Elderly patient with unresectable advanced­stage hepatocellular carcinoma who received atezolizumab plus bevacizumab and achieved a complete response: A case report.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis, particularly in patients with advanced-stage disease, elderly individuals and/or in those with poor liver function. Immune checkpoint inhibitor-containing therapies, such as atezolizumab, an anti-programmed death ligand-1 monoclonal antibody, plus bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, may be effective and safe therapeutic options for elderly patients with advanced-stage HCC. The present study reports the case of a male patient his 80s who consumed alcohol with unresectable advanced-stage HCC who received combination therapy comprising atezolizumab plus bevacizumab for 6 months. The patient achieved a complete response despite the discontinuation of treatment due to nephrotoxicity. It is critical for patients with HCC and a Child-Pugh A grade to continue therapy for HCC, even if they are older. The development of more effective therapies is required for patients with advanced-stage HCC with a worse liver function than those with a Child-Pugh A grade. The case described in the present study demonstrates the need for obtaining further evidence regarding the efficacy and safety of the combination therapy including atezolizumab plus bevacizumab for elderly patients with advanced-stage HCC.

Severe hepatitis E virus genotype 3b in a patient with alcohol­associated liver disease: A case report.

Hepatitis E virus (HEV) infection occasionally causes acute-on-chronic liver failure in patients with alcohol-associated cirrhosis. These reports have been published mainly from highly HEV genotype 1-endemic countries. The present study describes the case of a patient with severe HEV genotype 3b infection and alcohol-associated liver disease. A male patient in his 70s who consumed alcohol, and who had begun consuming alcohol at the age of 12, had high levels of alanine aminotransferase (ALT) and total bilirubin. The peak levels of ALT and total bilirubin were 1,067 IU/l and 26.3 mg/dl, respectively. A computed tomography scan revealed an atrophic liver. Upon admission, both anti-HEV immunoglobulin A and HEV RNA were positive, and his HEV was genotype 3b. He also had chronic kidney disease, as his estimated glomerular filtration rate was <45 ml/min/1.73 m2, and ribavirin could not be used. The abnormal levels of the liver function parameters of the patient gradually improved due to conservative treatment, and he was discharged on day 43. On the whole, the present study demonstrates that careful attention should be paid to patients with viral hepatitis, including hepatitis E, when alcohol-associated liver disease is present. Novel anti-HEV drugs need to be developed for severe HEV infections with chronic kidney disease.

Noninvasive rapid urinary trypsinogen-2 dipstick test for early exclusion of post-endoscopic retrograde cholangiopancreatography pancreatitis within hours after endoscopic retrograde cholangiopancreatography: Clinical diagnosis and considerations.

Objective: Few reports have explored the application of urinary trypsinogen-2 measurement in the early diagnosis of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis, and none have demonstrated the benefits of noninvasive testing. This study aimed to evaluate the clinical application of the rapid urinary trypsinogen-2 dipstick test (Nipro, Japan) compared with serum amylase and lipase levels for the early diagnosis of post-ERCP pancreatitis (PEP). Methods: A total of 100 consecutive patients (54 men and 46 women) who were admitted and underwent ERCP at Tokyo Medical University Hospital from August 2021 to December 2021 were recruited. All patients underwent rapid urinary trypsinogen-2 measurement using the dipstick test before and after ERCP. Measurements were taken 24 h before ERCP for pre-ERCP and 1-4 h after ERCP for post-ERCP. Additionally, serum amylase and lipase levels were measured at 8:00 a.m. of the day after ERCP (at least 8 h after ERCP), and their diagnostic abilities for PEP were compared and evaluated. Results: PEP occurred in 5/100 patients (5%). The sensitivity, specificity, positive predictive value, and negative predictive value of the dipstick test for diagnosing PEP were 100%, 83.2%, 23.8%, and 100%, respectively. These results were comparable to the diagnostic performance of serum amylase and lipase levels at 8:00 a.m. on the day after ERCP (at least 8 h after ERCP). However, false positives must be considered. Conclusion: The dipstick test may be useful in clinical practice as a noninvasive screening test for the early prediction of PEP.

Endoscopic ultrasound-guided biopsy using a three-prong asymmetry tip needle for pancreatic tumors and peridigestive tract lesions: Retrospective single-center study.

BACKGROUND: Endoscopic ultrasound-guided tissue acquisition is vital for diagnosing pancreatic and peridigestive tract lesions. A new three-prong asymmetry tip needle has been developed for this procedure. In this study, we retrospectively assessed the diagnostic ability, tissue collection volume, and procedural adverse events of the three-prong asymmetry tip needle for solid pancreatic, subepithelial, and other organ lesions. METHODS: We analyzed the data of 58 consecutive patients who underwent endoscopic ultrasound-guided tissue acquisition using a three-prong asymmetry tip needle between August 2022 and April 2023 at a single care center. RESULTS: The tissue collection rate was 91.4% with 89.7% accuracy, 89.3% sensitivity, 100% specificity, 100% positive predictive value, and 25% negative predictive value. No significant differences in collection rates or diagnostic performance were observed based on the target organ, puncture route, or lesion size. Using our original assessment method, the average histological core tissue score was 3.1 ± 0.8, whereas the blood contamination volume was 2.5 ± 0.8. Only one of 58 patients (1.7%) developed a pancreatic fistula of moderate severity as an adverse event. CONCLUSIONS: The three-prong asymmetry tip needle demonstrated good diagnostic capability and adequate sample volume with safety for pancreatic, subepithelial, and other organ lesions.

Recent advances in hepatitis A virus research and clinical practice guidelines for hepatitis A virus infection in Japan.

In 2018, there was a hepatitis A outbreak in Japan, and hepatitis A virus (HAV) infection is considered a sexually transmitted disease. In general, patients with hepatitis A should be given attention, and this disease should be prevented more than ever. The Japan Agency for Medical Research and Development (AMED) Hepatitis A and E viruses (HAV and HEV) Study Group has worked on the project to create "Recent Advances in Hepatitis A Virus (HAV) Research and Clinical Practice Guidelines for HAV Infection in Japan". The group consists of expert hepatologists and virologists who gathered at virtual meeting on August 5, 2023. Data about the pathogenesis, infection routes, diagnosis, complications, several factors for the severities, vaccination, and current and future treatments for hepatitis A were discussed and debated for a draft version. The participants assessed the quality of cited studies. The finalized recommendations are presented in this review. The recent advances in HAV research and clinical practice for HAV infection in Japan, have been reviewed by the AMED HAV and HEV Study Group.

Long-term outcomes after EUS-guided antegrade intervention for benign bilioenteric anastomotic stricture.

BACKGROUND AND AIMS: Bilioenteric anastomotic stricture (BES) is a well-known adverse event after bilioenterostomy. Recently, EUS-guided antegrade intervention (EUS-AI) has been developed for cases that are difficult to treat by balloon enteroscopy-assisted ERCP. However, no data are available on the long-term outcomes after EUS-AI. The main goal of the present study was to clarify the long-term outcomes of EUS-AI in such patients. METHODS: Between November 2013 and November 2021, 34 patients who were followed for more than 1 year after EUS-AI for BES were identified. The primary endpoint was the rate of stricture resolution. Secondary endpoints were factors associated with stricture resolution, rate of BES recurrence, rate of conversion to surgery, and rate of hepatic fibrosis progression during follow-up. RESULTS: The median follow-up period was 56.7 months. Stricture resolution was achieved in 17 of 34 patients (50%). A multivariate analysis confirmed that the presence of bile duct stones (odds ratio, 9.473; 95% confidence interval, 1.66-53.98; P = .01) was significantly associated with stricture resolution. The stricture recurrence rate was 33%, and the median time from stent removal to recurrence was 31.2 months. Four patients underwent surgery because of recurrent cholangitis. During the median follow-up period of 56.7 months, 25% progressed to hepatic fibrosis based on the Fibrosis-4 index grade. Interestingly, patients without cholangitis during follow-up did not show progression of hepatic fibrosis. CONCLUSIONS: EUS-AI has achieved acceptable long-term clinical outcomes. EUS-AI can be a viable alternative treatment of choice before surgical treatment in patients who are difficult to treat by conventional approaches.

Endoscopic retrieval of a proximally migrated fully covered self-expandable metal stent using biopsy forceps with a guiding sheath cannula.

Transpapillary endoscopic biliary drainage is the gold standard for resolving malignant biliary obstruction. Stent migration occasionally occurs and is troublesome to retrieve. Yamamoto and colleagues report with accompanying video on the successful retrieval of a proximally migrated stent using biopsy forceps through a guiding sheath cannula.

A fatal case of massive hemobilia caused by invasive pancreatic cancer with median arcuate ligament syndrome: A case report.

INTRODUCTION: In median arcuate ligament syndrome (MALS), the celiac artery is compressed, causing an arcade to develop in the pancreatic head, leading to ischemic symptoms and aneurysms. PATIENT CONCERNS: The patient was diagnosed with borderline resectable pancreatic cancer (PC) and MALS. Endoscopic biliary drainage with a covered metal stent (CMS) was performed for the obstructive jaundice. After the jaundice improved, a modified FOLFIRINOX regimen was initiated. Several days later, cardiopulmonary arrest occurred after hematemesis occurred. Cardiopulmonary resuscitation was performed, his blood pressure stabilized, and emergent upper endoscopy was performed. The CMS was dislodged and active bleeding was observed in the papillae. The CMS was replaced, and temporary hemostasis was achieved. Contrast-enhanced computed tomography revealed a diagnosis of extravasation from the posterior superior pancreaticoduodenal artery (PSPDA) into the biliary tract. Transcatheter arterial embolization was performed. However, the patient was subsequently diagnosed with hypoxic encephalopathy and died on day 14 of hospitalization. DIAGNOSIS: Biliary hemorrhage due to invasion of pancreatic cancer from the PSPDA associated with MALS. INTERVENTION: None. OUTCOMES: Biliary hemorrhage from the PSPDA was fatal in the patient with invasive PC with MALS. LESSONS: Since MALS associated with PC is not a rare disease, the purpose of this study was to keep in mind the possibility of fatal biliary hemorrhage.

Deciphering load attenuation mechanisms of the dentin-enamel junction: Insights from a viscoelastic constitutive model.

A considerable material discontinuity between the enamel and dentin might jeopardize the tooth's mechanical durability over time without the attenuation of the dentin-enamel junction (DEJ). However, the critical loading transmission mechanism at the DEJ remains understudied. This study aimed to define the extent and effective width of the DEJ, along with its mechanical competence. The presence of DEJ interphase layer was identified using a motif analysis based on the ion beam-transmission electron microscopy coupled with nanoindentation modulus mapping. For each region, nanoindentation load-displacement curves were recorded and mathematically analyzed using an appropriate viscoelastic constitutive model. The time-course of indenter penetration (creep) behavior of the tooth tissues can be mathematically approximated by the Kelvin-Voigt model in series, which determined the visco-contribution to the overall mechanical responses. Therefore, the elastic-plastic contribution can be distinguished from the overall mechanical responses of the tooth after subtracting the visco-contributions. During the loading period, the enamel behavior was dominated by elastic-plastic responses, while both the dentin and DEJ showed pronounced viscoelastic responses. The instantaneous modulus of the DEJ, which was measured by eliminating viscoelastic behavior from the raw load-displacement curve, was almost double that of the dentin. The DEJ was stiffer than the dentin, but it exhibited large viscoelastic motion even at the initial loading stage. This study revealed that the load attenuation competence of the DEJ, which involves extra energy expenditure, is mainly associated with its viscoelasticity. The mathematical analysis proposed here, performed on the nanoindentation creep behavior, could potentially augment the existing knowledge on hard-tissue biomechanics. STATEMENT OF SIGNIFICANCE: In this study, we undertake a rigorous mechanical characterization of the dentin-enamel junction (DEJ) using an advanced nanoindentation technique coupled with a pertinent viscoelastic constitutive model. Our approach unveils the substantial viscoelastic contribution of the DEJ during the initial indentation loading phase and offers an elaborate delineation of the DEJ interphase layer through sophisticated image analysis. These insights significantly augment our understanding of tooth durability. Importantly, our innovative mathematical analysis of creep behavior introduces a novel approach with profound implications for future research in the expansive field of hard-tissue biomechanics. The pioneering methodologies and findings presented in this work hold substantial potential to invigorate progress in biomaterials research and fuel further explorations into the functionality of biological tissues.

Muscle Cramps in Outpatients with Liver Diseases in Tokyo, Japan.

Background and Objectives: Muscle cramps are often observed in patients with liver diseases, especially advanced liver fibrosis. The exact prevalence of muscle cramps in outpatients with liver diseases in Japan is unknown. Patients and Methods: This study examined the prevalence of, and therapies for, muscle cramps in outpatients with liver diseases in Tokyo, Japan. A total of 238 outpatients with liver diseases were retrospectively examined. We investigated whether they had muscle cramps using a visual analog scale (VAS) (from 0, none, to 10, strongest), and also investigated their therapies. Results: Muscle cramps were observed in 34 outpatients with liver diseases (14.3%); their mean VAS score was 5.53. A multivariate analysis demonstrated that older age (equal to or older than 66 years) was the only significant factor as-sociated with muscle cramps. The prevalence of muscle cramps among patients with liver diseases seemed not to be higher. The problem was that only 11 (32.4%) of 34 outpatients received therapy for their muscle cramps. Conclusions: Only age is related to muscle cramps, which is rather weak, and it is possible that this common symptom may not be limited to liver disease patients.

Masitinib Inhibits Hepatitis A Virus Replication.

The hepatitis A virus (HAV) infection causes acute hepatitis. HAV also induces acute liver failure or acute-on-chronic liver failure; however, no potent anti-HAV drugs are currently available in clinical situations. For anti-HAV drug screening, more convenient and useful models that mimic HAV replication are needed. In the present study, we established HuhT7-HAV/Luc cells, which are HuhT7 cells stably expressing the HAV HM175-18f genotype IB subgenomic replicon RNA harboring the firefly luciferase gene. This system was made by using a PiggyBac-based gene transfer system that introduces nonviral transposon DNA into mammalian cells. Then, we investigated whether 1134 US Food and Drug Administration (FDA)-approved drugs exhibited in vitro anti-HAV activity. We further demonstrated that treatment with tyrosine kinase inhibitor masitinib significantly reduced both HAV HM175-18f genotype IB replication and HAV HA11-1299 genotype IIIA replication. Masitinib also significantly inhibited HAV HM175 internal ribosomal entry-site (IRES) activity. In conclusion, HuhT7-HAV/Luc cells are adequate for anti-HAV drug screening, and masitinib may be useful for the treatment of severe HAV infection.

Objective evaluation of the resistance forces of 22-gauge EUS-FNA and fine-needle biopsy needles.

Background and Objectives: EUS-guided tissue acquisition is routinely performed for the diagnosis of gastrointestinal tract and adjacent organ lesions. Recently, various types of needles have been developed. However, how the shape of the needle tip and echoendoscope tip angle affect puncturability, has not been clarified. The aim of this experimental study was to compare the puncturability of several 22-gauge EUS-FNA and EUS-guided fine-needle biopsy (EUS-FNB) needles, and to evaluate the effects of the needle tip shape and echoendoscope tip angle on tissue puncturability. Materials and Methods: The following six major FNA and FNB needles were evaluated: SonoTip® ProControl, EZ Shot 3 Plus, Expect™ Standard Handle, SonoTip® TopGain, Acquire™, and SharkCore™. The mean maximum resistance force against needle advancement was evaluated and compared under several conditions using an echoendoscope. Results: The mean maximum resistance force of the needle alone was higher for the FNB needles than for the FNA needles. The mean maximum resistance force of the needle in the echoendoscope with free angle demonstrated that the resistance forces were between 2.10 and 2.34 Newton (N). The mean maximum resistance force increased upon increases in angle of the tip of echoendoscope, particularly in the FNA needles. Among the FNB needles, SharkCore™ had the lowest resistance force (2.23 N). The mean maximum resistance force of the needle alone, the needle in the echoendoscope with free angle, and the needle in the echoendoscope with full-up angle for SonoTip® TopGain were all similar to that of Acquire™. Conclusion: SonoTip® TopGain had similar puncturability to Acquire™ in all tested situations. Regarding the puncturability, SharkCore™ is most suitable for insertion into target lesions, when tight echoendoscope tip angle is necessary.

Molecular Mechanisms, Diagnosis and Treatments in Digestive Malignancy.

In this Special Issue, "Molecular Mechanisms, Diagnosis and Treatments in Digestive Malignancy", of the International Journal of Molecular Sciences, a total of 10 impactful articles have been published [...].

Gut-Microbiota Dysbiosis in Stroke-Prone Spontaneously Hypertensive Rats with Diet-Induced Steatohepatitis.

Metabolic-dysfunction-associated fatty-liver disease (MAFLD) is the principal worldwide cause of liver disease. Individuals with nonalcoholic steatohepatitis (NASH) have a higher prevalence of small-intestinal bacterial overgrowth (SIBO). We examined gut-microbiota isolated from 12-week-old stroke-prone spontaneously hypertensive-5 rats (SHRSP5) fed on a normal diet (ND) or a high-fat- and high-cholesterol-containing diet (HFCD) and clarified the differences between their gut-microbiota. We observed that the Firmicute/Bacteroidetes (F/B) ratio in both the small intestines and the feces of the SHRSP5 rats fed HFCD increased compared to that of the SHRSP5 rats fed ND. Notably, the quantities of the 16S rRNA genes in small intestines of the SHRSP5 rats fed HFCD were significantly lower than those of the SHRSP5 rats fed ND. As in SIBO syndrome, the SHRSP5 rats fed HFCD presented with diarrhea and body-weight loss with abnormal types of bacteria in the small intestine, although the number of bacteria in the small intestine did not increase. The microbiota of the feces in the SHRSP5 rats fed HFCD was different from those in the SHRP5 rats fed ND. In conclusion, there is an association between MAFLD and gut-microbiota alteration. Gut-microbiota alteration may be a therapeutic target for MAFLD.

Drug Screening for Hepatitis A Virus (HAV): Nicotinamide Inhibits c-Jun Expression and HAV Replication.

Hepatitis A virus (HAV) infection often causes acute hepatitis, which results in a case fatality rate of 0.2% and fulminant hepatitis in 0.5% of cases. However, no specific potent anti-HAV drug is available on the market to date. In the present study, we focused on inhibition of HAV internal ribosomal entry site (IRES)-mediated translation and investigated novel therapeutic drugs through drug repurposing by screening for inhibitors of HAV IRES-mediated translation and cell viability using a reporter assay and cell viability assay, respectively. The initial screening of 1,158 drugs resulted in 77 candidate drugs. Among them, nicotinamide significantly inhibited HAV HA11-1299 genotype IIIA replication in Huh7 cells. This promising drug also inhibited HAV HM175 genotype IB subgenomic replicon and HAV HA11-1299 genotype IIIA replication in a dose-dependent manner. In the present study, we found that nicotinamide inhibited the activation of activator protein 1 (AP-1) and that knockdown of c-Jun, which is one of the components of AP-1, inhibited HAV HM175 genotype IB IRES-mediated translation and HAV HA11-1299 genotype IIIA and HAV HM175 genotype IB replication. Taken together, the results showed that nicotinamide inhibited c-Jun, resulting in the suppression of HAV IRES-mediated translation and HAV replication, and therefore, it could be useful for the treatment of HAV infection. IMPORTANCE Drug screening methods targeting HAV IRES-mediated translation with reporter assays are attractive and useful for drug repurposing. Nicotinamide (vitamin B3, niacin) has been shown to effectively inhibit HAV replication. Transcription complex activator protein 1 (AP-1) plays an important role in the transcriptional regulation of cellular immunity or viral replication. The results of this study provide evidence that AP-1 is involved in HAV replication and plays a role in the HAV life cycle. In addition, nicotinamide was shown to suppress HAV replication partly by inhibiting AP-1 activity and HAV IRES-mediated translation. Nicotinamide may be useful for the control of acute HAV infection by inhibiting cellular AP-1 activity during HAV infection processes.

Chronic Hepatitis C: Acute Exacerbation and Alanine Aminotransferase Flare.

The hepatitis C virus (HCV) causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, as well as extrahepatic manifestations such as malignant lymphoma. Currently, direct-acting antiviral agents (DAAs) against HCV infection can lead to a sustained virological response (SVR) in almost all HCV-infected patients. In this review article, we discuss acute exacerbation and alanine aminotransferase (ALT) flare in patients with chronic HCV infection. Although acute liver failure caused by HCV infection is rare, careful attention should be paid to the cases with ALT elevation during the natural course of chronic HCV infection. HCV genotype 2 infection, the use of rituximab, and a higher dose of corticosteroid are factors associated with HCV acute exacerbation and ALT flare. Treatment regimens for cancer have been interrupted or changed due to ALT flare due to HCV infection in some patients undergoing chemotherapy for cancer. The pathogenesis of HCV acute exacerbation and ALT flare could involve cellular as well as humoral immune responses. In the DAA era, the earlier introduction of DAAs may prevent chronic HCV-infected patients with acute exacerbation and ALT flare from developing into a more severe form, although DAAs may not be effective for all of them.

Efficacy of shear wave elastography for the diagnosis of chronic pancreatitis.

BACKGROUND/PURPOSE: Shear wave elastography (SWE) is a clinical method used to evaluate liver hardness. In this study, we assessed its applicability in assessing the pancreas and its potential for diagnosing chronic pancreatitis. METHODS: We performed SWE on 59 patients who underwent abdominal ultrasound, and measured the computed tomography (CT) values of the pancreas. Patients were classified as having a normal pancreas (NP), early chronic pancreatitis (ECP), or chronic pancreatitis (CP). SW elasticity (SWe), SW dispersion (SWd), and CT values between groups were analyzed. RESULTS: SWe significantly differed between the CP and NP/ECP groups (NP vs CP; P = 0.001, ECP vs CP; P = 0.026,), while SWd showed a significant difference only between the NP and CP group (NP vs CP; P = 0.001). The CT values were significantly different between the CP and NP/ECP groups (NP vs CP; P = 0.0006, ECP vs CP; P = 0.0027). CONCLUSION: Pancreatic SWE and CT values were helpful in the diagnosis of chronic pancreatitis. SWd may reveal status changes in ECP.