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Cervical esophageal adenocarcinoma has a low incidence rate and its treatment involves various strategies. We report a patient with locally advanced cervical to upper esophageal adenocarcinoma who was able to undergo induction chemotherapy and radical surgery. A 55-year-old man was diagnosed with a poorly differentiated adenocarcinoma between the cervical and upper thoracic esophagus. The primary lesion had infiltrated into the tracheal membrane and had metastasized into the cervical lymph nodes. The initial diagnosis was T4bN1M1 stage IVB. The lower edge of the tumor was close to the tracheal bifurcation, making it difficult to create a longitudinal tracheal foramen during surgery. Therefore, when biweekly-DCF therapy was performed as induction chemotherapy, the tumor shrank sufficiently and its infiltration into the tracheal membrane decreased subsequently. We performed total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route and a permanent tracheal foramen as a radical surgery. The pathological diagnosis was T2/MP, N1, and the effect of chemotherapy was grade 2. Cervical esophageal adenocarcinoma was rare, but technically reliable and safe oncologic surgery was possible after induction chemotherapy.

Introduction Acute funisitis, a granulocyte-related inflammation of the umbilical cord, is associated with chorioamnionitis and perinatal adverse events. However, there is no efficient procedure for detecting clinically relevant umbilical cord inflammation. The objective of this study was to identify such inflammation, based on immunohistochemical assessment of umbilical cord vasculitis patterns. Methods Accordingly, 261 cases were retrieved from a single medical institute. Using the well-established granulocyte marker CD15, we developed a five-tier umbilical cord inflammation-scoring system. Additionally, previous morphological assessments from pathological reports were compared to the immunohistochemical findings. Results Analysis of results based on our new scoring system revealed that severe umbilical phlebitis (score 3) was significantly associated with maternal inflammatory response and that severe umbilical arteriophlebitis (score 4) was correlated with low umbilical arterial blood pH, a feature linked to fetal mortality and morbidity. These results corresponded with and were validated by the morphology-based assessments. Additionally, immunohistochemical analysis revealed the clinical and pathological relevance of vitelline vasculitis, a recently proposed condition. We found that analyzing three umbilical cord sections enabled superior detection of severe umbilical vasculitis than analyzing two sections. However, whether these sections were sampled from multiple distant sites or a single localized site did not significantly affect the detection of clinically relevant inflammation. Discussion CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation. CD15 immunohistochemistry is a potent tool for observing the patterns of clinically relevant umbilical vasculitis, especially in cases that were indeterminate according to morphology alone. Sampling three umbilical cord sections was an efficient procedure for addressing the spatial heterogeneity of umbilical cord inflammation.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16INK4a and p14ARF (p19ARF in mice), encoding two unrelated proteins in alternative reading frames. Previous reports suggest that p16INK4a and p14ARF alterations independently exhibit differential roles, and p16INK4a is more closely associated with a poor prognosis in oral cancer. However, the role of p16INK4a-specific loss in oral squamous cell carcinogenesis remains unclear. The authors assessed chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced multistep oral squamous cell carcinogenesis in mice carrying p16INK4a-specific loss with retention of the p19ARF gene (p16INK4a-/-). 4NQO-treated p16-/- mice exhibited a higher incidence and multiplicity of oral squamous cell carcinoma (OSCC) development relative to 4NQO-treated wild-type mice. 4NQO-treated p16INK4a-/- OSCC cells exhibited higher proliferation and up-regulation of Arf, transcription factor E2f1, tumor protein p63 (tp63), and oncogenic ΔNp63, an isoform p63, compared with observations in 4NQO-treated wild-type OSCC cells. Furthermore, the overexpression of oncogenic ΔNp63 was associated with human OSCC. In conclusion, these results in mice indicate the biological significance of p16INK4a-specific loss with retention of p19ARF in oral squamous cell carcinogenesis, and ΔNp63 may be a potential target for OSCC.

Malignant pleural effusion (MPE) can accompany advanced lung adenocarcinoma. Recent studies suggest that MPE could contain a heterogeneous subpopulation of cells with stem-like properties, such as tumorigenicity and self-renewal, indicating that they could be the source of metastasis. Although previous studies analyzed the correlation between cancer stem cell (CSC) marker expression and clinical outcomes using lung cancer tissues, investigations regarding the association of MPE with CSC marker expression are limited. We performed immunohistochemistry to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and Sal-like 4 (SALL4) in 46 cell block samples of MPE from patients with lung adenocarcinoma. ALDH1-positive and SALL4-positive cancer cells in MPE were detected in 30 (65.2%) and 21 samples (45.7%), respectively. Cluster formation was detected in 26 samples (56.5%). The number of clusters was significantly higher in ALDH1-positive/SALL4-negative samples. SALL4 expression was inversely correlated with the cluster ratio (r = −0.356) and positively associated with the Ki-67 index (r = 0.326), suggesting that MPE cells with high SALL4 expression comprised the proliferative subpopulation. In conclusion, we demonstrated that MPE contains an ALDH1-positive/SALL4-negative subpopulation exhibiting cluster formation and a SALL4-positive proliferative subpopulation.

Background Kaposiform lymphangiomatosis (KLA) is a recently characterized systemic lymphatic anomaly. Activation of RAS/MAPK and PI3K/AKT/mTOR pathways may affect KLA pathogenesis, but the cellular basis of KLA is unclear. Abnormal-spindle endothelial cells that express lymphatic endothelial cell (LEC) markers are characteristic of KLA histopathology. This study evaluated patient-derived KLA cells to establish their morphological and biological characteristics. Procedure We established cell lines from primary KLA tissues of two patients with KLA and examined their morphological and functional characteristics, messenger RNA and protein expression profiles, gene mutations, and responses to inhibitors of the RAS/MAPK and PI3K/AKT/mTOR pathways. Results Both KLA cell lines showed spindle-shaped morphology, stained positive for podoplanin (PDPN), and exhibited impaired tube-formation properties. They expressed LEC marker PDPN and mesenchymal stem cell markers (CD90, CD105) in the absence of endothelial cell markers (CD34, CD31, VWF), per real-time polymerase chain reaction. Both mTOR inhibitor rapamycin and MEK inhibitor trametinib inhibited growth of the two cell lines. A NRAS p.Q61R variant was found in one of two independent KLA tissue samples, but not in the KLA cells (per targeted next-generation sequencing); and KLA cells with this variant had elevated AKT phosphorylation levels. ERK phosphorylation levels were undetectable in both KLA cell lines. Conclusions Inhibition of the RAS/MAPK and PI3K/AKT/mTOR pathways may represent potential therapeutic targets in KLA. These patient-derived KLA cell lines will be useful research tools to elucidate KLA etiology, and could pave the way for basic, translational, and preclinical studies of this disease.

Summary Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking, and IPNB pathogenesis remains unclear. Here, we use a doxycycline-inducible tetracycline (Tet)-on mice model to control fibroblast growth factor 10 (FGF10) expression, which regulates branching and tubule formation. FGF10-induced IPNB mimics the multifocal and divergent human IPNB phenotypes via the FGF10-FGF receptor 2 (FGFR2)-RAS-extracellular-signal-regulated kinase (ERK) signaling pathway. A paracrine/autocrine growth factor is sufficient to initiate and maintain IPNB originating from the peribiliary glands, including biliary stem/progenitor cells. With KrasG12D, p53, or p16 mutations or both, Fgf10-induced IPNB shows stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes and progression are suppressed by the inhibition of the FGF10-FGFR2-RAS-ERK signaling pathway, demonstrating that the signal is a therapeutic target for IPNB and associated carcinoma.

BackgroundCervical esophageal adenocarcinoma has a low incidence rate and its treatment involves various strategies. We report a patient with locally advanced cervical to upper esophageal adenocarcinoma, able to undergo induction chemotherapy and radical surgery. We report our case as a valuable clinical experience.Case presentationThe patient complained of throat stuffiness. We found a poorly differentiated adenocarcinoma between the cervical esophagus and the upper thoracic esophagus. The primary lesion had infiltrated into the tracheal membrane and had metastatized into the cervical lymph nodes. The initial diagnosis was T4bN1M0 stage IVA. The lower edge of the tumor was close to the tracheal bifurcation, making it difficult to create a longitudinal tracheal foramen during surgery. Therefore, when biweekly-DCF therapy was performed as induction chemotherapy, the tumor shrank sufficiently. Furthermore, tumor infiltration into the tracheal membrane decreased, allowing us to perform total laryngopharyngoesophagectomy with three-field lymph node dissection and reconstruction using free jejunal grafts and subtotal stomach via a posterior mediastinum route and a permanent tracheal foramen as a radical surgery. The pathological diagnosis was T2/MP, N1, and the effect of chemotherapy was grade 2. The patient is followed-up regularly.ConclusionsCervical esophageal adenocarcinoma was rare, but technically reliable and safe oncologic surgery was possible after induction chemotherapy.

The use of molecular biomarkers for the early detection of heart disease, before their onset of symptoms, is an attractive novel approach. Ideal molecular biomarkers, those that are both sensitive and specific to heart disease, are likely to provide a much earlier diagnosis, thereby providing better treatment outcomes. Galectin-3 is expressed by various immune cells, including mast cells, histiocytes and macrophages, and plays an important role in diverse physiological functions. Since galectin-3 is readily expressed on the cell surface, and is readily secreted by injured and inflammatory cells, it has been suggested that cardiac galectin-3 could be a marker for cardiac disorders such as cardiac inflammation and fibrosis, depending on the specific pathogenesis. Thus, galectin-3 may be a novel candidate biomarker for the diagnosis, analysis and prognosis of various cardiac diseases, including heart failure. The goals of heart disease treatment are to prevent acute onset and to predict their occurrence by using the ideal molecular biomarkers. In this review, we discuss and summarize recent developments of galectin-3 as a next-generation molecular biomarker of heart disease. Furthermore, we describe how galectin-3 may be useful as a diagnostic marker for detecting the early stages of various heart diseases, which may contribute to improved early therapeutic interventions.

Ischemia-reperfusion injuries produce reactive oxygen species that promote the peroxide lipid oxidation process resulting in the production of an endogenic lipid peroxide, 4-hydroxy-trans-2-nonenal (4-HNE), a highly cytotoxic aldehyde that induces cell death. We synthesized a novel 4-HNE scavenger - a carnosine-hydrazide derivative, l-carnosine hydrazide (CNN) - and examined its neuroprotective effect in a model of transient ischemia. PC-12 cells were pre-incubated with various doses (0-50 mmol/L) of CNN for 30 min, followed by incubation with 4-HNE (250 μM). An MTT assay was performed 24 h later to examine cell survival. Transient ischemia was induced by bilateral common carotid artery occlusion (BCCO) in the Mongolian gerbil. Animals were assigned to sham-operated (n = 6), placebo-treated (n = 12), CNN pre-treated (20 mg/kg; n = 12), CNN post-treated (100 mg/kg; n = 11), and histidyl hydrazide (a previously known 4-HNE scavenger) post-treated (100 mg/kg; n = 7) groups. Heat shock protein 70 immunoreactivity in the hippocampal CA1 region was evaluated 24 h later, while delayed neuronal death using 4-HNE staining was evaluated 7 days later. Pre-incubation with 30 mmol/L CNN completely inhibited 4-HNE-induced cell toxicity. CNN prevented delayed neuronal death by60% in the pre-treated group (p 0.001) and by40% in the post-treated group (p 0.01). Histidyl hydrazide post-treatment elicited no protective effect. CNN pre-treatment resulted in high heat shock protein 70 and low 4-HNE immunoreactivity in CA1 pyramidal neurons. Higher 4-HNE immunoreactivity was also found in the placebo-treated animals than in the CNN pre-treated animals. Our novel compound, CNN, elicited highly effective 4-HNE scavenging activity in vitro. Furthermore, CNN administration both pre- and post-BCCO remarkably reduced delayed neuronal death in the hippocampal CA1 region via its induction of heat shock protein 70 and scavenging of 4-HNE.

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.

Phactr1 (Phosphatase and actin regulator 1) is abundantly expressed in the central nervous system and considered to regulate various neuronal processes through the regulation of protein phosphorylation and actin cytoskeletal organization. In this study, we prepared a specific antibody against Phactr1, anti-Phactr1, and carried out biochemical and morphological analyses of Phactr1 with mouse brain tissues. Western blotting analyses revealed that Phactr1 was expressed in a tissue-dependent profile in the young adult mouse and in a developmental stage-dependent manner in the mouse brain. In primary cultured hippocampal neurons, while Phactr1 was diffusely distributed in the nucleus and cytoplasm, it was visualized in axon and dendrites with partial colocalization with synapses. Phactr1 was also detected in the synaptosomal and postsynaptic density fractions in biochemical fractionation. Immunohistochemical analyses clarified that Phactr1 was differentially expressed in cortical neurons during corticogenesis; the protein was frequently accumulated in the nucleus at the embryonic stage while it came to diffusely distribute in the cell body at the prepubertal stage. The obtained results suggest that Phactr1 takes part in neuronal functions regulated in a spatiotemporal manner.

// Ayumi Niwa 1, * , Seiya Kuwano 1, * , Hiroyuki Tomita 1 , Keita Kimura 1 , Yukiya Orihara 1 , Tomohiro Kanayama 1 , Kei Noguchi 1 , Kenji Hisamatsu 1 , Takayuki Nakashima 1 , Yuichiro Hatano 1 , Akihiro Hirata 2 , Tatsuhiko Miyazaki 3 , Kazuhiro Kaneko 4 , Takuji Tanaka 5 and Akira Hara 1 1 Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan 2 Division of Animal Experiment, Life Science Research Center, Gifu University, Gifu, Japan 3 Division of Pathology, Gifu University Hospital, Gifu, Japan 4 Department of Gastroenterology, Endoscopy Division, National Cancer Center Hospital East, Kashiwa, Japan 5 Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu, Japan * These authors have contributed equally to this work Correspondence to: Hiroyuki Tomita, email: h_tomita@gifu-u.ac.jp Keywords: duodenal neoplasms, beta-catenin Received: October 24, 2016 Accepted: February 27, 2017 Published: April 12, 2017 ABSTRACT Non-ampullary duodenal adenoma with activation of Wnt/β-catenin signalling is common in familial adenomatous polyposis (FAP) patients, whereas sporadic non-ampullary adenoma is uncommon. The adenoma-carcinoma sequence similar to colon cancer is associated with duodenal tumors in FAP, but not always in sporadic tumors. We obtained 37 non-ampullary duodenal tumors, including 25 adenomas and 12 adenocarcinomas, were obtained from biopsies and endoscopic resections. We performed immunohistochemistry for β-catenin, the hallmark of Wnt activation, and aldehyde dehydrogenase 1 (ALDH1), a putative cancer stem cell marker. In non-ampullary lesions, abnormal nuclear localization of β-catenin was observed in 21 (84.0%) of 25 adenomas and 4 (33.3%) of 12 adenocarcinomas. In the proximal duodenum, nuclear β-catenin was less frequent in both adenomas and adenocarcinomas. Gastric duodenal metaplasia (GDM) was observed only in the proximal duodenum. All adenomas with GDM were the gastric foveolar and pyloric gland types, and showed only membranous β-catenin. The intestinal-type adenomas had nuclear β-catenin in the proximal and distal duodenum. ALDH1-positive cells were more frequent in adenocarcinomas than adenomas. Nuclear β-catenin accumulation frequently occurred in ALDH1-positive cells in adenoma, but not in adenocarcinoma. In the non-ampullary proximal duodenum, Wnt/β-catenin pathway activation was more closely associated with adenomas than adenocarcinomas, and while it might cooperate with ALDH1 in adenoma, it does not in adenocarcinoma. The pathogenesis thus may differ between sporadic adenoma and adenocarcinoma of non-ampullary duodenal lesions, especially in the proximal and distal duodenum.

Background Symptomatic bilateral extracranial internal carotid artery (ICA) aneurysms at the subpetrosal portion are extremely rare, and their treatment strategy remains unknown. Clinical Presentation A 42-year-old man presented to our hospital with a 2-month history of sudden onset of hoarseness, dysarthria, and dysphagia. Magnetic resonance imaging, magnetic resonance angiography, and computed tomography angiography revealed extracranial bilateral ICA aneurysms at the subpetrosal portion. The left-sided aneurysm compressed the left-sided lower cranial nerves (IX, X, XI, and XII), whereas the right-sided aneurysm was asymptomatic. We prioritized the treatment of the right-sided aneurysm to prevent bilateral lower cranial nerve deficits. This strategy was used because aneurysm treatment is not guaranteed to cure the left-sided cranial nerve palsies that lasted for 2 months. The right-sided ICA aneurysm was treated with ICA ligation and high-flow extracranial–intracranial bypass using the radial artery as bypass graft. Stent-assisted coil embolization was performed to the left-sided ICA aneurysm after 17 days. The patient showed no right-sided symptoms, and his left-sided symptoms remarkably improved 1 year after surgery. Conclusion Our unique surgical strategy of prioritizing the aneurysm on the “asymptomatic” side may be one of the best treatment approaches in an extremely rare bilateral aneurysm case.

The cyclin-dependent kinase inhibitor 2A (CDKN2A)/alternate reading frame (ARF) locus consists of two overlapping tumor suppressor genes, p16

Serrated lesions in the colorectum are currently predominantly classified as hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas (TSAs) according to their morphology. However, the histological morphology and the molecular changes in the serrated lesions are still unclear. We performed immunohistochemistry for Ki67, p16INK4a, and WNT5A in human HPs (n=22), SSA/Ps (n=41), and TSAs (n=19). The distribution of Ki67 and p16INK4a positive cells in TSAs was different from that in HPs and SSA/Ps. Co-expression of Ki67 and P16INK4a was infrequent in HPs and SSA/Ps; p16INK4a-positive cells were found in the crypt cleft and stromal WNT5A-positive stromal cells were localized near the cleft in SSA/Ps, while intraepithelial lymphocytes (IELs) in SSA/Ps were more abundant than HPs. In conclusion, our study provides evidence that HPs branch because of the increase in and patchy distribution of senescent and proliferative cells, with increased and misdistributed stromal and inflammatory cells, which might contribute to creation of L- and/or T-shaped crypts, which are of distinctive shapes in SSA/Ps. Our findings may facilitate better understanding and therapy in the serrated lesions.

Prognosis after extracranial-intracranial (EC-IC) bypass surgery has only been studied for a few years and the benefits of this procedure are still controversial. In this single-center retrospective study, we examined the long-term prognosis of patients who underwent EC-IC bypass surgery. Subjects were patients with symptomatic internal carotid artery or intracranial lesion occlusive disease who underwent EC-IC bypass surgery between 1991 and 2003. Of these, long-term prognosis was examined in 57 patients (39 male, 18 female; mean age, 61.8 years) who showed good surgical outcomes 30 days after bypass surgery, measured as a 0-2 on the modified Rankin Scale (mRS). They were divided into 2 groups (survivors and non-survivors) and were analyzed to identify factors effecting long-term survival after bypass surgery. Sixteen patients (28%), whose mean follow-up period (survival time) was 8.3±3.8 years, died after the bypass surgery. The average follow-up period for the survivors was 12.0±1.1 years, which was significantly longer than that for the non-survivors (P

Evidence regarding intraductal papillary neoplasm of the bile duct (IPNB) as a new type of precancerous lesion of cholangiocarcinoma is limited. Moreover, a reproducible in vivo model is lacking and IPNB pathogenesis remains unclear. Here, we used a doxycycline-inducible Tet-on mice model facilitating the control of fibroblast growth factor 10 (FGF10) expression which contributes to branching and tubule formation. FGF10-induced IPNB mimicked the multifocal and divergent human IPNB phenotypes via the FGF10–FGFR2–RAS–ERK signalling pathway. A paracrine/autocrine growth factor was sufficient for the initiation and maintenance of IPNB originating from the peribiliary glands, including the biliary stem/progenitor cells. With KrasG12D, p53 and/or p16 gene alterations, Fgf10-induced IPNB showed stepwise carcinogenesis, causing associated invasive carcinoma. Fgf10-induced papillary changes were suppressed by FGF10–FGFR2–RAS–ERK signalling inhibition, which was inhibited with a MEK inhibitor, demonstrating that the signal is a novel therapeutic target for IPNB and associated carcinoma.

Glioblastoma (GBM) is the most common and the most malignant primary brain tumor and is characterized by rapid proliferation, invasion into surrounding normal brain tissues, and consequent aberrant vascularization. In these characteristics of GBM, invasive properties are responsible for its recurrence after various therapies. The histomorphological patterns of glioma cell invasion have often been referred to as the “secondary structures of Scherer.” The “secondary structures of Scherer” can be classified mainly into four histological types as (i) perineuronal satellitosis, (ii) perivascular satellitosis, (iii) subpial spread, and (iv) invasion along the white matter tracts. In order to develop therapeutic interventions to mitigate glioma cell migration, it is important to understand the biological mechanism underlying the formation of these secondary structures. The main focus of this review is to examine new molecular pathways based on the histopathological evidence of GBM invasion as major prognostic factors for the high recurrence rate for GBMs. The histopathology-based pharmacological and biological targets for treatment strategies may improve the management of invasive and resistant GBMs.

Background Direct and/or indirect bypass surgery is the established approach for preventing stroke in patients with moyamoya disease. However, conventional indirect revascularization, including encephalo-myo-synangiosis, has some disadvantages associated with the mass effect of the temporal muscle under the bone flap and postsurgical depression in the temporal region. We devised a novel indirect revascularization method, using only the temporal fascia, to address the aforementioned disadvantages. Methods A skin incision was performed along the superficial temporal artery. The temporal fascia was cut such that the base of the fascia flap was on the posterior side. The fascia and temporal muscles were dissected separately. After turning over the fascia, the muscle was cut such that the base of the muscle flap was on the anterior side. Craniotomy, direct bypass, and encephalo-duro-synangiosis were performed conventionally. Only the temporal fascia was used for indirect revascularization and duraplasty. The muscle was replaced in the anatomically correct position after replacing the bone flap. Results We performed the aforementioned surgery on 18 (13 women and 5 men) consecutive patients (21 cerebral hemispheres) enrolled between 2012 and 2016. The average age was 28.7 years. The mean follow-up period was 31.6 months. In 17 patients (94%), the symptoms and cerebral blood flow improved. Digital subtraction angiography showed satisfactory angiogenesis from the temporal fascia. Depression in the temporal region and atrophy of the temporal muscle were negligible. Conclusions This surgical technique provides good clinical and cosmetic outcomes. It may also be one of the good surgical treatments available for symptomatic moyamoya disease.

Background Some patients with moyamoya disease (MMD) show broad infarction with moderate internal carotid artery (ICA) stenosis, whereas others with complete ICA occlusion show no infarction. This suggests that other factors contribute to the occurrence of infarction. Contributing factors predictive of cerebral infarcts must be identified for the prevention of infarction and the consequent neurological deficits. Methods We examined data from 93 patients with confirmed MMD for the presence of infarction (n = 72), transient ischemic attack (TIA, n = 41), asymptomatic presentation (n = 51), or hemorrhage (n = 22) in 186 bilateral cerebral hemispheres. We analyzed the relationship between the occurrence of infarction and several clinical factors, such as steno-occlusive status or the site of the ICA and posterior cerebral artery (PCA). Results The incidence of PCA steno-occlusive lesions was significantly higher in infarcted (77.8%) than in non-infarcted hemispheres (TIA, 14.6%; asymptomatic, 9.8%; hemorrhagic 9.1%; P < 0.01). The steno-occlusive site of ICA was also a significant factor (P < 0.05). There was no significant correlation between the occurrence of infarction and the steno-occlusive status of the ICA or grade of the moyamoya vessels. Multivariate statistical analysis demonstrated that the PCA steno-occlusive changes were an important contributing factor for infarction (P < 0.0001). Conclusions This is the multivariate statistical analysis study identifying PCA steno-occlusive lesions as the most important independent factor that is predictive to cerebral infarction in moyamoya patients. The prediction and inhibition of PCA steno-occlusive changes may help to prevent cerebral infarction.

Liver bipotential stem/progenitor cells can give rise to both hepatocytes and cholangiocytes. These cells might also be potential sources of liver cancers, such as hepatocellular carcionoma (HCC) and cholangiocarcinoma (CCA), and both are heterogeneous malignancies. Further, combined HCC-intrahepatic CCA, a form of primary liver cancer showing features of both hepatocellular and biliary epithelial differentiation, has also been reported, supporting the existence of bipotent cancer stem cells in liver. HCC, CCA, and HCC-intrahepatic CCA are heterogeneous in the diagnosis by immunohistochemistry and include a subset of cells expressing various stem cell markers. In this chapter, we summarize the current knowledge of stem cells in normal liver and liver cancers and discuss the controversial points.

Oral squamous cell carcinoma (OSCC) develops through a multistep carcinogenic process involving field cancerization. The DEK gene is a proto‐oncogene with functions in genetic and epigenetic modifications, and has oncogenic functions, including cellular proliferation, differentiation, and senescence. DEK overexpression is associated with malignancies; however, the functional roles of DEK overexpression are unclear. We demonstrated that DEK‐expressing cells were significantly increased in human dysplasia/carcinoma in situ and OSCC. Furthermore, we generated ubiquitous and squamous cell‐specific doxycycline (DOX)‐inducible Dek mice (iDek and iDek‐e mice respectively). Both DOX+ iDek and iDek‐e mice did not show differences in the oral mucosa compared with DOX‐ mice. In the environment exposed to carcinogen, DOX‐treated (DOX+) iDek mice showed field cancerization and OSCC development. Microarray analysis revealed that DEK overexpression was mediated by the upregulation of DNA replication‐ and cell cycle‐related genes, particularly those related to the G 1/S transition. Tongue tumors overexpressing DEK showed increased proliferating cell nuclear antigen and elongator complex protein 3 expression. Our data suggest that DEK overexpression enhanced carcinogenesis, including field cancerization, in OSCC by stimulating the G 1/S phase transition and promoting DNA replication, providing important insights into the potential applications of DEK as a target in the treatment and prevention of OSCC.

Background: Treatment of anterior choroidal artery (AChA) aneurysms with endovascular coiling or surgical clipping may increase the risk of ischemic complications owing to the critical territory supplied by the AChA. We analyzed the surgical results of endovascular coiling and surgical clipping for AChA aneurysms performed in a single institution, as well as the role of indocyanine green-videoangiography (ICG-VAG) and motor-evoked potential (MEP). Methods: We analyzed 50 patients (51 aneurysms; 21 men, 29 women; mean age: 58 years) including 25 with subarachnoid hemorrhage treated with endovascular coiling or surgical clipping between April 1990 and October 2013. The complication rates and clinical outcomes of the coil group (mean follow-up: 61 months) and the clip group (mean follow-up: 121 months) were analyzed with a modified Rankin scale. Results: The overall clinical outcome of the coil group (95%) was better than that of the clip group (85%). Especially, the outcomes in the coil group were better in the first investigated period (1990–2007) (P < 0.05). However, after the introduction of ICG-VAG and MEP, the outcomes in the clip group improved significantly (P = 0.005), and treatment-related complications decreased from 20 to 4.7%. Eleven aneurysms (coil group: 8, clip group: 3) showed small neck remnants but no remarkable regrowth, except for 1 case during the mean follow-up period of 91 months. Conclusions: Surgical clipping of AChA aneurysms has become safer because of ICG-VAG and MEP monitoring. Coiling and clipping of AChA aneurysms showed good and comparable outcomes with these monitoring methods.

Hydrogen embrittlement is a serious problem in high-strength steels. Drawn pearlitic steel shows excellent resistance to hydrogen embrittlement despite its high strength, and aging treatment at a low temperature can simultaneously improve its strength and hydrogen-embrittlement resistance. To clarify the mechanism for this we have used thermal desorption analysis (TDA) and the newly developed precession electron diffraction analysis method in the transmission electron microscope. After aging at 100 °C for 10 min, the amount of hydrogen seen amount on the TDA curve reduced at around 100 °C. In contrast, when aging was performed at 300 °C, the hydrogen amount further reduced at around 100 °C and the unevenly deformed lamellar ferrite zone was locally recovered. For the samples that were aged at the low temperature, we confirmed that their yield strength and relaxation stress ratios increased simultaneously with improvement in the hydrogen-embrittlement property. We infer that segregation of carbon or formation of very fine carbide in dislocations during aging is the cause of these behaviors.

A 78-year-old Japanese man with adult-onset Still's disease that was refractory to conventional treatment, such as prednisolone (PSL) concomitant with methotrexate (MTX). Etanercept (50 mg/week) was added to PSL (12.5 mg/day) and MTX (12 mg/week). His manifestation improved dramatically, nonetheless massive edema of the periorbital region developed by the fourth injection, which kept his palpebral fissure completely closed. There was also a marked injection site reaction to etanercept. A diagnosis of angioedema due to etanercept was thus made, and the drug was discontinued. His angioedema began to ameliorate soon after antihistamines were introduced without any critical involvement, such as laryngeal obstruction.

Kenji Inoue1, Kei Noguchi1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, Tokyo; 22nd Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanPurpose: To prospectively evaluate the diurnal variation of intraocular pressure (IOP) during unoprostone treatment in 13 healthy volunteers.Method: IOP was measured by Goldmann applanation tonometry by the same observer every 3 hours from 9 am to 9 am the next morning. Unoprostone was then instilled at 9 am and 9 pm daily for 1 month. After 1 month, IOP was measured again with unoprostone instilled at 9 am and 9 pm during IOP measurement. We then compared the average daily IOP before and after the treatment (paired t-test).Results: After 1 month of treatment, the average IOP decreased at every time point but one (12 pm, 3 pm, 6 pm, 9 pm, 12 am, 3 am, and 9 am, but not at 6 am). There were no adverse reactions and none of the subjects discontinued unoprostone.Conclusion: The hypotensive effects of unoprostone persist throughout the day, but this study suggests that the effects may be weaker at nighttime and early in the morning.Keywords: unoprostone, intraocular pressure, diurnal variation, healthy volunteer

Background: Ischemic stroke associated with an anomaly of the middle cerebral artery (MCA) is a rare occurrence. The diagnosis is very difficult when there are steno-occlusive lesions associated with an accessory middle cerebral artery (AMCA). Case Description: A 77-year-old female with hypertension and hyperlipidemia experienced repeated transient ischemic attacks (TIAs) of motor aphasia and dysarthria. Although angiography showed only left intracranial occlusion, the fusion images of three-dimensional digital subtraction angiography (3-D DSA) showed complex steno-occlusive lesions and an AMCA related with the TIA. The cerebral blood flow (CBF) to the left frontal lobe was supplied by the AMCA, via the anterior communicating artery from the right internal carotid artery. The left temporal and parietal lobes were supplied by the stenotic MCA, via the left posterior communicating artery from the left posterior cerebral artery. Single-photon emission computed tomography showed a marked decrease in CBF to both the left frontal and temporal lobes. A left superficial temporal artery (STA)-to-left MCA double anastomosis was performed, in which each branch of the STA supplied branches of the AMCA and MCA. Conclusion: This is the first reported case of ischemic stroke in a patient with an AMCA. The exact diagnosis could be made only by using fusion images of 3-D DSA, which were useful for understanding the complicated CBF pattern and for the choice of recipient artery in bypass surgery.

Kenji Inoue1, Kei Noguchi1, Masato Wakakura1, Goji Tomita21Inouye Eye Hospital, 2Second Department of Ophthalmology, Toho University School of Medicine, Tokyo, JapanBackground: The purpose of this study was to evaluate the effects of topical nipradilol monotherapy for 5 years on intraocular pressure, visual field performance, and optic disk topography.Methods: Thirty patients with normal tension glaucoma were monitored for intraocular pressure every 1–3 months. A Humphrey visual field test and measurement of optic disk configuration using the Heidelberg retina tomograph II was done after every year of treatment and the results compared with those before treatment. Visual field performance was also evaluated by trend and event analysis.Results: The mean intraocular pressure ± standard deviation after 3 years of nipradilol treatment (14.1 ± 2.0 mmHg) and after 5 years of nipradilol treatment (13.7 ± 2.1 mmHg) was significantly lower than that before treatment (17.0 ± 1.8 mmHg, P< 0.0001). Heidelberg retina tomograph II parameters, such as mean cup depth and height variation contour after treatment, were significantly increased compared with those before treatment. Visual field performance worsened in eight eyes by trend analysis and eight eyes by event analysis.Conclusion: Nipradilol monotherapy was effective in reducing intraocular pressure over at least 5 years without worsening of optic disk topography. Furthermore, mean cup depth and height variation contour were also significantly improved. However, visual field performance worsened in 16.0% of patients with normal tension glaucoma.Keywords: nipradilol, intraocular pressure, Heidelberg retina tomograph II, trend analysis, event analysis