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BACKGROUND: Ventricular tachycardia (VT) associated with primary cardiac tumors (PCTs) originating from the ventricles is rare, but lethal, in young patients. OBJECTIVES: This study aimed to clarify the mechanisms underlying primary cardiac tumor-related ventricular tachycardia (PCT-VT) and establish a therapeutic strategy for this form of VT. METHODS: Among 67 patients who underwent surgery for VT at our institute between 1981 and 2020, 4 patients aged 1 to 34 years, including 3 males, showed PCT-VT (fibroma, 2; lipoma, 1; and hamartoma, 1), which was investigated using a combination of intraoperative electroanatomical mapping and histopathological studies. RESULTS: All 4 patients developed electrical storms of sustained VTs refractory to multiple drugs and repetitive endocardial ablations. The VT mechanism was re-entry, and intraoperative electroanatomical mapping showed a centrifugal activation pattern originating from the border between the tumor and healthy myocardium, where fractionated potentials were detected during sinus rhythm. Histopathological studies of serial sections of specimens acquired from these areas revealed tumor infiltration into the surrounding myocardium with cell disorganization, exhibiting myocardial disarray. Several myocardia entrapped in the tumor edges contributed to the development and sustainment of re-entrant VT activation. In the 2 patients in whom complete resection was unfeasible, encircling cryoablation to entirely isolate the unresectable tumor was effective in suppressing VT occurrence. CONCLUSIONS: The mechanism underlying PCT-VT involves re-entry localized at the tumor edges. Myocardial disarray associated with tumor infiltration is a substrate for this form of VT. Cryoablation along the border between the tumor and myocardium is a promising therapeutic option for unresectable PCT-VT.

DOI： 10.1016/j.jacep.2023.08.033

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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AIM: To clarify the clinicopathological characteristics and role of periglomerular angiogenesis in IgA nephropathy. METHODS AND RESULTS: The renal biopsy specimens of 114 patients with IgA nephropathy were examined. Among them, 46 (40%) showed periglomerular angiogenesis around the glomeruli. CD34 and α-smooth muscle actin (α-SMA) staining in serial sections revealed that these vessels contained CD34+ α-SMA+ microarterioles along with CD34+ α-SMA- capillaries. We termed these "periglomerular microvessels (PGMVs)". Patients with PGMVs (PGMV group) had clinically and histologically more severe disease than those without PGMVs (non-PGMV group) at the time of biopsy. Even after adjusting for age, there were significant differences in the degree of proteinuria and estimated glomerular filtration rate reduction between the PGMV and non-PGMV groups. The PGMV group showed a higher incidence of segmental and global glomerulosclerosis and crescentic lesions than the non-PGMV group (P < 0.01). Here, PGMVs were undetectable in the acute and active inflammation phase, but were observed in the acute to chronic or chronic glomerular remodelling phase. PGMVs mainly developed around glomerular adherent lesions to the Bowman's capsule with small or minimal glomerular sclerotic lesions. Conversely, they were rarely observed in segmental sclerosis areas. CONCLUSION: The PGMV group is clinically and pathologically more severe than the non-PGMV group; however, they were undetectable in segmental sclerosis with mesangial matrix accumulation. PGMVs might occur after acute/active glomerular lesions, suggesting that PGMVs may inhibit segmental glomerulosclerosis progression and could be a marker for good repair response after acute/active glomerular injury in severe IgA nephropathy cases.

DOI： 10.1111/his.14997

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BACKGROUND: Immune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain. CASE PRESENTATION: A 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3+ T cells and CD163+ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3+ T cells, CD8+ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8+ T cells. Infiltration of CD4+ T cells was noted without obvious CD4+ CD25+ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab. CONCLUSIONS: We herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8+ T cells and CD163+ macrophages, and none or few CD4+ CD25+ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.

DOI： 10.1186/s12882-023-03091-8

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Language：Japanese   Publisher：(一社)日本病理学会  

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We present a case of a drug-induced sarcoidosis-like reaction (DISR) in a 34-year-old female patient who had been receiving dupilumab for eosinophilic rhinosinusitis, for seven months. Computerized tomography scans revealed multiple lymphadenopathies, and biopsies performed on the lung and skin lesions showed the presence of non-caseating granulomas. The patient's serum levels of soluble interleukin-2 receptor and angiotensin-converting enzyme were elevated. There were no findings of Mycobacterium spp, or any other bacterial infections. Based on these findings, it was suspected that the sarcoidosis-like reaction observed in this patient was caused by dupilumab. Switching the patient's treatment from dupilumab to mepolizumab improved the DISR.

DOI： 10.1016/j.rmcr.2023.101883

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Background: The Kumamoto criteria have been proposed as a non-invasive screen for transthyretin amyloid cardiomyopathy. This study assessed the validity of the Kumamoto criteria externally. Methods and Results: The study included 138 patients (median age 73 years; 65% male) who underwent 99 mTc-pyrophosphate (PYP) scintigraphy. Patients were divided into 4 groups according to total scores on the Kumamoto criteria (i.e., 0-3) for the following 3 factors: high-sensitivity cardiac troponin T ≥0.0308 ng/mL, wide (≥120 ms) QRS, and left ventricular posterior wall thickness ≥13.6 mm. The diagnostic performance and positive predictive value (PPV) of the Kumamoto criteria for positive 99 mTc-PYP scintigraphy were validated. Eighteen (13%) patients were positive on 99 mTc-PYP scintigraphy. The Kumamoto criteria had a favorable diagnostic performance (area under the curve 0.808). The PPV for groups with scores of 0, 1, 2, and 3 was 0% (n=0/42), 11% (n=6/57), 21% (n=7/33), and 83% (n=5/6), respectively, which is lower, particularly for those with a score of 2, than in the original Kumamoto cohort. However, the PPV increased after combining the Kumamoto criteria with a history of orthopedic diseases (spinal canal stenosis and/or carpal tunnel syndrome). Conclusions: This study suggests that the Kumamoto criteria have a favorable diagnostic performance; however, the PPV may decrease depending on the study population. Combining the Kumamoto criteria with the presence of orthopedic disease may improve the PPV.

DOI： 10.1253/circrep.CR-22-0110

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：(公社)日本眼科手術学会  

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BACKGROUND: The intrauterine adverse environment during nephrogenesis reduces the nephron number, probably associates with impaired ureteric bud (UB) branching. METHODS: The kidneys in C57/BL6 mice were irradiated with a single dose of 10 gray (10 Gy) as adverse environment on postnatal day 3 (irradiated PND3 kidneys) after UB branching ceased. The renal functions and pathological findings of irradiated PND3 kidneys were compared with those of non-irradiated control and 10 Gy irradiation on PND14 (irradiated PND14 kidney) from 1 to 18 months. RESULTS: The number and density of glomeruli in irradiated PND3 kidneys were reduced by 1 month with renal dysfunction at 6 months. The morphologically incomplete glomeruli with insufficient capillaries were involuted by 1 month in the superficial cortex. Reduced tubular numbers and developmental disability with shortening renal tubules occurred in irradiated PND3 kidneys with impaired urine concentration at 6 months. Hypertrophy of glomeruli developed, and occasional sclerotic glomeruli appeared in the juxtamedullary cortex with hypertension and albuminuria at 12 to 18 months. CONCLUSIONS: The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of UB branching, and glomerular hypertrophy with occasional glomerulosclerosis developed accompanied with hypertension and albuminuria in the adulthood. IMPACT: The reduced number of nephrons with shortening renal tubules occurred with impaired renal functions in a postnatal adverse environment after cessation of ureteric bud branching. The reduced number of glomeruli were associated with not only the impaired formation of glomeruli but also involution of morphologically small incomplete glomeruli after an adverse environment. The insufficiently developed nephrons were characterized by the shortening renal tubules with impaired urine concentration. In addition, glomerular hypertrophy and occasional glomerulosclerosis developed with hypertension and albuminuria in adulthood. The present study can help to understand the risk of alternations of premature nephrons in preterm neonates.

DOI： 10.1038/s41390-022-02332-0

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Language：Japanese   Publisher：(一社)日本呼吸器内視鏡学会  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Activated monocytes/macrophages promote glomerular injury, including crescent formation, in anti-glomerular basement membrane (GBM) glomerulonephritis. Disulfiram, an alcohol-aversion drug, inhibits monocyte/macrophage migration by inhibiting FROUNT, a cytosolic protein that enhances chemokine receptor signaling. Our study found that disulfiram at a human equivalent dose successfully blocked albuminuria and crescent formation with podocyte loss, and later stage kidney fibrotic lesions, in a rat model of anti-GBM glomerulonephritis. A disulfiram derivative, DSF-41, with more potent FROUNT inhibition activity, inhibited glomerulonephritis at a lower dose than disulfiram. Disulfiram markedly reduced the number of monocytes or macrophages at the early stage of glomerulonephritis and that of CD3+ and CD8+ lymphocytes at the established stage. Impaired pseudopodia formation was observed in the glomerular monocytes/macrophages of the disulfiram group; consistent with the in vitro observation that disulfiram blocked chemokine-dependent pseudopodia formation and chemotaxis of bone marrow-derived monocytes/macrophages. Furthermore, disulfiram suppressed macrophage activation as revealed by reduced expression of inflammatory cytokines and chemokines (TNF-α, CCL2, and CXCL9) and reduced CD86 and MHC class II expressions in monocytes/macrophages during glomerulonephritis. The dramatic reduction in monocyte/macrophage number might have resulted from disulfiram suppression of both the chemotactic response of monocytes/macrophages and their subsequent activation to produce cytokines and chemokines, which further recruit monocytes. Additionally, FROUNT was expressed in CD68+ monocytes/macrophages infiltrating the crescentic glomeruli in human anti-GBM glomerulonephritis. Thus, disulfiram can be a highly effective and safe drug for the treatment of glomerulonephritis by blocking the chemotactic responses of monocytes/macrophages and their activation status in the glomerulus.

DOI： 10.1016/j.kint.2022.07.031

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Immunoglobulin (Ig) G4-positive cells are rarely observed in the lungs of patients with idiopathic interstitial pneumonias (IIPs). IgG1 may be more pathogenic than IgG4, with IgG4 having both pathogenic and protective roles in IgG4-related disease (IgG4-RD). However, the role of both IgG1 and IgG4 in IIPs remains unclear. We hypothesized that patients with IgG4-positive interstitial pneumonia manifest different clinical characteristics than patients with IgG4-RD. Herein, we identified the correlation of the degree of infiltration of IgG1- and IgG4-positive cells with IIP prognosis, using a Japanese nationwide cloud-based database. We included eighty-eight patients diagnosed with IIPs after multidisciplinary discussion, from April 2009 to March 2014. IgG4-positive cell infiltration was identified in 12/88 patients with IIPs and 8/41 patients with idiopathic pulmonary fibrosis (IPF). Additionally, 31/88 patients with IIPs and 19/41 patients with IPF were diagnosed as having IgG1-positive cell infiltration. IgG4-positive IIPs tended to have a better prognosis. Conversely, overall survival in cases with IgG1-positive IPF was significantly worse. IIPs were prevalent with IgG1- or IgG4-positive cell infiltration. IgG1-positive cell infiltration in IPF significantly correlated with a worse prognosis. Overall, evaluating the degree of IgG1-positive cell infiltration may be prognostically useful in cases of IPF.

DOI： 10.1038/s41598-022-13333-8

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Low-vacuum scanning electron microscopy (LV-SEM) is a powerful tool that allows to observe light microscopic specimens with periodic acid-silver methenamine (PAM) staining at a higher magnification, simply by removing the coverslip. However, it is not suitable for observation of immunohistochemistry (IHC) using 3,3'-diaminobenzidine (DAB) due to insufficient backscattered electron image. Traditional heavy metal enhancement techniques for DAB in IHC, (1) osmium tetroxide and iron, (2) cobalt, (3) methenamine silver (Ag), (4) gold chloride (Gold), and (5) both Ag and Gold (Ag + Gold), were examined by LV-SEM. Tissue specimens from Thy1.1 glomerulonephritis rat kidney stained with α-smooth muscle actin and visualized with DAB were enhanced by each of these enhancement methods. We found, in light microscopic and LV-SEM, that the enhancement with Ag, Gold, or Ag + Gold had better intensity and contrast than others. At a higher magnification, Ag + Gold enhancement showed high intensity and low background, although only Ag or Gold enhancement had nonspecific background. Even after observation by LV-SEM, the quality of specimens was maintained after remounting the coverslip. It was also confirmed that Ag + Gold enhancement could be useful for IHC using clinical human renal biopsy. These findings indicate that Ag + Gold provided an adequate enhancement in IHC for both LM and LV SEM observation.

DOI： 10.1369/00221554221102996

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Glomerular capillary aneurysms are distinctly rare and specific glomerular lesions characterized by aneurysmal dilatation of the glomerular capillaries. This formation is associated with glomerular capillary injuries with focal mesangiolysis. Here, we report a case of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) presenting with multiple glomerular capillary microaneurysms. A 53-year-old woman presented with persistent proteinuria and microhematuria. She had no underlying diseases, such as hematopoietic or lymphoproliferative disorders. A renal biopsy showed diffuse membranoproliferative lesions with foam cell infiltration and multiple microaneurysms of the glomerular capillary on light microscopy. Immunofluorescence analysis showed granular deposits of monoclonal immunoglobulin G3 kappa (IgG3κ), C1q, C3, and C4 in the glomeruli. Electron microscopy revealed different sizes of non-organized electron-dense deposits in the mesangial, subendothelial, and subepithelial areas. In addition, glomerular endothelial cells showed swelling and loss of fenestra or diffuse formation of fenestrated diaphragms, accompanied by irregular thinning of the glomerular basement membrane. Furthermore, immunostaining for CD31 (a marker for endothelial cell) and low-vacuum scanning electron microscopy study identified loss of endothelial cells in microaneurysm, suggesting severe glomerular endothelial cell injury. After a renal biopsy, only the medication for dyslipidemia was continued because there were no physical symptoms, such as edema, and urinary abnormalities continued with stable renal function. Further studies are needed to elucidate the pathogenesis of glomerular capillary injury in PGNMID and clarify the clinical and pathological characteristics of PGNMID with glomerular capillary microaneurysms.

DOI： 10.1007/s13730-021-00676-w

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A 59-year-old woman complaining of wet cough, hemoptysis, slight fever, anorexia, and malaise was admitted to hospital with suspected lobar pneumonia. She received treatment for myocardial infarction and deep venous thrombosis caused by familial protein C deficiency. Rapid deterioration due to respiratory failure occurred despite intensive care with broad-spectrum antibiotics. At a later date, sputum examination revealed the presence of Aspergillus niger. Based on clinical and autopsy findings, she was diagnosed with acute respiratory failure due to pulmonary aspergillosis with acute fibrinous and organizing pneumonia. This is the first reported case of pulmonary aspergillosis with acute fibrinous and organizing pneumonia complicated by calcium oxalate resulting from Aspergillus niger infection, leading to severe inflammation and tissue injury in the lungs.

DOI： 10.1016/j.rmcr.2022.101641

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OBJECTIVE: To investigate histologic features of immunological components in the primary tumor site of patients with cancer-associated myositis (CAM) by focusing on tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs), which play major roles in antitumor immunity. METHODS: Cancer-associated myositis patients were selected from the single-center idiopathic inflammatory myopathy cohort based on the availability of primary tumor specimens obtained before the introduction of immunomodulatory agents. Control cancer subjects without CAM were selected from the cancer tissue repository at a ratio of 1:2 matched for demographics and cancer characteristics of CAM cases. A series of immunohistochemical analyses was conducted using sequential tumor sections. TLS was defined as an ectopic lymphoid-like structure composed of DC-LAMP+ mature dendritic cells, CD23+ follicular dendritic cells (FDCs) and PNAd+ high endothelial venules. TLS distribution was classified into the tumor center, invasive margin, and peritumoral area. RESULTS: Six CAM patients and 12 matched non-CAM controls were eligible for the study. There was no apparent difference in the density or distribution of TILs between the groups. TLSs were found in 3 CAM patients (50%) and 4 non-CAM controls (33%). TLSs were exclusively located at the tumor center or invasive margin in CAM cases but were mainly found in the peritumoral area in non-CAM controls. FDCs and class-switched B cells colocalized with follicular helper T cells were abundantly found in the germinal center-like area of TLSs from CAM patients compared with those from non-CAM controls. CONCLUSION: The adaptive immune response within TLSs in the primary tumor site might contribute to the pathogenic process of CAM.

DOI： 10.3389/fmed.2022.1066858

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1111/cas.15228

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INTRODUCTION: Desmoplastic malignant pleural mesothelioma (DMPM) is a sarcoma type mesothelioma, comprising about 5% of malignant pleural mesotheliomas. Although effusion cytology is commonly used as the primary diagnostic approach for mesothelioma, this may not be useful for DMPM due to its desmoplastic nature and bland cellular atypia. We hereby report a case of DMPM diagnosed through autopsy along with its cytological features that have not been described previously. CASE PRESENTATION: A male in his 60s with a history of occupational asbestos exposure was referred to our hospital with right chest pain. Chest computed tomography scan showed right pleural effusion. Thirteen months later, the patient died of respiratory failure. In autopsy, the scrape-imprint smear and the pleural effusions cytology were performed. The scrape-imprint smear samples exhibited spindle cells with mild nuclear atypia and grooves with fibrous stroma. In the pleural effusion cytology, spindle cells having mild nuclear atypia and grooves with loose epithelial connections were observed. Histological examination of the right pleura showed spindle cells proliferating with dense collagen fibers, as seen in cytological samples, thus rendering the diagnosis of DMPM. Diagnosis was confirmed by fluorescence in situ hybridization. CONCLUSION: Cytological procedures, such as pleural effusion cytology and scrape-imprinting method, may be useful as an ancillary tool in the diagnosis of rare tumors such as DMPM.

DOI： 10.1272/jnms.JNMS.2022_89-605

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Introduction: To investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets. Methods: We analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non–IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science. Results: In IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-β1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-β1–induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression. Conclusions: CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC.

DOI： 10.1016/j.jtocrr.2021.100232

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BACKGROUND/AIM: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive tumor that is resistant to treatment. The expression and prognostic value of programmed cell death-ligand 1 (PD-L1) and its association with epithelial-mesenchymal transition (EMT) in PPC remains unclear. PATIENTS AND METHODS: The expression of PD-L1 and EMT markers, such as E-cadherin, vimentin, zinc finger E-box-binding homeobox 1 (ZEB-1), and cellular mesenchymal-epithelial transition (c-Met) was evaluated by immuno - histochemistry in 16 patients with PPC who underwent surgical resection. RESULTS: The expression of PD-L1 varied between carcinomatous and sarcomatous areas. Positive correlations between PD-L1 and vimentin expression in carcinomatous areas (r=0.668, p=0.005) and PD-L1 and ZEB-1 expression in sarcomatous areas (r=0.562, p=0.023) were found. High PD-L1 and ZEB-1 expression in sarcomatous areas predicted poor survival (p=0.045 and p=0.012, respectively). CONCLUSION: PD-L1 expression associated with ZEB1 expression in the sarcomatoid component of patients with PPC may be useful for predicting patient prognosis.

DOI： 10.21873/anticanres.15028

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Uterine leiomyosarcoma (ULMS) with osteoclast-like giant cells (OLGCs) has been reported as a rare phenomenon in ULMS, and its clinico-pathological features and tumorigenesis remain unclear. We recently reported high expression of receptor activator of nuclear factor κB ligand (RANKL) in ULMS with OLGCs. As osteoblasts produce RANKL, in this study, we analyzed the expression of Runt-related transcription factor 2 (RUNX2), a critical transcription factor for osteoblasts, and osteoclast-related proteins in three cases of ULMS with OLGCs as well as five conventional ULMSs and nine leiomyomas. Immunohistochemistry and real-time reverse transcription quantitative polymerase chain reaction analyses showed high expression of RUNX2 and RANKL in ULMS with OLGCs. In these cases, macrophages expressed receptor activator of nuclear factor κB (RANK), and OLGCs expressed osteoclast-related proteins (nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and cathepsin K). Accumulation sites of cathepsin K-positive OLGCs showed hemorrhagic appearance and degraded type IV collagen. We reviewed reported cases of ULMS with OLGCs, including ours, and found that they presented an aggressive course even at stage I. Furthermore, metastatic lesions showed similar histological features to those of OLGC association in ULMS. Here, we show that tumor cells in ULMS with OLGCs highly express RUNX2 and RANKL and that osteoclastic differentiation of macrophages occurs in the tumor tissue.

DOI： 10.1007/s00428-020-02996-1

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Pulmonary adenofibroma is a rare biphasic tumor that contains epithelial and stromal components. We report a case of pulmonary adenofibroma in which the tumor was resected by thoracoscopic surgery and the diagnosis was established by histopathology. A 59-year-old woman with a past medical history of pyelonephritis visited our hospital for evaluation of an abnormal opacity on a plain chest x-ray during a comprehensive medical examination. A follow-up chest x-ray showed enlargement of the lesion, and the patient was referred to our department for further management. Chest computed tomography revealed a well-circumscribed nodule measuring 1.4 cm in diameter in the upper lobe of the left lung. The chest imaging findings suggested a benign tumor, but because of evidence of lesion enlargement and elevated serum carcinoembryonic antigen levels, we performed wide wedge resection of the left upper lobe by video-assisted thoracoscopic surgery, for diagnosis and treatment. The resected specimen was submitted for rapid pathological diagnosis during the operation, and a benign tumor, possibly sclerosing pneumocytoma, was suspected. Therefore, we completed the operation with wide wedge resection. The final histopathological diagnosis was pulmonary adenofibroma. The patient had an uneventful postoperative course, and at this writing, 6 months postoperatively, there has been no evidence of tumor recurrence. We have reported this case of pulmonary adenofibroma because the tumor is rare, has not yet been well-characterized, and has an unclear prognosis. Collection of data from a larger number of patients is necessary.

DOI： 10.1272/jnms.JNMS.2021_88-516

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BACKGROUND: Epstein-Barr virus (EBV) is associated with the pathogenesis of a variety of malignancies, most notably lymphomas. Especially in the background of immunodeficiency, such as primary immunodeficiency disorder (PID) and post-transplant lymphoproliferative disorder (PTLD), the role of EBV might be crucial. PIDs are rare heterogeneous diseases affecting the development and/or the function of the innate and adaptive immune system. Malignancy is the second-highest cause of death after infection, and lymphoma accounts for about half of malignancies. The most frequently reported lymphoma type is diffuse large B-cell lymphoma (DLBCL) and the incidence of T-cell lymphoma is rare. PTLDs are also rare serious lymphoid and/or plasmacytic proliferative disorders that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT, but only a few cases have been reported in autologous HSCT (AutoHSCT) recipients. CASE PRESENTATION: A 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed with EBV-positive DLBCL. She was treated with R-CHOP, R-ACES, and AutoHSCT and went into remission. Four years later, computed tomography results revealed multiple lung nodules and abnormal infiltration, and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cβ1 gene. She was diagnosed with peripheral T-cell lymphoma, not otherwise specified, accompanied by notable granulomatous lesions. CONCLUSION: Here, as a unique case of metachronous B-cell and T-cell lymphoma, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AutoHSCT for EBV-positive DLBCL at the age of 53 years. These lung lesions of granulomatous T-cell lymphoma could be related to the underlying primary immunodeficiency background associated with sustained hypogammaglobulinemia.

DOI： 10.1186/s13000-020-01038-3

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Aortogenic embolic stroke (AES) is an important stroke mechanism. However, as many stroke patients have aortic atheromatous lesions, it is unclear whether these lesions are the cause of these strokes. Cholesterol crystals are the solid, crystalline form of cholesterol that is found in atherosclerosis, but not in cardiac diseases such as atrial fibrillation, valvular diseases, and cardiomyopathy. Therefore, if a cholesterol crystal is found in a thrombus removed by mechanical thrombectomy (MT), this makes it possible to diagnose a patient as having an atheromatous lesion. Here, we report an AES case with a cholesterol crystal found in a thrombus removed by MT. A 67-year-old man was admitted due to consciousness disturbance, aphasia, and right hemiplegia. Diffusion-weighted imaging (DWI) showed a hyperintense area in the left frontal lobe, and magnetic resonance angiography demonstrated a branch occlusion of the left middle cerebral artery (MCA). MT was performed 1.5 h after stroke onset, with the thrombus removed and a left occluded MCA completely recanalized. Carotid duplex ultrasonography did not reveal any plaque in the carotid artery. Echocardiography did not show any abnormal function or findings, including thrombus. Transesophageal echocardiography showed a 4.9 mm atheromatous lesion at the aortic arch. Therefore, we suspected this patient as having an AES due to the embolic source of atheromatous lesion at the aortic arch. Pathological examination of the embolus revealed a cholesterol crystal cleft in the thrombus. Therefore, we diagnosed this patient as having AES caused by an atheromatous lesion at the aortic arch.

DOI： 10.1016/j.jstrokecerebrovasdis.2020.105178

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DOI： 10.1002/joa3.12346

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/joa3.12346

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 88-year-old man suddenly presented with aphasia and right hemiparesis. The diffusion-weighted image of MRI showed ischemic lesions on the left middle cerebral artery area, and MRA showed the left intracranial artery (ICA) occlusion. Therefore, we diagnosed him as having acute ischemic stroke and treated with mechanical thrombectomy (MT). The DWI of MRI showed ischemic lesions on the left middle cerebral artery area, and MRA showed the left ICA occlusion. Therefore, we performed MT and continued best medical treatment, but ICA was reoccluded. Six day later, aspergillus was found in the thrombus from ICA. Then, we considered that ICA occlusion was caused by aspergillus. We experienced a patient specified the cause by thrombus pathology. The pathological diagnosis of the thrombus getting by MT is usefulness for stroke etiology.

DOI： 10.5692/clinicalneurol.cn-001400

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Language：Japanese   Publisher：(一社)日本神経学会  

症例は88歳の男性である。右麻痺、失語を認め救急搬送された。来院時の頭部MRI/Aにて左中大脳動脈領域に新規梗塞巣と左内頸動脈の閉塞を認めたため、機械的脳血栓回収療法を施行した。その後内科的治療を行うも、左内頸動脈は再閉塞した。血栓病理でアスペルギルス真菌塊を認めた。副鼻腔炎と骨破壊を認めており、アスペルギルスが内頸動脈に直接浸潤し、血栓を形成し、閉塞したことが考えられた。血栓病理によって原因の特定に至った症例を経験した。原因不明の脳梗塞は、機械的血栓回収療法によって回収された血栓を確認することで、原因が判明する可能性がある。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01550&link_issn=&doc_id=20200602480005&doc_link_id=1390285300159919360&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390285300159919360&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

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Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-β, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA-ILD by alleviating oxidative stress.

DOI： 10.1111/jcmm.14603

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2019-1602

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Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 μM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.

DOI： 10.1038/s41374-018-0158-9

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Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.

DOI： 10.1111/jcmm.14255

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BACKGROUND: Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease. METHODS: In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction. RESULTS: All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis. CONCLUSION: Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.

DOI： 10.1007/s10157-018-01687-1

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Multidisciplinary discussion (MDD) requiring close communication between specialists (clinicians, radiologists and pathologists) is the gold standard for the diagnosis of idiopathic interstitial pneumonias (IIPs). However, MDD by specialists is not always feasible because they are often separated by time and location. An online database would facilitate data sharing and MDD. Our aims were to develop a nationwide cloud-based integrated database containing clinical, radiological and pathological data of patients with IIPs along with a web-based MDD system, and to validate the diagnostic utility of web-based MDD in IIPs.Clinical data, high-resolution computed tomography images and lung biopsy slides from patients with IIPs were digitised and uploaded to separate servers to develop a cloud-based integrated database. Web-based MDD was performed using the database and video-conferencing to reach a diagnosis.Clinical, radiological and pathological data of 524 patients in 39 institutions were collected, uploaded and incorporated into the cloud-based integrated database. Subsequently, web-based MDDs with a pulmonologist, radiologist and pathologist using the database and video-conferencing were successfully performed for the 465 cases with adequate data. Overall, the web-based MDD changed the institutional diagnosis in 219 cases (47%). Notably, the MDD diagnosis yielded better prognostic separation among the IIPs than did the institutional diagnosis.This is the first study of developing a nationwide cloud-based integrated database containing clinical, radiological and pathological data for web-based MDD in patients with IIPs. The database and the web-based MDD system that we built made MDD more feasible in practice, potentially increasing accurate diagnosis of IIPs.

DOI： 10.1183/13993003.02243-2018

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DOI： 10.1007/s11748-019-01084-9

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BACKGROUND/AIM: Malignant mesothelioma (MM) is an aggressive tumor with poor prognosis. The establishment of a new diagnostic and therapeutic approach for MM is expected. This study investigated the diagnostic significance of tenascin XB (TNXB) for MM. MATERIALS AND METHODS: TNXB gene expression was found to be significantly higher in MM tumor tissues compared to paired normal tissues, as assessed by the Gene Expression Omnibus database. The inhibition of TNXB using small interfering RNAs suppressed the proliferation and colony formation of MM cells. Expression of TNXB and calretinin, a current diagnostic marker of MM, was evaluated by immunohistochemistry. RESULTS: The sensitivity and specificity of TNXB for MM were 80.0% and 69.5%, respectively. When the detection of TNXB was combined with that of calretinin, 83.3% of MM cases were detected. CONCLUSION: These findings suggest that TNXB is a novel diagnostic biomarker for MM. A combination of detecting TNXB and calretinin may be useful for the differential diagnosis of MM from lung adenocarcinoma.

DOI： 10.21873/anticanres.13156

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BACKGROUND: A right aortic arch is a congenital vascular anomaly that is present in up to 0.1% of pregnancies. The anomaly observed by fetal ultrasonography was recently reported to indicate vascular and chromosomal abnormalities that may complicate postnatal management. CASE PRESENTATION: We report the successful resection of a Kommerell's diverticulum with left subclavian artery transfer to the left carotid artery in a 5-month-old Japanese boy. The patient was prenatally diagnosed as having a right aortic arch, and a vascular ring was confirmed at 4 months of age with enhanced computed tomography. The pathology of the resected aortic wall revealed severe disruption and fragmentation of elastic fibers associated with a disarray of smooth muscle cells in the tunica media, and cystic medial necrosis with mucoid extracellular matrix deposition. CONCLUSION: These abnormal pathological findings supported the resection of Kommerell's diverticulum at this point of time, and division of the ligamentum arteriosus alone was not recommended. Early intervention in this condition once the diagnosis is made may thus be advocated. The fetal diagnosis of a right aortic arch may provide a clue to the possibility of a vascular ring.

DOI： 10.1186/s40792-019-0726-2

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An 82-year-old man with a recurrence of pulmonary pleomorphic carcinoma was treated with pembrolizumab. He achieved partial response after three cycles of pembrolizumab. However, he developed febrile neutropenia. A bone marrow aspiration sample revealed a decrease of mature neutrophils, and anti-neutrophil antibody was detected in blood. Computed tomography scans revealed consolidation in the right lung. Pathological findings in lung biopsy tissue revealed organizing pneumonia. Pembrolizumab-induced agranulocytosis and interstitial lung disease (ILD) were diagnosed. We initiated antibacterial therapy and granulocyte colony-stimulating factor (G-CSF). The neutrophil count immediately increased, and the fever decreased. The improvement of ILD was achieved without using systemic steroids. Moreover, the patient developed ocular myasthenia gravis induced by pembrolizumab. This is the first case report of pembrolizumab-induced agranulocytosis. Agranulocytosis was improved by administration of G-CSF without using systemic steroids. However, further studies are needed to determine the optimal treatment for patients with anti-neutrophil antibody whose tumor has progressed.

DOI： 10.1093/omcr/omy094

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Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.

DOI： 10.1038/s41598-018-33190-8

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Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy.

DOI： 10.18632/oncotarget.25531

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BACKGROUND/AIM: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC samples. Using 32 independent samples, we also evaluated PD-L1 expression in NSCLC patients with EGFR gene mutations treated by EGFR-TKIs. RESULTS: Overall survival of PD-L1-positive stages I-III NSCLC and stage I NSCLC and stages I-III squamous cell carcinoma (SQ) were significantly shorter than those of PD-L1-negative NSCLC (p<0.01 and p=0.02 and p=0.01, respectively). In stage I NSCLC and stages I-III SQ, PD-L1 expression was found to be independent predictor of death after multivariate analysis. Response to EGFR-TKIs was not significantly different between PD-L1-positive and PD-L1-negative NSCLC patients with EGFR mutations. CONCLUSION: PD-L1 expression was a significant independent predictor of poor outcome in NSCLC patients.

DOI： 10.21873/anticanres.12281

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Tokyo  

Background: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has recently been utilized to accurately detect the amyloid proteins of renal amyloidosis. The present study investigated the optimal procedures for analyzing samples by LCMS/MS, and the advantage of using this technique to diagnosis renal amyloidosis. Methods: To detect amyloid proteins, laser microdissected glomeruli from AL (n = 13) or AA (n = 10) renal amyloidosis patients were digested and analyzed by LCMS/MS. To determine the best procedures for analyzing samples by LCMS/MS, we examined the suitability of tissue samples, frozen or formalin-fixed paraffin-embedded (FFPE), the number of dissected glomeruli required for analysis (2, 10, or 50 glomeruli), and the amount of trypsin with or without dithiothreitol (DTT). We additionally compared the detection of amyloid proteins between immunostaining and LCMS/MS. Results: Examining 10 dissected glomeruli from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) without DDT made it possible to detect amyloid protein in all 10 AA and in 10 out of 12 AL amyloidosis cases. All AA amyloidosis cases were diagnosed using immunohistochemistry for amyloid A. With immunostaining, however, there were several inconclusive immunoglobulin and/or their light chain staining noted in the AA or AL amyloidosis cases. Even so, LCMS/MS was able to accurately detect amyloid protein in renal amyloidosis. Conclusion: The use of 10 laser microdissected glomeruli (170,000–220,000 µm2) with amyloid deposition from FFPE sections digested with trypsin 3 µL (0.1 mg/mL) allowed the accurate detection of amyloid protein in AA and AL amyloidosis.

DOI： 10.1007/s10157-018-1533-y

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DOI： 10.1016/j.ehpc.2018.06.003

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Immuno-checkpoint inhibitors (ICI) have become an effective treatment option for non-small-cell lung cancer patients. However, ICI therapy was reported to be less effective in patients with epidermal growth factor receptor (EGFR) mutations than in those with wild-type EGFR. We report here that an non-small-cell lung cancer patient with the EGFR mutant T790M showed a programmed cell death ligand 1 (PD-L1) expression level that increased from <25% to >90% after eighth-line osimertinib therapy. He was treated with pembrolizumab as a ninth-line treatment, and attained stable disease. After the pembrolizumab therapy, he was treated with gemcitabine, which produced a good response despite being the 10th-line treatment. We should consider administering ICI and chemotherapy even to EGFR mutant patients after failure of EGFR tyrosine kinase inhibitor, especially in cases with high PD-LI expression.

DOI： 10.2147/OTT.S168598

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Background: Although some articles have described renal sarcoidosis, the incidence among biopsy cases remains unclear. Here, we defined the incidence of renal sarcoidosis among renal biopsy cases and analyzed the clinical course. Methods: We performed an epidemiological study examining renal biopsy cases treated at 5 centers between January 2000 and September 2015 and identified 16 cases (7 men, 9 women; mean (±SD) age, 59.4±18.6 years) out of a total of 14191 renal biopsy cases. Renal involvement of sarcoidosis was defined as granulomatous tubulointerstitial nephritis, tubulointerstitial nephritis without granulomatous lesions, and renal calcinosis. Fifteen of the cases were treated with steroid therapy. One case initially received steroid pulse therapy. The outcome was evaluated based on the estimated glomerular filtration rate (eGFR), CKD stage, and the change in eGFR (ΔeGFR) after treatment. A favorable response was defined as ΔeGFR ≥25%. Results: The incidence of renal sarcoidosis was 0.11%. The mean eGFR was 28.2±16.1 mL/min/1.73 m2. At the last observation, the mean eGFR was 43.7±19.7 mL/min/1.73 m2. Although a favorable response to steroid therapy was found in the majority of cases (10/15, 67%), 12 of the 15 cases (80%) had residual renal dysfunction at the last observation and 8 cases (53%) had moderate to severe renal dysfunction. Conclusion: Renal sarcoidosis is extremely rare among renal biopsy cases. Among cases with an unfavorable response to steroid therapy, pathogenetic mechanisms other than sarcoidosis and severe nephron damage were observed. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 252-260).

DOI： 10.36141/svdld.v35i3.6655

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Language：English   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/1393003.congress-2017.PA901

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPANDIDOS PUBL LTD  

Cancer stem cell (CSC) properties have been recently proposed to explain tumor carcinogenesis and multi drug resistance in several human cancers, including non-small cell lung cancer (NSCLC). The present study examined the protein expression of three CSC-associated markers, namely ATP binding cassette subfamily B member 1 (ABCB1), aldehyde dehydrogenase 1 family member Al (ALDH1A1) and cluster of differentiation (CD) 44, by immunohistochemistry in 194 NSCLC patients who underwent complete resection of NSCLC tumors. The association between the expression of these proteins and patient prognosis was evaluated to clarify the prognostic significance of CSC-associated markers in NSCLC patients. Positive staining for ABCB1 demonstrated a trend toward worse survival compared with negative staining in stage I-III NSCLC. Negative staining for ALDH1 or CD/44 exhibited a trend toward worse survival compared with positive staining in stage I-III NSCLC. It was observed that patients with stage I lung adenocarcinoma (ADC) showing positivity for ABCB1 expression had significantly poorer survival than those with negative ABCB1 staining (P=0.03). Furthermore, stage I ADC patients with wild-type epidermal growth factor receptor (EGFR) who exhibited positive staining for ABCB1 had significantly shorter disease-free survival (DFS) compared with patients with negative staining for ABCB1 (P&lt;0.01). Analyses by univariate and multivariate Cox proportional hazards models revealed that ABCB1-positive staining was significantly associated with DFS and was an independent prognostic factor (hazard ratio, 3.49; P&lt;0.05) in these patients. These results suggest that ABCB1 protein expression is useful for predicting prognosis and selecting patients for post-operative therapy in stage I lung ADC patients, particularly those harboring wild-type EGFR.

DOI： 10.3892/ol.2017.6145

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Crystal-storing histiocytosis (CSH) is an uncommon finding in lymphoplasmacytic disorders that presents histiocytes with abnormal intralysosomal accumulations of immunoglobulin light chains as crystals of unknown etiology. A 38-year-old woman with antiphospholipid syndrome had a surgical lung biopsy because of multiple lung mass lesions. In a right middle lobe lesion, lymphoplasmacytic cells had a monocytoid appearance, destructive lymphoepithelial lesions, and positive immunoglobulin heavy chain (IGH) gene rearrangements. A right upper lobe lesion manifested proliferating rounded histiocytes with abundant, deeply eosinophilic cytoplasm and negative IGH gene rearrangements. Electron microscopy and mass spectrometry revealed a case of pulmonary CSH: abnormal proliferation of the immunoglobulin k chain of a variable region that may be crystallized within plasma cells and histiocytes. We report a rare case of localized pulmonary CSH complicating pulmonary mucosa-associated lymphoid tissue lymphoma with multiple mass lesions. We demonstrate advances in the understanding of the pathogenesis of CSH by various analyses of these lesions. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2016.10.028

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AXL, a receptor tyrosine kinase implicated in cell survival, proliferation, and migration, is also associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy. However, its prognostic significance in lung adenocarcinoma (AD) remains unclear. We therefore evaluated the prognostic significance of the expression of AXL and/or its ligand, growth arrest specific 6 (GAS6), in completely resected lung AD. We evaluated the relationship between AXL, GAS6, and vimentin expression, as determined by immunohistochemistry (IHC) analysis, with overall survival and disease-free survival in 113 patients with stages I-III lung AD. Protein expression was also assayed using western blot analysis in 10 lung AD cell lines. AXL-positive (AXL(+)), GAS6-positive (GAS6(+)), or AXL(+)/GAS6(+) staining was significantly associated with vimentin-positive (vimentin) expression. AXL(+)/GAS6(+) and vimentin showed a negative tendency toward an association with EGFR mutation. AXL(+), GAS6(+), or AXL(+)/GAS6(+) status significantly correlated with poor overall survival. In stage I cases, AXL(+)/VGAS6(+) status significantly correlated with poor overall survival and disease-free survival, especially in cases with wild-type EGFR. In multivariate analysis, AXL/GAS6 classifications in stage I as well as in stages I-III lung AD were found to be independent factors for poor patient outcomes. Unlike lung AD cell lines with mutant EGFR, almost all cells with wild-type EGFR showed AXL and vimentin co-expression as determined by western blotting. AXL(+) and GAS6(+) expression is relevant to a poor prognosis in resected lung AD patients at stage I. AXL/GAS6 might serve as crucial predictive and prognostic biomarkers and targets to identify individuals at high risk of post-operative death.

DOI： 10.3892/or.2017.5594

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Objective: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.
Methods: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.
Results: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy.
Conclusion: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

DOI： 10.1093/jjco/hyw043

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Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiat

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Differentiating low-grade lymphoma from preexisting sarcoidosis is difficult because of their pathological similarity. This article describes a case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis. The patient, a 45-year-old Japanese man, presented with a 10-year history of pulmonary sarcoidosis and 5-year history of ocular sarcoidosis with histologic findings. Because only the right S3 lung nodule had gradually enlarged, partial resection was performed. Pathological study revealed noncaseous epithelioid granulomas with lymphoplasmacytic proliferation but also marked lymphoid cell proliferation with lymphoepithelial lesion findings that differed from findings of typical sarcoid lesions. Our lymphoepithelial lesion evaluation via immunohistochemistry and analysis of Ig heavy-chain gene rearrangements with assessment of Propionibacterium acnes specific antibody reactions allow us to report, for the first time, this case of pulmonary mucosa-associated lymphoid tissue lymphoma associated with pulmonary sarcoidosis in exactly the same location, which may be significant for differentiating these diseases and understanding their pathogenic association. (C) 2016 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2015.12.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

The occurrence of osteoclast-like giant cells (OLGCs) in uterine leiomyosarcomas (LMSs) is a rare phenomenon. The nature of OLGCs and the significance of their accumulation in these tumors are poorly understood. Recent studies revealed that the formation of osteoclasts requires a specific cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), in bone. In this study, we investigated the expression of RANKL in 2 cases of uterine LMS with OLGCs by means of immunohistochemistry and compared the extent of RANKL expression with that in conventional uterine LMSs and leiomyomas by using real-time reverse-transcription quantitative polymerase chain reaction. Our cases of uterine LMS with OLGCs showed markedly high expression of RANKL messenger RNA with clear RANKL immunoreactivity compared with messenger RNA expression and immunoreactivity of conventional uterine LMSs and leiomyomas. These findings suggest that the tumors producing RANKL may account for accumulation of OLGCs in tumor tissue because of RANKL-related osteoclastogenesis. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.humpath.2015.04.018

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DOI： 10.1038/labinvest.2015.66

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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BACKGROUND: Non-small-cell lung cancers (NSCLCs) harboring translocations in anaplastic lymphoma kinase (ALK) are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. CASE PRESENTATION: We describe a case of post-operative local recurrence of lung adenocarcinoma in an 81 year-old male. He underwent radiation and received chemotherapy with docetaxel, but neither treatment regimen was effective. Following identification of ALK rearrangements, crizotinib treatment was initiated. After treatment with crizotinib for 5 days, adverse events including acute renal failure (grade 2/CTCAE ver4.0) and congestive heart failure (grade 3) occurred. Crizotinib modified treatment was required. Half dose of crizotinib treatment could not control tumor progression. Ultimately, crizotinib was administrated at a dose of 250 mg twice daily every 3 day dosing for 13 months with maintenance of the anti-tumor effect. CONCLUSION: This is the first case report that skip schedule was more effective than dose reduction daily in crizotinib administration for ALK rearranged NSCLC patient with severe adverse events.

DOI： 10.1186/s13104-015-1126-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1161/CIRCEP.114.002517

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DOI： 10.1038/labinvest.2013.103

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DOI： 10.1016/j.oooo.2013.01.002

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DOI： 10.1111/pin.12058

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Language：English   Publisher：1  

Orthotopic liver transplantation (OLT) in rats is technically feasible and useful for the assessment of clinical liver transplantation and analysis of inflammatory liver diseases. OLT in rats was pioneered by Lee et al. in 1973 using hand-suture techniques of all vessels. This model has not been widely used due to the long operative time and technical demand. The cuff method was introduced by Kamada in 1979, and today, the Kamada technique is the one most commonly used worldwide. However, this technique does not include hepatic artery reconstruction, although this procedure is routinely performed in clinical transplantation. Nevertheless, several techniques for hepatic artery reconstruction in rat OLT have been reported recently, and our group also developed a simple splint technique from recipient right renal artery to donor celiac axis bearing the hepatic artery. In the present article, we describe the Kamada technique, as a standard surgical method for rat OLT. In addition, we also describe our splint technique for hepatic artery reconstruction. Then, we compare the features of Kamada technique and our splint technique for hepatic artery reconstruction and all other surgical techniques currently in use for rat OLT. The widespread use of the rat OLT model should help to provide full assessment of transplant immunology and the mechanism and treatment of inflammatory liver diseases.<br>

DOI： 10.1272/jnms.80.4

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Language：English   Publisher：The Japanese Society of Internal Medicine  

We experienced a case of interstitial lung disease (ILD) that occurred one year after the start of everolimus therapy for renal cell carcinoma. The pathological features included interstitial pneumonia with granuloma formation. Everolimus is known to cause ILD; however, its pathology is unclear. Granuloma-forming interstitial pneumonia associated with everolimus is uncommon, although it may be one of the pathological patterns associated with everolimus-induced ILD. This is a slow-onset case of everolimus-induced ILD in a patient with renal cell carcinoma. Physicians should thus be aware of the potential for the development of ILD at any time during the administration of everolimus therapy.<br>

DOI： 10.2169/internalmedicine.52.8588

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Other Link： http://search.jamas.or.jp/link/ui/2014000469

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DOI： 10.1159/000348567

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Other Link： http://orcid.org/0000-0003-4495-7982

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DOI： 10.1272/jnms.79.496

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Other Link： http://orcid.org/0000-0003-4495-7982

Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: Matrix metalloproteinases (MMPs) are zinc endopeptidases that degrade extracellular matrix and are involved in the pathogenesis of ischemic damage in acute kidney injury (AKI). In the present study, we analyzed the role of MMP-2 in the repair process in ischemic AKI. Methods: AKI was induced in MMP-2 wild-type (MMP-2(+/+)) and MMP-2-deficient (MMP-2(-/-)) mice by 90-min renal artery clamping followed by reperfusion. Renal histology and the activity and distribution of MMP-2 were examined from day 1 to day 14. During the recovery from AKI, MMP-2(+/+) mice were also treated with MMP-2/MMP-9 inhibitor. Results: In both MMP-2(+/+) and MMP-2(-/-) mice, AKI developed on day 1 after ischemia/reperfusion with widespread acute tubular injury, but subsequent epithelial cell proliferation was evident on days 3-7. During the repair process, active MMP-2 and MMP-9 increased in regenerating tubular epithelial cells in MMP-2(+/+) mice on days 7-14, and the tubular repair process was almost complete by day 14. On the other hand, in MMP-2(-/-) mice, less prominent proliferation of tubular epithelial cells was evident on days 3 and 7, and damaged tubules that were covered with elongated and immature regenerated epithelial cells were identified on days 7 and 14. Incomplete recovery of injured microvasculature was also noted with persistent macrophage infiltration. Similarly, treatment with MMP-2/MMP-9 inhibitor resulted in impaired recovery in MMP-2(+/+) mice. Conclusion: MMP-2 is involved in tubular repair after AKI. The use of the MMP-2/MMP-9 inhibitor was a disadvantage when it was administered during the repair stage of ischemic AKI. Treatment with MMP inhibitor for AKI needs to be modified to enhance recovery from AKI. Copyright (C) 2013 S. Karger AG, Basel

DOI： 10.1159/000346569

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DOI： 10.1159/000346569

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：4  

Terasaki Y, Ohsawa I, Terasaki M, Takahashi M, Kunugi S, Dedong K, Urushiyama H, Amenomori S, Kaneko-Togashi M, Kuwahara N, Ishikawa A, Kamimura N, Ohta S, Fukuda Y. Hydrogen therapy attenuates irradiation-induced lung damage by reducing oxidative stress. Am J Physiol Lung Cell Mol Physiol 301: L415-L426, 2011. First published July 15, 2011; doi: 10.1152/ajplung.00008.2011.-Molecular hydrogen (H-2) is an efficient antioxidant that diffuses rapidly across cell membranes, reduces reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, and suppresses oxidative stress-induced injury in several organs. ROS have been implicated in radiation-induced damage to lungs. Because prompt elimination of irradiation-induced ROS should protect lung tissue from damaging effects of irradiation, we investigated the possibility that H-2 could serve as a radioprotector in the lung. Cells of the human lung epithelial cell line A549 received 10 Gy irradiation with or without H-2 treatment via H-2-rich PBS or medium. We studied the possible radioprotective effects of H-2 by analyzing ROS and cell damage. Also, C57BL/6J female mice received 15 Gy irradiation to the thorax. Treatment groups inhaled 3% H-2 gas and drank H-2-enriched water. We evaluated acute and late-irradiation lung damage after H-2 treatment. H-2 reduced the amount of irradiation-induced ROS in A549 cells, as shown by electron spin resonance and fluorescent indicator signals. H-2 also reduced cell damage, measured as levels of oxidative stress and apoptotic markers, and improved cell viability. Within 1 wk after whole thorax irradiation, immunohistochemistry and immunoblotting showed that H-2 treatment reduced oxidative stress and apoptosis, measures of acute damage, in the lungs of mice. At 5 mo after irradiation, chest computed tomography, Ashcroft scores, and type III collagen deposition demonstrated that H-2 treatment reduced lung fibrosis (late damage). This study thus demonstrated that H-2 treatment is valuable for protection against irradiation lung damage with no known toxicity.

DOI： 10.1152/ajplung.00008.2011

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DOI： 10.1016/j.transproceed.2011.04.024

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DOI： 10.1038/labinvest.2010.174

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Chronic obstructive pulmonary disease is mainly characterized by irreversible airflow limitation, and its major pathological change is alveolar destruction and enlargement, which induces emphysema. In this study, we used stereoscopic microscopy to observe the cut surfaces of 21 surgically resected or autopsied lungs showing centriacinar emphysema. We identified columnar structures of various sizes in the cystic spaces. These columnar structures constituted two types: one that was associated with pulmonary artery and another that was not. We examined these structures in detail by light microscopy and performed statistical analyses. Columnar structures without pulmonary artery showed destruction and accumulation of alveoli, including abnormally aggregated elastic fibers. In contrast, pulmonary architecture was preserved in columnar structures with pulmonary artery. In columnar structures without pulmonary artery, statistically significant correlations were observed between the thickness of columnar structures and size of centriacinar cystic spaces and between the thickness of columnar structures and aggregation of elastic fibers in columnar structures. Electron microscopy showed that the columns were composed of aggregated elastic fibers, collagen fibers, mesenchymal cells, pigmented macrophages, and the alveolar epithelial cells covering them. Immunohistochemistry showed that the aggregated elastic fibers were positive for alpha-1 antitrypsin. We concluded that columnar structures without pulmonary artery are a hallmark of alveolar wall destruction seen in pulmonary emphysema.

DOI： 10.1007/s00428-010-0903-y

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：(株)南江堂  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2010&ichushi_jid=J00974&link_issn=&doc_id=20100924190022&doc_link_id=issn%3D0022-1961%26volume%3D106%26issue%3D4%26spage%3D713&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0022-1961%26volume%3D106%26issue%3D4%26spage%3D713&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

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DOI： 10.1016/j.humpath.2009.04.019

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DOI： 10.1080/01913120902751197

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Language：English   Publishing type：Research paper (scientific journal)  

Patients with idiopathic pulmonary fibrosis (IPF) have an increased risk of developing lung cancer. To identify key molecules involved in malignant transformation in IPF, we analyzed the expression profiles of lung and lung tumor tissue from patients with lung cancer and IPF (lung cancer/IPF) using cDNA arrays and real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Reduced expression of the Smad4 gene was identified in all eight tumor samples from the lung cancer/IPF patients using real-time RT-PCR. Expression levels of Smad4 were significantly lower in tumors from lung cancer/IPF patients than in those from lung cancer patients without IPF or in lung cancer cell lines (p<0.01). Mutational analysis of TGF-β type II receptor and Smad4 was performed using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). The methylation status of the Smad4 promoter was analyzed using methylation-specific PCR with subsequent sequence analysis. No mutations were detected in the eight tumor samples, but hypermethylated regions were detected in the Smad4 promoter in two of the eight tumors with reduced Smad4 expression. Promoter reporter assays showed that the activity of the Smad4 promoter containing the sequence of the methylated region was significantly stronger than that of the Smad4 promoter with a deleted methylated region (p<0.002). Our findings indicate that the loss of the growth inhibitory response to TGF-β signaling may be crucial in pulmonary carcinogensis or in the progression of lung cancer in IPF patients in whom TGF-β is overexpressed; hypermethylation of the Smad4 promoter region may be one mechanism by which this occurs. These findings are useful for the development of preventive measures or treatment for lung cancer patients with IPF.

DOI： 10.3892/mmr_00000064

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DOI： 10.1272/jnms.75.48

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：日本神経学会  

We report a 41-year-old man whose initial neurological symptoms are atypical of Wegener's granulomatosis. The patient was admitted because he developed left ocular pain, headache, bilateral visual loss and left abducens nerve palsy. He was initially diagnosed with optic neuritis at ophthalmological department and steroid therapy was started. Although steroid therapy led to rapid recovery of visual acuity and eye movement, he was readmitted for seizure. Two weeks later, a second seizure attack occurred, followed by palsy of the left side of cranial nerves II, III, IV, V and VI. Brain MRI showed focal thickening and enhancement of the dura mater over left frontal lobe, leading to a new presumptive diagnosis of idiopathic hypertrophic cranial pachymeningitis. Steroid therapy was resumed and the symptoms improved rapidly. As right hemiparesis developed during the clinical course, another brain MRI was obtained. T2-weighted image showed a high intensity area in the left portion of the pons. 14 months later, recurrent epistaxis suggestive of Wegener's granulomatosis appeared. A subsequent nasopharyngeal mucosa biopsy revealed a necrotizing granulomatous inflammation. A significant elevation of PR-3 ANCA was also noted. A definitive diagnosis of Wegener's granulomatosis was established. The initial presentation of this case was of multiple cranial neuropathies with no superior respiratory tract symptoms, which are typical of early stage Wegener's granulomatosis. In patients with various central nervous system symptoms and MRI evidence of hypertrophic cranial pachymeningitis, a thorough clinical workup of vasculitis syndrome including Wegener's granulomatosis should be considered.

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Language：Japanese   Publisher：The Medical Association of Nippon Medical School  

An 80-year-old man died of rupture of the thoracic aorta 3 months after surgery for abdominal aortic aneurysm. Autopsy revealed that multiple penetrating atherosclerotic ulcers with intramural hematoma had resulted in psudoaneurysm of the abdominal aorta and dissection of the thoracic aorta. Differentiation from common aortic aneurysm or classic aortic dissection is important because pseudoaneurysm and aortic dissection related to penetrating atherosclerotic ulcer have a higher risk of rupture.&lt;br&gt;

DOI： 10.1272/manms.3.187

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Language：Japanese   Publisher：(株)南江堂  

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Other Link： http://search.jamas.or.jp/link/ui/2005061250

Language：Japanese   Publisher：克誠堂出版(株)  

27歳男.呼吸困難を主訴とした.13歳時よりウィルソン病の診断でD-ペニシラミンを服用し,喫煙歴は30本/日×8年間であった.肺機能の不可逆性閉塞性変化と労作時の低酸素血症を呈し,胸部HRCTでは両側肺の過膨張所見と低吸収域の散在を認めた.胸腔鏡下肺生検では小葉中心性ならびに胸膜下領域に気腫性変化を認め,壁には弾性線維増加を認めた.細気管支にも炎症所見や著明な弾性線維増加を認めたが,閉塞性細気管支炎の所見は認めなかったため肺気腫と診断した.発症の機序として,喫煙により障害された肺の細胞外基質がペニシラミンにより合成阻害され異常となった細胞外基質で置換された可能性があるため,D-ペニシラミンを塩酸トリエンチンに変更し禁煙指導を行い,外来で加療中である

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Other Link： http://search.jamas.or.jp/link/ui/2005100795

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Pulmonary adenocarcinoma composed of pure or predominant solid components is reported to be a highly malignant tumor. However, the existence of solid components and its connection with biological behavior have not been well documented. To answer this question, we histologically subclassified poorly differentiated adenocarcinoma (P/D Ad Ca) into solid type and non-solid type, and compared the biological behavioral characteristics.Material and Methods: All histological specimens of surgically resected primary lung carcinoma diagnosed as P/D Ca or large cell carcinoma in Nippon Medical School Hospital were re-evaluated according to the 1999 WHO manual. The cases re-evaluated as P/D Ad Ca were further divided into solid type and non-solid type according to our original definition: the solid type contains solid components where a glandular structure is not recognized in more than one high-power field, while in the non-solid type, a small glandular structure is observed in every high-power field. The differences in the occurrence of lymph node metastasis were assessed by Fisher's exact test.Results: Among 109 cases satisfying both histological and clinical investigation, 45 cases were re-evaluated as P/D Ad Ca; solid type (n=22), and non-solid type (n=23). Lymph node metastases occurred at a higher rate in the solid type than in the non-solid type (p<0.01).Conclusion: Patients with solid type Ad Ca have reached a more advanced stage than patients having non-solid type due to high metastatic rate to lymph nodes. These results suggest that we should not overlook solid components even if the solid components are the focal lesion. This sub-typing alerts clinicians to survey metastases, and may contribute to therapeutic strategies in the future.<br>

DOI： 10.1272/jnms.70.28

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

Matrix metalloproteinases (MMPs) have been implicated in the pathological processes of interstitial lung diseases. However, underlying mechanisms, particularly for activity levels and distribution of activated MMP-2 in the disease process, are yet to be elucidated. The present study investigated the immunolocalization of MMP-2, membrane type 1-matrix metalloproteinase (MT1-MMP), tissue inhibitor of metalloproteinase (TIMP)-2, p53, and Ki-67 in a rabbit model of bleomycin-induced pulmonary fibrosis. Gelatin zymography and in situ zymography were used to examine the activity and the localization of MMP-2. Furthermore, we performed Western blot and in situ hybridization for MT1-MMP, an activator for MMP-2. The total MMP-2 level estimated by gelatin zymography increased significantly at 3, 7, and 14 days after bleomycin administration, compared with controls. In the immunohistochemical study, immunoreaction for MMP-2 was strongest in alveolar epithelial cells among the cell populations. Swollen and/or elongated type 11 alveolar epithelial cells showed strong immunoreactions for MMP-2, MT1-MMP, and TIMP-2. After bleomycin administration, immunoreaction for p53 was observed in bronchiolar and alveolar epithelial cells. The proportion of p53-positive cells was high in epithelial cells from 1 to 14 days as MMP-2 levels were increased, suggesting that p53 may be responsible, at least in part, for the increase of MMP-2. The ratio of activated MMP-2 to total MMP-2 estimated by gelatin zymography increased significantly at 3, 7, 14, and 28 days after bleomycin treatment. In situ zymography revealed that type II alveolar epithelial cells degraded gelatin. An increased expression of MT1-MMP protein was observed by Western blot following administration of bleomycin. In situ hybridization demonstrated that type II alveolar epithelial cells gave intense signal for MT1-MMP mRNA. These results suggest that type II alveolar epithelial cells express MT1-MMP and activate MMP-2 on their cell surfaces, which may lead to the elongation and migration of alveolar epithelial cells in the repair process of bleomycininduced pulmonary fibrosis.

DOI： 10.1038/labinvest.3780344

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.20.3_265_4

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Language：Japanese   Publisher：(一社)日本病理学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：NATURE PUBLISHING GROUP  

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Language：Japanese   Publisher：日本医科大学医学会  

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Language：Japanese   Publisher：(一社)日本脳神経超音波学会  

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DOI： 10.15106/J00974.2016110035

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Language：Japanese   Publisher：(一社)日本病理学会  

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DOI： 10.2482/haigan.55.119

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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特発性肺線維症急性増悪の剖検15例で、臨床・病理を対比検討した。増悪から死亡までは3日〜6ヵ月、7例で増悪のきっかけは不明であった。全例で臨床病期に一致したDADがみられた。OP様像の目立つ症例は、血管再生不良、筋線維芽細胞化、DADへの移行像がありDADの一所見と理解されるが、同時に、特発性AIPとの類似性が示唆される。半数で、線維芽細胞巣が目立ち、IPFとして活動性が高いと判断される。(著者抄録)

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Language：Japanese   Publishing type：Meeting report   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：Japan Lung Cancer Society  

Objective. In 9 patients operated on for idiopathic interstitial pneumonia (IIP) associated with primary lung cancer, we clinicopathologically examined the predictive factors of postoperative acute exacerbation of IIP. Methods. We collected 9 patients who had been operated on for lung cancer and in whom a pathological diagnosis of usual interstitial pneumonia (UIP) pattern had been made based on resected tissues. We studied some predictive factors related to the acute exacerbation of IIP preoperatively and during operation, and analyzed the pathological findings of UIP. Results. The incidence of postoperative acute exacerbation of IIP was 22% (2 of 9 patients). No correlation between the two patients who developed acute exacerbation of IIP and the seven patients who did not was observed, in terms of CRP, LDH, WBC, PaO2 and %VC of preoperation, blood loss, operation time and postoperative maximum CPK. Pathologically, abundant fibroblastic foci were observed in 4 patients and a half of them developed acute exacerbation of IIP at 7 and 9 days postoperatively. Conclusion. It was difficult to predict the development of acute exacerbation of IIP because most patients were in a controlled stable state of IIP preoperatively. However, we considered that abundant fibroblastic foci in the tissue specimens known as pathologically active lesions of UIP were possibly one of the predictive factors in the acute exacerbation of IIP.

DOI： 10.2482/haigan.42.567

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

67歳男.アルミニウムの研磨業に2ヵ月従事し,約10年前より会社健診にて胸部X線上じん肺と診断されていた.経過中に発熱,労作時呼吸困難,四肢の痺れ,胸部X線上,新たに両側下肺野にスリガラス影が出現した.経気管支肺生検(TBLB)で,じん肺の所見に相当する線維化所見と,元素分析でアルミニウムの存在を証明し,アルミニウム肺と診断した.腎生検にて半月体形成性糸球体腎炎,小動脈の血管炎の所見を認め,血清の抗好中球細胞質抗体(P-ANCA)が陽性で,Microscopic-polyangiitis(MPA)と診断した.活動性の間質性肺炎の所見があり,MPAによる間質性肺炎がじん肺に加わった所見と判断した

CiNii Books

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Language：Japanese   Publisher：(NPO)日本呼吸器内視鏡学会  

DOI： 10.18907/jjsre.22.2_142_2

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

55歳男.&#039;94年気管支喘息の診断を受け加療中であった.&#039;95年胸部X線にて結節影を指摘され,胸腔鏡下肺生検施行.肺内リンパ節の診断と共に,肺好酸球浸潤を認めた.&#039;97年11月初旬より両下肢しびれ感,37.2℃の微熱,体重減少出現.精査加療目的にて当科入院となった.諸検査所見と臨床症状よりChurg-Strauss症候群と診断した.Prednisolone 60mgより治療開始し,臨床症状は両下肢しびれ感以外改善した.本症例は,喘息様症状発症1年後,血管炎症候発症2年前にChurg-Strauss症候群を示唆する肺好酸球浸潤が確認された貴重な症例と考えられる.又,肺内リンパ節合併の報告は著者等が検索した範囲では認められず,本症例は重喫煙者でないにも拘わらず,胸膜直下のリンパ組織が発達した珍しい症例であった

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症例は88歳の男性である。右麻痺、失語を認め救急搬送された。来院時の頭部MRI/Aにて左中大脳動脈領域に新規梗塞巣と左内頸動脈の閉塞を認めたため、機械的脳血栓回収療法を施行した。その後内科的治療を行うも、左内頸動脈は再閉塞した。血栓病理でアスペルギルス真菌塊を認めた。副鼻腔炎と骨破壊を認めており、アスペルギルスが内頸動脈に直接浸潤し、血栓を形成し、閉塞したことが考えられた。血栓病理によって原因の特定に至った症例を経験した。原因不明の脳梗塞は、機械的血栓回収療法によって回収された血栓を確認することで、原因が判明する可能性がある。(著者抄録)

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01550&link_issn=&doc_id=20200602480005&doc_link_id=1390285300159919360&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390285300159919360&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_3.gif

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BACKGROUND: Non-small-cell lung cancers (NSCLCs) harboring translocations in anaplastic lymphoma kinase (ALK) are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. CASE PRESENTATION: We describe a case of post-operative local recurrence of lung adenocarcinoma in an 81 year-old male. He underwent radiation and received chemotherapy with docetaxel, but neither treatment regimen was effective. Following identification of ALK rearrangements, crizotinib treatment was initiated. After treatment with crizotinib for 5 days, adverse events including acute renal failure (grade 2/CTCAE ver4.0) and congestive heart failure (grade 3) occurred. Crizotinib modified treatment was required. Half dose of crizotinib treatment could not control tumor progression. Ultimately, crizotinib was administrated at a dose of 250 mg twice daily every 3 day dosing for 13 months with maintenance of the anti-tumor effect. CONCLUSION: This is the first case report that skip schedule was more effective than dose reduction daily in crizotinib administration for ALK rearranged NSCLC patient with severe adverse events.

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Other Link： http://orcid.org/0000-0003-4495-7982

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Recent studies have suggested that some cases of familial interstitial pneumonia are associated with mutations in the gene encoding surfactant protein C (SFTPC). We report here a case of familial interstitial pneumonia in an adolescent boy whose paternal grandfather and father suffered from idiopathic interstitial pneumonia (IIP). The patient was asymptomatic but showed an abnormal shadow in the chest at his medical check-up. The surgical biopsy of the patient revealed non-specific interstitial pneumonia and showed pathological findings similar to those in his father's autopsy. Genomic DNA from blood leucocytes of the patient was sequenced for the Thy104His (Y104H) SFTPC mutation. Based on these results, he was diagnosed with SFTPC mutation-associated familial interstitial pneumonia. There has been no clinical, physiologic and radiologic progression for 4 years since the diagnosis. The relation between clinical manifestation and the mutation site of the patient may broaden the spectrum of SFTPC mutation-associated interstitial pneumonia.

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Language：English   Presentation type：Poster presentation  

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Language：English   Presentation type：Poster presentation  

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