Background and aims
The recent advancement of next-generation sequencing (NGS) has enabled the identification of cancer-related somatic aberrations in advanced gastric cancer. However, these remain ...unclear in early gastric cancers, especially in intramucosal gastric cancers.
Patients and methods
Thirty-one well-differentiated (tub1) intramucosal gastric cancers obtained by endoscopic submucosal dissection (ESD) from 29 patients were analyzed. After precise collection of tumors and non-tumors from formalin-fixed paraffin-embedded tissues using laser-captured microdissection (LCM), target sequencing analysis of 50 cancer-related genes was performed using an Ion-Proton sequencer.
Results
The most frequent hotspot mutation was found in
TP53
(17 lesions, 54.8%) followed by the
Wnt
-signaling pathway genes,
APC
and
CTNNB1
(6 lesions, 19.4%). The mutations in
TP53
and the
Wnt
-signaling genes were mutually exclusive (
p
= 0.004). There was a tendency that
H. pylori
infection (
p
= 0.082) and macroscopic protrusion (
p
= 0.095) was associated with the presence of these mutations. Only 10 lesions (59%) among 17 lesions with proven
TP53
mutations were positive for p53 immunostaining demonstrating the superiority of the mutational analysis. In addition, focal gene amplification of
ERBB2
(16%) was found frequently in these early stage lesions.
Conclusions
Using LCM and NGS, mutations in
TP53
and the
Wnt-
signaling pathway were frequently found and were mutually exclusive in the earliest stage of gastric carcinogenesis.
Hepatitis C virus (HCV) is a single-stranded RNA virus known for its high genetic variability owing to the lack of a proofreading mechanism of its RNA dependent RNA polymerase. Until now, numerous ...studies have been undertaken to clarify the correlation between pretreatment HCV genetic variability and the therapeutic response. Even with the recent combination therapy of peginterferon plus ribavirin for chronic hepatitis C, viral response is variable, and only half of treated patients could clear the virus sustained viral response (SVR). In this review, the contribution of viral genetic variability affecting the treatment outcome is discussed according to each HCV genomic region.
Objective Owing to advances in direct-acting antiviral (DAA) therapy, a considerable number of patients with hepatitis C virus (HCV)-positive hepatocellular carcinoma (HCC) are now able to achieve a ...sustained viral response (SVR) after curative treatment of HCC. However, the beneficial effect of a DAA-SVR on the survival remains unclear. Methods A total of 205 patients with HCC who were HCV-positive with Child-Pugh A at the onset from 2008 to 2018 were categorized into 2 groups: 140 patients untreated for HCV throughout the entire course after HCC development (untreated group) and 65 patients treated for HCV with DAAs following HCC treatment who achieved an SVR (SVR group). After propensity score matching, 63 patients from each group were selected. Using these patients, the survival and maintenance of Child-Pugh A after HCC treatment were compared between the untreated group and SVR group. Results There was a significant difference in the overall survival (p<0.001) and the rate of maintaining Child-Pugh A (p<0.001) between the groups. The 5-year survival rates were 96% (SVR group) and 60% (untreated group), and the proportions of patients with Child-Pugh A at 5 years after HCC treatment were 96% (SVR group) and 38% (untreated group). Conclusion In patients with HCV-positive HCC, achieving a DAA-SVR after HCC treatment significantly improved the overall survival rate compared with HCV-untreated patients. The contribution of DAA-SVR during the course of HCC treatment to a longer survival is mainly due to the prevention of the progression of Child-Pugh A to B/C. Further research is needed to determine whether aggressive antiviral therapy is also effective for HCC patients with Child-Pugh B/C.
Background
The damping ratio (DR) and the loss modulus (G″) obtained by 3D MR elastography complex modulus analysis has been reported recently to reflect early intrahepatic inflammation, and is ...expected to be a noninvasive biomarker of inflammation in nonalcoholic fatty liver disease (NAFLD). However, the role of the DR and the G″ in Japanese NAFLD patients remains unclear.
Methods
We enrolled 39 Japanese patients with NAFLD who underwent liver biopsy and 3D MR elastography within 1 month and analyzed the association between DR, G″, and histological activity.
Results
Regarding DR, no evident correlation was observed between the DR and histological activity (p = 0.14) when patients with all fibrosis stages were included. However, when patients were restricted up to stage F2 fibrosis, the association of the DR and inflammation became significant, the DR increasing with the degree of activity (p = 0.02). Among the constituents of fibrosis activity, ballooning correlated with the DR (p < 0.01) while lobular inflammation did not. Regarding G″, it was correlated with histological activity (p < 0.01), ballooning (p < 0.01), and lobular inflammation (p < 0.01) in patients with all fibrosis stages and in patients up to F2 fibrosis (p = 0.03 for activity and p = 0.04 for ballooning). The best cutoff value of DR for hepatitis activity in patients within the F2 stage was 0.094 (area under the receiver operating characteristic curve 0.775, 95% CI: 0.529–1.000) and G″ was 0.402 (area under the receiver operating characteristic curve 0.825, 95% CI: 0.628–1.000).
Conclusions
The DR and G″ reflected the histological activity in Japanese patients with NAFLD during the early stage, indicating these values for noninvasive diagnosis of inflammation in Japanese patients with NAFLD.
Background
The present study aimed to determine the ability of diagnosing malignancy and predicting malignant transformation in patients with IPMN using carcinoembryonic antigen (CEA) level in the ...pancreatic juice.
Methods
We enrolled patients with IPMN who underwent endoscopic retrograde pancreatography (ERP) between 2002 and 2018. We examined the ability of diagnosing malignancy in 63 patients who underwent surgery (surgical group). Furthermore, we examined the value of predicting malignant transformation in 52 patients who underwent follow-up for over 1 year after ERP (follow-up group).
Results
In the surgical group, the overall sensitivity and specificity of CEA level (≥ 97 ng/ml) in the pancreatic juice for diagnosing malignancy were 45% and 100%, respectively. The specificity was excellent for all IPMN types; however, the sensitivity was highest in main duct type, followed by mixed type and branch duct type. In the follow-up group, malignant transformation was observed in four patients (7.7%) during the follow-up, and the median time until malignant transformation was 58 months. High CEA level in the pancreatic juice demonstrated a statistically significant difference in multivariate analysis and was found to be an independent predictor of malignant transformation (hazard ratio 17;
P
= 0.02). The cumulative malignant transformation rate was significantly higher in the high CEA group than that in the low CEA group (5-year cumulative malignant transformation rates, 69% vs. 0%,
P
< 0.001).
Conclusions
Carcinoembryonic antigen level in the pancreatic juice is useful not only in diagnosing malignancy but also in predicting future malignant transformations in IPMN patients receiving follow-up.
Falls are caused by a combination of factors, including loss of lower limb muscle strength (LMS), and associated with declined performance status (PS). Age-related sarcopenia is generally associated ...with decreased muscle mass and strength of lower limb muscle but without a noticeable loss of those of upper limb or trunk muscle. However, no reports have focused on falls or LMS in chronic liver disease (CLD) patients. This study is the first to analyze the risk factors for falls in patients with CLD, focusing on LMS measurement using the Locomoscan. This study enrolled 315 CLD patients whose LMS was measured. The patients who experienced falls more than 1 year ago or during the observation period were classified as those who experienced falls. We found that risk factors for falls were PS1/2 and decreased LMS (< 0.32 N/kg). The group with sarcopenia had a higher frequency of decreased LMS (54 vs. 26%, p = 0.001) and falls (24 vs. 4.4%, p < 0.001) compared to the non-sarcopenia group. This study found that decreased LMS was an independent risk factor for falls. Assessment of LMS may be used as a better marker associated with the risk of falls in patients with CLD.
Background and Aims
Genetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC ...development, progression, and survival are unclear.
Methods
We investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology.
Results
We found recurrent mutations in several genes such as telomerase reverse transcriptase (
TERT
; 65 % of the total 104 HCCs),
TP53
(38 %),
CTNNB1
(30 %),
AXIN1
(2 %),
PTEN
(2 %), and
CDKN2A
(2 %).
TERT
promoter mutations were associated with older age (
p
= 0.005), presence of hepatitis C virus (HCV) infection (
p
= 0.003), and absence of hepatitis B virus (HBV) infection (
p
< 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without
TERT
promoter mutations, HBV integration into
TERT
locus was found in 47 % patients and was mutually exclusive to
TERT
promoter mutations. Most (89 %) HBV integrants were in the HBx region.
TP53
mutations were associated with HBV infection (
p
= 0.0001) and absence of HCV infection (
p
= 0.002).
CTNNB1
mutations were associated with absence of HBV infection (
p
= 0.010). Moreover,
TERT
promoter mutation was significantly associated with shorter disease-free survival (
p
= 0.005) and poor overall survival (
p
= 0.024).
Conclusions
Gene alterations in
TERT
promoter,
TP53
,
CTNNB1
, and HBV integration were closely associated with HCC development, and mutations in
TERT
promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC.
To clarify the genetic mutations associated with intraductal papillary mucinous neoplasms (IPMN) and IPMN-related pancreatic tumours, we conducted cancer-related gene profiling analyses using pure ...pancreatic juice and resected pancreatic tissues.
Pure pancreatic juice was collected from 152 patients nine with a normal pancreas, 22 with chronic pancreatitis (CP), 39 with pancreatic ductal adenocarcinoma (PDAC), and 82 with IPMN, and resected tissues from the pancreas were collected from 48 patients (six IPMNs and 42 PDACs). The extracted DNA was amplified by multiplexed polymerase chain reaction (PCR) targeting 46 cancer-related genes containing 739 mutational hotspots. The mutations were analysed using a semiconductor-based DNA sequencer.
Among the 46 cancer-related genes, KRAS and GNAS mutations were most frequently detected in both PDAC and IPMN cases. In pure pancreatic juice, GNAS mutations were detected in 7.7% of PDAC cases and 41.5% of IPMN cases (p<0.001 vs. others). All PDAC cases with GNAS mutations (n = 3) were accompanied by IPMN. Multivariate analysis revealed that GNAS mutations in IPMN cases were associated with dilated main pancreatic ducts (MPD, p = 0.016), while no statistically independent associations with clinical variables were observed for KRAS mutations. In the resected pancreatic tissues, GNAS mutations were detected in 50% of PDAC cases concomitant with IPMN, 33.3% of PDAC cases derived from IPMN, and 66.7% of IPMN cases, while no GNAS mutations were detected in cases of PDAC without IPMN.
The GNAS mutation was specifically found in the cases with IPMN and it was speculated that some PDACs might be influenced by the concomitant but separately-located IPMN in their pathogenic mechanism. Furthermore, the GNAS mutation was significantly associated with MPD dilatation in IPMN cases, suggesting its role in mucus hypersecretion.
Equine hepacivirus (EHcV) has been identified as a closely related homologue of hepatitis C virus (HCV) in the United States, the United Kingdom, and Germany, but not in Asian countries. In this ...study, we genetically and serologically screened 31 serum samples obtained from Japanese-born domestic horses for EHcV infection and subsequently identified 11 PCR-positive and 7 seropositive serum samples. We determined the full sequence of the EHcV genome, including the 3' untranslated region (UTR), which had previously not been completely revealed. The polyprotein of a Japanese EHcV strain showed approximately 95% homology to those of the reported strains. HCV-like cis-acting RNA elements, including the stem-loop structures of the 3' UTR and kissing-loop interaction were deduced from regions around both UTRs of the EHcV genome. A comparison of the EHcV and HCV core proteins revealed that Ile(190) and Phe(191) of the EHcV core protein could be important for cleavage of the core protein by signal peptide peptidase (SPP) and were replaced with Ala and Leu, respectively, which inhibited intramembrane cleavage of the EHcV core protein. The loss-of-function mutant of SPP abrogated intramembrane cleavage of the EHcV core protein and bound EHcV core protein, suggesting that the EHcV core protein may be cleaved by SPP to become a mature form. The wild-type EHcV core protein, but not the SPP-resistant mutant, was localized on lipid droplets and partially on the lipid raft-like membrane in a manner similar to that of the HCV core protein. These results suggest that EHcV may conserve the genetic and biological properties of HCV.
EHcV, which shows the highest amino acid or nucleotide homology to HCV among hepaciviruses, was previously reported to infect horses from Western, but not Asian, countries. We herein report EHcV infection in Japanese-born horses. In this study, HCV-like RNA secondary structures around both UTRs were predicted by determining the whole-genome sequence of EHcV. Our results also suggest that the EHcV core protein is cleaved by SPP to become a mature form and then is localized on lipid droplets and partially on lipid raft-like membranes in a manner similar to that of the HCV core protein. Hence, EHcV was identified as a closely related homologue of HCV based on its genetic structure as well as its biological properties. A clearer understanding of the epidemiology, genetic structure, and infection mechanism of EHcV will assist in elucidating the evolution of hepaciviruses as well as the development of surrogate models for the study of HCV.
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