Takashi Watanabe, Toshiyuki Ohtani, Masanori Aihara and Shogo Ishiuchi
Blockade of Ca++-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) inhibits the proliferation of human glioblastoma by inhibiting Akt phosphorylation, which is independent of the phosphatidylinositol 3-kinase pathway. Inhibiting platelet-derived growth factor receptor (PDGFR)–mediated phosphorylation causes growth inhibition in glioblastoma cells. The authors of this study investigated the effects of YM872 and AG1296, singly and in combination and targeting different pathways upstream of Akt, on Akt-mediated tumor growth in glioblastoma cells in vivo and in vitro.
The expression of AMPAR, PDGFR, and c-kit in glioblastoma cells was analyzed via immunofluorescence. Glioblastoma cells, both in culture and in xenografts grown in mice, were treated with YM872 and AG1296, singly or in combination. Inhibition of tumor growth was observed after treatment in the xenograft model. Cell proliferation assays were performed using anti–Ki 67 antibody in vivo and in vitro. The CD34-positive tumor vessel counts within the vascular hot spots of tumor specimens were evaluated. Phosphorylation of Akt was studied using Western blot analysis.
Combined administration of YM872 and AG1296 had a significant enhanced effect on the inhibition of cell proliferation and reduction of tumor vascularity in the xenograft model. These agents singly and in combination demonstrated a significant reduction of Akt phosphorylation at Ser473 and inhibition of tumor proliferation in vitro, although combined administration had no enhanced antitumor effects.
The strongly enhanced antitumor effect of this combination therapy in vivo rather than in vitro may be attributable to disruption of the aberrant vascular niche. This combination therapy might provide substantial benefits to patients with glioblastoma.
Masanori Aihara, Isao Naito, Tatsuya Shimizu, Masahiro Matsumoto, Ken Asakura, Naoko Miyamoto and Yuhei Yoshimoto
The first choice of treatment in cases of vertebral artery dissecting aneurysms (VADAs) is endovascular internal trapping (EIT) of the dissecting segment using coils. However, this procedure carries the risk of medullary infarction, and the risk factors for this complication are not well understood. This study investigated the risk factors causing medullary infarction.
One hundred patients who underwent EIT for VADAs were included in this study. Ninety-three patients presented with subarachnoid hemorrhage. In cases involving the posterior inferior cerebellar artery (PICA), partial internal trapping targeting the ruptured site was performed to preserve the PICA. The VADAs were classified into the distal VA stump group, proximal VA stump group, and entire VA stump group, according to the location of VA segments without adequate flow-out vessels (such as the PICA [VA stump]) at risk of delayed thrombosis. The occurrence of medullary infarction was examined in each group using diffusion-weighted MRI and/or clinical symptoms. Various measurements were performed on digital subtraction angiography, and the risk factors for medullary infarction were analyzed.
Medullary infarction occurred in 30 patients, affecting the posterolateral medulla in 27 patients and the anteromedial medulla in 3 patients. Medullary infarction occurred in 3 of 47 patients (6%) in the distal VA stump group, 10 of 19 patients (53%) in the proximal VA stump group, and 17 of 34 patients (50%) in the entire VA stump group. The length of trapping was significantly longer in the infarction group than in the noninfarction group but did not differ among the 3 groups. Total length (length of trapping plus VA stump) was a risk factor for medullary infarction in the proximal VA stumps.
The primary risk factor for medullary infarction after EIT is not the length of trapping; rather, it is the anatomical location of the VADAs. The risk of medullary infarction is low in cases with distal VA stumps, but the symptoms are severe. Preservation of the origin of the anterior spinal artery can reduce the risk of medullary infarction. The risk of medullary infarction is high in cases with proximal VA stumps, but the symptoms are mild. A shorter length of trapping, although less likely to lead to complications, cannot prevent medullary infarction because the total length depends on the anatomical location of the PICA and not on the surgical technique. Reconstructive therapy should be indicated for patients with ruptured VADAs at high risk of severe ischemic complications (e.g., patients with hypoplasia of the contralateral VA or cases involving the PICA or anterior spinal artery, which are inappropriate for partial internal trapping) or for patients with unruptured VADAs.
Kazuki Komiyama, Masahiko Tosaka, Hiroya Shimauchi-Ohtaki, Masanori Aihara, Tatsuya Shimizu and Yuhei Yoshimoto
Head CT is sometimes performed immediately after minor head injury; however, which cases develop into chronic subdural hematoma (CSDH) remains unclear. Here, the authors retrospectively reviewed the rare cases of CSDH treated surgically in which early head CT had been performed after the initial head trauma.
A total of 172 patients (133 male and 39 female, median age 76 years) underwent surgery for CSDH at Gunma University Hospital between April 2010 and December 2017. Among these patients were 23 who had visited Gunma University Hospital or a nearby hospital and had undergone head CT within 7 days after the initial head trauma. Characteristics of the initial head CT were examined to identify indicators of subsequent CSDH.
Among the 23 CSDH cases (17 male and 6 female, median age 80 years), CT scans were obtained on the day of the initial injury (day 0) in 19 cases (25 sides) and 1–7 days after injury in 12 cases (19 sides); scans were obtained during both periods in 8 cases (12 sides), so that a total of 44 sides were examined. These CT scans were divided into two groups according to when they were obtained; cases in which scans were taken during both periods were included in both groups. Head CT performed on the day of injury showed normal findings in 5 (20%) of 25 sides, thin subdural effusion (SDE) ≤ 6 mm in 16 (64%) of 25 sides, thick SDE > 6 mm in 3 (12%) of 25 sides, and acute subdural hematoma (ASDH) in 1 (4%) of 25 sides. CT from 1–7 days after trauma showed thick SDE in 9 (47%) of 19 sides, thin SDE in 8 (42%) of 19 sides, and ASDH in 2 (11%) of 19 sides. A high-density line in the lateral direction (onion skin–like) was found between the skull and the brain in 9 (35%) of 26 sides with SDE on initial CT 0–7 days after the injury.
ASDH was not a common cause of CSDH. Head CT at the time of trauma that precedes CSDH often showed SDE. Such SDE that precedes CSDH was often close to the detection limit of CT immediately after the injury but became more apparent from the day after the injury.