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.

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.

Neuroprotective Effects of Genome-Edited Human iPS Cell-Derived Neural Stem/Progenitor Cells on Traumatic Brain Injury.

Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI). Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (yCD-UPRT). NS/PCs derived from human iPSCs displayed stable and high transgene expression of yCD-UPRT following CRISPR/Cas9-mediated genome editing. In vivo bioluminescent imaging and histopathological analysis demonstrated that NS/PCs concentrated around the damaged cortex of the TBI mouse model. During the subacute phase, performances in both beam walking test and accelerating rotarod test were significantly improved in the treatment group transplanted with genome-edited iPSC-derived NS/PCs compared with the control group. The injury area visualized by extravasation of Evans blue was smaller in the treatment group compared with the control group, suggesting the prevention of secondary brain injury. During the chronic phase, cerebral atrophy and ventricle enlargement were significantly less evident in the treatment group. Furthermore, after 5-fluorocytosine (5-FC) administration, 5-fluorouracil converted from 5-FC selectively eliminated undifferentiated NS/PCs while preserving the adjacent neuronal structures. NS/PCs expressing yCD-UPRT can be applied for safe regenerative medicine without the concern for tumorigenesis.

Targeted embolisation for coexisting conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas with a varix on a shared drainer†.

BACKGROUND: The coexistence of vascular malformations in the conus medullaris and cauda equina has been rarely reported, and the complex angioarchitecture in multiple arteriovenous lesions remains poorly understood. CASE DESCRIPTION: A 17-year-old woman presented with a sudden-onset, stepwise worsening of weakness and pain in the bilateral legs. Angiography revealed conus medullaris arteriovenous malformation and cauda equina arteriovenous fistulas. One of the drainers was shared between the coexisting lesions and harboured a varix. Targeted embolisation of a fistulous point in the conus lesion was performed with precaution to prevent occluding the common drainage route, which led to symptom improvement with angiographical diminishment of the varix. CONCLUSIONS: Recognising that communications between drainers can be observed in multiple spinal arteriovenous lesions is important in facilitating a safe embolisation. Cautious assessment of angiogram with fusion images of cone-beam computed tomography and volumetric T2 magnetic resonance imaging can help in establishing the diagnosis and treatment strategy.

A case of refractory chronic subdural hematoma and internal carotid artery stenosis sequentially treated with surgical drainage, middle meningeal artery embolization, and carotid artery stenting.

Background: Both chronic subdural hematoma (CSDH) and ischemic cerebrovascular disease are commonplace in the clinical context, and their combination is sometimes experienced. We describe a unique and challenging case in which both therapeutic interventions were indispensable and performed in a sequential manner. This report aims to discuss the management of hemorrhagic and ischemic conditions where CSDH and carotid artery stenosis coexist. Case Description: An 83-year-old male presented with the left cerebral infarction due to the left internal carotid artery (ICA) stenosis. The coexisting left CSDH was surgically drained first. Then, the left middle meningeal artery (MMA) was endovascularly embolized to prevent hematoma recurrence under antiplatelet therapy, before the left carotid artery stenting (CAS) was successfully conducted. The subdural hematoma gradually grew but remained asymptomatic. However, he later presented with another stroke due to the progressive right ICA stenosis that had been conservatively treated initially. Emergency right CAS was required eventually. Conclusion: Under the circumstances where CSDH is present but antiplatelet therapy is inevitable, MMA embolization could be a reasonable treatment option to avoid additional surgical procedures. Furthermore, early intervention should be considered even for asymptomatic carotid stenosis in terms of shortening the administration period of antiplatelet agents.

A Case of Bilateral Cerebellar Chronic Encapsulated Intracerebral Hematoma with Rapidly Progressive Symptoms.

Chronic encapsulated intracerebral hematoma (CEIH) is a rare cerebrovascular disease featuring progressively expanding intracranial hematoma. We treated a man in his 70s with bilateral cerebellar CEIH. He had presented at another hospital with dizziness, and imaging showed two independent hemorrhagic space-occupying lesions in the bilateral cerebellar hemispheres. The symptoms progressed relatively rapidly, and there were signs of impending cerebellar herniation; he was transferred to our institution, and emergency surgery was performed. The operative findings included a hematoma with partial capsulation. We diagnosed CEIH from preoperative magnetic resonance imaging and computed tomography findings, clinical course, and pathological findings. The postoperative course was satisfactory. We present this case of bilateral cerebellar CEIH, as an extensive search of the literature suggests that this has not been reported before. Although CEIH is a condition that is usually hard to diagnose preoperatively, good outcomes can be achieved with appropriate surgical treatment. It is therefore important to keep this clinical entity in mind and not miss the right timing to operate.

[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.

Imaging of the venous plexus of Rektorzik using CT-digital subtraction venography: a retrospective study.

PURPOSE: The venous plexus of Rektorzik (VPR), first described by Rektorzik in 1858, is a venous plexus around the internal carotid artery in the carotid canal. However, the VPR has never been investigated using the recently developed imaging modalities. In this study, we analyzed the VPR using computed tomography-digital subtraction venography (CT-DSV). METHODS: This study included 253 patients who had undergone head CT-DSV. The presence or absence of the right and left VPRs and their connecting veins were visually examined by two researchers. RESULTS: The VPR was observed in 60 patients (24%), 39 of which showed VPR only on the right side, 10 only on the left side, and 11 on both sides. VPR was significantly more common on the right side (p = 0.0002) and was observed more frequently around the horizontal segment of the internal carotid artery than around the vertical segment. The most common veins identified as distal and proximal VPR connections were the cavernous sinus (63/71, 89%) and the anterior condylar confluence (27/71, 38%), respectively. The mean age was significantly lower in patients with the VPR than in those without (53 vs. 57 years, p = 0.02). CONCLUSION: The VPR was significantly more frequent on the right side and in younger patients but was not a radiographically constant structure. In most cases, the VPR connected the cavernous sinus and anterior condylar confluence. Preoperative evaluation of VPR may lead to refined surgical procedures.

A case of central nervous system lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates: a case report and literature review.

Lymphomatoid granulomatosis (LYG) is a rare lymphoproliferative disease with angiocentric and angiodestructive infiltrates, and by definition, Epstein-Barr virus (EBV)-associated B-cell malignancy. It most frequently involves the lung, and in some cases, the lesions are confined to the central nervous system (isolated CNS-LYG). However, it remains a controversial disease in terms of pathophysiology, especially in those confined to the CNS. We report the case of a 37-year-old man with CNS lesion pathologically characterized by angiocentric, T-cell-rich lymphoid cell infiltrates that resembled CNS-LYG. The lesion was clinically aggressive with subacute onset and irregular ring-like enhancement on MRI. The resected specimen showed no cytological atypia, EBV-infected cells, or monoclonality for IgH and TCR gene rearrangements. Considering the possibility of latent malignancy, the patient was successfully treated with corticosteroid and chemoradiotherapy with high-dose methotrexate. The present case and the literature suggest that EBV-negative CNS lesions with angiocentric lymphoid infiltrates are probably heterogeneous in their pathogenesis, including those that could fit into the so-called CNS-LYG and those with T-cell predominance. The accumulation of similar cases is warranted for the classification and appropriate treatment of these lesions.

Cerebrospinal fluid leakage due to nasoseptal flap partial necrosis: A pitfall for skull base reconstruction of endoscopic endonasal surgery.

BACKGROUND: Vascularized nasoseptal flaps allow for the reconstruction of large dural defects and have remarkably reduced the incidence of postoperative complications during endoscopic endonasal skull base surgery. Nevertheless, some complications related to nasoseptal flap have been reported. Flap necrosis is a rare, but serious issue is associated with meningitis and cerebrospinal fluid (CSF) leak. CASE DESCRIPTION: We performed endoscopic endonasal removal of the tuberculum sella meningioma in a 39-year-old woman with a history of Turner syndrome using abdominal fat, fascia, and a vascularized nasoseptal flap for dural and skull base defect reconstruction. After surgery, she developed CSF leak, and reoperation revealed partial necrosis of the septal flap that caused leakage. At this time, with a concern that removal of the necrotic part may lead to the insufficient size of the flap, we filled the gap tightly with fat pieces. However, the CSF leak recurred, and thus, we performed debridement of the necrotic region and reformed the multilayered reconstruction, following which she no longer experienced CSF leakage. CONCLUSION: Our case suggested that partial rather than total flap necrosis could occur, possibly due to variances of vascular anatomy, leading to focal ischemia. Debridement of the necrotic region may be an important solution for recurrent cerebrospinal leakage secondary to partial necrosis of a nasoseptal flap.