Effectiveness of antibiotic prophylaxis for acute esophageal variceal bleeding in patients with band ligation: A large observational study

BACKGROUND Esophageal variceal bleeding is a severe complication associated with liver cirrhosis and typically necessitates endoscopic hemostasis.The current standard treatment is endoscopic variceal ligation(EVL),and Western guidelines recom-mend antibiotic prophylaxis following hemostasis.However,given the impro-vements in prognosis for variceal bleeding due to advancements in the management of bleeding and treatments of liver cirrhosis and the global concerns regarding the emergence of multidrug-resistant bacteria,there is a need to reassess the use of routine antibiotic prophylaxis after hemostasis.AIM To evaluate the effectiveness of antibiotic prophylaxis in patients treated for EVL.METHODS We conducted a 13-year observational study using the Tokushukai medical database across 46 hospitals.Patients were divided into the prophylaxis group(received antibiotics on admission or the next day)and the non-prophylaxis group(did not receive antibiotics within one day of admission).The primary outcome was composed of 6-wk mortality,4-wk rebleeding,and 4-wk spontaneous bacterial peritonitis(SBP).The secondary outcomes were each individual result and in-hospital mortality.A logistic regression with inverse probability of treatment weighting was used.A subgroup analysis was conducted based on the Child-Pugh classification to determine its influence on the primary outcome measures,while sensitivity analyses for antibiotic type and duration were also performed.RESULTS Among 980 patients,790 were included(prophylaxis:232,non-prophylaxis:558).Most patients were males under the age of 65 years with a median Child-Pugh score of 8.The composite primary outcomes occurred in 11.2%of patients in the prophylaxis group and 9.5%in the non-prophylaxis group.No significant differences in outcomes were observed between the groups(adjusted odds ratio,1.11;95%confidence interval,0.61-1.99;P=0.74).Individual outcomes such as 6-wk mortality,4-wk rebleeding,4-wk onset of SBP,and in-hospital mortality were not significantly different between the groups.The primary outcome did not differ between the Child-Pugh subgroups.Similar results were observed in the sensitivity analyses.CONCLUSION No significant benefit to antibiotic prophylaxis for esophageal variceal bleeding treated with EVL was detected in this study.Global reassessment of routine antibiotic prophylaxis is imperative.

Clinical features of acute esophageal mucosal lesions and reflux esophagitis Los Angeles classification grade D: A retrospective study

BACKGROUND Acute esophageal mucosal lesions(AEMLs)are an underrecognized and largely unexplored disease.Endoscopic findings are similar,and a higher percentage of AEML could be misdiagnosed as reflux esophagitis Los Angeles classification grade D(RE-D).These diseases could have different pathologies and require different treatments.AIM To compare AEML and RE-D to confirm that the two diseases are different from each other and to clarify the clinical features of AEML.METHODS We selected emergency endoscopic cases of upper gastrointestinal bleeding with circumferential esophageal mucosal injury and classified them into AEML and RE-D groups according to the mucosal injury’s shape on the oral side.We examined patient background,blood sampling data,comorbidities at onset,endoscopic characteristics,and outcomes in each group.RESULTS Among the emergency cases,the AEML and RE-D groups had 105(3.1%)and 48(1.4%)cases,respectively.Multiple variables exhibited significantly different results,indicating that these two diseases are distinct.The clinical features of AEML consisted of more comorbidities[risk ratio(RR):3.10;95%confidence interval(CI):1.68–5.71;P<0.001]and less endoscopic hemostasis compared with RE-D(RR:0.25;95%CI:0.10–0.63;P<0.001).Mortality during hospitalization was higher in the AEML group(RR:3.43;95%CI:0.82–14.40;P=0.094),and stenosis developed only in the AEML group.CONCLUSION AEML and RE-D were clearly distinct diseases with different clinical features.AEML may be more common than assumed,and the potential for its presence should be taken into account in cases of upper gastrointestinal bleeding with comorbidities.

DFT-Based Chemical Reactivity Descriptors, Pharmacokinetics and Molecular Docking Studies of Thymidine Derivatives

Thymidine-containing derivatives are considered to be among the most significant derivatives in medicinal chemistry. In this study, we employed a combined computational approach involving density-functional theory (DFT) calculations, molecular docking simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) property predictions. Prediction of activity spectra for substances (PASS) revealed promising antiviral, antimicrobial and anti-carcinogenic activities of these thymidine derivatives. Using Gaussian 09, we optimized the molecular structures of the thymidine derivatives to obtain their stable conformations and calculate their electronic properties. Subsequently, molecular docking simulations were performed to explore the binding interactions between the thymidine derivatives and the active site of the Candida albicans (PDB: 1IYL and 2Y7L) proteins. The docking results were evaluated based on docking scores, hydrogen bonding, and hydrophobic interactions and revealed favorable binding interactions between the thymidine derivatives and the proteins, suggesting their potential as antifungal agents. The thermodynamic properties, including binding free energy, enthalpy, and entropy changes were determined to assess the stability and strength of the ligands-protein complexes. The calculated pharmacokinetic parameters, such as ADMET properties, provided insights into the drug-likeness and potential bioavailability of the thymidine derivatives. These results offer a foundation for further experimental investigations and the design of novel antifungal agents targeting Candida albicans infections.

Chronic thromboembolic pulmonary hypertension is associated with a loss of total lung volume on computed tomography

BACKGROUND Although lung volumes are usually normal in individuals with chronic thromboembolic pulmonary hypertension(CTEPH),approximately 20%-29%of patients exhibit a restrictive pattern on pulmonary function testing.AIM To quantify longitudinal changes in lung volume and cardiac cross-sectional area(CSA)in patients with CTEPH.METHODS In a retrospective cohort study of patients seen in our hospital between January 2012 and December 2019,we evaluated 15 patients with CTEPH who had chest computed tomography(CT)performed at baseline and after at least 6 mo of therapy.We matched the CTEPH cohort with 45 control patients by age,sex,and observation period.CT-based lung volumes and maximum cardiac CSAs were measured and compared using the Wilcoxon signed-rank test and the Mann-Whitney u test.RESULTS Total,right lung,and right lower lobe volumes were significantly reduced in the CTEPH cohort at follow-up vs baseline(total,P=0.004;right lung,P=0.003;right lower lobe;P=0.01).In the CTEPH group,the reduction in lung volume and cardiac CSA was significantly greater than the corresponding changes in the control group(total,P=0.01;right lung,P=0.007;right lower lobe,P=0.01;CSA,P=0.0002).There was a negative correlation between lung volume change and cardiac CSA change in the control group but not in the CTEPH cohort.CONCLUSION After at least 6 mo of treatment,CT showed an unexpected loss of total lung volume in patients with CTEPH that may reflect continued parenchymal remodeling.

Design of Novel Wound Dressing Composed of Collagen and Hyaluronic Acid Containing Epidermal Growth Factor

This research aims to develop a wound dressing composed of collagen (Col) and hyaluronic acid (HA) containing epidermal growth factor (EGF). First important issue is to contain EGF in the wound dressing in a stable state. The sheet-shaped sponge was manufactured by freeze-vacuum drying an aqueous solution of Col. Both sides of sponge were treated with ultraviolet (UV) irradiation to introduce intermolecular cross links between collagen molecules. This sponge was named Sponge-Col. Another sheet-shaped sponge was manufactured by freeze-vacuum drying an aqueous solution of HA containing EGF. This sponge was named Sponge-HA/EGF. The wound dressing was manufactured by laminating Sponge-Col on the top, Sponge-HA/EGF in the middle, and Sponge-Col on the bottom to create a sandwich structure. This method can prevent the reducing of EGF activity due to UV irradiation for intermolecular cross-linking. Second important issue is to enable gradual release of EGF from the wound dressing. The elution behavior of this wound dressing was investigated by measuring the weight change after immersion in water for a predetermined time. This wound dressing showed initially fast elution and subsequent very slow elution properties. The upper layer and lower layer Sponge-Col enabled gradual release of the middle layer Sponge-HA/EGF. This result suggests that EGF contained in the wound dressing is gradually released together with HA from the wound dressing. Third important issue is to provide moist wound-healing environment. The upper layer and lower layer Sponge-Col can provide the wound dressing with high water absorption and long-term water retention properties.

Biomarkers for the early diagnosis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the fifth most common cancer and the second leading cause of cancer-related deaths worldwide. Although the prognosis of patients with HCC is generally poor, the5-year survival rate is > 70% if patients are diagnosed at an early stage. However, early diagnosis of HCC is complicated by the coexistence of inflammation and cirrhosis. Thus, novel biomarkers for the early diagnosis of HCC are required. Currently, the diagnosis of HCC without pathological correlation is achieved by analyzing serum α.fetoprotein levels combined with imaging techniques. Advances in genomics and proteomics platforms and biomarker assay techniques over the last decade have resulted in the identification of numerous novel biomarkers and have improved the diagnosis of HCC. The most promising biomarkers,such as glypican-3, osteopontin, Golgi protein-73 and nucleic acids including microRNAs, are most likely to become clinically validated in the near future. These biomarkers are not only useful for early diagnosis of HCC, but also provide insight into the mechanisms driving oncogenesis. In addition, such molecular insight creates the basis for the development of potentially more effective treatment strategies. In this article,we provide an overview of the biomarkers that are currently used for the early diagnosis of HCC.

Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

It is estimated that 30% of the adult population in Japan is affected by nonalcoholic fatty liver disease (NAFLD). Fatty changes of the liver are generally diagnosed using imaging methods such as abdominal ultrasonography (US) and computed tomography (CT), but the sensitivity of these imaging techniques is low in cases of mild steatosis. Alanine aminotransferase levels may be normal in some of these patients, warranting the necessity to establish a set of parameters useful for detecting NAFLD, and the more severe form of the disease, nonalcoholic steatohepatitis (NASH). Although liver biopsy is currently the gold standard for diagnosing progressive NASH, it has many drawbacks, such as sampling error, cost, and risk of complications. Furthermore, it is not realistic to perform liver biopsies on all NAFLD patients. Diagnosis of NASH using various biomarkers, scoring systems and imaging methods, such as elastography, has recently been attempted. The NAFIC score, calculated from the levels of ferritin, fasting insulin, and type IV collagen 7S, is useful for the diagnosis of NASH, while the NAFLD fibrosis score and the FIB-4 index are useful for excluding NASH in cases of advanced fibrosis. This article reviews the limitations and merits of liver biopsy and noninvasive diagnostic tests in the diagnosis of NAFLD/NASH.

Inflammation-and stress-related signaling pathways in hepatocarcinogenesis

It has been established that cancer can be promoted and exacerbated by inflammation.Hepatocellular carcinoma(HCC) is the fifth most common cancer worldwide,and its long-term prognosis remains poor.Although HCC is a complex and heterogeneous tumor with several genomic mutations,it usually develops in the context of chronic liver damage and inflammation,suggesting that understanding the mechanism(s) of inflammation-mediated hepatocarcinogenesis is essential for the treatment and prevention of HCC.Chronic liver damage induces a persistent cycle of necroinflammation and hepatocyte regeneration,resulting in genetic mutations in hepatocytes and expansion of initiated cells,eventually leading to HCC development.Recently,several inflammation-and stress-related signaling pathways have been identified as key players in these processes,which include the nuclear factor B,signal transducer and activator of transcription,and stress-activated mitogen-activated protein kinase pathways.Although these pathways may suggest potential therapeutic targets,they have a wide range of functions and complex crosstalk occurs among them.This review focuses on recent advances in our understanding of the roles of these signaling pathways in hepatocarcinogenesis.

Is endoscopic papillary balloon dilatation really a risk factor for post-ERCP pancreatitis?

Endoscopic papillary balloon dilatation(EPBD) is useful for decreasing early complications of endoscopic retrograde cholangio-pancreatography(ERCP), including bleeding, biliary infection, and perforation, but it is generally avoided in Western countries because of a relatively high reported incidence of post-ERCP pancreatitis(PEP). However, as the efficacy of endoscopic papillary largeballoon dilatation(EPLBD) becomes widely recognized, EPBD is attracting attention. Here we investigate whether EPBD is truly a risk factor for PEP, and seek safer and more effective EPBD procedures by reviewing past studies. We reviewed thirteen randomised control trials comparing EPBD and endoscopic sphincterotomy(EST) and ten studies comparing direct EPLBD and EST. Three randomized controlled trials of EPBD showed significantly higher incidence of PEP than EST, but no study of EPLBD did. Careful analysis of these studies suggested that longer and higher-pressure inflation of balloons might decrease PEP incidence. The paradoxical result that EPBD with small-calibre balloons increases PEP incidence while EPLBD does not may be due to insufficient papillary dilatation in the former. Insufficient dilatation could cause the high incidence of PEP through the use of mechanical lithotripsy and stress on the papilla at the time of stone removal. Sufficient dilation of the papilla may be useful in preventing PEP.

Postoperative bleeding in patients on antithrombotic therapy after gastric endoscopic submucosal dissection

To investigated the relationship between postoperative bleeding following gastric endoscopic submucosal dissection (ESD) and individual antithrombotic agents. METHODSA total of 2488 gastric neoplasms in 2148 consecutive patients treated between May 2001 and June 2016 were studied. The antithrombotic agents were categorized into antiplatelet agents, anticoagulants, and other antithrombotic agents, and we included combination therapies [e.g., dual antiplatelet therapy (DAPT)]. The risk factors associated with post-ESD bleeding, namely, antithrombotic agents overall, individual antithrombotic agents, withdrawal or continuation of antithrombotic agents, and bleeding onset period (during the first six days or thereafter), were analyzed using univariate and multivariate analyses. RESULTSThe en bloc resection and complete curative resection rates were 99.2% and 91.9%, respectively. Postoperative bleeding occurred in 5.1% cases. Bleeding occurred in 10.3% of the patients administered antithrombotic agents. Being male (P = 0.007), specimen size (P < 0.001), and antithrombotic agent used (P < 0.001) were independent risk factors for postoperative bleeding. Heparin bridging therapy (HBT) (P = 0.002) and DAPT/multidrug combinations (P < 0.001) were independent risk factors associated with postoperative bleeding. The bleeding rate of the antithrombotic agent continuation group was significantly higher than that of the withdrawal group (P < 0.01). Bleeding within postoperative day (POD) 6 was significantly higher in warfarin (P = 0.015), and bleeding after POD 7 was significantly higher in DAPT/multidrug combinations (P = 0.007). No thromboembolic events were reported. CONCLUSIONWe must closely monitor patients administered HBT and DAPT/multidrug combinations after gastric ESD, particularly those administered multidrug combinations after discharge.

Potentiality of immunotherapy against hepatocellular carcinoma

Hepatocellular carcinoma(HCC),the predominant form of primary liver cancer,is the fifth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence,treatment options remain limited for advanced HCC,and as a result prognosis continues to be poor. Current therapeutic options,surgery,chemotherapy and radiotherapy,have only modest efficacy. New treatment modalities to prolong survival and to minimize the risk of adverse response are desperately needed for patients with advanced HCC. Tumor immunotherapy is a promising,novel treatment strategy that may lead to improvements in both treatment-associated toxicity and outcome. The strategies have developed in part through genomic studies that have yielded candidate target molecules and in part through basic biology studies that have defined the pathways and cell types regulating immune response. Here,we summarize the various types of HCC immunotherapy and argue that the newfound field of HCC immunotherapy might provide critical advantages in the effort to improve prognosis of patients with advanced HCC. Already several immunotherapies,such as tumor-associated antigen therapy,immune checkpoint inhibitors and cell transfer immunotherapy,have demonstrated safety and feasibility in HCC patients. Unfortunately,immunotherapy currently has low efficacy in advanced stage HCC patients; overcoming this chal lenge will place immunotherapy at the forefront of HCC treatment,possibly in the near future.

Contrast enhanced ultrasound of hepatocellular carcinoma

Sonazoid(Daiichi Sankyo,Tokyo,Japan),a secondgeneration of a lipid-stabilized suspension of a perfluorobutane gas microbubble contrast agent,has been used clinically in patients with liver tumors and for harmonic gray-scale ultrasonography(US)in Japan since January 2007.Sonazoid-enhanced US has two phases of contrast enhancement:vascular and late.In the late phase of Sonazoid-enhanced US,we scanned the whole liver using this modality at a low mechanical index(MI)without destroying the microbubbles, and this method allows detection of small viable hepatocellular carcinoma(HCC)lesions which cannot be detected by conventional US as perfusion defects in the late phase.Re-injection of Sonazoid into an HCC lesion which previously showed a perfusion defect in the late phase is useful for confirming blood flow intothe defects.High MI intermittent imaging at 2 frames per second in the late phase is also helpful in differentiation between necrosis and viable hypervascular HCC lesions.Sonazoid-enhanced US by the coded harmonic angio mode at a high MI not only allows clear observation of tumor vessels and tumor enhancement, but also permits automatic scanning with Sonazoidenhanced three dimensional(3D)US.Fusion images combining US with contrast-enhanced CT or contrastenhanced MRI have made it easy to detect typical or atypical HCC lesions.By these methods,Sonazoidenhanced US can characterize liver tumors,grade HCC lesions histologically,recognize HCC dedifferentiation, evaluate the efficacy of ablation therapy or transcatheter arterial embolization,and guide ablation therapy for unresectable HCC.This article reviews the current developments and applications of Sonazoid-enhanced US and Sonazoid-enhanced 3D US for diagnosing and treating hepatic lesions,especially HCC.

Prospective study of differential diagnosis of hepatic tumors by pattern-based classification of contrast-enhanced sonography

AIM: To prospectively evaluate the usefulness of a pattern-based classification of contrast-enhanced sonographic findings for differential diagnosis of hepatic tumors. METHODS: We evaluated the enhancement pattern of the contrast-enhanced sonography images in 586 patients with 586 hepatic lesions, consisting of 383 hepatocellular carcinomas, 89 metastases, and 114 hemangiomas. After injecting a galactose-palmitic acid contrast agent, lesions were scanned by contrast- enhanced harmonic gray-scale sonography in three phases: arterial, portal, and late. The enhancement patterns of the initial 303 lesions were classified retrospectively, and multiple logistic regression analysis was used to identify enhancement patterns that allowed differentiation between hepatic tumors. We then used the pattern-based classification of enhancement we had retrospectively devised to prospectively diagnose 283 liver tumors. RESULTS: Seven enhancement patterns were found to be significant predictors of different hepatic tumors. The presence of homogeneous or heterogeneous enhancement both in the arterial and portal phase was the typical enhancement pattern for hepatocellular carcinoma, while the presence of peritumoral vessels in the arterial phase and ring enhancement or a perfusion defect in the portal phase was the typical enhancement pattern for metastases, and the presence of peripheral nodular enhancement both in the arterial and portal phase was the typical enhancement pattern forhemangioma. The sensitivity, specificity, and accuracy of prospective diagnosis based on the combinations of enhancement patterns, respectively, were 93.2%, 96.2%, and 94.0% for hepatocellular carcinoma, 87.9%, 99.6%, and 98.2% for metastasis, and 95.6%, 94.1%, and 94.3% for hemangioma. CONCLUSION: The pattern-based classification of the contrast-enhanced sonographic findings is useful for differentiating among hepatic tumors.

Differentiation of focal liver lesions using three-dimensional ultrasonography: Retrospective and prospective studies

AIM: To differentiate focal liver lesions based on enhancement patterns using three-dimensional ultrasonography (3D US) with perflubutane-based contrast agent.METHODS: Two hundred and eighty two patients with focal liver lesions,including 168 hepatocellular carcinomas (HCCs),63 metastases,40 hemangiomas and 11 focal nodular hyperplasias (FNHs),were examined by 3D US with perflubutane-based contrast agent.Tomographic ultrasound images and sonographic angiograms were reconstructed.Among 282 lesions,enhancement patterns of 163 lesions between January 2007 and October 2007 were analyzed retrospectively.Then from November 2007 to May 2008,compared with contrast-enhanced (CE) 2D US,CE 3D US was performed on 119 lesions for prospective differential diagnosis.Sensitivity,specificity,area under receiver operating characteristic curve (Az) and inter-reader agreement were assessed.RESULTS: With the tridimensional view,dominant enhancement patterns were revealed as diffuse enhancement or peripheral ring-like enhancement,followed with washout change for HCCs or metastases,respectively,and peripheral nodular enhancement or diffuse enhancement with spoke-wheel arteries,followed by persistent enhancement for hemangiomas or FNHs,respectively.At CE 3D US,the prospective differentiation of lesions showed sensitivity 92% (mean for two readers),specificity 91% and Az value 0.95 for HCCs,84%,97%,and 0.95 for metastases,91%,98%,and 0.98 for hemangiomas and 80%,99%,and 0.99 for FNHs,respectively,while good to excellent inter-reader agreement was achieved.No significant difference exists between prospective diagnosis accuracy at CE 3D US and that at CE 2D US.CONCLUSION: CE 3D US provides a spatial perspective for liver tumor enhancement,and could help in differentiating focal liver lesions.

Clinicopathological features of early gastric cancers arising in Helicobacter pylori uninfected patients

BACKGROUND Persistent Helicobacter pylori(H.pylori)infection causes chronic inflammation,atrophy of the gastric mucosa,and a high risk of developing gastric cancer.In recent years,awareness of eradication therapy has increased in Japan.As H.pylori infections decrease,the proportion of gastric cancers arising from H.pylori uninfected gastric mucosa will increase.The emergence of gastric cancer arising in H.pylori uninfected patients though rarely reported,is a concern to be addressed and needs elucidation of its clinicopathological features.AIM To evaluate the clinicopathological features of early gastric cancer in H.pyloriuninfected patients.METHODS A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019.Of these,30 lesions in 30 patients were diagnosed as H.pylori-uninfected gastric cancer(Hp UIGC).We defined a patient as H.pylori-uninfected using the following three criteria:(1)The patient did not receive treatment for H.pylori,which was determined by investigating medical recordsand conducting patient interviews;(2)Lack of endoscopic atrophy;and(3)The patient was negative for H.pylori after being tested at least twice using various diagnostic methods,including serum anti-H.pylori-Ig G antibody,urease breath test,rapid urease test,and microscopic examination.RESULTS The frequency of Hp UIGC was 1.2%(30/2462)for the patients in our study.The study included 19 males and 11 females with a mean age of 59 years.The location of the stomach lesions was divided into three sections;upper third(U),middle third(M),lower third(L).Of the 30 lesions,15 were U,1 was M,and 14 were L.Morphologically,17 lesions were protruded and flat elevated type(0-I,0-IIa,0-IIa+IIc),and 13 lesions were flat and depressed type(0-IIb,0-IIc).The median tumor diameter was 8 mm(range 2-98 mm).Histological analysis revealed that22 lesions(73.3%)were differentiated type.The Hp UIGC lesions were classified into fundic gland type adenocarcinoma(7 cases),foveolar type welldifferentiated adenocarcinoma(8 cases),intestinal phenotype adenocarcinoma(7 cases),and pure signet-ring cell carcinoma(8 cases).Among 30 Hp UIGCs,24 lesions(80%)were limited to the mucosa;wherein,the remaining 6 lesions showed submucosal invasion.One of the submucosal invasive lesions showed more than 500μm invasion.The mucin phenotype analysis identified 7 Hp UIGC with intestinal phenotype and 23 with gastric phenotype.CONCLUSION We elucidated the clinicopathological characteristics of Hp UIGC,revealing recognition not only undifferentiated-type but also differentiated-type.In addition,intestinal phenotype tumors were also observed and could be an important tip.

Diagnosis and therapeutic strategies for small bowel vascular lesions

Small bowel vascular lesions, including angioectasia (AE), Dieulafoy’s lesion (DL) and arteriovenous malformation (AVM), are the most common causes of obscure gastrointestinal bleeding. Since AE are considered to be venous lesions, they usually manifest as a chronic, well-compensated condition. Subsequent to video capsule endoscopy, deep enteroscopy can be applied to control active bleeding or to improve anemia necessitating blood transfusion. Despite the initial treatment efficacy of argon plasma coagulation (APC), many patients experience re-bleeding, probably because of recurrent or missed AEs. Pharmacological treatments can be considered for patients who have not responded well to other types of treatment or in whom endoscopy is contraindicated. Meanwhile, a conservative approach with iron supplementation remains an option for patients with mild anemia. DL and AVM are considered to be arterial lesions;therefore, these lesions frequently cause acute life-threatening hemorrhage. Mechanical hemostasis using endoclips is recommended to treat DLs, considering the high re-bleeding rate after primary APC cauterization. Meanwhile, most small bowel AVMs are large and susceptible to re-bleeding therefore, they usually require surgical resection. To achieve optimal diagnostic and therapeutic approaches for each type of small bowel lesion, the differences in their epidemiology, pathology and clinical presentation must be understood.

Cellular reprogramming and hepatocellular carcinoma development

Hepatocellular carcinoma(HCC)is one of the most common cancers,and is also the leading cause of death worldwide.Studies have shown that cellular reprogramming contributes to chemotherapy and/or radiotherapy resistance and the recurrence of cancers.In this article,we summarize and discuss the latest findings in the area of cellular reprogramming in HCC.The aberrant expression of transcription factors OCT4,KLF4,SOX2,c-MYC,NANOG,and LIN28 have been also observed,and the expression of these transcription factors is associated with unfavorable clinical outcomes in HCC.Studies indicate that cellular reprogramming may play a critical role in the occurrence and recurrence of HCC.Recent reports have shown that DNA methylation,miRNAs,tumor microenvironment,and signaling pathways can induce the expression of stemness transcription factors,which leads to cellular reprogramming in HCC.Furthermore,studies indicate that therapies based on cellular reprogramming could revolutionize HCC treatment.Finally,a novel therapeutic concept is discussed:reprogramming control therapy.A potential reprogramming control therapy method could be developed based on the reprogramming demonstrated in HCC studies and applied at two opposing levels:differentiation and reprogramming.Our increasing understanding and control of cellular programming should facilitate the exploitation of this novel therapeutic concept and its application in clinical HCC treatment,which may represent a promising strategy in the future that is not restricted to liver cancer.

Successful initial ablation therapy contributes to survival in patients with hepatocellular carcinoma

AIM： To evaluate the outcome predictors of percutaneous ablation therapy in patients with unresectable hepatocellular carcinoma （HCC）, especially to identify whether the initial treatment response contributes to the survival of the patients. METHODS： The study cohort included 153 patients with single （102） and two or three （51） HCC nodules 5 cm or less in maximum diameter. As an initial treatment, 110 patients received radiofrequency ablation and 43 patients received percutaneous ethanol injection. RESULTS： The Kaplan-Meier estimates of overall 3- and S-year survival rates were 75% and 59%, respectively. The log-rank test revealed statistically significant differences in the overall survivals according to ChildPugh class （P = 0.0275）, tumor size （P = 0.0130）, serum albumin level （P = 0.0060）, serum protein induced by vitamin K absence or antagonist Ⅱ level （P = 0.0486）, and initial treatment response （P = 0.0130）. The independent predictors of survival were serum albumin level （dsk ratio, 3.216; 950 CI, 1.407-7.353; P = 0.0056） and initial treatment response （risk ratio, 2.474; 95% CI, 1.076-5.692; P = 0.0330） based on the Cox proportional hazards regression models. The patients had a serum albumin level 3.5 g/dL and the 3- and 5-year survival rates of 86% and 82%. CONCLUSION： In HCC patients treated with percutaneous ablation therapy, serum albumin level and initial treatment response are the independent outcome predictors.

Can the biliary enhancement of Gd-EOB-DTPA predict the degree of liver function?

BACKGROUND: Excretion of gadolinium-ethoxybenzyl-diethyl- enetriamine pentaacetic acid (Gd-EOB-DTPA) in the bile may be related to liver function, because of elimination from the liver after preferential uptake by hepatocytes. The purpose of this study was to investigate the relation between liver and biliary enhancement in patients with or without liver dysfunction, and to compare the tumor-to-liver contrast in these patients. METHODS: Forty patients [group 1: normal liver and Child Pugh class A in 20 patients, group 2: Child-Pugh class B in 18 patients and Child-Pugh C in 2] were evaluated. All patients underwent MR imaging of the liver using a 1.5-Tesla system. T1 weighted 3D images were obtained at 5, 10, 15 and 20 minutes after Gd-EOB-DTPA injection. The relation between group 3 (total bilirubin <1.8 mg/dL) and group 4 (total bilirubin ≥1.8 mg/dL) was investigated at 20 minutes. Liver and biliary signals were measured, and compared between groups 1 and 2 or groups 3 and 4. Tumor-to-liver ratio was also evaluated between groups 1 and 2. Scheffé’s post-hoc test after two-way repeated measures ANOVA and Pearson’s correlation test were used for statistical analysis. RESULTS: Liver enhancement showed significant difference at all time points between groups 1 and 2. Biliary enhancement did not show a significant difference between groups 1 and 2 at 5 minutes, but did at 10, 15 and 20 minutes. At 20 minutes significant differences between groups 3 and 4 were seen for liver and biliary enhancement. At all time points, liver enhancement correlated with biliary enhancement in both groups. At 5 minutes and 20 minutes, statistical differences between groups 1 and 2 were seen for tumor-to-liver ratio.CONCLUSIONS: The degree of biliary enhancement has a close correlation to that of liver enhancement. It is especially important that insufficient liver enhancement causes lower tumor-to-liver contrast in the hepatobiliary phase of Gd-EOB- DTPA.

Regenerative therapy for neuronal diseases with transplantation of somatic stem cells

Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem(ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease,cerebral infarction and congenital neuronal diseases.Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However,non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors,gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here,the recent progress of regenerative therapies using various somatic stem cells is described.