Abundant recent data suggest that sessile serrated adenoma/polyp (SSA/P) is an early precursor lesion in the serrated pathway of carcinogenesis. It is believed that SSA/Ps develop cancer by an SSA/P-dysplasia-carcinoma sequence. Hyperplastic polyps (HPs) share some histologic and molecular characteristics with SSA/P, but it is unclear whether SSA/Ps are derived from HPs or whether they develop by a different pathogenetic pathway. Previous studies have shown that serrated polyps from Korean patients show different prevalence rates of certain molecular abnormalities compared with similar lesions from American patients, and this suggests that lifestyle and dietary factors may influence the serrated neoplasia pathway. The purpose of this study was to evaluate the molecular features of HPs and SSA/Ps, the latter both with and without dysplasia, from Korean patients and to compare the findings with similar lesions from American patients. One hundred and eleven serrated polyps, consisting of 45 HPs (30 microvesicular, 11 goblet cell, 4 mucin depleted) and 56 SSA/Ps (36 with dysplasia, 20 without dysplasia), were retrieved from the pathology files of a large medical center in Korea and 38 SSA/P from American patients were evaluated for BRAF and KRAS mutations, microsatellite instability, and hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT), hMLH1, adenomatous polyposis coli (APC), p16, methylated in tumor-1 (MINT-1), MINT2, and MINT31. Methylation of hMLH1 was performed using 2 different sets of primers. Twenty-three conventional adenomas from Korean patients were included as controls. The data were compared between polyp subtypes and between polyps in the right versus the left colon. With regard to HP, KRAS mutations were present in 31.1% of polyps and BRAF mutations in 46.7% of polyps. KRAS mutations were significantly more common in goblet cell HP and BRAF in microvesicular HP (MVHP). Methylation of MGMT, hMLH1, APC, p16, MINT1, MINT2, and MINT31 were present in 42.2%, 64.4% (and 24.4%), 37.8%, 60%, 68.9%, 51.1%, and 60% of HPs. CpG island methylator phenotype high was noted in 60% of HPs. Methylation of hMLH1, p16, MINT2, and MINT31 were more frequent in MVHPs compared with other types of HPs. In contrast, SSA/Ps showed KRAS and BRAF mutations in 12.5% and 60.7% of cases, respectively. Methylation of all tumor-related genes, except hMLH1 (23.2% using 1 type of primers) and APC (37.5%), occurred in >50% of lesions, and CpG island methylator phenotype (CIMP) high was noted in 76.8% of cases. None of the molecular findings were significantly more common in SSA/P with, versus those without, dysplasia, but only 2 of the 36 polyps with dysplasia were of the conventional adenomatous type; the remainder (34 of 36) was of the serrated type. Nevertheless, both SSA/P with conventional adenomatous dysplasia showed methylation of MGMT, APC, MINT1, and MINT31 and were CIMP high. BRAF mutations, methylation of most tumor related genes, and CIMP high occurred more frequently in HPs and SSA/Ps in the right colon, com...

A safe use of intermittent hepatic inflow occlusion (IHIO) has been reported for living donor hepatectomy. However, it remains unclear whether the maneuver is safe in steatotic donors. In addition, the respective importance of macrosteatosis (MaS) and microsteatosis (MiS) is an important issue. Thus, we compared MiS and MaS with respect to the tolerance of hepatic ischemia/reperfusion (IR) injury induced by IHIO. One hundred forty-four donors who underwent a right hepatectomy were grouped according to the presence of MaS and MiS: a non-MaS group (n 5 68) versus an MaS group (n 5 76) and a non-MiS group (n 5 51) versus an MiS group (n 5 93). The coefficients of the regression lines between the cumulative IHIO time and the peak postoperative transaminase concentrations were used as surrogate parameters indicating the tolerance of hepatic IR injury. The coefficients were significantly greater for the MaS group versus the non-MaS group (4.12 6 0.59 versus 2.22 6 0.46 for alanine aminotransferase, P 5 0.01). Conversely, the MiS and non-MiS groups were comparable. A subgroup analysis of donors who underwent IHIO for >30 minutes showed that MaS significantly increased the transaminase concentrations, whereas MiS had no impact. Also, IHIO for >30 minutes significantly increased the biliary complication rate for MaS donors (12.1% for 30 minutes versus 32.6% for >30 minutes, P 5 0.04), whereas MiS donors were not affected. In conclusion, the tolerance of hepatic IR injury might differ between MaS livers and MiS livers. It would be rational to assign more clinical importance to MaS versus MiS. We further recommend limiting the cumulative IHIO time to 30 minutes or less for MaS donors undergoing right hepatectomy. Liver Transpl 20:775-783, 2014. V C 2014 AASLD.

Cancer-associated fibroblasts (CAFs) play important roles in cancer progression. Twist1 was recently reported to be a key regulator of CAFs in gastric cancer, but its role in other types of cancer remains unclear, especially for esophageal squamous cell carcinoma (ESCC). We assessed the Twist1 expression on stromal fibroblasts using immunohistochemistry in 169 tissue specimens from ESCC patients, and performed in vitro and in vivo experiments to confirm the role of Twist1 in CAFs of ESCC. And we investigated the biological pathways that are activated in Twist1-high ESCC using The Cancer Genome Atlas (TCGA) data. The expression of Twist1 in stromal fibroblasts was observed in 89.9% of ESCC patients and positively associated with the increased depth of tumor invasion, lymph node metastasis, and advanced clinical stage, and a significant adverse prognostic factor in overall survival. Twist1-expressing stromal fibroblasts also expressed representative CAF markers, and co-localization of Twist1 and CAF markers were confirmed by confocal immunofluorescence imaging. Bioinformatic analysis of mRNA expression data of esophageal cancer from TCGA revealed that gene sets of CAFs were highly enriched in Twist1-high ESCC. Depletion of Twist1 in ex vivo cultured ESCC CAFs induced significant decrease in migration, invasion, colony formation, sphere formation, and contractibility of ESCC cancer cells compared to control CAFs. Furthermore, Twist1-expressing fibroblasts remarkably enhanced the in vivo tumorigenicity of ESCC in a xenograft model. In conclusion, Twist1 could be a novel CAF marker for the prognostic evaluation of ESCC patients as well as a potent therapeutic target for ESCC.

Liver steatosis mostly exists in a mixed form of macrosteatosis (MaS) and microsteatosis (MiS). This coexistence is responsible for previous conflicting results regarding the importance of MiS in liver transplantation. We aimed to evaluate the independent effect of MiS on posttransplant outcomes with the exclusion of the confounding effect of MaS. Seventy-one living donors who had pure MiS (defined as an MiS degree > 5% without MaS) were matched 1:1 with control donors, and 66 recipients who received pure MiS grafts were matched 1:1 with control recipients on the basis of propensity scores. Matched variables included the donor age, remnant liver volume, cold ischemia time, graft-to-recipient weight ratio and Model for End-Stage Liver Disease score. The degree of pure MiS ranged from 5% to 50%. Donors in the control and pure MiS groups were comparable with respect to peak postoperative transaminase concentrations [alanine aminotransferase (ALT): 194 versus 176 IU/L, P 5 0.61] and postoperative complications. Recipients in the control and pure MiS groups were comparable with respect to recipient (P 5 0.15) and graft survival rates (P 5 0.56) as well as peak postoperative transaminase concentrations (ALT: 266 versus 281 IU/L, P 5 0.88), and graft regeneration rates at 2 weeks (61% versus 59%, P 5 0.73). The 2 groups were also comparable with respect to major complications, primary graft dysfunction/nonfunction, intensive care unit/hospital stays, and metabolic diseases. In conclusion, MiS alone does not seem to impair the posttransplant outcomes of living donors and their recipients. The interaction between MiS and MaS, and the effect of a greater degree of MiS are the next important topics to be further evaluated in the mixed steatosis population. Liver

Background/Aim: Epithelioid hemangioendothelioma (EHE) of the liver is an uncommon vascular tumor with variable clinical courses ranging from stable disease to fatal outcome. EHE can mimic epithelioid angiosarcoma, which has a more aggressive behavior, especially in a small biopsy sample. EHEs are known to have the WWTR1-CAMTA1 fusion gene, and nuclear expression of CAMTA1 by immunohistochemistry (IHC) has been reported in about 90% of EHEs in multiple organs. Our study aimed to validate the diagnostic utility of CAMTA1 expression in EHEs, especially in the liver. Patients and Methods: IHC was performed using anti-CAMTA1 antibody in 34 tumors (24 hepatic EHEs and 10 angiosarcomas). In CAMTA1-negative EHEs, TFE3 IHC was performed. Results: Of the 24 hepatic EHEs, 22 (91.6%) showed nuclear staining for CAMTA1. One of two CAMTA1negative cases showed TFE3 positivity. The other case was negative for TFE3. Meanwhile, all 10 angiosarcoma cases had no CAMTA1 expression. Conclusion: CAMTA1 is a highly sensitive and specific marker for diagnosis of hepatic EHE. It is helpful for differentiation of hepatic EHE and angiosarcoma, especially in small biopsy samples.

CD13 may be a marker for onychofibroblasts within nail matrix onychodermis. We demonstrate CD13 expression in the specialized mesenchymes of both nail and hair.

The prognostic role of MYC has been well documented in non-central nervous system diffuse large B-cell lymphoma; however, it remains controversial in central nervous system diffuse large B-cell lymphoma. To investigate the prognostic value of MYC, we analyzed the MYC protein expression by immunohistochemistry, mRNA expression by RNA in situ hybridization, and gene status by fluorescence in situ hybridization in 74 cases of central nervous system diffuse large B-cell lymphoma. Moreover, we examined the correlation between MYC translocation, mRNA expression, and protein expression. The mean percentage of MYC immunopositive cells was 49%. Using a 44% cutoff value, 49 (66%) cases showed MYC protein overexpression. The result of mRNA in situ hybridization using the RNA scope technology was obtained using the H-scoring system; the median value was 34.2. Using the cutoff value of 63.5, 16 (22%) cases showed MYC mRNA overexpression. MYC gene rearrangement was detected in five out of 68 (7%) cases. MYC translocation showed no statistically significant correlation with mRNA expression; however, all MYC translocation-positive cases showed MYC protein overexpression, with a higher mean percentage of MYC protein expression than that of translocation-negative cases (78 vs 48%, P=0.001). The level of MYC mRNA expression was moderately correlated with the level of MYC protein expression (P<0.001). The mean percentage of MYC protein expression in the high MYC mRNA group was higher than that in the low MYC mRNA group (70 vs 47%, P<0.001). A univariate analysis showed that age over 60 years, Eastern Cooperative Oncology Group (ECOG) performance status ≥2 and MYC protein overexpression were significantly associated with an increased risk of death. MYC translocation and MYC mRNA expression had no prognostic significance. On multivariate analysis, MYC protein overexpression and ECOG score retained prognostic significance.

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