Advances in discovery of novel investigational agents for functional cure of chronic hepatitis B:A comprehensive review of phases II and III therapeutic agents

Chronic hepatitis B virus(HBV)infection affects over 295 million people globally and an estimated 1.6 million people in the United States.It is associated with significant morbidity and mortality due to cirrhosis,liver failure,and liver cancer.Antiviral therapy with oral nucleos(t)ide analogues is associated with high rates of virologic suppression,which in turn has been associated with a decreased risk of liver complications.However,current antiviral regimens are limited by concerns with adverse effects,adherence,resistance,long-term treatment,and ongoing risk for liver events.Novel investigational agents are currently in development and are targeted at achieving functional cure with sustained hepatitis B surface antigen(HBsAg)loss and suppression of HBV DNA.Herein we review key evidence from phases II and III trials defining the efficacy and safety profiles for key investigational agents for functional cure of chronic hepatitis B,including core/capsid inhibitors,entry inhibitors,RNA interference(siRNA/ASO),HBsAg inhibitors,Toll-like receptor agonists,checkpoint inhibitors,and therapeutic vaccines.

Resection of pancreatic cystic neoplasms in recurrent acute pancreatitis prevents recurrent pancreatitis but does not identify more malignancies

BACKGROUND Recurrent acute pancreatitis(RAP)may be a presenting feature of and an indication for resection of pancreatic cysts,including intra-ductal papillary mucinous neoplasm(IPMN).Few data are available regarding the prevalence of malignancy and post-operative RAP in this population.AIM To study the role of resection to help prevent RAP and analyze if presentation as RAP would be a predictor for malignancy.METHODS This retrospective study assessed 172 patients who underwent surgical resection of pancreatic cystic neoplasms at a university hospital between 2002 and 2016.The prevalence of preoperative high-risk cyst features,and of neoplasia was compared between patients with and without RAP.To identify the cause of pancreatitis,all the patients had a detailed history of alcohol,smoking,medications obtained,and had cross-sectional imaging(contrast-enhanced computed tomography/magnetic resonance imaging)and endoscopic ultrasound to look for gallstone etiology and other structural causes for pancreatitis.The incidence of RAP post-resection was the primary outcome.RESULTS IPMN accounted for 101 cases(58.7%){[branch duct(BD)59(34.3%),main duct(MD)42](24.4%)}.Twenty-nine(16.9%)presented with RAP(mean 2.2 episodes):15 had BD-IPMN,8 MD-IPMN,5 mucinous cystic neoplasm and 1 serous cystic neoplasm.Malignancy was similar among those with vs without RAP for all patients[6/29(20.7%)vs 24/143(16.8%)]and IPMN patients[6/23(26.1%)vs 23/78(29.5%)],although tended to be higher with RAP in BD-IPMN,[5/15(33.3%)vs 3/44(6.8%),P=0.04].At mean follow-up of 7.2 years,1(3.4%)RAP patient had post-resection RAP.The mean episodes of acute pancreatitis before vs after surgery were 3.4 vs 0.02(P<0.0001).CONCLUSION Malignancy was not increased in patients with pancreatic cystic neoplasms who have RAP compared to those without RAP.In addition,specific cyst characteristics were not clearly associated with RAP.The incidence of RAP was markedly decreased in almost all patients following cyst resection.

Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy

Cirrhosis is a leading cause of morbidity and mortality,impacting more than 120 million people worldwide.Although geographic differences exist,etiologic factors such as alcohol use disorder,chronic viral hepatitis infections,and non-alcoholic fatty liver disease are prevalent in nearly every region.Historically,significant effort has been devoted to modifying these risks to prevent disease progression.Nevertheless,more than 11%of patients with compensated cirrhosis experience hepatic decompensation each year.This transition signifies the most important prognostic factor in the natural history of the disease,corresponding to a decline in median survival to below 2 years.Over the past decade,the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized,and non-selective beta-blockers have emerged as the most effective option to date.However,a critical therapeutic gap still exists,and additional therapies have been proposed,including statins,rifaximin,and sodium-glucose cotransporter-2 inhibitors.Based on the results of innovative retrospective analyses and small-scale prospective trials,these pharmacotherapies represent promising options,but further studies,including randomized controlled trials,are necessary before they can be incorporated into clinical use.This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.

Emerging concepts in the care of patients with cirrhosis and septic shock

Septic shock impacts approximately 6% of hospitalized patients with cirrhosis and is associated with high rates of morbidity and mortality. Although a number of landmark clinical trials have paved the way for incremental improvements in the diagnosis and management of septic shock in the general population, patients with cirrhosis have largely been excluded from these studies and critical knowledge gaps continue to impact the care of these individuals. In this review,we discuss nuances in the care of patients with cirrhosis and septic shock using a pathophysiology-based approach. We illustrate that septic shock may be challenging to diagnose in this population in the context of factors such as chronic hypotension, impaired lactate metabolism, and concomitant hepatic encephalopathy. Furthermore, we demonstrate that the application of routine interventions such as intravenous fluids, vasopressors, antibiotics, and steroids should be carefully considered among those with decompensated cirrhosis in light of hemodynamic, metabolic, hormonal, and immunologic disturbances. We propose that future research should include and characterize patients with cirrhosis in a systematic manner, and clinical practice guidelines may need to be refined accordingly.

RNA modifications in the progression of liver diseases:from fatty liver to cancer

Non-alcoholic fatty liver disease(NAFLD)has emerged as a prominent global health concern associated with high risk of metabolic syndrome,and has impacted a substantial segment of the population.The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis(NASH),which can progress to cirrhosis and hepatocellular carcinoma(HCC)and is increasingly becoming a prevalent indication for liver transplantation.The existing therapeutic options for NAFLD,NASH,and HCC are limited,underscoring the urgent need for innovative treatment strategies.Insights into gene expression,particularly RNA modifications such as N6methyladenosine(m^(6)A),hold promising avenues for interventions.These modifications play integral roles in RNA metabolism and cellular functions,encompassing the entire NAFLD-NASH-HCC progression.This review will encompass recent insights on diverse RNA modifications,including m^(6)A,pseudouridine(Ψ),N^(1)-methyladenosine(m^(1)A),and 5-methylcytidine(m^(5)C)across various RNA species.It will uncover their significance in crucial aspects such as steatosis,inflammation,fibrosis,and tumorigenesis.Furthermore,prospective research directions and therapeutic implications will be explored,advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions.

Recipient functional status impacts on short and long-term intestinal transplant outcomes in United States adults

BACKGROUND Recipient functional status prior to transplantation has been found to impact post-transplant outcomes in heart,liver and kidney transplants.However,information on how functional status,before and after transplant impacts post-transplant survival outcomes is lacking.AIM To investigate the impact of recipient functional status on short and long term intestinal transplant outcomes in United States adults.METHODS We conducted a retrospective cohort study on 1254 adults who underwent first-time intestinal transplantation from 2005 to 2022.The primary outcome was mortality.Using the Karnofsky Performance Status,functional impairment was categorized as severe,moderate and normal.Analyses were conducted using Kaplan-Meier curves and multivariable Cox regression.RESULTS The median age was 41 years,majority(53.4%)were women.Severe impairment was present in 28.3%of recipients.The median survival time was 906.6 days.The median survival time was 1331 and 560 days for patients with normal and severe functional impairment respectively.Recipients with severe impairment had a 56%higher risk of mortality at one year[Hazard ratio(HR)=1.56;95%CI:1.23–1.98;P<0.001]and 58%at five years(HR=1.58;95%CI:1.24–2.00;P<0.001)compared to patients with no functional impairment.Recipients with worse functional status after transplant also had poor survival outcomes.CONCLUSION Pre-and post-transplant recipient functional status is an important prognostic indicator for short-and long-term intestinal transplant outcomes.

Treatment of portal hypertension

Portal hypertension is the main complication of cirrhosis and is defined as an hepatic venous pressure gradient （HVPG） of more than 5 mmHg. Clinically significant portal hypertension is defined as HVPG of 10 mmHg or more. Development of gastroesophageal varices and variceal hemorrhage are the most direct consequence of portal hypertension. Over the last decades significant advancements in the field have led to standard treatment options. These clinical recommendations have evolved mostly as a result of rando.mized controlled trials and consensus conferences among experts where existing evidence has been reviewed and future goals for research and practice guidelines have been pro- posed. Management of varices/variceal hemorrhage is based on the clinical stage of portal hypertension. No specific treatment has shown to prevent the formation of varices. Prevention of first variceal hemorrhage depends on the size/characteristics of varices. In patients with small varices and high risk of bleeding, nonselective β-blockers are recommended, while patients with medium/large varices can be treated with either β-blockers or esophageal band ligation. Standard ofcare for acute variceal hemorrhage consists of vasoacrive drugs, endoscopic band ligation and antibiotics prophylaxis. Transjugular intrahepatic portosystemic shunt （TIPS） is reserved for those who fail standard of care or for patients who are likely to fail （＂early TIPS＂）. Prevention of recurrent variceal hemorrhage consists of the combination of β-blockers and endoscopic band ligation.

Hydroxycut hepatotoxicity:A case series and review of liver toxicity from herbal weight loss supplements

Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxicity, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the setting of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements, and their individual components which have demon-strated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted.

Environmental risk factors for inflammatory bowel diseases: Evidence based literature review

AIM: To advances in genetics and immunology have contributed to the current understanding of the pathogenesis of inflammatory bowel diseases(IBD). METHODS: The current opinion on the pathogenesis of IBD suggests that genetically susceptible individuals develop intolerance to dysregulated gut microflora(dysbiosis) and chronic inflammation develops as a result of environmental insults. Environmental exposures are innumerable with varying effects during the life course of individuals with IBD. Studying the relationship between environmental factors and IBD may provide the missing link to increasing our understanding of the etiology and increased incidence of IBD in recent years with implications for prevention, diagnosis, and treatment. Environmental factors are heterogeneous and genetic predisposition, immune dysregulation, or dysbiosis do not lead to the development of IBD in isolation. RESULTS: Current challenges in the study of environmental factors and IBD are how to effectively translate promising results from experimental studies to humans in order to develop models that incorporate the complex interactions between the environment, genetics, immunology, and gut microbiota, and limited high quality interventional studies assessing the effect of modifying environmental factors on the natural history and patient outcomes in IBD.CONCLUSION: This article critically reviews the current evidence on environmental risk factors for IBD and proposes directions for future research.

Pseudocirrhosis in a pancreatic cancer patient with liver metastases: A case report of complete resolution of pseudocirrhosis with an early recognition and management

We report a case of pseudocirrhosis arising in the setting of regression of liver metastases from pancreatic cancer. A 55-year-old asymptomatic woman presented to our clinic with newly diagnosed metastatic pancreatic cancer with extensive liver metastases. She underwent systemic chemotherapy with gemcitabine and oxaliplatin (GEMOX). After 8 cycles of therapy, she had a remarkable response to the therapy evidenced by decline of carcinoembryonic antigen (CEA) and CA19 by > 50% and nearly complete resolution of hepatic metastases in computed tomography (CT) scan. Shortly after, she developed increasing bilateral ankle edema and ascites, associated with dyspnea, progressive weight gain, and declining performance status. Gemcitabine and oxaliplatin were discontinued as other causes of her symptoms such as congestive heart disease or venous thrombosis were ruled out. CT scan 6 mo after the initiation of GEMOX revealed worsening ascites with a stable pancreatic mass. However, it also revealed a lobular hepatic contour, segmental atrophy, and capsular retraction mimicking the appearance of cirrhosis. She was managed with aggressive diuresis and albumin infusions which eventually resulted in a resolution of the above- mentioned symptoms as well as complete resolution of pseudocirrhotic appearance of the liver and ascites in CT scan. This case demonstrates that pancreatic cancer patients can develop pseudocirrhosis. Clinicians and radiologist should be well aware of this entity asearly recognition and management can lead to a near complete recovery of liver function and much improved quality of life as illustrated in this case.

Combination strategies for pharmacologic treatment of nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation,and hepatocyte injury with or without fibrosis. It has emerged as thesecond leading indication for liver transplantation with a rising death rate in thenon-transplantable population. While there are many drugs in evaluation,currently no approved therapies are on the market for this condition. Given thisimportance, the Food and Drug Administration has provided formal guidanceregarding drug development for stopping or reversing NASH or NASH associatedfibrosis. The complex pathogenesis of NASH and its bidirectional relationshipwith metabolic syndrome has highlighted multiple drugs of interest thataddress metabolic, inflammatory, and fibrotic factors. A few promising liverspecific targets include farnesoid X receptor agonists and peroxisome proliferatoractivatedreceptor agonists. Previously studied drug classes such as glucagon-likepeptide-1 analogs or sodium/glucose transport protein 2 inhibitors have alsodemonstrated ability to improve hepatic steatosis. Here we discuss currentrationale, scientific work, and preliminary data in combining multiple drugs forthe purposes of a multimodal attack on the pathogenesis of NASH. We highlightmultiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve aresponse rate higher than previously assessed monotherapies for this condition.Ultimately, one of these combination strategies may rise above in its safety andefficacy to become a part of a standardized approach to NASH.

Alternative uses of lumen apposing metal stents

The advent of lumen apposing metal stents(LAMS)has revolutionized the management of many complex gastroenterological conditions that previously required surgical or radiological interventions.These procedures have garnered popularity due to their minimally invasive nature,higher technical and clinical success rate and lower rate of adverse events.By virtue of their unique design,LAMS provide more efficient drainage,serve as conduit for endoscopic access,are associated with lower rates of leakage and are easy to be removed.Initially used for drainage of pancreatic fluid collections,the use of LAMS has been extended to gallbladder and biliary drainage,treatment of luminal strictures,creation of gastrointestinal fistulae,pancreaticobiliary drainage,improved access for surgically altered anatomy,and drainage of intra-abdominal and pelvic abscesses as well as post-surgical fluid collections.As new indications of endosonographic techniques and LAMS continue to evolve,this review summarizes the current role of LAMS in the management of these various complex conditions and also highlights clinical pearls to guide successful placement of LAMS.

Endoscopic treatment of gastroparesis

Gastroparesis has traditionally been a largely medically managed disease with refractory symptoms typically falling under the umbrella of the surgical domain.Surgical options include, but are not limited to, gastrostomy,jejunostomy, pyloromyotomy, or pyloroplasty,and the Food and Drug Administration approvedgastric electrical stimulation implantation. Endoscopic management of gastroparesis most commonly involves intrapyloric botulinum toxin injection; however, there exists a variety of endoscopic approaches on the horizon that have the potential to radically shift standard of care.Endoscopic management of gastroparesis seeks to treat delayed gastric emptying with a less invasive approach compared to the surgical approach. This review will serve to highlight such innovative and potentially transformative, endoscopic interventions available to gastroenterologists in the management of gastroparesis.

Salmonella Berta myocarditis:Case report and systematic review of non-typhoid Salmonella myocarditis

AIM: To study trends in the epidemiology,clinical presentation,microbiology and prognosis of nontyphoid Salmonella(NTS) myocarditis.METHODS: We performed a systematic literature search for all reported NTS cases. The search yielded 838 publications. A total of 21 papers were deemed eligible. No language restrictions were enforced. Articles that were not written in English were translated. Pre-specified data such as clinical presentation,electrocardiogram(ECG) changes,transthoracic echocardiographic findings,cardiac magnetic resonance findings,microbiology cultures,Salmonella species,inflammatory markers(erythrocyte sedimentation rate and C-reactive protein),cardiac biomarkers and severity of illness were collected using data extraction sheets. Cases were classified by age into 2 groups; pediatric cases(defined as < 18 years old) and adult cases(defined ≥ 18 years old). The mean age of patients and standard deviations were calculated. The data was analyzed with IBM SPSS Statistics(Windows,Version 20.0. Armonk,NY: IBM Corp.) for demographic characteristics,presenting symptoms,microbiology,diagnostic methods,treatment modalities and outcome.RESULTS: From the selected articles,we identified a total of 24 individual cases with verifiable data. There were 20 males with a male to female ratio of 5:1. The mean age at presentation was 30.8 years(range 1 mo-67 years),16% of cases were children aged < 18 years. Most patients presented with chest pain,fever,and abdominal pain. The most common ECG finding was ST elevation. Cardiac biomarkers were elevated in around 70% of cases. Salmonella Enteritidis was the most common NTS isolated. Definitive diagnosis was established by blood and stool cultures in most of the cases. The pediatric and adults cases had similar incidence of bacteremia(40% vs 36.8%) while the pediatric group had more stool cultures positive compared to the adult group(100% vs 63.1%). Eightythree percent of patients received antibiotics and 58% were successfully treated through conservative management. The overall mortality was 24% and 42% of patients required intensive care.CONCLUSION: This systematic review of published cases shows that NTS myocarditis occurs predominantly in young adults and carries a poor prognosis.

Risk of post-operative complications associated with anti-TNF therapy in inflammatory bowel disease

There have been increasing concerns regarding the safety of perioperative anti-tumour necrosis factor (anti-TNF) α agents. We performed a literature review to evaluate the post-operative complications associated with perioperative anti-TNF use in patients with inflammatory bowel disease. A comprehensive review was performed with a literature search utilizing Pub Med, Cochrane, OVID and EMBASE databases according to published guidelines. To date, there are only data for infliximab. There are three published studies which have assessed post-operative complications with perioperative infliximab use in patients with Crohn' s disease (CD), four studies in ulcerative colitis (UC) patients, and one study on both CD and UC patients. Two out of the three studies in CD patients showed no increased post-operative complications associated with perioperative infliximab. Two out of four studies in UC patients also did not show an increase in post-operative complications, and the combined study with CD and UC patients did not show an increased risk as well. Studyresults could not be combined secondary to significant differences in study designs, patient population and definition of their endpoints. There appears to be a risk of post-operative complications associated with TNF therapy in some patients. Based on these data, careful patient selection and prospective data collection should be performed.

TRADITIONAL CHINESE TREATMENT OF CHRONIC GASTRITIS WITH GASTRIC DYSPLASIA——A Clinical Analysis of 70 Cases

Chronic gastritis is a common disease mostfrequently occurring in persons over middle age.With the widespread use of the fibergastroscopicbiopsy technique,an increasing number ofchronic gastritis cases with gastric dysplasia havebeen found.It is generally recognized that mo-derate and severe dysplasia are precancerouslesions.According to reports from

Digital chromoendoscopy utilization in clinical practice: A survey of gastroenterologists in Connecticut

AIM:To use a survey to characterize and identify potential barriers to the use of digital chromoendoscopy(DC)by practicing gastroenterologists.METHODS:An anonymous,internet-based survey was sent to gastroenterologists in Connecticut who were members of one of three national gastrointestinal organizations.The survey collected demographic information,frequency of DC use,types of procedures that the respondent performs,setting of practice(academic vs community),years out of training,amount of training in DC,desire to have DC training and perceived barriers to DC use.Responses were collected anonymously.The primary endpoint was the proportion of endoscopists utilizing DC.Associations between the various data collected were analyzed usingχ2 test.RESULTS:One hundred and twenty-four gastroenterologists(48%)of 261 who received the online survey responded.Seventy-eight percent of surveyed gastroenterologists have used DC during the performance of upper endoscopy and 81%with lower endoscopy.DC was used in more than half of procedures by only 14%of gastroenterologists during upper endoscopy and 12%during lower endoscopy.Twenty-three percent(upper)and 21%(lower)used DC more than one quarter of the time.DC was used for 10%or less of endoscopies by 60%(upper)and53%(lower)of respondents.Endoscopists reported lack of training as the leading deterrent to DC use with36%reporting it as their primary deterrent.Eighty-nine percent of endoscopists never received formal training in DC.Lack of time(30%of respondents),lack of evidence(24%)and lack of reimbursement(10%)were additional deterrents.There were no differences in DC use relative to academic vs community practice setting or years out of training.CONCLUSION:DC is used infrequently by most endoscopists,primarily due to a lack of training.Training opportunities should be expanded to meet the interest expressed by the majority of endoscopists.

Impact of epinephrine volume on further bleeding due to high-risk peptic ulcer disease in the combination therapy era

BACKGROUND In monotherapy studies for bleeding peptic ulcers,large volumes of epinephrine were associated with a reduction in rebleeding.However,the impact of epinephrine volume in patients treated with combination endoscopic therapy remains unclear.AIM To assess whether epinephrine volume was associated with bleeding outcomes in individuals who also received endoscopic thermal therapy and/or clipping.METHODS Data from 132 patients with Forrest class Ia,Ib,and IIa peptic ulcers were reviewed.The primary outcome was further bleeding at 7 d;secondary outcomes included further bleeding at 30 d,need for additional therapeutic interventions,post-endoscopy blood transfusions,and 30-day mortality.Logistic and linear regression and Cox proportional hazards analyses were performed.RESULTS There was no association between epinephrine volume and all primary and secondary outcomes in multivariable analyses.Increased odds for further bleeding at 7 d occurred in patients with elevated creatinine values(aOR 1.96,95%CI 1.30-3.20;P<0.01)or hypotension requiring vasopressors(aOR 6.34,95%CI 1.87-25.52;P<0.01).Both factors were also associated with all secondary outcomes.CONCLUSION Epinephrine maintains an important role in the management of bleeding ulcers,but large volumes up to a range of 10-20 mL are not associated with improved bleeding outcomes among individuals receiving combination endoscopic therapy.Further bleeding is primarily associated with patient factors that likely cannot be overcome by increased volumes of epinephrine.However,in carefully-selected cases where ulcer location or size pose therapeutic challenges or when additional modalities are unavailable,it is conceivable that increased volumes of epinephrine may still be beneficial.

New uses for an old remedy:Digoxin as a potential treatment for steatohepatitis and other disorders

Repurposing of the widely available and relatively cheap generic cardiac glycoside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases.Over the past several years,there have been significant advances in the study of digoxin pharmacology and its potential noncardiac clinical applications,including anti-inflammatory,antineoplastic,metabolic,and antimicrobial use.Digoxin holds promise in the treatment of gastrointestinal disease,including nonalcoholic steatohepatitis and alcoholassociated steatohepatitis as well as in obesity,cancer,and treatment of viral infections,among other conditions.In this review,we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.

Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD) is the most common chronic liver disease in the United States and represents an increasingly important etiology of hepatocellular carcinoma(HCC) with annual cumulative incidence rates ranging from 2% to 12% in cohorts of NAFLD cirrhosis. While the risk of progression of NAFLD to HCC remains higher among patients with fibrosis or cirrhosis, an increasing amount of literature describes NAFLD-HCC as a disease that can occur in the absence of cirrhosis. Efforts to characterize the pathogenesis of NAFLD-HCC have suggested mechanisms that strongly associate with states of hyperinsulinemia and chronic inflammation, cellular mechanisms including adaptive immune responses and hepatic progenitor cell populations, and genetic polymorphisms including mutations of PNPLA3. Current literature describes NAFLD-HCC mostly as a disease of late presentation with lower rates of receipt of curative therapy and worse prognosis. However, a growing body of evidence has reported comparable and potentially more favorable disease-free and overall survival rates among patients with NAFLD-HCC after receipt of curative treatment. This review summarizes current evidence of epidemiology, pathophysiology, disease presentation, demand and receipt of curative therapy, post-treatment outcomes, and overall survival of NAFLD-associated HCC.