Clinical features and management of primary sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts,resulting in cirrhosis and need for liver transplantation and reduced life expectancy.The majority of cases occur in young and middle-aged men,often in association with inflammatory bowel disease.The etiology of primary sclerosing cholangitis includes immune-mediated components and elements of undefined nature.No effective medical therapy has been identified.The multiple complications of primary sclerosing cholangitis include metabolic bone disease,dominant strictures,bacterial cholangitis,and malignancy,particularly cholangiocarcinoma,which is the most lethal complication of primary sclerosing cholangitis.Liver transplantation is currently the only life-extending therapeutic alternative for patients with end-stage disease,although recurrence in the allografted liver has been described.A PSC-like variant attracting attention is cholangitis marked by raised levels of the immunoglobulin G4 subclass,prominence of plasma cells within the lesions,and steroid responsiveness.

Limited, local, extracolonic spread of mucinous appendiceal adenocarcinoma after perforation with formation of a malignant appendix-to-sigmoid fistula: Case report and literature review

A 68-year-old man presented with progressive right lower quadrant abdominal pain and tenderness without rebound tenderness, and with constipation during the prior 9 mo. Abdomino-pelvic computed tomography and magnetic resonance imaging demonstrated a dilated appendix forming a fistula to the sigmoid colon. Open laparotomy revealed a bulky abdominal tumor involving appendix, cecum, and sigmoid, and extending up to adjacent viscera, without ascites or peritoneal implants. The abdominal mass was removed en bloc, including resection of sigmoid colon, cecum(with preservation of ileocecal valve), appendix, right vas deferens, testicular vessels, and minimal amounts of anterior abdominal wall; and shaving off of small parts of the walls of the urinary bladder and small bowel. Gross and microscopic pathologic examination revealed an appendix-to-sigmoid malignant fistula secondary to perforation of mucinous adenocarcinoma of the appendix with minimal local spread(stage T4). However, the surgical margins were clear, all 13 resected lymph nodes were cancer-free, and pseudomyxoma peritonei or peritoneal implants were not present. The patient did well during 1 year of follow-up with no clinical or radiologic evidence of local recurrence, metastases, or pseudomyxoma peritonei despite presenting with extensive stage T4 cancer that was debulked without administering chemotherapy, and despite presenting with malignant appendiceal perforation. This case illustrates the non-aggressive biologic behavior of this low-grade malignancy. The fistula may have prevented free spillage of cancerous cells and consequent distant metastases by containing the appendiceal contents largely within the colon.

Characterization of CD133^+ parenchymal cells in the liver:Histology and culture

AIM:To reveal the characteristics of CD133+ cells in the liver.METHODS:This study examined the histological characteristics of CD133+ cells in non-neoplastic and neoplastic liver tissues by immunostaining,and also analyzed the biological characteristics of CD133+ cells derived from human hepatocellular carcinoma(HCC) or cholangiocarcinoma cell lines.RESULTS:Immunostaining revealed constant expression of CD133 in non-neoplastic and neoplastic biliary epithelium,and these cells had the immunophenotype CD133+/CK19+/HepPar-1-.A small number of CD133+/CK19-/HepPar-1+ cells were also identified in HCC and combined hepatocellular and cholangiocarcinoma.In addition,small ductal structures,resembling the canal of Hering,partly surrounded by hepatocytes were positive for CD133.CD133 expression was observed in three HCC(HuH7,PLC5 and HepG2) and two cholangiocarcinoma cell lines(HuCCT1 and CCKS1).Fluorescence-activated cell sorting(FACS) revealed that CD133+ and CD133-cells derived from HuH7 and HuCCT1 cells similarly produced CD133+ and CD133-cells during subculture.To examine the relationship between CD133+ cells and the side population(SP) phenotype,FACS was performed using Hoechst 33342 and a monoclonal antibody against CD133.The ratios of CD133+/CD133-cells were almost identical in the SP and non-SP in HuH7.In addition,four different cellular populations(SP/CD133+,SP/CD133-,non-SP/CD133+,and non-SP/CD133-) could similarly produce CD133+ and CD133-cells during subculture.CONCLUSION:This study revealed that CD133 could be a biliary and progenitor cell marker in vivo.However,CD133 alone is not sufficient to detect tumor-initiating cells in cell lines.

Early apoptosis and cell death induced by ATX-S10Na(Ⅱ)-mediated photodynamic therapy are Bax- and p53-dependent in human colon cancer cells

AIM: To investigate the roles of Bax and p53 proteins in photosensitivity of human colon cancer cells by using lysosome-localizing photosensitizer, ATX-S10Na (Ⅱ).METHODS: HCT116 human colon cancer cells and Bax-null or p53-null isogenic derivatives were irradiated with a diode laser. Early apoptosis and cell death in response to photodynamic therapy were determined by MTT assays, annexin V assays, transmission electron microscopy assays, caspase assays and western blotting.RESULTS: Induction of early apoptosis and cell death was Bax- and p53-dependent. Bax and p53 were required for caspase-dependent apoptosis. The levels of anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-xL, were decreased in Bax- and p53-independent manner.CONCLUSION: Our results indicate that early apoptosis and cell death of human colon cancer cells induced by photodynamic therapy with lysosome-localizing photosensitizer ATX-S10Na (Ⅱ) are mediated by p53-Bax network and low levels of Bcl-2 and Bcl-xL proteins. Our results might help in formulating new therapeutic approaches in photodynamic therapy.

Mini-loop ligation of a bleeding duodenal Dieulafoy's lesion

Two percent of gastrointestinal hemorrhages are caused by Dieulafoy's lesions, which are located in duodenum in only 15% of cases. There are no recommendations regarding the prime endoscopic treatment technique for this condition. A 61-year-old woman presented with melena without signs of hemodynamic instability. During an urgent upper endoscopy, blood oozing from the normal mucosa of the duodenum was seen and this was classified as a Dieulafoy's lesion. A mini-loop was opened at the rim of a transparent ligation chamber, at the end of the endoscope, and after aspiration of the lesion, closed and detached. Complete hemostasis was achieved without early or postponed complications. In every day clinical practice, mini-loop ligation is rarely used because of possible complications, such as site ulceration, organ perforation, re-bleeding and possible inexperience of the operator. To the best of our knowledge this is the first case of successful treatment of bleeding duodenal Dieulafoy's lesion by mini-loop ligation.

Direct-acting antiviral agents against hepatitis C virus and lipid metabolism

Hepatitis C virus(HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response(SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type Ⅰ and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

Characteristics of Clostridium difficile infection in patients hospitalized with myelodysplastic syndrome or acute myelogenous leukemia

AIM To evaluate factors associated with Clostridium difficile infection (CDI) and outcomes of CDI in the myelodysplastic syndrome(MDS) and acute myeloid leukemia (AML) population.METHODS After IRB approval,all MDS/AML patients hospitalized at the University of Maryland Greenebaum Comprehensive Cancer Center between August 2011 and December 2013 were identified.Medical charts were reviewed for demographics,clinical information,development of CDI,complications of CDI,and mortality.Patients with CDI,defined as having a positive stool PCR done for clinical suspicion of CDI,were compared to those without CDI in order to identify predictors of disease.A t-test was used for comparison of continuous variables and chisquare or Fisher's exact tests were used for categorical variables,as appropriate.RESULTS Two hundred and twenty-three patients (60.1% male,mean age 61.3 years,13% MDS,87% AML) had 594 unique hospitalizations during the study period.Thirtyfour patients (15.2%) were diagnosed with CDI.Factors significantly associated with CDI included lower albumin at time of hospitalization (P < 0.0001),prior diagnosis of CDI (P < 0.0001),receipt of cytarabine-based chemotherapy (P = 0.015),total days of neutropenia (P = 0.014),and total days of hospitalization (P = 0.005).Gender (P = 0.10),age (P = 0.77),proton-pump inhibitor use (P = 0.73),receipt of antibiotics (P = 0.66),and receipt of DNA hypomethylating agent-based chemotherapy (P = 0.92) were not significantly associated with CDI.CONCLUSION CDI is common in the MDS/AML population.Factors significantly associated with CDI in this population include low albumin,prior CDI,use of cytarabine-based chemotherapy,and prolonged neutropenia.In this study,we have identified a subset of patients in which prophylaxis studies could be targeted.

Update on the endoscopic treatments for achalasia

Achalasia is the most common primary motility disorder of the esophagus and presents as dysphagia to solids and liquids. It is characterized by impaired deglutitive relaxation of the lower esophageal sphincter. Highresolution manometry allows for definitive diagnosis and classification of achalasia, with type Ⅱ being the most responsive to therapy. Since no cure for achalasia exists, early diagnosis and treatment of the disease is critical to prevent end-stage disease. The central tenant of diagnosis is to first rule out mechanical obstruction due to stricture or malignancy, which is often accomplished by endoscopic and fluoroscopic examination. Therapeutic options include pneumatic dilation(PD), surgical myotomy, and endoscopic injection of botulinum toxin injection. Heller myotomy and PD are more efficacious than pharmacologic therapies and should be considered first-line treatment options. Per oral endoscopic myotomy(POEM) is a minimally-invasive endoscopic therapy that might be as effective as surgical myotomy when performed by a trained and experienced endoscopist, although long-term data are lacking. Overall, therapy should be individualized to each patient's clinical situation and based upon his or her risk tolerance, operative candidacy, and life expectancy. In instances of therapeutic failure or symptom recurrence re-treatment is possible and can include PD or POEM of the wall opposite the site of prior myotomy. Patients undergoing therapy for achalasia require counseling, as the goal of therapy is to improve swallowing and prevent late manifestations of the disease rather than to restore normal swallowing, which is unfortunately impossible.

Obstructive jaundice due to a rare periampullary tumor

Gangliocytic paraganglioma is a rare neuroendocrine tumor predominantly arising in the second part of the duodenum with rare local recurrence or metastasis to regional lymph nodes.A 92-year-old female presented with obstructive jaundice.On exam she had pale conjunctiva and icteric sclera.Abdominal examination revealed tenderness in the upper abdomen.Laboratory data was consistent with obstructive jaundice.Computed tomography of the abdomen revealed a dilated gall bladder and a common bile duct(CBD)with no evidence of liver lesions or pancreatic head mass.Endoscopic ultrasonography revealed a 1 cm isoechoic submucosal nodule at the periampullary area,dilated CBD(9 mm),a prominent pancreatic duct(4.1 mm)and a hydropic gall bladder with no stones.Endoscopic retrograde cholangiopancreaticography was performed to relieve obstruction and showed a 1 cm periampullary mass which underwent an en-bloc snare resection.Histopathology analyses with immunohistochemical stains were positive for cytokeratin,synaptophysin,S-100 protein,neuron specific enolase and negative for actin and desmin consistent with periampullary gangliocytic paraganglioma.Periampullary gangliocytic paraganglioma is a rare benign tumor of the small bowel.Common presentation includes abdominal pain and obstructive jaundice which should be included in differential diagnosis of obstructive jaundice.Endoscopic resection is a curative therapy in the absence of local invasion or distant metastasis.

Eight-week ledipasvir/sofosbuvir in non-cirrhotic, treatment-na?ve hepatitis C genotype-1 patients with hepatitis C virus-RNA < 6 million: Single center, real world effectiveness and safety

AIM To evaluate sustained viral response(SVR) of 8-wk ledipasvir/sofosbuvir therapy among non-cirrhotic, genotype-1 hepatitis C virus(HCV) patients with RNA < 6 million IU/m L.METHODS We performed a retrospective cohort study to examine SVR rates, predictors of treatment failure and safety analysis of 8-wk ledipasvir/sofosbuvir(LDV/SOF) therapy among non-cirrhotic, genotype 1 HCV patients with viral load < 6 million IU/m L. Primary outcome was an achievement of SVR at 12 wk after treatment. Secondary outcomes were identifying predictors of treatment failure and adverse events during treatment.RESULTS Total 736 patients: 55% males, 51% Caucasians and 65% were genotype 1a. Non-cirrhotic state of 53% was determined by clinical judgment(imaging, AST, platelet count) and 47% had documented liver fibrosis testing(biopsy, vibration-controlled transient elastography, serum biomarkers). Overall SVR12 was 96%. No difference in SVR12 was seen between patients whose non-cirrhotic state was determined by clinical judgment and patients who had fibrosis testing. Age groups, gender, ethnicity and genotype 1 subtype did not predict SVR. Non-cirrhotic state determined by clinical judgment based on simple, non-invasive tests were not associated with lower SVR [OR = 1.02, 95%CI: 0.48-2.17, P = 0.962]. The AUROC for hepatitis C RNA viral load was 0.734(P < 0.001, 95%CI: 0.66-0.82). HCV RNA 2.2 million IU/m L was identified as the cutoff value with sensitivity 73% and specificity 64%. HCV RNA < 2.2 million IU/m L was associated with significantly higher SVR 98% with OR = 0.22(95%CI: 0.1-0.49, P < 0.001) compared to SVR 92% in HCV RNA ≥ 2.2 million IU/m L. No death or morbidities were reported.CONCLUSION Our outcomes validate safety and effectiveness of 8-wk LDV/SOF therapy in non-cirrhotic, untreated HCV genotype 1 patients with HCV RNA < 6 million IU/m L.

Progression from low-grade dysplasia to malignancy in patients with Barrett's esophagus diagnosed by two or more pathologists

AIM To evaluate annual incidence of low grade dysplasia(LGD) progression to high grade dysplasia(HGD) and/or esophageal adenocarcinoma(EAC) when diagnosis was made by two or more expert pathologists.METHODS Studies evaluating the progression of LGD to HGD or EAC were included. The diagnosis of LGD must be made by consensus of two or more expert gastrointestinal pathologists. Articles were searched in Medline, Pubmed, and Embase. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the I2 statistic. RESULTS Initial search identified 721 reference articles, of which 53 were selected and reviewed. Twelve studies(n = 971) that met the inclusion criteria were included in this analysis. Among the total original LGD diagnoses in the included studies, only 37.49% reached the consensus LGD diagnosis after review by two or more expert pathologists. Total follow up period was 1532 patient-years. In the pooled consensus LGD patients, the annual incidence rate(AIR) of progression to HGD and or EAC was 10.35%(95%CI: 7.56-13.13) and progression to EAC was 5.18%(95%CI: 3.43-6.92). Among the patients down staged from original LGD diagnosis to No-dysplasia Barrett's esophagus, the AIR of progression to HGD and EAC was 0.65%(95%CI: 0.49-0.80). Among the patients down staged to Indefinite for dysplasia, the AIR of progression to HGD and EAC was 1.42%(95%CI: 1.19-1.65). In patients with consensus HGD diagnosis, the AIR of progression to EAC was 28.63%(95%CI: 13.98-43.27). CONCLUSION When LGD is diagnosed by consensus agreement of two or more expert pathologists, its progression towards malignancy seems to be at least three times the current estimates, however it could be up to 20 times the current estimates. Biopsies of all Barrett's esophagus patients with LGD should be reviewed by two expert gastroenterology pathologists. Follow-up strict surveillance programs should be in place for these patients.