Yasuhiro Ushijima

Hepatocellular carcinoma with a pseudocapsule on gadolinium-enhanced MR images: correlation with histopathologic findings.

PURPOSE To evaluate the characteristics of hepatocellular carcinoma (HCC) with a pseudocapsule on dynamic magnetic resonance (MR) images. MATERIALS AND METHODS The institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. Dynamic MR studies of surgically resected 106 HCCs in 93 patients were retrospectively reviewed. A false-positive fibrous capsule (FC) on dynamic MR images was considered to be a pseudocapsule. Pathologic specimens of HCCs with a pseudocapsule were reviewed. The differences in size, tumor grade, the degree of liver fibrosis and background liver diseases, and the incidence of vascular invasion were compared between HCCs with a pseudocapsule on MR images and those with FC at histologic examination by using Student t, Kruskal-Wallis, and chi(2) tests. RESULTS The sensitivity, specificity, and accuracy of dynamic MR in the diagnosis of histologic FC were 94.0% (47 of 50), 73.2% (41 of 56), and 83.0% (88 of 106), respectively. There were 15 (14.2%) HCCs with a pseudocapsule. The pathologic specimens suggested possible causes of the pseudocapsule that included prominent sinusoids (n = 6), peritumoral fibrosis mimicking bridging fibrosis (n = 3), and both (n = 5). In one case, the capsulated HCC was surrounded by a well-differentiated HCC component. The mean size of a HCC with a pseudocapsule tended to be smaller than that with histologic FC, although it was not significant (mean +/- standard deviation: 2.8 cm +/- 1.0 vs 3.5 cm +/- 2.0, P = .09). Liver cirrhosis was less frequent in HCCs with a pseudocapsule than in those with a histologic FC (one of 14 [7.1%] vs 20 of 49 [40.8%], P < .05). The tumor grades were not significantly different, and the incidence of vascular invasion after standardizing the tumor size (<or=4 cm) was similar (five of 14 [35.7%] vs 12 of 37 [32.4%]). CONCLUSION Dynamic MR imaging is accurate in depicting FC in HCCs. HCC with a pseudocapsule at MR possibly consists of peritumoral sinusoids and/or fibrosis. The pseudocapsule may be similar to histologic FC in terms of tumor invasiveness.

Mutator Phenotype of MUTYH-null Mouse Embryonic Stem Cells

To evaluate the antimutagenic role of a mammalian mutY homolog, namely the Mutyh gene, which encodes adenine DNA glycosylase excising adenine misincorporated opposite 8-oxoguanine in the template DNA, we generated MUTYH-null mouse embryonic stem (ES) cells. In the MUTYH-null cells carrying no adenine DNA glycosylase activity, the spontaneous mutation rate increased 2-fold in comparison with wild type cells. The expression of wild type mMUTYH or mutant mMUTYH protein with amino acid substitutions at the proliferating cell nuclear antigen binding motif restored the increased spontaneous mutation rates of the MUTYH-null ES cells to the wild type level. The expression of a mutant mMUTYH protein with an amino acid substitution (G365D) that corresponds to a germ-line mutation (G382D) found in patients with multiple colorectal adenomas could not suppress the elevated spontaneous mutation rate of the MUTYH-null ES cells. Although the recombinant mMUTYH(G365D) purified from Escherichia coli cells had a substantial level of adenine DNA glycosylase activity as did wild type MUTYH, no adenine DNA glycosylase activity was detected in the MUTYH-null ES cells expressing the mMUTYH(G365D) mutant protein. The germ-line mutation (G382D) of the human MUTYH gene is therefore likely to be responsible for the occurrence of a mutator phenotype in these patients.

Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: A retrospective review

Objectives:To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy. Background:The most appropriate resection line for MD-IPMNs remains an unresolved issue. Methods:Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas. Results:Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD-IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs. Conclusions:One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs.

High-risk stigmata of the 2012 international consensus guidelines correlate with the malignant grade of branch duct intraductal papillary mucinous neoplasms of the pancreas

Objectives The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, “high-risk stigmata” and “worrisome features,” and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs. Methods The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated. Results The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs. Conclusions The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy.

Hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase of gadoxetic acid-enhanced MRI in patients with chronic liver disease: Prediction of malignant transformation

PURPOSE To investigate the predictive factors of malignant transformation of hypovascular hepatic nodule showing hypointensity in the hepatobiliary phase images of gadoxetic acid-enhanced MRI (HHN). MATERIALS AND METHODS The clinical data and imaging findings of dynamic contrast-enhanced computed tomography (DCE-CT) and gadoxetic acid-enhanced MRI for a total of 103 HHNs in 24 patients with chronic liver disease were retrospectively investigated. After the results of follow-up examinations were investigated, HHNs were categorized into the three groups for each comparison: (1) nodules with enlargement and/or vascularization and others, (2) nodules with only enlargement and others, (3) nodules with only vascularization and others. Enlargement and/or vascularization during the follow-up period were defined as malignant transformation of HHN. The frequency of each clinical datum and imaging finding in each group was compared to identify the predictive factors for malignant transformation in HHN. RESULTS Multivariate analysis showed that a nodule size of 9 mm or more on the initial gadoxetic acid-enhanced MRI was a significant predictive factor for the enlargement and/or vascularization of HHN (P<0.05). On the other hand, the hypoattenuation on the delayed phase imaging of the initial DCE-CT was a significant predictive factor for the enlargement or vascularization of HHN (P<0.05). CONCLUSION A nodule size of 9 mm or more on the initial gadoxetic acid-enhanced MRI and hypoattenuation on the delayed phase imaging of initial DCE-CT would be helpful for predicting the outcome of HHN in patients with a risk of hepatocellular carcinoma.

Detection of hepatocellular carcinoma (HCC) using super paramagnetic iron oxide (SPIO)-enhanced MRI: Added value of diffusion-weighted imaging (DWI)

To evaluate whether diffusion‐weighted imaging (DWI) improves the detection of hepatocellular carcinoma (HCC) on super paramagnetic iron oxide (SPIO)‐enhanced MRI.

A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA

2-Hydroxy-2-deoxyadenosine triphosphate (2-OH-dATP), generated by the oxidation of dATP, can be misincorporated by DNA polymerases opposite guanine in template DNA during DNA replication, thus causing spontaneous mutagenesis. We demonstrated that mouse MUTYH (mMUTYH) has a DNA glycosylase activity excising not only adenine opposite 8-oxoguanine (8-oxoG) but also 2-hydroxyadenine (2-OH-A) opposite guanine, using purified recombinant thioredoxin-mMUTYH fusion protein. mMUTYH formed a stable complex with duplex oligonucleotides containing an adenine:8-oxoG pair, but the binding of mMUTYH to oligonucleotides containing a 2-OH-A:guanine pair was barely detectable, thus suggesting that mMUTYH recognizes and interacts with these two substrates in a different manner which may reflect the difference in the base excision repair process for each substrate. Mutant mMUTYH with G365D amino acid substitution, corresponding to a G382D germline mutation of human MUTYH found in familial adenomatous polyposis patients, almost completely retained its DNA glycosylase activity excising adenine opposite 8-oxoG; however, it possessed 1.5% of the wild-type activity excising 2-OH-A opposite guanine. Our results imply that the reduced repair capacity of the mutant hMUTYH(G382D), which inefficiently excises 2-OH-A opposite guanine, results in an increased occurrence of somatic G:C to T:A transversion mutations in the APC gene as well as tumorigenesis in the colon.

Imaging of cholangiolocellular carcinoma of the liver

AIM Cholangiolocellular carcinoma (CoCC) is currently considered to originate from hepatic progenitor cells. The purpose of this study was to evaluate the imaging features of cholangiolocellular carcinoma of the liver. MATERIALS AND METHODS Five cases of surgically resected cases of CoCC from 4 institutions were retrospectively evaluated. All of the five patients underwent contrast-enhanced dynamic CT. MRI and angio-CT including CT during arterioportography (CTAP) and CT during hepatic arteriography were performed in 3 and 2 patients, respectively. Histological evaluation was also performed and was correlated with radiographic findings. RESULTS On dynamic CT or MRI, the lesions presented hypervascular tumors with delayed washout in 2 cases and in the other 3 cases, the lesions showed peripheral enhancement with concentric delayed filling. On CTAP, the continued existence of portal veins or tiny spots of portal flow was identified in the tumors. Fibrous capsule or tumor necrosis was not observed. CONCLUSION CoCC tumors have the dual imaging characteristics of hepatocellular carcinoma and cholangiocarcinoma. The absence of a fibrous capsule, the absence of tumor necrosis, peripheral location within the liver, and the presence of portal venous penetration within the tumor also appear to be characteristic features.

Noninvasive estimation of hepatic steatosis using plain CT vs. Chemical-shift MR imaging: Significance for living donors

To compare plain computed tomography (CT) and chemical‐shift MR imaging (CSI) for establishing a noninvasive method to estimate the degree of steatosis.

Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis.

The present study was undertaken to elucidate germ line mutations of the base excision repair gene, MUTYH, in Japanese patients with adenomatous polyposis. We screened germ line mutations of adenomatous polyposis coli (APC) gene and MUTYH in 66 Japanese patients with adenomatous polyposis. APC was screened by the protein truncation test, while MUTYH was screened by polymerase chain reaction‐based single‐strand conformation polymorphism and direct sequencing. The nicking assay was applied in order to evaluate the DNA glycosylase activity of the identified MUTYH variant. In this study, Seven MUTYH variants were identified in 16 of 21 APC‐negative patients. Q324H mutation was the most frequent mutation, with an allele frequency of 49%. Two patients carried biallelic mutations other than Q324H; a patient had biallelic G272E and A359V mutations, while the other had compound heterozygotes of P18L and G25D mutations. Nicking assay for G272E using the corresponding mouse MUTYH mutant with G257E revealed that G272E is a variant to cause an impaired DNA glycosylase activity. Homozygous MUTYH mutation accounts for approximately 10% of Japanese patients with adenomatous polyposis. G272E may be one of the mutations specific to patients with adenomatous polyposis in East Asia.