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Neural vasculature forms the blood–brain barrier against the delivery of systemically administered therapeutic drugs into parenchyma of neural tissues. Therefore, procedures to open the blood–brain barrier with minimal damage to tissues would lead to the great progress in therapeutic strategy for intractable neural diseases. In this study, through analyses with mouse in vitro brain microvascular endothelial cells and in vivo neural vasculature, we demonstrate that the administration of cyclophilin A (CypA), a ligand of basigin which is expressed in barrier-forming endothelial cells, realizes the artificial opening of blood–brain barrier. Monolayers of endothelial cells lost their barrier properties through the disappearance of claudin-5, an integral tight junction molecule, from cell membranes in a transient and reversible manner. Furthermore, the intravenous injection of a single dose of CypA into mice resulted in the opening of blood–brain barrier for a certain period which enabled the enhanced delivery of systemically administered doxorubicin into the parenchyma of neural tissues. These findings that the pre-injection of a single dose of CypA realizes an artificial, transient as well as reversible opening of blood–brain barrier are considered to be a great step toward the establishment of therapeutic protocols to overcome the intractability of neural diseases.

Air leakage is a common complication after pulmonary resection, and fibrin glue is used as a sealant to reduce postoperative air leakage. It is generally recognized that fibrin glue‐induced adverse events are rare. Herein, we report a rare case of suspected fibrin glue‐induced acute eosinophilic pneumonia (AEP). A 72‐year‐old man underwent right lower lobectomy and mediastinal lymph node dissection for right lower lung cancer. Fibrin glue was sprayed to cover the interlobar surface of the right upper and middle lobes. On postoperative day 10, computed tomography (CT) revealed ground‐glass shadows around the interlobar surface of the remaining lobes of the right lung. Although antibacterial drugs were administered for suspected bacterial pneumonia, fever spike, shortness of breath, and exacerbation of ground‐glass shadows were observed. Peripheral blood and bronchoalveolar lavage fluid showed increased eosinophil count, supporting the diagnosis of AEP. Pneumonia resolved after prednisolone administration. At one‐year follow‐up, CT showed no AEP recurrence. Drug‐induced pneumonia usually develops in the bilateral lung and rarely in the hemilateral lung. In this case, pneumonia was localized around the site covered with fibrin glue, suggesting fibrin glue‐induced AEP. Thus, the use of fibrin glue should be carefully considered during pulmonary resection., This is a report of a rare case of suspected fibrin glue‐induced acute eosinophilic pneumonia after pulmonary resection. Pneumonia developed around the site covered with fibrin glue, and resolved after prednisolone administration. Thus, the use of fibrin glue should be carefully considered during pulmonary resection.

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.

Lung cancer sometimes develops on the wall of a giant emphysematous bulla (GEB). Herein, we describe a rare case in which lung cancer developed in lung tissue compressed by GEBs. A 62‐year‐old man underwent a computed tomography (CT) scan that revealed two right GEBs. A tumor was suspected in the highly compressed right upper lobe. Since the right bronchus was significantly shifted toward the mediastinum, it was difficult to perform a bronchoscopy. We inserted thoracic drains into the GEBs, and a subsequent CT scan revealed re‐expansion of the remaining right lung and a 3.3 cm tumor in the right upper lobe. The shift of the right bronchus was improved, and bronchoscopy was performed. The tumor was diagnosed as non‐small cell lung cancer (NSCLC). Additionally, the GEBs were found to have originated from the right lower lobe. We performed a right upper lobectomy, mediastinal lymph node dissection, and bullectomy of the GEBs via video‐assisted thoracoscopic surgery. In preoperative evaluation of a GEB, assessing re‐expansion and lung lesions of the remaining lung is important, and intracavity drainage of a GEB may be useful. Key points Significant findings of the study Cancer that develops in lung tissue highly compressed by a giant emphysematous bulla is difficult to diagnose.In the preoperative evaluation of a giant emphysematous bulla, assessing re‐expansion and lung lesions of the remaining lung is important. What this study adds After performing intracavity drainage of a giant emphysematous bulla, the remaining lung re‐expands, and the bronchial shift improves; subsequently, bronchoscopy makes it possible to diagnose lung cancer in the remaining lung., Lung cancer that develops in lung tissue highly compressed by a giant emphysematous bulla is rare, and is difficult to diagnose. After performing intracavity drainage of a giant emphysematous bulla, the remaining lung re‐expands and the bronchial shift improves; subsequently, bronchoscopy makes it possible to diagnose lung cancer in the remaining lung.

A preoperative validation system for predicting the clinical outcome of extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM) is required, as EPP for MPM is one of the most invasive operation types. Recently, several inflammatory and nutritional parameters, such as C-reactive protein (CRP) and albumin, have been re-focused on as useful prognostic factors for several types of cancer; however, few of these reports involved MPM.As a retrospective study, clinicopathological characteristics and preoperative inflammatory and nutritional parameters were calculated in consecutive patients with MPM who underwent EPP. The prognostic value of the variables was examined using Cox regression, and the candidate preoperative parameters were entered into a multivariate model to determine their independent effects.Of the 61 eligible cases, the CRP/albumin ratio (CAR) was associated with histology, and the CRP index multiplied by the neutrophil ratio (C-NR index) was associated with histology and pathological stage. Patients with CAR0.125 had a significantly poor survival outcome, and patients with a C-NR index0.58 also had a significantly poor prognosis. Multivariate analysis showed that age, histology, CRP, albumin, CAR, and C-NR index were independent predictors of 5-year overall survival.Our results demonstrated that the CAR and C-NR indices are promising preoperative predictive parameters for the clinical outcomes of EPP in patients with MPM.

Introduction: The objective of the study was to investigate the correlation between differences between imaging modalities and histological heterogeneity in minimally enhancing glioma. Methods: A prospective study was performed in 11 patients with minimally enhancing glioma (10%. The correlation between the imaging discrepancy and histological heterogeneity was investigated. Results: The average T/N ratio for the T2/FL+/MET+ area in grade II glioma (2.08 ± 0.4) was smaller than that in grade III (4.19 ± 2.4), whereas that for the T2/FL+/MET− area was similar in grade II (1.07 ± 0.2) and III (1.07 ± 0.1). The average T/N ratio for the T2/FL+/MET+ area in grade II and III was higher than that for the T2/FL+/MET− area (p

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.

Purpose Glioblastoma is still intractable despite the progress in therapies, and the intractability is attributable to a minor population of stem-like tumor cells. As a niche harboring quiescent stem-like tumor cells with potentially high tumorigenicity, we have specified an area around large ischemic necrosis, termed ‘peri-necrotic niche’, in glioblastoma. In this study, the behavior of tumor cells inside and outside the peri-necrotic niche was analyzed to find out molecules responsible for reactivation of quiescent stem-like tumor cells to proliferate outside the niche. Methods Expression of Ki-67 and GINS complex composed of SLD5, PSF1, PSF2 and PSF3 was analyzed by immunohistochemistry in human glioblastoma tissue samples. Proliferation assays, immunoblotting and siRNA experiments were performed using a glioblastoma cell line. Results Immunohistochemical analysis revealed quiescent and proliferative phenotypes of tumor cells inside and outside the niche, respectively, and the proliferation was spatially correlated with the expression of GINS components in tumor cells. To mimic the tissue microenvironment inside versus outside the niche, glioblastoma cells were cultured under hypoxic versus normoxic conditions, or without versus with serum. Quiescence and proliferation of tumor cells were reversibly determined by the microenvironment inside and outside the niche, respectively, and proliferative activities paralleled the expression levels of GINS components. Furthermore, the reactivation of proliferation after reoxygenation or serum replenishment was suppressed in quiescent tumor cells with PSF1 knockdown. Conclusions These findings indicate the essential role of GINS complex in the switch between quiescence and proliferation of tumor cells inside and outside the peri-necrotic niche.

Bronchopleural fistula is one of the most serious postoperative complications caused by the incomplete healing of a bronchial stump. Fibroblasts play an important role in wound healing by facilitating connective tissue formation and inducing angiogenesis. We developed a method for production of multilayered fibroblast sheets that secreted some growth factors and promoted wound healing. The present study aimed to assess the treatment effect of multilayered fibroblast sheets on bronchial stump healing. In this rat model, left pneumonectomy was performed, and multilayered fibroblast sheets derived from autologous oral mucosal tissues were transplanted to the bronchial stump. The changes in the bronchial stump were examined macroscopically, histologically, and mechanically. The fibroblast sheets promoted the formation of thick connective tissues around the bronchial stump. The formed connective tissues were accompanied by new blood vessels, and fibrosis was observed over time. Then, 7 days after the transplantation of the fibroblast sheets, the bronchial wall became significantly thicker, and the area of the blood vessels for the bronchial wall tissues was significantly larger in the experimental group than in the control group. In addition, the burst pressure in the bronchial stump was significantly higher in the experimental group than in the control group. Bronchial stumps were reinforced by the transplantation of multilayered fibroblast sheets derived from autologous oral mucosal tissues.

Dedifferentiation has been implicated in β cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound β cell loss, with an increase in α cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of β cell failure during the course of diabetes progression in humans., Islet remodeling with dedifferentiation is a pathologic mechanism of β celldysfunction and lost during the course of progression in human type 2 diabetes.

Pancreatic trauma involving ductal injury is rare but is associated with high morbidity and mortality. The benefit of endoscopic retrograde pancreatography and stent placement is unclear because there are only a few case reports on endoscopically treated pancreatic duct transection at the pancreatic head. We report a rare case of grade IV pancreatic trauma successfully treated with endoscopic pancreatic stent, which we believe makes significant contribution to the existing literature. A 17-year-old man with blunt pancreatic trauma was referred to our hospital and was diagnosed with grade IV pancreatic injury using endoscopic retrograde pancreatography. The patient was successfully managed with endoscopic pancreatic duct stenting. Although stent replacement was required three times and a trivial ductal stricture remained, the patient finally became stent-free without any symptoms and further adverse events. Endoscopic retrograde pancreatography is highly advantageous for early detection and evaluation of the severity of ductal injury. Subsequent stent insertion is well tolerated in hemodynamically stable patients and is especially beneficial for the treatment of pancreatic head injuries because it allows avoidance of sub-total pancreatectomy or high-risk reconstructive surgery. Nevertheless, the long-term outcomes and appropriate management of main pancreatic duct strictures due to stents remain to be determined. Accumulation of similar case experiences is essential to address these issues., Highlights • We report a case of pancreatic head injury treated with endoscopic pancreatic stent. • Endoscopic retrograde pancreatography enables early detection of ductal injury. • Ductal stent is useful for pancreatic head trauma patient if hemodynamically stable.

A 90-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed a lesion with multiple nodules covered with abundant mucus at the hepatic flexure. Computed tomography showed a dilated appendix attached distally to the hepatic flexure. Right hemicolectomy was performed, and the pathological examination revealed a mucinous appendiceal adenocarcinoma infiltrating the hepatic flexure without pseudomyxoma peritonei. The patient is doing well without recurrence 12 months postoperatively. Extraperitoneal drainage of the malignant ascites caused by the fistula may allow for an early diagnosis, while also making it possible to successfully resect the lesion, thus resulting in a favorable outcome.

Background Pleomorphic carcinoma (PC) of the lung is a rare histological type of lung carcinoma. The association between computed tomography (CT) findings and histology with outcome remains unclear. We examined the relationships between CT features and histopathologic findings, and evaluated the impact of CT features and other clinicopathologic factors on survival. Methods Thirty-five consecutive patients with PC of the lung who underwent surgery between October 2010 and December 2015 were enrolled in this study. The 35 tumors were classified with or without air bronchogram in the tumors, and with or without intratumoral ground glass opacity (GGO) on CT. Results Air bronchogram and GGO were detected in 12 (34.3%) and 5 (14.3%) tumors, respectively. Multivariate analysis revealed that air bronchogram was significantly associated with the presence of adenocarcinoma components with lepidic growth patterns (P = 0.005), and predominance of adenocarcinomas (P = 0.026). GGO was significantly associated with the presence of adenocarcinoma component with lepidic growth pattern (P = 0.010). Air bronchogram was an independent favorable prognostic factor for overall survival, whereas GGO did not have a significant effect on survival. Conclusion Air bronchogram observed in PCs of the lung is strongly related with histological components of the tumor and favorable outcome.

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.

Human papillomavirus (HPV)-unrelated head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease, and there are no suitable prognostic or predictive markers. The SET and MYND domain-containing protein 2 (SMYD2), a lysine methyltransferase for histone H3K36 and p53K370, that regulates transcription was previously found to be a cancer-promoting gene in esophageal squamous cell carcinoma. In this study, we investigated whether SMYD2 is a possible oncogene and a prognostic indicator in HPV-unrelated, multiple and nonmultiple HNSCC. Among 197 HPV-unrelated HNSCC cases, overexpression of SMYD2 protein was detected in 75 (60%) of 126 nonmultiple cases and 51 (70%) of 71 multiple cases. In nonmultiple cases, patients with SMYD2-overexpressing tumors had a worse overall survival rate than did those with nonexpressing tumors (P = .017, log-rank test), and SMYD2 positivity was independently associated with overall survival in the multivariate analysis (P = .003). In both nonmultiple and multiple groups, the combination of SMYD2 and p53 immunopositivity was a significant prognostic indicator (P = .027 and .015). In 5 HNSCC cell lines, overexpression of SMYD2 messenger RNA and protein was observed, but there was no notable amplification at 1q32-41.1. The proliferation of UM-SCC-17B HPV-unrelated HNSCC cell line was inhibited by knockdown of SMYD2 gene expression. These findings suggest that SMYD2 plays a role in tumor progression and might be a useful prognosticator in HPV-unrelated, nonmultiple HNSCC.

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.

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.