Methotrexate­associated B­cell lymphoproliferative disease that exhibits hematuria due to urinary bladder lesions: A case report.

Methotrexate (MTX)-related lymphoproliferative disease (LPD) is one of the most prominent late complications associated with MTX treatment. Although MTX-related LPD exhibits a relatively high incidence of extranodal disease, the incidence of disease in a urinary bladder is very low. The present study reports the case of a patient with MTX-related LPD involving a urinary bladder mass. A 75-year-old female patient, who had been receiving MTX for ~15 years, was referred to the hospital due to fever and hematuria. A computed tomography scan revealed the thickening of the urinary bladder wall, hydronephrosis and lymph node swelling. The histopathological findings of the urinary bladder mass resulted in a diagnosis of MTX-related LPD. Although MTX withdrawal did not have any effect, the subsequent chemotherapy resulted in complete remission. Although MTX-related LPD in the bladder is rare, it is pertinent to consider MTX-related LPD when hematuria is observed during MTX therapy.

Left Atrial Remodeling Related to Disproportionately Low B-Type Natriuretic Peptide in Acute Heart Failure Patients with Atrial Fibrillation.

The diagnostic performance of B-type natriuretic peptide (BNP) for acute heart failure (HF) is impaired in patients with atrial fibrillation (AF). Increased AF burden in HF is associated with left atrial (LA) remodeling. Recent studies have revealed that LA remodeling may affect LV filling. We hypothesized that LA remodeling affects BNP secretion in acute HF conditions. The study investigated the clinical impact of LA remodeling on admission BNP levels in acute HF patients with and without AF. Consecutive acute HF hospitalized patients (n = 899) were divided into groups with (n = 382) or without AF (n = 507) and subdivided into disproportionately low BNP (LB) (≤200 pg/ml), medium BNP (200 to 600 pg/ml) and high BNP (≥600 pg/ml) subgroups. The AF group had a higher proportion of patients with LB than the non-AF group (23.6% vs 16.6%, p = 0.009). BNP levels in both groups were positively correlated with LV end-diastolic volume and negatively correlated with LV ejection fraction in both groups. In contrast, BNP was positively correlated with LA volume index in the non-AF group, but negatively correlated in the AF group. The survival rates were significantly higher in the LB group than in the other groups in non-AF. Conversely, there were no significant differences across all groups in AF patients. In conclusion, in patients with acute HF and AF, disproportionately low BNP levels are associated with LA structural remodeling and poor prognosis.

Prognostic impact of a reduction in the fibrosis-4 index among patients hospitalized with acute heart failure.

Although the fibrosis-4 index (FIB-4) is associated with right atrial pressure or prognosis in acute heart failure (AHF), the prognostic impact of its reduction during hospitalization remains uncertain. We included 877 patients (age, 74.9 ± 12.0 years; 58% male) hospitalized with AHF. The reduction in FIB-4 was defined as: (FIB-4 on admission-FIB-4 at discharge)/FIB-4 on admission × 100. Patients were divided into low (< 1.0%, n = 293), middle (1.0-27.4%, n = 292), and high (> 27.4%, n = 292) FIB-4 reduction groups. The primary outcome was a composite of all-cause death or heart failure rehospitalization within 180 days. The median FIB-4 reduction was 14.7% (interquartile range - 7.8-34.9%). The primary outcome was observed in 79 (27.0%), 63 (21.6%), and 41 (14.0%) patients in the low, middle, and high FIB-4 reduction groups, respectively (P = 0.001). Adjusted Cox proportional-hazards analysis revealed that the middle and low FIB-4 reduction groups were associated with the primary outcome, independent of the pre-existing risk model including baseline FIB-4 ([high vs. middle] hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.10-2,63, P = 0.017; [high vs. low] HR: 2.16, 95% CI 1.41-3.32, P < 0.001). FIB-4 reduction provided additional prognostic value to the baseline model, including well-known prognostic factors ([continuous net reclassification improvement] 0.304; 95% CI 0.139-0.464; P < 0.001; [integrated discrimination improvement] 0.011; 95% CI 0.004-0.017; P = 0.001). Additionally, the combination of the reduction in FIB-4 and brain natriuretic peptide was useful for risk stratification. In conclusion, among patients hospitalized with AHF, a greater FIB-4 reduction during hospitalization was associated with better prognoses.

Prognostic Impact of Multiple Drug Use at Discharge in Patients Hospitalized with Heart Failure.

The association between polypharmacy/multiple drug use (MDU) and prognosis in patients hospitalized with heart failure (HF) is unclear. It is also unknown whether the prognostic values of MDU vary depending on the presence/absence of a previous history of HF and preserved/reduced left ventricular ejection fraction (LVEF). We analyzed consecutive 1,034 patients hospitalized with HF (age, 74.9 ± 11.5 years; 58.7% male). MDU was defined as ≥5 drugs at discharge. The primary endpoint was a composite of all-cause death and HF readmission. MDU was observed in 695 patients (67.2%). Patients with MDU use had higher prevalences of a previous history of HF, reduced LVEF, and comorbidities than those without MDU. Cox proportional hazard analysis showed that MDU was significantly associated with the primary endpoint after adjustment for possible confounders (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.03-1.79; P = 0.030). There was significant interaction between the presence/absence of a history of HF and the prognostic impact of MDU (HF history [-]: HR, 0.86; 95% CI, 0.54-1.40; P = 0.553; HF history [+]: HR, 1.72; 95% CI, 1.16-2.55; P = 0.007; P for interaction = 0.005). However, there was no significant interaction between preserved/reduced LVEF and the prognostic impact of MDU (P for interaction = 0.274). In conclusion, MDU at discharge is an independent risk factor for the composite of death or HF readmission in patients hospitalized with HF. We observed a significant interaction between the presence of de novo versus recurrent HF and the prognostic value of MDU.

Fibrosis-4 index identifies worsening renal function associated with adverse outcomes in acute heart failure.

AIMS: Worsening renal function (WRF) often develops during heart failure (HF) treatment. However, prognostic implications of WRF in acute HF remain controversial, and risk stratification of WRF is challenging. Although the fibrosis-4 index (FIB-4) was initially established as a liver fibrosis marker, recent studies show that high FIB-4 is associated with venous congestion and poor prognosis in acute HF. This study aimed to evaluate whether FIB-4 could identify prognostically relevant and non-relevant WRF in patients with acute HF. METHODS AND RESULTS: We retrospectively analysed data from a single-centre registry on acute HF at our university hospital between January 2015 and June 2021. This study included patients with acute HF aged ≥20 years who were immediately hospitalized and had brain natriuretic peptide levels ≥100 pg/mL at admission. WRF was defined as increases of ≥0.3 mg/dL and >25% in serum creatinine level from admission to discharge. FIB-4 scores were calculated before discharge. The primary endpoint was all-cause mortality within 1 year of discharge. Based on the presence of WRF and whether FIB-4 scores were above the median, patients were stratified into four groups: no WRF and lower FIB-4 scores, no WRF and higher FIB-4 scores, WRF and lower FIB-4 scores, and WRF and higher FIB-4 scores. The patients were followed up via clinical visits or telephone interviews. Clinical outcomes were collected from the electronic medical records. RESULTS: Of the 969 patients hospitalized for acute HF (76 ± 11 years, 59% men), 118 patients (12%) had WRF at discharge. The median (interquartile range) FIB-4 score at discharge was 2.36 (1.55-3.25). The primary endpoint occurred in 136 patients (14.0%). The 1 year mortality rates were 10.5% in the no WRF and lower FIB-4 scores (≤2.36) group (n = 428), 16.1% in the no WRF and higher FIB-4 scores (>2.36) group (n = 423), 12.5% in the WRF and lower FIB-4 scores group (n = 56), and 25.8% in the WRF and higher FIB-4 scores group (n = 62) (P = 0.005). Kaplan-Meier analysis demonstrated higher all-cause mortality in the WRF and higher FIB-4 group (log-rank P = 0.003). In the Cox regression analysis, only the WRF and higher FIB-4 scores group was associated with an increased risk of mortality compared with the no WRF and lower FIB-4 scores group (hazard ratio = 2.11, 95% confidence interval: 1.07-4.18, P = 0.032), despite adjusting for other confounding factors. CONCLUSIONS: FIB-4 is a valuable risk stratification marker for WRF in patients with acute HF. The underlying mechanism and potential clinical importance of these observations require further investigation.

[A Case of Perforation at the Stump of Descending Colon after Hartmann's Operation Performed after Transverse Colostomy].

A 77-year-old man with complaining of anemia and abdominal pain was admitted to our hospital. An abdominal computed tomography showed the sigmoid colon tumor with bowel obstruction. Laparoscopic transverse colostomy was performed to release intestinal obstruction. After first operation, he was diagnosed the sigmoid colon cancer: cT4b(bladder), cN0, cM0, and cStage Ⅱc. Radical laparoscopic operation(Hartmann's operation)was performed. On the 4th postoperative day, fecal juice was discharged from the abdominal drain placed in the Douglas fossa, so emergency laparotomy was performed. The intraoperative findings showed perforation in the blind end of the descending colon. The descending colon was resected from a site approximately 5 cm anal side of the transverse colostomy to the blind end. It was thought that perforation occurred due to an increase in internal pressure in the residual intestinal tract after Hartmann's surgery without blood flow disorder. We believe that further attention is required to the management of residual intestinal tract at the blind end for the obstructive colorectal cancer.

Prognostic Value of the FAN Score, a Combination of the Fibrosis-4 Index, Albumin-Bilirubin Score and Neutrophil-Lymphocyte Ratio, in Patients Hospitalized with Heart Failure.

The fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio are all prognostic markers in patients with heart failure. Recently, the FAN score, which includes all 3 of these markers, was developed as a useful risk stratification tool in patients with cancer. However, its cut-off values have not been validated for heart failure. We aimed to investigate the optimal cut-off and prognostic values of the FAN score in patients with heart failure. We analyzed 669 consecutive patients hospitalized with heart failure (age, 75.8 ± 11.3 years). Their median values of the fibrosis-4 index, albumin-bilirubin score, and neutrophil-lymphocyte ratio at discharge were 2.12, -2.25, and 2.41, respectively. The FAN score for heart failure (HF-FAN score) was calculated using these median values. The primary outcome was a composite of all-cause death and heart failure rehospitalization. Patients were divided into 4 groups according to HF-FAN scores of 0 (n = 112), 1 (n = 231), 2 (n = 242) and 3 (n = 84). Patients with HF-FAN scores of 3 were older, had higher brain natriuretic peptide levels, and larger inferior vena cava diameters. Kaplan-Meier analysis showed a direct correlation between higher HF-FAN scores and occurrence of the primary endpoint (log-rank P < 0.001). Cox proportional hazard analysis revealed a higher HF-FAN score was significantly associated with a worse prognosis even after adjustment for possible prognostic factors. Changing from the FAN score to HF-FAN score provided significant continuous net reclassification improvement. In conclusion, the HF-FAN score at discharge was useful for risk stratification in patients hospitalized with heart failure. The HF-FAN score might be more suitable for patients with heart failure than the FAN score.

Mucinous cystic neoplasm of the liver with polypoid nodule prolapsing into the bile duct: a case report and review of literature.

BACKGROUND: Mucinous cystic neoplasm of the liver (MCN-L) is a rare cystic tumor as defined by the 2010 World Health Organization classification. MCN-L usually does not communicate with or grow into the bile duct. Herein, we present a rare case of MCN-L with a polypoid nodule protruding into the bile duct. CASE PRESENTATION: A 69-year-old woman was referred to our hospital for elevated serum liver enzyme levels and obstructive jaundice. The patient also complained of abdominal pain in the right hypochondriac region. Abdominal ultrasonography showed a cystic lesion in segment 4 (S4) of the liver. Computed tomography revealed a 4-cm multilocular cystic lesion with a thick wall and multiple septal formations, showing a cyst-in-cyst appearance in S4. Endoscopic retrograde cholangiography showed a contrast defect between the left hepatic duct and the common bile duct, which was suspected to be a nodular lesion in the bile duct. Bile cytology and biopsy of the nodular lesion showed no malignant findings. Based on these findings, the differential diagnosis in this patient included intraductal papillary neoplasm of the bile duct and MCN-L, which had malignant potential. The patient underwent left hemihepatectomy, including caudate lobe excision with bile duct resection and right hepatocholangiojejunostomy. Macroscopic findings showed a 40 × 29 mm multilocular cystic lesion with a polypoid nodule that protruded into the left intrahepatic bile duct. As an ovarian-like stroma was observed in both cystic and polypoid lesions microscopically, the histopathological diagnosis was MCN-L. The postoperative course was uneventful, and the patient was discharged 24 days after surgery. The patient is currently alive without recurrence 22 months after the surgery. CONCLUSION: Although MCN-L rarely communicates with the bile duct, it is necessary to consider that MCN-L could grow into the bile duct, occasionally causing obstructive jaundice.

Prognostic value of the liver fibrosis marker fibrosis-5 index in patients with acute heart failure.

AIMS: Recently, liver fibrosis markers, such as the fibrosis-4 index (FIB-4), have been shown to be associated with prognosis in patients with heart failure. The fibrosis-5 (FIB-5) index, which assesses albumin, alkaline phosphatase, aspartate transaminase, alanine aminotransferase and platelet count, is a simple liver fibrosis marker that was reported to be superior to FIB-4 for differentiation of liver fibrosis. This study aimed to compare the prognostic value of FIB-4 and FIB-5 in patients with heart failure. METHODS AND RESULTS: The FIB-4 and FIB-5 scores were calculated at discharge in 906 patients hospitalized with heart failure. The patients were stratified into three groups based on their FIB-5 scores: low (n = 303), middle (n = 301), and high (n = 302) FIB-5 groups. The primary endpoint was a composite of cardiac death or rehospitalization for heart failure. The low FIB-5 group was older and had larger inferior vena cava diameters and higher brain natriuretic peptide levels than the other two groups. The primary endpoint occurred in 156 (51.5%), 110 (36.5%), and 54 patients (17.9%) in the low, middle, and high FIB-5 groups, respectively (P < 0.001). On Cox proportional hazard analysis, the low FIB-5 was independently associated with the primary endpoint after adjustment for confounding factors. The association was consistent in both patients with preserved and reduced left ventricular ejection fraction (LVEF), and there was no significant interaction between LVEF phenotypes in terms of the prognostic impact of FIB-5 (P for interaction = 0.311). FIB-5 was superior to FIB-4 as a prognostic indicator of the primary endpoint (continuous net reclassification improvement, 0.530; 95% confidence interval [CI], 0.399-0.662; P < 0.001; integrated discrimination improvement, 0.072; 95% CI, 0.057-0.088; P < 0.001). CONCLUSIONS: The FIB-5 is a useful risk stratification marker with better prognostic value than FIB-4 in patients hospitalized with heart failure.

Oncogenic FGFR1 mutation and amplification in common cellular origin in a composite tumor with neuroblastoma and pheochromocytoma.

Neuroblastoma (NB) and pheochromocytoma (PCC) are derived from neural crest cells (NCCs); however, composite tumors with NB and PCC are rare, and their underlying molecular mechanisms remain unknown. To address this issue, we performed exome and transcriptome sequencing with formalin-fixed paraffin-embedded (FFPE) samples from the NB, PCC, and mixed lesions in a patient with a composite tumor. Whole-exome sequencing revealed that most mutations (80%) were shared by all samples, indicating that NB and PCC evolved from the same clone. Notably, all samples harbored both mutation and focal amplification in the FGFR1 oncogene, resulting in an extraordinarily high expression, likely to be the main driver of this tumor. Transcriptome sequencing revealed undifferentiated expression profiles for the NB lesions. Considering that a metastatic lesion was also composite, most likely, the primitive founding lesions should differentiate into both NB and PCC. This is the first reported case with composite-NB and PCC genetically proven to harbor an oncogenic FGFR1 alteration of a common cellular origin.

Protein-losing enteropathy caused by disseminated Mycobacterium avium complex infection in a patient receiving antiretroviral therapy: an autopsy case report.

BACKGROUND: Disseminated Mycobacterium avium complex infection is an important indicator of acquired immunodeficiency syndrome (AIDS) in patients with advanced human immunodeficiency virus (HIV) infection. Effective antiretroviral therapy has dramatically reduced the incidence of and mortality due to HIV infection, although drug resistance and poor medication adherence continue to increase the risk of disseminated M. avium complex infection. However, gastrointestinal lesions in cases of disseminated M. avium complex infection resulting in protein-losing enteropathy have been rarely discussed. Therefore, we present a case of protein-losing enteropathy caused by disseminated M. avium complex infection in a patient undergoing antiretroviral therapy. CASE PRESENTATION: A 29-year-old man was diagnosed with AIDS 4 years ago and was admitted for a 10-month history of refractory diarrhea and fever. Despite receiving antiretroviral therapy, the viral load remained elevated due to poor medication adherence. The patient was diagnosed with disseminated M. avium complex infection and started on antimycobacterial drugs 2 years before admission. However, the infection remained uncontrolled. The previous hospitalization 1 year before admission was due to hypoalbuminemia and refractory diarrhea. Upper gastrointestinal endoscopy revealed a diagnosis of protein-losing enteropathy caused by intestinal lymphangiectasia, and treatment with intravenous antimycobacterial drugs did not resolve his intestinal lymphangiectasia. The patient inevitably died of sepsis. CONCLUSIONS: Clinical remission is difficult to achieve in patients with AIDS and protein-losing enteropathy caused by disseminated M. avium complex infection due to limited options of parenteral antiretroviral drugs. This report highlights the importance of identifying alternative treatments (such as an injectable formulation) for patients who do not respond to antiretroviral therapy due to protein-losing enteropathy with disseminated M. avium complex infection.

Rhabdoid tumor predisposition syndrome with renal tumor 10 years after brain tumor.

We report a case of rhabdoid tumor predisposition syndrome with a renal tumor developing 10 years after a brain tumor, which demonstrated an unexpectedly favorable outcome. A 2-year-old boy underwent gross total resection of a brain tumor located in the fourth ventricle, and received adjuvant chemotherapy and radiotherapy. At the age of 11 years, a renal tumor was found and nephrectomy was performed. He is currently alive without evidence of disease over 2 years without postoperative therapy. Histologically, rhabdoid cells were observed in both brain and renal tumors. Loss of SMARCB1 (also known as INI1) expression was found in the nucleus of both tumor cells. Genetic testing revealed pathogenic variants of SMARCB1 exon 5 in the renal tumor and SMARCB1 exon 9 in the brain tumor. In addition, heterozygous deletion of 22q11.21-q11.23 containing the SMARCB1 locus was shared by both tumors and this deletion was identified in normal peripheral blood. Considering the histopathological and genetic findings, our case was considered to be rhabdoid tumor predisposition syndrome with atypical teratoid/rhabdoid tumor and late-onset rhabdoid tumor of the kidney.

Relation of Aspartate Aminotransferase to Alanine Aminotransferase Ratio to Nutritional Status and Prognosis in Patients With Acute Heart Failure.

Elevated liver fibrosis markers are associated with worse prognosis in acute heart failure (AHF). The aspartate aminotransferase to alanine aminotransferase ratio (AAR) is one such fibrosis marker, and low ALT is a surrogate marker of malnutrition. Here, we evaluated the association between AAR and nutritional status and prognosis in patients with AHF. Consecutive 774 patients who were admitted due to AHF were divided into 3 groups according to AAR at discharge: first tertile, AAR<1.16 (n = 262); second tertile, 1.16≤AAR<1.70 (n = 257); and third tertile, AAR≥1.70 (n = 255). Nutritional indices and a composite of all-cause death or HF rehospitalization were compared in the 3 tertiles. Patients in the third AAR tertile were older and had lower body mass index than patients in other AAR tertiles. A higher AAR was associated with worse nutritional indices (i.e., controlling nutritional status score, geriatric nutritional risk index, and prognostic nutritional index). Clinical outcome rates significantly increased along AAR tertiles (first tertile, 28%; second tertile, 43%; third tertile, 58%, p < 0.001). Cox proportional hazards models including potential prognostic factors revealed high AAR was an independent prognostic factor of AHF. In conclusion, AAR at discharge may be associated with nutritional status and worse clinical outcomes in patients with AHF.

A case of esophageal squamous cell carcinoma with neuroendocrine, basaloid, and ciliated glandular differentiation.

Esophageal carcinomas have multidirectional differentiation abilities and different histological components have been reported. Herein, we report a case of esophageal carcinoma with four different differentiations. A 64-year-old man was referred to our hospital for treatment of an esophageal tumor detected during an esophagogastroduodenoscopy, which revealed an elevated lesion accompanied by a slightly depressed lesion in the middle of the esophagus. Examination of the biopsy specimen obtained from the elevated lesion revealed an adenocarcinoma, while that from the depressed lesion revealed a squamous cell carcinoma. Fluorodeoxyglucose-position emission tomography and enhanced computed tomography showed an esophageal carcinoma in the middle of the esophagus with no signs of metastasis. The preoperative diagnosis was adenosquamous cell carcinoma classified as T2N0M0 according to the TNM classification (seventh edition). Thoracoscopic esophagectomy was performed. Examination of the resected specimen revealed esophageal squamous cell carcinoma with neuroendocrine, basaloid, and ciliated glandular differentiation. Although they may be totipotent, an esophageal carcinoma consisting of four components is extremely rare. Moreover, ciliated glandular differentiation is rarely observed in the esophagus, except in individuals with bronchial esophageal duplication cysts and adenocarcinoma arises from a Barrett's esophagus.

Accumulation of 8-hydroxydeoxyguanosine, L-arginine and Glucose Metabolites by Liver Tumor Cells Are the Important Characteristic Features of Metabolic Syndrome and Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis.

To uncover mechanisms and explore novel biomarkers of obesity, type 2 diabetes (T2DM) and nonalcoholic steatohepatitis (NASH)-associated hepatocarcinogenesis, cellular and molecular alterations in the liver, and hepatocellular carcinomas (HCCs) were investigated in NASH model 60-week-old Tsumura, Suzuki, Obese Diabetic (TSOD) mice and NASH HCC patients. Markedly elevated lipid deposition, inflammation, fibrosis, and peroxisome proliferation in the liver, preneoplastic lesions, and HCCs of TSOD mice were accompanied by accumulation of polysaccharides in the cellular cytoplasm and nuclei and increase of oxidative DNA damage marker, 8-hydroxydeoxyguanosine (8-OHdG) formation in the liver and altered foci. Metabolomics of TSOD mice HCCs demonstrated significant elevation of the concentration of amino acid L-arginine, phosphocreatine, S-adenosylmethionine/S-adenosylhomocysteine ratio, adenylate, and guanylate energy charges in coordination with tremendous rise of glucose metabolites, mostly fructose 1,6-diphosphate. L-arginine accumulation in HCCs was associated with significant under-expression of arginase 1 (ARG1), suppression of the urea cycle, methionine and putrescine degradation pathways, activation of Ser and Thr kinase Akt AKT, phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinase 1/2 (ERK1/2) kinases, ß-catenin, mammalian target of rapamycin (mTOR), and cell proliferation. Furthermore, clinicopathological analysis in 20 metabolic syndrome/NASH and 80 HCV-positive HCC patients demonstrated significant correlation of negative ARG1 expression with poor tumor differentiation, higher pathological stage, and significant decrease of survival in metabolic syndrome/NASH-associated HCC patients, thus indicating that ARG1 could become a potential marker for NASH HCC. From these results, formation of oxidative stress and 8-OHdG in the DNA and elevation of glucose metabolites and L-arginine due to ARG1 suppression in mice liver cells are the important characteristics of T2DM/NASH-associated hepatocarcinogenesis, which may take part in activating oxidative stress resistance, synthesis of phosphocreatine, cell signaling, methylation, and proliferation.

Dimethylarsinic acid (DMA) enhanced lung carcinogenesis via histone H3K9 modification in a transplacental mouse model.

Pregnant CD-1 mice received 200 ppm dimethylarsinic acid (DMA) in the drinking water from gestation day 8-18, and tumor formation was assessed in offspring at the age of 84 weeks. DMA elevated the incidence of lung adenocarcinoma (10.0%) and total tumors (33.3%) in male offspring compared to male control offspring (1.9 and 15.1%, respectively). DMA also elevated the incidence of hepatocellular carcinoma (10.0%) in male offspring compared to male control offspring (0.0%). DMA and its metabolites were detected in the lungs of transplacental DMA-treated neonatal mice. Transplacental DMA exposure increased cell proliferation in the epithelium in the lungs of both neonatal and 6-week-old male mice. Microarray and real-time PCR analyses detected high expression of keratin 8 (Krt8) in the lungs of both neonatal and 6-week-old DMA-treated mice. Western blot analysis indicated that DMA elevated methylation of histone H3K9, but not H3K27, in the lungs of male mice. Importantly, chromatin immunoprecipitation sequencing (ChIP-seq) analysis using an H3K9me3 antibody found differences in heterochromatin formation between mice exposed to DMA and the controls. Notably, ChIP-seq analysis also found regions of lower heterochromatin formation in DMA-treated mice, and one of these regions contained the Krt8 gene, agreeing with the results obtained by microarray analysis. High expression of Krt8 was also detected in adenoma and adenocarcinoma of the lung in male offspring. Overall, these data indicate that transplacental DMA treatment enhanced lung and liver carcinogenesis in male mice. In the lung, DMA caused aberrant methylation of histone H3K9, increased Krt8 expression, and enhanced cell proliferation.

Promotion effects of acetoaceto-o-toluidide on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats.

Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen.

Adult-Onset Mixed Germ Cell Tumor Composed Mainly of Yolk Sac Tumor Around the Pineal Gland: A Case Report and Review of the Literature.

BACKGROUND: Mixed germ cell tumors (MGCTs) usually occur in children. In the present report, we discuss an extremely rare case of adult-onset MGCT composed mainly of yolk sac tumor (YST) around the pineal gland. CASE DESCRIPTION: A 54-year-old Japanese man presented with disturbance of consciousness, Parinaud's syndrome, and gait disturbance. Magnetic resonance imaging revealed a pineal mass lesion, and subtotal resection of the tumor was achieved. The histologic diagnosis was MGCT, consisting mainly of YST. Although he underwent 5 courses of chemotherapy and craniospinal irradiation after surgery, tumor dissemination could not be controlled, and he died 10 months postoperatively. CONCLUSION: The present case highlights the need for clinicians to include YST in the differential diagnosis of acute progressive lesions around the pineal region, even in adult patients.

Histological and genetic analysis of anaplastic pleomorphic xanthoastrocytoma suspected of malignant progression over a 12-year clinical course.

We report a case of anaplastic PXA for which histological study and molecular analysis were performed at the time of the first resection and two recurrences. A 15-year-old girl had a temporal lobe tumor that had been followed as a cystic lesion from three years of age without histopathological examination. The first and second surgical specimens exhibited typical histological features of PXA such as nuclear and cytoplasmic pleomorphism. In addition, microvascular proliferation was observed in the second surgical specimen. On the other hand, nuclear pleomorphism was unclear in the third surgical specimen and it was mainly composed of spindle cells. Palisading necrosis was observed. Mitotic figures and the Ki-67 proliferation index gradually increased. BRAF V600E and TERT promoter mutation were detected in the first, second, and third surgical specimens. In addition, PTEN mutation and CDNK2A deletion were detected in the third surgical specimen. Considering the histopathological and genetic changes over time, we concluded that our case of anaplastic PXA underwent malignant progression.