Genomic Analysis of Undifferentiated Carcinoma of the Pancreas with Squamous Differentiation: A Case Report.

Pancreatic cancer is an intractable malignancy associated with a dismal prognosis. Undifferentiated carcinoma, a rare subtype, poses a clinical challenge owing to a limited understanding of its molecular characteristics. In this study, we conducted genomic analysis specifically on a case of undifferentiated carcinoma of the pancreas exhibiting squamous differentiation. An 80-year-old male, previously treated for colorectal cancer, presented with a mass with central cystic degeneration in the pancreatic tail. The mass was diagnosed pathologically as undifferentiated carcinoma of the pancreas with squamous differentiation. Despite surgical resection and chemotherapy, the patient faced early postoperative recurrence, emphasizing the aggressive nature of this malignancy. Genomic analysis of distinct histologic components revealed some common mutations between undifferentiated and squamous components, including Kirsten rat sarcoma virus (KRAS) and TP53. Notably, the squamous component harbored some specific mutations in SMARCA4 and SMARCB1 genes that code for members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. The common mutations in the undifferentiated and squamous cell carcinoma components from this analysis suggest that they originate from a common origin. The discussion also underscores the scarcity of genomic analyses on undifferentiated carcinoma of the pancreas, with existing literature pointing to SWI/SNF complex-related gene mutations. However, our case introduces chromatin remodeling factor mutations as relevant in squamous differentiation. In conclusion, this study provides valuable insights into the genomic landscape of undifferentiated pancreatic carcinoma with squamous differentiation. These findings suggest the importance of further research and targeted therapies to improve the management of undifferentiated carcinoma of the pancreas and enhance patient outcomes.

Penetration of duodenal wall by proximal end of biliary straight plastic stent in a patient with ampullary carcinoma.

A 70-year-old woman presented to our hospital with abdominal discomfort. Gastrointestinal endoscopy revealed an ampullary tumor, while a biopsy revealed a pathological diagnosis of adenocarcinoma. No distant metastases were observed and neoadjuvant chemotherapy and surgical resection were planned. Shortly thereafter, she developed obstructive jaundice due to the ampullary carcinoma. The patient underwent endoscopic retrograde cholangiopancreatography, during which a straight plastic stent was placed in the bile duct. The patient was discharged without complications. Neoadjuvant chemotherapy was initiated. Two months later, she was readmitted for surgery while asymptomatic. Endoscopic retrograde cholangiopancreatography was scheduled to replace the stent with a nasobiliary drainage tube for the surgery. Endoscopic imaging revealed that the proximal end of the stent had penetrated the duodenum on the oral side of the ampullary carcinoma. The distal end of the stent was grasped with forceps and the stent was successfully removed. A catheter was inserted into the bile duct orifice and cholangiography was performed, which revealed that the distal bile duct and the duodenum had formed a fistula. A guidewire was placed in the bile duct via the papilla and a nasobiliary drainage tube was placed. After endoscopic retrograde cholangiopancreatography, the patient exhibited smooth progress without issue. Pancreaticoduodenectomy was performed on the fourth day after the nasobiliary drainage tube placement, and the patient's postoperative course was uneventful. The proximal end of a biliary stent penetrating the duodenal wall is an infrequent phenomenon. This case report highlights a rare but noteworthy adverse event associated with straight biliary plastic stent placement.

Safety of endoscopic ultrasound-guided fine-needle aspiration for pancreatic solid mass in the elderly: A single-center retrospective study.

AIM: There are few reports on the safety of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in the elderly. In this study, we investigated the safety of EUS-FNA for pancreatic solid masses in patients aged ≥80 years. METHODS: This is a single-center retrospective study. A total of 600 patients with pancreatic solid masses who underwent EUS-FNA under midazolam-based sedation at our institution between September 2016 and December 2022 were enrolled in this study. Eligible patients were divided into two groups: an elderly group aged ≥80 (n = 84), as well as a nonelderly group aged ≤79 (n = 516). These two groups were compared. RESULTS: The elderly group required significantly fewer midazolam doses for sedation (P < 0.001). Adverse events occurred in eight patients (1.3%), including one (1.2%) and seven (1.4%) in the elderly and nonelderly groups, respectively (P = 0.90). There were no cases of early adverse events in the elderly group and six cases (1.2%) in the nonelderly group (P = 0.32). There was one case of late adverse events in both the elderly and nonelderly groups (P = 0.14), and both were needle tract seeding. There was no significant difference between the two groups in the proportion of cases in which percutaneous oxygen saturation decreased to ≤90% during the EUS-FNA. CONCLUSIONS: Our analysis suggests that EUS-FNA for pancreatic solid masses can be safely performed in patients aged >80 years without increasing the adverse event rate compared to nonelderly patients aged <80 years. Geriatr Gerontol Int 2023; 23: 836-841.

Endoscopic Transpapillary Stenting for Malignant Hilar Biliary Stricture: Side-by-Side Placement versus Partial Stent-in-Stent Placement.

BACKGROUND/AIMS: Endoscopic uncovered metal stent (UMS) placement has been widely performed for unresectable hilar malignant biliary stricture (UHMBS). Two stenting methods are used for the two bile duct branches: side-by-side placement (SBS) and partial stent-in-stent placement (PSIS). However, it remains controversial whether SBS or PSIS is superior. This study aimed to compare SBS and PSIS in UHMBS cases with UMS placement in two branches of the IHD. METHODS: This retrospective study included 89 cases of UHMBS treated with UMS placement through the SBS or PSIS technique using endoscopic retrograde cholangiopancreatography at our institution. Patients were divided into two groups, SBS (n = 64) and PSIS (n = 25), and compared. RESULTS: Clinical success was achieved in 79.7% and 80.0% in the SBS and PSIS groups, respectively (p = 0.97). The adverse event rate was 20.3% and 12.0% in the SBS and PSIS groups, respectively (p = 0.36). The recurrent biliary obstruction (RBO) rate was 32.8% and 28.0% in the SBS and PSIS groups, respectively (p = 0.66). The median cumulative time to RBO was 224 and 178 days in the SBS and PSIS groups, respectively (p = 0.52). The median procedure time was 43 and 62 min in the SBS and PSIS groups, respectively, which was significantly longer in the PSIS group (p = 0.014). CONCLUSIONS: No significant differences were noted in the clinical success rate, adverse event rate, time to RBO, or overall survival between the SBS and PSIS groups, other than the significantly longer procedure time in the PSIS group.

Feasibility of Biliary Drainage Using a Novel Integrated Biliary Stent and Nasobiliary Drainage Catheter System for Acute Cholangitis.

Background Acute cholangitis is caused by cholestasis and bacterial infection, and if exacerbated, sepsis may occur and be fatal. Biliary drainage is recommended for acute cholangitis regardless of severity, except in some cases of mild acute cholangitis, in which antibiotics are effective. A novel integrated device comprising a biliary drainage stent and a nasobiliary drainage tube, called the UMIDAS NB stent (UMIDAS Inc., Kanagawa, Japan), was developed. In this study, we evaluated the efficacy and safety of biliary drainage using the UMIDAS NB stent outside type for acute cholangitis in clinical practice. Methods Patients with acute cholangitis with common bile duct stones or distal biliary strictures who underwent biliary drainage with the UMIDAS NB stent outside type at our institution between January 2022 and December 2022 were examined retrospectively. The UMIDAS NB stent outside type was placed transpapillary using endoscopic retrograde cholangiopancreatography (ERCP). Patients with biliary drainage stent placement other than the UMIDAS NB stent outside type on the same ERCP session and patients with acute cholecystitis were excluded. Results A total of 13 patients were included in this study. The severity of cholangitis was mild in four cases, moderate in five, and severe in four. There were eight cases of common bile duct stones and five cases of pancreatic cancer. The stent diameter was 7 French scale (Fr) in five cases and 8.5 Fr in eight cases. The median procedure time was 20 minutes. Clinical success was achieved in all 13 patients (100%). No treatment-related adverse events were observed. Unintended removal of the nasobiliary drainage tube was not observed. There were no cases of biliary drainage stent dislocation with nasobiliary drainage tube removal. Conclusions Although the sample size was small, our study demonstrated that biliary drainage with the UMIDAS NB stent outside type was effective and safe for patients with acute cholangitis who had common bile duct stones or distal biliary strictures, regardless of the severity of cholangitis.

Efficacy and Safety of Electrohydraulic Lithotripsy Using Peroral Cholangioscopy under Endoscopic Retrograde Cholangiopancreatography Guidance in Older Adults: A Single-Center Retrospective Study.

Background and objectives: The safety of electrohydraulic lithotripsy (EHL) in older adults remains unclear. We aimed to investigate the efficacy and safety of EHL using peroral cholangioscopy (POCS) under endoscopic retrograde cholangiopancreatography (ERCP) guidance in older adults aged ≥80 years. Materials and Methods: This retrospective clinical study was conducted at a single center. Fifty patients with common bile duct stones who underwent EHL using POCS under ERCP guidance at our institution, between April 2017 and September 2022, were enrolled in this study. The eligible patients were divided into an elderly group (n = 21, age ≥80 years) and a non-elderly group (n = 29, age ≤79 years), and were analyzed. Results: A total of 33 and 40 EHL procedures were performed in the elderly and non-elderly groups, respectively. After excluding cases in which stone removal was performed at other institutions, complete removal of common bile duct stones was confirmed in 93.8% and 100% of the elderly and non-elderly groups, respectively (p = 0.20). The mean number of ERCPs required for complete removal of bile duct stones was 2.9 and 4.3 in the elderly and non-elderly groups, respectively (p = 0.17). In the EHL session, the overall occurrence of adverse events was eight and seven in the elderly (24.2%) and non-elderly (17.5%) groups, respectively; however, the difference was insignificant (p = 0.48). Conclusions: EHL using POCS under ERCP guidance is effective in patients aged ≥80 years and there was no significant increase in adverse event rates compared to those aged ≤79 years.

Alteration of the tumor microenvironment by pharmacological inhibition of EZH2 in hepatocellular carcinoma.

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive component 2 is overexpressed in a variety of cancers and recognized as a therapeutic target molecule. However, EZH2 possesses immunomodulatory functions in the tumor microenvironment (TME). The impact of EZH2 on TME of hepatocellular carcinoma (HCC) using immunocompetent mouse model was evaluated in the present study. UNC1999, an EZH2 inhibitor, impaired growth of the murine HCC cells (H22 cells) and induced apoptosis in a dose-dependent manner. Although UNC1999 significantly inhibited the growth of H22 cells-derived and Hepa1-6 cells-derived tumors in nonobese diabetic/severe combined immunodeficiency mice, its antitumor effect was diminished in allogenic BALB/c and C57BL/6 mice. Flow cytometric analyses of TME cells in BALB/c mice demonstrated a significant decrease in the number of interferon­Î³+ CD8+ T cells and regulatory T cells and a significant increase in the number of myeloid-derived suppressor cells (MDSCs). Administration of Gr-1 neutralizing antibody concomitant with UNC1999 restored antitumor effect accompanied by an increase in the number of CD8+ T cells followed by a decrease in the number of MDSCs. Chemokine antibody array demonstrated an enhanced expression of chemokines responsible for MDSCs recruitment such as C5a, CCL8, and CCL9. In conclusion, the study results demonstrated that EZH2 inhibitor contributed to attenuation of tumor immunity caused by TME arrangement. Combination therapy with EZH2 inhibitors and agents that reduce MDSCs might represent a novel therapeutic strategy for HCC.

Secondary Sclerosing Cholangitis After Emphysematous Cholecystitis.

A 64-year-old woman was diagnosed with emphysematous cholecystitis. An open cholecystectomy was performed immediately. After the cholecystectomy, jaundice and multiple bile duct strictures that were not present preoperatively appeared. The patient was diagnosed with sclerosing cholangitis secondary to emphysematous cholecystitis. Endoscopic biliary stenting and endoscopic biliary balloon dilatation were performed. However, jaundice did not improve. She developed candidemia 75 days after cholecystectomy. The patient died of multiple organ failures 92 days after cholecystectomy. Although rare, secondary sclerosing cholangitis occurred after emphysematous cholecystitis, and endoscopic treatment was ineffective in this case.

Successful Identification of a Novel Therapeutic Compound for Hepatocellular Carcinoma Through Screening of ADAM9 Inhibitors.

BACKGROUND/AIM: MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed. MATERIALS AND METHODS: To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells. RESULTS: CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells. CONCLUSION: CCL347 has potential as a novel therapeutic drug for HCC.

Phase II study comparing nasal pressure monitoring with capnography during invasive endoscopic procedures: a single-center, single-arm trial.

Nasal pressure signal is commonly used to evaluate obstructive sleep apnea. This study aimed to assess its safety for respiratory monitoring during sedation. A total of 45 adult patients undergoing sedation with propofol and fentanyl for invasive endoscopic procedures were enrolled. While both nasal pressure and capnograph signals were continuously recorded, only the nasal pressure signal was displayed. The primary outcome was the incidence of oxygen desaturation below 90%. The secondary outcomes were the ability to predict the desaturation and incidence of harmful events and false alarms, defined as an apnea waveform lasting more than 3 min without desaturation. Of the 45 participants, 43 completed the study. At least one desaturation event occurred in 12 patients (27.9%; 95% confidence interval 15.3-43.7%). In these 12 patients, more than half of the desaturation events were predictable in 9 patients by capnography and 11 patients by nasal pressure monitoring (p = 0.59). In the 43 patients, false alarms were detected in 7 patients with capnography and 11 patients with nasal pressure monitoring (p = 0.427). Harmful events unrelated to nasal pressure monitoring occurred in 2 patients. Nasal pressure monitoring is safe and possibly useful for respiratory monitoring despite false alarms during sedation.

Bile proteome analysis by high-precision mass spectrometry to examine novel biomarkers of primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown etiology that affects the intra- and extrahepatic bile ducts. The present study examined the utility of a bile proteome analysis using a high-sensitivity mass spectrometer to comprehensively screen for novel PSC biomarkers. METHODS: Bile endoscopically collected from patients with PSC, common bile duct stones, and biliary tract cancer were subjected to high-precision liquid chromatography/mass spectrometry. Some of the proteins specifically up-regulated in the bile of the PSC group were re-examined by an enzyme-linked immunosorbent assay. RESULTS: A total of 8094 proteins were successfully identified and 332 were specifically up-regulated in the PSC group. The bioinformatics analysis showed that proteins involved in the proliferation and activation of diverse inflammatory cells were up-regulated in the PSC group. A receiver operating characteristic curve analysis showed good area under the curve values for interleukin-8 and annexin A1 (ANXA1) (0.836 and 0.914, respectively). Immunostaining for ANXA1 revealed its strong expression in inflammatory cells infiltrating the peripheral biliary tract in PSC livers. CONCLUSION: A bile proteome analysis is a useful tool for elucidating the pathogenesis of PSC and developing new diagnostic approaches. Therefore, ANXA1 has potential as a bile biomarker for PSC.

Miglustat, a glucosylceramide synthase inhibitor, mitigates liver fibrosis through TGF-ß/Smad pathway suppression in hepatic stellate cells.

Transforming growth factor (TGF)-ß/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-ß/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-ß/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-ß and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-ß-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-ß/Smad pathway.

Feasibility of endoscopic ultrasound-guided hepaticogastrostomy using a 22-gauge needle.

This study aimed to evaluate the feasibility of performing endoscopic ultrasound-guided hepaticogastrostomy using a 22-gauge fine-needle aspiration needle. This was a single-center retrospective study. Fourteen patients who underwent endoscopic ultrasound-guided hepaticogastrostomy with a 22-gauge fine-needle aspiration needle were examined. Fourteen eligible patients were included in this study. The age of patients ranged from 55 to 93 years, with a median of 76 years. Of patients with existing underlying diseases, there were 8 cases of pancreatic cancer (57.1%), 2 cases of metastatic liver tumor (14.3%), 2 cases of bile duct stones (14.3%), 1 case of hilar cholangiocarcinoma (7.1%), and 1 case of gallbladder cancer (7.1%). Regarding gastrointestinal anatomy, there were 11 cases (78.6%) of normal and 3 cases (21.4%) of gastric resection with Roux-en-Y. Reasons for endoscopic ultrasound-guided hepaticogastrostomy were duodenal obstruction in 7 cases (50.0%), surgically altered anatomy in 3 cases (21.4%), and 4 cases (28.6%) of failed endoscopic retrograde cholangiopancreatography. Technical success was achieved in 11 cases (78.6%). Subsequently, 11 cases of technical success were analyzed. There were 5 cases of puncturing B2 (45.5%). The puncture bile duct diameter ranged from 3.1 to 5.7 mm, with a median of 4.4 mm. endoscopic ultrasound-guided antegrade procedures was combined with endoscopic ultrasound-guided hepaticogastrostomy in 2 cases (18.2%). Clinical success was achieved in all the cases. The procedure time ranged from 15 to 93 minutes, with a median duration of 35 minutes. Regarding the type of stent placed in hepaticogastrostomy, a plastic stent was placed in 10 cases (90.9%) and a metal stent was placed in 1 case (9.1%). Early adverse events occurred in 4 cases (36.4%), and all of these cases developed biliary peritonitis, late adverse events occurred in 1 case (9.1%), this was biloma. A change to a 0.025-inch guidewire during the procedure was required in 8 cases (72.7%). Esophageal puncture was not performed. endoscopic ultrasound-guided hepaticogastrostomy using a 22-gauge fine-needle aspiration needle is effective. However, in 72.7% of the cases started using the 0.018-inch guidewire, the guidewire was exchanged for a 0.025-inch guidewire during procedure.

"Salvage techniques" are the key to overcome difficult biliary cannulation in endoscopic retrograde cholangiopancreatography.

Although the efficacy and safety of salvage techniques for biliary cannulation in endoscopic retrograde cholangiopancreatography (ERCP) have been reported, few reports analyzed the choice of techniques and their clinical outcomes in large cohorts. This study aimed to evaluate the outcomes of biliary cannulation in patients with native papillae. We retrospectively identified 1021 patients who underwent initial ERCP from January 2013 to March 2020. We investigated background factors, treatment details, cannulation success rates, and adverse event rates. Then we analyzed a series of treatment processes, including salvage techniques such as double guidewire technique (DGT), needle knife pre-cutting (NKP), and transpancreatic pre-cut papillotomy (TPPP). The initial ERCP success rate using standard technique alone was 62.8%, which increased to 94.3% including salvage techniques. Salvage techniques were frequently required in patients with long oral protrusions (OR 2.38; 95% CI 1.80-3.15; p < 0.001). A total of 503 cases (49.3%) had long oral protrusions, 47.5% of which required the salvage techniques, much higher than 27.5% of not-long cases. Patients with long oral protrusions had a higher frequency of NKP. In conclusion, patients with long oral protrusions frequently required salvage techniques. Salvage techniques may help to overcome many difficult biliary cannulation cases.

The RNA-Binding Protein ELAVL1 Regulates Hepatitis B Virus Replication and Growth of Hepatocellular Carcinoma Cells.

Previous RNA immunoprecipitation followed by proteomic approaches successfully demonstrated that Embryonic Lethal, Abnormal Vision, Drosophila-Like 1 (ELAVL1) interacts with hepatitis B virus (HBV)-derived RNAs. Although ELAVL family proteins stabilize AU-rich element (ARE)-containing mRNAs, their role in HBV transcription remains unclear. This study conducted loss-of-function assays of ELAVL1 for inducible HBV-replicating HepAD38 cells and HBx-overexpressed HepG2 cells. In addition, clinicopathological analyses in primary hepatocellular carcinoma (HCC) surgical samples were also conducted. Lentivirus-mediated short hairpin RNA knockdown of ELAVL1 resulted in a decrease in both viral RNA transcription and production of viral proteins, including HBs and HBx, probably due to RNA stabilization by ELAVL1. Cell growth of HepAD38 cells was more significantly impaired in ELAVL1-knockdown than those in the control group, with or without HBV replication, indicating that ELAVL1 is involved in proliferation by factors other than HBV-derived RNAs. Immunohistochemical analyses of 77 paired HCC surgical specimens demonstrated that diffuse ELAVL1 expression was detected more frequently in HCC tissues (61.0%) than in non-tumor tissues (27.3%). In addition, the abundant expression of ELAVL1 tended to affect postoperative recurrence in HBV-related HCC patients. In conclusion, ELAVL1 contributes not only to HBV replication but also to HCC cell growth. It may be a potent therapeutic target for HBV-related HCC treatment.

A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-Ay mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-Ay mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.

Effect of Atezolizumab plus Bevacizumab in Patients with Hepatocellular Carcinoma Harboring CTNNB1 Mutation in Early Clinical Experience.

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1. These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

Feasibility of a Single Pigtail Stent Made by Cutting a Nasobiliary Drainage Tube in Endoscopic Transpapillary Gallbladder Stenting for Acute Cholecystitis.

Background and objective In this study, we aimed to evaluate the efficacy and safety of a single pigtail stent made by cutting a nasobiliary drainage tube (NBD stent) by comparing the clinical outcomes of using an NBD stent and those of using a ready-made double pigtail stent (RDP stent) in endoscopic gallbladder stenting (EGBS) for acute cholecystitis. Materials and methods This was a single-center retrospective study involving 20 cases that had technical success with EGBS for acute cholecystitis; the patients were divided into two groups: those using NBD stent (NBD group) and those using RDP stent (RDP group). The baseline characteristics and clinical outcomes were compared between the two groups. Results There were 13 patients in the NBD group and seven in the RDP group. The rates of clinical success (NBD group: 92% vs. RDP group: 100%, p=0.45) did not differ significantly between the groups. Regarding adverse events, gallbladder perforation occurred in one case in the NBD group; however, no other adverse events occurred in either group (NBD group: 7.7% vs. RDP group: 0%, p=0.45). The stent patency periods did not differ significantly between the groups [NBD group: 43 (12-64) days vs. RDP group: 97 (58-215) days, p=0.17]. The stent patency period in cases of long-term stent placement after EGBS was 1,381 days and 1,579 days in the NBD group and 305 days in the RDP group, respectively. Conclusion NBD stents are considered as effective as RDP stents in EGBS for acute cholecystitis. They are highly versatile and can be used for both bridging to surgery and long-term stent placement.

Liver cirrhosis is a risk factor for poor prognosis of acute cholangitis caused by choledocholithiasis.

INTRODUCTION AND OBJECTIVES: Acute cholangitis, which is characterized by biliary infection and acute liver injury, may impact cirrhosis prognosis. However, the prognosis itself remains unclear. MATERIALS AND METHODS: This multicenter retrospective cohort study compared the mortality and liver function change between patients with and without cirrhosis who underwent endoscopic treatment for acute cholangitis caused by choledocholithiasis between January 2004 and December 2019. RESULTS: We analyzed 699 patients, 44 of whom had cirrhosis. The cirrhotic group had a significantly higher 30-day mortality rate than the noncirrhotic group (14% vs. 1%; P < 0.001). The cirrhotic group also had significantly lower total bilirubin and albumin recovery. However, all patients with cirrhosis who survived achieved total-bilirubin recovery, and 91% achieved albumin recovery within 90 days. In multivariable Cox regression analysis, the independent risk factors for total-bilirubin recovery included cirrhosis (hazard ratio, 0.37; 95%CI, 0.24‒0.58; P < 0.001) and high total-bilirubin level (0.46; 95%CI, 0.34‒0.60; P < 0.001), whereas those for albumin recovery were cirrhosis (0.51; 95%CI, 0.33‒0.79; P = 0.002), high age (0.62; 95%CI, 0.47‒0.82; P < 0.001), organ dysfunction (0.62; 95%CI, 0.39‒0.96; P = 0.03), low albumin level (0.57; 95%CI, 0.36‒0.91; P = 0.02), and high C-reactive protein level (0.73; 95%CI, 0.56‒0.95; P = 0.02). CONCLUSIONS: Patients with cirrhosis complicated with acute cholangitis had poor prognosis. Recovery of liver function after endoscopic treatment was slow; nevertheless, most patients who survived could recover within 90 days.

Diagnostic value of peroral cholangioscopy in addition to computed tomography for indeterminate biliary strictures.

BACKGROUND: Peroral cholangioscopy (POCS) has been used to overcome the difficulty in diagnosing indeterminate biliary stricture or tumor spread. However, the value of adding POCS to computed tomography (CT) remains unclear. Our aim was to evaluate the diagnostic value of adding POCS to CT for indeterminate biliary stricture and tumor spread by interpretation of images focusing on the high diagnostic accuracy of visual findings in POCS. METHODS: We retrospectively identified 52 patients with biliary stricture who underwent endoscopic retrograde cholangiography (ERC) at our institution between January 2013 and December 2018. Two teams, each composed of an expert endoscopist and surgeon, performed the interpretation independently, referring to the CT findings of the radiologist. The CT + ERC + POCS images (POCS group) were evaluated 4 weeks after the evaluation of CT + ERC images (CT group). A 5-point scale (1: definitely benign to 5: definitely malignant) was used to determine the confident diagnosis rate, which was defined as an evaluation value of 1 or 5. Tumor spread was also evaluated. RESULTS: In the evaluation of 45 malignant diagnoses, the score was significantly closer to 5 in the POCS group than in the CT group in both teams (P < 0.001). The confident diagnosis rate was significantly higher for the POCS group (92% and 73%) than for the CT group (25% and 12%) in teams 1 and 2, respectively (P < 0.001). We found no significant difference in diagnostic accuracy for tumor spread between the groups. CONCLUSION: Visual POCS findings confirmed the diagnosis of biliary strictures. POCS was useful in cases of indefinite diagnosis of biliary strictures by CT.