Successful intrahepatic cholangiocarcinoma conversion surgery after administration of fibroblast growth factor receptor inhibitor.

We describe a case of a 47-year-old male patient with initially unresectable intrahepatic cholangiocarcinoma of the right liver lobe with tumor thrombi extending from the right bile duct to the common and left bile ducts. Conventional chemotherapy with gemcitabine and cisplatin for 19 months resulted in progressive disease. Subsequently, a comprehensive genome profile revealed fibroblast growth factor receptor 2 rearrangement, and hence, pemigatinib administration was initiated. After 6 months of pemigatinib therapy, significant shrinking of the tumor and disappearance of the tumor thrombi in the common and left bile duct were observed. Subsequently, the patient underwent conversion surgery, resulting in successful radical resection of the tumor. The patient has been disease-free for 7 months.

[Gallbladder carcinosarcoma associated with pancreaticobiliary maljunction with biliary dilation:a case report].

A 68-year-old female patient was referred to our hospital with acute cholangitis. Computed tomography revealed common bile duct dilatation, gallbladder fundal tumor, and gallbladder wall thickening attached to the tumor. Cholangiography revealed pancreaticobiliary maljunction with biliary dilation. The patient was diagnosed with pancreaticobiliary maljunction with biliary dilation and gallbladder cancer and underwent liver S4b+5 and bile duct resection and reconstruction. Pathological results revealed that the gallbladder fundal tumor included sarcoma, and the gallbladder wall thickening had adenocarcinoma;thus, the patient was diagnosed with gallbladder carcinosarcoma.

Endoscopic ultrasound-guided fine needle biopsy diagnosis of circumferentially extraluminal mucosa-associated lymphoid tissue lymphoma in the transverse colon: a case report.

A 61-year-old man present to us with continued abdominal pain without abdominal tenderness for 1 month. Blood testing showed elevated biliary enzymes and inflammation. Contrast-enhanced computed tomography (CT) revealed thickening of the transverse colon with relatively strong enhancement but no bile duct dilatation. Colonoscopy revealed localized edema and granular mucosa in the transverse colon. Fluoroscopic endoscopy exhibited the absence of haustra. Multiple biopsies were performed, but differentiation between mild inflammation and mucosa-associated lymphoid tissue (MALT) lymphoma was inconclusive. To establish a definitive diagnosis, transgastric endoscopic ultrasound-guided fine needle biopsy of the hypoechoic mass was performed. Histopathological analysis exhibited the proliferation of small-sized lymphocytes. Fluorescence in situ hybridization revealed the characteristic API2-MALT1 translocation of MALT lymphoma. We performed liver biopsy to investigate biliary enzyme elevation. Histopathology confirmed lymphocytic infiltration within Glisson's capsule. Immunohistochemistry showed positive for CD20 and negative for CD3 and CD5, signifying the infiltration of MALT lymphoma in the liver. Based on these findings, we diagnosed MALT lymphoma, Lugano classification Stage IV. We performed bendamustine-rituximab (BR)-combined therapy. After six courses of BR-combined therapy, colonoscopy revealed improvement in the lead pipe sign and CT revealed disappearance of the mass.

Natural excretion of a metallic susceptor originating from an ingested heated tobacco stick.

Key Clinical Message: Clinicians should not only consider the presence of metallic foreign bodies within the digestive tract but also contemplate the possibility of nicotine poisoning during the diagnostic process. Abstract: When clinicians encounter cases of accidental ingestion of some types of heated tobacco, they must consider not only nicotine poisoning but also the possibility of a metallic foreign body within the digestive tract during diagnosis. In children, even sharp or relatively large ingested foreign bodies can spontaneously pass below the esophagus. Considering that this 12-mm metal piece is small, natural excretion may be considered rather than endoscopic removal.

Incidental detection of upper gastrointestinal epithelial neoplasia by screening endoscopy prior to endoscopic ultrasonography in patients with pancreaticobiliary disease.

BACKGROUND: Screening esophagogastroduodenoscopy plays an important role in the early detection of upper gastrointestinal cancer. To provide more opportunities for patients with pancreaticobiliary disease to undergo this screening, we have performed esophagogastroduodenoscopy prior to endoscopic ultrasonography. However, the usefulness of this protocol is not elucidated. This study aimed to investigate the utility of screening esophagogastroduodenoscopy in this protocol in the detection of upper gastrointestinal epithelial neoplasms. METHODS: The outcomes of screening esophagogastroduodenoscopy performed prior to endoscopic ultrasonography in patients with pancreaticobiliary disease at our hospital between April 2020 and September 2022 were investigated. A logistic regression model was used to identify factors affecting the detection of epithelial neoplasms. Additionally, we compared the detection rate of gastric epithelial neoplasms between screening esophagogastroduodenoscopy performed prior to endoscopic ultrasonography and that performed at our medical checkup center. RESULTS: A total of 615 screening esophagogastroduodenoscopies prior to endoscopic ultrasonography were performed, and 12 (2.0%) epithelial neoplasms were detected, including esophageal lesions (n = 2) and gastric lesions (n = 10). Of these lesions, 75% (9/12) underwent curative endoscopic resection. A multivariate analysis showed that open-type gastric mucosal atrophy (odds ratio, 7.7; 95% confidence interval, 1.5-38.4; p = 0.01) and the use of magnification endoscopy (odds ratio, 7.3; 95% confidence interval, 1.9-27.9; p < 0.01) independently affected the detection of epithelial neoplasms. The detection rate of gastric epithelial neoplasms was significantly higher using this protocol than that in our medical checkup center (1.6% versus 0.2%, p < 0.01). CONCLUSIONS: A protocol of screening esophagogastroduodenoscopy prior to endoscopic ultrasonography may be recommended because epithelial neoplasms could be detected at a non-negligible rate.

Case report: A pediatric case of repeated false-positive urea breath test for Helicobacter pylori without decreased gastric acid secretion.

The urea breath test (UBT) is often used to diagnose Helicobacter pylori infection and for its eradication. However, this text can give positive results even for other urease-active bacteria other than H. pylori. Even after the successful eradication of H. pylori, the presence of other urease-active bacteria in the gut and oral cavity can lead to positive UBT results in patients with decreased gastric acid secretion. Herein, a 15-year-old boy was diagnosed with H. pylori infection through the testing and treatment program for H. pylori for third-year junior high-school students in Saga Prefecture initiated in 2016. He underwent triple therapy comprising vonoprazan; however, UBT was found to be positive even after therapy. The results remained positive even after fourth-line eradication therapy. Stool antigen, PCR using gastric fluid, microscopy, culture, and rapid urease tests were all negative. Pepsinogen levels were normal, and none of the findings suggested autoimmune gastritis. Gastric microflora analysis revealed oral flora showing urease activity. UBT is considered useful for determining the successful eradication of H. pylori; however, it may give false-positive results for both H. pylori infection and eradication judgment. Although the patient did not have autoimmune gastritis or decreased gastric acid secretion, it is presumed that oral commensal bacteria showing urease activity inhabited the stomach, resulting in the persistently positive UBT results. In conclusion, repeated false-positive UBT results for H. pylori may occur even without gastric acid hyposecretion. If H. pylori eradication is unsuccessful based on UBT, additional test by stool H. pylori antigen tests should be considered.

Gallbladder perforation following peroral cholangioscopy-guided lithotripsy: A case report.

Peroral cholangioscopy-guided lithotripsy is highly effective in clearing difficult bile duct stones. It can cause adverse events, such as cholangitis and pancreatitis; however, gallbladder perforation is extremely rare. Herein, we describe the case of a 77-year-old woman who developed gallbladder perforation following peroral cholangioscopy -guided lithotripsy. She was referred to our hospital to treat multiple large bile duct stones. She underwent peroral cholangioscopy-guided lithotripsy because of conventional lithotripsy failure. After a cholangioscope was advanced into the bile duct, saline irrigation was used for visualization. Electronic hydraulic lithotripsy was performed, but it took time for fragmentation because the calculus was hard. The 2-h endoscopic procedure did not completely remove the stone, and treatment was discontinued after placing a biliary plastic stent and nasobiliary tube. After the endoscopic procedure, she started experiencing right hypochondrial pain, which worsened the next day. Computed tomography showed a gallbladder wall defect in the gallbladder fundus with pericholecystic fluid. She was diagnosed with gallbladder perforation and underwent emergency surgery. A perforation site was found at the gallbladder fundus. Open cholecystectomy, choledochotomy, and extraction of residual bile duct stones were performed. The patient was discharged 9 days post-surgery without any complications. The saline irrigation used for visualization may have caused a surge in intra-gallbladder pressure, resulting in gallbladder perforation. Therefore, endoscopists may need to conserve irrigation water during peroral cholangioscopy-guided lithotripsy.

Porous honeycomb film membranes enhance endothelial barrier integrity in human vascular wall bilayer model compared to standard track-etched membranes.

In vitro vascular wall bilayer models for drug testing and disease modeling must emulate the physical and biological properties of healthy vascular tissue and its endothelial barrier function. Both endothelial cell (EC)-vascular smooth muscle cell (SMC) interaction across the internal elastic lamina (IEL) and blood vessel stiffness impact endothelial barrier integrity. Polymeric porous track-etched membranes (TEM) typically represent the IEL in laboratory vascular bilayer models. However, TEM stiffness exceeds that of diseased blood vessels, and the membrane pore architecture limits EC-SMC interaction. The mechanical properties of compliant honeycomb film (HCF) membranes better simulate the Young's modulus of healthy blood vessels, and HCFs are thinner (4 vs. 10 µm) and more porous (57 vs. 6.5%) than TEMs. We compared endothelial barrier integrity in vascular wall bilayer models with human ECs and SMCs statically cultured on opposite sides of HCFs and TEMs (5 µm pores) for up to 12 days. Highly segregated localization of tight junction (ZO-1) and adherens junction (VE-cadherin) proteins and quiescent F-actin cytoskeletons demonstrated superior and earlier maturation of interendothelial junctions. Quantifying barrier integrity based on transendothelial electrical resistance (TEER), membranes showed only minor but significant TEER differences despite enhanced junctional protein localization on HCF. Elongated ECs on HCF likely experienced greater paracellular diffusion than blocky ECs on TEM. Also, larger populations of plaques of connexin 43 subunit-containing gap junctions suggested enhanced EC-SMC communication across the more porous, thinner HCF. Compared with standard TEMs, engineered vascular wall bilayers cultured on HCFs better replicate physiologic endothelial barrier integrity.

Endoscopic ultrasound-guided fine-needle biopsy for the diagnosis of gastric metastasis from breast cancer mimicking primary linitis plastica: A case report.

For gastric lesions in a patient with a history of breast cancer, it is essential to distinguish between primary gastric cancer and gastric metastasis from breast cancer. However, gastric metastasis from breast cancer often mimics primary linitis plastica, and histological diagnosis may be difficult with conventional endoscopic biopsies. Herein, we describe the case of a 75-year-old woman who presented at our hospital with epigastralgia and vomiting. She had a history of mastectomy for carcinoma of the right breast and had received hormone therapy as adjuvant therapy. Computed tomography at arrival showed thickening of the gastric wall at the antrum and peritoneal dissemination. Esophagogastroduodenoscopy showed mucosal swelling of the antrum and stenosis of the pylorus, and histological diagnosis failed with conventional endoscopic biopsies. Endoscopic ultrasound-guided fine-needle biopsy using a Franseen needle was performed, and a diagnosis of gastric metastasis from breast cancer was made. She received hormone therapy and chemotherapy after deployment of a metallic stent for gastric outlet obstruction. To the best of our knowledge, this is the first case of gastric metastasis from breast cancer diagnosed using endoscopic ultrasound-guided fine-needle biopsy.

Diplogonoporiasis Following the Consumption of Raw Juvenile Japanese Anchovy.

Human diplogonoporiasis caused by the tapeworm Diplogonoporus balaenopterae has been rarely reported in Japan in the last decade. A 38-year-old man complained of a fever, diarrhea, intermittent abdominal pain, and worm excretion. He had a history of consuming raw juvenile Japanese anchovy one month earlier. On admission, the patient had acute enteritis and received intravenous fluids. During hospitalization, he excreted a white worm in his stool. On a macroscopic examination, the worm was found to be a tapeworm with scolexes. His health improved spontaneously without taking anthelmintic agents. Based on the genetic analysis, the tapeworm was identified as Diplogonoporus balaenopterae.

Human Vascular Wall Microfluidic Model for Preclinical Evaluation of Drug-Induced Vascular Injury.

Drug-induced vascular injury (DIVI) in preclinical animal models often leads to candidate compound termination during drug development. DIVI has not been documented in human clinical trials with drugs that cause DIVI in preclinical animals. A robust human preclinical assay for DIVI is needed as an early vascular injury screen. A human vascular wall microfluidic tissue chip was developed with a human umbilical vein endothelial cell (HUVEC)-umbilical artery smooth muscle cell (vascular smooth muscle cell, VSMC) bilayer matured under physiological shear stress. Optimized temporal flow profiles produced HUVEC-VSMC bilayers with quiescent endothelial cell (EC) monolayers, EC tight junctions, and contractile VSMC morphology. Dose-response testing (3-30 µM concentration) was conducted with minoxidil and tadalafil vasodilators. Both drugs have demonstrated preclinical DIVI but lack clinical evidence. The permeability of severely damaged engineered bilayers (30 µM tadalafil) was 4.1 times that of the untreated controls. Immunohistochemical protein assays revealed contrasting perspectives on tadalafil and minoxidil-induced damage. Tadalafil impacted the endothelial monolayer with minor injury to the contractile VSMCs, whereas minoxidil demonstrated minor EC barrier injury but damaged VSMCs and activated ECs in a dose-response manner. This proof-of-concept human vascular wall bilayer model of DIVI is a critical step toward developing a preclinical human screening assay for drug development. Impact statement More than 90% of drug candidates fail during clinical trials due to human efficacy and toxicity concerns. Preclinical studies rely heavily on animal models, although animal toxicity and drug metabolism responses often differ from humans. During the drug development process, perfused in vitro human tissue chips could model the clinical drug response and potential toxicity of candidate compounds. Our long-term objective is to develop a human vascular wall tissue chip to screen for drug-induced vascular injury. Its application could ultimately reduce drug development delays and costs, and improve patient safety.

Drug Transcellular Transport Assay Using a High Porosity Honeycomb Film.

In vitro transport studies across cells grown on culture inserts are widely used for evaluating pharmacokinetic characteristics such as intestinal membrane permeability. However, measurements of the apparent permeability coefficient of highly lipophilic compounds are often limited by transport across the membrane filters, not by transport across the cultured cells. To overcome this concern, we have investigated the utility of a high-porosity membrane honeycomb film (HCF) for transcellular transport studies. Using the HCF inserts, the apparent permeability coefficient (Papp) of the drugs tested in LLC-PK1 and Caco-2 cells tended to increase with an increase in lipophilicity, reaching a maximum Papp value at Log D higher than 2. In contrast, using the commercially available Track-Etched membrane (TEM) inserts, a maximum value was observed at Log D higher than 1. The basolateral to apical transport permeability Papp(BL→AP) of rhodamine 123 across LLC-PK1 cells that express P-glycoprotein (P-gp) cultured on HCF inserts and TEM inserts was 2.33 and 2.39 times higher than the reverse directional Papp(AP→BL) permeability, respectively. The efflux ratio (Papp(B-A)/Papp(A-B)) of rhodamine 123 in LLC-PK1 expressing P-gp cells using HCF inserts was comparable to that obtained using TEM inserts, whereas the transported amount in both directions was significantly higher when using the HCF inserts. Accordingly, due to the higher permeability and high porosity of HCF membranes, it is expected that transcellular transport of high lipophilic as well as hydrophilic compounds and substrate recognition of transporters can be evaluated more accurately by using HCF inserts.

Dilated main pancreatic duct can be a negative predictor of pancreatitis related to biliary SEMS insertion across the papilla.

OBJECTIVES: Post-ERCP pancreatitis (PEP) after self-expandable metallic stent (SEMS) insertion across the papilla of Vater is an important adverse event that affects the patient's quality of life (QOL). We examined the predictive factors of PEP after SEMS insertion to treat obstructive jaundice due to malignancy. METHODS: Ninety patients who underwent biliary SEMS insertion for biliary obstruction due to malignancy at Iwata City Hospital between 2010 and 2018 were reviewed. We evaluated the relationship between the incidence of PEP after biliary SEMS insertion and clinical factors. We measured the thickness of the pancreatic parenchyma and diameter of the main pancreatic duct (MPD) at the left side of the corpus vertebrae. RESULTS: Mild and severe PEP were diagnosed in 10 (11.1%) and 1 (1.1%) patients, respectively. Only the thickness of the pancreatic parenchyma and diameter of MPD significantly differed between the PEP and non-PEP groups. The incidence of PEP among patients whose thickness of the pancreatic parenchyma at the left side of the corpus vertebrae was less than 9.5 mm (0%) on computed tomography was lower than that in patients whose thickness was 9.5 mm or greater (34.4%). Similarly, a wider (5 mm or more) diameter of MPD (4.3%) reduced the incidence of PEP compared with a narrower diameter (40.0%). Logistic regression analysis revealed that the probability of PEP decreases 3.91 times for every 1-mm increase in MPD diameter (95% CI 1.23-12.4, p = .02). CONCLUSION: Based on our study, a dilated MPD is a negative predictive factor of pancreatitis related to biliary SEMS insertion.

Polydom Is an Extracellular Matrix Protein Involved in Lymphatic Vessel Remodeling.

RATIONALE: Lymphatic vasculature constitutes a second vascular system essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9ß1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS: We generated Polydom-deficient mice. Polydom-/- mice showed severe edema and died immediately after birth because of respiratory failure. We found that although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom-/- embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2 (forkhead box protein c2), a transcription factor involved in lymphatic remodeling, was decreased in Polydom-/- mice. Polydom bound to the lymphangiogenic factor Ang-2 (angiopoietin-2), which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for angiopoietins were also decreased in Polydom-/- mice. CONCLUSIONS: Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Ang-2 and Tie1/Tie2 receptor system.

Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel.

Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.

Improvement of gastroesophageal reflux disease in Japanese patients with spinal kyphotic deformity who underwent surgical spinal correction.

BACKGROUND AND AIM: Spinal kyphotic deformity occasionally results in gastroesophageal reflux disease (GERD). The effects of acid reflux on the esophagus in kyphotic patients are unclear, however, and it is unknown whether acid reflux, endoscopic GERD, and reflux-related symptoms improve following surgical spinal correction in these patients. Herein, we investigated the characteristics of GERD in kyphotic patients and the improvement in GERD following surgical correction. METHODS: In 48 patients with severe kyphotic deformity scheduled for surgical spinal correction, we conducted esophagogastroduodenoscopy, 24-h pH monitoring and three questionnaire surveys, including the frequency scale for the symptoms of GERD (FSSG). We repeated these measurements after surgical correction and compared pre- and post-surgery values. RESULTS: Of 48 patients, 70.8% [95% CI: 55.9-83.0%, 34/48] had endoscopically evaluated esophageal mucosal injury. Regarding pH before surgery, 64.9% (CI: 47.5-79.8%, 24/37) had abnormal acid reflux (intraesophageal pH < 4 more than 5% of the time). FSSG score was significantly associated with the severity of GERD, and the positive rate was 52.6% (CI: 35.8-69.0%, 20/38). Following surgical correction, esophageal mucosal injury improved endoscopically in 90% of patients, and median total FSSG score significantly decreased from 8 (0-30) to 5 (0-19) (P = 0.005). Regarding pH after surgery, prevalence of abnormal acid reflux decreased from 66.7% (95% CI: 41.0-86.7%) to 33.3% (95% CI: 13.3-59.0%) (P = 0.045). CONCLUSION: Surgical spinal correction in kyphosis patients improves not only kyphotic deformity-related disorders but also esophageal mucosal injury, abnormal acid reflux, and reflux-related symptoms.