High-Mannose-Type Glycan of Basigin in Endothelial Cells Is Essential for the Opening of the Blood-Brain Barrier Induced by Hypoxia, Cyclophilin A, or Tumor Necrosis Factor-α.

Pathologic opening of the blood-brain barrier accelerates the progression of various neural diseases. Basigin, as an essential molecule for the opening of the blood-brain barrier, is a highly glycosylated transmembrane molecule specified in barrier-forming endothelial cells. This study analyzed the involvement of basigin in the regulation of the blood-brain barrier focusing on its glycosylation forms. First, basigin was found to be expressed as cell surface molecules with complex-type glycan as well as those with high-mannose-type glycan in barrier-forming endothelial cells. Monolayers of endothelial cells with suppressed expression of basigin with high-mannose-type glycan were then prepared and exposed to pathologic stimuli. These monolayers retained their barrier-forming properties even in the presence of pathologic stimuli, although their expression of basigin with complex-type glycan was maintained. In vivo, the blood-brain barrier in mice pretreated intravenously with endoglycosidase H was protected from opening under pathologic stimuli. Pathologically opened blood-brain barrier in streptozotocin-injected mice was successfully closed by intravenous injection of endoglycosidase H. These results show that high-mannose-type glycan of the basigin molecule is essential for the opening of the blood-brain barrier and therefore a specific target for protection as well as restoration of pathologic opening of the blood-brain barrier.

Congenital Pulmonary Lymphangiectasia Masked by Postoperative Pulmonary Venous Obstruction in an Infant with Total Anomalous Pulmonary Venous Connection.

Congenital pulmonary lymphangiectasia (CPL) is associated with fetal pulmonary venous obstructive physiology. The precise morbidity of CPL is unknown as CPL is generally fatal in neonates. Here, we report an infant with secondary CPL in total anomalous pulmonary venous connection (TAPVC). He developed severe pulmonary hypertension (PH) after corrective surgery for TAPVC. However, cardiac catheterization showed mild left pulmonary venous obstruction (PVO), which was deemed unnecessary for re-intervention. He died at 11 months-old due to an exacerbation of PH. Autopsy revealed medial hypertrophy of the pulmonary arteries, mild left PVO, and marked dilatation and proliferation of the pulmonary lymphatics which might have been involved in the PH, although CPL was not conclusively identified based on the previous biopsy findings. We should be aware of the possibility of CPL in addition to postoperative PVO when encountering patients with fetal pulmonary venous obstructive physiology. Furthermore, a cautious approach to the interpretation of lung biopsy results is warranted.

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

[A Case Report of Multiple Endocrine Neoplasia Type 2A(MEN2A)Diagnosed with Medullary Thyroid Carcinoma].

We experienced a case of multiple endocrine neoplasia type 2A(MEN2A)diagnosed with medullary thyroid carcinoma. The patient was a 50s woman who was referred for a thyroid nodule detected in the right lobe during a carotid ultrasound examination. After undergoing a hemithyroidectomy, it was determined that the tumor was medullary carcinoma. RET gene test was performed, confirming a mutation at codon768, leading to the diagnosis of MEN2A. A completion thyroidectomy was performed to remove the remaining thyroid tissue. Postoperatively, the patient is undergoing systemic surveillance.

[A Case of Advanced Adenocarcinoma at the Esophagogastric Junction That Exhibited pCR by Preoperative SOX Therapy].

Although neoadjuvant chemotherapy(NAC)is an effective treatment option for advanced adenocarcinoma at the esophagogastric junction (AEG), there is no sufficient evidence of this in Japan. We report a case of advanced AEG with pathological complete response(pCR)after NAC with S-1 and oxaliplatin(SOX). A 39-year-old man was diagnosed with advanced AEG cT3(SS)N0M0, cStage ⅡB. A total of 3 courses of SOX was administered. After the chemotherapy, the primary tumor showed a significant reduction in size. Subsequently, laparoscopic proximal gastrectomy, D1+ lymphadenectomy and double-flap technique reconstruction were performed. Histopathological examinations showed no residual cancer cells in the resected specimen. Thus, preoperative SOX therapy can be one of the useful treatment strategies for advanced AEG.

Hypoxia-induced disruption of neural vascular barrier is mediated by the intracellular induction of Fe(II) ion.

Neural vascular barrier maintains the optimal tissue microenvironment of central nervous system in which neural cells can function normally. In various neural diseases, the decrease in oxygen concentration, hypoxia, of affected tissues is known to accelerate the disease progression through disruption of neural vascular barrier. Therefore, the clarification of mechanisms underlying hypoxia-induced disruption of neural vascular barrier would definitely lead to the establishment of new effective therapies for intractable neural diseases. In the present study, we first found that hypoxia disrupts neural vascular barrier through pathways independent of HIF-1α and HIF-2α. Then, with a specific fluorescence probe for ferrous, Fe(II) ion, we have obtained the interesting data showing that hypoxia increased the intracellular level of Fe(II) ion in endothelial cells of our in vitro model for neural vascular barrier, and that hypoxia-induced disruption of neural vascular barrier could be inhibited by chelating Fe(II) ion in endothelial cells. Furthermore, in the presence of a reducing reagent for reactive oxygen species (ROS), hypoxia could not disrupt the neural vascular barrier despite that the hypoxic increase in intracellular level of Fe(II) ion was confirmed in endothelial cells. These results indicate that hypoxia-triggered increase in the level of intracellular Fe(II) ion and subsequent production of ROS, probably through Fenton reaction, are the essential pathway mediating the disruption of neural vascular barrier under hypoxia.

A surgical strategy using a fusion image constructed from 11C-methionine PET, 18F-FDG-PET and MRI for glioma with no or minimum contrast enhancement.

The objective of this study was to investigate the distribution of 11C-methionine (MET) and F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) imaging and the hyperintense area in T2 weighted imaging (T2WI) in glioma with no or poor gadolinium enhancement in magnetic resonance imaging (GdMRI). Cases were also analyzed pathologically. We prospectively investigated 16 patients with non- or minimally enhancing (< 10% volume) glioma. All patients underwent MET-PET and FDG-PET scans preoperatively. After delineating the tumor based on MET uptake, integrated 3D images from FDG-PET and MRI (GdMRI, T2WI or FLAIR) were generated and the final resection plane was planned. This resection plane was determined intraoperatively using the navigation-guided fencepost method. The delineation obtained by MET-PET imaging was larger than that with GdMRI in all cases with an enhanced effect. In contrast, the T2WI-abnormal signal area (T2WI+) tended to be larger than the MET uptake area (MET+). Tumor resection was > 95% in the non-eloquent area in 4/5 cases (80%), whereas 10 of 11 cases (90.9%) had partial resection in the eloquent area. In a case including the language area, 92% resection was achieved based on the MET-uptake area, in contrast to T2WI-based partial resection (65%), because the T2WI+/MET- area defined the language area. Pathological findings showed that the T2WI+/MET+ area is glioma, whereas 6 of 9 T2WI+/MET- lesions included normal tissues. Tissue from T2W1+/MET+/FDG+/GdMRI+ lesions gave an accurate diagnosis of grade in six cases. Non- or minimally enhancing gliomas were classified as having a MET uptake area that totally or partially overlapped with the T2WI hyperintense area. Resection planning with or without a metabolically active area in non- or minimally enhancing gliomas may be useful for accurate diagnosis, malignancy grading, and particularly for eloquent area although further study is needed to analyze the T2WI+/MET- area.

A primary extradural malignant rhabdoid tumor at the craniovertebral junction in a 3-year-old boy.

INTRODUCTION: Malignant rhabdoid tumor (MRT) is a highly aggressive childhood neoplasm and mainly presents in kidney and brain. We report the case of a patient with extrarenal extracranial MRT in the craniovertebral junction (CVJ). CASE REPORT: A 3-year-old boy presented with tetraparesis that had rapidly developed for 2 weeks. The tumor was located in the ventral side of the C1 and C2 extradural space and had invaded the lower clivus. The symptom recovered after subtotal resection of the tumor through a lateral approach with removal of bilateral lateral masses at C1 and instrumental occipital-C2 posterior fusion. Definite histological diagnosis of the extradural tumor was difficult; however, a metastatic lesion in the rib showed a proliferation of INI1/SMARCB1-negative spindle and rhabdoid cells, indicating the tumor was MRT. Stereotactic CyberKnife radiotherapy with a marginal dose of 26 Gy contributed to control of local regrowth of the tumor before histopathological confirmation and induction of chemotherapy with ifosfamide, cisplatin, and etoposide. The patient survived for 29 months without local recurrence of the tumor and with independent activity, however then died of multiple metastases. CONCLUSION: Treatment strategies for MRT in the CVJ should include an optimal surgical approach for reduction of tumor volume and stabilization of the spine, followed by high dose chemotherapy. Stereotactic radiotherapy may be useful for local control.

Induction of artificial cancer stem cells from tongue cancer cells by defined reprogramming factors.

BACKGROUND: The cancer stem cells (CSCs), a small subpopulation of cells in tumor are responsible for the tumor initiation, growth, recurrence and metastasis of cancer, as well as resistance of cancers to drugs or radiotherapy. CSCs are an important target for the development of novel strategies in cancer treatment. However, CSCs-targeted new anti-cancer drug discovery is currently hindered by the lack of easy and reliable methods for isolating, collecting and maintaining sufficient number of CSCs. Here, we examined whether introduction of defined reprogramming factors (Oct4, shp53, Sox2, Klf4, l-Myc and Lin28) into HSC2 tongue cancer cells could transform the HSC2 into HSC2 with CSCs properties. METHODS: We introduced the defined reprogramming factors into HSC2 tongue cancer cells via episomal vectors by electroporation method to generate transfectant cells. We investigated the malignant properties of the transfectant cells by cell proliferation assay, migration assay, wound healing assay, sphere formation assay, chemosensitivity and radiosensitivity assay in vitro; and also examined the tumorigenic potential of the transfectants in vivo. RESULTS: The transfectant cells (HSC2/hOCT3/4-shp53-F, HSC2/hSK, HSC2/hUL, HSC2/hOCT3/4-shp53-F + hSK, HSC2/hOCT3/4-shp53-F + hUL, HSC2/hSK + hUL, HSC2/hOCT3/4-shp53-F + hSK + hUL) displayed a malignant phenotype in culture and form tumors on the back of nude mice more efficiently than parental HSC2 and control HSC2/EGFP transfectant cells. They exhibited increased resistance to chemotherapeutic agents; 5-fluorouracil, cisplatin, docetaxel, trifluorothymidine, zoledronic acid, cetuximab, bortezomib and radiation when compared with HSC2 and HSC2/EGFP. Among all the transfected cells, HSC2/hOCT3/4-shp53-F + hSK + hUL cell containing all of the reprogramming factors showed the most aggressive and malignant properties and presented the highest number of spheres in the culture medium containing human recombinant fibroblast Growth Factor-2 (FGF-2) and epidermal Growth Factor (EGF). CONCLUSION: These findings suggest that artificial cancer stem cells obtained by the induction of cellular reprogramming may be useful for investigating the acquisition of potential malignancy as well as screening the CSCs-targeting drugs.

IgG4-related disease manifesting the gastric wall thickening.

IgG4-related disease (IgG4-RD) is a recently designated disease entity and its full picture has not yet been elucidated. Here, we report an unusual case of a patient with gastric wall thickening secondary to IgG4-RD. A 68-year-old male visited our hospital with itchy skin lesions and an episode of organizing pneumonia. On the suspicion of malignancy-associated skin lesions, computed tomography (CT) was performed. The CT revealed prominent thickening of the gastric wall. Due to the possibility of malignancy, the patient underwent distal gastrectomy. Histopathological examination showed fibrosis of the submucosa and prominent thickening of the muscularis propria. Most of infiltrating cells were IgG4-positive plasma cells. Post-operative blood test revealed significantly high serum levels of total IgG and IgG4. Based on these histological features, the patient was given a definitive diagnosis of IgG4-RD. Further accumulation of cases like the present case that develop IgG4-RD with rare manifestations would lead to the elucidation of pathogenesis.

[A Case of Carcinoma Associated with an Anal Fistula Repaired Using a Hatchet Flap after Neoadjuvant Chemoradiotherapy].

The patient was a 53-year-old man who complained of perianal pain. He had a 20-year history of an anal fistula. There was a 10 cm tumor with mucin-like discharge on the left side of the anus. His CEA level was high, at 7.3 ng/mL, and T2-weighted MRI revealed a multilocular cystic tumor with high signal intensity. The second biopsy result indicated mucinous adenocarcinoma. We performed neoadjuvant chemoradiotherapy. The chemotherapy regimen was TS-1 with radiation therapy, along with 4-port irradiation(50.4 Gy)of the primary tumor, located at the interior of the pelvis and inguinal lymph nodes. At the time of treatment completion, a partial response(PR)was observed, and a complete response(CR)was obtained after 6 months. We performed laparoscopic abdominoperineal resection. The large defect in the perianal skin and the pelvic cavity was repaired using a hatchet flap. The final diagnosis was confirmed as mucinous adenocarcinoma, pT4b, ly0, v0, N0, pPM0, pDM0, pRM0, pStage II . The patient was discharged 20 days after surgery. There is no indication of recurrence of the cancer after 1 year, and he continues to visit the outpatient clinic for regular follow-ups. Neoadjuvant chemoradiotherapy was effective in this case.

Steps toward safe cell therapy using induced pluripotent stem cells.

The enthusiasm for producing patient-specific human embryonic stem cells using somatic nuclear transfer has somewhat abated in recent years because of ethical, technical, and political concerns. However, the interest in generating induced pluripotent stem cells (iPSCs), in which pluripotency can be obtained by transcription factor transduction of various somatic cells, has rapidly increased. Human iPSCs are anticipated to open enormous opportunities in the biomedical sciences in terms of cell therapies for regenerative medicine and stem cell modeling of human disease. On the other hand, recent reports have emphasized the pitfalls of iPSC technology, including the potential for genetic and epigenetic abnormalities, tumorigenicity, and immunogenicity of transplanted cells. These constitute serious safety-related concerns for iPSC-based cell therapy. However, preclinical data supporting the safety and efficacy of iPSCs are also accumulating. In this Review, recent achievements and future tasks for safe iPSC-based cell therapy are summarized, using regenerative medicine for repair strategies in the damaged central nervous system (CNS) as a model. Insights on safety and preclinical use of iPSCs in cardiovascular repair model are also discussed.

MRI findings and pathological features in early-stage glioblastoma.

Magnetic resonance imaging (MRI) is an important diagnostic tool for glioblastoma, with almost all cases showing characteristic imaging findings such as a heterogeneous-ring enhanced pattern associated with significant edema. However, MRI findings for early-stage glioblastoma are less clear. In this study, a retrospective review of MRI findings in five patients showed slight T2WI signal changes on initial scans that developed into typical imaging findings of a ring-like or heterogeneously enhanced bulky tumor within 6 months. The diagnoses based on initial MRI were low grade glioma in three cases, venous thrombosis in one case, and uncertain in one case. Four cases were treated with gross total resection, while one case underwent biopsy. Immunohistochemical examinations showed that two cases were p53-positive, and that all cases were IDH1 R132H-negative and had overexpression of EGFR. FISH analysis showed that all cases were 1p19q LOH-negative. De novo glioblastoma was the final diagnosis in all cases. Our results show that initial MRI findings in early-stage glioblastoma of small ill-defined T2WI hyperintense lesions with poor contrast develop to bulky mass lesions with typical findings for glioblastoma in as short a period as 2.5 months. The early MRI findings are difficult to distinguish from those for non-neoplastic conditions, including ischemic, degenerative or demyelinating processes. Thus, there is a need for proactive diagnosis of glioblastoma using short-interval MRI scans over several weeks, other imaging modalities, and biopsy or resection, particularly given the extremely poor prognosis of this disease.

Atypical extraventricular neurocytoma in a 3-year-old girl: case report with radiological-pathological correlation.

BACKGROUND: Extraventricular neurocytoma (EVN) is a rare neuronal tumor histologically similar to central neurocytoma but arising in the brain parenchyma outside the ventricles. The minority of EVNs show atypical features including increased proliferative index, microvascular proliferation, or necrosis, and are called atypical EVN. Most of atypical EVNs occur in adults, and the tumors in children are extremely rare. A radiological-pathological correlation and radiological clue to atypical EVNs have not been clarified. CASE REPORT: We report a case of atypical EVN in a 3-year-old girl. Magnetic resonance imaging (MRI) revealed an extraventricular intraparenchymal tumor in the left frontal lobe, which was composed of homogeneous well-demarcated cystic component and peripheral ill-delineated solid component with enhancement. Angiography demonstrated vascular proliferation and arteriovenous shunting in the tumor. Histologically, the resected tumor was diagnosed as atypical EVN. Types of the tumor borders (well-circumscribed or infiltrative) and MRI findings correlated closely. Morphology of the tumor vasculature was remarkable for microvascular proliferation and dilated, thickened veins, which corresponded to the angiographic features. CONCLUSION: Although rare, atypical EVN should be included in the differential diagnosis of a cystic mass in the cerebral hemispheres in children. Radiological evaluation of tumor borders and angiographic characteristics might be useful for predicting atypicality of the tumor.

Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice.

Once their safety is confirmed, human-induced pluripotent stem cells (hiPSCs), which do not entail ethical concerns, may become a preferred cell source for regenerative medicine. Here, we investigated the therapeutic potential of transplanting hiPSC-derived neurospheres (hiPSC-NSs) into nonobese diabetic (NOD)-severe combined immunodeficient (SCID) mice to treat spinal cord injury (SCI). For this, we used a hiPSC clone (201B7), established by transducing four reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc) into adult human fibroblasts. Grafted hiPSC-NSs survived, migrated, and differentiated into the three major neural lineages (neurons, astrocytes, and oligodendrocytes) within the injured spinal cord. They showed both cell-autonomous and noncell-autonomous (trophic) effects, including synapse formation between hiPSC-NS-derived neurons and host mouse neurons, expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. These positive effects resulted in significantly better functional recovery compared with vehicle-treated control animals, and the recovery persisted through the end of the observation period, 112 d post-SCI. No tumor formation was observed in the hiPSC-NS-grafted mice. These findings suggest that hiPSCs give rise to neural stem/progenitor cells that support improved function post-SCI and are a promising cell source for its treatment.

Association of the five-factor personality model with prefrontal activation during frontal lobe task performance using two-channel near-infrared spectroscopy.

AIM: The aim of this study was to investigate the biological background of the five-factor model using near-infrared spectroscopy and cognitive tasks. METHODS: Twenty right-handed healthy volunteers participated in this study. Their personality traits were assessed using the NEO Five-Factor Inventory, and changes in oxyhemoglobin concentration ([oxy-Hb]) were measured during cognitive tasks using a wireless near-infrared spectroscopy. RESULTS: The average [oxy-Hb] in the right prefrontal area had a significant positive correlation with the agreeableness score during the Stroop test at incongruent stimulus block. For the verbal fluency task, there were no significant correlations of bilateral [oxy-Hb] changes with any items. CONCLUSION: Higher agreeableness scores may involve less suppression to the default mode network related to resting state brain function. Keeping selective attention during the Stroop test may require more power of concentration than retrieving words during the verbal fluency task.

[Assessment of traumatic rib fractures caused by traffic accident].

We reviewed 66 cases of traumatic rib fracture by traffic accident between January 2009 and December 2011. The age of patients ranged from 18 to 88 years, with an average age of 55.6, and they were predominantly male. They met with traffic accident when driving automobiles in 30 cases, driving motorcycles in 15 cases, and walking in 9 cases. The average number of fractured ribs was 4.1±3.2.Multiple rib fractures were observed in 75.8% of patients. Injuries other than rib fractures were involved in all patients who suffered over 7 rib fractures. Except one who died of pneumonia 62 days after traffic accident, 7 of 8 patients died within 48 hours:6 in a shock state and 1 in cardiac pulmonary arrest on arrival. About 80 % of the patients with rib fractures were hospitalized. As traffic accidents could cause any type of injuries including rib fractures, it is important to examine the whole body when patients were transported to a hospital.

[Two cases of dural metastasis of breast cancer].

The first case of dural metastasis occurred in a 60s years old woman, who presented with bone metastasis to the right breast. Nine months later, disorientation and left hemiplegia developed, the right coronal bone metastasis enlarged, and dural metastases were detected close to the tumor, as observed by using cranial magnetic resonance imaging (MRI). Whole brain radiation and chemotherapy(weekly paclitaxel)were administered. The right coronal bone metastasis reduced remarkably, and the dural metastases almost disappeared, as observed on a cranial MRI scan. The second case of dural metastasis occurred in a 50s years old woman who presented with multiple bone metastases. Extensive bone metastases to the skull and dural metastases to the side of the head were observed on cranial MRI scans. Subsequently, the patient experienced a severe headache, and whole brain radiation and pharmacotherapy with anastrozole and trastuzumab were administered. Cranial MRI revealed that the skull bone metastasis reduced and the dural metastases almost disappeared. We report that radiotherapy and pharmacotherapy were effective in these 2 cases of dural metastases of breast cancer.

[A case of gallbladder carcinoma following cholecystogastric fistula].

A 79-year-old woman with pneumobilia and liver dysfunction was admitted to our hospital. ERCP and gastrointestinal endoscopy revealed choledochal stones and a cholecystogastric fistula at the greater curvature of the gastric antrum. The risk of cholecystectomy and fistulectomy appeared to be extremely high for this patient because of her advanced age and low respiratory function due to interstitial pneumonia. Therefore, only an endoscopic lithotomy was performed, and the cholecystogastric fistula remained. However, after 2 years of follow-up, she developed an advanced gallbladder carcinoma. This finding suggests that cholecystogastric fistula is a risk factor for gallbladder carcinoma. Because of the difficulty of early detection of gallbladder carcinoma associated with cholecystogastric fistula, both fistulectomy and cholecystectomy are necessary when cholecystogastric fistula is diagnosed.