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Abstract Aims Myocardial fibrosis of the left ventricle (LV) is a prognostic factor in dilated cardiomyopathy (DCM). This study aims to evaluate whether fibrosis of right ventricular (RV) endomyocardial biopsy (EMB) can predict the degree of LV fibrosis beforehand in DCM. Methods and results Fibrosis extent in 70 RV‐EMB specimens of DCM diagnosis was compared with that in the whole cross‐sectional LV of excised hearts in the same patients (52 explanted hearts for transplant and 18 autopsied hearts). The median interval between biopsy and excision was 4.1 (0.13–19.3) years. The fibrosis area ratio of the EMBs and excised hearts were evaluated via image analysis. The distribution of cardiovascular magnetic resonance–late gadolinium enhancement (LGE) in the intraventricular septum was classified into four quartile categories. The fibrosis area ratio in RV‐EMB correlated significantly with that in the short‐axis cut of the LV of excised hearts (r = 0.82, P

Abstract Coronavirus disease 2019 (COVID‐19) is often accompanied by pneumonia and can be fatal. We report a case of COVID‐19‐associated myocardial injury mimicking fulminant myocarditis. Endomyocardial biopsy revealed numerous von Willebrand factor‐rich microthrombi with small myocardial necrotic areas, complement deposits in small vessels/microthrombi, and macrophage‐predominant interstitial infiltration. These findings, distinct from those of typical lymphocytic myocarditis, show diffuse endothelial injury, complement activation, and activated macrophages as characteristic features of COVID‐19‐associated pathogenesis. Dysregulated serum cytokine profiles predicting severe/critical COVID‐19‐associated myocardial injury were also determined. This case emphasizes the occurrence of fatal cardiac manifestation with microthrombotic injury in the early stage of COVID‐19.

Abstract We present a diagnostically challenging case of intimal sarcoma of the pulmonary artery (PA) due to the histologic finding of a sclerosing appearance with no appreciable spindle/pleomorphic cell proliferation. Initial endarterectomy specimens were composed of sclerosing extracellular matrix with a few bland cells, some recanalization, and fibrin thrombi, impeding the confirmation of intimal sarcoma as these findings were also consistent with chronic thromboembolic pulmonary hypertension. However, the patient experienced recurrence 5 years later, and the second endarterectomy specimens revealed more firm and solid mass and the proliferation of atypical spindle/pleomorphic cells within a myxomatous matrix in the distal PA, leading to the definitive diagnosis of undifferentiated intimal sarcoma of the PA. The archival specimens from the endarterectomy confirmed intense MDM2 expression by immunohistochemistry, suggesting its role as a potential diagnostic marker for intimal sarcoma. This case highlights that prominent sclerosing extracellular matrix with very few atypical cells should raise the possibility of intimal sarcoma of the PA and that high index of suspicion, generous sampling, and ancillary tests are critical for accurate diagnosis. In this case, the tumor was incidentally removed by endarterectomy, resulting in 5 years of survival.

Abstract Background Coronavirus disease 2019 (COVID-19) has spread worldwide. Vaccination is now recommended as one of the effective countermeasures to control the pandemic or prevent the worsening of symptoms. However, its adverse effects have been attracting attention. Here, we report an autopsy case of multiple thromboses after receiving the first dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) in an elderly woman. Case presentation A 72-year-old woman with a history of diffuse large B-cell lymphoma in the stomach and hyperthyroidism received the first dose of the BNT162b2 mRNA vaccine and died 2 days later. The autopsy revealed multiple microthrombi in the heart, brain, liver, kidneys, and adrenal glands. The thrombi were CD61 and CD42b positive and were located in the blood vessels primarily in the pericardial aspect of the myocardium and subcapsular region of the adrenal glands; their diameters were approximately 5–40 μm. Macroscopically, a characteristic myocardial haemorrhage was observed, and the histopathology of the characteristic thrombus distribution, which differed from that of haemolytic uraemic syndrome and disseminated intravascular coagulation, suggested that the underlying pathophysiology may have been similar to that of thrombotic microangiopathy (TMA). Conclusion This is the first report on a post-mortem case of multiple thromboses after the BNT162b2 mRNA vaccine. The component thrombus and characteristic distribution of the thrombi were similar to those of TMA, which differs completely from haemolytic uraemic syndrome or disseminated intravascular coagulation, after vaccination. Although rare, it is important to consider that fatal adverse reactions may occur after vaccination and that it is vital to conduct careful follow-up.

Abstract Aims Cancer therapy‐related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors. Methods and results We performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient‐related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H‐score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H‐score; 63 (9.109) vs. 33 (5.099), P 4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P

Electrocardiography abnormalities have been occasionally reported at the onset of stroke. Simultaneous electrocardiographic abnormalities and stroke require a rapid differentiated diagnosis among several diseases. However, direct causal relationships remain unclear. A 92-year-old woman presented to our emergency department in a sudden-onset coma. The patient suffered from huge acute ischemic stroke with bilateral internal carotid artery occlusion assessed by brain magnetic resonance imaging, and her electrocardiography showed ST-segment elevation at II, III, aVF and V4–6, and atrial fibrillation (AF). However, the etiology of the medical condition was clinically unknown. Eventually, the patient died on day 4 of hospitalization before the diagnosis could be completed. Therefore, an autopsy was performed to investigate pathological findings after obtaining informed consent from the family. A postmortem pathological evaluation demonstrated that fibrin mural thrombi in the left atrial appendage (LAA), and the cerebral and coronary arteries possessed CD31-positive endothelial cells, and CD68-positive and CD168-positive macrophages in a similar fashion, suggesting the fibrin thrombi observed in the three sites implicated to be identical. We concluded that nearly concurrent cerebral and coronary artery embolism because of the fibrin thrombi in LAA developed by AF. Simultaneous cerebral infarction and myocardial infarction are referred to as cardiocerebral infarction (CCI), a rare disorder for which clear pathomechanisms remain unknown, although several mechanisms of CCI have been proposed. We first revealed the clear pathology of CCI using the autopsy. Additional pathological studies are warranted to establish clear pathomechanisms and preventive strategies of CCI.

Immune checkpoint inhibitor (ICI)-related myocarditis has been reported to appear in the early phase after ICI initiation. Herein, we report the case of a 78-year-old man with non-small cell lung cancer. Pembrolizumab was introduced as first-line therapy. After 9 months, second-line therapy, including bevacizumab, was initiated. After another 7 months, echocardiography showed diffuse left ventricular dysfunction. Based on the histopathologic examination of the myocardium, the patient was diagnosed with ICI-related myocarditis. Initiation of prednisolone therapy improved cardiac function. This case of late-onset ICI-related myocarditis illustrates that endomyocardial biopsy can be useful in the differential diagnosis of cancer-related left ventricular dysfunction. Résumé: Il a été rapporté qu’une myocardite pouvait survenir peu après l’instauration d’un traitement par des inhibiteurs des points de contrôle immunitaire (ICI). Nous présentons le cas d’un homme de 78 ans atteint d’un cancer du poumon non à petites cellules. Le pembrolizumab a été administré comme traitement de première intention. Neuf mois plus tard, un traitement de deuxième intention par le bévacizumab a été instauré. Après sept autres mois, l’échocardiographie a montré une dysfonction ventriculaire gauche diffuse. À la suite des résultats de l’examen histopathologique du myocarde, une myocardite liée aux ICI a été diagnostiquée. L’instauration d’un traitement par la prednisolone a amélioré la fonction cardiaque du patient. Ce cas de myocardite tardive liée aux ICI montre l’utilité éventuelle de la biopsie de l’endomyocarde dans le diagnostic différentiel d’une dysfonction ventriculaire gauche liée au cancer.

A 49-year-old female was admitted to our hospital with malaise and gross hematuria. As ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13) activity was absent and the ADAMTS13 inhibitor was detected, she was diagnosed with acquired thrombotic thrombocytopenic purpura (TTP). In addition to plasma exchange and corticosteroid therapy, she received rituximab therapy for inhibitor boosting but died suddenly of a cardiac arrest on day 9. The postmortem revealed microvascular platelet thrombi in multiple organs. In this case, the deterioration of the patient’s clinical status was considered to have been caused by inhibitor boosting-induced systemic microvascular occlusion. In particular, her sudden death may have been due to cardiovascular microthrombosis. Since inhibitor boosting can cause TTP patients to deteriorate rapidly, it is crucial to manage TTP patients who undergo inhibitor boosting appropriately. The monitoring of cardiac complications in TTP patients may also be essential, especially in the acute phase.

Abstract Aims Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms‐like tyrosine kinase‐1 (Flt‐1) is correlated with renal function, and PlGF/Flt‐1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples. Methods and results The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P

Aim: To clarify whether there is any association between the extent of Chlamydia pneumoniae (C. pneumoniae ) infection and plaque instability or post–directional coronary atherectomy (DCA) restenosis, we determined the frequency of C. pneumoniae infection and its localization in symptomatic coronary atherosclerotic plaques using specimens obtained from DCA. Methods and results: Immunohistochemistry (IHC) and real-time polymerase chain reaction (RT-PCR) revealed the existence of C. pneumoniae in all 50 specimens of coronary atherosclerotic plaques obtained by DCA. C. pneumoniae –positive cell ratio determined with IHC or copy numbers of C. pneumoniae DNA detected by RT-PCR did not differ significantly between patients with stable angina pectoris and those with acute coronary syndrome (IHC: 16.4 ± 7.6% vs 18.0 ± 7.1%, P = .42; RT-PCR: no. of cases with high copy numbers 12/25 vs 10/25, P = .78), or between patients with subsequent post-DCA restenosis and those without (IHC: 17.1 ± 8.0% vs 18.0 ± 7.4%, P = .74; RT-PCR: 5/12 vs 10/21, P = 1.00). Conclusions: C. pneumoniae was highly prevalent in coronary atherosclerotic plaques of patients who underwent DCA. However, the extent of C. pneumoniae infection in coronary atherosclerotic plaques was not associated with plaque instability or post-DCA restenosis.

Abstract Background Pseudosarcomatous myofibroblastic proliferation is a rare proliferative lesion of the submucosal stroma characterized by myofibroblast proliferation and inflammatory cell infiltration, and is mainly reported in the urinary system. Case presentation We report a 65-year-old male who was referred to our emergency room with right-side iliac fossa pain. The pain gradually worsened for approximately 2 months, and rebound tenderness was positive. Blood examination showed severe inflammatory findings, and enhanced computed tomography revealed a heterogeneous contrast-enhancing mass lesion measured to be 55 × 50 mm in size at the lower right abdomen. Based on these results, the patient was diagnosed with appendicitis with an abdominal abscess. As the inflammation was severe, we drained the abscess before performing surgery. Approximately 1 month after the abscess diminished, interval appendectomy was performed. Macroscopic findings of the resected specimen showed a perforated diverticulum of the appendix and a small adjacent nodule measured to be 14 mm in size. Histopathological examination with hematoxylin and eosin staining revealed that the nodule consisted of fibroblast proliferation and inflammatory cell infiltration. Furthermore, immunohistochemical examination showed positive for smooth muscle actin and desmin and negative for S-100, c-kit, and anaplastic lymphoma kinase. Based on these histopathological results, we diagnosed the nodule as an unusual case of a pseudosarcomatous myofibroblastic proliferation associated with perforation of the diverticulum of the appendix. Conclusion Herein, we report a rare case of a pseudosarcomatous myofibroblastic proliferation that occurred in the appendix with diverticulitis.

BackgroundCardiac troponin-T (TNNT2) is exclusively present in cardiac muscle. Measurement of TNNT2 is used for diagnosing acute coronary syndrome. However, its expression may not be limited in myocardium. This study aimed at evaluating the expression of TNNT2 in neoplastic tissues.Methods and ResultsWe used paraffin-embedded blocks of 68 patients with lung cancer (age, 68 ± 11 years old; early-stage, 33; advance-stage, 35) at Miyazaki University Hospital, Japan between January 1, 2017, and March 31, 2019. We stained the slide sections with primary monoclonal antibody against TNNT2 protein, and assessed the frequency of positive staining, and its association with pathological severity. In addition, we examined whether TNNT2 gene is detected in lung cancer tissues of four patients using reverse transcription-polymerase chain reaction. Immunoreactivity for TNNT2 protein was present in the cytoplasm and nucleus of lung cancer cells. The frequency was 37% (25 of 68) in all patients and was irrespective of histologic type (six of 13, squamous cell carcinoma; 18 of 50, adenocarcinoma; 0 of 4, neuroendocrine cell carcinoma; 1 of 1, large cell carcinoma). The prevalence increased with pathological staging [9% (3 of 33) at early-stage (Stage 0–I); 63% (22 of 35) at advance-stage (Stage II–IV and recurrence)]. In addition, frequency of positive staining for TNNT2 increased with pleural (χ2 = 5.877, P = 0.015) and vascular (χ2 = 2.449, P = 0.118) invasions but decreased with lymphatic invasion (χ2 = 3.288, P = 0.070) in specimens performed surgical resection. Furthermore, TNNT2 mRNA was detected in the resected squamous cell carcinoma and adenocarcinoma tissues.ConclusionsOur data suggest the aberrant expression of TNNT2 in lung cancer and its prevalence increases with pathological severity.

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor‐kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)‐induced hypertension. Methods and Results Mortality was higher (P

Activation of the classical complement pathway plays a major role in regulating atherosclerosis progression, and it is believed to have both proatherogenic and atheroprotective effects. This study focused on C1q, the first protein in the classical pathway, and examined its potentialities of plaque progression and instability and its relationship with clinical outcomes. To assess the localization and quantity of C1q expression in various stages of atherosclerosis, immunohistochemistry, western blotting, and real-time polymerase chain reaction (PCR) were performed using abdominal aortas from eight autopsy cases. C1q immunoreactivity in relation to plaque instability and clinical outcomes was also examined using directional coronary atherectomy (DCA) samples from 19 patients with acute coronary syndromes (ACS) and 18 patients with stable angina pectoris (SAP) and coronary aspirated specimens from 38 patients with acute myocardial infarction. C1q immunoreactivity was localized in the extracellular matrix, necrotic cores, macrophages and smooth muscle cells in atherosclerotic lesions. Western blotting and real-time PCR illustrated that C1q protein and mRNA expression was significantly higher in advanced lesions than in early lesions. Immunohistochemical analysis using DCA specimens revealed that C1q expression was significantly higher in ACS plaques than in SAP plaques. Finally, immunohistochemical analysis using thrombus aspiration specimens demonstrated that histopathological C1q in aspirated coronary materials could be an indicator of poor medical condition. Our results indicated that C1q is significantly involved in atherosclerosis progression and plaque instability, and it could be considered as one of the indicators of cardiovascular outcomes.

We present the unexpected death of an elderly man who died from saddle thromboemboli in the pulmonary artery trunk and organized thrombi in the distal arteries in every lobe. The inferior vena cava was compressed between the horseshoe kidney and ossified spinal ligament, thereby generating fresh thrombi (aged within three days) composed of numerous erythrocytes, platelets, neutrophils, and fibrin fibers. Cardiac hypertrophy with a myocardial lesion reduces the cardiac reserve. The lobar and segmental arteries contained not only fresh emboli but also mural and luminal thrombi at various stages of organization. Organized thrombi with recanalized neo-vessels were further connected with collateral bronchial artery circulation. These remodeling reactions maintained pulmonary blood flow until the last embolization. A year prior to his death, the patient became aware of his illness. Four months before death, he was hospitalized and pulmonary emboli were found, but neither their cause nor origin was detected. The clinical course, histological, and computed tomography findings imply that repeated inferior vena cava compression generated thrombi, resulting in pulmonary embolization and remodeling.

Introduction: The correlation between the composition of thrombi retrieved by mechanical thrombectomy (MT) and stroke etiology is inconclusive. We describe a case with atherosclerotic components in thrombi retrieved by MT for acute internal carotid artery (ICA) occlusion.Case Presentation: A 69-year-old man with acute onset of global aphasia and right hemiplegia was transferred to our institute. His baseline National Institutes of Health Stroke Scale score was 24. Magnetic resonance imaging demonstrated acute ischemic stroke in the left parietal lobe. Magnetic resonance angiography revealed occlusion of the left ICA. MT was attempted for acute left ICA occlusion. The initial angiography showed occlusion of the proximal ICA, while intraprocedural angiography revealed a large thrombus that extended from the cervical ICA to the intracranial ICA. Successful reperfusion was achieved by five passes using stent retrievers and an aspiration catheter. A large volume of red thrombus was retrieved by each pass. The final angiogram showed successful reperfusion with modified Thrombolysis in Cerebral Ischemia grade 2b and severe stenosis in the proximal ICA. Neck magnetic resonance imaging showed severe left ICA stenosis with a vulnerable plaque. Hence, his stroke etiology was determined as large artery atherosclerosis. Histopathological examination of the retrieved thrombi revealed atheromatous components, including cholesterol clefts, foam cells, and a necrotic core.Conclusions: Atherosclerotic components in retrieved thrombi might provide useful clues for diagnosing stroke pathogenesis. Further studies are warranted to clarify the utility of assessing atheromatous components in retrieved thrombi in diagnosing stroke etiology.

We report an autopsy case of a 69-year-old female with cervical cancer. She was given bevacizumab-containing chemotherapy for 4 months. After two years of chemotherapy, she developed congestive heart failure (CHF) with left ventricular dysfunction. Cardiac magnetic resonance (CMR) imaging revealed late gadolinium enhancement (LGE) of linear mid-wall delayed enhancement located in the basal to the mid-septal wall, suggesting bevacizumab-related cardiotoxicity. Although she was treated with cardioprotective medications and discharged, she eventually died from worsening CHF a year later, and we conducted an autopsy. Histopathological examination revealed diffuse fibrosis in the myocardium, and the area where LGE was present on CMR showed thinning and wavy changes in cardiomyocytes with diffuse interstitial fibrosis and edema.

A middle-aged woman with unrepaired congenital heart disease died suddenly from asphyxia due to hemoptysis. Postmortem computed tomography, autopsy, and histological examinations revealed the presence of an aneurysm and dissection of the right main pulmonary artery with intraluminal thrombus. The observed congenital heart diseases included patent ductus arteriosus, ventricular septal defect, and right-sided aorta. These anomalies predisposed her to left to right shunt, resulting not only in pulmonary artery hypertension and right ventricular hypertrophy, but also pulmonary artery aneurysm and dissection. Histological examinations confirmed the presence of medial degeneration and elastic fiber disruption, as well as muscular hyperplasia of the vasa vasorum and follicular infiltration of the lymphocytes and plasma cells in the main pulmonary artery. These changes may have contributed to the pathogenesis of the aneurysm and dissection through the induction of arterial wall fragility. Histology demonstrated, in addition to findings of pulmonary hypertension, such as plexiform lesions, medial-intimal hyperplasia, and veno-occlusive lesion, unique findings related to multiple dissections of the intra-pulmonary elastic arteries, which may have caused the lethal hemoptysis.

Abstract Background An esophageal neuroendocrine carcinoma arising in Barrett’s esophagus is extremely rare. Here, we report a case of an esophageal neuroendocrine carcinoma with a well-differentiated adenocarcinoma component arising in Barrett’s esophagus and review the literature. Case presentation A 71-year-old man with no symptoms was admitted to our hospital because of the detection of an esophagogastric junction tumor on regular upper endoscopy screening. Endoscopy revealed a sliding hiatal hernia and an approximately 10 mm elevated mass at the esophagogastric junction. Biopsy showed a moderately differentiated tubular adenocarcinoma. Computed tomography did not indicate lymph node metastasis or distant metastasis. Proximal gastrectomy with D1 lymph node dissection was performed along with jejunal interposition. On immunohistochemical staining, the tumor was positive for chromogranin A and synaptophysin. Ki-67 was positive in 40% of the tumor cells. The histological diagnosis was a neuroendocrine carcinoma with a well-differentiated adenocarcinoma component arising in Barrett’s esophagus. The postoperative course was good, and the patient was discharged on the twentieth postoperative day. He has remained free of the disease at 36 months postoperatively. Conclusions Barrett’s esophagus may be related to the development of a neuroendocrine carcinoma.

Liquid-based cytology (LBC) analysis of sputum is a useful diagnostic and prognostic tool for detecting lung cancer. DNA and RNA derived from lung cancer cells can be used for this diagnosis. However, the quality of cytological material is not always adequate for molecular analysis due to the effect of formalin in the commercially available fixation kits. In this study, we examined DNA and RNA extraction methods for LBC analysis with formalin fixation, using lung carcinoma cell lines and sputum. The human non-small cell lung cancer cell lines were fixed with LBC fixation reagents, such as CytoRich red preservative. Quantification of thyroid transcription factor-1 (TTF-1) and actin mRNA, epidermal growth factor receptor (EGFR) DNA in HCC827, H1975, and H1299 cells, and mutation analysis of EGFR in HCC827 and H1975 cells were performed by quantitative PCR (qPCR) and fluorescence resonance energy transfer (FRET)-based preferential homoduplex formation assay (F-PHFA) method, respectively. mRNA and DNA extracted from cell lines using RNA and/or DNA extraction kits for formalin-fixed paraffin-embedded (FFPE) fixed with various LBC solutions were efficiently detected by qPCR. The detection limit of EGFR mutations was at a rate of 5% mutated positive cells in LBC. The detection limit of the EGFR exon 19 deletion in HCC827 was detected in more than 1.5% of the positive cells in sputum. In contrast, the detection limit of the T790M/L858R mutation in H1975 was detected in more than 13% of the positive cells. We also detected EGFR mutations using next generation sequencing (NGS). The detection limit of NGS for EGFR mutation was lower than that of the F-PHFA method. Furthermore, more than 0.1% of positive cells could be cytomorphologically detected. Our results demonstrate that LBC systems are powerful tools for cytopathological and genetic analyses. However, careful attention should be paid to the incidence of false negative results in the genetic analysis of EGFR mutations detected by LBC.

Perineurioma is a mesenchymal neoplasm best known in soft-tissue pathology. A colonic perineurioma is a relatively recently described entity and sometimes encountered in specimens from the large intestine, especially distal colon. Without its recognition, a perineurioma can be misdiagnosed as other more common gastrointestinal spindle cell neoplasms. Here, we describe a case of colonic perineurioma with polypoid growth extruding into the intestinal lumen. Case. A woman in her seventh decade of life underwent a follow-up colonoscopy after an uneventful resection of a benign colonic polyp. A previously undetected 6-mm polyp was found in the sigmoid colon and was resected endoscopically. Microscopic examination of the lesion revealed a proliferation of bland spindle cells in the lamina propria mucosae, which were immunohistochemically positive for epithelial membrane antigen, claudin 1, and glucose transporter-1. A colonic perineurioma was diagnosed.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) technology is widely used for the diagnosis of pancreatic masses. However, in some cases, inadequate tissue volume or difficulty of morphological diagnosis are constraining factors for adequate cytopathological evaluation. K-ras mutation is the most frequently acquired genetic abnormality, occurring in approximately 90% of all patients with pancreatic ductal adenocarcinoma (PDAC). In the present study, the clinical utility of residual liquid-based cytology (LBC) specimens obtained using EUS-FNA for K-ras mutation analysis was evaluated.In this study, 81 patients with pancreatic lesions were examined. The cell block (CB) specimens separated from EUS-FNA samples were morphologically evaluated by hematoxylin-eosin (HE) staining. Final diagnoses were confirmed by CB specimens, surgical resection specimens, diagnostic imaging, and clinical follow-up. Genomic DNA of residual LBC specimens stored at 4°C for several months were extracted and assessed for K-ras mutations using a fluorescence resonance energy transfer-based preferential homoduplex formation assay.K-ras mutation analysis using residual LBC samples was successful in all cases. The sensitivity, specificity, and accuracy of CB examination alone were 77.4%, 100%, and 81.3%, respectively, and those of the combination of CB examination and K-ras mutation analysis were 90.3%, 92.3%, and 90.7%, respectively. Furthermore, K-ras mutations were detected in 8 (57.1%) of 14 PDAC samples for which the CB results were inconclusive.These findings suggest that K-ras mutation analysis using residual LBC specimens improves the diagnostic accuracy of EUS-FNA.

The platelet receptor CLEC-2 is involved in thrombosis/hemostasis, but its ligand, podoplanin, is expressed only in advanced atherosclerotic lesions. We investigated CLEC-2 ligands in vessel walls. Recombinant CLEC-2 bound to early atherosclerotic lesions and normal arterial walls, co-localizing with vascular smooth muscle cells (VSMCs). Flow cytometry and immunocytochemistry showed that recombinant CLEC-2, but not an anti-podoplanin antibody, bound to VSMCs, suggesting that CLEC-2 ligands other than podoplanin are present in VSMCs. VSMCs stimulated platelet granule release and supported thrombus formation under flow, dependent on CLEC-2. The time to occlusion in a FeCl3-induced animal thrombosis model was significantly prolonged in the absence of CLEC-2. Because the internal elastic lamina was lacerated in our FeCl3-induced model, we assume that the interaction between CLEC-2 and its ligands in VSMCs induces thrombus formation. Protein arrays and Biacore analysis were used to identify S100A13 as a CLEC-2 ligand in VSMCs. However, S100A13 is not responsible for the above-described VSMC-induced platelet activation, because S100A13 is not expressed on the surface of normal VSMCs. S100A13 was released upon oxidative stress and expressed in the luminal area of atherosclerotic lesions. Suspended S100A13 did not activate platelets, but immobilized S100A13 significantly increased thrombus formation on collagen-coated surfaces. Taken together, we proposed that VSMCs stimulate platelets through CLEC-2, possibly leading to thrombus formation after plaque erosion and stent implantation, where VSMCs are exposed to blood flow. Furthermore, we identified S100A13 as one of the ligands on VSMCs.

Identification of the regulators of vascular inflammation is important if we are to understand the molecular mechanisms leading to atherosclerosis and consequent ischemic heart disease, including acute myocardial infarction. Gene polymorphisms in family with sequence similarity 5, member C (FAM5C) are associated with an increased risk of acute myocardial infarction, but little is known about the function of this gene product in blood vessels. Here, we report that the regulation of the expression and function of FAM5C in endothelial cells. We show here that FAM5C is expressed in endothelial cells in vitro and in vivo. Immunofluorescence microscopy showed localization of FAM5C in the Golgi in cultured human endothelial cells. Immunohistochemistry on serial sections of human coronary artery showed that FAM5C-positive endothelium expressed intercellular adhesion molecule-1 (ICAM-1) or vascular cell adhesion molecule-1 (VCAM-1). In cultured human endothelial cells, the overexpression of FAM5C increased the reactive oxygen species (ROS) production, nuclear factor-κB (NF-κB) activity and the expression of ICAM-1, VCAM-1 and E-selectin mRNAs, resulting in enhanced monocyte adhesion. FAM5C was upregulated in response to inflammatory stimuli, such as TNF-α, in an NF-κB- and JNK-dependent manner. Knockdown of FAM5C by small interfering RNA inhibited the increase in the TNF-α-induced production of ROS, NF-κB activity and expression of these leukocyte adhesion molecule mRNAs, resulting in reduced monocyte adhesion. These results suggest that in endothelial cells, when FAM5C is upregulated in response to inflammatory stimuli, it increases the expression of leukocyte adhesion molecules by increasing ROS production and NF-κB activity.

The adventitia is suggested to contribute to vascular remodeling; however, the site-selective inflammatory responses in association with the development of atherosclerosis remain to be elucidated.Wild-type or apolipoprotein E knockout male C57BL/6J background mice were fed standard chow for 16, 32, and 52 weeks, and the morphology of the aortic arch, descending aorta, and abdominal aorta was compared. Atheromatous plaque formation progressed with age, particularly in the aortic arch and abdominal aorta but not in the descending aorta. In addition, we found that the numbers of macrophages, T-lymphocytes, and microvessels, assessed by anti-F4/80, CD3, and CD31 antibodies, were higher in the adventitia of the abdominal aorta at 52 weeks. These numbers were positively correlated with plaque formation, but negatively correlated with elastin content, resulting in the enlargement of the total vessel area. In aortic tissues, interleukin-6 levels increased in the atheromatous plaque with age, whereas the level of regulated on activation, normal T cell expressed and secreted (RANTES) increased with age, and compared with other sites, it was particularly distributed in inflammatory cells in the adventitia of the abdominal aorta.This study suggests that adventitial inflammation contributes to the age-dependent structural alterations, and that the activation/inactivation of cytokines/chemokines is involved in the process.