Jiro Akimoto

Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors

OBJECT The objective of the present study was to perform a prospective evaluation of the potential efficacy and safety of intraoperative photodynamic therapy (PDT) using talaporfin sodium and irradiation using a 664-nm semiconductor laser in patients with primary malignant parenchymal brain tumors. METHODS In 27 patients with suspected newly diagnosed or recurrent primary malignant parenchymal brain tumors, a single intravenous injection of talaporfin sodium (40 mg/m(2)) was administered 1 day before resection of the neoplasm. The next day after completion of the tumor removal, the residual lesion and/or resection cavity were irradiated using a 664-nm semiconductor laser with a radiation power density of 150 mW/cm(2) and a radiation energy density of 27 J/cm(2). The procedure was performed 22-27 hours after drug administration. The study cohort included 22 patients with a histopathologically confirmed diagnosis of primary malignant parenchymal brain tumor. Thirteen of these neoplasms (59.1%) were newly diagnosed glioblastomas multiforme (GBM). RESULTS Among all 22 patients included in the study cohort, the 12-month overall survival (OS), 6-month progression-free survival (PFS), and 6-month local PFS rates after surgery and PDT were 95.5%, 91%, and 91%, respectively. Among patients with newly diagnosed GBMs, all these parameters were 100%. Side effects on the skin, which could be attributable to the administration of talaporfin sodium, were noted in 7.4% of patients and included rash (2 cases), blister (1 case), and erythema (1 case). Skin photosensitivity test results were relatively mild and fully disappeared within 15 days after administration of photosensitizer in all patients. CONCLUSIONS Intraoperative PDT using talaporfin sodium and a semiconductor laser may be considered as a potentially effective and sufficiently safe option for adjuvant management of primary malignant parenchymal brain tumors. The inclusion of intraoperative PDT in a combined treatment strategy may have a positive impact on OS and local tumor control, particularly in patients with newly diagnosed GBMs. Clinical trial registration no.: JMA-IIA00026 (https://dbcentre3.jmacct.med.or.jp/jmactr/App/JMACTRS06/JMACTRS06.aspx?seqno=862).

Preliminary clinical report on safety and efficacy of photodynamic therapy using talaporfin sodium for malignant gliomas.

OBJECTIVES To investigate the safety and efficacy of photodynamic therapy (PDT) using talaporfin sodium in patients with surgically, completely unresectable malignant gliomas with invasion into the eloquent areas of the brain associated with language and motor functions. MATERIALS AND METHODS Subjects consisted of consecutive 14 adult patients with malignant gliomas that were shown on preoperative diagnostic imaging to have invaded the eloquent areas of the brain. Of these, 6 patients had newly diagnosed tumors and 8 patients had recurrent tumors. In 15 craniotomy and tumor resection procedures, PDT was used as additional intraoperative treatment 24 h after 40 mg/m(2) of talaporfin sodium had been injected intravenously. After the tumor bulk had been resected as extensively as possible either 1 or 2 sites of probable tumor invasion in the bottom of resection cavity were irradiated superficially with a 664-nm diode laser for 180 s (27 J/cm(2)) at a power density of 150 mW/cm(2). RESULTS PDT achieved a response rate of 80% at the treated sites in the 6 patients with newly diagnosed malignant gliomas. In these patients, the median progression-free survival time was 23 months. The median survival time in 3 patients who died was 26 months, and the remaining 3 patients survived for more than 3 years with a good Karnofsky Performance Scale (KPS). In the 8 patients with recurrent tumors who received PDT, their response rate was low (25.0%), their gliomas recurred 3 months after PDT, and their survival time was only 9 months following PDT. No adverse events directly attributable to PDT occurred in any patients. Protection against light was only required for approximately 3 days after PDT. CONCLUSION We examined the safety and efficacy of PDT using talaporfin sodium as an additional intraoperative treatment for malignant glioma. PDT in addition to surgical resection achieved better therapeutic results than conventional protocols, especially in patients with newly diagnosed malignant gliomas. However, the current methodology has some limitations with respect to patients with recurrent tumors. Larger-scale studies are required to confirm the clinical feasibility of PDT plus surgery.

PRIMARY INTRACRANIAL MALIGNANT SCHWANNOMA OF TRIGEMINAL NERVE. A CASE REPORT WITH REVIEW OF THE LITERATURE

Summary¶ The authors report a rare case of primary intracranial malignant schwannoma of the trigeminal nerve occuring in a 30-year-old woman without von Recklinghausens neurofibromatosis (VRNF). The tumour arose from the intracranial part of the left trigeminal nerve, without skull base destruction. The tumour was partially removed operatively, followed by focal 50Gy irradiation, but unfortunately the tumour showed rapid regrowth. A second operation was attempted, but she died of cerebral infarction soon after operation. Histologically, the original tumour was characterized by the presence of foci of extremely high cellularity, pleomorphism and mitosis in an otherwise typical benign schwannoma. Immunohistochemically, the tumour cells were positive for S-100 protein even in the atypical areas, suggesting the tumour to be of Schwann cell origin. However, the recurrent tumour was composed of undifferentiated spindle cells, which were negative for S-100 protein. Thus, it is possible to consider that the S-100 protein expression could reflect the degree of differentiation of Schwann cells. Furthermore, the postoperative irradiation might have exacerbated the malignant progression in the present case.

Photodynamic therapy of C6-implanted glioma cells in the rat brain employing second-generation photosensitizer talaporfin sodium

OBJECT The usefulness of photodynamic therapy (PDT) as a local therapy for malignant glioma was evaluated by investigating histological changes in a rat C6 glioma model treated with a combination of talaporfin sodium, a water-soluble photosensitizer derived from chlorophyll and exposure to a diode laser. METHODS Glioma cells (C6) at the confluence stage were transplanted stereotactically into the right frontal lobe of SD rats. Five days later, the rats underwent right frontal craniotomy and intravenous administration of talaporfin sodium. One hour after talaporfin sodium administration, each rat was irradiated by a 664 nm diode laser beam. The brain was removed 1, 3 or 6h after laser irradiation for histological examination of tumor-affected brain tissue and surrounding normal brain tissue. RESULTS In addition to the tumor mass, tumor cells invading surrounding edematous brain tissue were seen in untreated rats, ranging from the brain surface to a depth of 2mm. One hour after PDT, coagulation necrosis as well as disappearance of indication of cell viability such as disappearance of tumor cell processes and foamy changes of cytoplasm were noted in the tumor tissue at a depth of 0.5mm, accompanied by reduction of cytoplasmic glial fibrillary acidic protein (GFAP) expression and appearance of granular M30 cytodeath positivity. Three hours later, the cytoplasm of the residual tumor cells showed disappearance of GFAP expression and increased expression of M30 cytodeath. Six hours later, the foamy cytoplasm of swollen tumor cells demonstrated strong positivity for M30 cytodeath. CONCLUSION PDT using talaporfin sodium induced coagulation necrosis and apoptosis in rats with C6 glioma.

Expression of hydroxyindole-O-methyltransferase enzyme in the human central nervous system and in pineal parenchymal cell tumors.

Pineal parenchymal tumor (PPT) cells usually show immunoreactivity for synaptophysin, neuron-specific enolase, neurofilament protein, class III &bgr;-tubulin, tau protein, PGP9.5, chromogranin, serotonin, retinal S-antigen, and rhodopsin, but these markers are not specific for PPTs. Melatonin is produced and secreted mainly bypineal parenchymal cells; hydroxyindole-O-methyltransferase (HIOMT) catalyzes the final reaction in melatonin biosynthesis. We hypothesized that HIOMT could serve as a tumor marker of PPTs, and we investigated HIOMT localization and HIOMT expression in samples of normal human tissue and in PPTs, primitive neuroectodermal tumors, and medulloblastomas. In normal tissue, HIOMT was expressed in retinal cells, pineal parenchymal cells, neurons of the Edinger-Westphal nucleus, microglia, macrophages, thyroid follicular epithelium, principal and oxyphil cells of parathyroid gland, adrenal cortical cells, hepatic parenchymal cells, renal tubule epithelium, and enteroendocrine cells of stomach and duodenum. The HIOMT was also expressed in all 46 PPTs studied. The proportions of HIOMT-immunoreactive cells successively decreased in the following tumors: pineocytoma, pineal parenchymal tumor of intermediate differentiation, and pineoblastoma. A few HIOMT-immunoreactive cells were observed in one of 6 primitive neuroectodermal tumors and 23 of 42 medulloblastomas. These results indicate that HIOMT immunohistochemistry may be useful for the diagnosis of PPTs and be a prognostic factor in PPTs.

Photodynamic Therapy for Malignant Brain Tumors

Photodynamic therapy (PDT) using talaporfin sodium together with a semiconductor laser was approved in Japan in October 2003 as a less invasive therapy for early-stage lung cancer. The author believes that the principle of PDT would be applicable for controlling the invading front of malignant brain tumors and verified its efficacy through experiments using glioma cell lines and glioma xenograft models. An investigator-initiated clinical study was jointly conducted with Tokyo Women’s Medical University with the support of the Japan Medical Association. Patient enrollment was started in May 2009 and a total of 27 patients were enrolled by March 2012. Of 22 patients included in efficacy analysis, 13 patients with newly diagnosed glioblastoma showed progression-free survival of 12 months, progression-free survival at the site of laser irradiation of 20 months, 1-year survival of 100%, and overall survival of 24.8 months. In addition, the safety analysis of the 27 patients showed that adverse events directly related to PDT were mild. PDT was approved in Japan for health insurance coverage as a new intraoperative therapy with the indication for malignant brain tumors in September 2013. Currently, the post-marketing investigation in the accumulated patients has been conducted, and the preparation of guidelines, holding training courses, and dissemination of information on the safe implementation of PDT using web sites and videos, have been promoted. PDT is expected to be a breakthrough for the treatment of malignant glioma as a tumor cell-selective less invasive therapy for the infiltrated functional brain area.

Usefulness of embolization of the middle meningeal artery for refractory chronic subdural hematomas

Background: Chronic subdural hematoma (CSDH) is generally treated by burr hole irrigation. However, sometimes repeated recurrence is observed, and treatment may consequently become difficult. We examined the efficacy of embolization of the middle meningeal artery (MMA) for such cases. Methods: We considered embolization of the MMA for three patients who had refractory CSDH with repeated recurrence and two CSDH patients who were at risk of recurrence and showed signs of recurrence after surgery. A microcatheter was advanced through the MMA as peripherally as possible, and embolization was performed with 15-20% n-butyl-2-cyanoacrylate or 200 μm polyvinyl alcohol particles. Results: Embolization was performed in the three patients who had refractory CSDH with repeated recurrence: The procedure was performed after burr hole irrigation of the hematoma in two patients and before the irrigation in one patient. In the two CSDH patients at risk of recurrence, embolization was performed when signs of recurrence appeared. The timing of embolization differed for each patient. However, in all the patients, the hematoma tended to decrease in size, and no recurrence was observed. Conclusion: Embolization of the MMA is effective for refractory CSDH or CSDH patients with a risk of recurrence, and is considered an effective therapeutic method to stop hematoma enlargement and promote resolution.

Photodynamic therapy with talaporfin sodium induces dose-dependent apoptotic cell death in human glioma cell lines

OBJECTIVE To investigate the kinetics of cell death in human glioma cell lines induced by photodynamic therapy (PDT) with the second-generation photosensitizer talaporfin sodium (TS) and a 664-nm diode laser. MATERIALS AND METHODS Three human glioma cell lines (T98G, A172, U251) were studied. After incubation of the cell lines with various concentrations of TS for 4 h, PDT using diode laser irradiation at 33 mW/cm² and 10 J/cm² was performed. Cell viability and changes in cell morphology were examined by the Cell Counting Kit-8 assay and phase-contrast microscopy, respectively. In addition, to evaluate the pathology of cell death, changes in cell viability after treatment with a caspase activation inhibitor and an autophagy inhibitor were also examined. RESULTS In all 3 human glioma cell lines, TS induced dose-dependent cell death. However, the 50% lethal dose of TS varied among these cell lines. The main morphological feature of cell death was shrinkage of the cell body, and the number of cells with this morphological change increased in a time-dependent manner, resulting in cell death. In addition, a dose-dependent improvement in cell viability by the caspase inhibitor Z-VAD-fmk was observed. CONCLUSION PDT with TS induces dose-dependent apoptosis in human glioma cell lines. However, the sensitivity to PDT varied among the cell lines, indicating a possible difference in the intracellular content of TS, or a difference in the susceptibility to the intracellular oxidative stress caused by PDT.

Differential expression of oxidized/native lipoprotein(a) and plasminogen in human carotid and cerebral artery plaques.

OBJECTIVE Lipoprotein(a) [Lp(a)] is a risk factor for stroke, as has recently been further confirmed by meta analysis, and consists of low-density lipoprotein and apolipoprotein(a), which shares a significant amino acid homology with plasminogen. Oxidized Lp(a) [Ox-Lp(a)] is a more pathogenic species of Lp(a). A monoclonal antibody, specific to Ox-Lp(a), distinguishes immunolocalization of Ox-Lp(a) from that of Lp(a) and that of plasminogen which carries highly homologous domains. It is worth examining their possibly differential immunolocalizations around atherosclerotic lesions in human carotid and cerebral arteries. METHODS AND RESULTS Stage-related differences in immunolocalization of Ox-Lp(a), native Lp(a), and plasminogen were investigated in various atherosclerotic lesions of the human carotid (obtained from 13 patients undergoing carotid endarterectomy) and cerebral arteries (from 11 cadavers). Native Lp(a) was seen in the fibrous cap, extracellular matrix, endothelial cells, and subendothelial layer. Unorganized mural thrombi were positive for plasminogen, but not Lp(a). In contrast, fibrin deposits in thickened intima were positive for Lp(a), but not plasminogen. Ox-Lp(a)-like immunoreactivity was seen in endothelial cells in the early stage of atherosclerosis. Ox-Lp(a) deposition was more abundant in synthetic phase vascular smooth muscle cells (VSMC) than in contractile phase VSMC. CONCLUSION We demonstrated differential immunoexpression patterns between native Lp(a) and plasminogen, and suggested that Lp(a)-plasminogen interaction may play a part in differential mechanisms in all atherosclerotic lesions of human carotid and cerebral arteries. The preferential presence of Ox-Lp(a) seen in endothelial cells suggests initial dysfunction of endothelial cells in atherosclerosis. The relative abundance of Ox-Lp(a) in synthetic phase VSMC is associated with their phenotypic changes during the progression of atherosclerosis.

Epithelioid glioblastoma: a case report.

A 43-year-old woman who had undergone breast cancer surgery 1 year previously complained of headache and nausea. Her brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a well-circumscribed, heterogeneously enhanced tumor in the right thalamus. She underwent gross total resection of the tumor followed by radiochemotherapy, and her clinical course was uneventful after surgery. Histological examination revealed a moderate number of tumor cells with fine bipolar processes in a mucoid matrix, which suggested pilocytic astrocytoma. The tumor was associated with microvascular proliferation but did not show significant mitosis or necrosis. In some areas, it had an epithelioid appearance, with ribbon-like, cribriform, and pseudoglandular patterns involving cuboid-shaped cells showing nuclear atypia and mitotic figures. Immunohistochemically, the tumor cells were positive for glial fibrillary acidic protein (GFAP) and vimentin in the area resembling pilocytic astrocytoma, but in the epithelioid area they were negative for GFAP and vimentin as well as for breast cancer markers, including AE1/AE3. The proliferating potential, represented by the MIB-1 labeling index, was high (82.5%) in the area of epithelioid appearance, compared to only 3% in the area of pilocytic astrocytoma-like appearance. As a rare histoarchitectural variant of glioblastoma, the epithelioid pattern may represent a very primitive tumor cell phenotype. Typically, this pattern is characterized by well-circumscribed masses, although its clinical significance is unknown.