The present status and problems with diagnosis and management of dysplasia/colitic cancer in ulcerative colitis

Patients with long-standing UC (ulcerative colitis) have an increased risk of colorectal cancer. Colonoscopic surveillance for UC patients is generally accepted to reduce mortality due to colitic cancer. However, the diagnosis and management of dysplasia remain controversial. The literature about the present status of and problems with diagnosis and management of dysplasia/colitic cancer was reviewed. The problems that arise are: (1) the surveillance program is different in each guideline; (2) the biopsy number that the guidelines propose for surveillance is too large to observe, and there is no adequate evidence of benefit from this number; (3) direct evidence to prove the efficacy of the present surveillance methods is not shown; (4) significant variability is thought to exist between diagnosticians in the diagnosis of low-grade dysplasia (LGD) and indefinite dysplasia (IND); (5) a consensus has not been reached about the management of flat LGD; (6) there is disagreement about the definition of dysplasia-associated lesions (DALM), and there are cases where the differentiation of DALM, adenoma-like mass (ALM)/adenoma-like dysplasia (ALD), sporadic adenoma and even inflammatory polyps is difficult.     

Nonalcoholic steatohepatitis and hepatocellular carcinoma in galectin‐3 knockout mice

Aim: Nonalcoholic fatty liver disease (NAFLD) represents a growing health concern due to its rapidly increasing prevalence worldwide. Nonalcoholic steatohepatitis (NASH) is a progressing form of NAFLD, and recently many studies have reported that it could eventually develop into hepatocellular carcinoma (HCC). We previously reported that 6‐month‐old male galectin‐3 knockout (gal3^?/?) mice developed clinicopathological features similar to those of NAFLD in humans. Our aim was to investigate the changes in liver histology in gal3^?/? mice by long‐term observation. Methods: We initially investigated three 15‐month‐old gal3^?/? mice, of which two developed multiple liver nodules with dysplastic changes. Then, we histopathologically examined the liver specimens of the 15‐, 20‐ and 25‐month‐old gal3^?/? mice and attempted to evaluate the liver morphology by contrast enhanced computed tomography (CT) before sacrifice. Results: At the age of 15 months or later, gal3^?/? mice developed liver nodules with varying degrees of architectural and nuclear atypia based on mild to moderate delicate zone 3 fibrosis. In addition, we successfully confirmed the presence of some of the liver nodules by CT. We report herein that gal3^?/? mice develop dysplastic liver nodules and HCC. Conclusions: We believe that it would be interesting to use this murine model to investigate liver carcinogenesis based on a natural history of NAFLD. Furthermore, CT scanning might be a useful tool for longitudinal evaluation of morphological changes in vivo.     

Double SCN5A mutation underlying asymptomatic Brugada syndrome

OBJECTIVES: The purpose of this study was to identify risk markers in patients with Brugada syndrome. BACKGROUND: Patients with Brugada syndrome who experience syncope or aborted sudden death are at high risk for recurrent lethal arrhythmias. The prognosis and therapeutic approaches in asymptomatic individuals with a Brugada-type ECG (asymptomatic Brugada syndrome) are controversial. METHODS: We genetically screened 30 asymptomatic probands (29 men and 1 woman; mean age 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with Brugada syndrome were excluded from the study. RESULTS: Twenty-nine of 30 patients (96.7%) remained symptom-free for at least 3 years. One patient (case 1) with a family history of sudden death died suddenly during sleep. Ventricular fibrillation was induced by programmed electrical stimulation in 14 of 18 subjects (78%), but none of these 18 subjects developed spontaneous ventricular arrhythmias. Genetic screening failed to identify SCN5A mutations in most cases but demonstrated a novel double missense mutation (K1527R and A1569P) located on the same allele in another asymptomatic subject (case 2). Heterologously expressed mutant Na channels exhibited a negative shift of steady-state inactivation (9.2 mV) and enhanced slow inactivation, suggesting this individual harbors a subclinical channel dysfunction compatible with symptomatic Brugada syndrome. CONCLUSIONS: Asymptomatic individuals with a Brugada-type ECG generally have a better prognosis than their symptomatic counterparts, but a subgroup of these individuals may have a poor prognosis. Severe Na channel dysfunction as a result of SCN5A mutations may not be sufficient to cause symptoms or arrhythmias in patients with Brugada syndrome, suggesting unknown factors or modifier genes influence arrhythmogenesis.     

Immunological detection of severe acute respiratory syndrome coronavirus by monoclonal antibodies

In order to establish immunological detection methods for severe acute respiratory syndrome coronavirus (SARS-CoV), we established monoclonal antibodies directed against structural components of the virus. B cell hybridomas were generated from mice that were hyper-immunized with inactivated SARS-CoV virion. By screening 2,880 generated hybridomas, we established three hybridoma clones that secreted antibodies specific for nucleocapsid protein (N) and 27 clones that secreted antibodies specific for spike protein (S). Among these, four S-protein specific antibodies had in vitro neutralization activity against SARS-CoV infection. These monoclonal antibodies enabled the immunological detection of SARS-CoV by immunofluorescence staining, Western blot or immunohistology. Furthermore, a combination of monoclonal antibodies with different specificities allowed the establishment of a highly sensitive antigen-capture sandwich ELISA system. These monoclonal antibodies would be a useful tool for rapid and specific diagnosis of SARS and also for possible antibody-based treatment of the disease.     

Recent advances in endoscopic management of difficult bile duct stones

Endoscopic treatment is now recognized worldwide as the first‐line treatment for bile duct stones. Endoscopic sphincterotomy combined with basket and/or balloon catheter is generally carried out for stone extraction. However, some stones are refractory to treatment under certain circumstances, necessitating additional/other therapeutic modalities. Large bile duct stones are typically treated by mechanical lithotripsy. However, if this fails, laser or electrohydraulic lithotripsy (EHL) is carried out under the guidance of conventional mother‐baby cholangioscopy. More recently, direct cholangioscopy using an ultrathin gastroscope and the newly developed single‐use cholangioscope system – the SpyGlass direct visualization system – are also used. In addition, extracorporeal shock wave lithotripsy has also been used for stone fragmentation. Such fragmentation techniques are effective in cases with impacted stones, including Mirizzi syndrome. Most recently, endoscopic papillary large balloon dilationhas been introduced as an easy and effective technique for treating large and multiple stones. In cases of altered anatomy, it is often difficult to reach the papilla; in such cases, a percutaneous transhepatic approach, such as EHL or laser lithotripsy under percutaneous transhepatic cholangioscopy, can be a treatment option. Moreover, enteroscopy has recently been used to reach the papilla. Furthermore, an endoscopic ultrasound‐guided procedure has been attempted most recently. In elderly patients and those with very poor general condition, biliary stenting only is sometimes carried out with or without giving subsequent dissolution agents.     

A case of refractory cutaneous polyarteritis nodosa in a patient with hepatitis B carrier status successfully treated with tumor necrosis factor alpha blockade

We describe a patient with refractory cutaneous polyarteritis nodosa (CPAN) with hepatitis B virus (HBV) carrier status who was successfully treated with tumor necrosis factor alpha (TNF-α) blockade, using etanercept, and we review 5 similar cases. We administered etanercept because of the occurrence of repeated flares despite aggressive therapy. C-reactive protein normalization; prednisolone dose-sparing; and absence of any adverse events, including HBV reactivation with nucleotide analogue administration, or renal dysfunction, have been achieved for 8 months. TNF-α blockade should be considered for intractable CPAN.     

Drug-induced liver injury associated with Agaricus blazei Murill which is very similar to autoimmune hepatitis

Agaricus blazei Murill (ABM) is one of the most popular complementary alternative medicines (CAM). We experienced a case of a 60-year-old woman with severe hepatitis associated with extract of ABM and extract of Ganoderma lucidum, and a case of a 75-year-old man with drug-induced liver injury (DILI) associated with extract of ABM and fucoidan. Their clinical courses from the start of CAM until the onset of DILI were observed unexpectedly, because they were under observation for stable malignant neoplasms: stage III malignant thymoma and stage IV lung cancer, respectively. However, they did not talk about taking CAM with their physicians. There were two common points between these two cases. First, they were diagnosed as compatible with DILI by using an international diagnostic scale, the Roussel Uclaf Causality Assessment Method. The second point was that histological findings of the liver were very similar to autoimmune hepatitis (AIH). In addition, serum immunoglobulin G and zinc sulfate turbidity tests gradually increased from the start of CAM to the onset of DILI. Their clinical course and liver histology suggested that the immunostimulating action of ABM caused liver injury which was very similar to that seen in AIH.     

The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis

Background

The cholangioscopic features of IgG4-related sclerosing cholangitis (IgG4-SC) remain undefined. The aim of this study was to clarify these endoscopic features using peroral video cholangioscopy (PVCS) in IgG4-SC patients.

Methods

PVCS was performed in 33 patients: IgG4-SC (n = 13); primary sclerosing cholangitis (PSC; n = 5); and cholangiocarcinoma (n = 15), which included hilar cholangiocarcinoma (HCCA; n = 5) and distal cholangiocarcinoma (DCCA; n = 10).

Results

The most frequent findings on PVCS in the IgG4-SC patients were dilated (62 %) and tortuous (69 %) vessels, and absence of partially enlarged vessels. The incidence of dilated and tortuous vessels was significantly higher in IgG4-SC patients than in PSC patients (p = 0.015). Scarring and pseudodiverticula were found significantly more often in PSC patients than in IgG4-SC patients (p = 0.001 and p = 0.0007, respectively). The incidence of partially enlarged vessels was significantly higher in DCCA patients than in IgG4-SC patients (p = 0.004). In contrast, the incidence of dilated vessels was significantly higher in IgG4-SC patients than in HCCA patients (p = 0.015). PVCS performed after corticosteroid therapy showed resolution of bile duct stenosis and dilated, tortuous, or partially enlarged vessels, as well as resolution of friability in all patients with IgG4-SC.

Conclusion

Cholangioscopy was useful in differentiating IgG4-SC from PSC. In addition, monitoring the patterns of proliferative vessels on PVCS may be useful to differentiate IgG4-SC from cholangiocarcinoma.