Clipping on Crossed Wrapping Method for Ruptured Blood Blister-Like Aneurysm of the Internal Carotid Artery: Technical Note and Long-Term Results.

BACKGROUND: We have been performing the clipping on crossed wrapping (COCW) method using 2 strips of cotton on patients with an internal carotid artery blood blister-like aneurysm (IC-BLA). This method is reliable in preventing the clips from slipping off and the aneurysm walls from being damaged during clipping, and it enables more appropriate and safer clipping. Here we report the technical details of this method and the long-term outcomes of patients receiving this procedure. METHODS: Fifteen of 1275 (1.5%) patients with a ruptured cerebral aneurysm who received treatment at the Saiseikai Kumamoto Hospital during the period from January 1, 1999, to December 31, 2016, had an IC-BLA. All 15 patients were treated with COCW, except for the first patient, who was treated using a single strip of cotton. The long-term outcome of the treatment was analyzed. RESULTS: The mean follow-up period was 74 months. The first patient experienced rerupture of an aneurysm 10 days after the operation. No complications or regrowth of an aneurysm were observed in the remaining 14 patients during the follow-up period, except for 1 patient who received a reoperation for the regrowth of an aneurysm. As the final outcome, the numbers of patients with a Modified Rankin Score of 0, 3, and 6 were 13, 1, and 1, respectively. CONCLUSIONS: It is suggested that COCW is a treatment that enables safe and long-term management of lesions in IC-BLAs.

Multiple Cerebral Aneurysms Associated With Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of approximately one in every 3000 births. NF1 is mainly recognized as a tumor suppressor. Vasculopathy in NF1 is well described in the literature, but the association between NF1 and cerebral aneurysm has not been determined. We report a case of a 67-year-old female with NF1 accompanied by 8 cerebral aneurysms. Two of the patient's unruptured aneurysms, the large distal anterior cerebral artery (ACA) aneurysm and anterior communicating artery aneurysm, were initially treated with microsurgical clipping. The peripheral ACA aneurysm gradually increased in size and ruptured after 5 years. Coil embolization was performed for the ruptured aneurysm. Four of the 5 remaining unruptured aneurysms were treated surgically. The patient is currently well, without neurological deficit, and coil embolization is scheduled for the last remaining aneurysm. NF1 is a probable risk factor for multiple cerebral aneurysms due to vessel wall vulnerability. Therapeutic indications for patients with NF1 who show multiple cerebral aneurysms include strict follow-up and aggressive treatment to avoid subarachnoid hemorrhage.

Internal carotid artery aneurysms diagnosed after stereotactic radiosurgery for a growth hormone-secreting pituitary adenoma: a case report and literature review.

Radiation therapy is associated with the subsequent development of cerebral aneurysms; however, stereotactic radiosurgery (SRS)-associated aneurysm cases have not been well documented, with only 18 cases reported to date. We present a case of intracranial aneurysms with the rupture occurring 20 years after SRS for a growth hormone-producing pituitary adenoma. This is the first report of aneurysms diagnosed following transsphenoidal surgery and SRS for pituitary adenoma. We believe that the aneurysm reported here is a consequence of the SRS treatment, and thus this may be a very rare long-term complication following radiation treatments.

Modified frailty index predicts postoperative outcomes of spontaneous intracerebral hemorrhage.

OBJECTIVES: Frailty is an indispensable concept among elderly. The purpose of this study was to determine the association between modified frailty index (mFI) and the postoperative outcome of surgery for spontaneous intracerebral hemorrhage (sICH). PATIENTS AND METHODS: Outcome measures included an unfavorable outcome (modified Rankin Scale score of 4-6) or mortality at 6-8 months after hemorrhage. The prognostic ability of mFI was assessed by comparing adjusted and nonadjusted effects with the Hemphill's ICH score. The performance of the ICH score combined with mFI was assessed for discriminative ability. RESULTS: In total, 156 patients satisfied the inclusion criteria. Multivariate analyses revealed that higher mFI was significantly associated with an unfavorable outcome (p-value = 0.004) and mortality (p-value < 0.001). Compared with the ICH score alone, the ICH score combined with mFI revealed significantly higher discriminative ability for predicting postoperative outcome. CONCLUSION: mFI was a useful and reliable predictor of postoperative unfavorable outcome for sICH. Frailty may be an important essence to be considered before operation for sICS in the aging society.

Delayed Development of Aneurysms Following Gamma Knife Surgery for Trigeminal Neuralgia: Report of 2 Cases.

BACKGROUND: Delayed development of intracranial aneurysms is an extremely rare complication of gamma knife surgery (GKS), with only 6 cases been reported to date. There are no reported cases after GKS performed to treat trigeminal neuralgia (TN). Of the 6 aforementioned cases, none referred to the natural history or pathophysiology of GKS-related intracranial aneurysm formation. CASE DESCRIPTION: We treated 2 patients with subarachnoid hemorrhage (SAH) resulting from rupture of an intracranial aneurysm that developed long after GKS. Case 1 involved a 77-year-old man who had undergone GKS to treat recurrent TN after microvascular decompression surgery. At 13 years after the GSK, he developed SAH from a ruptured left anterior inferior cerebellar artery in close vicinity to the left trigeminal nerve. He died from a premature rupture before intervention could be instituted. Case 2 involved a 72-year-old woman who developed SAH at 9 years after undergoing GKS for TN. A ruptured left superior cerebellar artery aneurysm was treated successfully with endovascular occlusion of the parent artery. She recovered well after the surgery, and was discharged to the rehabilitation hospital with a modified Rankin Scale score of 2. CONCLUSION: Long-term observations are necessary after GKS performed for TN owing to the possibility of formation of intracranial aneurysms near the irradiated region.

Characteristics of brain metastases from esophageal carcinoma.

BACKGROUND: Esophageal carcinoma (EC) is a major malignancy with a poor prognosis. Although esophageal cancers rarely metastasize to the brain, the number of patients diagnosed with brain metastases (BM) from EC is steadily increasing. Therefore, the risk factors for BM from EC should be known. Here we reviewed our experiences and the previous literature regarding BM from EC. METHODS: Between 2000 and 2013, we retrospectively reviewed the clinical features and neurological findings of 19 patients diagnosed with and treated for BM from EC to determine the clinical risk factors and features. RESULTS: In all patients, the lesions were partially or completed located in the thoracic esophagus, and the average size of the EC lesion at diagnosis was 5.8 ± 2.9 cm, which was smaller than the previously reported size of EC lesions accompanied by BM. Patients without lung metastases were more common than those with lung metastases. The lesions in the 13 patients included squamous cell carcinoma (SqCC) in 9 (69.2%) and small cell carcinoma (SmCC) in 3 (23.0%). Six patients were not examined. Although there was no trend toward a higher incidence of BM in patients with adenocarcinoma and SqCC, this trend was observed in patients with SmCC. Excluding a single patient with SmCC, all patients had beyond stage III disease at EC diagnosis. CONCLUSIONS: Our study suggests that BM can occur in patients with EC lesions smaller than those previously reported; moreover, SmCC may be a risk factor for BM from EC.

Can sufficient preoperative information of intracranial aneurysms be obtained by using 320-row detector CT angiography alone?

PURPOSE: To determine whether sufficient pre-surgical treatment information of unruptured intracranial aneurysms can be obtained by using 320-row detector CT angiography (CTA) alone. MATERIALS AND METHODS: We enrolled 40 consecutive patients with unruptured intracranial aneurysms. All patients were prospectively conducted to perform 320-detector CTA as the only preoperative modality. Two blinded readers independently assessed CTA images. Interobserver agreement and the agreement between CTA and surgical findings were determined by calculating the κ coefficient. The referring neurosurgeons judged the usefulness of the information provided by CTA for treatment decisions. RESULTS: All patients had surgery without intraarterial digital subtraction angiography. Agreement between CTA and surgical findings was excellent for the aneurysm location (κ = 1.0) and good for the shape (κ = 0.71), neck (κ = 0.74) and its relationship with adjacent branches (κ = 0.71). Information obtained with 320-detector CTA was highly useful for surgical treatment in 37 of 40 (93 %) patients, although small perforators deriving from the aneurysm in 2 cases were not fully visualized on CTA images. CONCLUSION: In most patients with unruptured intracranial aneurysms, sufficient pre-surgical treatment information can be obtained by using 320-detector CTA alone.

Strategy for treating unruptured vertebral artery dissecting aneurysms.

BACKGROUND: The natural course of unruptured vertebral artery dissecting aneurysms (VADAs) remains unclear. OBJECTIVE: The purpose of this retrospective study was to develop a strategy for treating unruptured VADAs based on long-term follow-up. METHODS: Our study population consisted of 100 patients with unruptured VADAs; in 66, the initial symptom was headache only, 30 presented with ischemic symptoms and 4 with mass effect. All underwent magnetic resonance imaging and magnetic resonance angiography at the time of admission and 2 weeks and 1, 3, 6, 12, and 24 months after the onset. If the dissection site was demonstrated to be enlarged on magnetic resonance imaging and magnetic resonance angiography without the manifestation of new symptoms, the patients received additional treatment to prevent bleeding. RESULTS: Of the 100 patients, 4 underwent early intervention because of symptom exacerbation. The other 96 were initially treated conservatively; during follow-up, 5 manifested lesion enlargement on magnetic resonance angiography. Nine patients received additional treatment; 1 underwent direct surgery with trapping of the dissection site, and 8 underwent coil embolization. The other 91 patients continued to be treated conservatively; the dissection site remained unchanged in 70, improved or healed in 18, and disappeared in 3 patients. We treated 38 patients with recurrent ischemic attacks with antiplatelet therapy. No patients experienced bleeding or permanent neurological deficits during follow-up. CONCLUSION: The nature of an unruptured VADA is not highly aggressive. However, if the dissection site enlarges without the manifestation of new symptoms, it should be occluded. In patients with recurrent ischemic attacks antiplatelet therapy should be considered.

Postoperative quality of life of patients treated for asymptomatic unruptured intracranial aneurysms.

OBJECT: The aim of this study was to assess the quality of life (QOL) of patients who underwent surgery for asymptomatic unruptured intracranial aneurysms (UIAs). METHODS: The authors assessed QOL in 149 patients who had undergone microsurgical clipping of asymptomatic UIAs. They surveyed these patients using universal methods such as the 36-Item Short Form Health Survey (SF-36) for health-related QOL and the Hospital Anxiety and Depression Scale for anxiety and depression assessments. RESULTS: The patients' mean scores for each of the eight domains of SF-36 were comparable to those of a Japanese reference population. Analysis of data from the average-QOL and low-QOL subgroups showed that the low-QOL group contained a higher number of patients with preexisting heart diseases and restricted activities of daily living. Operative procedures and complications did not affect QOL. CONCLUSIONS: Because 86% of the patients who underwent surgery manifested a QOL similar to the reference population, the authors suggest that elective surgery for asymptomatic UIAs is a reasonable treatment, especially in patients who are troubled by the risk of rupture. Postoperative decreases in QOL are not invariably attributable to the operation or its associated complications, but may be correlated with other chronic disorders. To select the appropriate treatment for asymptomatic UIAs, neurosurgeons and patients need information on the expected postoperative QOL.

[Self-assesed quality of life in patients who underwent surgery for asymptomatic meningiomas].

The aim of our study was to assess the quality of life (QOL) of patients operated on for asymptomatic meningioma and to assess the correlation between QOL and operative complications. Of 21 surgically treated patients, 6 (28.6%) presented with persistent neurological impairments or events considered to be treatment-related. Seventeen patients participated in the QOL survey using MOS Short-Form 36-Item Health Survey (SF-36) for health-related QOL issues and the Hospital Anxiety and Depression Scale (HADS) for anxiety nd depression assessment. The mean scores for each of the 8 domains of SF-36 were comparable with these of a Japanese reference population. When we divided the patients into 2 groups according to the degree of headache, activity of daily living, or complications, the QOL of patients with persistent headache declined in the SF-36 domains related to physical function and vitality. Minor neurological impairments developed by 4 patients did not affect their QOL. In conclusion, surgery for asymptomatic meningioma has no negative impact on postoperative QOL if the surgical complications are minor. On the other hand, physical activities in some patients were hampered due to persistent headache. Besides the treatment-related morbidity and mortality rates, QOL issues should also be included in treatment indications for asymptomatic meningioma.

Single nucleotide polymorphism 309 affects murin-double-minute 2 protein expression but not glioma tumorigenesis.

Murin-double-minute 2 (MDM2) is an important negative regulator of the p53 tumor suppressor, and affects the p53 protein level and transcriptional activity. The genotype of the single nucleotide polymorphism in the promoter region of MDM2 (single nucleotide polymorphism [SNP] 309) is associated with the MDM2 protein expression level and the onset age of several types of cancer. The SNP309 genotype was investigated in 254 Japanese patients with glioma and 50 healthy subjects. The genotype frequency of SNP309 was T/T homozygous in 62 patients (24%), T/G heterozygous in 126 (50%), and G/G homozygous in 66 (26%) of the glioma patients, and was similar in the healthy subjects. The G/G ratio was higher in our Japanese subjects than in Western populations. Immunohistochemical study of glioma tissues showed that the G/G genotype was associated with higher expression of MDM2 protein compared to the T/T genotype, suggesting that SNP309 attenuates MDM2 protein expression in vivo. However, no association was found between the SNP309 genotype and the histological grade of glioma, age at disease onset, or p53 gene mutation rate. In our study population, SNP309 affected MDM2 protein level, but had no significant involvement in glioma tumorigenesis.

Improvement of quality of life in patients surgically treated for asymptomatic unruptured intracranial aneurysms.

OBJECTIVE: To compare the preoperative and postoperative health-related quality of life (QOL) and psychological state of patients with asymptomatic unruptured intracranial aneurysms (ICAs) who underwent elective surgery. METHODS: Out of 67 patients who underwent neck clipping of ICAs, we assessed the QOL of 61 patients using Short Form-36 (SF-36); their psychological state was rated on the Hospital Anxiety and Depression Scale (HADS) before, 3 months, and 1 and 3 years after treatment. RESULTS: The preoperative mean scores for each of the eight SF-36 domains except bodily pain were significantly lower in the study population than in the reference population. 14 (20.9%) patients experienced surgical complications defined as neurological deterioration and/or abnormal CT findings within 30 days of the operation. Despite some complications, the QOL of all operated patients returned to the mean level of the reference population 3 years after treatment. At 3 months after surgery, the scores for psychosocial activities and general health perception were transiently below the preoperative levels. According to the HADS, the patients experienced mild anxiety before the operation; it disappeared by the third postoperative month. CONCLUSIONS: Preoperatively, patients with unruptured ICAs reported a significantly decreased QOL. It further declined transiently after elective surgery, but it returned to the mean level recorded for the reference population within 3 years. Our findings suggest that these patients derived significant QOL benefits from their surgery. Hence subjective QOL issues should be considered in deciding whether treatment-related risks and their natural history, such as their potential rupture, warrant surgery of asymptomatic unruptured ICAs.

Cavernous malformation of the optic chiasm: case report.

We report a 14-year-old boy with cavernous malformation of the optic chiasm. He had a 2-year history of gradually worsening visual disturbance. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a suprasellar mass, findings compatible with craniopharyngioma. The mass was biopsied and histological examination confirmed cavernous malformation. On the second day after the biopsy, he suffered chiasmal apoplexy due to intratumoural haemorrhage, lost visual acuity and developed a field cut. Cavernous malformations arising from the optic nerve and chiasm are extremely rare; only 29 cases have been reported to date. Most patients manifested acute visual acuity and visual field disturbances. Although MRI findings of cavernous malformations in the brain parenchyma have been reported, MRI findings on the optic nerve and chiasm may not be completely diagnostic. Of the 29 documented patients, 16 underwent total resection of the lesion without exacerbation of their preoperative symptoms; in some cases, resection was complicated by risk of damage to the surrounding neural tissue. As patients may suffer intratumoural haemorrhage after biopsy or partial removal of the lesion, the advisability of surgical treatment of cavernous malformations of the optic nerve and chiasm must be considered carefully.

Combination electro-gene therapy using herpes virus thymidine kinase and interleukin-12 expression plasmids is highly efficient against murine carcinomas in vivo.

We report the use of plasmid DNA-mediated combination gene therapy for tumor-bearing mice using in vivo electroporation, also called electro-gene therapy (EGT), that resulted in uncomplicated and complete cures in more than 90% of the mice. Subcutaneously inoculated CT26 tumors in syngeneic BALB/c mice were subjected to repeated EGT treatments consisting of intratumoral co-injection of naked plasmids encoding the cytokine interleukin-12 (IL-12) (p35 and p40 subunits) and the suicide gene herpes simplex virus thymidine kinase (HSV-tk), followed by in vivo electroporation. The early anti-tumor effect was always stronger, and the rate of cure, as seen in the long-term follow-up, was always greater in the groups treated with combination EGT than in those treated with IL-12 or HSV-tk EGT alone. Systemic levels of IL-12 and IFN-gamma increased in both combination and IL-12-alone EGT-treated groups. Moreover, combination EGT for established subcutaneous tumors strongly reduced hematogenous lung metastases and increased survival time when live CT26 tumor cells were injected through the tail vein. Limited experiments on C57/B16 mice with murine melanoma also showed very similar trends. These results suggest that this simple and safe method of plasmid-mediated combination EGT may provide a potentially effective gene therapy for cancer.

Combination of IL-12 and IL-18 of electro-gene therapy synergistically inhibits tumor growth.

BACKGROUND: We previously showed that IL-12 electro-gene therapy (EGT) induces significant antitumor immunity. However, because interleukin (IL)-18 acts synergistically with IL-12 to augment Th1 responses and interferon (IFN)-gamma, we designed an EGT protocol using IL-12 + IL-18 with the aim of enhancing the antitumor effects obtained with IL-12 alone. MATERIALS AND METHODS: Expression plasmids harboring the gene for IL-12 or IL-18 were cotransferred to subcutaneous murine CT26 tumors. Subsequent expression of IFN-gamma and the presence of CD8+ T cells within treated tumors were analyzed by semiquantitative RT-PCR. RESULTS: IL-12 + IL-18 EGT inhibited tumor growth significantly better than IL-12 EGT, which was consistent with significantly higher intratumoral levels of IFN-gamma. Enhanced infiltration of tumor tissues by CD8+ T cells was confirmed with both IL-12 and IL-12 + IL-18 EGT. Finally, IL-12 + IL-18 EGT, but not IL-12 EGT, significantly suppressed untreated contralateral tumors. CONCLUSION: EGT with IL-12 and IL-18 is potentially an effective antitumor gene therapy.

Usefulness of multiple-site venous sampling in the treatment of adrenocorticotropic hormone-producing pituitary adenomas.

BACKGROUND: While venous sampling for adrenocorticotropic hormone (ACTH) may be the most accurate way to establish a diagnosis of Cushing's disease, its usefulness for lateralization of adenomas is limited even in combination with simultaneous bilateral sampling methods. Therefore, to increase accuracy in predicting the lateralization of adenomas, we performed a trial in which we carried out simultaneous venous sampling from multiple sites of the cavernous sinus (CS) and inferior petrosal sinus (IPS). Here we report on the usefulness of our method in the correct tumor lateralization in patients with Cushing's disease. METHODS: Eighteen patients with Cushing's disease underwent simultaneous bilateral ACTH sampling. The samples were obtained from the anterior, middle, and posterior CS and the IPS. CS sampling after stimulation with corticotropin-releasing hormone (CRH) was also performed. The central-to-peripheral ACTH ratio (c/p ratio) was calculated using sampling data from each site; the lateralizing gradients (right versus left) were calculated using the c/p ratio. Instead of the conventional method where the lateralization gradient is based on sampling data from a single site, we used the distribution of the c/p ratio determined from multiple-site data. RESULTS: There was no significant difference in the mean lateralization gradient obtained from each set of sampling data (p > 0.05). With the conventional method, correct tumor lateralization was obtained in 50% of tumors in the IPS; 72.2 to 77.8% of tumors in the CS; and 77.8% of tumors in the middle CS after CRH. Our method using ACTH contour analysis based on multiple sites produced correct results in all 18 of the patients examined. The difference in correct calls between the conventional method and our method was significant (p < 0.05). CONCLUSIONS: Multiple-site sampling of ACTH is valuable for lateralizing the adenoma in patients with Cushing's disease; it produces more correct results than does single venous sampling.

Neurofibromatosis type I tumor suppressor neurofibromin regulates neuronal differentiation via its GTPase-activating protein function toward Ras.

Neurofibromin, the neurofibromatosis type 1 (NF1) gene product, contains a central domain homologous to a family of proteins known as Ras-GTPase-activating proteins (Ras-GAPs), which function as negative regulators of Ras. The loss of neurofibromin function has been thought to be implicated in the abnormal regulation of Ras in NF1-related pathogenesis. In this study, we found a novel role of neurofibromin in neuronal differentiation in conjunction with the regulation of Ras activity via its GAP-related domain (GRD) in neuronal cells. In PC12 cells, time-dependent increases in the GAP activity of cellular neurofibromin (NF1-GAP) were detected after NGF stimulation, which were correlated with the down-regulation of Ras activity during neurite elongation. Interestingly, the NF1-GAP increase was due to the induction of alternative splicing of NF1-GRD type I triggered by the NGF-induced Ras activation. Dominant-negative (DN) forms of NF1-GRD type I significantly inhibited the neurite extension of PC12 cells via regulation of the Ras state. NF1-GRD-DN also reduced axonal and dendritic branching/extension of rat embryonic hippocampal neurons. These results demonstrate that the mutual regulation of Ras and NF1-GAP is essential for normal neuronal differentiation and that abnormal regulation in neuronal cells may be implicated in NF1-related learning and memory disturbance.

Prognostic factors in patients who survived more than 10 years after undergoing surgery for metastatic brain tumors: report of 5 cases and review of the literature.

BACKGROUND: Although the overall prognosis of patients with metastatic brain tumors is dismal, a small number survive longer than 10 years after craniotomy. We report 5 patients who survived for more than 10 years after undergoing treatment for metastatic brain tumor. METHODS: The 5 patients who survived for more than 10 years after undergoing craniotomy were among 56 consecutively treated patients with solitary metastatic brain tumors. We retrospectively examined their clinical course, treatment, and variables associated with their longer survival and compared these 5 patients with other reported cases of metastatic brain tumor. RESULTS: The histologic tumor types and the sites of origin of the primary tumor varied: two were from lung cancer and one each was from colon cancer, renal cell, and cervical carcinoma of the uterus. Common features among the long-term survivors were: systemic disease was absent, the metastatic tumor was located in the non-eloquent area of the non-dominant hemisphere, they were in good neurologic condition before surgery, there was a long interval between the diagnosis and treatment of the primary lesion and the diagnosis of the brain metastasis, and the patients received postoperative irradiation/chemotherapy. CONCLUSION: Aggressive surgical treatment may be justified in young patients with a solitary metastatic brain tumor, as long as they are free of active systemic metastases.

Expression of Hqk encoding a KH RNA binding protein is altered in human glioma.

The quaking gene family encodes single KH domain RNA-binding proteins that play vital roles in cell differentiation, proliferation, and apoptotic processes. The human quaking gene, Hqk, maps to 6q25-q26, where cytogenetic alterations associated with a variety of human malignancies, including gliomas have been reported. To assess possible relationships of Hqk with human diseases such as glial tumors, we first isolated the Hqk gene, characterized its structure and expression pattern, and carried out mutational analysis of Hqk in primary tumor samples. The Hqk gene contains 8 exons spanning a approximately 200 kb genomic region, and generating at least four alternatively spliced transcripts, Hqk-5, Hqk-6, Hqk-7 and Hqk-7B, of which Hqk-7 is abundantly expressed in brain. Analysis of primary tumors demonstrated a high incidence of expression alterations of Hqk in gliomas (30%; 6/20), but not in other tumors such as schwannomas (0/3), or meningiomas (0/8). Among the tumor samples showing expression alterations, two were devoid of all three major transcripts, one was missing only the Hqk-5 message, and only the Hqk-7 message was absent in two cases. Our results thus imply the involvement of Hqk in human glial tumor progression.