Motomasa Furuse

The distribution of vascular endothelial growth factor-producing cells in clinical radiation necrosis of the brain: pathological consideration of their potential roles.

The cell type and localization of vascular endothelial growth factor (VEGF)-producing cells in human radiation necrosis (RN) are investigated from a histopathological and immunohistochemical standpoint using clinical specimens. Eighteen surgical specimens of symptomatic RN in the brain were retrospectively reviewed. These cases included different original histological tumor types and were treated with different radiation modalities. Histological analyses were performed using hematoxylin and eosin (H&E) staining, and anti-VEGF and anti-hypoxia-inducible factor (HIF)-1α immunohistochemistry. H&E staining showed marked angiogenesis and reactive astrocytosis at the perinecrotic area. The most prominent vasculature in this area was identified as telangiectasis. Immunohistochemistry indicated that HIF-1α was expressed predominantly in the perinecrotic area and that a large majority of VEGF-expressing cells were reactive astrocytes intensively distributed in this area. VEGF produced by the reactive astrocytes localized mainly in the perinecrotic area might be a major cause of both angiogenesis and the subsequent perilesional edema typically found in RN of the brain. The benefits of anti-VEGF antibody (bevacizumab) treatment in RN may be that VEGF secretion from the perinecrotic tissue is inhibited and that surgery would remove this tissue; both of these benefits result in effective reduction of edema associated with RN.

Cavernous malformation after radiation therapy for astrocytoma in adult patients: report of 2 cases.

SummaryRadiation-induced cavernous malformations are rarely reported, and most cases have been children. We describe two adult patients with cavernous malformation after irradiation for astrocytoma. Magnetic resonance (MR) imaging, at their ages of 53 years, showed a cavernous malformation in the irradiated field 26 and 10 years after resection and irradiation, respectively. Cavernous malformations were confirmed by the histopathological examination in the both cases. Radiation-induced cavernous malformations are rare in adult patients with astrocytoma. One reason why we found two such cases was that these patients had been successfully treated for astrocytoma and had long follow-up periods.

Inflammation as well as angiogenesis may participate in the pathophysiology of brain radiation necrosis

Radiation necrosis (RN) after intensive radiation therapy is a serious problem. Using human RN specimens, we recently proved that leaky angiogenesis is a major cause of brain edema in RN. In the present study, we investigated the same specimens to speculate on inflammations effect on the pathophysiology of RN. Surgical specimens of symptomatic RN in the brain were retrospectively reviewed by histological and immunohistochemical analyses using hematoxylin and eosin (H&E) staining as well as immunohistochemical staining for VEGF, HIF-1α, CXCL12, CXCR4, GFAP, CD68, hGLUT5, CD45, IL-1α, IL-6 TNF-α and NF-kB. H&E staining demonstrated marked angiogenesis and cell infiltration in the perinecrotic area. The most prominent vasculature was identified as thin-walled leaky angiogenesis, i.e. telangiectasis surrounded by prominent interstitial edema. Two major cell phenotypes infiltrated the perinecrotic area: GFAP-positive reactive astrocytes and CD68/hGLUT5-positive cells (mainly microglias). Immunohistochemistry revealed that CD68/hGLUT5-positive cells and GFAP-positive cells expressed HIF-1α and VEGF, respectively. GFAP-positive cells expressed chemokine CXCL12, and CD68/hGLUT5-positive cells expressed receptor CXCR4. The CD68/hGLUT5-positive cells expressed pro-inflammatory cytokines IL-1α, IL-6 and TNF-α in the perinecrotic area. VEGF caused leaky angiogenesis followed by perilesional edema in RN. GFAP-positive cells expressing CXCL12 might attract CXCR4-expressing CD68/hGLUT5-positive cells into the perinecrotic area. These accumulated CD68/hGLUT5-positive cells expressing pro-inflammatory cytokines seemed to aggravate the RN edema. Both angiogenesis and inflammation might be caused by the regulation of HIF-1α, which is well known as a transactivator of VEGF and of the CXCL12/CXCR4 chemokine axis.

Pathophysiology, Diagnosis, and Treatment of Radiation Necrosis in the Brain

New radiation modalities have made it possible to prolong the survival of individuals with malignant brain tumors, but symptomatic radiation necrosis becomes a serious problem that can negatively affect a patient’s quality of life through severe and lifelong effects. Here we review the relevant literature and introduce our original concept of the pathophysiology of brain radiation necrosis following the treatment of brain, head, and neck tumors. Regarding the pathophysiology of radiation necrosis, we introduce two major hypotheses: glial cell damage or vascular damage. For the differential diagnosis of radiation necrosis and tumor recurrence, we focus on the role of positron emission tomography. Finally, in accord with our hypothesis regarding the pathophysiology, we describe the promising effects of the anti-vascular endothelial growth factor antibody bevacizumab on symptomatic radiation necrosis in the brain.

Bevacizumab Treatment for Symptomatic Radiation Necrosis Diagnosed by Amino Acid PET

Bevacizumab is effective in treating radiation necrosis; however, radiation necrosis was not definitively diagnosed in most previous reports. Here we used amino acid positron emission tomography to diagnose radiation necrosis for the application of bevacizumab in treating progressive radiation necrosis. Lesion/normal tissue ratios of <2.5 on (18)fluoride-labeled boronophenylalanine-positron emission tomography were defined as an indication of effective bevacizumab treatment. Thirteen patients were treated with bevacizumab at a dose of 5 mg/kg every 2 weeks. Two patients were excluded because of adverse events. The median reduction rate in perilesional edema was 65.5%. Karnofsky performance status improved in six patients after bevacizumab treatment. Lesion/normal tissue ratios on (18)fluoride-labeled boronophenylalanine-positron emission tomography (P = 0.0084) and improvement in Karnofsky performance status after bevacizumab treatment (P = 0.0228) were significantly associated with reduced rates of perilesional edema. Thus, (18)fluoride-labeled boronophenylalanine-positron emission tomography could be useful for diagnosing radiation necrosis and predicting the efficacy of bevacizumab in progressive radiation necrosis.

Delayed brain radiation necrosis: pathological review and new molecular targets for treatment

Delayed radiation necrosis is a well-known adverse event following radiotherapy for brain diseases and has been studied since the 1930s. The primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination. This primary pathology leads to tissue inflammation and ischemia, inducing various tissue protective responses including angiogenesis. Macrophages and lymphocytes then infiltrate the surrounding areas of necrosis, releasing inflammatory cytokines such as interleukin (IL)-1α, IL-6, and tumor necrosis factor (TNF)-α. Microglia also express these inflammatory cytokines. Reactive astrocytes play an important role in angiogenesis, expressing vascular endothelial growth factor (VEGF). Some chemokine networks, like the CXCL12/CXCR4 axis, are upregulated by tissue inflammation. Hypoxia may mediate the cell–cell interactions among reactive astrocytes, macrophages, and microglial cells around the necrotic core. Recently, bevacizumab, an anti-VEGF antibody, has demonstrated promising results as an alternative treatment for radiation necrosis. The importance of VEGF in the pathophysiology of brain radiation necrosis is being recognized. The discovery of new molecular targets could facilitate novel treatments for radiation necrosis. This literature review will focus on recent work characterizing delayed radiation necrosis in the brain.

The roles of platelet-derived growth factors and their receptors in brain radiation necrosis

BackgroundBrain radiation necrosis (RN) occurring after radiotherapy is a serious complication. We and others have performed several treatments for RN, using anticoagulants, corticosteroids, surgical resection and bevacizumab. However, the mechanisms underlying RN have not yet been completely elucidated. For more than a decade, platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been extensively studied in many biological processes. These proteins influence a wide range of biological responses and participate in many normal and pathological conditions. In this study, we demonstrated that PDGF isoforms (PDGF-A, B, C, and D) and PDGFRs (PDGFR-α and β) are involved in the pathogenesis of human brain RN. We speculated on their roles, with a focus on their potential involvement in angiogenesis and inflammation in RN.MethodsSeven surgical specimens of RN, obtained from 2006 to 2013 at our department, were subjected to histopathological analyses and stained with hematoxylin and eosin. We qualitatively analyzed the protein expression of each isoform of PDGF by immunohistochemistry. We also examined their expression with double immunofluorescence.ResultsAll PDGFs were expressed in macrophages, microglia, and endothelial cells in the boundary of the core of RN, namely, the perinecrotic area (PN), as well as in undamaged brain tissue (UB). PDGF-C, D and PDGFR-α were also expressed in reactive astrocytes in PN. PDGFs and PDGFR-α were scarcely detected in UB, but PDGFR-β was specifically expressed in endothelial cells not only in PN but also in UB.ConclusionsPDGFs/PDGFRs play critical roles in angiogenesis and possibly in inflammation, and they contribute to the pathogenesis of RN, irrespective of the original tumor pathology and applied radiation modality. Treatments for the inhibition of PDGF-C, PDGF-D, and PDGFR-α may provide new approaches for the treatment of RN induced by common radiation therapies.

Bevacizumab treatment of symptomatic pseudoprogression after boron neutron capture therapy for recurrent malignant gliomas. Report of 2 cases

BACKGROUND Bevacizumab, an anti-vascular endothelial growth factor antibody, has been used for the treatment of radiation necrosis. Thus far, however, there has been no definitive report on its use for the treatment of symptomatic pseudoprogression. Here we report 2 cases of successful treatment with bevacizumab for symptomatic pseudoprogression after boron neutron capture therapy (BNCT) was applied for recurrent malignant gliomas. METHODS Two recurrent malignant gliomas received BNCT. Both cases were treated with intravenous administration of bevacizumab at the deterioration that seemed to be symptomatic pseudoprogression. RESULTS The first case was recurrent glioblastoma multiforme and the second was recurrent anaplastic oligoastrocytoma. Both cases recurred after standard chemoradiotherapy and were referred to our institute for BNCT, which is tumor-selective particle radiation. Just prior to neutron irradiation, PET with an amino acid tracer was applied in each case to confirm tumor recurrence. Both cases showed deterioration in symptoms, as well as on MRI, at intervals of 4 months and 2 months, respectively, after BNCT. For the first case, a second PET was applied in order to confirm no increase in tracer uptake. We diagnosed both cases as symptomatic pseudoprogression and started the intravenous administration of 5 mg/kg bevacizumab biweekly with 6 cycles. Both cases responded well to this, showing rapid and dramatic improvement in neuroimaging and clinical symptoms. No tumor progression was observed 8 months after BNCT. CONCLUSIONS Bevacizumab showed marked effects on symptomatic pseudoprogression after BNCT. BNCT combined with bevacizumab may prolong the survival of patients with recurrent malignant gliomas.

Rapid induction of brain hypothermia by endovascular intra-arterial perfusion

Abstract Objectives: Achieving rapid, brain cooling has potentially important clinical implications. To investigate potential practicalities, we induced brain hypothermia in canines by perfusing cooled crystalloid solution into the carotid artery using an extracorporeal cooling-filtration system. Methods: Ringers solution cooled to ∼6.5°C was infused at a rate of 3 ml/kg/min for 30 minutes into the right common carotid artery through an angiographic catheter via the right femoral artery in six adult canines (13.81 ± 0.60 kg). Excessive fluid was ultrafiltrated through a venovenous extracorporeal circuit via the right femoral vein. Temperature was monitored in the cerebral hemispheres, the rectum and the vena cava. The extracellular lactate concentrations were measured by microdialysis in the frontal lobes. Results: Right brain temperature decreased to 33.6 ± 2.0°C from 37.7 ± 1.1°C 30 minutes after initiation of perfusion, while left brain and rectal temperatures were 34.3 ± 1.7 and 34.1 ± 1.3°C, respectively. The cooling rate of the right cerebral hemisphere was 4.2 ± 1.1°C/30 minutes and advanced compared with the rectum (p<0.01), the left cerebral hemisphere and the vena cava (both p<0.05). There was no significant increase in the extracellular lactate concentrations in the cerebral hemispheres. Hemoglobin, hematocrit and cardiac function significantly changed during perfusion (p<0.05). Conclusions: Brain hypothermia was rapidly and safely induced using an intra-arterial crystalloid infusion and an extracorporeal cooing-filtration system. With refinement and further assessment of metabolic and physiologic parameters, the method holds a potential for clinical utility.

Effects of intravascular perfusion of cooled crystalloid solution on cold-induced brain injury using an extracorporeal cooling-filtration system.

Summary¶Background. We evaluated cerebral metabolic change during brain hypothermia with intravascular perfusion of cooled crystalloid solution using an extracorporeal cooling-filtration system and cerebroprotective effects of this hypothermia on brain injury in an animal model. Method. Microdialysis probes were implanted into the bilateral parietal cortices. A cold-induced brain injury was produced behind the microdialysis probe on the right parietal cortex. Immediately after injury in the cooled group (n=9), Ringer’s solution cooled to 5 °C was infused into the right vertebral artery after occlusion of the bilateral common carotid and the left vertebral arteries. Excessive fluid was ultrafiltrated by a dialyzer. Brain temperature was maintained at about 20 °C for 60 minutes. In 7 dogs, three neck arteries were occluded for 60 minutes after injury without cooled fluid infusion. The extracellular concentrations of glutamate, lactate, and pyruvate were measured serially for 180 minutes after injury. Findings. Extracellular glutamate concentrations in the cooled group did not increase, while there was a significant increase in the injured hemisphere as compared to the uninjured hemisphere in the non-cooled group (P<0.05). Extracellular lactate concentrations increased slightly after occlusion in both groups. The depth of cortical injury was limited in the cooled group, but extended into the white matter in the non-cooled group up to 240 minutes after injury. Interpretation. Occlusion of three main arteries induced ischaemia under critical threshold in canine brains. Under this condition, intravascular cooling with crystalloid solution suppressed accumulation of extracellular glutamate and reduced tissue damage in the early phase after cold-induced brain injury, as cerebroprotective effects. This information suggests that a method employing brain hypothermia via intra-arterial cooling with an extracorporeal cooling-filtration system has potential to achieve successful, safe, selective brain cooling.