A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Outcomes of Patients with Child-Pugh B and Unresectable Hepatocellular Carcinoma Undergoing First-Line Systemic Treatment with Sorafenib, Lenvatinib, or Atezolizumab Plus Bevacizumab.

INTRODUCTION: Systemic therapy is recommended for patients with Child-Pugh A in hepatocellular carcinoma (HCC). We analyzed the outcomes of a cohort of patients with HCC who received either sorafenib (Sor), lenvatinib (Len) or atezolizumab plus bevacizumab (Atezo + Bev) as first-line systemic therapy for HCC, with the aim of identifying prognostic factors for survival. METHODS: A total of 825 patients with advanced HCC and Child-Pugh A or B received either Sor, Len or Atezo + Bev as first-line systemic therapy. Liver function was assessed according to the Child-Pugh score and the modified albumin-bilirubin (mALBI) grade. RESULTS: Prognosis was analyzed according to liver function such as Child-Pugh classifications, scores, and mALBI grades that worsened with a decline in liver function (p <0.001 for all). A Child-Pugh score of 7 was a factor significantly associated with OS. In patients with a Child-Pugh score of 7, an mALBI grade of 3 was an independent predictor of OS. In Child-Pugh B patients with HCC, receiving Atezo + Bev was identified as a factor associated with PFS. CONCLUSION: Determining the hepatic reserve of patients with unresectable HCC might be useful for identifying patents suitable for systemic treatment for HCC. Atezo + Bev might prolong the PFS of patients with a Child-Pugh score of 7.

Clinical features and images of malignant lymphoma localized in the pancreatic head to differentiate from pancreatic ductal adenocarcinoma: a case series study.

BACKGROUND: Pathological examination by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been reported to be useful in diagnosing pancreatic malignant lymphoma (ML), but some ML cases are difficult to be differentiated from pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective study included 8 patients diagnosed with ML that had a pancreatic-head lesion at initial diagnosis and 46 patients with resected PDAC in the pancreatic head between April 2006 and October 2021 at our institute. ML and PDAC were compared in terms of patients' clinical features and imaging examinations. RESULTS: The median tumor size was larger in ML than in PDAC (45.8 [24-64] vs. 23.9 [8-44] mm), but the median diameter of the caudal main pancreatic duct (MPD) was larger in PDAC (2.5 [1.0-3.5] vs. 7.1 [2.5-11.8] mm), both showing significant differences between these malignancies (both, P < 0.001). In the analysis of covariance, MLs showed a smaller caudal MPD per tumor size than PDACs, with a statistical difference (P = 0.042). Sensitivity and specificity using sIL-2R ≥ 658 U/mL plus CA19-9 < 37 U/mL for the differentiation of ML from PDAC were 80.0% and 95.6%, respectively. CONCLUSIONS: Diagnosing pancreatic ML using cytohistological examination through EUS-FNA can be difficult in some cases. Thus, ML should be suspected if a patient with a pancreatic tumor has a small MPD diameter per tumor size, high serum sIL-2R level, normal CA19-9 level. If the abovementioned features are present and still cannot be confirmed as PDAC, re-examination should be considered.

Long-standing diabetes mellitus increases concomitant pancreatic cancer risk in patients with intraductal papillary mucinous neoplasms.

BACKGROUND: When monitoring patients with an intraductal papillary mucinous neoplasm (IPMN), it is important to consider both IPMN-derived carcinoma and concomitant ductal adenocarcinoma (PDAC). The latter is thought to have a poorer prognosis. We retrospectively analyzed the risk factors for concomitant PDAC in IPMN. METHODS: In total, 547 patients with pancreatic cysts, including IPMNs inappropriate for surgery on initial diagnosis, encountered from April 2005 to June 2019, were reviewed. We performed surveillance by imaging examination once or twice a year. RESULTS: Five IPMNs with high-grade dysplasia and one IPMN associated with invasive carcinoma were encountered. In comparison, 14 concomitant PDACs were encountered. The prognosis was very poor for concomitant PDACs. All 14 PDAC patients had IPMNs. In patients with IPMNs, long-standing diabetes mellitus was the only significant risk factor for concomitant PDAC in both univariate and multivariate analyses (P < 0.001 and P < 0.01, respectively). Furthermore, patients with IPMNs and diabetes mellitus had a high frequency of concomitant PDACs (9.5%, 9/95) in a median 48-month surveillance period. CONCLUSIONS: When monitoring IPMNs, the development of not only IPMN-derived carcinomas but also concomitant PDACs should be considered. During this period, it may be prudent to concentrate on patients with other risk factors for PDAC, such as long-standing diabetes mellitus.

Comparison of the Clinical Outcome of Ramucirumab for Unresectable Hepatocellular Carcinoma with That of Prior Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. METHODS: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. RESULTS: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. CONCLUSION: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.

A case of intraductal tubulopapillary neoplasm of the pancreas in a branch duct: a rare case report and literature review.

BACKGROUND: Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a new disease concept defined by the World Health Organization in 2010. ITPN progresses with tubulopapillary growth in the pancreatic duct and is known to have a fair prognosis. Localization in the main pancreatic duct (MPD) is one characteristic. There are few case reports of ITPN in a branch of the pancreatic duct (BD). CASE PRESENTATION: We encountered a case of ITPN localized in BD. An 85-year-old man was followed after colonic surgery for rectal carcinoma. An abdominal computed tomography scan revealed a cystic mass in the pancreatic head and further examination was done. A T2 weighted intension picture in magnetic resonance imaging showed a 20 mm cystic lesion with an internal mass of 15 mm. Duodenal papilla were slightly open and endoscopic retrograde pancreatography revealed mild and diffuse dilatation of the main pancreatic duct and mucin in the MPD. In consideration with the image examinations, we diagnosed the tumor as an intraductal papillary mucinous neoplasm with carcinoma because of its large mural nodule (> 10 mm in size) in a cyst. Consequently, a pancreaticoduodenectomy was performed. Macroscopically, a white solid tumor sized 2.5 × 1.8 × 1.0 was identified in the head of the pancreas. The cut surface of the resected pancreas showed a side-branch type intraductal tumor with tubulopapillary architecture without mucin secretion. Immunohistochemical staining was positive for MUC1, and negative for MUC2 and MUC5AC. The final diagnosis was determined to be pancreatic ITPN from BD. At the time of this report (48 months post-surgery), the patient remains disease-free without evidence of recurrence. CONCLUSION: ITPNs localized in BD are rare and diagnosis prior to surgery is difficult. In our case, the shape was round, not papillary, and with little fluid. These characteristics are different from a branch duct type IPMN and can be a clue to suspect ITPN in BD.

[A case of Salmonella bacteremia in an otherwise healthy young man].

A 19-year-old man was admitted to our hospital because of persistent fever of >38°C for 6 days and diarrhea for 4 days. Initially, he was treated for infectious enteritis, but on his second day in the hospital, the two sets of blood cultures came back positive. Cultures from the blood and stool yielded Salmonella sp. (Group O4). The patient's symptoms improved after treatment with fluoroquinolone-based antimicrobial agents for 14 days. Cases of nontyphoidal Salmonella bacteremia are rare;therefore, we reported this case with bibliographic consideration of the risk factors for Salmonella bacteremia.

Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population.

A previous genome-wide association study (GWAS) performed in 963 Japanese individuals (487 primary biliary cholangitis [PBC] cases and 476 healthy controls) identified TNFSF15 (rs4979462) and POU2AF1 (rs4938534) as strong susceptibility loci for PBC. In this study, we performed GWAS in additional 1,923 Japanese individuals (894 PBC cases and 1,029 healthy controls), and combined the results with the previous data. This GWAS, together with a subsequent replication study in an independent set of 7,024 Japanese individuals (512 PBC cases and 6,512 healthy controls), identified PRKCB (rs7404928) as a novel susceptibility locus for PBC (odds ratio [OR] = 1.26, P = 4.13 × 10-9). Furthermore, a primary functional variant of PRKCB (rs35015313) was identified by genotype imputation using a phased panel of 1,070 Japanese individuals from a prospective, general population cohort study and subsequent in vitro functional analyses. These results may lead to improved understanding of the disease pathways involved in PBC, forming a basis for prevention of PBC and development of novel therapeutics.

[Surgical Resection of Hepatic Portal Lymph Node Metastasis after Repeated Treatment for Hepatocellular Carcinoma Recurrence].

We encountered a case of hepatic portal lymph node metastasis after repeated treatment for hepatocellular carcinoma (HCC)recurrence. A 73-year-old male patient underwent partial gastrectomy following rupture of a gastrointestinal stromal tumor 8 years ago. A 70mm tumor was simultaneously revealed in the posterior segment of the liver, and imatinib treatment was initiated based on the diagnosis of a metastatic liver tumor. Due to the absence of an increasing tendency in the tumor, extended posterior segmentectomy was performed, and the pathological diagnosis was moderately differentiated HCC. During observation, transcatheter arterial chemoembolization(TACE)plus radiofrequency ablation(RFA)therapy was performed twice, and partial resection of the liver was performed once again for HCC recurrence. Recently, PIVKA-Ⅱ showed a high value of 1,720mAU/mL, and follow-up computed tomography showed HCC recurrence in S4/8 and hepatic portal lymph node metastasis. TACE was administered for recurrent lesions in S4/8, and surgical resection of the hepatic portal lymph node was performed together. The pathological diagnosis revealed extensive liver tissue necrosis and moderately-topoorly differentiated HCC in the excised lymph nodes. Lymph node metastasis of HCC is rare, and in this case, a change in lymph flow caused by repeated treatment for HCC recurrence was considered a factor influencing the course.

BEN3/BIG2 ARF GEF is Involved in Brefeldin A-Sensitive Trafficking at the trans-Golgi Network/Early Endosome in Arabidopsis thaliana.

Membrane traffic at the trans-Golgi network (TGN) is crucial for correctly distributing various membrane proteins to their destination. Polarly localized auxin efflux proteins, including PIN-FORMED1 (PIN1), are dynamically transported between the endosomes and the plasma membrane (PM) in the plant cells. The intracellular trafficking of PIN1 protein is sensitive to the fungal toxin brefeldin A (BFA), which is known to inhibit guanine nucleotide exchange factors for ADP ribosylation factors (ARF GEFs) such as GNOM. However, the molecular details of the BFA-sensitive trafficking pathway have not been fully revealed. In a previous study, we identified an Arabidopsis mutant BFA-visualized endocytic trafficking defective 3 (ben3) which exhibited reduced sensitivity to BFA in terms of BFA-induced intracellular PIN1 agglomeration. Here, we show that BEN3 encodes a member of BIG family ARF GEFs, BIG2. BEN3/BIG2 tagged with fluorescent proteins co-localized with markers for the TGN/early endosome (EE). Inspection of conditionally induced de novo synthesized PIN1 confirmed that its secretion to the PM is BFA sensitive, and established BEN3/BIG2 as a crucial component of this BFA action at the level of the TGN/EE. Furthermore, ben3 mutation alleviated BFA-induced agglomeration of another TGN-localized ARF GEF, BEN1/MIN7. Taken together, our results suggest that BEN3/BIG2 is an ARF GEF component, which confers BFA sensitivity to the TGN/EE in Arabidopsis.

Endoscopic submucosal dissection of early colorectal neoplasms with a monopolar scissor-type knife: short- to long-term outcomes.

Background and study aims Endoscopic submucosal dissection (ESD) for colorectal neoplasms remains challenging because of technical issues imposed by the complex anatomical features of the large intestine. We evaluated the feasibility, and the short- and long-term clinical outcomes of ESD for early colorectal neoplasms performed using the Stag-beetle Knife Jr. (SB Knife Jr.) Patients and methods We retrospectively assessed 228 patients who underwent ESD for 247 colorectal lesions with the SB Knife Jr. Clinicopathological characteristics of the neoplasms, complications, and various short- and long-term outcomes were evaluated. Results Mean tumor size was 34.3 mm and median procedure time was 76 minutes. The SB Knife Jr. achieved 98.4 % en bloc resection, 93.9 % complete resection, and 85.4 % curative resection. No perforations occurred during the procedure, and a delayed bleeding rate of 2.4 % was observed. Long-term outcomes were favorable with no distant recurrence, 1.1 % local recurrence, a 5-year overall survival rate of 94.1 % and 5-year tumor-specific survival rate of 98.6 % in patients with cancer. Conclusions ESD using the SB Knife Jr. is technically efficient and safe in treating early colorectal neoplasms and is associated with favorable short- and long-term outcomes.

A case of ileus due to radiation enteritis 19 years after radiotherapy.

A 73-year-old female visited our hospital complaining of nausea and epigastric pain because of ileus. She had a history of two laparotomy procedures in her youth, interferon treatment for chronic hepatitis C, and radiation therapy for uterine cervical cancer 19 years ago. Transanal double-balloon enteroscopy demonstrated annular stenosis with ulceration of the anal side of the dilated small intestine. Therefore, surgical resection was performed, and late radiation enteritis was diagnosed on histopathological examination. We report a case of ileus due to radiation enteritis 19 years after radiotherapy.

High-grade pancreatic intraepithelial neoplasia diagnosed based on changes in magnetic resonance cholangiopancreatography findings: A case report.

BACKGROUND: High-grade pancreatic intraepithelial neoplasia (PanIN) exhibits no mass and is not detected by any examination modalities. However, it can be diagnosed by pancreatic juice cytology from indirect findings. Most previous cases were diagnosed based on findings of a focal stricture of the main pancreatic duct (MPD) and caudal MPD dilatation and subsequent pancreatic juice cytology using endoscopic retrograde cholangiopancreatography (ERCP). We experienced a case of high-grade PanIN with an unclear MPD over a 20-mm range, but without caudal MPD dilatation on magnetic resonance cholangiopancreatography (MRCP). CASE SUMMARY: A 60-year-old female patient underwent computed tomography for a follow-up of uterine cancer post-excision, which revealed pancreatic cysts. MRCP revealed an unclear MPD of the pancreatic body at a 20-mm length without caudal MPD dilatation. Thus, course observation was performed. After 24 mo, MRCP revealed an increased caudal MPD caliber and a larger pancreatic cyst. We performed ERCP and detected atypical cells suspected of adenocarcinoma by serial pancreatic juice aspiration cytology examination. We performed a distal pancreatectomy and obtained a histopathological diagnosis of high-grade PanIN. Pancreatic parenchyma invasion was not observed, and curative resection was achieved. CONCLUSION: High-grade Pan-IN may cause MPD narrowing in a long range without caudal MPD dilatation.

Proportion of Neutrophils in White Blood Cells as a Useful Marker for Predicting Bacteremic Acute Cholangitis.

Objective A positive hemoculture in acute cholangitis is serious, but a blood culture result cannot be obtained at the initial diagnosis and so cannot be used for the severity assessment and decision-making concerning urgent/early biliary drainage. Accordingly, a predictor for bacteremia at the initial diagnosis of acute cholangitis would be particularly useful. We investigated the association between neutrophil proportions in white blood cell counts (%Neutro) and bacteremic acute cholangitis. Methods Of 166 patients with acute cholangitis who were diagnosed with the Tokyo Guidelines 2018/2013 from April 2015 to March 2017, a total of 94 underwent blood culture assessments and were divided into those with a positive hemoculture (n=48) and a negative hemoculture (n=46) and then compared. A receiver operating characteristic curve analysis was used to evaluate the predictive ability of %Neutro and other inflammatory markers. Results The %Neutro values were significantly higher in the positive hemoculture group than in the negative hemoculture group (91.7±4.0% vs. 82.5±9.0%, p<0.0001). A cut-off %Neutro value of 89.7% was strongly associated with bacteremia (area under the curve 0.86, sensitivity 77.1%, specificity 80.4%). A %Neutro of ≥89.7% was a predictor of a positive hemoculture in univariate (p<0.0001) and multivariate analyses (p<0.001). Patients with a %Neutro ≥89.7% needed early biliary drainage more frequently than others (30/46, 65.2% vs. 18/48, 37.5%, p=0.0063). Conclusion %Neutro is an independent predictor of bacteremia in patients with acute cholangitis and may contribute to decision-making concerning early biliary drainage.

Efficacy of a novel integrated biliary stent and nasobiliary catheter system for accidental tube deviation in biliary drainage.

Background and study aims Endoscopic nasobiliary drainage is accompanied by a risk of accidental removal of the nasobiliary drainage (NBD) tube, especially through self-removal in elderly patients. We studied the usefulness of an integrated biliary stent and nasobiliary catheter system (UMIDAS NB stent) for biliary drainage in case of accidental NBD tube removal. Patients and methods From April to November 2022, we placed a UMIDAS NB stent in 30 patients with acute cholangitis or obstructive jaundice. We evaluated the plastic stent (PS) position at the time of accidental stent removal and before the planned endoscopic procedure. In addition, we studied the ratio of successful biliary drainage and complications based on the usage of UMIDAS. Results All 11 patients with accidental stent removal exhibited correct PS position in X-ray fluoroscopy. Of the 19 patients with planned NBD tube removal, three had complete PS migration into the common bile duct and three had incomplete migration (the duodenal side flap entered the bile duct). In summary, 80% (24/30) of PS were in the correct position, and all patients had successful biliary drainage and no complications. Conclusions The UMIDAS NB stent might be useful for biliary drainage in patients with a high risk of NBD tube self-removal.

Metastatic pancreatic ductal adenocarcinoma followed by a fatal diffuse large B-cell lymphoma: A rare case report and literature review.

RATIONALE: Recently, the incidence of polyoncosis has been increasing due to advancements in treatment, such as antitumor therapy, which led to a prolonged survival. However, few patients with metastatic pancreatic ductal adenocarcinoma (PDAC) develop second tumors, which render a poor prognosis. We report a rare case of PDAC, which is metachronous with a fatal malignant lymphoma (ML). PATIENT CONCERNS: A 68-year-old woman who had been monitored due to liver cirrhosis secondary to hepatitis C virus infection presented with a 10-mm pancreatic head cancer with lung metastasis and had started an anticancer therapy with gemcitabine. Approximately 18 months after diagnosis, lymphadenopathies around the pancreas were noted, which eventually spread to the entire body over time. DIAGNOSIS: Diffuse large B-cell lymphoma was diagnosed using biopsies from cervical lymph nodes. INTERVENTIONS AND OUTCOMES: The patient started a gemcitabine + rituximab regimen; however, the patient died from cachexia-associated lymphoma progression, not PDAC. LESSONS: ML should be considered when intra-abdominal lymphadenopathies are detected in patients with pancreatic cancer, and ML should be differentiated from lymph node metastasis of pancreatic cancer.

A case of pancreatic adenosquamous carcinoma with direct invasion to the gastrointestinal tract through the retention cyst wall: A rare case report.

A 62-year-old man presented with a 7-cm cystic lesion with irregularly thickened cyst wall in contact with the pancreatic tail. The pancreatic tail was described as hypoechoic on endoscopic ultrasonography. The cyst subsequently increased rapidly to 13 cm, and surgery was performed. This revealed adenosquamous carcinoma in the pancreatic tail to have invaded the stomach and transverse colon along the cyst wall. The cyst was diagnosed as a retention cyst due to pancreatic tail tumor. Invasion of nearby organs by a pancreatic cancer via the retention cyst wall is very rare, but it is necessary to keep the potential for such progress in mind.

Therapeutic Efficacy and Safety of Lenvatinib after Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2-12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months-not reached) and 4.0 months (range, 2.5-6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02-0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003-0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.