Archie Defillo and Eric S. Nussbaum
Eiichi Nakai, Mitsuhiro Takemura, Motonobu Nonaka, Yu Kawanishi, Noritaka Masahira and Tetsuya Ueba
The diagnosis of CSF hypovolemia remains controversial. The primary diagnostic factor relies on confirmation of leakage of the CSF based on reduced spinal fluid pressure. Determining the specific leakage site is the most important issue for effective treatment but remains a difficult task. Although CT myelography, radioisotope cisternography, and MRI are commonly performed in the diagnosis of CSF hypovolemia, these techniques can rarely identify the precise leakage site. Therefore, an epidural blood patch is performed in the lumbar spine in many cases.
This study reports a new diagnostic modality that can help to confirm the leakage site. Fat-suppressed T2-weighted sagittal images were compared before and after the infusion of 20 ml of saline into the subarachnoid space of the lumbar region to detect the specific leakage site with high probability. Three patients were successfully treated by the epidural blood patch based on data obtained with the new diagnostic modality. Two patients were treated in the cervical region and 1 in the lumbar region. The use of fat-suppressed T2-weighted sagittal images after saline infusion could be a relevant diagnostic modality compared with images obtained by CT myelography, radioisotope cisternography, and ordinary MRI to achieve accurate diagnosis and effective treatment of patients with CSF hypovolemia.
Tetsuya Ueba, Hiroshi Abe, Juntaro Matsumoto, Toshio Higashi and Tooru Inoue
A 19-month-old child was gradually suffering from gait disturbance and was referred by his pediatrician to the authors' institution. Spinal MRI showed Gd-enhanced spinal cord tumor and congestive myelopathy. Intraoperatively the lesion was seen to be a hemangioblastoma. Because discrimination of the arterialized draining veins from the feeding arteries was difficult, indocyanine green videography was conducted to differentiate them. Real-time evaluation by FLOW 800 revealed that the slope of the average signal intensity in the feeding artery was steeper than that of the arterialized veins. The tumor was successfully resected, and postoperative indocyanine green videography showed total removal of the tumor as a signal-negative region; the circulation time between the feeding artery and the main draining vein was prolonged from 2.5 to 5.5 seconds. Indocyanine green videography and real-time evaluation by FLOW 800 were objective and effective for the excision of a tumor retaining the arteriovenous shunt. The patient recovered from congestive myelopathy and gait disturbance.
Tetsuya Ueba, Masakazu Okawa, Hiroshi Abe, Masani Nonaka, Mitsutoshi Iwaasa, Toshio Higashi, Tooru Inoue and Koichi Takano
Indocyanine green (ICG) videography is commonly used in the neurosurgical field for minimally invasive neurosurgery. The aim of this study was to evaluate a new intraoperative imaging modality by performing transdural ICG videography during surgery for meningiomas.
Between March 2011 and April 2012, 10 patients with meningiomas received intravenous injection of 12.5 mg ICG just prior to dural opening. The cases comprised 8 convexity meningiomas and 2 foramen magnum meningiomas. Efficacy of the transdural ICG videography was assessed in terms of the tumor volume, the circulation time from the first appearance of the vessel to the appearance of the venous sinus, the tendency to bleed, and the discrimination of the venous sinus.
The mean tumor volume was 71.6 ± 87.9 ml (the mean is expressed ± SD throughout). The cortical arteries, veins, and the venous sinus were identified by the ICG videography transdurally. The projection of the meningiomas was identified by a shadow (which the authors call the eclipse sign). Total eclipse signs were obtained in 8 cases and partial eclipse signs were obtained in 2 cases; tumor volume in the latter was more than 200 ml. In 5 of 10 cases the adjacent venous sinuses were exposed and were successfully visualized by ICG videography in 5.92 ± 1.05 seconds from the first appearance of the vessel. In 5 of 10 cases the total and the partial eclipse signs were diminished in 3.46 ± 1.31 seconds. The diminishment of the total and the partial eclipse sign was earlier than the visualization of the venous sinus (p = 0.011, t-test), revealing bleeding from the tumor that was observed until coagulation of the feeding arteries from the intracranial arteries.
Prior to opening of the dura mater, transdural ICG videography was used successfully to visualize the dural attachment of meningiomas and the venous sinus, resulting in safe and appropriate dural opening. The diminishment of the total and partial eclipse signs may represent significant feeding from the intracranial arteries and a tendency to bleed during resection.
Nozomu Murai, Tetsuya Ueba, Jun A. Takahashi, Hong-Qiong Yang, Haruhiko Kikuchi, Hiroshi Hiai, Masakazu Hatanaka and Manabu Fukumoto
✓ Basic fibroblast growth factor (bFGF) is mitogenic to neuroectoderm- and mesoderm-derived cells and is a potent angiogenic factor. Abundant amounts of this factor and its receptor are detected in human glioma tissues and cells, and bFGF in glioma is thought to be involved in autonomous cell growth as an autocrine growth factor. A neutralizing mouse monoclonal antibody (MAb) against bFGF, 3H3 MAb, has been shown to inhibit both in vitro and in vivo growth of human glioma cell lines. This study shows that the human glioma cell lines U-87MG and U-251MG, which express high levels of bFGF and its receptor, can be induced to undergo apoptosis when cultured with 3H3 MAb. It is also demonstrated that 3H3 MAb can cause apoptosis in the same glioma cells that were transplanted into nude mice. Furthermore, enforced overexpression of bcl-2 protein by gene transfection prevented 3H3 MAb-induced apoptosis of glioma cells. It is concluded that induction of apoptosis by the neutralizing antibody is a promising therapeutic strategy for glioma.
Hitoshi Fukuda, Hitoshi Ninomiya, Yusuke Ueba, Tsuyoshi Ohta, Toshiaki Kaneko, Tomohito Kadota, Fumihiro Hamada, Naoki Fukui, Motonobu Nonaka, Yuya Watari, Shota Nishimoto, Maki Fukuda, Satoru Hayashi, Tomohiko Izumidani, Hiroyuki Nishimura, Akihito Moriki, Benjamin Lo and Tetsuya Ueba
Several environmental factors have been reported to correlate with incidence of spontaneous subarachnoid hemorrhage (SAH). However, because of different patient selection and study designs among these studies, meteorological factors that trigger the incidence of SAH in a short hazard period remain unknown. Among meteorological factors, daily temperature changes may disrupt and violate homeostasis and predispose to cerebrovascular circulatory disturbances and strokes. The authors aimed to investigate whether a decline in the temperature from the highest of the previous day to the lowest of the event day (temperature decline from the previous day [TDP]) triggers SAH in the prefecture-wide stroke database.
All 28 participating institutions with primary or comprehensive stroke centers located throughout Kochi Prefecture, Japan, were included in the study. Data collected between January 2012 and December 2016 were analyzed, and 715 consecutive SAH patients with a defined date of onset were enrolled. Meteorological data in this period were obtained from the Kochi Local Meteorological Observatory. A case-crossover study was performed to investigate association of TDP and other environmental factors with onset of SAH.
The increasing TDP in 1°C on the day of the SAH event was associated with an increased incidence of SAH (OR 1.041, 95% CI 1.007–1.077) after adjustment for other environmental factors. According to the stratified analysis, a significant association between TDP and SAH was observed in women, patients < 65 years old, and patients with weekday onset. Among these factors, increasing TDP had a great impact on SAH onset in patients < 65 years old (p = 0.028, Mann-Whitney U-test).
TDP, temperature decline from the highest of the previous day to the lowest of the day, was correlated with the incidence of spontaneous SAH, particularly in younger patients < 65 years old.
Naoki Fukui, Toshio Yawata, Takahito Nakajo, Yu Kawanishi, Youichirou Higashi, Tatsuyuki Yamashita, Takaaki Aratake, Koichi Honke and Tetsuya Ueba
Glioma stem cells (GSCs) are responsible for tumor initiation, therapeutic resistance, and recurrence. CD146 is mainly expressed in dividing GSCs and regulates cell cycle progression. However, the evaluation of the efficacy of targeted therapy against CD146 in vivo remains to be investigated. In this study, the authors aimed to develop gene therapy targeting GSCs using chitosan oligosaccharide lactate (COL) nanoparticles (NPs) conjugated with folic acid–polyethylene glycol (FA-PEG-COL NPs) for in vitro and in vivo delivery of CD146 small-interfering RNA (siCD146) and to determine the effect of CD146 knockdown on tumor growth.
To examine the uptake of NPs by tumor cells, immunofluorescence staining, flow cytometry, and in vivo imaging were performed. The knockdown effect of siCD146 was measured by western blot and water-soluble tetrazolium salt–8 assay in mouse glioma cells. The efficacy of siRNA therapy–targeted GSCs was evaluated by monitoring tumor growth through in vivo imaging and histological analysis.
In vivo accumulation of the FA-PEG-COL NPs in subcutaneous and intracranial gliomas following NP administration via a mouse tail vein was observed. Additionally, in vitro delivery of siCD146 ionically cross-linked NPs, reduced CD146 levels, and suppressed growth in the glioma tumor sphere. Evaluation of the in vivo therapeutic effects of siCD146–cross-linked NPs in a mouse glioma model revealed significant suppression of intracranial tumor growth, with complete removal of the tumor observed in some mice on histological examination. Furthermore, delivery of siCD146 significantly reduced the Ki-67 index in residual tumor tissues relative to that in control mice.
CD146 is a potential therapeutic target, and folic acid–conjugated NPs delivering siRNA may facilitate gene therapy in malignant gliomas.
Tomokazu Aoki, Jun A. Takahashi, Tetsuya Ueba, Natsuo Oya, Masahiro Hiraoka, Kunihiko Matsui, Tsugiya Fukui, Yasuaki Nakashima, Masatsune Ishikawa and Nobuo Hashimoto
This Phase II study was performed to determine the safety, tolerability, and efficacy of combining nimustine (ACNU)–carboplatin-vincristine-Interferon-β (IFNβ) chemotherapy.
Ninety-seven patients with Karnofsky Performance Scale scores of 50 or greater were enrolled in the study. Nimustine (60 mg/m), carboplatin (110 mg/m), vincristine (0.6 mg/m), and IFNβ (10 μg) were administered on Day 1 concomitant with radiotherapy (63 Gy); vincristine (0.6 mg/m) and IFNβ (10 μg) on Days 8 and 15; and IFNβ alone (10 μg) three times per week throughout the course of radiotherapy. Fifty-six days after radiotherapy ended, the time schedule for chemotherapy was reset and ACNU, carboplatin, vincristine, and IFNβ were again administered on the new Day 1 and vincristine and IFNβ on the new Days 8 and 15. This course was repeated every 56 days. Instances of nonhematological toxicity were rare and mild. During the course of radiotherapy, the percentages of patients who experienced Grade 3 toxicity were 14% with neurocytopenia and 7% with thrombocytopenia. Seven percent of all adjuvant chemotherapy cycles following radiotherapy were associated with Grade 3 toxicity, as manifested in neurocytopenia or thrombocytopenia. No instance of Grade 4 toxicity was observed. The median duration of progression-free survival was 10 months (95% confidence interval [CI] 8–12 months) and the median duration of overall survival was 16 months (95% CI 13–20 months).
The combination of ACNU-carboplatin-vincristine-IFNβ chemotherapy and radiotherapy is safe and well tolerated, and may prolong survival in patients with glioblastoma multiforme.
Tomokazu Aoki, Tomohiko Mizutani, Kuniharu Nojima, Takehisa Takagi, Ryosuke Okumura, Yoshiaki Yuba, Tetsuya Ueba, Jun A. Takahashi, Shin-Ichi Miyatake, Kazuhiko Nozaki, Waro Taki and Masao Matsutani
The prognosis of recurrent glioblastoma multiforme (GBM) remains unsatisfactory. The authors conducted a Phase II study of ifosfamide, carboplatin, and etoposide (ICE) for a first recurrence of GBM to determine whether it prolonged a patient's good-quality life.
This trial was an open-label, single-center Phase II study. Forty-two patients with a first GBM relapse after surgery followed by standard radiotherapy (60 Gy) and first-line temozolomide- or nimustine-based chemotherapy were eligible to participate. The primary end point was progression-free survival at 6 months after the ICE treatment (PFS-6), and secondary end points were response rate, toxicity, and overall survival. Chemotherapy consisted of ifosfamide (1000 mg/m2 on Days 1, 2, and 3), carboplatin (110 mg/m2 on Day 1), etoposide (100 mg/m2 on Days 1, 2, and 3), every 6 weeks.
Progression-free survival at 6 months after ICE treatment was 35% (95% CI 22–50%). The median duration of PFS was 17 weeks (95% CI 10–24 weeks). The response rate was 25% (95% CI 9–34%). Adverse events were generally mild and consisted mainly of alopecia.
This regimen was well tolerated and has some activity and could be one of the options for patients with recurrent GBM.