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.

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.

Adult-onset Still's Disease Diagnosed during Puerperium with Liver Dysfunction in Pregnancy and Liver Failure of the Infant.

Most cases of liver dysfunction in pregnancy are pregnancy-related, but the onset of systemic autoimmune diseases is also differentiated. A 24-year-old woman presented with liver dysfunction at 28 weeks' gestation with suspected autoimmune hepatitis and started taking ursodeoxycholic acid. She gave birth prematurely at 35 weeks' gestation, and the infant presented with pancytopenia and liver failure but survived because of liver transplantation. Since the patient had major symptoms during the puerperium, she was diagnosed with adult-onset Still's disease. When encountering a patient with liver dysfunction during pregnancy, we should also consider the onset of autoimmune diseases.

Serrated polyps in patients with ulcerative colitis: Unique clinicopathological and biological characteristics.

BACKGROUND: Serrated polyps have recently been reported in patients with ulcerative colitis (UC); however, their prevalence and detailed characteristics remain unclear. METHODS: The prevalence and clinicopathological and biological characteristics of serrated polyps in patients with UC were retrospectively examined in a single tertiary inflammatory bowel disease center in Japan from 2000 to 2020. RESULTS: Among 2035 patients with UC who underwent total colonoscopy, 252 neoplasms, including 36 serrated polyps (26 in colitis-affected segments, 10 in colitis-unaffected segments), were identified in 187 patients with UC. The proportion of serrated polyps was 1.8% (36/2035). Serrated polyps in colitis-affected segments were common with extensive colitis (88%), history of persistent active colitis (58%), and long UC duration (12.1 years). Serrated polyps in colitis-affected segments were more common in men (88%). Of the 26 serrated polyps in colitis-affected segments, 15, 6, and 5 were categorized as sessile serrated lesion-like dysplasia, traditional serrated adenoma-like dysplasia, and serrated dysplasia not otherwise specified, respectively. Sessile serrated lesion-like dysplasia was common in the proximal colon (67%) and with BRAF mutation (62%), whereas traditional serrated adenoma-like dysplasia and serrated dysplasia not otherwise specified were common in the distal colon (100% and 80%, respectively) and with KRAS mutations (100% and 75%, respectively). CONCLUSIONS: Serrated polyps comprised 14% of the neoplasias in patients with UC. Serrated polyps in colitis-affected segments were common in men with extensive and longstanding colitis, suggesting chronic inflammation in the development of serrated polyps in patients with UC.

Long-term clinical and real-world experience with Crohn's disease treated with anti-tumor necrosis factor-α antibodies.

BACKGROUND/AIMS: Although anti-tumor necrosis factor (TNF)-α agents are important therapeutic drugs for Crohn's disease (CD), data regarding their long-term sustained effects are limited. Herein, we evaluated the long-term loss of response (LOR) to anti-TNF-α agents in patients with CD. METHODS: This retrospective study included patients with CD who started treatment with infliximab or adalimumab as a first-line therapeutic approach. The cumulative event-free, retention, and surgery-free rates after the start of biological therapy were analyzed. Secondary LOR was analyzed in patients who achieved corticosteroid-free clinical remission after the start of biological therapy. Cox proportional hazards models were used to analyze the predictive factors of secondary LOR. RESULTS: The cumulative event-free rates at 1, 2, 5, and 10 years were 83.3%, 75.1%, 37.4%, and 23.3%, respectively. The incidence of LOR was 10.6% per patient-year of follow-up. At 12-14 weeks after the start of biological therapy, the proportion of patients with a C-reactive protein to albumin (CRP/ALB) ratio ≥0.18 was significantly higher in patients with LOR (P<0.001). Multivariate analysis indicates that a CRP/ALB ratio ≥0.18 (hazard ratio [HR], 5.86; 95% confidence interval [CI], 1.56-22.0; P=0.009) and upper gastrointestinal tract inflammation (HR, 3.00; 95% CI, 1.26-7.13; P=0.013) were predictive factors of secondary LOR. CONCLUSIONS: Although anti-TNF-α agents contributed to long-term clinical remission of CD, the annual incidence of secondary LOR was 10.6%. The CRP/ALB ratio at 3 months after the start of biological therapy and upper gastrointestinal tract inflammation were identified as predictive factors of secondary LOR.

[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.

Pruritus is common in patients with chronic liver disease and is improved by nalfurafine hydrochloride.

Pruritus is known to be a common complication in hepatitis patients, but the exact frequency and degree are not fully elucidated. Thus, we evaluated pruritus of 450 patients with chronic liver disease at our hospital. Pruritus was observed in 240 (53%) of the patients. Pruritus was significantly associated with males (OR = 1.51, P = 0.038) and patients with alkaline phosphatase (ALP) ≥ 200 U/L (OR = 1.56, P = 0.0495) and was significantly less in HBsAg-positive patients (OR = 0.449, P = 0.004). Seasonally, there was no difference in the frequency of pruritus between summer and winter. Of the 24 refractory pruritus patients treated with nalfurafine, 17 (71%) indicated improvement of itch, which is defined as a decrease in the visual analog scale score ≥ 30 mm. Pruritus was improved by nalfurafine both during daytime and nighttime in the Kawashima's scores evaluation. All patients who received nalfurafine exhibited improved Kawashima's scores ≥ 1 point during the daytime or nighttime. In conclusion, pruritus occurred in > 50% of patients with chronic liver disease, and predictors of pruritus were males and ALP ≥ 200 U/L. Nalfurafine may be useful for pruritus, regardless of whether daytime or nighttime.

Efficacy of Ustekinumab Against Spondyloarthritis Associated with Crohn's Disease: A Case Report and Review of the Literature.

Spondyloarthritis (SpA) is a known extraintestinal complication in inflammatory bowel disease (IBD). However, since the prevalence of SpA is lower in Japan than in Europe, some patients may be inaccurately diagnosed and treated. Although non-steroidal anti-inflammatory drugs (NSAIDs) remain the mainstay treatment for IBD-related SpA, anti-tumor necrosis factor-α antibody and ustekinumab have demonstrated efficacy in patients with SpA refractory to NSAIDs. We report here a case of Crohn's disease with SpA, as an extraintestinal manifestation, in which ustekinumab proved extremely effective, not only for alleviating the arthritis but also against skin manifestations and scleritis. Only a few studies have documented the therapeutic effects of ustekinumab against SpA associated with IBD; therefore, its efficacy remains unclear.

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.

Appropriate Timing of Discontinuation of Tacrolimus Therapy for Refractory Ulcerative Colitis.

BACKGROUND AND OBJECTIVES: Tacrolimus is very effective at inducing remission in patients with refractory ulcerative colitis. However, the optimal time-point for the discontinuation of tacrolimus is controversial because administration of tacrolimus for > 3 months is currently not approved for insurance reimbursement in Japan. We conducted this study to determine the optimal time of discontinuation of tacrolimus in patients with ulcerative colitis. METHODS: Of 38 patients who received tacrolimus as remission induction therapy for refractory active ulcerative colitis between 2009 and 2018, this study included 21 patients who received tacrolimus for ≥ 3 months before being switched to thiopurines. These patients were divided into two groups for analysis: the confirmed switch (CS) group (n = 13), in which tacrolimus was switched to azathioprine after endoscopic confirmation of mucosal improvement, and the mandatory switch (MS) group (n = 8), in which tacrolimus was switched to a thiopurine agent without endoscopic confirmation of improvement. RESULTS: The relapse rates after the switch to azathioprine were 23% and 88% in the CS and MS groups, respectively (p = 0.0075). No patient of the CS group underwent surgery, while 50% of patients of the MS group underwent surgery (p = 0.0117). The cumulative event-free rates at 6 months, 1 year, and 2 years were 92%, 92%, and 65%, respectively, in the CS group and 15%, 15%, and 0%, respectively, in the MS group (p < 0.0001). The incidence rate of adverse reactions was 31% in the CS group and 13% in the MS group, but there were no serious adverse reactions. CONCLUSIONS: It seems preferable to discontinue tacrolimus after endoscopic confirmation of mucosal healing. However, attention should be paid to the potential occurrence of adverse reactions associated with long-term tacrolimus therapy.

Short- and long-term efficacy of adalimumab salvage therapy after failure of calcineurin inhibitors in steroid-refractory ulcerative colitis.

OBJECTIVE: Calcineurin inhibitors are highly effective in patients with corticosteroid-refractory ulcerative colitis (UC). When therapy with calcineurin inhibitors fails, adalimumab can be considered to avoid colectomy. The efficacy and safety of this sequential alternative salvage therapy remain unknown. Therefore, the present study was performed to investigate the short- and long-term efficacy and safety of adalimumab after failure of calcineurin inhibitors in corticosteroid-refractory UC. MATERIALS AND METHODS: Patients with a corticosteroid-refractory flare of UC who did not respond to calcineurin inhibitors and received continuing salvage therapy with adalimumab were included in this retrospective, observational, single-centre study. The cumulative rates of colectomy were calculated using the Kaplan-Meier method. Clinical remission and response were evaluated based on the Rachmilewitz index. The cumulative rates of colectomy were calculated. Predictive factors for clinical remission and colectomy were identified. In the safety evaluation, any adverse event occurring after the administration of adalimumab was considered. RESULTS: Forty-one patients were enrolled; 78% had extensive colitis and 87% had moderate to severe colitis. Seventeen patients (41%) underwent colectomy during the follow-up period. At week 8, 26, and 52 after adalimumab injection, 27%, 39%, and 32% of patients achieved clinical remission, respectively. The adverse event rate was 17%, including one case of tuberculosis. CONCLUSIONS: The efficacy of adalimumab for calcineurin inhibitor-refractory UC was examined for the first time. Treatment with adalimumab avoided the need for colectomy in two-thirds of patients with corticosteroid-refractory UC in whom calcineurin inhibitors had failed. However, attention is needed to avoid adverse events, especially infection.

Does long-term efficacy differ between infliximab and adalimumab after 1 year of continuous administration?: A STROBE-compliant retrospective cohort study.

Although biologics are important inflammatory bowel disease therapies, loss of response (LOR) remains problematic. We evaluated LOR to biologics in our Crohn disease (CD) patients receiving biologics. Of 137 biologic-treated CD patients, 68 continuously receiving the same biologic type for at least 1 year were divided into 2 groups: infliximab (IFX) (n = 39) and adalimumab (ADA) (n = 29). Clinical courses were compared at biologic introduction and at 1 year. Both groups were retrospectively analyzed for LOR at and beyond 1 year after biologic introduction (study endpoint). Patients were then divided into LOR and non-LOR groups to identify factors predicting LOR. At 1 year after biologic introduction, decreases in CD activity index were 94 ±â€Š105 in the IFX and 102 ±â€Š89 in the ADA group, not significantly different. Blood test data did not differ between these groups. LOR occurred in 14 IFX and 5 ADA group patients. Event-free rates at 5 years after biologic introduction were 62% in the IFX and 61% in the ADA group. Patients achieving clinical remission 1 year after biologic introduction accounted for 69% of the IFX and 90% of the ADA group, while respective rates of secondary LOR at 5 years were 32% and 26%. C-reactive protein (CRP) at biologic introduction (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.04-2.06; P = .02) and age at CD onset (OR, 1.1; 95% CI, 1.01-1.20; P = .03) predicted LOR. As to IFX and ADA efficacies after 1 year of administration, there were no significant differences in event-free rates for the 5 years after biologic introduction or the secondary LOR rate. CRP at biologic introduction and age at CD onset predicted LOR.