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Abstract Background Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A) is an autoimmune inflammatory central nervous system disorder characterized by the detection of autoantibodies that recognize GFAP in CSF. The pathogenesis of GFAP-A is poorly understood. Some patients had a neoplasm detected and GFAP expressed by neoplasms is plausible as immunogen triggering paraneoplastic neurological autoimmunity. Case presentation We report a case of 76-year-old female patient with GFAP-A complicated with breast cancer. She presented with altered consciousness, nuchal rigidity, speech disturbances, and weakness. Her clinical symptoms were improved by immunotherapy and cancer treatments. Immunohistochemical analysis showed that the restricted tumor expressed GFAP. The infiltration of CD3 + T cells were observed in the peritumoral and intratumoral areas. The most common infiltrating lymphocytes were CD8 + T cells. CD4 + T cells and CD20 + B cells were also observed in the predominant peritumoral area. Conclusions These results suggest that GFAP-A may occur in a paraneoplastic neurological syndrome associated with breast cancer.

Acute iron overload is known to exert deleterious effects in the liver, but detailed pathology has yet to be documented. Here, we report pathological findings in an autopsy case of acute iron toxicity and validation of the findings in mouse experiments. In a 39-year-old woman who intentionally ingested a large amount of sodium ferrous citrate (equivalent to 7.5 g of iron), severe disturbance of consciousness and fulminant hepatic failure rapidly developed. Liver failure was refractory to treatment and the patient died on Day 13. Autopsy revealed almost complete loss of hepatocytes, while bile ducts were spared. To examine the detailed pathologic processes induced by excessive iron, mice were orally administered equivalent doses of ferrous citrate. Plasma aminotransferase levels markedly increased after 6 h, which was preceded by increased plasma iron levels. Hepatocytes were selectively damaged, with more prominent damage in the periportal area. Phosphorylated c-Jun was detected in hepatocyte nuclei after 3 h, which was followed by the appearance of γ-H2AX expression. Hepatocyte injury in mice was associated with the expression of Myc and p53 after 12 and 24 h, respectively. Even at lethal doses, the bile ducts were morphologically intact and fully viable. Our findings indicate that acute iron overload induces hepatocyte-specific liver injury, most likely through hydroxyl radical-mediated DNA damage and subsequent stress responses.

Abstract Purpose Heparan sulfate (HS) is one of the factors that has been suggested to be associated with angiogenesis and invasion of glioblastoma (GBM), an aggressive and fast-growing brain tumor. However, it remains unclear how HS of endothelial cells is involved in angiogenesis in glioblastoma and its prognosis. Thus, we investigated the effect of endothelial cell HS on GBM development. Methods We generated endothelial cell-specific knockout of Ext1, a gene encoding a glycosyltransferase and essential for HS synthesis, and murine GL261 glioblastoma cells were orthotopically transplanted. Two weeks after transplantation, we examined the tumor progression and underlying mechanisms. Results The endothelial cell-specific Ext1 knockout (Ext1 CKO ) mice exhibited reduced HS expression specifically in the vascular endothelium of the brain capillaries compared with the control wild-type (WT) mice. GBM growth was significantly suppressed in Ext1 CKO mice compared with that in WT mice. After GBM transplantation, the survival rate was significantly higher in Ext1 CKO mice than in WT mice. We investigated how the effect of fibroblast growth factor 2 (FGF2), which is known as an angiogenesis-promoting factor, differs between Ext1 CKO and WT mice by using an in vivo Matrigel assay and demonstrated that endothelial cell-specific HS reduction attenuated the effect of FGF2 on angiogenesis. Conclusions HS reduction in the vascular endothelium of the brain suppressed GBM growth and neovascularization in mice.

Heparan sulfate (HS) is a glycocalyx component present in the extracellular matrix and cell-surface HS proteoglycans (HSPGs). Although HSPGs are known to play functional roles in multiple aspects of tumor development and progression, the effect of HS expression in the tumor stroma on tumor growth in vivo remains unclear. We conditionally deleted Ext1, which encodes a glycosyltransferase essential for the biosynthesis of HS chains, using S100a4-Cre (S100a4-Cre; Ext1f/f) to investigate the role of HS in cancer-associated fibroblasts, which is the main component of the tumor microenvironment. Subcutaneous transplantation experiments with murine MC38 colon cancer and Pan02 pancreatic cancer cells demonstrated substantially larger subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Additionally, the number of myofibroblasts observed in MC38 and Pan02 subcutaneous tumors of S100a4-Cre; Ext1f/f mice decreased. Furthermore, the number of intratumoral macrophages decreased in MC38 subcutaneous tumors in S100a4-Cre; Ext1f/f mice. Finally, the expression of matrix metalloproteinase-7 (MMP-7) markedly increased in Pan02 subcutaneous tumors in S100a4-Cre; Ext1f/f mice, suggesting that it may contribute to rapid growth. Therefore, our study demonstrates that the tumor microenvironment with HS-reduced fibroblasts provides a favorable environment for tumor growth by affecting the function and properties of cancer-associated fibroblasts, macrophages, and cancer cells.

Abstract Background Intestinal-type adenocarcinoma is widely detected in the gastrointestinal tract, head and neck, lower respiratory and urinary systems. Determining the nature (monoclonal or multicentric) of the intestinal adenocarcinoma is sometimes a diagnostic challenge owing to its occurrence at various locations of the body, especially in the lower gastrointestinal tract. Herein, we successfully diagnosed metastatic colon cancer in the small intestine using tumor protein 53 gene (TP53) mutation analysis. Case presentation An 83-year-old woman presented with severe abdominal pain and nausea at the emergency department of the hospital. Her history included surgery and adjuvant chemotherapy for colon and breast cancers. Abdominal computed tomography revealed small intestinal dilation, which was associated with the mural nodule detected on fluorodeoxyglucose positron emission tomography. Laparoscopy-assisted small bowel resection was performed based on the diagnosis of small bowel obstruction, probably due to recurrence of the colon or breast cancer. Macroscopically, an ulcerated tumor was present in the resected small intestine. Histologically, the cancer cells showed infiltrative growth of colonic dysplastic glands, whose non-specific finding made it difficult to determine the relationship with past colon cancers. Retrospective pathological examination confirmed that the previous breast and colon carcinomas were primary cancers. Immunohistochemical analysis revealed that the small intestinal and colon cancer cells showed diffuse positive tumor protein 53 (p53) expression. However, the breast cancer cells showed only weakly positive p53 expression. In addition, TP53 mutational analysis detected an identical missense mutation (p.T211I) between the two intestinal cancers. Moreover, further molecular genetic work-up revealed that both small intestinal and colon adenocarcinomas harbored an identical missense mutation (p.G12D) of KRAS gene. In conclusion, the small intestinal cancer in this case was identified as a metastatic adenocarcinoma arising from a past colon cancer. Conclusions Genetic analyses help in clarifying the identity of the cells in multiple cancer cases. In morphologically indeterminate cases, molecular analysis of common cancer-related genes can be useful for a precise and reproducible diagnosis.

Every cancer carries genomic mutations. Although almost all these mutations arise after fertilization, a minimal count of cancer predisposition mutations are already present at the time of genesis of germ cells. Of the cancer predisposition genes identified to date, BRCA1 and BRCA2 have been determined to be associated with hereditary breast and ovarian cancer syndrome. Such cancer predisposition genes have recently been attracting attention owing to the emergence of molecular genetics, thus, affecting the strategy of cancer prevention, diagnostics, and therapeutics. In this review, we summarize the molecular significance of these two BRCA genes. First, we provide a brief history of BRCA1 and BRCA2, including their identification as cancer predisposition genes and recognition as members in the Fanconi anemia pathway. Next, we describe the molecular function and interaction of BRCA proteins, and thereafter, describe the patterns of BRCA dysfunction. Subsequently, we present emerging evidence on mutational signatures to determine the effects of BRCA disorders on the mutational process in cancer cells. Currently, BRCA genes serve as principal targets for clinical molecular oncology, be they germline or sporadic mutations. Moreover, comprehensive cancer genome analyses enable us to not only recognize the current status of the known cancer driver gene mutations but also divulge the past mutational processes and predict the future biological behavior of cancer through the molecular trajectory of genomic alterations.

Ovarian tumors include neoplasms derived from somatic cells and germ cells, including teratoma. Sometimes, tumors of the somatic cell type may develop from teratoma, causing diagnostic perturbation. We experienced a case of a tumor composed of several types of tissue in the ovary with a teratoma. When findings of teratoma and somatic tumor coexist in an ovary, it is difficult to differentiate whether a somatic tumor was mixed with a teratoma or a teratoma unitarily caused transformation to a somatic cell tumor. A 72-year-old Japanese woman (gravida, 3; para, 1) presented to our hospital with severe constipation and frequent urination, and a large intrapelvic tumor was detected by computed tomography (CT). Soon after admission, ultrasonography (US) and magnetic resonance imaging (MRI) revealed a large multilocular cystic tumor on her left ovary. Based on the clinical diagnosis of ovarian cancer, she underwent a left ovariectomy, appendectomy, and partial omentectomy. We observed an ovarian tumor consisting of teratoma, primitive neuroectodermal tumor (PNET), adenocarcinoma, various types of sarcomas, and clear cell carcinoma on the H and E-stained sections. The component of clear cell carcinoma showed a nuclear positive reaction against PAX8 and napsin A, as well as a loss of ARID1A, suggesting typical endometriosis-derived clear cell carcinoma. On the other hand, the expression of ARID1A was maintained in teratoma, PNET, non-specific adenocarcinoma, and various types of sarcomas, suggesting that these tumors had an origin different from that of clear cell carcinoma. These findings indicated that the ovarian tumor of this patient contained a clear cell carcinoma derived from a somatic cell and a teratoma that transformed to a wide variety of somatic cell types of tumors, which coexisted on one ovary. The appropriate use of immunohistochemistry was diagnostically effective in this case.

Malignant pleural effusion (MPE) can accompany advanced lung adenocarcinoma. Recent studies suggest that MPE could contain a heterogeneous subpopulation of cells with stem-like properties, such as tumorigenicity and self-renewal, indicating that they could be the source of metastasis. Although previous studies analyzed the correlation between cancer stem cell (CSC) marker expression and clinical outcomes using lung cancer tissues, investigations regarding the association of MPE with CSC marker expression are limited. We performed immunohistochemistry to examine the expression of aldehyde dehydrogenase 1 (ALDH1) and Sal-like 4 (SALL4) in 46 cell block samples of MPE from patients with lung adenocarcinoma. ALDH1-positive and SALL4-positive cancer cells in MPE were detected in 30 (65.2%) and 21 samples (45.7%), respectively. Cluster formation was detected in 26 samples (56.5%). The number of clusters was significantly higher in ALDH1-positive/SALL4-negative samples. SALL4 expression was inversely correlated with the cluster ratio (r = −0.356) and positively associated with the Ki-67 index (r = 0.326), suggesting that MPE cells with high SALL4 expression comprised the proliferative subpopulation. In conclusion, we demonstrated that MPE contains an ALDH1-positive/SALL4-negative subpopulation exhibiting cluster formation and a SALL4-positive proliferative subpopulation.

The use of molecular biomarkers for the early detection of heart disease, before their onset of symptoms, is an attractive novel approach. Ideal molecular biomarkers, those that are both sensitive and specific to heart disease, are likely to provide a much earlier diagnosis, thereby providing better treatment outcomes. Galectin-3 is expressed by various immune cells, including mast cells, histiocytes and macrophages, and plays an important role in diverse physiological functions. Since galectin-3 is readily expressed on the cell surface, and is readily secreted by injured and inflammatory cells, it has been suggested that cardiac galectin-3 could be a marker for cardiac disorders such as cardiac inflammation and fibrosis, depending on the specific pathogenesis. Thus, galectin-3 may be a novel candidate biomarker for the diagnosis, analysis and prognosis of various cardiac diseases, including heart failure. The goals of heart disease treatment are to prevent acute onset and to predict their occurrence by using the ideal molecular biomarkers. In this review, we discuss and summarize recent developments of galectin-3 as a next-generation molecular biomarker of heart disease. Furthermore, we describe how galectin-3 may be useful as a diagnostic marker for detecting the early stages of various heart diseases, which may contribute to improved early therapeutic interventions.

Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.

Abstract Background The superiority of Enhanced Cognitive Behavior Therapy (CBT-E) with regard to weight gain and improvement of psychopathology of eating disorders for patients with anorexia nervosa (AN) over other psychotherapies and treatment as usual (TAU) has not been demonstrated in randomized controlled trials (RCTs). However, a previous RCT showed that patients with AN whose baseline body mass index (BMI) was less than 17.5 kg/m2 gained more weight when treated with CBT-E than with other psychotherapies. The aim of the study is to compare the efficacy of CBT-E and TAU for patients with AN. It was hypothesized that CBT-E would be superior to TAU, at least in terms of weight gain, as most patients with AN are likely to have a BMI lower than 17.5 kg/m2. Methods/design A randomized parallel-group multicenter trial will be conducted in three teaching hospitals in Japan between January 2023 and March 2026. Patients with DSM-5 AN, aged 16 years and older, with a BMI equal to or above 14.0 and below 18.5 will be eligible to participate. 56 patients will be randomly and evenly assigned to two intervention groups (CBT-E and TAU). Those assigned to CBT-E will be offered 25–40 sessions in accordance with their initial BMI. Patients assigned to TAU will have at least one session every 2 weeks, with the number of sessions and treatment period not fixed in advance. The primary outcome is BMI at 40 weeks after treatment initiation. The secondary outcomes are the results from the Japanese version of the Eating Disorder Examination Questionnaire and Clinical Impairment Assessment questionnaire to measure eating disorder psychopathology and psychological impairment. The follow-up assessment will be performed 6 months after the 40-week assessment. Discussion This multi-center randomized controlled study will probably evaluate the efficacy of CBT-E compared with TAU for patients with more severe AN than in previous studies since Japanese patients are likely to have a lower BMI than those in Western countries. While it may be difficult to generalize the results of a study conducted in Japan, it would be valuable to clarify the efficacy of CBT-E as a treatment package. Trial registration UMIN, UMIN000048847. Registered 12 Sep 2022.

Abstract Background We previously reported a case that led us to hypothesize that decreased production of thrombopoietin (TPO) leads to thrombocytopenia in patients with anorexia nervosa (AN) with severe liver dysfunction and that prolonged prothrombin time-international normalized ratio (PT-INR) predicts thrombocytopenia in such cases. To validate this hypothesis, we report another case in which TPO levels were measured. In addition, we examined the association between prolonged PT-INR and thrombocytopenia in such patients. Main body Similar to the previously reported patient, a patient with AN with severe liver dysfunction showed that TPO levels increased after improvements in liver enzyme levels and PT-INR, followed by recovery of platelet count. In addition, a retrospective study was also conducted to review patients with AN whose liver enzyme levels were > 3 × the upper limit of normal (aspartate aminotransferase > 120 U/L or alanine aminotransferase > 135 U/L). The study included 58 patients and showed a correlation coefficient of -0.486 (95% confidence interval [CI], -0.661 to -0.260; P