EUS-guided fine-needle biopsy sampling of solid pancreatic tumors with 3 versus 12 to-and-fro movements: a multicenter prospective randomized controlled study.

BACKGROUND AND AIMS: A novel EUS-guided fine-needle biopsy sampling (EUS-FNB) needle enabled physicians to obtain sufficient pathologic samples with fewer to-and-fro movements (TAFs) within the lesion. We compared the diagnostic yields of EUS-FNB with 3 and 12 TAFs at each puncture pass. METHODS: The primary endpoint of this multicenter, noninferiority, crossover, randomized controlled trial involving 6 centers was diagnostic sensitivity. Secondary endpoints were diagnostic accuracy and quantity and quality evaluation of EUS-FNB specimens. Length of the macroscopically visible core (MVC) and microscopic histologic quantity were used for quantitative evaluation. Macroscopic visual and microscopic histologic evaluations were performed for qualitative evaluation. RESULTS: Among 110 patients (220 punctures, 110 for 3 TAFs and 12 TAFs each), 105 (210 punctures) had malignant histology. Diagnostic sensitivity for malignancy of 3 TAFs (88.6%) was not inferior to that of 12 TAFs (89.5%; difference, -.9%; 95% confidence interval, -9.81 to 7.86). Diagnostic accuracy for malignancy was 92.7% for 3 TAFs and 94.6% for 12 TAFs. Overall median MVC length was 13.5 mm in both groups. The 3-TAF group had a significantly higher rate of score ≥3 on macroscopic visual quality evaluation than the 12-TAF group (71.8% vs 52.7%, P = .009). No significant intergroup differences existed in microscopic histologic quantity and quality evaluations (quantity evaluation, 88.2% for 3 TAFs vs 83.6% for 12 TAFs; quality evaluation, 90.0% for 3 TAFs vs 89.1% for 12 TAFs). CONCLUSIONS: Diagnostic sensitivity and accuracy of EUS-FNB with 3 TAFs were not inferior to those with 12 TAFs for solid pancreatic lesions. The 3-TAF group showed significantly less blood contamination in sampled tissues than the 12-TAF group. (Clinical trial registration number: UMIN000037309.).

Nicolaioidesin C: An Antiausterity Agent Shows Promising Antitumor Activity in a Pancreatic Cancer Xenograft Mouse Model.

Human pancreatic tumors are hypovascular in nature, and their tumor microenvironment is often characterized by hypoxia and severe nutrient deprivation due to uncontrolled heterogeneous growth, a phenomenon known as "austerity". However, pancreatic tumor cells have the inherent ability to adapt and thrive even in such low nutrient and hypoxic microenvironments. Anticancer drugs such as gemcitabine and paclitaxel, which target rapidly proliferating cells, are often ineffective against nutrient-deprived pancreatic cancer cells. In order to overcome this limitation, the search for novel agents that can eliminate cancer cells' adaptations to nutrition starvation, also known as "antiausterity" agents, represents a promising strategy to make the cancer cells susceptible to treatment. The natural product (+)-nicolaioidesin C (Nic-C) was found to have potent antiausterity activity against the PANC-1 human pancreatic cancer cell line in a nutrient-deprived condition. However, its efficacy in vivo remained untested. To address this, we synthesized Nic-C in its racemic form and evaluated its antitumor potential in a human pancreatic cancer xenograft model. Nic-C inhibited pancreatic cancer cell migration and colony formation and significantly inhibited tumor growth in MIA PaCa-2 xenografts in a dose-dependent manner. Furthermore, Nic-C inhibited the Akt/mTOR and autophagy signaling pathways in both in vitro and in vivo studies. Metabolomic profiling of in vivo tumor samples suggests that Nic-C downregulates amino acid metabolism while upregulating sphingolipid metabolism.

The potential diagnostic significance of crypt differentiation in gastric dysplasia.

AIMS: This study investigated the relationship between the differentiation of tumour cells into crypts, which is determined by cell differentiation into Paneth and neuroendocrine cells, and tumour infiltration in gastric dysplasia. METHODS AND RESULTS: The lesions were endoscopically biopsied low-grade dysplasia (LGD), endoscopically resected high-grade dysplasia (HGD) or cancer with submucosal invasion. LGD (n = 32) displayed crypt differentiation across the entire width of the tumour in all cases. Crypt differentiation was identified as a characteristic of tumours with low biological malignancy. HGD (n = 40) included tumours with a mixture of areas with and without crypt differentiation (n = 25) and tumours with crypt differentiation throughout the entire width (n = 15). Of the cancers with submucosal invasion (n = 30), the morphological progression of the HGD area with crypt differentiation, the HGD area without crypt differentiation and invasive cancer without crypt differentiation was confirmed for 23 samples. In two lesions, invasive cancer without crypt differentiation developed from HGD without crypt differentiation throughout the tumour width. In five samples, well-differentiated tubular adenocarcinoma with crypt differentiation developed from HGD with crypt differentiation and invaded with lamina propria-like stroma. CONCLUSIONS: Loss of crypt differentiation could be an objective indicator of infiltration in the progression of HGD to invasive cancer. The invasive potential of dysplasia depends upon the presence or absence of crypt differentiation.

Hyodeoxycholic Acid (HDCA) Prevents Development of Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice: Possible Role of Synergism between DSS and HDCA in Increasing Fecal Bile Acid Levels.

Secondary bile acids (SBAs) with high hydrophobicity are abundant in the colonic lumen. However, both aggravating and protective roles of SBAs have been proposed in the pathogenesis of inflammatory bowel diseases (IBDs). We observed that oral administration of hyodeoxycholic acid (HDCA), a hydrophilic bile acid, prevented the development of dextran sulfate sodium (DSS)-induced colitis in mice. We then examined the individual effects of DSS and HDCA as well as their combined effects on fecal bile acid profile in mice. HDCA treatment increased the levels of most of fecal bile acids, whereas DSS treatment had limited effects on the levels of fecal bile acids. The combined treatment with DSS and HDCA synergistically increased the levels of fecal chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) in feces, which are potent activators of the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). The overall hydrophobicity of fecal bile acids was not modified by any treatments. Our data suggest that the preventive effect of HDCA on DSS-induced colitis in mice is due to the synergism between DSS and HDCA in increasing the levels of the fecal bile acids with potencies to activate FXR and TGR5.

Sebaceous adenoma occurring within an intracranial dermoid cyst.

Among intracranial cystic lesions, dermoid cysts and epidermoid cysts are relatively common benign tumors. In a small number of these tumors, it is known that squamous cell carcinomas arise in the lining epithelium of the cysts. Among tumors derived from the appendage, only one case of hidradenoma within a dermoid cyst and no cases of sebaceous tumor have been reported previously. In the present case, a protruding lesion was present in the cystic wall, and it was composed of two cell types: sebaceous cells (sebocytes) and basaloid/germinated cells, being characteristic of this tumor. It is essential to distinguish it from other sebaceous lesions such as hyperplasia, sebaceoma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation derived from the epidermis. The critical distinguishing points in making a differential diagnosis among these lesions are the ratio of the two cell types and the presence or absence of other components such as hair sacs, invasion or cellular atypia. Immunohistochemical examination revealed that the tumor cells were positive for the epithelial markers, such as cytokeratin (CK)14, p63, p40, high-molecular CK, and adipophilin; these findings are peculiar to sebaceous adenoma. Although there have been several similar case reports of sebaceous tumors associated with dermmoid cysts in the ovaries, most of the intracranial lesions were squamous cell carcinomas that developed within the cysts, and there has been no precedent showing an association with a sebaceous tumor. The present report describes the first case of sebaceous adenoma that occurred in an intracranial dermoid cyst.

Macroscopic visible core length can predict the histological sample quantity in endoscopic ultrasound-guided tissue acquisition: Multicenter prospective study.

OBJECTIVES: Measurement of the macroscopic visible core (MVC) length during macroscopic on-site quality evaluation (MOSE) may allow estimation of sample adequacy for next-generation sequencing (NGS), and prediction of correct diagnosis in endoscopic ultrasound-guided tissue acquisition (EUS-TA) of pancreatic masses. METHODS: This multicenter prospective study included consecutive patients who underwent EUS-TA for pancreatic masses using a 22-G Franseen needle. MVC length and pathological samples obtained from two needle passes were analyzed on a per-pass basis. Outcome measures included respective correlations of MVC length with histological sample quantity and diagnostic yields. RESULTS: The analysis included 204 passes from 102 EUS-TAs. MVC length correlated positively with histological sample quantity (P < 0.01). On the receiver operating characteristic curve for MVC length, the cut-off value and area under the curve for obtaining a candidate sample for NGS were 30 mm and 0.74 (95% confidence interval [CI] 0.65-0.83), respectively. On multivariate analysis, MVC length ≥30 mm was a significant factor affecting suitability for NGS (odds ratio 6.19; 95% CI 2.72-14.10). Histologic diagnostic yield correlated positively with MVC length (P = 0.01); however, there was no positive correlation between MVC length and overall (histology plus cytology) diagnostic yield. CONCLUSIONS: Measuring MVC length to predict histological sample quantity on MOSE may be of clinical significance during EUS-TA using a 22-G Franseen needle. It may be an effective method, particularly while submitting samples for NGS. REGISTRATION: University Hospital Medical Information Network Trials Registry (UMIN000036528).

Effect of Continuous Feeding of Ayu-Narezushi on Lipid Metabolism in a Mouse Model of Metabolic Syndrome.

Ayu-narezushi, a traditional Japanese fermented food, comprises abundant levels of lactic acid bacteria (LAB) and free amino acids. This study aimed to examine the potential beneficial effects of ayu-narezushi and investigated whether ayu-narezushi led to improvements in the Tsumura Suzuki obese diabetes (TSOD) mice model of spontaneous metabolic syndrome because useful LAB are known as probiotics that regulate intestinal function. In the present study, the increased body weight of the TSOD mice was attenuated in those fed the ayu-narezushi-comprised chow (ayu-narezushi group) compared with those fed the normal rodent chow (control group). Serum triglyceride and cholesterol levels were significantly lower in the Ayu-narezushi group than in the control group at 24 weeks of age. Furthermore, hepatic mRNA levels of carnitine-palmitoyl transferase 1 and acyl-CoA oxidase, which related to fatty acid oxidation, were significantly increased in the ayu-narezushi group than in the control group at 24 weeks of age. In conclusion, these results suggested that continuous feeding with ayu-narezushi improved obesity and dyslipidemia in the TSOD mice and that the activation of fatty acid oxidation in the liver might contribute to these improvements.

Risk factors for spontaneous miscarriage above 12 weeks or premature delivery in patients undergoing cervical polypectomy during pregnancy.

BACKGROUND: It currently remains unknown whether the resection of cervical polyps during pregnancy leads to miscarriage and/or preterm birth. This study evaluated the risk of spontaneous PTB below 34 or 37 weeks and miscarriage above 12 weeks in patients undergoing cervical polypectomy during pregnancy. METHODS: This was a retrospective monocentric cohort study of patients undergoing cervical polypectomy for clinical indication. Seventy-three pregnant women who underwent polypectomy were selected, and risk factors associated with miscarriage above 12 weeks or premature delivery below 34 or 37 weeks were investigated. A multivariable regression looking for predictors of spontaneous miscarriage > 12 weeks and PTB < 34 or 37 weeks were performed. RESULTS: Sixteen patients (21.9%, 16/73) had spontaneous delivery at < 34 weeks or miscarriage above 12 weeks. A univariate analysis showed that bleeding before polypectomy [odds ratio (OR) 7.7, 95% confidence interval (CI) 1.6-37.3, p = 0.004], polyp width ≥ 12 mm (OR 4.0, 95% CI 1.2-13.1, p = 0.005), the proportion of decidual polyps (OR 8.1, 95% CI 1.00-65.9, p = 0.024), and polypectomy at ≤10 weeks (OR 5.2, 95% CI 1.3-20.3, p = 0.01) were significantly higher in delivery at < 34 weeks than at ≥34 weeks. A logistic regression analysis identified polyp width ≥ 12 mm (OR 11.8, 95% CI 2.8-77.5, p = 0.001), genital bleeding before polypectomy (OR 6.5, 95% CI 1.2-55.7, p = 0.025), and polypectomy at ≤10 weeks (OR 5.9, 95% CI 1.2-45.0, p = 0.028) as independent risk factors for predicting delivery at < 34 weeks. Polyp width ≥ 12 mm and bleeding before polypectomy are risk factors for PTB < 37 wks. CONCLUSIONS: Our cohort of patients undergoing polypectomy in pregnancy have high risks of miscarriage or spontaneous premature delivery. It is unclear whether these risks are given by the underlying disease, by surgical treatment or both. This study establishes clinically relevant predictors of PTB are polyp size> 12 mm, bleeding and first trimester polypectomy. PTB risks should be exposed to patients and extensively discussed with balancing against the benefits of intervention in pregnancy.

CDKN2A, CDK1, and CCNE1 overexpression in sebaceous gland carcinoma of eyelid.

PURPOSE: To investigate the overexpression of genes in sebaceous gland carcinoma (SGC) of the eyelid compared to sebaceous adenoma of the eyelid in order to elucidate the molecular mechanism underlying pathogenesis. METHODS: We performed histopathological examination of eyelid tissues surgically removed from four patients diagnosed with SGC (cases 1-3) and sebaceous adenoma (case 4) of the eyelid. Next, we performed global gene expression analysis of surgical tissue samples using a GeneChip® system and the Ingenuity Pathways Knowledge Base. The results of the GeneChip® analysis were explored with quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RESULTS: In the SGC samples, we found that 211, 199, and 199 genes, respectively, showed ≥ 2.0-fold higher expression than those in the sebaceous adenoma sample (case 4); 194 genes were common to all three SGC samples. For the 194 genes with upregulated expression, functional category analysis showed that SGC of the eyelid employed a unique gene network, including cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 1 (CDK1), and cyclin E1 (CCNE1), which are related to cell cycle progression, incidence of tumor, and cell viability. Furthermore, qRT-PCR analysis showed that the expression levels of CDKN2A, CDK1, and CCNE1 were significantly upregulated in all SGC cases compared to those in the sebaceous adenoma case. These data were similar to the results of microarray analysis. CONCLUSION: Overexpression of cell cycle-related genes CDKN2A, CDK1, CCNE1, and their gene network may help elucidate the pathogenic pathway of SGC of the eyelid at the molecular level.

Autoantibodies reactive to PEP08 are clinically related with morbidity and severity of interstitial lung disease in connective tissue diseases.

Anti-Ro52 autoantibodies (Ro52-autoAbs) appear in the sera of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Studies using patient sera have shown a correlation between the generation of Ro52-autoAbs and the clinical morbidity and severity of CTD with ILD. In this study, we used a single B-cell manipulating technology and obtained 12 different monoclonal Ro52-autoAbs (mRo52-autoAbs) from the selected four patients suffering from severe ILD with a high titer of Ro52-autoAbs in their sera. Western blot analysis revealed that 11 of 12 mRo52-autoAbs bound to the coiled-coil domain of Ro52. Competitive ELISA demonstrated that mRo52-autoAbs competed with each other to bind to Ro52. Epitope mapping showed that two of them specifically bound to a peptide (PEP08) in the coiled-coil domain. We then examined the titer of Ro52-autoAbs in the sera of 192 CTD patients and assessed the relationship between the serum levels of Ro52-autoAbs that were reactive to PEP08 peptide and the clinical morbidity and severity of ILD. Statistical analysis revealed that the production of PEP08-reactive Ro52-autoAbs correlated with the morbidity and severity of ILD in CTD. Assessment of the production of PEP08-reactive Ro52-autoAbs in autoimmune diseases is useful for predicting the clinical morbidity of ILD.

SKL2001 suppresses colon cancer spheroid growth through regulation of the E-cadherin/ß-Catenin complex.

Aberrant activation of Wnt signaling plays a pivotal role in the development of human cancers including colon cancer. Small compounds that regulate Wnt signaling are attractive candidate for the colon cancer therapy. Here, we showed that SKL2001, which has been identified as an activator for Wnt signaling by disrupting the Axin/ß-Catenin complex, negatively regulates growth of colon cancer spheroids cultured in the 3D condition that simulates tumor microenvironment in vivo. SKL2001 inhibited proliferation of colon cancer cells cultured in 3D spheroid and induced them accumulation in the G0/G1 phase of the cell cycle with a reduced c-myc level. To examine the potential of arrested cells to recover, colon cancer spheroids that were treated with SKL2001 were then cultured in the SKL2001-free medium. We found that SKL2001-treated cells were resumed cell cycle progression and proliferated in the SKL2001-free medium. Notably, SKL2001 facilitated round-shape spheroid formation. This was associated with upregulated expressions of E-cadherin and ß-Catenin. These findings suggest that SKL2001 can suppress colon cancer spheroid growth through regulating cell cycle progression and cadherin/catenin mediated cell-cell contact.

Aberrant iron metabolism might have an impact on progression of diseases in Tsumura Suzuki obese diabetes mice, a model of spontaneous metabolic syndrome.

Tsumura Suzuki obese diabetes (TSOD) mice spontaneously develop obesity and type 2 diabetes with aberrant accumulation of excessive iron in the spleen. Aberrantly accumulated iron may cause oxidative stress and result in various symptoms of metabolic syndrome in the mice. We investigated iron metabolism and oxidative stress in TSOD mice. Male TSOD and control mice were killed at 2, 3, 6, and 8 months of age, and blood and tissue samples were collected. The serum levels of ferritin and oxidized low-density lipoprotein (OxLDL) were measured. Total glutathione concentrations of liver and spleen were also measured. Serum ferritin and OxLDL were higher in TSOD mice than in control mice at 2 and 6 months. In addition, the glutathione concentrations in TSOD mice were lower in the liver and higher in the spleen at 3 and 6 months than those in control mice. These results suggest that abnormal iron metabolism and imbalanced oxidative stress occurs in young and old TSOD mice. We propose herein that TSOD mice might be a unique and valuable model for investigating the role of iron metabolism in pathogenesis of metabolic syndrome.

Analysis of KRAS mutations in cases of metastatic colorectal cancer at a single institution in Tochigi, Japan.

OBJECTIVE: Colorectal cancer patients bearing wild-type KRAS benefit from anti-epidermal growth factor receptor (EGFR) antibody treatment. Since clinical studies showed the efficacy of anti-EGFR antibody treatment for metastatic colorectal cancer (mCRC), we analyzed KRAS mutations in mCRC to gain insight into the association between these mutations and clinicopathological characteristics. METHODS: KRAS mutations were analyzed in 109 tissue samples of mCRC using amplification refractory mutation system-Scorpion (ARMS/S) assay (68 samples) and direct sequencing (41 samples). RESULTS: In the ARMS/S assay, 36.5 and 7.4% of mCRCs harbored mutations at codons 12 and 13, respectively. In direct sequencing, corresponding values were 24.4 and 19.5%. Overall, 37.6% (codon 12/13, 25.7/11.9%) of mCRCs harbored KRAS mutations. No significant differences were found between KRAS mutations and clinicopathological variables. Among mCRC patients <65 years of age, the incidence of KRAS mutations at codon 13 was significantly higher in female than male patients (p = 0.035). CONCLUSION: The incidence of KRAS mutations in mCRC was similar to that of non-mCRC as previously reported. KRAS codon 13 mutations might be associated with younger female patients with mCRC, but further investigation is necessary to clarify the association between this type of mutation and metastatic potential in female CRC patients.

Neonatal monosodium glutamate treatment causes obesity, diabetes, and macrovesicular steatohepatitis with liver nodules in DIAR mice.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome (MS). Monosodium glutamate (MSG)-treated ICR mice is a useful model of MS and NASH, but it shows the different patterns of steatosis from human NASH. Because inbred aged DIAR (ddY, Institute for Animal Reproduction) mice spontaneously show the similar pattern of steatosis as NASH, we analyzed their liver pathology after administering MSG. METHODS: MSG-treated DIAR mice (DIAR-MSG) and untreated DIAR mice (DIAR-controls) were sacrificed and assessed histopathologically at 29, 32, 40, 48, and 54 weeks of age. The NASH activity score, body mass index, blood glucose level, and oral glucose tolerance test were also assessed. RESULTS: The body mass index and blood glucose levels of DIAR-MSG were significantly higher than controls. The oral glucose tolerance test revealed a type 2 diabetes pattern in DIAR-MSG. The livers of DIAR-MSG mice showed macrovesicular steatosis, lobular inflammation with neutrophils, and ballooning degeneration after 29 weeks. At 54 weeks, mild fibrosis was observed in 5/6 DIAR-MSG and 2/5 DIAR-control mice. In imaging mass spectrometry analysis, cholesterol as well as triglyceride accumulated in the liver of DIAR-MSG mice. Atypical liver nodules were also observed after 32 weeks in DIAR-MSG, some with cellular and structural atypia mimicking human hepatocellular carcinoma. The NASH activity score of DIAR-MSG after 29 weeks was higher than that of control mice, suggesting the development of NASH. CONCLUSIONS: DIAR-MSG had NASH-like liver pathology and liver nodules typically associated with MS symptoms. DIAR-MSG provides a valuable animal model to analyze NASH pathogenesis and carcinogenesis.

A case of extranodal NK/T-cell lymphoma, nasal type, diagnosed by scraping cytology of the maxillary gingiva.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is often seen in the head and neck region, but there have been rare instances of this disease with initial presentation as a lesion in the oral mucosa. The patient, a woman in her seventh decade of life, presented with an ulcer in the maxillary gingiva, and scraping cytology and biopsy were performed. Cytological specimens showed solitary or small aggregating cells with marked atypia in a necrotic background. Tumor cells were detected that had various nuclear shapes and azure granules in the cytoplasm. Biopsy showed that the tumor cells had diffusely infiltrated or interdigitated into the subepithelium. Immunohistochemistry revealed that the tumor cells had T- and NK cell phenotypes and were Epstein-Barr virus-encoded small RNA (EBER) positive, leading to a diagnosis of ENKTL. Thus, when nonepithelial tumor cells in a necrotic background and prominent atypia are found, as in this case, it is important to carefully observe for azurophil granules in the cytoplasm for differential diagnosis considerations.

Verifying a novel bile cytology scoring system.

BACKGROUND: The scoring system for bile cytology (SSBC) aims to improve bile cytology diagnostic accuracy. Here, the practicality of SSBC was verified by multiple cytotechnologists. METHODS: Bile cytological specimens were evaluated by 24 cytotechnologists using SSBC. The samples were assessed before using the SSBC (first-time assessment) according to three categories: benign, indeterminate, and malignant. A first scoring evaluation (FSE) was then performed using SSBC; each item in the scoring system was classified as present or absent. After distributing an instruction sheet with diagnostic criteria, a second scoring evaluation (SSE) was performed using SSBC. Each method was evaluated using diagnostic accuracy and interobserver and intraobserver agreement. RESULTS: Several samples were assessed as indeterminate in the first-time assessment. Although the specificity of the SSE improved, the sensitivity and accuracy decreased compared with those of the FSE. The overall interobserver agreement was fair for all parameters, including abnormal chromatin, irregular internuclear distances, irregularly overlapped nuclei, irregular cluster margins, and final evaluation in the FSE and SSE. The final evaluation by histological type exhibited slight agreement for well-differentiated tubular adenocarcinoma and almost perfect agreement for poorly differentiated tubular adenocarcinoma in the FSE and SSE. For moderately differentiated tubular adenocarcinoma, agreement was moderate in the FSE and fair in the SSE. For cholangitis, a slight agreement was observed in the FSE, which improved to fair in the SSE. CONCLUSIONS: Although the SSBC is expected to improve specificity, there exists ambiguity regarding SSBC criteria and interindividual assessment differences. Therefore, the objective assessment method should be revised.

Hepatocellular carcinoma in a transplanted donor liver and colon cancer developing in a patient with a complex background: A case report.

The development of tumors in livers transplanted from hepatitis B virus (HBV)-negative donors to patients with hepatitis B and cirrhosis is rare. The present study describes the case of a woman in her 60s who developed hepatocellular carcinoma (HCC) in her grafted liver, 19 years after transplantation, as well as a metachronous colorectal tumor. The pathological findings, including clinical, immunohistochemical and molecular results, are described in the present case report. The liver tumor was a conventional HCC and the colorectal tumor comprised a tubular adenocarcinoma. Immunohistochemistry of both tumors showed a loss of expression of mutL homolog 1 and postmeiotic segregation increased 2 in the tumor cells, confirming microsatellite instability-high (MSI-H) status. Furthermore, a molecular study detected the presence of genes located on the Y chromosome in the normal and tumor tissues of the liver, proving that the HCC occurred in the grafted liver. The present report also discusses that prolonged use of immunosuppressive drugs to prevent post-transplant rejection, poorly controlled diabetes mellitus and MSI-H may have contributed to the risk of tumor development.

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome.

Metabolic syndrome is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases that affect the entire body. The hepatic manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). The basic pathogenesis of NAFLD/NASH remains controversial because it is difficult to clarify the disease process of NASH on the basis of metabolic syndrome alone. To determine the pathogenesis and effective treatment, an excellent animal model of NASH is required. Tsumura Suzuki obese diabetes (TSOD) male mice spontaneously develop diabetes mellitus, obesity, glucosuria, hyperglycemia, and hyperinsulinemia without any special treatments such as gene manipulation. In this study, we examined the histopathological characteristics of visceral fat and liver of 56 male TSOD mice aged 4-17 months and 9 male Tsumura Suzuki non-obesity (control) mice aged 6-12 months. In the visceral fat, enlargement of adipocytes and perivascular and pericapsular CD8-positive lymphoid aggregation were observed in 4-month-old mice. Abnormal expression of tumor necrosis factor-α, interleukin-6, and lipid peroxidation endo products was observed in macrophages. In the liver, microvesicular steatosis, hepatocellular ballooning, and Mallory bodies were observed in 4-month-old mice, with severity worsening with increasing time. These pathological findings in the liver mimic those seen in patients with NASH. Interestingly, small liver nodules with high cellularity and absence of portal tracts were frequently observed after 12 months. Most of them showed nuclear and structural atypia, and mimicked human hepatocellular carcinoma. The degree of steatosis in the non-tumor portions of the liver improved when the liver nodules developed. These findings were not observed in control mice. Here, we report that TSOD male mice spontaneously developed NAFLD without any special treatment, and that these mice are a valuable model for assessing NASH and NASH carcinogenesis owing to metabolic syndrome.