With regard to complications of portal vein (PV) and inferior vena cava (IVC) thrombosis in autosomal dominant polycystic kidney disease (ADPKD), several cases have been reported based on imaging findings. However, only one autopsy case has been described and no systematic analysis has been conducted to date. This retrospective study aimed to review autopsy cases from our department over the past 37 years to clarify the frequency and background factors of thrombosis formation in ADPKD. Among 4001 autopsies performed at our institution from 1987 to 2023, 10 ADPKD cases were identified. We examined the presence of thrombus in these 10 cases and compared pleural effusion and ascites volumes, major organ weights, and clinicopathological factors between cases with thrombus and those without. Among 10 ADPKD cases, thrombi were identified in four cases in which autopsies were performed relatively recently. These thrombi were distributed in the PV, IVC, and their branches. Compared to non-thrombotic cases, those with thrombi showed a statistically significant increase in kidney weight and tended to have a higher frequency of complications such as sepsis and severe aortic atherosclerosis. This study reports the first systematic autopsy-based investigation of PV and IVC thrombosis in ADPKD. Thrombosis was found at a high frequency of 40

BACKGROUND:Parathyroid tumors are classified by the World Health Organization as adenomas, atypical tumors, or carcinomas. While the loss of parafibromin expression and a Ki-67 labeling index >5% are well known markers of malignancy, the role of fascin, an actin-bundling protein implicated in cancer invasion and metastasis, has not yet been investigated in parathyroid tumors. METHODS:We examined fascin expression by immunohistochemistry in 19 carcinomas, 16 atypical tumors, 23 adenomas and 14 normal parathyroid tissues. Staining for parafibromin and Ki-67 was also performed. Fascin expression was evaluated semiquantitatively, with cases scoring ≥3 considered positive. Associations with parafibromin and Ki-67 were analyzed, and clinicopathological correlations were assessed. RESULTS:Fascin positivity was observed in 0% of normal tissues, 21.7% of adenomas, 50.0% of atypical tumors, and 42.1% of carcinomas. Nuclear fascin expression was more frequent in atypical tumors (25.0%) and carcinomas (42.1%) than in adenomas (4.3%). Parafibromin loss was detected in 43.7% of atypical tumors and 89.5% of carcinomas but not in adenomas or normal tissues. Ki-67 labeling index >5% was detected in 31.3% of atypical tumors, and 63.2% of carcinomas. Fascin-positive cases showed a higher rate of parafibromin negativity (p = 0.0071), whereas fascin expression was not correlated with Ki-67. All recurrent cases were fascin-positive, parafibromin-negative, and had a Ki-67 labeling index >5%. CONCLUSION:Although fascin immunostaining was not superior to parafibromin or Ki-67 for differential diagnosis, its higher expression in atypical tumors and carcinomas and its presence in recurrent cases indicate that fascin expression is associated with aggressive clinicopathological features.

Fukutin, the gene responsible for Fukuyama congenital muscular dystrophy (FCMD), is involved in the glycosylation of α-dystroglycan (α-DG). On the other hand, fukutin is expressed in various organs, and the roles of fukutin in non-neuromuscular tissues are not fully elucidated. In the present immunohistochemical study of uterine cervical carcinoma, Ki-67-positive cells tended to be more in areas showing weaker expression of fukutin. In HeLa cells, Ki-67-positive cells were increased after the suppression of fukutin by RNAi, and were decreased by overexpression of fukutin. Similar results were obtained upon phosphorylation of histone H3 at serine 10, which is enriched during mitosis. Interestingly, Aurora-A kinase (AURKA), one of the proteins regulating Ser10 phosphorylation of histone H3, was highly expressed in HeLa cells, and the phosphorylation of AURKA was reduced by overexpression of fukutin. Furthermore, fukutin is co-localized with targeting protein for Xklp2 (TPX2), a protein enhancing AURKA activity. Fukutin may be able to suppress cell proliferation by reducing AURKA phosphorylation, probably competing with TPX2.

BACKGROUND:Cancer-associated thrombosis (CAT) is a well-known complication of malignant tumors. It has been predominantly reported in mucin (MUC)-producing adenocarcinomas, with MUC secreted by the tumor thought to be involved in the thrombotic mechanism. However, studies comparing tumor and thrombus areas are scarce. METHODS:In this study, we examined the immunohistochemical characteristics of 18 autopsy specimens of tumor and thrombus sections (CAT) and control specimens of 25 tumors without thrombus and 16 thrombi without tumors. Immunohistochemistry was performed using antibodies associated with coagulation and MUC, including tissue factor (TF), thrombin, MUC2, MUC5AC, and MUC6. RESULTS:It was revealed that TF was predominantly positive in the tumor sections of CAT compared with tumors without thrombus (P<0.0001), and MUC2 expression was significantly higher in thrombus sections of CAT than that in thrombi without tumors (P<0.0001). In the thrombus region, TF positivity was inversely correlated with MUC2 positivity. CONCLUSIONS:These results suggest that the expression of TF in tumor tissues is involved in the pathogenesis of CAT, and furthermore, that MUC2 contributes to thrombus formation in CAT via a pathway other than TF. In the future, these immunohistochemical analyses will help predict CAT in cancers and detect hidden cancers in patients with thrombosis.

Here, we report a case of antineutrophil cytoplasmic antibody (ANCA)-associated central nervous system (CNS) vasculitis that mimicked a brain tumor. The patient presented with progressive right upper arm weakness. Brain magnetic resonance imaging (MRI) revealed large tumor-like lesions in the left frontal and parietal lobes, with patchy and irregular enhancement with gadolinium and edema. Based on the clinical course and radiological findings, a brain tumor was suspected, and stereotactic brain biopsy was performed. Brain histopathology revealed necrotic tissue and lymphocyte infiltration around small vessels and blood vessel walls. Although the patient's clinical course and pathological findings suggested primary angiitis of CNS (PACNS), double staining for myeloperoxidase (MPO) and CD31 (a neutrophil marker) revealed infiltration of MPO-positive neutrophils in the blood vessel walls. Therefore, we diagnosed the patient with ANCA-associated CNS vasculitis. Because CNS vasculitis, including PACNS, presents nonspecific clinical findings and can depict brain tumor-like MRI findings, CNS vasculitis should be carefully differentiated from brain tumors. Additionally, double staining for MPO and CD31 might be useful for evaluating the pathogenesis of CNS vasculitis.

We herein report an autopsy case of a fulminant Clostridium perfringens (C. perfringens or Welch bacilli) infection in a healthy adult. A 72-year-old, immunocompetent man visited the emergency department with lower back pain, and blood test revealed hemolytic attack. His condition rapidly worsened with severe acidosis and anemia, and he died despite symptomatic treatment. An autopsy examination demonstrated an abscess with necrosis and air spaces in the right lobe of his liver. Numerous Gram-positive bacilli were seen in the liver and bone marrow, and C. perfringens was identified in culture of the antemortem blood sample. Of note, a mucosal epithelium of the ileum showed loss of tight junctions (claudin 4), suggesting the involvement of C. perfringens toxins with its systemic spreading. Welch toxins were suggested to be involved in serious pathological conditions such as hemolytic anemia and systemic infections, and it is necessary to raise Welch infection as one of the differential diagnoses for fulminant systemic infections even in healthy individuals.

DNA methylation is crucial for chromatin structure and gene expression and its aberrancies, including the global “hypomethylator phenotype”, are associated with cancer. Here we show that an underlying mechanism for this phenotype in the large proportion of the highly lethal brain tumor glioblastoma (GBM) carrying receptor tyrosine kinase gene mutations, involves the mechanistic target of rapamycin complex 2 (mTORC2), that is critical for growth factor signaling. In this scenario, mTORC2 suppresses the expression of the de novo DNA methyltransferase (DNMT3A) thereby inducing genome-wide DNA hypomethylation. Mechanistically, mTORC2 facilitates a redistribution of EZH2 histone methyltransferase into the promoter region of DNMT3A, and epigenetically represses the expression of DNA methyltransferase. Integrated analyses in both orthotopic mouse models and clinical GBM samples indicate that the DNA hypomethylator phenotype consistently reprograms a glutamate metabolism network, eventually driving GBM cell invasion and survival. These results nominate mTORC2 as a novel regulator of DNA hypomethylation in cancer and an exploitable target against cancer-promoting epigenetics.

In the fifth edition of the World Health Organization's (WHO) classification of tumors of the central nervous system (CNS), molecular analysis is required for not only determining each tumor type but assessing its prognosis based on malignancy (CNS WHO grade). A notable example is the loss of tumor suppressor gene cyclin-dependent kinase inhibitor 2A (CDKN2A), and CDKN2A homozygous deletion (HD) is a novel CNS WHO grade 4 marker in isocitrate dehydrogenase gene (IDH)-mutant astrocytoma. However, incorporating molecular workup into the "routine diagnostics" of each brain tumor type remains a major challenge, especially in resource-limited settings, including low- and middle-income countries. We herein validated the usefulness of p16 and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) as potential surrogates for the assessment of CDKN2A status in 20 IDH-mutant astrocytoma cases. Of note, loss or retention of p16 and MTAP could accurately predict CDKN2A HD (p16: 87.5%, MTAP: 88.9%) or non-HD (p16: 100%, MTAP: 100%) with a single marker alone. Importantly, we revealed contributing factors to gray-zone IHC results (p16: 5-20%, MTAP: mosaic), including (1) hemizygous deletion of CDKN2A, (2) degenerative findings, and (3) intratumoral CDKN2A HD heterogeneity, the detailed histologic and molecular assessment of which would be a key to achieving integrated assessment of malignancy in IDH-mutant astrocytoma. We characterized the pitfalls of each method and provided for the first time a practical flowchart of astrocytoma grading, contributing to a normalization of WHO2021-based molecular diagnostics in resource-limited settings.

Nuclear protein in testis (NUT) carcinoma is a rare but highly aggressive carcinoma, driven by genetic rearrangement of the NUT midline carcinoma family member 1 (NUTM1) gene on chromosome 15q14. Recently, a tight link has been suggested between genetic abnormalities and subsequent metabolic and epigenetic dysregulation to drive the progression of malignant tumors. However, it remains elusive whether such reprogramming could contribute to the pathogenesis of NUT carcinoma. We herein report an autopsy case of NUT carcinoma arising in the retroperitoneum of a 31-year-old male. Notably, reprogramming of glycolytic metabolism and epigenetic histone modifications was observed in this unusual NUT carcinoma case, and this phenomenon was further confirmed by an in vitro cell culture model with bromodomain containing 4 (BRD4)-NUT overexpression. The rationale for documenting the case is based on our findings to reveal that metabolic and epigenetic reprogramming could be one of the contributing factors to the pathogenesis of NUT carcinoma, which could be exploitable as a novel therapeutic target for this rare and aggressive cancer type.

Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy, but the spinal cord is rarely examined. Here we report a case of DMD with interesting spinal cord findings. In a 37-year-old man with DMD accompanied by hypoxic encephalopathy from the age of 32 years, autopsy showed amyotrophic lateral sclerosis-like pyramidal tract degeneration over the entire spinal cord, presumably due to hypoxic encephalopathy. Furthermore, anterior horn cells exhibited Wallerian degeneration-like changes. To investigate more about the pathogenesis, an immunohistochemical study using anti-synaptophysin, glutamic acid decarboxylase (GAD), postsynaptic density protein-95 (PSD-95) and choline acetyltransferase (ChAT) antibodies was performed. Immunostaining for synaptophysin showed that the number of synapses around anterior horn cell were decreased, contrary to the finding of teenage DMD, in which the number of synapses were increased, probably due to the reaction toward the reduced anterior horn cell activity. The decrease of synapses of the present case may be mainly due to hypoxic encephalopathy, based on the degeneration of the pyramidal tract. Another interesting finding is that GAD was strongly positive in the cytoplasm of anterior horn cells, which may be explained by Wallerian degeneration-like mechanism. Moreover, the expression of PSD-95 is increased in anterior horn cells. Compensation for postsynaptic damage can be considered, since dystrophin is necessary for maintaining the post-synaptic maintenance. There were no apparent differences in ChAT immunostaining. Further investigation is necessary whether these findings are characteristic of long-term surviving cases accompanied by hypoxic encephalopathy.

Background: In coronary atherosclerotic disease, the proliferation of intimal smooth muscle cells (SMCs) is regarded as beneficial with respect to stable and unstable plaques, but is thought detrimental in discussions on coronary stent restenosis. To resolve this discrepancy, we focused on the quality, not quantity, of intimal SMCs in coronary atherosclerotic disease. Methods: Autopsied coronary artery specimens from seven patients implanted with bare metal stents (BMS), three with paclitaxel-eluting stents (PES), and 10 with sirolimus (rapamycin)-eluting stents (SES) were immunostained for SMC markers. Cultured human coronary artery SMCs were also treated with sirolimus and paclitaxel. Results: Intimal SMC differentiation, estimated by the ratio of h-caldesmon + cells to & alpha;-smooth muscle actin + ( & alpha;-SMA + ) cells, was significantly increased whereas dedifferentiation, estimated from the ratio of fibroblast activation protein alpha (FAP & alpha;) + cells to & alpha;-SMA + cells, was significantly decreased, in tissues of SES compared with BMS cases. No difference in the degree of differentiation was found between PES and BMS cases or between the three groups in nonstented arteries used as controls. Correlation analyses for each field of view revealed a significant positive correlation between h-caldesmon and calponin staining but significant negative correlations with FAP & alpha; staining in & alpha;-SMA + cells. Cultured SMCs were shorter (dedifferentiated) and showed an increased FAP & alpha;/ & alpha;-SMA protein when treated with paclitaxel, whereas they became elongated (differentiated) and showed increased calponin/ & alpha;-SMA proteins with sirolimus. Conclusions: The SMCs of the coronary intima may differentiate after SES implantation. SMC differentiation may explain both the plaque stabilization and reduced risk of reintervention associated with SES. & COPY; 2023 Elsevier Inc. All rights reserved.

L-type neutral amino acid transporter 1 (LAT1) is a heterodimeric membrane transport protein involved in neutral amino acid transport. LAT1 is highly expressed in various malignant solid tumors and plays an essential role in cell proliferation. However, its role in malignant lymphoma remains unknown. Here, we evaluated LAT1 expression level in tissues from 138 patients with Non-Hodgkin lymphoma (NHL). Overexpression of LAT1 was confirmed in all types of NHL and we found that there is a significant correlation between the level of LAT1 expression and lymphoma grade. The LAT1 expression was higher in aggressive types of lymphomas when compared with static types of lymphomas, suggesting that active tumor proliferation requires nutrient uptake via LAT1. The expression level of LAT1 was inversely correlated with patients' survival span. Furthermore, pharmacological inhibition of LAT1 by a specific inhibitor JPH203 inhibits lymphoma cell growth. In conclusion, our study demonstrated that LAT1 expression can be used as a prognostic marker for patients with NHL and targeting LAT1 by JPH203 can be a novel therapeutic modality for NHL.

Introduction: Currently, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can be induced to differentiate at the cellular level but not to form mature tissues or organs suitable for transplantation. ESCs/iPSCs form immature teratomas after injection into immunodeficient mice. In humans, immature teratomas often transform into fully differentiated mature teratomas after administration of anticancer agents. Methods: We first investigated the ability of cisplatin to induce changes in mouse ESCs/iPSCs in vitro. Next, we designed experiments to analyze ESC/iPSC-derived immature teratoma tissue in vivo after treatment of cisplatin. Groups of six mice carrying ESC- or iPSC-derived teratomas were given either low or high dose intraperitoneal injection of cisplatin, while the control group received saline for 4 weeks. Results: Treatment of ESC/iPSC cultures with cisplatin for 3 days caused a dose-related decrease in cell numbers without inducing any morphological changes to the cells. ESC/iPSC-derived teratomas showed lower growth rates with a significantly higher mature components ratio in a concentration dependent manner after cisplatin treatment (P < 0.05); however, immunohistochemical analyses demonstrated a significantly reduced PCNA labelling index and an increase in an apoptosis marker on immature neural components (P < 0.05) along with emergence of h-Caldesmon(+) mature smooth muscle cells in treated mice. Moreover, newly differentiated components not found in the control group, such as mature adipose tissue, cartilage, and pancreas, as well as striated muscle, salivary glands, gastric mucosa with fundic glands, and hair follicles emerged. The identities of these components were confirmed by immunostaining for specific markers. Conclusions: Cisplatin has the ability to reduce immature components in ESC/iPSC-derived teratomas, presumably through apoptosis, and also to induce them to differentiate. (C) 2021, The Japanese Society for Regenerative Medicine. Production and hosting by Elsevier B.V.

ABSTRACT:Cancer-associated fibroblasts (CAFs) have been attracting attention in recent years, but their nature has not been fully elucidated. Although CAFs have been recognized as an important therapeutic target, therapeutic agents have not been developed to date. CAFs are characterized by their high migration rate and involvement in epithelial-to-mesenchymal transition with some displaying a dendritic morphology that is reminiscent of fascin expression.The present study was designed to immunohistochemically investigate fascin expression in lung adenocarcinoma including CAFs and compare the results with existing CAF markers.We immunohistochemically investigated fascin expression in not only cancer tissue but also CAFs from 26 autopsy cases of lung adenocarcinoma. Immunohistochemistry of α-smooth muscle actin and fibroblast activation protein was also performed.Fascin-positive staining in CAFs was observed in all cases, with a strong correlation observed with existing CAF markers α-smooth muscle actin and fibroblast activation protein (P < .001). In addition, the proportion of tumor cells showing fascin-positive staining was found to correlate with its expression in CAFs (P < .05).We propose that CAFs express fascin, and that fascin may mediate crosstalk between cancer tissue and CAFs. Fascin might be a novel therapeutic target for treatments that target the cancer stroma.

J-STAGE Advance Publication released online January 18, 2020 Mailing address: Scientific Committee of the Japanese Circulation Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho, Chiyoda-ku, Tokyo 100-0011, Japan. E-mail: meeting@j-circ.or.jp This English document is a digest version of JCS 2017 Guidelines on Management of Vasculitis Syndrome reported at the Japanese Circulation Society Joint Working Groups perfomed in 2017 (Website: http://www.j-circ.or.jp/guideline/pdf/JCS2017_isobe_d.pdf). Refer to Appendix 1 for the detailes of members. JCS Joint Working Group (consists of 12 groups): Japanese Circulation Society, Japan Radiological Society, Japanese Ophthalmological Society, The Japanese Association for Thoracic Surgery, The Japanese Society for Vascular Surgery, Japan Pediatric Society, The Japanese Society for Cardiovascular Surgery, Japanese College of Cardiology, Japanese Society of Nephrology, The Japanese Society of Pathology, Japanese College of Angiology, Japan College of Rheumatology, and The Japan Research Committee of the Ministry of Health, Labour and Welfare for Intractable Vasculitis (JPVAS) ISSN-1346-9843 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp JCS 2017 Guideline on Management of Vasculitis Syndrome ― Digest Version ―