Search

The presence of esophageal varices (EV) is a phenotype of portal hypertension, and the indications of liver resection for hepatocellular carcinoma (HCC) in patients with concomitant EV are conflicting. This retrospective study aimed to elucidate if there is justification for liver resection in patients with EV. The surgical outcomes were compared between the patients who underwent resection for HCC with EV (EV group) and those without EV (non-EV group) after propensity-score matching. More bleeding was prevalent (P < 0.001) and refractory ascites was more frequently observed (P = 0.031) in the EV group (n = 277) compared with the non-EV group (n = 277); however, the numbers of patients with morbidities (P = 0.740) and re-operation (P = 0.235) were not significantly different between the two groups. After a median follow-up period of 3.0 years, the median overall and recurrencefree survival periods of patients with EV were 4.8 years (95% confidence interval [CI], 4.1-5.9) and 1.7 years (1.5-2.0), respectively, and were significantly shorter than those of patients without EV (7.6 years [95% CI, 6.3.9.7], P < 0.001, and 2.2 years [1.9-2.5], P = 0.016). On multivariate analysis, the independent factors for overall survival in the EV group were indocyanine green clearance rate at 15 minutes, des-gamma carboxyprothrombin, and the presence of multiple tumors. Considering that liver resection for patients with EV can be safely performed, it should not be contraindicated. However, surgical outcomes of these patients were unsatisfactory, suggesting that candidates for resection for HCC should be carefully selected.

A low platelet count, one of parameters of portal hypertension, is clinically a predictor of postoperative mortality, while platelets induce tumor development during growth factor secretion. In this study, we retrospectively investigated whether high platelet count negatively affects the survival of patients with hepatocellular carcinoma (HCC). Patients undergoing initial and curative resection for HCC were included. Surgical outcomes were compared between the high platelet (platelet count ≥ 20 × 104/μL) and control (< 20 × 104/μL) groups in patients without cirrhosis and between the low platelet (< 10 × 104/μL) and control (≥ 10 × 104/μL) groups in patients with cirrhosis. Among patients without cirrhosis, tumor was larger (P < 0.001) and tumor thrombus was more frequent (P < 0.001) in the high-platelet group than in the control group. After a median follow-up period of 3.1 years (range 0.2-16.2), median overall survival was 6.3 years (95% confidence interval [CI], 5.3-7.8) and 7.6 years (6.6-10.9) in the high-platelet (n = 273) and control (n = 562) groups, respectively (P = 0.027). Among patients with cirrhosis, liver function was worse (P < 0.001) and varices were more frequent (P < 0.001) in the low-platelet group. The median overall survival of patients in the low-platelet group (n = 172) was significantly shorter than that of patients in the control group (n = 275) (4.5 years [95% CI, 3.7-6.0] vs. 5.9 years [4.5-7.5], P = 0.038). Taken together, thrombocytopenia indicates poor prognosis in HCC patients with cirrhosis, while thrombocytosis is a poor prognostic predictor for those without cirrhosis.

C-reactive protein (CRP)- and albumin (Alb)-based scoring systems are available for predicting the prognosis of patients with diverse forms of gastrointestinal cancer, but their utility for patients with intrahepatic cholangiocarcinoma (ICC) is still unclear. This study aimed to elucidate whether a high CRP/Alb ratio is associated with the surgical outcome of ICC patients. Patients who underwent initial and curative resection for ICC were included in this study, and were divided into the High and Low CRP/Alb groups based on their preoperative CRP and Alb values. The surgical outcomes were compared between the two groups. The median CRP/Alb ratio amongst 88 patients was 0.033 (range, 0.019-3.636); 44 patients with CRP/Alb > 0.033 were allocated to the High CRP/Alb group and 44 patients were allocated to the Low CRP/Alb group. The operative data did not differ between the two groups, while the tumor status was more advanced in the High CRP/Alb group. The median overall survival was 2.4 years (95% CI, 1.4-3.3) and 8.9 years (3.8-NA) in the High and Low CRP/Alb groups, respectively (P < 0.001), and recurrence-free survival was 0.5 years (95% CI, 0.3-0.7) and 7.7 years (1.3-NA), respectively (P < 0.001). In a multivariate analysis, the independent factors for overall survival were High CRP/Alb (P = 0.017) and multiple nodules (P = 0.008). Taken together, the survival of ICC patients in the High CRP/Alb group was reduced compared to that of patients in the Low CRP/Alb group due to the advanced stage of the tumor as well as malnutrition.

Despite curative resection, hepatocellular carcinoma (HCC) has a high probability of recurrence. We validated the potential role of liver resection (LR) for recurrent HCC. Patients with intrahepatic recurrence with up to three lesions were included. We compared survival times of patients undergoing their first LR to those of patients undergoing repeated LR. Then, survival times of the patients who had undergone LR and transcatheter chemoembolization (TACE) for recurrent HCC after propensity score matching were compared. After a median follow-up period of 3.1 years (range, 0.2–16.3), median overall survival times were 6.5 years (95% CI 6.0–7.0), 5.7 years (5.2–6.2), and 5.1 years (4.9–7.3) for the first LR (n = 1234), second LR (n = 273), and third LR (n = 90) groups, respectively. Severe complications frequently occurred in the first LR group (p = 0.059). Operative times were significantly longer for the third LR group (p = 0.012). After the first recurrence, median survival times after one-to-one pair matching were 5.7 years (95% CI 4.5–6.5) and 3.1 years (2.1–3.8) for the second LR group (n = 146) and TACE group (n = 146), respectively (p

Aim Although radiofrequency ablation (RFA) is an effective local treatment of hepatocellular carcinoma (HCC), local recurrence is relatively frequent. We aimed to elucidate the validity of salvage liver resection for recurrent HCC after RFA. Methods Patients who underwent liver resection for recurrent HCC after RFA (LR after RFA) and those who underwent second liver resection for recurrent HCC (second LR) were included. The short-term outcomes were compared between the two groups. The survival rates between the two groups were compared after propensity-score matching to adjust for the variables, including patient background, liver function, and tumor status. Results Major resection was frequently carried out in the LR after RFA group, but there was no significant difference both in operative data and complication rate between LR after RFA (n = 54) and second LR (n = 266) groups. After a median follow-up period of 1.8 years (range, 0.2-10.5), the median overall survival was 4.4 years (95% confidence interval [CI], 2.2 - not applicable) and 5.6 years (95% CI, 4.5-7.3; P = 0.023) in the LR after RFA group (n = 54) and second LR group (n = 54), respectively, and recurrence-free survival was 1.3 years (0.4-2.2) and 1.2 years (0.5-1.8, P = 0.469), respectively. The only independent factor for overall survival of the LR after RFA group was local recurrence (hazard ratio, 2.73; 1.06-9.00). Conclusions Salvage liver resection of recurrent HCC after RFA could be recommended due to the safety of the procedure, especially in patients without local tumor progression after RFA.

BackgroundSerotonin contributes to liver cancer progression; however, it also plays a pivotal role in liver regeneration after partial resection. This study aims to elucidate whether high serum serotonin is a prognostic factor for patients with hepatocellular carcinoma (HCC).MethodsWe measured the pre-operation serum serotonin level of patients with HCC. Based on the median value of serum serotonin, patients were divided into the high serotonin group and the low serotonin group. The survival rates after operation were compared between the two groups.ResultsThe median serum serotonin level for 176 patients was 90.5 ng/mL (range, 1.0 − 399.5); 88 patients with serum serotonin level ≥ 90.5 were allocated to the high serotonin group and 88 patients to the low serotonin group. Histological findings showed that tumor stage was not different between the two groups. After a median follow-up period of 3.2 years (range, 0.9 − 7.4), median overall survival was 6.6 years (95% confidence interval [CI], 5.7–NA) and 5.7 years (95% CI, 3.5–NA) in the high and the low serotonin groups, respectively (P = 0.042). The median recurrence-free survival of patients in the high serotonin group (2.2 years [95% CI, 1.7–3.2]) tended to be longer than that of patients in the low serotonin group (2.0 years [1.0–2.2]) (P = 0.091). The independent variables for overall survival were the high serum serotonin level (P = 0.049) and des-gamma-carboxy prothrombin level (P = 0.032).ConclusionsHigh serum serotonin could be a favorable prognostic factor for HCC patients undergoing liver resection.Trial registrationThe study was approved (protocol number: 131) by the institutional review boards of Nihon University on December 15 in 2011.

Liver stiffness measurement using magnetic resonance elastography can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection for hepatocellular carcinoma. The aim of this prospective study was to investigate whether preoperative liver stiffness measurement by magnetic resonance elastograhy can predict recurrence after curative resection for hepatocellular carcinoma.Patients who underwent preoperative liver stiffness measurement and curative resection for hepatocellular carcinoma were enrolled in this study. Potential associations between liver stiffness measurement, along with other clinical and pathologic variables, and intrahepatic hepatocellular carcinoma recurrence were analyzed.In total, 156 patients were included in this study. During a median follow-up period of 25.1 months (range, 6.0-60.5 months), 72 (46.1%) patients with hepatocellular carcinoma had an intrahepatic recurrence. The median disease-free period after resection was 17.9 months (range, 1.0-60.5 months). In the multivariate analysis, liver stiffness measurement (hazard ratio, 1.27; 95% confidence interval, 1.11-1.43; P.001) and vascular invasion (hazard ratio, 1.96; 95% confidence interval, 1.15-3.25; P = .013) were identified as independent predictors of recurrence. When the optimal cutoff point was set at 4.53 kPa using the minimal P value approach, the disease-free period after curative resection in 71 patients with a liver stiffness measurement value ≥4.53 kPa (11.3 months [range, 2.0-60.5 months]) was significantly shorter than that of 85 patients with a liver stiffness measurement value4.53 kPa (22.5 months [range, 1.1-60.5 months]; P.001).Liver stiffness measurement using magnetic resonance elastography is a useful preoperative predictor of intrahepatic recurrence after curative resection for hepatocellular carcinoma.

Multiplicity is one of the characteristics of hepatocellular carcinoma (HCC), and patients with multiple HCC (≤ 3 nodules) are recommended as candidates for liver resection. To confirm the validity of resecting multiple HCC, we compared the surgical outcomes in patients with synchronous and metachronous multiple HCC. Patients who underwent resection for multiple HCC (2 or 3 nodules) were classified into the "synchronous multiple HCC" group, while those undergoing resection for solitary HCC and repeated resection for 1 or 2 recurrent nodules within 2 years after initial operation were classified into the "metachronous multiple HCC" group. After one-to-one matching, longer operation time and more bleeding were seen in the synchronous multiple HCC group (n = 98) than those in the metachronous multiple HCC group (n = 98); however, the complication rates were not different between the two groups. The median overall survival times were 4.0 years (95% CI, 3.0-5.9) and 5.9 years (4.0-NA) for the synchronous and metachronous multiple HCC (after second operation) groups, respectively (P = 0.041). The recurrence-free survival times were shorter in the synchronous multiple HCC group than in the metachronous multiple HCC group (median, 1.5 years [95% CI, 0.9-1.8] versus 1.8 years, [1.3-2.2]) (P = 0.039). On multivariate analysis, independent factors for overall survivals in the synchronous multiple HCC group were older age, cirrhosis, larger tumor, and tumor thrombus. Taken together, resection of metachronous multiple HCC still has good therapeutic effect, even better than synchronous multiple HCC, so resection is suggested for metachronous multiple HCC.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

AIM Repeat resection for intrahepatic recurrent hepatocellular carcinoma (HCC) is effective for the long-term survival of patients; however, little is known about the surgical outcomes of extrahepatic nodules. The aim of this study is to investigate whether resection can contribute to the survival of patients with extrahepatic recurrent HCC. METHODS Under the conditions that intrahepatic recurrent HCC was absent or controlled by locoregional therapies, patients who had resectable extrahepatic recurrent HCC in the lymph nodes, adrenal gland, peritoneum, lung, or brain were included in this study. The survival of patients who did (Surgical group) and did not (Non-surgical group, underwent other therapies) undergo resection for extrahepatic recurrent HCC was compared. RESULTS Thirty-eight and 26 patients were included in the Surgical and Non-surgical groups, respectively. No patient had severe postoperative complications. After a median follow-up of 1.2 (range, 0.2-8.8) years, the median cumulative incidence of extrahepatic recurrent HCC was 1.2 years (95% confidence interval [CI], 0.4-3.5) in the Surgical group. The median overall survival was 5.3 (95% CI, 2.5-8.8) and 1.1 (0.8-2.3) years in the Surgical and Non-surgical groups, respectively (P

Aim Diabetes mellitus (DM) is a potential risk factor for hepatocarcinogenesis, especially in patients with hepatitis C virus (HCV) infection. We aimed to elucidate whether DM influences the surgical outcomes of patients with hepatocellular carcinoma (HCC). Methods Our patients were routinely controlled to keep urinary glucose excretion to less than 3.0 g/day before surgery, and the serum glucose level under 200 mg/dL after surgery. The surgical outcomes and postoperative complications of 112 patients with HCV-related HCC with DM (DM group) were compared to those of 112 propensity-matched patients without DM (non-DM group). Results After a median follow-up of 3.2 years (range, 0.2–11.3 years), the median overall (5.2 years; 95% confidence interval, 3.8–6.5 years) and recurrence-free survival (2.2 years; 1.7–2.9 years) in the DM group were not significantly different from those (6.3 years; 5.4–7.1 years, P = 0.337; and 2.2 years; 1.7–3.6 years, P = 0.613) in the non-DM group. The independent factors related to overall survival were the background liver (hazard ratio, 2.06; 95% confidence interval, 1.27–3.39, P = 0.014) and tumor differentiation grade (2.07; 1.14–4.05, P = 0.015). Thirty-two patients (28.5%) in the DM group and 32 patients (28.5%) in the non-DM group had morbidities after operation, with no significant difference between the groups (P = 1.000). Furthermore, postoperative control status of DM did not affect the prognostic outcome. Conclusion Diabetes mellitus does not affect the surgical outcomes of patients with HCV-related HCC, and it is not an unfavorable factor when selecting candidates for liver resection of HCC.

OBJECTIVE Early diagnosis and treatment of cancer may contribute substantially to complete cure, but it remains unknown whether treatment of early hepatocellular carcinoma can actually result in cure. This study was performed to clarify the cancer risk of the background liver after treating early hepatocellular carcinoma. METHODS Early hepatocellular carcinoma is defined as very well-differentiated cancer containing Glisson's triad. The cumulative incidence of classical hepatocellular carcinoma, hypervascular liver cancer detected on imaging studies, after resection of early hepatocellular carcinoma positive for anti-hepatitis C antibody (early hepatocellular carcinoma group, n = 105) was compared with that in patients with chronic liver disease positive for anti-hepatitis C antibody (control group, n = 751) and propensity score-matched patients after resection of classical hepatocellular carcinoma (classical hepatocellular carcinoma group, n = 105). RESULTS After a median follow-up of 4.8 years (range, 0.3-15.0), the cumulative incidence of classical hepatocellular carcinoma at 5 years was 56.9% (95% confidence interval, 44.2-67.7%) in the early hepatocellular carcinoma group and 70.6% (52.5-81.8%) in the classical hepatocellular carcinoma group as compared with 4.6% (2.8-6.4%) in the control group. The risk of the development of classical hepatocellular carcinoma in the early hepatocellular carcinoma group was significantly higher than that in the control group (hazard ratio, 17.5; 95% confidence interval, 12.1-25.3; P

Background Incidental detection of nonenhancing tumors during imaging studies for patients with classical hepatocellular carcinoma is not unusual. These tumors are considered to have a high potential of malignant transformation. The aim of this study was to clarify the natural history of such tumors. Methods In 93 patients who underwent liver resection for hepatocellular carcinoma, 138 nonenhancing or enhancing nodules without washout were detected during dynamic computed tomography and observed without further treatments. We subsequently compared the cumulative occurrence of new hepatocellular carcinomas to that of the malignant transformation of these lesions. We additionally compared the appearance of new hepatocellular carcinomas between the patients with ( n = 93) and without ( n = 782) nonenhancing lesions or enhancing lesions without washout. Results After a median follow-up period of 0.7 years (range, 0.2–6.8), the median intervals from resection to the appearance of new classical hepatocellular carcinoma and malignant transformation of nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2–1.9) and 2.3 years (1.9–6.8 years; P = .002), respectively. On the other hand, the median intervals from resection to the appearance of new lesions in patients with and without nonenhancing lesions or enhancing lesions without washout were 1.6 years (95% confidence interval, 1.2–1.9) and 2.1 years (1.9–2.1 years; P = .031), respectively. Conclusion During the natural history of nonenhancing lesions and enhancing lesions without washout that coexist with hepatocellular carcinoma, new lesions often develop prior to the malignant transformation of these lesions. This should be considered a risk factor for the appearance of new hepatocellular carcinoma.

Early hepatocellular carcinoma (HCC) is defined as a very well differentiated liver cancer with the presence of stromal invasion to the remaining Glisson's triad within the tumor (carcinoma in situ), which consists of small hepatocytes with little cellular atypia but with structural atypia. Different from classical HCC, early HCC is macroscopically characterized by indistinct margins and clinically detected as hypovascular lesion by imaging modalities. When such small-sized precursor lesions reach 1.5 to 2.0 cm in diameter, less differentiated cancerous tissues arise within the tumor and develop, finally replacing the very well differentiated HCC. Thus, early HCC originates from chronic liver disease and develops into classical HCC in stepwise manner. To identify sequential genetic alterations in stepwise hepatocarcinogenesis, transcriptome and whole-exome sequences were performed on 47 early and 105 classical HCCs, and molecular aberrations containing somatic mutations, gene expression, fusion events, and copy number aberrations were compared between two groups. In addition, integrating the molecular alterations from different methods, we distinguished genetic driver aberrations from by-chance changes that are not relevant to cancer genome and elucidated recurrent pathways responsible for initiation and progression in stepwise hepatocarcinogenesis. Expression profile of early HCC was different from that of classical HCC, and chromosomal aberrations, somatic mutations, and gene fusion events were significantly frequent in classical HCC. By exome sequencing, mutation of CTNNB1, CSMD3, AXIN1, COL11A1, TSC2, and ATM were often observed in both groups, while those of TP53, ARID2 and ALPK2 were significantly frequent in classical HCC. Integrated analysis showed that distinct expression profile in early HCC would define it as another molecular entity from classical HCC due to its different mutation pattern. Prevalence of somatic mutations of CTNNB1 and p53/RB pathway genes were common, while those of ARID2 and AKT/PI3K pathway genes were significantly frequent in classical HCC. Unexpectedly, WNT target genes were up-regulated only in classical HCC with CTNNB1 mutation, and even down-regulated in those with AXIN1 mutation. Similarly, cell cycle genes related with p53/RB pathway were up-regulated only in classical HCC. Taken together, despite of frequent mutations in CTNNB1 and TP53 in early HCC, additional mutational events such as SWI/SNF complexes and AKT/PI3K pathway will be required for transcriptional activation of downstream targets in HCC progression. Furthermore, TERT is the most frequently up-regulated in early HCC by various mechanisms: recurrent gene fusion including 3 prime portion of TERT such as SLC12A7-TERT (8.5%), focal gain of 5p15.33 (19.1% vs 12.3%), hepatitis B virus integration (2.1% vs 3.8%), and TERT promoter mutation (63.8% vs 59.0%). Despite of driver genes mutation, their pathways are not aberrantly activated and therefore, early HCC is a precursor in accordance with clinical characteristics different from classical HCC. Citation Format: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani. Integrated genomic analysis identified sequential molecular aberrations in stepwise progression from early to classical hepatocellular carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-30.

Anti‐epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti‐EGFR treatment. We investigated the genome‐wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti‐EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti‐EGFR treatment for KRAS wild‐type metastatic CRC. Then we analyzed the associations between genome‐wide DNA methylation status and clinical response to anti‐EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression‐free survival, 0.27; 95% confidence interval, 0.13–0.57, P

We aimed to assess the diagnostic performance of MR elastography (MRE) in predicting esophageal varices (EVs) in patients with chronic liver disease. We prospectively performed liver (LSM) and spleen stiffness measurements (SSM) using MRE and endoscopic screening for EVs to determine if patients with hepatocellular carcinoma were eligible for resection. We investigated whether LSM, SSM, and other non-invasive preoperative parameters were associated with the presence of EVs. In order to predict EVs, 211 patients were divided into training (n = 140) and test (n = 71) groups. A nomogram was built using independent factors based on logistic regression analysis in the training group and its accuracy was validated using an independent cohort. Forty-six patients (21.8%) were diagnosed as having EVs (mild, n = 36; severe, n = 10). According to multiple regression analysis, LSM (odds ratio, 2.362; 95% confidence interval [CI], 1.341–4.923; p = 0.001) and SSM (1.489; 1.095–2.235; p = 0.010) were independent predictors of EVs in the training group. The nomogram showed good discrimination, with a C-index of 0.942 (95% CI, 0.892–0.974) through internal validation, and good calibration. Application of the nomogram in the test group still gave good discrimination (C-index, 0.948; 95% CI, 0.868–0.995). The combination of LSM and SSM using MRE is an accurate tool to identify patients at risk for EVs. • Performance of MR elastography can estimate the presence of esophageal varices non-invasively. • Liver and spleen stiffness measurements are independent predictors for esophageal varices. • The nomogram using a combination of liver and spleen stiffness measurements allows for the risk of esophageal varices.

Background Liver stiffness measurement (LSM) has recently become available for assessment of liver fibrosis. We aimed to develop a prediction model for liver fibrosis using clinical variables, including LSM. Methods We performed a prospective study to compare liver fibrosis grade with fibrosis score. LSM was measured using magnetic resonance elastography in 184 patients that underwent liver resection, and liver fibrosis grade was diagnosed histologically after surgery. Using the prediction model established in the training group, we validated the classification accuracy in the independent test group. Results First, we determined a cut-off value for stratifying fibrosis grade using LSM in 122 patients in the training group, and correctly diagnosed fibrosis grades of 62 patients in the test group with a total accuracy of 69.3%. Next, on least absolute shrinkage and selection operator analysis in the training group, LSM (r = 0.687, P

Cirrhosis is associated with blood loss during liver resection and postoperative complications. The liver stiffness measurement has recently become available for assessment of liver fibrosis.This prospective study was performed to predict postoperative outcomes of liver resection. The liver stiffness measurement was measured prospectively using magnetic resonance elastography for patients who had undergone liver resection for malignancy. We investigated whether the liver stiffness measurement by magnetic resonance elastography is correlated with liver fibrosis and postoperative outcomes.The median liver stiffness measurement by magnetic resonance elastography in 175 patients was 3.4 (range: 1.5-11.3) kPa, and the pathologic grade of liver fibrosis was significantly correlated with the liver stiffness measurement (r = 0.68, P .001). The median blood loss during transection per unit area was 4.1 mL/cmThe liver stiffness measurement by magnetic resonance elastography could be used as a predictive marker for the risk of major complications due to blood loss during liver resection.

Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought to determine the association between H3F3A mutations and adult thalamic glioma.Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes--including cancer-related genes and chromatin-modifier genes--were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome.Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17-46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.

Background/Aim: VAX014 minicells (VAX014) have been previously characterized as an integrin-specific oncolytic biotherapeutic agent. The present study was designed to evaluate the potential of VAX014 as an immediate post-operative intravesical adjuvant therapy in the treatment of non-muscle invasive bladder cancer (NMIBC). Materials and Methods: The ability of VAX014 to kill a panel of dissociated urothelial carcinoma cell lines was tested in vitro. In vivo experiments were conducted using a single intravesical dose of VAX014 in the anti-implantation variation of the MB49 syngeneic orthotopic bladder cancer model with tumor implantation and overall survival rates serving as study endpoints. Results: VAX014 rapidly killed dissociated urothelial carcinoma cells, while single dose in vivo pharmacology studies demonstrated the dose-dependent ability of VAX014 to prevent tumor implantation and development, ultimately resulting in a significant survival advantage compared to controls. Conclusion: These results suggest that VAX014 holds potential as an immediate post-operative adjuvant therapy in NMIBC.

Hypovascular tumors associated with hepatocellular carcinoma (HCC) can be diagnosed, but it remains unknown whether such lesions should be treated immediately. This study aimed to clarify the clinical significance of treating hypovascular liver nodules. After diagnosis of hypovascular tumors smaller than 3 cm, 104 patients underwent liver resection immediately (Group 1), while 93 patients were placed under observation (Group 2). In Group 1, 98 patients were diagnosed as having HCC (Group 1′), while 80 patients in Group 2 underwent liver resection after vascularization or appearance of other hypervascular HCC (Group 2′), eight patients had been observed, and five patients could not undergo operation due to appearance of other multiple HCCs. To avoid lead time bias for tumor vascularization, survival rates of patients after diagnosis of hypovascular tumors as well as those after operation in the two groups were compared. After a median follow-up of 3.3 years (range 0.6–11.2), the 5-year overall survival rates after liver resection of Group 1′ (74.8 %; 95 % CI 64.3–86.1) was significantly higher than that of Group 2′ (59.2 %; 46.4–75.6; P = 0.027). However, the 5-year overall survival rates after diagnosis of hypovascular liver nodules of Group 1′ (74.7 %; 66.1–85.0) was not significantly different from that of Group 2′ (77.1 %; 67.0–88.6; P = 0.761). Consequently, the 5-year overall survival rate after diagnosis of Group 2 (75.6 %; 64.7–83.1) was not significantly different from that of Group 1 (73.2 %; 67.5–86.1; P = 0.591) by intention-to-treat analysis. It is not necessary to treat hypovascular liver tumors immediately after diagnosis.

Background In liver resection, bile leakage remains the most common cause of operative morbidity. In order to predict the risk of this complication on the basis of various factors, we developed a clinical score system to predict the potential risk of bile leakage after liver resection. Methods We analyzed the postoperative course in 518 patients who underwent liver resection for malignancy to identify independent predictors of bile leakage, which was defined as “a drain fluid bilirubin concentration at least three times the serum bilirubin concentration on or after postoperative day 3,” as proposed by the International Study Group of Liver Surgery. To confirm the robustness of the risk score system for bile leakage, we analyzed the independent series of 289 patients undergoing liver resection for malignancy. Results Among 81 (15.6 %) patients with bile leakage, 76 had grade A bile leakage, and five had grade C leakage and underwent reoperation. The median postoperative hospital stay was significantly longer in patients with bile leakage (median, 14 days; range, 8 to 34) than in those without bile leakage (11 days; 5 to 62; P = 0.001). There was no hepatic insufficiency or in-hospital death. The risk score model was based on the four independent predictors of postoperative bile leakage: non-anatomical resection (odds ratio, 3.16; 95 % confidence interval [CI], 1.72 to 6.07; P

T-593 (osutidine, CAS 140695-21-2) is a new anti-ulcer agent that consists of two enantiomers, (+) (R) T-593 and (-)-(S)-T-593. The present study was designed to investigate the effects of T-593, (+)-(R)-T-593 and (-) (S) T-593 on ethanol-induced gastric damage in rats. Rats were given intraperitoneal administration of vehicle, racemic T-593, (+) (R)-T-593 or (-) (S)-T-593. 30 min later, the rats intragastrically received a 1 ml solution of 40 % ethanol, and 30 min thereafter, they were sacrificed for assessment of gastric damage. Gastric hemodynamics were assessed by reflectance spectrophotometry and laser Doppler flowmetry during the experiment. Gastric damage was significantly suppressed by racemic T-593 in a dose-depenent manner. While 60 mg/kg of (+)-(R) T-593 and (-)-(S) T-593 also suppressed ethanol-induced gastric injury, the same dose of racemic T-593 exerted the most potent anti-ulcerative activity. Both (+) (R) T-593 and racemic T-593 in creased gastric mucosal blood flow and abolished gastric mucosal blood flow stasis induced by 40 % ethanol. Although (-) (S) T-593, which antagonizeshist amine H 2 -receptors, exerts an anti-ulcerative effect, (+) (R) T-593 also protects the gastric mucosa from ethanol induced injury, possibly by influencing gastric mucosal hemodynamics. Thus racemic T-593 may protect the gastric mucosa by antagonizing H 2 receptors and by enhancing gastric circulation in rats.

Double-balloon endoscopy (DBE) examinations are not yet widely accepted as routine procedures for examining the small bowel of patients with Crohn's disease (CD).To evaluate the feasibility and usefulness of DBE for CD in tertiary-care hospitals.Between July 2004 and September 2008, 1444 DBE procedures were performed for 704 patients in 6 tertiary-care hospitals. Patient profile, indication, diagnosis and treatment of DBE were evaluated using a multicenter database.DBE examinations were most frequently performed in 75 patients with CD, corresponding to 10.5% of all the patients examined by DBE. Fifty patients were diagnosed with CD before DBE, while DBE was performed for the diagnosis of 25 new CD patients. Small bowel lesions were often detected even when the terminal ileum was not involved. In the 75 patients, 21 patients were asymptomatic at the time of DBE examinations. Active inflammatory lesions were detected in 51.2% of the CD patients, and were even detected in 33.3% of the asymptomatic CD patients. The treatment was altered in 53.3% of the CD patients after the DBE evaluation. No severe complications were experienced.DBE procedures can be safely performed in patients with CD and should be considered for the precise evaluation of and to determine the treatment strategy for CD.

Interstitial cells of Cajal (ICC) play important roles in autonomic gut motility as electrical pacemakers and mediators of neural regulation of smooth muscle functions. Insufficiency of ICC has been reported in a wide range of gut dysmotilities. Thus, restoration of ICC may be a therapeutic modality in these diseases. Here we provide evidence that transplanted bone marrow (BM) cells can restore gut dysmotility in part via transdifferentiation to ICC. Bone marrow cells obtained from Kit insufficient W/W v mice or syngeneic GFP-transgenic mice with wild-type Kit were transferred to W/W v recipients. Whole gut transit time and gastric emptying were examined 5 and 6 weeks after BM transplantation, respectively, and ICCs were identified in whole mounts, frozen sections and transmission electron immunomicroscopy of the gut smooth muscle layers using specific antibodies. Transplantation of wild-type BM into W/W v mice significantly improved whole gut transit time and gastric emptying. Fluorescent immunohistochemistry revealed GFP+Kit+ cells in the myenteric plexus, deep muscular plexus, and submucosal plexus smooth muscle layers of the stomach, small intestine, and colon, respectively. In the whole mounts, GFP+Kit+ cells were bipolar and spindle shaped, and transmission electron immunomicroscopy showed GFP+ cells rich in mitochondria and endoplasmic reticulum between gut smooth muscle layers, suggesting the presence of GFP+ cells with morphological characteristics of ICC. These results suggest that BM contains cells that may incorporate into ICC networks and improve dysmotility in W/W v mice. Thus, BM transplantation may become to a new therapeutic modality for gut dysmotilities due to ICC insufficiency.

Background: The involvement of bone marrow (BM) in tumor-stroma reactions or tumor development has not been examined in a cancer allograft, which has otherwise been appropriate for assessing therapeutic modalities. We investigated the fate of BM-derived cells in colon cancer allografts and liver metastases in mice. Methods: C57BL/6 mice were irradiated and rescued by BM transplantation from green fluorescent protein (GFP)-transgenic mice. MC38 colon cancer cells were stably transfected with the pDsRed gene in order to identify tumor cells by fluorescence. These were inoculated into the mice to generate subcutaneous allografted tumors or liver metastases. The tumors were observed under confocal microscopy and fluorescent immunohistochemistry to determine the fate of tumor versus BM-derived cells. Results: GFP-positive (GFP+) cells were consistently identified as vimentin+, α-smooth muscle actin (αSMA)+, spindle-shaped stromal cells in both the subcutaneous tumors and the liver metastases. GFP+ cells of leukocyte lineage also infiltrated the tumors. Neither GFP+ CD31+ endothelial cells nor GFP+ DsRed+ cells were detected in the tumor. Conclusions: BM-derived cells frequently and consistently infiltrated the tumor allografts and metastases as interstitial cells and leukocytes. Cells derived from the fusion of BM cells and tumor cells were not observed. This model may be appropriate for the clarification of the effects of anticancer therapies and the study of BM-derived cells in tumor–host interactions.

Musashi-1 (Msi-1), a mammalian neural RNA-binding protein, has been found to play important roles in the maintenance of stem cell states and differentiation in neural stem cells and mouse intestinal cells. We explored Msi-1 expression and its potential implications in the human stomach. Reverse transcription-PCR revealed that Msi-1 levels were significantly higher in the corpus than in antrum in Helicobacter pylori (Hp)-infected patients (n = 49) (P < 0.00001) in paired biopsy samples, whereas they were low and comparable at these two sites in Hp-negative patients (n = 31). Msi-1 levels were significantly higher in the Hp-infected corpus (n = 107) than in the Hp-negative corpus (n = 69) (P < 0.00000001). Immunohistochemistry and in situ hybridization demonstrated that Msi-1 was expressed at the base and neck/isthmus region of the fundic glands and partly co-expressed in Ki-67-positive cells in the corpus and antrum. Msi-1 levels correlated with Hp density (P < 0.05). Based on these results, we conclude that Hp infection strongly induces Msi-1 in the corpus. Given its expression in dividing cells, Msi-1 may modulate the state of gastric progenitor cells.

Bone-marrow-derived cells (BMDCs) transdifferentiate into various types of gastrointestinal cells. The precise transdifferentiation of BMDCs in gut regeneration, however, is controversial. In this study, we examined the transdifferentiation of BMDCs in the regeneration of damaged colonic epithelia. Lethally irradiated wild-type female mice (C57BL/6) were rescued by bone marrow transplantation from male green fluorescent protein transgenic mouse donors. Chronic colitis was induced by administering 3% dextran sulfate sodium (DSS) in the drinking water for 5 days on day 28 after the bone marrow transplantation. The mice were killed on day 25 after DSS administration. BMDC phenotypes were examined by confocal microscopy and fluorescence immunohistochemistry. BMDCs were frequently observed in the vimentin-positive colonic interstitial cells, which also expressed α-smooth muscle actin and had a spindle-like morphology, but did not express leukocyte common antigen. Green-fluorescent-protein-positive cells were rarely or less frequently found in Ki-67-positive proliferating cells, cytokeratin-positive epithelial cells, or CD31-positive endothelial cells. BMDCs frequently transdifferentiated into subepithelial myofibroblasts and fibroblasts, and often continued to reside in the colonic subepithelia after the experimental colitis had healed. In conclusion, our data indicate the fate of BMDCs, which might be involved in the healing process of the colon after DSS-induced colitis. Our data show that BMDCs contribute to colonic interstitial cells after the colitis has healed. Understanding the fate of BMDCs may be important for stem cell therapy by BMDCs.

Cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colorectal cancers. For treatment of advanced cancers, combination of COX-2 inhibitors and chemotherapy has been attempted, but the results are still controversial. In the present study, the effects of the COX-2 inhibitor celecoxib on the anticancer potential of chemotherapy, and its mechanisms of action were investigated in point of the angiogenesis, using an advanced cancer model in mice. BALB/c mice were inoculated with colon 26 cells. After the allograft grew up to 5 mm in diameter, the animals received celecoxib, 5FU, or a combination of 5FU and celecoxib (5FU/celecoxib). After 21-days of the treatment, 5FU/celecoxib significantly inhibited the tumor growth and the tumor vessel density compared with the other groups. Celecoxib, 5FU or 5FU/celecoxib significantly suppressed the VEGF content in tumor tissues. 5FU/celecoxib also enhanced IFN-γ levels in tumor tissue, which could be involved in the potent antitumor effects of 5FU/celecoxib. This hypothesis was proven, because in IFN-γ knockout (IFN-γ−/−) mice, the inhibitory effects of 5FU/celecoxib on angiogenesis and tumor growth were significantly impaired compared with that in wild type mice. These results suggest that celecoxib enhances the antitumor effect of 5FU against an advanced colon cancer model by suppressing angiogenesis. In addition to VEGF, IFN-γ has pivotal roles in tumor suppression induced by celecoxib. © 2007 Wiley-Liss, Inc.

Background: Asthma-COPD overlap syndrome (ACOS) phenotype is not yet well characterized, and its diagnosis is sometimes difficult. Aims and objectives: Because clinical markers might be useful to distinguish ACOS from asthma and COPD, we analyzed clinical data from each to discover such markers. Methods: We performed cross-sectional analysis on 100 patients with asthma, 23 with COPD, and 15 with ACOS at our center from January 2012 through November 2014 under an informed consent from each patient with an institutional approval. ACOS was defined as patients diagnosed with both asthma and COPD. Results: Age and Brinkman Index were significantly higher in the ACOS group versus the asthma group (p Conclusion: When comparing the phenotype of ACOS with asthma and COPD in clinical settings, our results nearly correspond to those of past reports. Although these reports showed lower respiratory function and more acute exacerbation in ACOS, our results did not show such tendencies. This study failed to find any useful markers for diagnosis of ACOS, and therefore, further investigation should be necessary.

Background: Bronchial asthma (BA) is a common disease that is characterized by airway inflammation. Recently many patients achieve good control with anti-inflammatory treatment. However some patients have persistent symptoms and airflow limitation even during such intervention. Therefore, pursuing appropriate biomarkers reflecting severity is crucial for disease monitoring. Oxidative stress is attracting attention as one of the important pathophysiological factors in BA. Aims and objectives: We investigated the magnitudes of oxidative stress and other biomarkers in patients with BA to clarify relationship between severity and various biomarkers. Methods: We enrolled patients who attended our hospital due to BA from January 2012 to January 2015. Oxidative stress was evaluated by reactive oxygen metabolite (ROM) levels using the d-ROMs test (Diacron International, Grosetto, Italy). We examined characteristics of clinical history and laboratory findings. Results: One hundred and six patients (67 women, mean age: 52.3±16.5, 12 current smokers, 23 ex-smokers) were included in this study. Thirty four patients had airflow limitation (FEV1/FVC < 0.7). ROM levels were negatively correlated with %FEV1 (r = -0.21, p < 0.05). Serum IL-8 concentrations were also negatively correlated with FEV1/FVC (r = -0.37, p < 0.05) and %FEV1 (r = -0.42, p < 0.05). WBC and eosinophil counts, FeNO levels were not correlated with FEV1/FVC and %FEV1. Conclusions: ROM levels and serum IL-8 concentrations had significantly negative correlation with degrees of airflow limitation. These biomarkers may be useful in the management of BA.

金沢大学医薬保健研究域医学系, Correction to: PLoS ONE https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128066

Bone marrow contains hematopoietic stem cells, nonhematopoietic mesenchymal stem cells, and several precursor cells for osteoblasts, chondrocytes, adipocytes, myocytes, hepatocytes, and even neural cells. Research findings indicate that multipotent stem cells in the adult body may be used to recover the lost functions of damaged tissues. This study examined the involvement of bone marrow-derived cells in the regeneration of the stomach after experimental gastric ulcers were produced in rats. We transplanted the bone marrow of transgenic rats that expressed green fluorescence protein (GFP) throughout the body. Twenty-one days after the bone marrow transplantation (BMT), gastric ulceration was induced, using absolute ethanol. Control animals received saline. After various observation periods, rats harboring GFP-positive bone marrow-derived cells were killed, and the tissues were removed and processed to prepare paraffin-embedded sections. Cells expressing GFP were identified by conventional immunohistochemistry, using anti-GFP antibody. To identify whether cells expressing GFP were epithelial cells or interstitial cells such as fibroblasts, serial sections were examined with anti-cytokeratin antibody or anti-vimentin antibody, respectively. Furthermore, to confirm that cells expressing GFP were epithelial cells or interstitial cells, we used double-staining analysis with anti-GFP antibody or anti-cytokeratin antibody, respectively. GFP-positive, bone marrow-derived cells were found in the cytokeratin-positive gastrointestinal epithelium, as well as among vimentin-positive interstitial cells. Interestingly, the proportions of GFP-positive, cytokeratin-positive epithelial cells and vimentin-positive interstitial cells were significantly greater in the ethanol-treated damaged stomachs than in the saline-treated controls. The present study clearly demonstrates that bone marrow-derived cells are involved in the regeneration of the stomach after ethanol-induced ulcers in rats.

A case of juvenile hepatocellular carcinoma (HCC) with congestive liver cirrhosis is reported. The patient was a 21-year-old woman. She had been diagnosed as having transposition of the great arteries, type 2, in 1978. She underwent the Mustard operation, but suffered from chronic heart failure. In 1995, she experienced abdominal pain and underwent examination. The laboratory data were normal, except for elevated total bilirubin (5.2 mg/dl). Blood examinations were performed at frequent intervals, and the total bilirubin level fluctuated between 0.9 and 8.1 mg/dl over the next 4 years, but the transaminase level remained normal. In 1999, she experienced abdominal pain again and was admitted to our hospital. Computed tomography showed four space-occupying lesions in the liver; 45 mm, 20 mm, 12 mm, and 10 mm in size. She was diagnosed as having HCC, and transcatheter arterial chemoembolization and percutaneous ethanol injection therapy were performed. Histology of the cancerous and the noncancerous liver tissue revealed HCC, moderately differentiated type, in cirrhotic liver with congestion. This patient had no background factors of liver disease, except for liver congestion, associated with the chronic heart failure. Because most patients with cardiac cirrhosis die of cardiac disease, only a small number of these patients develop liver failure. However, the incidence of HCC in patients with congestive liver disease is likely to increase in the future, as survival time is prolonged with the advances in treatment for chronic heart failure. Therefore, patients with congestive liver disease should be followed, taking into account the possibility of HCC.

Bone marrow is reported to contain hematopoietic stem cells and other adult somatic stem cells that have phenotypes of cells composing tissues other than bone marrow. To explore the implication of bone marrow-derived cells in the treatment of inflammatory bowel diseases, experimental colitis was induced in wild-type rats after transplantation of bone marrow from transgenic rats expressing green fluorescence protein (GFP). Chronic colitis was induced 21 days later using 30 mg 2,4,6-trinitrobenzenesulfonic acid (TNBS). Control rats received saline. At 28, 56, and 224 days after TNBS administration, rats were euthanized, and tissues were removed and processed for paraffin-embedded sections. Cells derived from bone marrow were identified by immunohistochemistry using anti-GFP antibody. To identify the phenotypes of the cells expressing GFP, we conducted serial-section analysis and double-staining analysis using antibodies against cytokeratin (epithelial cells) or vimentin (interstitial cells). In the present study, GFP-positive, bone marrow-derived cells occupied 37.6% and 4.25% of the colonic epithelium at 28 days and 56 days after the induction of TNBS-colitis, respectively. Also, significant amounts of mucosal and submucosal interstitial cells were derived from the bone marrow. These findings showed that a large amount of bone marrow-derived cells were involved in regeneration of the colon after experimental colitis in rats.

Background: Biliary tract cancer is a highly fatal disease with poor prognosis, but the aetiology is poorly understood. Aim: We aimed to identify Helicobacter bilis infection in the gallbladder in patients with biliary tract disease. Methods: Archival gallbladder specimens from 34 patients (14 males and 20 females) with an average age of 61.4 ′ 12.2 years (mean ′ SE) were retrieved, consisting of 11 cases of gallbladder cancer, three of bile duct cancer, 16 of cholecystolithiasis and four of pancreatic cancer. DNA was extracted and nested PCR using primers specific for 16S rRNA of H. bilis was performed. Results: Amplification was observed in 3 of 11 gallbladder cancer cases (27.2%) and one of three cases with biliary duct cancer (33.3%). In total, four of 14 cases with biliary tract cancer were positive for H. bilis (28.6%). In addition, the presence of H. bills was shown in two of 16 cases (12.5%) with cholecystolithiasis. Notably, although the number of cases examined was small, none of the four cases with pancreatic cancer showed the presence of H. bilis infection in the gallbladder without apparent abnormalities. Conclusion: H. bilis infection may play a role in biliary tract disease, particularly in biliary tract cancer.

Background and Aim: We examined the incidence of symptomatic gastroesophageal reflux disease (GERD) in patients with type 2 diabetes mellitus (DM). Methods: Patients comprised those with DM or chronic hepatitis C (CHC) who visited Osaka Prefectural General Hospital in the same study period. Reflux symptoms were examined using a self-administered questionnaire. A total score of 4 or more was considered an indication of symptomatic GERD. Disease duration, hemoglobinA1c and diabetic complications were assessed. Results: Patients with DM (n = 241) or CHC (n = 42) were recruited for the study. Of the 241 patients with DM, 100 (41.5%) reported experiencing upper gastrointestinal symptoms, whereas only 9 of 42 (21.4%) patients with CHC reported upper gastrointestinal symptoms (P = 0.0137). Sixty-one patients (25.3%) with DM had reflux symptoms but only four patients (9.5%) with CHC reported reflux symptoms. The incidence of symptomatic GERD was significantly higher in patients with DM than in those with CHC (P = 0.0219). Patients with DM for less than 5 years had a 2.4-fold higher incidence of GERD than patients with CHC. The incidence tended to rise with increased disease duration. Patients with diabetic complications reported reflux symptoms more frequently. The incidence decreased, however, in DM patients who had these conditions for more than 16 years. Conclusions: Type 2 diabetes mellitus is a risk factor for symptomatic GERD. In DM patients, use of oral hypoglycemic agents, body mass index, disease duration and the quality of diabetic control influenced the incidence of GERD. © 2004 Blackwell Publishing Asia Pty Ltd

症例は72歳, 男性. 初診時, 血管侵襲 (Vp2) を伴う肝両葉多発病変で, 一部に hypovascular な領域を伴う Stage IV A肝細胞癌であった. 初回治療として one shot シスプラチン動注化学療法を施行し, 病巣の著明な縮小を認め, 局所治療可能となった. 引き続き肝動脈塞栓術, ラジオ波焼灼術, エタノール注入術による集学的治療を行ったところ, 残存腫瘍は消失した. 以後の異時性異所性再発を認めたが, 局所治療による制御可能であり, 初発より3年6カ月経過した現在, 外来にて経過観察中である.進行肝細胞癌に対する初回治療としてシスプラチン動注化学療法が極めて有効な症例であった.

Background and Aim: Little is known about the clinical efficacy of cotherapy of ecabet sodium, a mucoprotective agent, and a histamine H2-receptor antagonist. The aim of the present study was to assess its additive benefit in combination with cimetidine for gastric ulcer. Methods: In this prospective randomized study, after gastric ulcer was confirmed by endoscopy, 200 patients in 47 hospitals received either ecabet sodium 1 g b.i.d and cimetidine 400 mg b.i.d. (EC), or cimetidine 400 mg b.i.d. alone (C) for 8 weeks. Healing was examined by endoscopy at 4 and 8 weeks. Results: Of the intention-to-treat (ITT) population (EC, 103; C, 97), 181 patients comprised the per protocol (PP) analysis (EC, 93; C, 88). At 4 weeks, healing rates were significantly higher in the EC group (60%) than in the C group (36%) ( p

Gastrin, PGs, and growth factors have important roles in maintaining gastrointestinal mucosal integrity. Cyclooxygenases (COX-1 and COX-2) are the key enzymes involved in PG synthesis. This study aimed to clarify the mechanisms of gastric mucosal protection by gastrin. Fasted rats were administered subcutaneous gastrin 17 with or without gastrin receptor antagonist YM022 pretreatment. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) and COX-2 expression were examined using Western blot analysis. Another series of experiments investigated 1) PGE2 levels in gastric mucosa, 2) the protective action of gastrin against gastric damage by acidified ethanol, 3) the effects of a specific HB-EGF-neutralizing antibody on gastrin-induced COX-2 expression, and 4) the effects of a specific COX-2 inhibitor NS-398 on PGE2 synthesis and the mucosal protection afforded by gastrin. Gastrin dose-dependently increased HB-EGF, COX-2 expression, and PGE2 levels and reduced gastric damage. However, pretreatment with YM022 dose-dependently abolished such effects of gastrin. A specific HB-EGF- neutralizing antibody and an EGF receptor inhibitor decreased gastrin-induced COX-2 expression. NS-398 blocked gastrin-induced PGE2 synthesis and mucosal protection. In conclusion, this study demonstrates that gastrin enhances gastric mucosal integrity through COX-2, which is partially mediated by HB-EGF, and PGE2 upregulation in rats.

Background: Although proton pump inhibitors (PPI) and H2-receptor antagonists (H2-RA) are routinely used in the treatment of reflux esophagitis (RE), no consensus has been reached yet as to whether the first-choice drug should be PPI or H2-RA. In this study, the effects of omeprazole (OMP) and famotidine (FAM) on RE have been examined in a randomized comparative study. Methods: Protocols of OMP 20 mg once daily or FAM 20 mg twice daily for 8 weeks were allocated to 56 cases with RE at random, using an envelope randomization method. Their efficacy in achieving healing was examined endoscopically and a relief from subjective symptoms was compared. Results: Patient's background such as sex, age, recurrence, hiatal hernia, smoking and drinking habits, and complications, and the severity of esophagitis at the time of enrolment were not significantly different between the two groups. Healing in the OMP group and the FAM group was observed in 72 and 32% (P = 0.025) of patients at week 4 and 95 and 53% (P = 0.003) of patients at week 8, respectively. Subjective symptoms were relieved more frequently in the OMP group (at week 2, 67% compared with 29%, P = 0.005; at week 4, 95% compared with 55%, P = 0.009), but this superiority was not significant at week 8 (94% compared with 65%, P = 0.085). No serious adverse events occurred. Conclusions: Omeprazole provided quicker healing and a greater relief from subjective symptoms than did FAM in the treatment of RE, and was considered more suitable as a first-choice drug. © 2002 Blackwell Publishing Asia Pty Ltd

Background and Aims:Helicobacter pylori infection is associated with peptic ulcers; however, it is unclear whether the bacterium delays ulcer healing. We investigated the influence of H. pylori on ulcer healing in mice. We also examined the influence of H. pylori infection on angiogenesis. Methods: An acetic acid ulcer was made in male BALB/c mice. Three days later (day 0), the animals were inoculated with H. pylori SS1 strain. The healing process of the ulcer was examined macroscopically and microscopically on days 0, 6 and 9. The index of angiogenesis was also determined using carmine dye injection. Results: On day 0, angiogenesis began at the ulcer margin while the mucosal epithelia had not yet regenerated. On days 6 and 9, angiogenesis and epithelial regeneration developed and ulcer size reduced. These phenomena were significantly suppressed in mice infected with H. pylori. Conclusion:Helicobacter pylori infection significantly suppressed angiogenesis and delayed ulcer healing. These results indicate that H. pylori plays an important role in ulcer healing. © 2002 Blackwell Publishing Asia Pty Ltd

There is considerable interest in the involvement of cyclooxygenase-2 (COX-2) in colon carcinogenesis and its progression, because nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality from colon cancer and COX-2 is one of the known targets of NSAIDs. COX-2 mRNA and protein levels are increased in colon cancer tissues from patients and in some colon cancer cell lines. The relationship between COX-2 and colon cancer is further confirmed by studies using the murine models of adenomatous polyposis coli, in which NSAIDs and gene knockouts reduce the number of spontaneously developing intestinal polyps. COX-2 expression in intestinal epithelial cells increases resistance to apoptosis, promotes tumor angiogenesis, and enhances invasion and metastasis. COX-2 expression in stromal cells appears to have a role in tumor angiogenesis because tumor growth is attenuated when colon cancer cells are implanted in COX-2 knockout mice due to a decreased vascular supply to the tumors. Although NSAIDs act via COX-2 to inhibit colon cancer growth, there also appear to be COX-2 independent actions for NSAIDs. COX-2 selective inhibitors can be the core drugs for the prevention and the treatment of colon cancer.

Background & Aims: Src activation is correlated with progression of colorectal cancer (CRC). CRCs accompanied by ulcerative colitis, chronic inflammation in the colon, often have elevated Src activity, and ulcerative colitis–related CRCs are more likely to become invasive, whereas Ras activation is rarely associated with this disease. The aim of this study was to investigate the effects of a proinflammatory cytokine, tumor necrosis factor α (TNF-α), on the invasive properties of epithelial cells constitutively expressing activated Ras or Src. Methods: A cell line derived from intestinal epithelia was transfected with a v-src – or v-H-ras –expressing vector. The effect of TNF-α on morphologic changes in colonies cultured in soft agar was determined. Src protein kinase activity, peroxide production, E-cadherin expression levels, and the phosphorylation status of β-catenin and E-cadherin were determined. The invasive potential of these cells was determined by measuring cell motility and using an in vitro invasion assay. Results: TNF-α altered the colony morphology of src-, but not ras-expressing cells. TNF-α increased peroxide production, leading to Src protein expression as well as Src activity in src transfectants. Activation of Src by TNF-α led to reduced E-cadherin levels and enhanced invasion of src transfectants. Pyrrolidine dithiocarbamate and herbimycin A inhibited these effects. Conclusion: These results indicate that Src kinase activation enhances the response of epithelial cells to TNF-α leading to increased invasion through mechanisms that involve production of reactive oxygen intermediates. GASTROENTEROLOGY 2002;122:331-339

Multiple hepatocellular carcinoma (HCC) is categorized into two types; multicentric hepatocarcinogenesis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is quite difficult to determine it correctly even after histological diagnosis. In order to determine multiple HCC as MC or IM, we compared pairs of multiple HCC samples from 40 patients with multiple HCC and 2 patients with pairs of primary HCC and extrahepatic metastasis such as adrenal grand and lung metastasis with regard to molecular aberrations. Exome sequence showed that more than 70% of somatic mutations were common in the pairs of IM, which were consistent with the result of a pair of primary HCC and extrahepatic metastasis, while no common somatic mutations was detected in genomic-MC (gMC) pairs. Notably, more than 60% of clinically metachronous-MC cases were diagnosed as genomic-IM (gIM) due to the concordance of mutation and shows significantly frequent tumor thrombus, suggesting that gIM pairs developed from the common ancestor. In addition, cell-free DNA was analyzed using exome sequence in five patients with recurrent HCC, and found that somatic mutations of cell free DNA were similar to the primary HCC only in gIM but not in gMC cases. Taken together, comparison of mutations in a pair of HCCs makes it possible to classify multiple HCCs into MC and IM, which is difficult to be correctly determined in clinical practice. Furthermore liquid biopsy for mutation analysis is available to make treatment plans for multiple HCC patients. Citation Format: Yutaka Midorikawa, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shingo Tsuji, Genta Nagae, Tadatoshi Takayama, Hiroyuki Aburatani. Genetic diagnosis of multiple hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4392. doi:10.1158/1538-7445.AM2017-4392

307 Background: Multiple hepatocellular carcinoma (HCC) is categorized into 2 types; multicentric carcinogeneis (MC) and intrahepatic metastasis (IM). Although discrimination of the types of multiple HCC is of clinical importance, it is difficult to determine it correctly even after histological diagnosis. Methods: In order to classify multiple HCC into MC and IM, we compared pairs of multiple HCC and matched non-tumoral liver samples from 22 patients who were clinically diagnosed MC and 8 patients with IM with regard to molecular aberrations using next generation sequencer. Results: Exome sequence showed that among the 22 patients with clinical MC, 7 patients were genetically determined as having IM (gIM) because of the concordance of mutations, while all the patients with clinical IM were as having MC (gMC). In 15 patients with gIM, 125 mutations (90.6%) per patient were common, which were consistent with the result of a pair of primary HCC, and only a few passenger mutations were different between IM specimens suggesting that IM pairs developed from the common ancestor. On the other hand, 138 somatic mutations per tumor, and no common somatic mutations were identified in the 15 patients with gMC. Clinically, vascular invasion was significantly frequent in gIM group ( P = 0.007). On the other hand, after a median follow-up of 2.56 years (range; 0.27−6.32 years), the median overall survivals were 3.7 years (95%CI, 1.26–6.14) and 3.37 years (2.02−6.32, P = 0.712) in the patients with IM and MC, respectively. The 3-year rates of overall survival were 71.7% and 65.1% in the two groups, respectively. Conclusions: Taken together, genetic comparison of mutations in a pair of HCCs makes it possible to classify MC and IM, which is available to make treatment plan for multiple HCC patients.

Only a few papers have focused on the surgical outcomes of patients with hepatocellular carcinoma (HCC) associated with the metabolic syndrome. We compared the outcomes of patients with metabolic HCC with those of patients with non-B, non-C HCC associated with other etiologies.Metabolic HCC was defined as HCC arising in patients with at least three of the following metabolic disorders: central obesity, dyslipidemia, hypertension, and diabetes mellitus. A total of 246 patients with non-B, non-C HCC were divided into three groups: metabolic HCC (n = 35), alcoholic HCC (n = 114), and cryptogenic HCC (n = 97). Clinical characteristics, surgical data, and survival were compared among the three groups.Metabolic HCC was diagnosed at a significantly higher age than alcoholic (75 vs. 68 years, P = 0.004) and cryptogenic HCCs (75 vs. 71 years, P = 0.027). Postoperative complications occurred significantly higher in patients with metabolic HCC compared with those with cryptogenic HCC (40.0 vs. 22.7 %, P = 0.049). Especially, pulmonary complications were significant in metabolic HCC compared with cryptogenic HCC (22.9 vs. 8.2 %, P = 0.023). The overall survival rates in the metabolic, alcoholic, and cryptogenic HCC groups were 96.7 % (95 % CI, 90.5-100), 96.3 % (95 % CI, 92.8-99.9), and 95.6 % (95 % CI, 91.5-99.9) at 1 year, respectively, and 87.2 % (95 % CI, 74.5-100), 82.9 % (95 % CI, 74.6-92.2), and 84.5 % (95 % CI, 75.7-94.3) at 3 years, respectively (P = 0.84). The disease-free survival rates in each group were 74.4 % (95 % CI, 60.5-91.5), 76.9 % (95 % CI, 69.2-85.5), and 74.3 % (95 % CI, 65.0-84.8) at 1 year, respectively, and 29.3 % (95 % CI, 16.6-51.8), 39.0 % (95 % CI, 29.7-51.2), and 41.1 % (95 % CI, 29.7-56.8) at 3 years, respectively, (P = 0.90).Metabolic HCC patients have specific risks of postoperative complication related to the metabolic syndrome.

Introduction: Pseudomonas aeruginosa community‐acquired pneumonia is an extremely rare clinical presentation but has been recognized in anecdotal reports, even in previously healthy patients. Case presentation: We describe a previously healthy man who developed P. aeruginosa community‐acquired pneumonia (CAP). He died of septic shock with rapidly progressive pulmonary consolidation in the right upper lobe (RUL). We reviewed the literature for P. aeruginosa CAP and identified 19 patients of whom 85 % (n = 17) had cavitations and/or consolidations in the RUL. We found that the odds ratio for death of shock at initial presentation was 8.333 (P = 0.046, 95 % confidence interval 1.034–67.142). We also found that P. aeruginosa CAP should be considered when individuals present with rapidly expanding cavitary pneumonia and/or consolidations in the RUL accompanied by septic shock, even if they have no known severe underlying disease and were previously healthy. Conclusion: We showed here that radiological findings of P. aeruginosa CAP, such as cavitary pneumonia and/or consolidation in the RUL, might be a clinical clue to a diagnosis of CAP as well as the presence of septic shock.