Ionizing irradiation is a well‑established therapeutic modality for malignant gliomas. Due to its high cellular uptake, 5‑aminolevulinic acid (ALA) is used for fluorescence‑guided resection of malignant gliomas. We have previously shown that 5‑ALA sensitizes glioma cells to irradiation in vitro. The aim of the present study was to assess whether 5‑ALA acts as a radiosensitizer in experimental glioma in vivo. Rats were subcutaneously injected with 9L gliosarcoma cells and administered 5‑ALA. The accumulation of 5‑ALA‑induced protoporphyrin IX was confirmed by high‑performance liquid chromatography (HPLC) analysis. Subcutaneous (s.c.) tumors were subsequently irradiated with 2 Gy/day for five consecutive days. In the experimental glioma model, high‑performance liquid chromatography analysis revealed a high level of accumulation of 5‑ALA‑induced protoporphyrin IX in s.c. tumors 3 h after 5‑ALA administration. Multi‑dose ionizing irradiation induced greater inhibition of tumor growth in rats that were administered 5‑ALA than in the non‑5‑ALA‑treated animals. Immunohistochemical analysis of the s.c. tumors revealed that numerous ionized calcium‑binding adapter molecule 1 (Iba1)‑positive macrophages gathered at the surface of and within the s.c. tumors following multi‑dose ionizing irradiation in combination with 5‑ALA administration. By contrast, the s.c. tumors in the control group scarcely showed aggregation of Iba1‑positive macrophages. These results suggested that multi‑dose ionizing irradiation with 5‑ALA induced not only a direct cytotoxic effect but also enhanced the host antitumor immune response and thus caused high inhibition of tumor growth in experimental glioma.

Abstract. Meningioma accounts for ~25% of all primary intracranial neoplasms and the incidence increases with age. Prvios population-based studies demonstrated that the annual incidence of intracranial meningiomas was 1.2-3.1/100,000 population. In particular, the incidence of this disease among the elderly is high. Recently, increased life expectancy and greater use of diagnostic radiological imaging led to an increased incidence in the diagnosis of intracranial meningiomas, both symptomatic and asymptomatic, in the elderly. Thus, neurosurgeons may be increasingly confronted with the management of intracranial meningiomas in the elderly. In practice, it is often difficult for physicians to determine whether traditional surgical resection is the optimal management strategy for intracranial meningiomas in the elderly. However, reported clinical studies about the outcome of surgical resection of intracranial meningiomas in the elderly are limited. Increased risk of mortality and morbidity associated with surgical treatment for intracranial meningiomas in the elderly compared with younger patients have been controversial. In the present study, the clinical features of intracranial meningiomas in 70 consecutive intracranial meningioma patients that underwent surgical treatment at the affiliated hospital of University of Occupational and Environmental Health between 2007 and 2013 were assessed. In addition, patient selection and surgical management of intracranial meningioma in elderly patients was discussed. Preoperative factors, including symptoms, tumor location, tumor size, Karnofsky Performance Scale (KPS) score and American Society of Anesthesiology (ASA) score, and postoperative factors, including pathological diagnosis, tumor proliferation index (Ki-67), resection rate (Simpson grade), length of hospital stay and discharge destination were retrospectively analyzed in patients aged ≥75 years (n=16; elderly group) and <75 years (n=54; younger group). Outcomes were assessed 6 months after surgery. Multivariate logistic regression revealed that tumor resection rate (Simpson grade III-V) was an important predictor of surgical complications (odds ratio, 5.662; 95% confidence interval, 1.323-24.236; P= 0.0194). Perioperative morbidity was not correlated with age (>75 years), tumor location, tumor size, KPS score or ASA score. Thus, the present study indicated that age is not associated with surgical outcome in elderly meningioma patients. Regardless of patient age, the decision to perform surgical resection should be made on an individual basis wherein tumor characteristics and the general health of the patient are considered.

Abstract. Postoperative adjuvant radiotherapy has important roles in multimodal treatment for highly aggressive malignant gliomas. Previously, we demonstrated that multi-dose ionizing irradiation with repetitive administration of 5-aminolevulinic acid (5-ALA) enhanced the host antitumor response and strongly inhibited tumor growth in experimental glioma. However, the mechanism of the radiosensitizing effect of 5-ALA is not known. Ionizing irradiation not only causes reactive oxygen species (ROS) formation initially by water radiolysis but also induces delayed production of mitochondrial ROS for mediating the long-lasting effects of ionizing irradiation on tumor cells. 5-ALA leads to high accumulation of protoporphyrin IX (PpIX) in the mitochondria of tumor cells, yet can also improve dysfunction of the mitochondrial respiratory chain in tumor cells. Here, we assessed the effect of 5-ALA-induced PpIX synthesis and delayed production of intracellular ROS after ionizing irradiation with 5-ALA in glioma cells in vitro. Temporal changes in intracellular 5-ALA-induced PpIX synthesis after ionizing irradiation in glioma cell lines were evaluated using flow cytometry (FCM). Then, the effect of 5-ALA on delayed production of intracellular ROS 12 h after ionizing irradiation in glioma cells was evaluated by FCM and confocal laser scanning microscopy. Ionizing irradiation had no effect on 5-ALA-induced PpIX synthesis in glioma cells. Delayed intracellular production of ROS was significantly higher than that just after ionizing irradiation, but 5-ALA pretreatment strongly enhanced the delayed intracellular production of ROS, mainly in the cytoplasm of glioma cells. This 5-ALA-induced increase in the delayed production of ROS tended to be higher in the case of 5-ALA treatment before rather than after ionizing irradiation. These results suggest that 5-ALA can affect tumor cells under ionizing irradiation, and greatly increase secondary intracellular production of ROS long after ionizing irradiation, thereby causing a radiosensitizing effect in glioma cells.

5-Aminolevulinic acid (5-ALA) can accumulate protoporphyrin IX (PpIX) in tumour cell mitochondria and is well known for its utility in fluorescence-guided resection of malignant gliomas as a live molecular marker. Previously, we and other authors demonstrated that 5-ALA has a radiosensitizing effect for tumours. In the present study, we aimed to investigate the mechanism underlying the radiosensitizing effect of 5-ALA by focusing on glioma cell mitochondria. Using an enhancer (ciprofloxacin) of 5-ALA-induced PpIX accumulation, we evaluated the influence of ionizing irradiation (IR) and delayed reactive oxygen species (ROS) production 12 h after IR by colony-forming assay and flow cytometry (FCM) with different amounts of PpIX accumulation. The mitochondrial mass and mitochondrial electron transport chain (mtETC) activity were evaluated by FCM and western blot analysis. Cell death and delayed ROS production after IR in glioma cells were increased in proportion to 5-ALA-induced PpIX accumulation. Delayed ROS production enhanced by 5-ALA localized to the glioma cell mitochondria. Mitochondrial mass and mitochondrial complex III activity, among mtETC factors, were also increased 12 h after IR in glioma cells in proportion to 5-ALA-induced PpIX accumulation with some variation. These results suggest that 5-ALA enhances IR-induced mitochondrial oxidative stress and leads to increased cell death with mitochondrial changes, thereby acting as a targeting mitochondrial drug, and so‑called radiosensitizer in glioma cells.

Study Design Case report. Objective Malignant mesothelioma (MM) is an uncommon tumor of the pleural epithelium with a predilection for local spread into adjacent tissues. The sarcomatoid type accounts for ∼10% of MM cases and is associated with poorer survival than the epithelioid, desmoplastic, and biphasic types. MM commonly presents with involvement of the vertebral body or epidural space. However, intradural spinal extension of MM is extremely rare. Only eight cases of intradural spinal extension have been reported. We report this rare case and discuss the clinical manifestations of intradural spinal extension of MM with literature review. Methods This report describes the case of a 62-year-old man with Brown-Séquard syndrome and radiculopathy of the left C5 nerve root detected during treatment for pleural sarcomatoid MM. Magnetic resonance imaging (MRI) showed an intramedullary lesion at the C3 level and a small nodule at the left C5 nerve root with cervical canal stenosis. Results The patient underwent surgery, and intramedullary metastasis of sarcomatoid MM was diagnosed. Subsequently, radiotherapy was administered, resulting in temporary improvement of the patient's condition. Thereafter, his condition gradually deteriorated, and follow-up MRI showed a more extensive residual C3 intramedullary lesion. Thus, a second surgery was performed after chemotherapy, but the patient died 5 months after the initial diagnosis. Conclusion We present this rare case, and emphasize intramedullary spinal cord metastasis of MM as differential diagnosis in primary cord lesion.