aged 23-89 years underwent 18F-fluciclovine PET; 31/45 patients (68.9%) were male, and 30/45 patients (66.7%) were suspected to have high-grade glioma. The PPV of 18F-fluciclovine PET in the Gd (-) PET ( +) area was 88.0% (22/25 areas, 95% confidence interval: 70.0-95.8). The extent of planned tumor resection was modified in 47.2% (17/36 cases) after 18F-fluciclovine PET scan, with an extension of area in 30.6% (11/36 cases) and reduction in 16.7% (6/36 cases). Furthermore, tissue samples collected from PET ( +) areas tended to have a higher malignancy grade compared with those from PET (-) areas. Overall, 18F-fluciclovine was well tolerated. CONCLUSION: 18F-fluciclovine PET/CT is useful for determining the extent of tumor resection at surgical planning, and may serve as a safe and effective diagnostic tool for patients with suspected glioma. TRIAL REGISTRATION: These trials were registered in the Japan Pharmaceutical Information Center Clinical Trials Information (JapicCTI-152986, JapicCTI-152985).

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.

Myoinositol to Total Choline Ratio in Glioblastomas as a Potential Prognostic Factor in Preoperative Magnetic Resonance Spectroscopy.

Isocitrate dehydrogenase (IDH) wild-type diffuse astrocytic tumors tend to be pathologically diagnosed as glioblastomas (GBMs). We previously reported that myoinositol to total choline (Ins/Cho) ratio in GBMs on magnetic resonance (MR) spectroscopy was significantly lower than that in IDH-mutant gliomas. We then hypothesized that a low Ins/Cho ratio is a poor prognosis factor in patients with GBMs, IDH-wild-type. In the present study, we calculated the Ins/Cho ratios of patients with GBMs and investigated their progression-free survival (PFS) and overall survival (OS) to determine their utility as prognostic marker. We classified patients with GBMs harboring wild-type IDH (n = 27) into two groups based on the Ins/Cho ratio, and compared patient backgrounds, pathological findings, PFS, OS, and copy number aberrations between the high and low Ins/Cho groups. Patients with GBMs in the low Ins/Cho ratio group indicated shorter PFS (P = 0.021) and OS (P = 0.048) than those in the high Ins/Cho group. Multivariate analysis demonstrated that the Ins/Cho ratio was significantly correlated with PFS (hazard ratio 0.24, P = 0.028). In conclusion, the preoperative Ins/Cho ratio can be used as a novel potential prognostic factor for GBM, IDH-wild-type.

Association of preoperative seizures with tumor metabolites quantified by magnetic resonance spectroscopy in gliomas.

Seizures are common in patients with gliomas; however, the mechanisms of epileptogenesis in gliomas have not been fully understood. This study hypothesized that analyzing quantified metabolites using magnetic resonance spectroscopy (MRS) might provide novel insights to better understand the epileptogenesis in gliomas, and specific metabolites might be indicators of preoperative seizures in gliomas. We retrospectively investigated patient information (gender, age at diagnosis of tumor, their survival time) and tumor information (location, histology, genetic features, and metabolites according to MRS) in patients with gliomas. The data were correlated with the incidence of seizure and analyzed statistically. Of 146 adult supratentorial gliomas, isocitrate dehydrogenase (IDH) mutant tumors significantly indicated higher incidence of preoperative seizures than IDH wild-type gliomas. However, MRS study indicated that glutamate concentration in IDH wild-type gliomas was higher than that in IDH mutant gliomas. Glutamate was not associated with high frequency of preoperative seizures in patients with gliomas. Instead, increased total N-acetyl-L-aspartate (tNAA) was significantly associated with them. Moreover, multivariable analysis indicated that increased level of tNAA was an independent predictor of preoperative seizures. According to MRS analysis, tNAA, rather than glutamate, might be a useful to detect preoperative seizures in patient with supratentorial gliomas.

Cone-Beam Computed Tomography Fusion Technique for Vascular Assessment of Skull Base Meningiomas.

OBJECTIVE: Cone-beam computed tomography (CBCT) images for skull base tumors provide detailed vascular information and localization in regard to surrounding bony structures. We report use of the CBCT fusion technique for skull base meningiomas. METHODS: Six patients with petroclival or petrotentorial meningiomas supplied by multiple arterial systems were preoperatively evaluated using CBCT fusion imaging. Fusion images were reconstructed from three-dimensional rotational angiography with contrast agent injections from the internal carotid artery (ICA) and external carotid artery in 4 cases, vertebral artery and external carotid artery in 1 case, and ICA and vertebral artery in 1 case. RESULTS: The feeding pedicles and tumor stains from 2 arterial systems were differentiated by separate colors. The courses and territories of the ICA dural feeders or ICA/vertebral artery pial feeders were easily distinguished from the external carotid artery dural feeders. Anastomoses between thin feeders from different arterial systems could be detected. Mixed stain (stain with both colors) was observed in some tumor compartments, suggesting dual supply from 2 arterial systems and the presence of peritumoral anastomoses. All patients underwent preoperative embolization without complications. CONCLUSIONS: CBCT fusion images clearly visualized the feeders from each arterial system, the vascular compartments within the tumor, and possible peritumoral anastomoses. This technique provides a substantial contribution to both preoperative embolization and surgical resection of skull base meningiomas.

Anti-EGFR VHH-armed death receptor ligand-engineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers.

Basal-like breast cancer (BLBC) shows brain metastatic (BM) capability and overexpresses EGFR and death-receptors 4/5 (DR4/5); however, the anatomical location of BM prohibits efficient drug-delivery to these targetable markers. In this study, we developed BLBC-BM mouse models featuring different patterns of BMs and explored the versatility of estem cell (SC)-mediated bi-functional EGFR and DR4/5-targeted treatment in these models. Most BLBC lines demonstrated a high sensitivity to EGFR and DR4/5 bi-targeting therapeutic protein, EVDRL [anti-EGFR VHH (EV) fused to DR ligand (DRL)]. Functional analyses using inhibitors and CRISPR-Cas9 knockouts revealed that the EV domain facilitated in augmenting DR4/5-DRL binding and enhancing DRL-induced apoptosis. EVDRL secreting stem cells alleviated tumor-burden and significantly increased survival in mouse models of residual-tumor after macrometastasis resection, perivascular niche micrometastasis, and leptomeningeal metastasis. This study reports mechanism based simultaneous targeting of EGFR and DR4/5 in BLBC and defines a new treatment paradigm for treatment of BM.