[Rectal tumor differentiating into neuroendocrine lineage:a case report].

A 79-year-old woman underwent colonoscopy that revealed a 30-mm-sized nodular, mixed-type, lateral spreading tumor-granular in the lower rectum. Endoscopic submucosal dissection was performed, and the pathological findings indicated a mostly adenoma-type tumor with synaptophysin, cluster of differentiation 56-positive, and chromogranin A-negative associated with neuroendocrine carcinoma. Surgical resection was performed owing to vascular invasion, and the lymph node metastasis of the endocrine carcinoma component was observed. Thus, we reported a rare case of the coexistence of adenoma and neuroendocrine carcinoma.

Usefulness of the G8 Geriatric Assessment Tool as a Prognostic Factor in Gemcitabine Plus Nab-paclitaxel Combination Therapy for Elderly Patients with Pancreatic Cancer.

Introduction: The usefulness of various prognostic factors for advanced pancreatic cancer (APC) has been reported, but the number of elderly patients in these studies is disproportionately fewer than those in general practice. This study aimed to examine the prognostic factors for elderly patients with APC receiving gemcitabine plus nab-paclitaxel (GnP) considering the G8 geriatric assessment tool. Methods: We retrospectively analyzed 77 elderly (≥65 years old) patients with APC who received GnP as first-line chemotherapy at our hospital. We used the receiver operating characteristic curve to set the optimal cutoff value for G8. Univariate and multivariate Cox regression models were applied to study independent prognostic factors. Results: The progression-free survival was 5.5 months, and the overall survival (OS) was 12.0 months in all patients. The most optimal cutoff of G8 was 10.5. OS of G8 ≥10.5 patients was superior to that of G8 <10.5 patients (18.5 versus 8.0 months). Multivariate analysis showed that Eastern Cooperative Oncology Group performance status 1 (hazard ratio [HR] 3.00, p = 0.02), neutrophil-lymphocyte ratio ≥3.9 (HR 2.73, p = 0.03), and G8 geriatric assessment <10.5 (HR 5.38, p < 0.001) were independent negative prognostic factors. Conclusions: G8 is useful for predicting prognoses in elderly patients with APC receiving GnP.

Analysis of direct-acting antiviral-resistant hepatitis C virus haplotype diversity by single-molecule and long-read sequencing.

The method of analyzing individual resistant hepatitis C virus (HCV) by a combination of haplotyping and resistance-associated substitution (RAS) has not been fully elucidated because conventional sequencing has only yielded short and fragmented viral genomes. We performed haplotype analysis of HCV mutations in 12 asunaprevir/daclatasvir treatment-failure cases using the Oxford Nanopore sequencer. This enabled single-molecule long-read sequencing using rolling circle amplification (RCA) for correction of the sequencing error. RCA of the circularized reverse-transcription polymerase chain reaction products successfully produced DNA longer than 30 kilobase pairs (kb) containing multiple tandem repeats of a target 3 kb HCV genome. The long-read sequencing of these RCA products could determine the original sequence of the target single molecule as the consensus nucleotide sequence of the tandem repeats and revealed the presence of multiple viral haplotypes with the combination of various mutations in each host. In addition to already known signature RASs, such as NS3-D168 and NS5A-L31/Y93, there were various RASs specific to a different haplotype after treatment failure. The distribution of viral haplotype changed over time; some haplotypes disappeared without acquiring resistant mutations, and other haplotypes, which were not observed before treatment, appeared after treatment. Conclusion: The combination of various mutations other than the known signature RAS was suggested to influence the kinetics of individual HCV quasispecies in the direct-acting antiviral treatment. HCV haplotype dynamic analysis will provide novel information on the role of HCV diversity within the host, which will be useful for elucidating the pathological mechanism of HCV-related diseases.

Spontaneous portosystemic shunt diameter predicts liver function after balloon-occluded retrograde transvenous obliteration.

BACKGROUND AND AIM: Recently, balloon-occluded retrograde transvenous obliteration (BRTO), performed for spontaneous portosystemic shunts (SPSS), has been receiving attention as a measure to improve liver function in cirrhotic patients with portal hypertension. However, it is unclear whether SPSS diameter is associated with changes in hepatic venous pressure gradient (HVPG) and liver function after BRTO. METHODS: In 34 cirrhotic patients receiving BRTO for hepatic encephalopathy/gastric varices, the association of SPSS diameter with liver function at baseline and 6 months after BRTO and the accompanying changes in HVPG were investigated. RESULTS: Patients had Child-Pugh (CP) scores of A/B/C (7/19/8), SPSS diameters of ≤10 mm/11-20 mm/<20 mm (8/21/5), and an average observation period of 3.2 (0.3-8.5) years. SPSS diameter was significantly associated with male sex, alcohol use, and values of albumin, prothrombin time (PT%), and NH3 at baseline. Moreover, the SPSS diameter was significantly correlated with the changes in HVPG observed upon BRTO (r = 0.55, P = 0.005), and a large shunt diameter was significantly associated with a greater increase in HVPG. At 6 months, significant improvements in albumin, PT%, bilirubin, and NH3 were observed overall, but the improvement was marked in those with larger shunt diameters if they had CP A/B. CONCLUSION: SPSS diameter was strongly associated with liver function at baseline and after BRTO and also with changes in HVPG, indicating that SPSS diameter is an important predictor of BRTO outcome.

Usefulness of Cell-Free Human Telomerase Reverse Transcriptase Mutant DNA Quantification in Blood for Predicting Hepatocellular Carcinoma Treatment Efficacy.

Although the usefulness of liquid biopsy as a biomarker in the treatment of hepatocellular carcinoma (HCC) has been suggested, its usefulness in transcatheter arterial chemoembolization (TACE) or tyrosine kinase inhibitor (TKI) therapies has not been reported in detail. In this study, we investigated the clinical value of a cell-free (cf)DNA quantification system targeting the human telomerase reverse transcriptase (hTERT) promoter mutation in advanced HCC treatment. Plasma from 67 patients with advanced HCC, treated with TACE and TKI, was used for extraction of cfDNA. We defined cfDNA with the hTERT promoter C228T mutation as circulating mutant DNA (mutant DNA) and without the mutation as circulating wild-type DNA (wild-type DNA). We analyzed the changes in mutant and wild-type DNA levels during HCC treatment and examined the relationship between changes in the cfDNA level and the clinical course. Mutant DNA was detected in 73.1% (49/67) of the patients during HCC treatment. In univariate analysis, factors associated with detection of mutant DNA before treatment were the intrahepatic maximum tumor diameter (P = 0.015) and protein induced by vitamin K absence (PIVKAII) (P = 0.006). The degree of mutant DNA change after TACE was significantly correlated with tumor volume (P < 0.001), reflecting the treated tumor volume. Responders with peak cfDNA levels within 1 week of TKI initiation had significantly better progression-free survival than nonresponders (P = 0.004). Conclusion: Changes in blood hTERT promoter mutant DNA levels during TACE or TKI treatment indirectly reflect the amount of HCCs and are useful for predicting long-term treatment responses.

Asymptomatic Common Bile Duct Stones Are Associated with Increased Risk of Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis.

Introduction: Common bile duct stones (CBDS) are a common disease that can cause biliary complications, including cholangitis, obstructive jaundice, and biliary pancreatitis. Regardless of the presence or absence of symptoms, endoscopic removal of CBDS is generally recommended, but endoscopic retrograde cholangiopancreatography (ERCP) is a high-risk procedure with complications, such as post-ERCP pancreatitis (PEP). As few reports have addressed the risk of PEP by focusing on asymptomatic CBDS, the purpose of this study is to examine the incidence of PEP for asymptomatic CBDS. Methods: This retrospective study included data from 302 patients with naive papilla who underwent therapeutic ERCP for CBDS between January 2012 and December 2019 at our hospital. Univariate and multivariate logistic regression models were used to investigate independent risk factors for PEP. Results: Of the 302 patients, 32 were asymptomatic, and the remaining 270 were symptomatic. Five asymptomatic patients (15.6%) suffered from mild PEP, whereas 10 (3.7%) symptomatic patients suffered from PEP (9 were mild, and 1 was severe). Univariate analysis identified deep cannulation time more than 10 min, endoscopic papillary balloon dilation (EPBD), and asymptomatic CBDS as risk factors for PEP, whereas multivariate analysis revealed deep cannulation time more than 10 min (odds ratio (OR), 6.67; p < 0.001), EPBD (HR, 5.70; p < 0.001), and asymptomatic CBDS (HR, 5.49; p < 0.001) as independent risk factors for PEP. Conclusions: A wait-and-see approach may be an option for the management of asymptomatic CBDS. EPBD may be avoided, especially in case of asymptomatic or if difficult for bile duct cannulation.

Fracture of a Self-expandable Metallic Stent Inserted for Malignant Gastric Outlet Obstruction.

Duodenal stenting has gradually been established as the first-line treatment for malignant gastric outlet obstruction (GOO). We encountered a case of duodenal stent fracture in a 76-year-old woman with gastric cancer and GOO. She underwent self-expandable metallic stent (SEMS) placement. The SEMS was found to be fractured 4 weeks after its placement. We removed the broken part of the stent and placed a second SEMS. SEMS fracture is a rare and - to the best of our knowledge - unreported complication; hence, clinicians and their patients should be aware of this possibility.

Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy.

AIM: Recently, serum hepatitis B virus (HBV)-RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV-RNA sequence compared with those of HBV-DNA during the emergence of antiviral resistance are yet to be elucidated. METHODS: First, we quantified serum HBV-RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV-RNA/HBV-DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. RESULTS: Serum HBV-RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen-positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core-related antigen was significantly correlated with serum HBV-RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV-RNA immediately before the breakthrough. However, NA-resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA-resistant HBV-RNA sequence rate was correlated with the peak HBV-DNA titer multiplied by the HBV-DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV-DNA following the addition of new NA. CONCLUSION: Serum HBV-RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core-related antigen. The dynamics of HBV-RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver.

Utility of the simplified measurements of muscle mass in patients with gastrointestinal and chronic liver diseases.

Sarcopenia is an important prognostic factor in patients with gastrointestinal and chronic liver diseases. Computed tomography and bioelectrical impedance analysis are the gold standards for measuring skeletal muscle mass for the diagnosis of decreased muscle mass, but there are some institutions where BIA and CT cannot be carried out. We evaluated the utility of simplified methods for measuring muscle mass; the psoas muscle mass index (PMI) method, simple PMI method, and arm muscle area (AMA) method. This retrospective study included 331 patients with gastrointestinal diseases and 81 patients with chronic liver diseases who were admitted from June 2018 to December 2019 at Municipal Hospital of Kofu. The skeletal muscle mass was measured using the PMI via the volume analyzer SYNAPSE VINCENT ver3.0, simple PMI based on CT imaging, and AMA method. Positive correlations were found between muscle mass measured by PMI and simple PMI, PMI and AMA, and simple PMI and AMA in patients with gastrointestinal diseases (correlation coefficients = 0.76, 0.57, 0.47, respectively, p < 0.001). Positive correlations were observed between muscle mass measured by PMI and simple PMI, PMI and AMA, and simple PMI and AMA in chronic liver diseases (correlation coefficients = 0.77, 0.53, 0.45, respectively, p < 0.001). Measurement of muscle mass by the AMA method showed some correlation with the PMI method. Measurement of muscle mass by the simple PMI method showed correlation with the PMI method. These simplified methods can be alternative methods of evaluating muscle mass in patients with gastrointestinal and chronic liver disease.

Relationship between presarcopenia and event occurrence in patients with primary hepatocellular carcinoma.

Presarcopenia is a prognostic factor in patients with hepatocellular carcinoma (HCC). The Japan integrated staging (JIS) score is a prognostic method that combines the Child-Turcotte-Pugh classification and the tumor-node-metastasis (TNM) staging for HCC. We investigated the relationship between presarcopenia, the JIS score, and prognosis in patients with primary HCC. This retrospective study included 153 patients with primary HCC who were hospitalized from October 2011 to March 2018 at Municipal Hospital of Kofu. The skeletal muscle mass was measured using simplified psoas muscle mass index (PMI) based on CT imaging, and PMI using the volume analyzer SYNAPSE VINCENT ver3.0. We diagnosed presarcopenia based on the cut off value according to the assessment criteria for sarcopenia in liver disease defined by the Japan Society of Hepatology. Forty-three patients (28%) were diagnosed with presarcopenia. The median event-free survival was significantly worse in patients with presarcopenia than those without presarcopenia (P = 0.016). In multivariate analysis, presence of presarcopenia, JIS score ≥3, alpha-fetoprotein ≥200 ng/ml, and prothrombin induced by vitamin K absence-II ≥ 200 mAU/ml were significant prognostic factors. Among the patients with JIS scores ≥3, there was no difference in the event occurrence rate with presence of presarcopenia (P = 0.96). Among the patients with JIS scores ≤2, the median event-free-survival was significantly shorter in those with presarcopenia than those without presarcopenia (P = 0.045). Presarcopenia was an independent prognostic factor in patients with primary HCC. In patients with JIS scores ≤2, the median event-free survival was significantly shorter in those with presarcopenia compared to those without presarcopenia. In the patients with JIS scores ≥3, there was no difference in the event occurrence rates in those with and without presarcopenia.

Cancer-related genetic changes in multistep hepatocarcinogenesis and their correlation with imaging and histological findings.

AIM: The landscape of cancer-related genetic aberrations in hepatocellular carcinoma (HCC) has gradually become clear through recent next-generation sequencing studies. However, it remains unclear how genetic aberrations correlate with imaging and histological findings. METHODS: Using 117 formalin-fixed paraffin-embedded specimens of primary liver tumors, we undertook targeted next-generation sequencing of 50 cancer-related genes and digital polymerase chain reaction of hTERT. After classifying tumors into several imaging groups by hierarchal clustering with the information from gadoxetic acid enhanced magnetic resonance imaging, contrast-enhanced computed tomography, contrast-enhanced ultrasound, and diffusion-weighted imaging magnetic resonance imaging, the correlation between genetic aberrations and imaging and histology were investigated. RESULTS: Most frequent mutations were hTERT (61.5%), followed by TP53 (42.7%), RB1 (24.8%), and CTNNB1 (18.8%). Liver tumors were classified into six imaging groups/grades, and the prevalence of hTERT mutations tended to increase with the advancement of imaging/histological grades (P = 0.026 and 0.13, respectively), whereas no such tendency was evident for TP53 mutation (P = 0.78 and 1.00, respectively). Focusing on the mutations in each tumor, although the variant frequency (VF) of hTERT did not change (P = 0.36 and 0.14, respectively) in association with imaging/histological grades, TP53 VF increased significantly (P = 0.004 and <0.001, respectively). In multivariate analysis, stage III or IV (hazard ratio, 3.64; P = 0.003), TP53 VF ≥ 50% (hazard ratio, 3.79; P = 0.020) was extracted as an independent risk for recurrence in primary HCC patients. CONCLUSIONS: Increased prevalence of hTERT mutation and increased TP53 mutation VF are characteristic features of HCC progression, diagnosed with imaging/histological studies.

Extravasation and fluid collection on computed tomography imaging in patients with colonic diverticular bleeding.

OBJECTIVE: We evaluated the characteristics of patients with diverticular bleeding in whom emergency endoscopy should be proactively performed and those in whom it is unnecessary for spontaneous hemostasis following conservative treatment. METHODS: This study involved 132 patients in whom diverticular bleeding was diagnosed on lower gastrointestinal endoscopy. We evaluated the rate of identification of the bleeding diverticulum during endoscopy and the rate of spontaneous hemostasis following conservative treatment. RESULTS: In 26 patients (20%), bleeding diverticulum was identified during endoscopy. Extravasation or fluid collection on CT imaging was an important factor of successful identification of the bleeding source on endoscopy. Of the 104 patients in the conservative treatment group, 91 (87%) were able to be discharged after spontaneous hemostasis. Univariate analysis revealed a high rate of spontaneous hemostasis in patients without extravasation and fluid collection on CT imaging, those without adhesion of blood during endoscopy, those without diabetes, and those with a hemoglobin level ≥10 g/dL. CONCLUSION: In patients with colonic diverticular bleeding, extravasation or fluid collection on CT is an important factor related to the identification of the bleeding diverticulum. Patients without characteristic CT findings had a high rate of spontaneous hemostasis after conservative treatment. BACKGROUND: Diverticular bleeding is the most frequent cause of lower gastrointestinal bleeding accounting for 20%-40% of all cases in Japan and 20%-48% of all those in the Western countries[1, 2]. The prevalence of colonic diverticula tends to increase with age; thus, the overall prevalence of diverticular bleeding is expected to increase in the future. In Japan, the Japanese Gastroenterological Association published guidelines on colonic diverticulitis in 2017; these guidelines recommend the performance of lower gastrointestinal endoscopic examination within 24 h in patients with lower gastrointestinal bleeding suspected to be diverticular bleeding[3]. It has been reported that, for patients with lower gastrointestinal bleeding, urgent endoscopy helps avoid embolotherapy, colectomy, massive blood transfusion, and repeat bleeding[1, 4, 5]. However, it is often difficult to identify the bleeding point [6]; further, there are many challenging cases wherein it is difficult to decide whether urgent endoscopy should be performed in situations where there is insufficient medical staff, such as during nighttime and on holidays. Bleeding is reported to stop spontaneously with conservative treatment alone in 70% of diverticular bleeding cases[7, 8]. In particular, when determining the treatment policy for diverticular bleeding and in the case of patients at high risk of complications following endoscopy, such as older patients, those with poor performance status or cardiovascular disease, and those in whom spontaneous hemostasis can be expected, urgent endoscopy should be avoided, and elective endoscopy should be selected. Therefore, the type of cases wherein urgent endoscopy is effective and the type wherein it is unnecessary need to be clarified. Thus far, there have been very few reports of the characteristics of patients with diverticular bleeding in whom spontaneous hemostasis was achieved. We aimed to assess the characteristics of patients in whom emergency endoscopy should be proactively performed and those for whom it is unnecessary. Thus, we retrospectively analyzed the identification rate for the responsible diverticulum in patients with diverticular bleeding and the rate of spontaneous hemostasis following conservative treatment.

Utility of Prognostic Prediction Models in the Terminal Stage of Gastrointestinal Cancer.

PURPOSE: For patients receiving palliative care, information about prognosis is important to help them set priorities and expectations for care and to assist clinicians in decision-making. The purpose of this study was to investigate prognostic models applicable to the terminal stage of gastrointestinal cancer, especially in terms of accuracy of prediction regarding 3-week survival. METHODS: We validated retrospectively the accuracy of a prognosis prediction model for 354 end-stage gastrointestinal cancer patients who underwent palliative care at our hospital. Using receiver operating characteristic analysis and the area under the curve (AUC), we selected the cut-off value for 3-week survival and evaluated the predictive ability using sensitivity, specificity, positive predictive value, negative predictive value, and accurate diagnosis rate. RESULTS: In our analysis of various models, Palliative Prognostic Index (PPI) and Biological Prognostic Score (BPS) version 3 showed excellent predictive performance with AUCs of 0.85 and 0.83, respectively, and accurate diagnosis rates of 80.0 and 79.0, respectively. BPS version 2 showed fair predictive performance with an AUC of 0.76 and an accurate diagnosis rate of 72.0. Using these models, stratification of prognostic prediction was possible. CONCLUSIONS: PPI and BPS were found to be accurate prediction models for short-term survival of terminal gastrointestinal cancer patients.

Late evening snacks with branched-chain amino acids improve the Fischer ratio with patients liver cirrhosis at fasting in the next morning.

BACKGROUND & AIMS: A late evening snack (LES) is recommended as a nutritional therapy for liver cirrhosis to minimize early starvation. In patients with liver cirrhosis, the maintenance of the branched-chain amino acid (BCAA) levels is important during muscle synthesis at night. Therefore, we investigated the effects of a LES with BCAAs on the Fischer ratio in patients with liver cirrhosis. METHODS: This study included 10 outpatients with liver cirrhosis who did not consume a LES. Regarding the patient characteristics, the mean age was 73.1 ± 8.9 years, the male:female ratio was 5:5, and the mean body mass index was 23.3 ± 2.4 kg/m2. The etiology was hepatitis C virus in eight patients and alcoholism in two patients. Amino acid levels were measured in all 10 patients at four time points: before LES (control) and 1 month after the administration of each BCAA. The administration levels included 1) LES: BCAA-enriched enteral nutrition (BCAA-EN) containing BCAAs 6.1 g as a LES; 2) GP-no LES: BCAA-enriched granule product (BCAA-GP) containing 4 g BCAAs per pack, two packs per day, and BCAA-EN until dinner containing BCAAs in total 14.1 g per day; and 3) GP-LES: BCAA-GP, two packs per day, and BCAA-EN as a LES containing BCAAs in total 14.1 g per day. The Friedman nonparametric test with a post-hoc Dunn's multiple comparison was used for statistical analyses. RESULTS: There were no significant changes in body weight and serum albumin levels between the three types of BCAA administration. Valine significantly increased following LES and GP-LES, isoleucine significantly increased following GP-LES, and tyrosine significantly decreased following LES and GP-LES compared with those in the control. There was no significant difference in the leucine and phenylalanine levels among the groups. The Fischer ratio in the LES (2.2 ± 0.8) and GP-LES (2.3 ± 0.8) groups were significantly higher than that in the control (1.8 ± 0.6), but there was no significant difference compared with the Fischer ratio in the GP-no LES (1.8 ± 0.7) group. Furthermore, the Fischer ratio was significantly higher in the GP-LES group than in the GP-no LES group. CONCLUSION: These results suggested that it is not only the amount of BCAAs, but also LES with BCAAs, which is needed to improve the Fischer ratio at fasting.

HBV preS deletion mapping using deep sequencing demonstrates a unique association with viral markers.

AIM: Deletions are observed frequently in the preS1/S2 region of hepatitis B virus (HBV) genome, in association with liver disease advancement. However, the most significant preS1/S2 region and its influences on viral markers are unclear. METHODS: The preS1/S2 HBV regions of 90 patients without antiviral therapy were subjected to deep sequencing and deleted regions influencing viral markers were investigated. RESULTS: From the deletion frequency analysis in each patient, deletions were observed most frequently in the preS2 codon 132-141 region. When the patients were divided into three groups (0-0.1%: n = 27, 0.1%-10%: n = 34, 10-100%: n = 29), based on the deletion frequency, FIB-4 (p < 0.01), HBV DNA (p < 0.01), HBcrAg (p < 0.01) and preS1/S2 start codon mutations (p < 0.01, both) were significantly associated with the deletion. When clinical and viral markers were investigated by multivariate analysis for their association with the deletion, FIB-4 (p < 0.05), HBcrAg (p < 0.05), and preS1 start codon mutation (p < 0.01) were extracted as independent variables. When the influence of the preS codon 132-141deletions on HBsAg and HBcrAg, relative to HBV DNA, was investigated, the HBsAg/HBV DNA ratio was lower (0-10% vs. 10%-100%, p<0.05), while the HBcrAg/HBV DNA rati o was higher (0-0.1% vs. 10%-100%, p<0.05) in the presence of the preS codon 132-141deletions. CONCLUSION: The preS codon.132-141 deletions have a significant influence on the clinical characteristics and viral markers, even when present as a minor population. Importantly, the preS codon 132-141 deletions have a clear influence on the viral life cycle and pathogenesis.

Hepatitis B virus (HBV)-infected patients with low hepatitis B surface antigen and high hepatitis B core-related antigen titers have a high risk of HBV-related hepatocellular carcinoma.

AIM: Although the viral markers hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HbcrAg) could reflect intrahepatic hepatitis B virus (HBV) replication activity and constitute important biomarkers for hepatocellular carcinoma (HCC), the value of using these two markers in combination for assessing HCC risk has not been clarified in detail. METHODS: Four hundred and forty-nine consecutive patients with chronic HBV infection were included in the study and the association of HBsAg and HBcrAg with HCC risk was investigated cross-sectionally, as well as longitudinally. RESULTS: When the high value cut-offs of HBsAg and HBcrAg were defined as 3.0 log IU/mL and 3.0 log U/mL, respectively, patients with a history of HCC were found frequently in the low HBsAg group (P = 0.002) and high HBcrAg group (P < 0.001). When HBsAg and HBcrAg were combined, an HCC history was most frequent in the subset with low HBsAg and high HBcrAg, among the HBeAg-negative patients (odds ratio [OR], 7.83; P < 0.001), irrespective of nucleos(t) ide analogue (NA) therapy (NA: OR, 4.76; P < 0.001; non-NA: OR, 9.60; P < 0.001). In a longitudinal analysis of the subsequent development of HCC, carried out on the 338 patients without an HCC history at enrollment, HCC developed significantly more frequently in the low HBsAg/high HBcrAg group (P = 0.005). CONCLUSIONS: Patients with low HBsAg/high HBcrAg values are at high risk of developing HBV-related HCC, according to this cross-sectional and longitudinal analysis, indicating that the combination of HBsAg and HBcrAg values is an excellent biomarker for assessing HCC risk.

Association between alanine aminotransferase elevation and UGT1A1*6 polymorphisms in daclatasvir and asunaprevir combination therapy for chronic hepatitis C.

BACKGROUND: Liver damage presented as alanine aminotransferase (ALT) elevation and high ALT-caused treatment discontinuation occurs with high frequency in Japanese patients receiving daclatasvir plus asunaprevir (DCV/ASV) therapy for hepatitis C virus (HCV) infection, and its mechanism is unknown. METHODS: A total of 247 Japanese patients consisting of two independent cohorts with genotype-1b HCV infection receiving DCV/ASV therapy were included. The association of ALT levels during therapy and single nucleotide polymorphisms (SNP) of five drug-metabolizing enzyme loci selected for their possible influence on NS3/4A and NS5A inhibitors was investigated. RESULTS: Among five SNPs, we found a significant correlation between the presence of the UGT1A1 rs4148323 A allele and ALT elevation (Grade 3 elevation in AA 57%, AG 18%, and GG 4%, P = 8.4E - 06) and drug discontinuation (AA 22%, AG 11%, and GG 2.5%, P = 8.7E - 04), while no association was observed with ALT values at baseline (Grade 3 elevation AA 0%, AG 4%, and GG 2%, P = 0.5). In contrast, patients with risk A allele for drug-induced ALT elevation had a tendency to respond more favorably to treatment (AA 100%, AG 93%, and GG 90%, P = 0.29). CONCLUSIONS: Through the analysis we suggest that the A allele in UGT1A1 rs4148323 (UGT1A1*6), which is highly prevalent in the Japanese population, should be considered a risk for the development of DCV/ASV therapy-induced ALT elevation. Pretreatment SNP testing of UGT1A1*6 might be beneficial for the prediction of liver damage induced by DCV/ASV or even by DCV/ASV plus beclabuvir.

Performance status and neutrophil-lymphocyte ratio are important prognostic factors in elderly patients with unresectable pancreatic cancer.

BACKGROUND: The usefulness of various prognostic factors for pancreatic cancer (PC) has been reported, but the number of elderly patients in these studies is disproportionately fewer compared with those in everyday practice. The purpose of this study was to investigate the prognostic factors for unresectable PC in elderly patients. METHODS: We retrospectively analyzed 67 elderly (age ≥75 years) patients with unresectable PC who underwent chemotherapy between January 2006 and December 2014 at our hospital. Univariate and multivariate Cox regression models were applied to investigate independent prognostic factors. RESULTS: Multivariate analysis revealed that an increased neutrophil-lymphocyte ratio (NLR) [hazard ratio (HR) 1.91, P=0.03] and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (HR 2.74, P=0.01) were independent negative prognostic factors. CONCLUSIONS: The two prognostic factors identified herein are useful in the identification of patients with a poor prognosis and subsequent administration of supportive care alone, which may help avoid the unnecessary adverse effects and complications of systemic chemotherapy.

Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma.

Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections (N = 141) and non-B, non-C etiology (N = 30). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs.

Deep sequencing and phylogenetic analysis of variants resistant to interferon-based protease inhibitor therapy in chronic hepatitis induced by genotype 1b hepatitis C virus.

UNLABELLED: Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non-SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy. IMPORTANCE: In the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated.