Publications by authors named "Eiichi Morii"

320 Publications

Immunoscore Signatures in Surgical Specimens and Tumor-Infiltrating Lymphocytes in Pretreatment Biopsy Predict Treatment Efficacy and Survival in Esophageal Cancer.

Ann Surg 2021 Jul 29. Epub 2021 Jul 29.

Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan Department of Pathology, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Osaka, Japan Department of Pathology, Osaka International Cancer Institute, Osaka, Osaka, Japan.

Objectives: Tumor-infiltrating lymphocytes (TILs) have long been recognized as playing an important role in tumor immune microenvironment. Lately, the Immunoscore (IS) has been proposed as a new method of quantifying the number of TILs in association with patient survival in several cancer types.

Methods: In 300 preoperatively untreated esophageal cancer (EC) patients who underwent curative resection at two different institutes, immunohistochemical staining using CD3 and CD8 antibodies was performed to evaluate IS, as objectively scored by auto-counted TILs in the tumor core and invasive margin. In addition, in pre-neoadjuvant chemotherapy (pre-NAC) endoscopic biopsies of a different cohort of 146 EC patients who received NAC, CD3 and CD8 were immunostained to evaluate TIL density.

Results: In all cases, the IS-high (score 3-4) group tended to have better survival (5-year overall survival [OS] of the IS-high vs low group: 77.6 vs 65.8%, P = 0.0722) than the IS-low (score 1-2) group. This trend was more remarkable in cStage II-IV patients (70.2 vs 54.5%, P = 0.0208) and multivariate analysis of OS further identified IS (hazard ratio 2.07, P = 0.0043) to be an independent prognostic variable. In preNAC biopsies, NAC-responders had higher densities than non-responders of both CD3+ (P = 0.0106) and CD8+ cells (P = 0.0729) and, particularly CD3+ cell density was found to be an independent prognostic factor (hazard ratio 1.75, P = 0.0169).

Conclusions: The IS signature in surgical specimens and TIL density in preNAC-biopsies could be predictive markers of clinical outcomes in EC patients.
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http://dx.doi.org/10.1097/SLA.0000000000005104DOI Listing
July 2021

Durable response of chemotherapy for cancer of unknown primary with unfavorable subset developed in retroperitoneal space.

IJU Case Rep 2021 Jul 27;4(4):255-258. Epub 2021 May 27.

Department of Urology Graduate School of Medicine Osaka University Osaka Japan.

Introduction: Carcinoma of unknown primary site is a heterogeneous group of cancer that is defined by the presence of metastatic disease with no identified primary tumor at initial presentation. Carcinoma of unknown primary site patients with unfavorable subsets particularly show poor prognosis with a median survival of 6-9 months with the treatment of empirical pactitaxel and carboplatin therapy (TC therapy). Recently, several studies have attempted to increase the response rate on the basis of prediction of the primary site by immunohistochemical tests or molecular profiling assays.

Case Presentation: We report the case of a 77-year-old woman who presented with a mass on the left side of the abdominal aorta. Careful clinical and laboratory examinations could not identify the site of primary cancer. Pathologic examination of biopsied tissue revealed the tumor as undifferentiated carcinoma, which reached the diagnosis of carcinoma of unknown primary site with unfavorable subsets. She received empirical TC therapy and had prolonged survival of 26 months. After reviewing the pathological findings carefully, we noticed that Gross Cystic Disease Fluid Protein-15 showed positive in the tumor, leading to the suspicion of breast cancer as the primary site. The specific therapy for breast cancer is similar to the empirical TC therapy in carcinoma of unknown primary site, which may contribute durable response in this patient.

Conclusion: Site-specific therapy based on careful immunohistochemical tests may improve the efficacy for carcinoma of unknown primary site patients with unfavorable prognosis subset.
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http://dx.doi.org/10.1002/iju5.12302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255281PMC
July 2021

Clear Cell Carcinoma in the Oral Cavity with Three Novel Types of EWSR1-ATF1 Translocation: A Case Report.

Head Neck Pathol 2021 Jul 12. Epub 2021 Jul 12.

Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Clear cell carcinoma (CCC) is a rare epithelial malignant tumor of the salivary glands. It is characterized by tumor cells with clear cytoplasm, hyalinized stroma, and most importantly the fusion genes EWSR1-ATF1, EWSR1-CREM, and EWSR1-PLAG1. Break-apart FISH has been performed for multiple CCC cases, but direct sequencing analysis has been performed in relatively few. Herein, we report an interesting case of CCC harboring three EWSR1-ATF1 translocations: EWSR1 exon 8-ATF1 exon 4, EWSR1 exon 7-ATF1 exon 4, and EWSR1 exon 7-ATF1 exon 5. This case indicates the possibility of independent EWSR1-ATF1 gene translocations, and could provide insight into CCC tumorgenesis.
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http://dx.doi.org/10.1007/s12105-021-01356-yDOI Listing
July 2021

Amyotrophic lateral sclerosis with speech apraxia, predominant upper motor neuron signs, and prominent iron accumulation in the frontal operculum and precentral gyrus.

Neuropathology 2021 Aug 4;41(4):324-331. Epub 2021 Jul 4.

Department of Neurology, Osaka University Graduate School of Medicine, Suita, Japan.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease; transactivation response DNA-binding protein of 43 kDa (TDP-43) and iron accumulation are supposed to play a crucial role in the pathomechanism of the disease. Here, we report an unusual case of a patient with ALS who presented with speech apraxia as an initial symptom and upper motor neuron deficiencies. In the early clinical stages, single-photon emission computed tomography visualized focal hypoperfusion of the right frontal operculum, and magnetic resonance imaging identified a hypointense area along the frontal lobe on T2-weighted images. Neuropathological examination revealed that neuronophagia of Betz cells, gliosis, appearance of phosphorylated TDP-43 (p-TDP-43)-positive glial and neuronal inclusions, and prominent iron accumulation were frequently visible in the precentral gyrus. TDP-43 pathology and focal iron accumulation were also visible in the frontal operculum, but only a mild neuronal loss and a few p-TDP-43-positive neuronal and glial inclusions were found in the hypoglossal nucleus of the medulla oblongata and anterior horn of the spinal cord. Immunoblot analysis revealed an atypical band pattern for ALS. In our case, abnormal TDP-43 and iron accumulation might possibly have caused neurodegeneration of the frontal operculum, in tandem or independently; it might then have spread into the primary motor area. Our results suggest a causative association between TDP-43 and iron accumulation in the pathomechanisms of ALS presenting with upper motor neuron signs.
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http://dx.doi.org/10.1111/neup.12763DOI Listing
August 2021

Transcriptomics Identify Thrombospondin-2 as a Biomarker for Nonalcoholic Steatohepatitis and Advanced Liver Fibrosis.

Hepatology 2021 Jun 9. Epub 2021 Jun 9.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.

Background And Aims: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers.

Approach And Results: Global RNA sequencing of liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well distinguished NASH from nonalcoholic fatty liver (NAFL), and NASH patients exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified proteins upregulated in NASH and/or advanced fibrosis (stage F3-4), including matricellular glycoprotein thrombospondin-2 (TSP-2), encoded by the thrombospondin 2 (THBS2) gene. The intrahepatic THBS2 expression level showed the highest areas under the receiver operating characteristic curves (AUROCs) of 0.915 and 0.957 for diagnosing NASH and advanced fibrosis, respectively. THBS2 positively correlated with inflammation and ballooning according to NAFLD activity score, serum aspartate aminotransferase and hyaluronic acid (HA) levels, and NAFLD Fibrosis Score (NFS). THBS2 was associated with extracellular matrix and collagen biosynthesis, platelet activation, caspase-mediated cleavage of cytoskeletal proteins, and immune cell infiltration. Serum TSP-2 expression was measured in 213 patients with biopsy-proven NAFLD, was significantly higher in NASH than in NAFL, and increased parallel to fibrosis stage. The AUROCs for predicting NASH and advanced fibrosis were 0.776 and 0.856, respectively, which were comparable to Fibrosis-4 index, serum HA level, and NFS in advanced fibrosis diagnosis. Serum TSP-2 level and platelet count were independent predictors of NASH and advanced fibrosis. Serum TSP-2 levels could stratify NAFLD patients according to the risk of hepatic complications, including liver cancer and decompensated cirrhotic events.

Conclusions: TSP-2 may be a useful biomarker for NASH and advanced fibrosis diagnosis in NAFLD patients.
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http://dx.doi.org/10.1002/hep.31995DOI Listing
June 2021

An Older Thrombus Delays Reperfusion after Mechanical Thrombectomy for Ischemic Stroke.

Thromb Haemost 2021 Jun 2. Epub 2021 Jun 2.

Department of Neurology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background:  Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism.

Methods:  We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age.

Results:  Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content ( < 0.001) and higher extent of NETosis ( = 0.006). Restricted mean survival time analysis revealed that older thrombi were associated with longer puncture-to-reperfusion times (difference: 15.6 minutes longer for older thrombi,  = 0.002). This association remained significant even after adjustment for erythrocyte content and the extent of NETosis (adjusted difference: 10.8 minutes, 95% confidence interval [CI]: 0.6-21.1 minutes,  = 0.039). Compared with fresh thrombi, older thrombi required more device passes before reperfusion ( < 0.001) and were associated with poorer functional outcomes (adjusted common odds ratio: 0.49; 95% CI: 0.24-0.99).

Conclusion:  An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy.
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http://dx.doi.org/10.1055/a-1522-4507DOI Listing
June 2021

A deep learning system to diagnose the malignant potential of urothelial carcinoma cells in cytology specimens.

Cancer Cytopathol 2021 May 12. Epub 2021 May 12.

Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: Although deep learning algorithms for clinical cytology have recently been developed, their application to practical assistance systems has not been achieved. In addition, whether deep learning systems (DLSs) can perform diagnoses that cannot be performed by pathologists has not been fully evaluated.

Methods: The authors initially obtained low-power field cytology images from archived Papanicolaou-stained urinary cytology glass slides from 232 patients. To aid in the development of a diagnosis support system that could identify suspicious atypical cells, the images were divided into high-power field panel image sets for training and testing of the 16-layer Visual Geometry Group convolutional neural network. The DLS was trained using linked information pertaining to whether urothelial carcinoma (UC) in the corresponding histology specimen was invasive or noninvasive, or high-grade or low-grade, followed by an evaluation of whether the DLS could diagnose these characteristics.

Results: The DLS achieved excellent performance (eg, an area under the curve [AUC] of 0.9890; F1 score, 0.9002) when trained on high-power field images of malignant and benign cases. The DLS could diagnose whether the lesions were invasive UC (AUC, 0.8628; F1 score, 0.8239) or high-grade UC (AUC, 0.8661; F1 score, 0.8218). Gradient-weighted class activation mapping of these images indicated that the diagnoses were based on the color of tumor cell nuclei.

Conclusions: The DLS could accurately screen UC cells and determine the malignant potential of tumors more accurately than classical cytology. The use of a DLS during cytopathology screening could help urologists plan therapeutic strategies, which, in turn, may be beneficial for patients.
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http://dx.doi.org/10.1002/cncy.22443DOI Listing
May 2021

Primary Alveolar Soft Part Sarcoma of Cheek: Report of a Case and Review of the Literature.

Head Neck Pathol 2021 Apr 11. Epub 2021 Apr 11.

Department of Oral Pathology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Alveolar soft part sarcoma (ASPS) is a rare soft tissue sarcoma characterized by an alveolar or organoid arrangement of polygonal tumour cells separated by fibrovascular septa. A specific fusion gene [ASPS critical region 1 (ASPSCR1)-TFE3] was detected in ASPS. Despite being a slow-growing tumour without pain and dysfunction, ASPS is characterized by early metastasis, which leads to poor prognosis. Herein, we report a rare case of primary ASPS of the cheek harbouring ASPSCR1 (exon 7)-TFE3 (exon 5) fusion gene in a 21 year-old woman. This tumour was a well-circumscribed, smooth, round mass that was clinically suspected as a benign tumour. However, histologically, it was observed that the polygonal tumour cells were arranged in solid and alveolar growth patterns. Post-operative examination of the whole body excluded the possibility of metastasis at other sites. Thus, careful immunohistochemical and genetic analyses, as well as whole-body examination, demonstrated that the tumour was a primary ASPS of the cheek.
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http://dx.doi.org/10.1007/s12105-021-01324-6DOI Listing
April 2021

Identification of CXCL12-abundant reticular cells in human adult bone marrow.

Br J Haematol 2021 May 10;193(3):659-668. Epub 2021 Apr 10.

Laboratory of Stem Cell Biology and Developmental Immunology, Immunology Frontier Research Center, World Premier International Research Center (WPI), Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Suita, Japan.

A population of mesenchymal stem cells, termed CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing cells, are the major cellular component of niches for haematopoietic stem cells (HSCs) in murine bone marrow. CAR cells are characterized by several salient features, including much higher expression of CXCL12, stem cell factor (SCF), forkhead box C1 (FOXC1) and early B-cell factor 3 (EBF3), which are essential for HSC maintenance, than other cells. However, the human counterpart of CAR cells has not been fully described. Here, we show the presence of cells expressing much higher CXCL12 than other cells in human adult bone marrow using a flow cytometry-based in situ technique that enables high-throughput detection of mRNA at single-cell resolution. Most CXCL12 cells expressed high levels of SCF, FOXC1 and EBF3 and had the potential to differentiate into adipocytes and osteoblasts. Histologically, the nuclei of CXCL12 cells were identified and quantified by EBF3 expression in fixed marrow sections. CXCL12 cells sorted from residual bone marrow aspirates of chronic myeloid leukaemia patients expressed reduced levels of CXCL12, SCF, FOXC1 and EBF3 in correlation with increased leukaemic burden. Together, we identified the human counterpart of CAR cells, enabling the evaluation of their alterations in various haematological disorders by flow cytometric and histological analyses.
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http://dx.doi.org/10.1111/bjh.17396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252541PMC
May 2021

Bcl-2-negative IGH-BCL2 translocation-negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl-2-positive IGH-BCL2 translocation-positive follicular lymphoma.

Histopathology 2021 Apr 7. Epub 2021 Apr 7.

Department of Pathology, Sakai City Medical Center, Osaka, Japan.

Aims: Follicular lymphoma (FL), comprising a minor subset of primary thyroid lymphomas, is divided into two groups based on Bcl-2 expression and IGH-BCL2 translocation. The clinicopathological features exhibited by Bcl-2-negative IGH-BCL2 translocation-negative FL of the thyroid (Bcl-2 /IGH-BCL2 tFL) are different from those of conventional FL; however, its lymphomagenesis remains unclear. Here, we collected samples from seven patients with Bcl-2 /IGH-BCL2 tFL to investigate their epigenetic and genetic aberrations.

Methods And Results: The immunohistochemical profiles of epigenetic modifiers and the methylation status of histones were examined, including EZH2, MLL2/KMT2D, CBP/CREBBP, EP300, H3K27me3 and H3K4me3, in Bcl-2 /IGH-BCL2 tFL and Bcl-2-positive IGH-BCL2 translocation-positive FL of the thyroid (Bcl-2 /IGH-BCL2 tFL). Most Bcl-2 /IGH-BCL2 tFLs retained the positivity of epigenetic modifiers and lower expression of H3K27me3, although Bcl-2 /IGH-BCL2 tFLs exhibited aberrant immunohistochemical patterns of EZH2 and CBP/CREBBP and overexpression of H3K27me3. Samples from seven cases were further analysed using targeted sequencing, focusing on the exons of 409 key tumour suppressor genes and oncogenes. Bcl-2 /IGH-BCL2 tFLs do not have pathogenic mutations of epigenetic modifiers, such as EZH2, MLL2/KMT2D, MLL3/KMT2C, EP300 and ARID1A, which have been reported in FLs in the literature, whereas Bcl-2 /IGH-BCL2 tFLs are probably pathogenic/pathogenic missense mutations or frameshift mutations of these genes. Additionally, novel mutations in TET2 and EP400 were detected in Bcl-2 /IGH-BCL2 tFLs.

Conclusions: Different genetic and epigenetic abnormalities might be involved in the oncogenesis of Bcl-2 /IGH-BCL2 tFLs from Bcl-2 /IGH-BCL2 tFLs and other FLs.
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http://dx.doi.org/10.1111/his.14378DOI Listing
April 2021

Schlafen 11 predicts response to platinum-based chemotherapy in gastric cancers.

Br J Cancer 2021 Jul 30;125(1):65-77. Epub 2021 Mar 30.

Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Background: Although unresectable or recurrent gastric cancers (GC) are frequently treated with platinum-based chemotherapy, response to treatment remains unpredictable. Because Schlafen 11 (SLFN11) is recently identified as a critical determinant of platinum sensitivity, we investigated the potential clinical utility of SLFN11 in the treatment of GC.

Methods: We analysed the correlation between SLFN11 expression and overall survival in 169 GC patients by our established immunohistochemical approach. The impact of SLFN11 expression on the response to platinum and transition of SLFN11 expression upon long-term treatment with platinum were examined using GC cell lines and organoids.

Results: GC patients with high-SLFN11 expression exhibited significantly better survival than those with low-SLFN11 expression, and the significance increased when we selected patients treated with platinum-based chemotherapy. Knockout of SLFN11 and reactivation of SLFN11 in GC cells conferred resistance and sensitivity to platinum, respectively. In GC cells and organoids, long-term treatment with oxaliplatin suppressed SLFN11 expression while imparting drug resistance. The acquired resistance to oxaliplatin was reversed by reactivation of SLFN11 with epigenetic modifying drugs.

Conclusions: This is the first report revealing definitive clinical implications of SLFN11 in the treatment of GC patients and providing novel strategies for the drug selection based on SLFN11 expression.
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http://dx.doi.org/10.1038/s41416-021-01364-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257722PMC
July 2021

An immature inhibin-α-expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis.

Cancer Med 2021 03 20;10(5):1485-1500. Epub 2021 Feb 20.

Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.

Inhibin-α, a member of transforming growth factor-β, is elevated in multiple tumors, but its specific roles are poorly understood. Here, we examined the feature of inhibin-α-expressing cells in ovarian tumors. Immunohistochemically, inhibin-α-expressing tumor cells were detected only in ovarian clear cell carcinoma (OCCC) among various types of ovarian tumors. By comparing the expression of inhibin-α and Ki-67, inhibin-α-expressing tumor cells were revealed to be less proliferative. When spheroids and chemoresistant cells were derived from OCCC cell lines, the expression level of inhibin-α was elevated, and that of an immature marker, aldehyde dehydrogenase, was also elevated. In consistent with this, inhibin-α expression was correlated with other immature markers, such as OCT3/4 and SOX2, and inversely correlated with proliferative marker MKI67 in public database on OCCC. Knockdown of inhibin-α in OCCC cell decreased chemoresistance. Moreover, prognostic analysis with 69 surgically resected OCCC cases revealed that the increased inhibin-α expression was an independent unfavorable prognostic factor. These findings suggested that inhibin-α-expressing subpopulation of OCCC tumor cells appeared to be less proliferative, immature, and angiogenic and to be related to acceleration of malignant progression.
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http://dx.doi.org/10.1002/cam4.3801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940216PMC
March 2021

Identification of fucosylated haptoglobin-producing cells in pancreatic cancer tissue and its molecular mechanism.

Glycoconj J 2021 Feb 1;38(1):45-54. Epub 2021 Feb 1.

Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, 565-0871, Japan.

Fucosylated haptoglobin is a well-established glyco-biomarker of pancreatic cancer. We recently established a novel anti-glycan antibody (10-7G mAb) that specifically recognizes fucosylated haptoglobins, including prohaptoglobin (proHpt). Serum concentrations of the 10-7G value, as measured by ELISA, were increased in patients with pancreatic cancer relative to the healthy controls. However, it is currently unknown which specific tissue or cell type produces fucosylated haptoglobins or proHpt. In the present study, we performed immunohistochemical (IHC) and ELISA analyses of pancreatic cancer tissue samples using 10-7G mAb. Among 21 pancreatic tissue sections, only 1 showed direct staining of pancreatic cells with the 10-7G mAb. However, 12 of the 21 sections stained positively for immune cells. Although there was no significant difference in the 10-7G expression between the positive and negative staining IHC groups, the median value of serum 10-7G was slightly higher in IHC-positive cases. Among many assayed leukemic cell lines, differentiated THP-1 cells (a human acute monocytic leukemia cell line) were found to have the highest levels of proHpt, per Western blot using 10-7G mAb. Interestingly, production of proHpt in vitro was dramatically increased under either hypoxic conditions or after IL-6 treatment. These results suggest that immune cells, including macrophages, in the pancreatic tissue microenvironment produce fucosylated haptoglobin and proHpt. Thus, fucosylated haptoglobins can be detected by the 10-7G mAb and may be a promising biomarker for pancreatic cancer.
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http://dx.doi.org/10.1007/s10719-020-09970-8DOI Listing
February 2021

Epigenetic suppression of SLFN11 in germinal center B-cells during B-cell development.

PLoS One 2021 29;16(1):e0237554. Epub 2021 Jan 29.

Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.

Background: SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development.

Objective: To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers.

Methods: We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells.

Results: SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside.

Conclusions: The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846023PMC
April 2021

Detection of fucosylated haptoglobin using the 10-7G antibody as a biomarker for evaluating endoscopic remission in ulcerative colitis.

World J Gastroenterol 2021 Jan;27(2):162-175

Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan.

Background: Inflammatory bowel disease (IBD) is a chronic, relapsing inflammation of the digestive tract. Although fecal and serum biomarkers have been extremely important and supportive for monitoring of IBD, their low sensitivity and high variability characteristics limit clinical efficacy. Thus, the establishment of better biomarkers is expected. Fucosylation is one of the most important glycosylation modifications of proteins. Fucosylated haptoglobin (Fuc-Hpt) is used as a biomarker for several cancers and inflammation-related diseases. We recently established a novel glycan monoclonal antibody (mAb), designated 10-7G, which recognizes Fuc-Hpt. We developed an enzyme-linked immunosorbent assay (ELISA) to measure serum levels of Fuc-Hpt (10-7G values).

Aim: To investigate the usefulness of the serum 10-7G values as a potential biomarker for monitoring disease activity in IBD.

Methods: This was a case control study. Intestinal tissues of IBD patients ( = 10) were examined immunohistochemically using the 10-7G mAb. We determined 10-7G values using serum from patients with ulcerative colitis (UC, = 110), Crohn's disease ( = 45), acute enteritis (AE, = 11), and healthy volunteers (HVs) who exhibited normal ( = 20) or high ( = 79) C-reactive protein (CRP) levels at medical check-up. We investigated the correlation between the 10-7G value and various clinical parameters of IBD patients by correlation analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the usefulness of the 10-7G values as a biomarker for clinical and endoscopic remission of UC compared to conventional serum biomarkers.

Results: In the immunohistochemical analysis, positive 10-7G mAb staining was observed in lymphocytes infiltrating into inflammatory sites of the mucosal layer and lymphoid follicles. The 10-7G values were significantly higher in patients with IBD ( < 0.001) and AE ( < 0.05) compared with HVs. In addition, 10-7G values were correlated with clinical examination parameters related to inflammation in patients with UC, particularly the CRP level ( = 0.525, = 0.003) and clinical activity index score ( = 0.435, = 0.038). However, there was no correlation between 10-7G values and CRP in HVs with high CRP levels, suggesting that the 10-7G values is not the same as a general inflammation biomarker. ROC curve analysis showed that area under the curve (AUC) value of 10-7G values for the diagnosis of endoscopic remission was higher than other biomarkers (AUC value = 0.699).

Conclusion: The serum 10-7G value is a novel biomarker for evaluating intestinal inflammation and endoscopic mucosal healing in UC.
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http://dx.doi.org/10.3748/wjg.v27.i2.162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807302PMC
January 2021

Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis.

Metabolites 2021 Jan 2;11(1). Epub 2021 Jan 2.

Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Cancer cells face various metabolic challenges during tumor progression, including growth in the nutrient-altered and oxygen-deficient microenvironment of the primary site, intravasation into vessels where anchorage-independent growth is required, and colonization of distant organs where the environment is distinct from that of the primary site. Thus, cancer cells must reprogram their metabolic state in every step of cancer progression. Metabolic reprogramming is now recognized as a hallmark of cancer cells and supports cancer growth. Elucidating the underlying mechanisms of metabolic reprogramming in cancer cells may help identifying cancer targets and treatment strategies. This review summarizes our current understanding of metabolic reprogramming during cancer progression and metastasis, including cancer cell adaptation to the tumor microenvironment, defense against oxidative stress during anchorage-independent growth in vessels, and metabolic reprogramming during metastasis.
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http://dx.doi.org/10.3390/metabo11010028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824065PMC
January 2021

Resolution of Pancreatic Duct Dilatation After Resection of Main-Duct Intraductal Papillary Mucinous Neoplasm.

Am Surg 2020 Dec 15:3134820973740. Epub 2020 Dec 15.

Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.

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http://dx.doi.org/10.1177/0003134820973740DOI Listing
December 2020

The expression of trefoil factor 3 is related to histologic subtypes and invasiveness in lung adenocarcinoma.

Oncol Lett 2021 Jan 19;21(1):63. Epub 2020 Nov 19.

Department of Pathology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Adenocarcinoma is the most common histological type of lung cancer and has various histologic subtypes, including lepidic, papillary, acinar and invasive mucinous adenocarcinoma. Histologic subtypes are associated with tumor invasiveness. For example, the lepidic subtype is less invasive than the papillary/acinar subtype. Trefoil factor 3 (TFF3) is a small secreting protein that is a member of the trefoil factor family, which is involved in mucosal stabilization and repair through its mitogenic and antiapoptotic activities. TFF3 overexpression is associated with various types of cancer. In lung cancer, TFF3 is expressed significantly in adenocarcinoma. However, the relationship between TFF3 expression and histologic subtypes in lung adenocarcinoma is unclear. The current study immunohistochemically revealed that, beside invasive mucinous carcinoma, the expression of TFF3 in papillary and acinar adenocarcinoma was significantly higher than that in lepidic adenocarcinoma. To further confirm these results, the expression of TFF3 in cases with both lepidic and papillary/acinar areas were examined. The expression of TFF3 in papillary/acinar areas was significantly higher when compared with lepidic areas in a single sample. Furthermore, using the lung adenocarcinoma cell line A549, TFF3-knockdown cells were generated. The results revealed that knockdown of TFF3 attenuated invasion. and immunohistochemical assays using clinical samples demonstrated that TFF3 expression was associated with lung adenocarcinoma invasiveness. To the best of our knowledge, the current study is the first to report that TFF3 expression was associated with the histologic subtypes of lung adenocarcinoma.
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http://dx.doi.org/10.3892/ol.2020.12325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709562PMC
January 2021

Skull Base Metastasis of Breast Cancer With Oculomotor and Trochlear Nerve Palsy.

Ear Nose Throat J 2020 Oct 9:145561320963676. Epub 2020 Oct 9.

Department of Otorhinolaryngology-Head and Neck Surgery, 13013Osaka University Graduate School of Medicine, Osaka, Japan.

Skull base metastatic tumors are rare. Breast cancer in particular can cause bone metastases after a long period of time. A 70-year-old woman presented with multiple cranial nerve palsy. Magnetic resonance imaging revealed a lesion that extended from the orbit to the base of the skull, and the patient was referred to our department. Ophthalmological evaluation showed left visual acuity impairment, left oculomotor nerve palsy, and left trochlear nerve palsy. Endoscopic biopsy performed 5 years after the completion of breast cancer treatment revealed skull base metastases. In unilateral multiple cranial nerve palsy, the possibility of skull base metastases should be considered.
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http://dx.doi.org/10.1177/0145561320963676DOI Listing
October 2020

Impact of DNA integrity on the success rate of tissue-based next-generation sequencing: Lessons from nationwide cancer genome screening project SCRUM-Japan GI-SCREEN.

Pathol Int 2020 Dec 8;70(12):932-942. Epub 2020 Oct 8.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

In the nationwide cancer genome screening project SCRUM-Japan GI-SCREEN, 2590 archival formalin-fixed paraffin-embedded (FFPE) tumor tissues from 19 institutions were analyzed with two tissue-based next-generation sequencing (NGS) panels at the Clinical Laboratory Improvement Amendments (CLIA)-certified College of American Pathologists (CAP)-accredited central laboratory. The Oncomine Cancer Research Panel (OCP; 143 genes) succeeded in producing validated results for only 68.3% of the samples (%OCP-success). CE-IVD (25 genes) succeeded in 45.9% of the OCP-failed samples, leading to an overall NGS success (%combined-success) rate as high as 82.9%. Among 2573 samples, the DNA-integrity (ΔC )-high (ΔC  < 4.4, n = 1253) samples showed significantly higher %OCP- and %combined-success rates (90.2% and 97.4%, respectively) than the DNA-integrity-intermediate (4.4 < ΔC  < 6.3, n = 911; 68.9% and 88.7%) and DNA-integrity-low ones (ΔC  > 6.3 or polymerase chain reaction-failed, n = 409; 5.6% and 24.7%). Other factors associated with NGS success included the FFPE-sample storage period (<4 years), the specimen type (surgical) and the primary tumor site (colorectal). Multivariable analysis revealed DNA integrity as the factor with the strongest independent association with NGS success, although it was suggested that other institution-specific factors contribute to the discordance of inter-institutional NGS success rates. Our results emphasize the importance of DNA quality in FFPE samples for NGS tests and the impact of DNA integrity on quality monitoring of pathology specimens for achieving successful NGS.
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http://dx.doi.org/10.1111/pin.13029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820973PMC
December 2020

Detection of Phosphorylated Alpha-Synuclein in the Muscularis Propria of the Gastrointestinal Tract Is a Sensitive Predictor for Parkinson's Disease.

Parkinsons Dis 2020 23;2020:4687530. Epub 2020 Sep 23.

Department of Neurology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. Lewy bodies and neurites, the pathological hallmarks of PD, are found in the enteric nervous system (ENS) as well as the central nervous system. Constipation is a well-documented premotor symptom in PD, and recent reports have demonstrated Lewy pathology in gastrointestinal (GI) tissues of PD patients prior to the onset of motor symptoms.

Objective: In the present study, we assessed Lewy pathology in the GI tracts of seven PD patients who had undergone a gastrectomy, gastric polypectomy, or colonic polypectomy prior to the onset of motor symptoms in order to assess whether the presence of pathological Syn in the ENS could be a predictor for PD.

Methods: GI tissue samples were collected from control patients and patients with premotor PD. Immunohistochemistry was performed using primary antibodies against -synuclein (Syn) and phosphorylated Syn (pSyn), after which Lewy pathology in each sample was assessed.

Results: In all control and premotor PD patients, accumulation of Syn was observed in the myenteric plexus in both the stomach and colon. In 82% (18/22) of control patients, mild-to-moderate accumulation of Syn was observed in the submucosal plexus. However, there was no deposition of pSyn in the ENS of control patients. In patients with premotor PD, abundant accumulation of Syn was observed in the myenteric plexus, similar to control patients. On the other hand, pSyn-positive aggregates were also observed in the nerve fibers in the muscularis propria in all examined patients with premotor PD (100%, 3/3), while the deposition of pSyn in the submucosal plexus was only observed in one patient (14%, 1/7).

Conclusion: Our results suggest that the detection of pSyn, but not Syn, especially in the muscularis propria of GI tracts, could be a sensitive prodromal biomarker for PD.
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http://dx.doi.org/10.1155/2020/4687530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530470PMC
September 2020

Pathological Regression of Lymph Nodes Better Predicts Long-term Survival in Esophageal Cancer Patients Undergoing Neoadjuvant Chemotherapy Followed by Surgery.

Ann Surg 2020 Jul 14. Epub 2020 Jul 14.

*Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan †Department of Surgery, Osaka General Medical Center, Osaka, Japan ‡Department of Surgery, Faculty of Medicine, Kindai University, Osaka, Japan §Department of Pathology, Graduate School of Medicine, Osaka University, Osaka, Japan.

Objective: To evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC.

Summary Of Background Data: The pathological response to preoperative treatment is commonly evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery.

Methods: We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III, <10%; and IV, 0%. We analyzed the correlation of grade with clinico-pathological parameters.

Results: Among 319 patients with clinically positive LNs, pathological LN regression grades were I/II/III/IV in 115/51/58/95 patients, and 191 patients (59.9%) showed discordance between the PT and LN pathological regression grades. LN regression grade significantly correlated with cN positive number, ypTNM, lymphovascular invasion, and clinical/pathological PT response. Multivariate analysis for recurrence-free survival revealed that LN regression grade [hazard ratio (HR) = 2.25, P < 0.001], ypT (HR = 1.65, P = 0.005), and ypT (HR = 1.62, P = 0.004) were independent prognostic factors, but not pathological PT regression grade (P = 0.67).

Conclusions: Compared to PT response, pathological LN response better predicted long-term survival in EC patients who received NAC plus curative surgery.
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http://dx.doi.org/10.1097/SLA.0000000000004238DOI Listing
July 2020

A Potential Mechanism of Anticancer Immune Response Coincident With Immune-related Adverse Events in Patients With Renal Cell Carcinoma.

Anticancer Res 2020 Sep;40(9):4875-4883

Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background/aim: Some reports showed encouraging efficacy of immune checkpoint inhibitors among patients who experienced immune-related adverse events (irAEs). Thus, characterization of T-cell repertoire and immune signatures in peripheral blood mononuclear cells (PBMCs) and tumors before and after immune checkpoint inhibitors treatment should contribute to better understanding of irAE-provoked anticancer immune responses.

Materials And Methods: We applied expression analysis of immune-related genes and T-cell receptor sequencing in tumor and PBMCs from five patients with renal cell carcinoma before combined immunotherapy and at the onset of severe irAEs.

Results: We found that the cluster of differentiation 8 (CD8)/forkhead box P3(FOXP3), granzyme B(GZMB)/CD3, perforin 1(PRF1)/CD3 and programmed cell death 1(PD1)/CD8 expression ratios were significantly elevated in PBMCs at the onset of irAEs. In addition, we found expansion of certain T-cell clones in metastatic tissue after irAEs, which were already increased in peripheral blood at the onset of irAEs.

Conclusion: irAE-provoked T-cells may also circulate and attack distant tumors, leading to durable response in patients with irAEs.
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http://dx.doi.org/10.21873/anticanres.14490DOI Listing
September 2020

Clear Cell Carcinoma of Palatal Minor Salivary Gland Harboring a Novel EWSR1-ATF1 Fusion Gene: Report of a Case and Review of the Literature.

Head Neck Pathol 2021 Jun 20;15(2):676-681. Epub 2020 Aug 20.

Department of Oral Pathology, Graduate School of Dentistry, Osaka University, 1-8 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Clear cell carcinoma (CCC) is a rare low-grade malignant salivary gland carcinoma. EWSR1-ATF1 fusion has been characterized as a consistent finding in CCC, with breakpoints described between EWSR1 exon 11 and ATF1 exon 3. So far, over 100 cases of CCC harboring EWSR1 rearrangement arising from salivary gland of the oral cavity have been reported. Although EWSR1 involvement in these cases was confirmed by EWSR1 break-apart FISH indicating the translocation, sequence analysis for EWSR1-ATF1 fusion type has been reported only in three cases of CCC so far. Herein, we report a CCC case with novel EWSR1-ATF1 fusion (EWSR1 exon 15 and ATF1 exon 5) arising in minor salivary gland and review the role of the chimeric variants in some malignancies with EWSR1-ATF1 rearrangement. Current tumor was composed of the small nests of clear tumor cells and hyalized fibrous stroma. Immunohistochemically, the tumor was positive for AE1/AE3, CK5/6 and p63, negative for S100, Melan-A, SMA and CD10. After 8 months of follow-up, there are no evidence of recurrence.
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http://dx.doi.org/10.1007/s12105-020-01211-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134619PMC
June 2021

A case of repeat resection for recurrent pulmonary metastasis from sebaceous gland carcinoma.

Surg Case Rep 2020 Aug 12;6(1):206. Epub 2020 Aug 12.

Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, 2-2 (L5), Yamadaoka, Suita, 565-0871, Japan.

Background: Sebaceous gland carcinoma (SGC) of the eyelid is an aggressive malignant eyelid tumor, and it can metastasize to the regional lymph nodes and distant organs. There have been only a few reported cases of patients who underwent pulmonary metastasectomy for metastatic SGC. We herein report a patient who underwent repeat pulmonary metastasectomies for recurrent pulmonary metastases from SGC.

Case Presentation: Bilateral small pulmonary nodules were detected in a 59-year-old woman with a history of eyelid SGC. She underwent wide wedge resection of the left lower lobe, and the disease was diagnosed as pulmonary metastases from SGC. Six months after the first pulmonary resection, CT showed that the nodules of right S2 and S10 had increased in size, and three small nodules had newly appeared in the right lung. The patient therefore underwent six wide wedge resections of the right lung through thoracotomy. After that, she underwent pulmonary metastasectomy 2 times. Ninety months after the first pulmonary resection, the patient is doing well without disease.

Conclusions: Given that a long-term survival was ultimately achieved in the present case, repeat pulmonary metastasectomy may be beneficial for recurrent pulmonary metastasis from SGC.
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http://dx.doi.org/10.1186/s40792-020-00947-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423815PMC
August 2020

A Case of Lymphocytic Myocarditis with Eosinophilic Degranulation Successfully Treated with Steroid Therapy.

Case Rep Cardiol 2020 28;2020:8887726. Epub 2020 Jul 28.

Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.

A 49-year-old woman was admitted with suspicion of acute myocarditis. On the next day after admission, her serum troponin I level continued to rise, indicating progression of myocardial damage. Moreover, her symptoms persisted, and left ventricular ejection fraction did not improve. Because of a predominant infiltration of lymphocytes in the myocardial specimens, lymphocytic myocarditis was diagnosed. However, a close observation of the specimens revealed eosinophil degranulation. Based on this finding, intravenous steroid therapy was initiated. High-dose methylprednisolone led to rapid and appreciable improvements in symptoms and left ventricular function within 12 hours after the first administration, which was followed by normalization of serum troponin I level. Steroid therapy was switched to oral administration and tapered carefully. There was no recurrence of left ventricular dysfunction or elevation of serum troponin I level. In eosinophilic myocarditis, eosinophil degranulation has been recognized as an important finding associated with progression of inflammation and myocardial damage. However, no attention has been paid to the presence and clinical implications of eosinophil degranulation in lymphocytic myocarditis. This case indicates that eosinophil degranulation in lymphocytic myocarditis may be an important finding associated with a high therapeutic response to steroid therapy.
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http://dx.doi.org/10.1155/2020/8887726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407015PMC
July 2020

HTR3A is correlated with unfavorable histology and promotes proliferation through ERK phosphorylation in lung adenocarcinoma.

Cancer Sci 2020 Oct 17;111(10):3953-3961. Epub 2020 Aug 17.

Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan.

Lung cancer is the leading cause of cancer death around the world. Adenocarcinoma is the most common histological type and has various histologic subtypes: lepidic, acinar, papillary, solid, and invasive mucinous adenocarcinoma. Histologic subtypes are related to invasiveness of tumors; eg, lepidic subtype is less invasive than acinar/papillary subtype. HTR3A is the main subunit of 5-hydroxytryptamine 3 (5-HT3) receptors, which are the only ligand-gated ion channels in seven families of 5-HT receptors. Although 5-HT3 receptor is expressed mainly throughout the central and peripheral nervous systems, some papers report the effect of 5-HT3 receptors on tumor cells, including lung cancer. However, whether HTR3A correlates with histopathological findings such as the histologic subtypes or the distribution in an individual sample remains unclear. Immunohistochemically, we revealed that the higher expression level of HTR3A was detected in acinar, papillary, and solid adenocarcinoma than in adenocarcinoma in situ and lepidic adenocarcinoma; the former was a more aggressive subtype than the latter. We also showed the relationship between HTR3A expression and Ki-67 positivity, widely used as a proliferation marker. Moreover, we generated HTR3A-knockdown lung adenocarcinoma cells and showed that the HTR3A knockdown attenuated proliferation by ERK phosphorylation. Our results indicated that HTR3A expression was related to proliferation in lung adenocarcinoma, by means of both in vitro and immunohistochemical assays on clinical samples. We showed the therapeutic potential of a 5-HT3 receptor antagonist, tropisetron, for the treatment of lung adenocarcinoma.
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http://dx.doi.org/10.1111/cas.14592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540989PMC
October 2020

Nonlinear Optics with Near-Infrared Excitation Enable Real-Time Quantitative Diagnosis of Human Cervical Cancers.

Cancer Res 2020 09 23;80(17):3745-3754. Epub 2020 Jul 23.

Department of Immunology and Cell Biology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Histopathologic analysis through biopsy has been one of the most useful methods for the assessment of malignant neoplasms. However, some aspects of the analysis such as invasiveness, evaluation range, and turnaround time from biopsy to report could be improved. Here, we report a novel method for visualizing human cervical tissue three-dimensionally, without biopsy, fixation, or staining, and with sufficient quality for histologic diagnosis. Near-infrared excitation and nonlinear optics were employed to visualize unstained human epithelial tissues of the cervix uteri by constructing images with third-harmonic generation (THG) and second-harmonic generation (SHG). THG images enabled evaluation of nuclear morphology in a quantitative manner with six parameters after image analysis using deep learning. It was also possible to quantitatively assess intraepithelial fibrotic changes based on SHG images and another deep learning analysis. Using each analytical procedure alone, normal and cancerous tissue were classified quantitatively with an AUC ≥0.92. Moreover, a combinatory analysis of THG and SHG images with a machine learning algorithm allowed accurate classification of three-dimensional image files of normal tissue, intraepithelial neoplasia, and invasive carcinoma with a weighted kappa coefficient of 0.86. Our method enables real-time noninvasive diagnosis of cervical lesions, thus constituting a potential tool to dramatically change early detection. SIGNIFICANCE: This study proposes a novel method for diagnosing cancer using nonlinear optics, which enables visualization of histologic features of living tissues without the need for any biopsy or staining dye.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0348DOI Listing
September 2020

Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway.

Diagn Pathol 2020 Jul 25;15(1):98. Epub 2020 Jul 25.

Department of Pathology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Background: Fibro-adipose vascular anomaly (FAVA) is a new entity of vascular anomalies with somatic and mosaic gain-of-function mutations of the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA). PIK3CA mutation excessively activates mammalian target of rapamycin (mTOR) pathway, which promotes angiogenesis and lymphangiogenesis. Histologically, FAVA is composed of intramuscular fibrous and adipose tissues with venous malformation (VM). Although sirolimus known as a mTOR inhibitor has good response to FAVA, expression pattern of the mTOR pathway was still unclear. Herein, we immunohistochemically investigated three novel FAVA patients with an emphasis on the mTOR pathway (p-S6K1, p-4EBP1 and p-AKT).

Case Presentation: Case 1: A 10-year-old female had complained of pain in the left thigh since she was 6-year-old. Under the clinical diagnosis of VM, she underwent surgical resection for the lesion. Case 2: A 29-year-old female patient had complained of discomfort and mild pain in the left shoulder since she was 18-year-old. After childbirth, she had severe ongoing pain and contracture of the shoulder. Under clinical diagnosis of VM, surgical resection was performed. Case 3: A 53-year-old female had complained of pain and knee restriction after surgical treatment of a knee tumor at the age of 31. Under the clinical diagnosis of atypical lipomatous tumor or high grade liposarcoma, surgical resection was performed. Histologically, all three patients presented with characteristic features of fibrous and adipose tissues with abnormal vessels within the skeletal muscle, leading to diagnosis of FAVA. Although VM has been reported as an important finding in FAVA, immunohistological findings demonstrated that abnormal vessels comprised complex of VM and lymphatic malformation (LM) in all cases. Furthermore, besides vascular malformation, abnormal fibrous and adipose tissues of FAVA expressed mTOR pathway components.

Conclusions: We presented three new cases of FAVA. Histological and immunohistochemical analyses revealed that VM and LM complex was an important finding in FAVA, and that the mTOR pathway components were expressed in abnormal fibrous tissue, adipose tissue and vascular malformation. These findings suggested that FAVA might be a mesenchymal malformation caused by PI3K/AKT/mTOR pathway.
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http://dx.doi.org/10.1186/s13000-020-01004-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382067PMC
July 2020

A Case of Endonasal Endoscopic Surgery for Intraorbital Metastasis of Gastric Ring Cell Carcinoma.

Ear Nose Throat J 2020 Jul 22:145561320943372. Epub 2020 Jul 22.

Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.

Gastric signet ring cell carcinoma has well-known metastatic features, including peritoneal dissemination and carcinomatous lymphangitis of the lung, but no intraorbital metastases were reported previously. A woman in her 60s developed left eye pain, sudden vision loss, and headache 12 years after gastric cancer treatment. Symptoms did not improve despite steroid pulses. Craniotomy showed no malignant findings. The patient was referred to our department for symptomatic relief and biopsy due to the lack of a definitive diagnosis and no improvement in her ocular pain. Endonasal endoscopic surgery was performed for diagnostic purposes and to relieve symptoms through orbital decompression. Preoperative computed tomography examination revealed a tumor at the left medial orbit, extending to the orbital apex. Orbital decompression through the open left medial orbital wall was performed with biopsy of the intraorbital tumor. Pathological findings were consistent with metastatic signet ring cell carcinoma. Pain and subjective improvement of visual acuity were noted the day after surgery. Twelve months postoperatively, diplopia remains, but there has been no worsening of symptoms.
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http://dx.doi.org/10.1177/0145561320943372DOI Listing
July 2020
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