Effects of pemafibrate on primary biliary cholangitis with dyslipidemia.

AIM: The purpose of this study was to examine the effect of pemafibrate (PEM) in primary biliary cholangitis (PBC) patients with dyslipidemia. METHODS: Patients who were diagnosed with PBC between June 2018 and December 31, 2020 were included in the study if they also had dyslipidemia and their alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) levels remained above the normal range despite taking 600 mg/day ursodeoxycholic acid (UDCA) for at least 6 months. Patients who were treated with UDCA alone were administered PEM as an add-on (PEM-add group), and patients who were treated with UDCA and bezafibrate (BEZ) for at least 6 months were given PEM instead of BEZ (PEM-switch group). Clinical parameters were compared in all patients, and the levels of ALP, GGT, the estimated glomerular filtration rate (eGFR), and creatinine (Cr) were compared between the PEM-add and PEM-switch groups. Improvement in cholangitis was also evaluated. RESULTS: In the PEM-add group, both ALP and GGT improved in 40 of 46 patients (87.0%). In the PEM-switch group, both ALP and GGT improved in 15 of 29 patients (51.7%). In the PEM-switch group, however, significant improvement was seen in eGFR and Cr. CONCLUSIONS: Administration of PEM is effective in PBC patients with dyslipidemia who are refractory to UDCA monotherapy. In patients using both UDCA and BEZ, there was an advantage in switching to PEM if they had renal damage; however, improvement of ALP and GGT occurred in about 50%.

[A case of gastric hamartomatous inverted polyp (GHIP), preoperatively diagnosed based on EUS findings].

We report the case of a patient with a gastric hamartomatous inverted polyp (GHIP) and discuss the relevant literature. A 65-year-old woman was referred to our hospital because of a slow-growing pedunculated polyp measuring 30mm in diameter, present in the greater curvature of the fundic region of the stomach. It was covered with normal gastric mucosa, and the top was reddish. A biopsy specimen taken from the reddish area;it showed inflamed gastric mucosa with hyperplastic and mildly distorted foveolar glands. Abdominal contrast computed tomography showed a protruding tumor that was unevenly enhanced and contained multiple cystic lesions inside. Endoscopic ultrasonography (EUS, Olympus GIF-UCT260) showed a heterogeneous tumor with multiple anechoic or low-echoic cystic lesions, originating from the second or third layer of the stomach wall. The patient had no clinical symptoms, no family history, and no laboratory data abnormalities. Based on these findings, we diagnosed her with GHIP. As the polyp had shown an increase in size (5mm/5 years) and about 20% of GHIPs were reported to coexist with precancerous or cancerous lesions, we performed endoscopic polypectomy. The tumor was histologically characterized by submucosal growth of hypertrophic glands with cystic dilatation, accompanied by smooth muscle proliferation, branching from the bundles. Thus, the final diagnosis was GHIP. Though GHIP is a rare and basically benign polyp, the rate with gastric cancer was reported to be relatively high. EUS findings are important for the diagnosis and when GHIP is suspected, the lesion requires to be monitored closely. If there are some signs that suggest a malignancy (growth, changes in surface mucosa, etc.), endoscopic en bloc resection or surgical resection should be considered.

The role of calcium-binding protein S100g (CalbindinD-9K) and annexin A10 in acute pancreatitis.

BACKGROUND: We reported that the pancreas of the interferon-regulatory factor (IRF) 2 knock-out (KO) mouse represents an early phase of acute pancreatitis, including defective regulatory exocytosis, intracellular activation of trypsin, and disturbance of autophagy. The significantly upregulated and downregulated genes in the IRF2 KO pancreas have been reported. The catalogue of gene transcripts included two types of calcium-binding proteins (S100 calcium binding protein G [S100g] and Annexin A10 [Anxa10]), which were highly upregulated in the IRF2 KO pancreas. As the intracellular calcium signal plays a pivotal role in regulatory exocytosis and its disturbance is related to pancreatitis, we then evaluated the role of S100g and Anxa10 in acute pancreatitis. METHOD: We induced cerulein-pancreatitis in wild-type mice and examined the changes in the expression of these genes by qPCR and immunohistochemistry. We constructed S100g-overexpressing or Anxa10-overexpressing AR42J cells (AR42J-S100g, AR42J-Anxa10). We examined the changes in amylase secretion, intracellular calcium ([Ca2+]i), and cell viability in these cells, when incubated with cholecystokinin (CCK). RESULTS: The expression of S100g and Anxa10 was increased in cerulean-induced pancreatitis. The acini were patchily stained for S100g and the cytosol of acini was evenly but weakly stained for Anxa10. Stimulation with 100pM CCK-8, decreased amylase secretion and inhibited the [Ca2+]i increase in AR42J-S100g cells. These effects were weak in AR42J-Anxa10 cells. Cell viability was not changed by incubation with cerulein. CONCLUSION: In cerulean pancreatitis, the expression of S100g and Anxa10 was induced in the acini. S100g may work as a Ca2+ buffer in acute pancreatitis.

The efficacy of endoscopic submucosal dissection for colorectal tumors extending to the dentate line.

PURPOSE: Although endoscopic submucosal dissection (ESD) is becoming the mainstay of the treatment strategies, rather than surgical treatment, for colorectal tumors extending to the dentate line, ESD is technically more difficult. This study was aimed at assessing the usefulness of ESD for the treatment of colorectal tumors extending to the dentate line. METHODS: This study included 531 patients with colorectal tumors who underwent colorectal ESD between 2008 and 2015. They were divided into three groups: rectal tumors extending to the dentate line (anorectal group), those not extending to the dentate line (proximal rectal group), and colonic tumors (colonic group), and a retrospective comparative analysis was carried out. RESULTS: Of the total patients, 18 (3.4%) had lesions extending to the dentate line area. The procedure times were 103.4 ± 84.0, 80.4 ± 64.3, and 71.8 ± 52.3 min, respectively (P = 0.0318). All the patients in the anorectal group were operated by operators who had performed at least 20 colorectal ESDs (P < 0.0001). No significant difference among the three groups was found in the en bloc resection rate, complete resection rate, or curative resection rate. Although no significant difference in the incidence of perforation was observed among the three groups, intraoperative bleeding was observed in 61% of the patients in the anorectal group (P < 0.0001). CONCLUSIONS: ESD is an effective treatment strategy for colorectal tumors extending to the dentate line. However, it seems that anorectal ESD, which is technically more difficult than colorectal ESD, should be performed by operators with ample experience in performing ESD.

Malignant transformation of a gastric hyperplastic polyp in a context of Helicobacter pylori-negative autoimmune gastritis: a case report.

BACKGROUND: Gastric foveolar hyperplastic polyps (GFHPs) are common findings in clinical practice. GFHPs commonly arise in a background of chronic atrophic gastritis, including autoimmune gastritis (type A gastritis), and have a potential risk of malignant transformation. CASE PRESENTATION: In 2005, a 55-year-old Japanese woman underwent upper endoscopy at another hospital and was found to have a pedunculated polyp (10 mm in diameter) on the greater curvature of the lower gastric body. On biopsy, the polyp was diagnosed as a GFHP. Nine years later, the polyp had grown to 20 mm in diameter, and the biopsy specimen taken at this time showed tubular adenocarcinoma. On admission to our hospital, the serum Helicobacter Pylori (H. pylori) immunoglobulin G antibody and stool H. pylori antigen were both negative. Anti-gastric parietal cell antibody was positive, as was the anti-intrinsic factor antibody, and the fasting serum gastrin level was markedly increased. In 2014, en bloc resection of the pedunculated polyp was performed by endoscopic submucosal dissection. The final histological diagnosis was adenocarcinoma of the stomach with submucosal and lymphatic invasion. Subsequently, additional radical distal gastrectomy was performed. At the latest follow-up (12 months postoperatively), no recurrence was noted. CONCLUSIONS: We here reported a rare case of malignant transformation of GFHP arising in a context of type A gastritis. To our knowledge, there are no previous reports on malignant transformation of GFHP with submucosal and lymphatic invasion arising in a background of type A gastritis in the English literature. Further, there is currently no effective treatment other than endoscopic or surgical treatment for such cases. Given the potential risk of malignant transformation due to hypergastrinemia, we consider that endoscopic treatment should be considered as a first-line therapy when a malignant growth is suspected.

[A case of triple-negative breast cancer responding to multidisciplinary treatment containing bevacizumab].

We report a case of a 64-year-old woman with Stage IV breast cancer who responded well to chemotherapy containing bevacizumab. She noticed a left breast tumor with acute progression and was diagnosed as having Stage IV, estrogen receptor( ER)(-), progesterone receptor(PgR)(-), human epidermal growth factor receptor 2(HER2)(-)breast cancer (T4cN3cM1[lymph nodes]). She received 5 courses of adriamycin(60mg/m / 2)plus cyclophosphamide(600mg/m2)(AC therapy)and 4 courses of weekly paclitaxel(PTX 90mg/m / 2)plus bevacizumab(AVA 10 mg/m2)as systemic therapy. Computed tomography(CT)and magnetic resonance imaging(MRI)revealed a complete response(CR). After local resection of the breast tumor and radiation to the breast and regional lymph nodes, capecitabine therapy was initiated. Currently, at 5 months after surgery, no new lesion has been detected.

Successful Response to Golimumab in a Case of Relapsing Polychondritis Overlapping with Ulcerative Colitis.

A 51-year-old Japanese man was diagnosed with left-sided ulcerative colitis (UC) at age 41. He was treated with mesalazine and azathioprine and maintained remission. At age 51, the patient developed bloody stools, abdominal pain, scleritis, arthritis, cough, bloody sputum, and pericardial effusion. Considering that pericardial effusion is an atypical extraintestinal complication of UC, and the patient met the diagnostic criteria for relapsing polychondritis (RP), a diagnosis of RP complicating a relapse of UC was made. Steroid therapy was administered, and both diseases improved. Golimumab, an anti-tumor necrosis factor-α inhibitor, was introduced as maintenance therapy for UC. All symptoms, including pericardial effusion, improved. Subsequently, no relapse of UC or RP was observed. As only a few cases of RP overlapping with UC have been reported and no treatment protocol has been established, we considered this case valuable and worthy of publication.

Successful Fistula Closure After Treatment with Colostomy and Infliximab in a Patient with Ulcerative Colitis Complicated by Rectovaginal Fistula.

The patient was a 50-year-old Japanese woman who was diagnosed with total-colitis-type ulcerative colitis (UC) at the age of 26 years. She was treated with mesalazine and azathioprine, and her disease activity was well controlled. At the age of 50 years, the patient was experiencing fever, abdominal pain, diarrhea, bloody stool, and anal pain, which led to a diagnosis of a relapse of UC. Although steroid therapy was administered and tended to improve her symptoms, fecaloid vaginal discharge occurred, and rectovaginal fistula (RVF) was confirmed. Colostomy was performed, and infliximab was initiated as maintenance therapy for UC. All symptoms improved, and RVF closure was confirmed 6 months after the initiation of infliximab. To date, she has been free from relapse of UC. There have been only a few reports of UC complicated by RVF, and this condition is often difficult to treat. To the best of our knowledge, no other case of UC complicated by RVF in which the fistula was closed after treatment with colostomy and infliximab has been previously reported; thus, our report of the present case is valuable to the literature.

Late-onset Wilson Disease in a Patient Followed-up for Nonalcoholic Fatty Liver Disease.

A 73-year-old woman was referred to our hospital for persistent liver dysfunction. When the patient was 45 years old, her youngest sister had been diagnosed with Wilson disease (WD). The patient therefore underwent several family screening tests, all of which were unremarkable. She had an annual medical checkup and was diagnosed with liver dysfunction and fatty liver at 68 years old. A liver biopsy and genetic testing were performed, and she was diagnosed with WD; chelation therapy was then initiated. In patients with hepatic disorders and a family history of WD, multiple medical examinations should be conducted, as the development of WD is possible regardless of age.

Primary Bile Duct Diffuse Large B-cell Lymphoma Diagnosed by Repeated Endoscopic Ultrasound-guided Fine-needle Aspiration and Endoscopic Retrograde Cholangiopancreatography.

A 54-year-old man was admitted with obstructive jaundice. Computed tomography showed common bile duct stricture and a tumor around the celiac artery. Repeated endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) as well as a laparotomic biopsy around the celiac artery were diagnostically unsuccessful. Since the bile duct stricture progressed, EUS-FNA and ERCP were performed a third time, finally leading to the diagnosis of diffuse large B-cell lymphoma. The treatment plan and prognosis of obstructive jaundice differ greatly depending on the disease. It is important to conduct careful follow-up and repeated histological examinations with appropriate modifications until a diagnosis is made.

INSL5 may be a unique marker of colorectal endocrine cells and neuroendocrine tumors.

Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosal healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5-RXFP4 signaling might play a role in an autocrine/paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors.

Functional roles of TGF-ß1 in intestinal epithelial cells through Smad-dependent and non-Smad pathways.

BACKGROUND AND AIMS: Transforming growth factor-ß1 (TGF-ß1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-ß1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells. METHODS: We used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-ß1/Smad signaling molecules was examined. We evaluated the effect of TGF-ß1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine. RESULTS: IEC-6 cells produced TGF-ß1 and expressed functional TGF-ß/Smad signaling molecules. The addition of TGF-ß1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts. CONCLUSIONS: TGF-ß1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways.

Usefulness of Serum Leucine-rich Alpha 2 Glycoprotein in Crohn's Disease: Is There Any Difference between Small Intestine and Colonic Lesions?

Background: The usefulness of leucine-rich alpha 2 glycoprotein (LRG) to evaluate Crohn's disease (CD) activity differs among various intestinal lesions. We aimed to evaluate the association between endoscopic disease activity based on the Simple Endoscopic Score for Crohn's disease (SES-CD) and LRG level separately for small intestinal and colonic lesions. Methods: We examined the correlation between LRG level and SES-CD and performed receiver operating characteristic (ROC) analysis to determine the LRG cutoff value in 141 patients who underwent endoscopy (total 235 measurements). Furthermore, the LRG cutoff value was analyzed by comparing small intestinal and colonic lesions. Results: LRG levels were significantly higher in patients without mucosal healing than in those with mucosal healing (15.9 µg/mL vs 10.5 µg/mL, P < .0001). The LRG cutoff value for mucosal healing was 14.3 µg/mL (area under the ROC curve [AUC]: 0.80; sensitivity: 0.89; specificity: 0.63). The LRG cutoff value for patients with type L1 was 14.3 µg/mL (sensitivity: 0.91; specificity: 0.53), and that for patients with type L2 was 14.0 µg/mL (sensitivity: 0.95; specificity: 0.73). The diagnostic performance (AUC) of LRG and C-reactive protein (CRP) for mucosal healing was, respectively, 0.75 and 0.60 (P = 0.01) in patients with type L1 and 0.80 and 0.85 (P = 0.90) in patients with type L2. Conclusions: The optimal LRG cutoff value for evaluating mucosal healing in CD is 14.3 µg/mL. LRG is more useful than CRP for predicting mucosal healing in patients with type L1. The superiority of LRG to CRP differs between small intestinal and colonic lesions.

A case of needle tract seeding that seemed to be caused by endoscopic ultrasound-guided fine-needle aspiration.

A 66-year-old man underwent a single endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) session and distal pancreatectomy for the pancreatic body adenocarcinoma measuring 12 mm in diameter. At 3 years after surgery, we diagnosed needle tract seeding (NTS) and performed total gastrectomy. NTS can occur with small tumors or after a single session of EUS-FNA.