Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016.

AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

Correction to: The search, coagulation, and clipping (SCC) method prevents delayed bleeding after gastric endoscopic submucosal dissection.

The article "The search, coagulation, and clipping (SCC) method prevents delayed bleeding after gastric endoscopic submucosal dissection", written by Motoi Azumi, Manabu Takeuchi, Youhei Koseki, Masaru Kumagai, Yoko Kobayashi, Masafumi Takatsuna, Aiko Yoshioka, Seiichi Yoshikawa, Tsutomu Miura, and Shuji Terai, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 28 September 2018 without open access.

The search, coagulation, and clipping (SCC) method prevents delayed bleeding after gastric endoscopic submucosal dissection.

BACKGROUND: Delayed bleeding is an important complication after gastric endoscopic submucosal dissection (ESD). The search, coagulation, and clipping (SCC) method can be used to prevent delayed bleeding after ESD. However, its safety and efficacy are unclear. We compared the SCC method with post-ESD coagulation (PEC) to clarify the safety and efficacy of the SCC method for preventing delayed bleeding after gastric ESD. METHODS: This retrospective study included 438 patients (478 lesions) who underwent gastric ESD. Multivariate logistic regression analysis was performed to identify the significant independent factors associated with delayed bleeding and we performed propensity-score matching (PSM) to reduce the effect of procedure-selection bias of SCC method. RESULTS: Of the 438 patients, 216 underwent PEC and 222 underwent SCC. Delayed bleeding was significantly less common in the SCC than in the PEC (2.6% vs. 7.2%; P = 0.013). Among patients treated with antithrombotic therapy, the delayed bleeding rate was lower in the SCC group than in the PEC group; however, the difference was not significant (P = 0.15). The SCC method was found to be a significant independent factor for the prevention of delayed bleeding. PSM was performed in 156 patients in the PEC group and SCC group. There was a significant difference in the incidence of bleeding in the PEC and SCC groups (P = 0.013). No patient had perforation/bleeding associated with the SCC method. CONCLUSIONS: Our findings suggest that the SCC method is a simple, safe, and effective approach for preventing delayed bleeding after gastric ESD.

Endoscopic Submucosal Dissection for Gastric Tube Carcinoma after Esophagectomy Contributes to Long-Term Outcomes.

The incidence of gastric tube carcinoma (GTC) after esophagectomy for esophageal carcinoma has increased in recent years. Surgical removal of the reconstructed gastric tube is associated with high mortality, and endoscopic submucosal dissection (ESD) is a promising alternative. There are limited reports of ESD for GTC. This study investigated the efficacy and safety of ESD in GTC. This single-center retrospective study examined patients who underwent ESD for GTC after esophagectomy at our institution between 2003 and 2018. The curability of GTC with ESD was evaluated histologically according to the Japanese Gastric Cancer Treatment Guidelines. Patient characteristics and procedural and long-term outcomes were analyzed. Overall, 31 patients (29 men and 2 women; median age, 73 years) with 45 GTC lesions underwent ESD. The mean period between primary esophagectomy and the diagnosis of GTC was 10.6 years. Bleeding during ESD was noted in two patients (6.5%). No other adverse or fatal events such as perforation were noted. Complete resection and curative resection were documented in 80.6% and 48.4% of cases, respectively. The 3-year and 5-year overall survival rates were 67.6% and 47.7%, respectively. The 3-year and 5-year disease-specific survival rates were 100% and 92.9%, respectively. One patient died of GTC, and fourteen patients died of other diseases, including primary carcinoma in five cases. ESD was safe and provided good long-term outcomes in patients with GTC. Regular long-term gastroscopy is required for the early detection of GTC. Patients with GTC after esophagectomy for esophageal carcinoma have a high risk of other primary carcinomas or comorbidities after ESD.

Methotrexate-associated proliferative disorder in the lower esophagus extending to the gastroesophageal junction: A case report.

A 64-year-old woman was receiving oral methotrexate (MTX) for rheumatoid arthritis (RA) for 15 years. She underwent esophagogastroduodenoscopy because of discomfort in the chest. Endoscopic findings revealed an ulcer in the lower esophagus extending to the gastroesophageal junction (EGJ). The ulcer occupied half of the esophageal lumen and had a sharp and clear margin. Magnifying narrow-band imaging endoscopy revealed the deposition of white plaque, and there were few microvessels in the edge and bottom of the ulcer. Histologic examination of the biopsy specimens from the oral edge of the lesion revealed proliferation of atypical lymphoid cells (immunophenotype results: CD20 [+], CD3 [partially +], CD5 [-], and BCL-2 [-]]. The patient was diagnosed with methotrexate-associated lymphoproliferative disorder (MTX-LPD) and was advised to stop MTX intake. After 2 months of stopping MTX, the ulcer was found to be almost regressed and showed signs of healing. MTX-LPD in the lower esophagus extending to the EGJ is extremely rare. This case can help in expanding the understanding of esophageal MTX-LPD.

Endoscopic Findings and Treatment of Gastric Neoplasms in Familial Adenomatous Polyposis.

PURPOSE: Gastric neoplasia is a common manifestation of familial adenomatous polyposis (FAP). This study aimed to elucidate the clinical characteristics, endoscopic features including fundic gland polyposis (FGPsis), and treatment outcomes of gastric neoplasms (GNs) in patients with FAP. MATERIALS AND METHODS: A total of 35 patients diagnosed with FAP, including nine patients from four pedigrees who underwent esophagogastroduodenoscopy (EGD), were investigated regarding patient characteristics, GN morphology, and treatment outcomes. RESULTS: Twenty-one patients (60.0%) had 38 GNs; 33 (86.8%) and 5 (13.2%) were histologically diagnosed with adenocarcinoma and adenoma, respectively. There were no specific patient characteristics related to GNs. Nodule-type GNs were more prevalent in patients with FGP than without (52.2% vs. 0.0%, P=0.002) in the upper body of the stomach. Conversely, depressed-type GNs were fewer in patients with FGPsis than in those without (13.0% vs. 73.3%, P<0.001). Slightly elevated-type GNs were observed in both groups (34.8% vs. 20.0%, P=0.538). Even within pedigrees, the background gastric mucosa and types of GNs varied. In total, 24 GNs were treated with endoscopic submucosal dissection (ESD) and eight with endoscopic mucosal resection (EMR). EMR was selected for GNs with FGPsis because of the technical difficulty of ESD, resulting in a lower en bloc resection rate (62.5% vs. 100%, P=0.014). CONCLUSIONS: Our study indicates the necessity of routine EGD surveillance in patients diagnosed with FAP. Notably, the morphology and location of GNs differed between patients with and without FGPsis. Endoscopic treatment and outcomes require more attention in cases of FGPsis.

A case of Helicobacter pylori -negative early gastric adenocarcinoma with gastrointestinal phenotype.

A 40-year-old man with slightly depressed (0-IIc) type gastric cancer of the pyloric anterior gastric area underwent pre-operative screening for tetralogy of Fallot and endoscopic submucosal dissection (ESD) and was tested for Helicobacter pylori antigens and antibodies. Both tests were negative. He did not have a history of eradication. Pathological diagnosis of ESD showed a well-differentiated adenocarcinoma. The tumor was CD10-positive, MUC5AC-negative, and MUC6-confocal positive; it showed differentiation with gastrointestinal phenotype. Moreover, the tumor cells were lysozyme-positive, resembling Paneth cells. Mucosal glands exhibited intestinal metaplasia on the anal side of the tumor lesion. On the oral side of the tumor, metaplasia was non-existent, with normal pyloric glands present in the mucosal layer. The patient was not infected with H. pylori ; however, intestinal metaplasia existed around the early gastric cancer. This suggested that the intestinal metaplasia occurred due to bile reflux, and the gastric neoplasia arose with the metaplasia without an H. pylori infection. This case may potentially help explain gastric cancer development in the absence of H. pylori infection.

Achalasia in a Patient with Myotonic Dystrophy.

Myotonic dystrophy is a progressive disorder mainly affecting the voluntary muscles. We herein report a rare case of myotonic dystrophy complicated with high-resolution manometry-defined achalasia, the pathology of which is absent relaxation of the smooth muscles of lower esophageal sphincter (LES). In the present case, achalasia was considered a complication of myotonic dystrophy instead of sporadic achalasia, as on performing high-resolution manometry, the finding of an impaired LES relaxation (myotonic phase) changed to a totally emaciated LES function (muscle weakness phase) as myotonic dystrophy progressed.

Case of early-stage gastric cancer identified in the gastric mucosa with lanthanum phosphate deposition.

Background and study aims A 78-year-old man with Helicobacter pylori infection had been undergoing hemodialysis for chronic renal failure and receiving lanthanum carbonate preparations for 3 years. Endoscopy revealed fine white granular discoloration throughout the stomach, a moderately reddish depression on the lesser curvature of the gastric angle, and white granular discoloration in the surrounding area. A magnified image using narrow-band imaging showed that the depressed part had irregular vascular and pit structures. We established a diagnosis of intramucosal gastric cancer and performed endoscopic submucosal dissection. Histopathological examination revealed a well-differentiated adenocarcinoma that was confined to the mucosa of the depressed area. Moreover, using an electron probe microanalyzer-equipped electron microscope, we found that the degree of lanthanum deposition was lower in the tumor region than in the non-tumor region. Thus, the current case can help in understanding the relationship between lanthanum deposition and early-stage gastric cancer. Because gastric cancers can occur in lanthanum deposit-containing mucosa, esophagogastroduodenoscopy should be used carefully after understanding the characteristics of early- stage gastric cancer in such cases.

Myofibroblasts of the muscle layer stimulate the malignant potential of colorectal cancer.

Myofibroblasts of colorectal cancer (CRC) have been associated with histopathological factors such as lymph node metastasis, liver metastasis and local recurrence. However, few studies have assessed the association between these malignant potentials and the myofibroblast distribution in CRC. We aimed to evaluate the relationship between clinical factors and myofibroblast distribution around CRC invasive lesions. The study included 121 cases of pT3 CRC that were diagnosed at stage II or III. Myofibroblast density of the following three histological layers was measured: the submucosa (SM), muscularis propria (MP) and subserosa (SS). We analyzed the relationship between the clinicopathological factors and myofibroblast density by studying the histopathological features of the three layers. The myofibroblast density of the MP layer was significantly higher in the groups with high-frequency lymphatic and venous invasion than the groups with low-frequency lymphatic (P<0.001) and venous (P<0.01) invasion, respectively. In the positive lymph node metastasis group, the myofibroblast density at the MP layer was significantly higher than that in the negative lymph node metastasis group (P<0.001). The high myofibroblast density group at the MP layer was significantly associated with poor overall survival (P<0.003). Our study indicated that myofibroblasts are a type of cancer-associated fibroblasts and that the myofibroblast distribution contributes to the malignant potential of CRC. Furthermore, we demonstrated that myofibroblasts present at the MP layer play an important role in the malignant potential and poor prognosis of patients with CRC.

Myofibroblast distribution is associated with invasive growth types of colorectal cancer.

Both the invasive growth types of colorectal cancer (CRC) and the number of myofibroblasts have been associated with histopathological factors such as lymph node and liver metastasis, and local recurrence. However, there are few studies, that have assessed the association between invasive growth type and myofibroblast distribution in CRC. We aimed to evaluate the relationship between the clinicopathological factors of CRC and two invasive growth types, the expanding and infiltrating types. We categorized 150 cases of pT3 CRC into the expanding and infiltrating types and measured the myofibroblast density of three histological layers: the submucosa (SM), the muscularis propria (MP) and the subserosa (SS). We compared these two invasive growth types and analyzed the relationship between clinicopathological factors and myofibroblast density. Myofibroblast density was significantly higher in the infiltrating type than that in the expanding type (P<0.05). In the lymph node metastasis-positive group of the infiltrating type, myofibroblast density in MP was significantly higher than that in the lymph node metastasis-negative group (P<0.001). In the infiltrating type, the group with the higher level of lymphatic invasion had a significantly higher density of myofibroblasts in the MP than the group with the lower level of lymphatic invasion (P<0.01). These results suggest that myofibroblasts participate more in the infiltrating type compared with the expanding type of CRC. It would appear that myofibroblasts present in the MP play an important role in the malignant potential of the infiltrating type compared to the expanding type.

Clinicopathological significance of gastric poorly differentiated medullary carcinoma.

Poorly differentiated gastric adenocarcinoma of solid type is known to show a clinicopathological diversity, but its morphological characteristics have rarely been investigated. In this study, we defined poorly differentiated medullary carcinoma indicating the following three characteristics: (i) more than 90% of the entire tumor were composed of poorly differentiated adenocarcinoma in a medullary growth, (ii) the tumor exhibited an expansive growth at the tumor margin, and (iii) special types such as an α-fetoprotein-producing carcinoma, neuroendocrine carcinoma, and carcinoma with lymphoid stroma were excluded. Based on the definition, we subclassified the poorly differentiated gastric adenocarcinoma of solid type into the two groups: medullary carcinoma and non-medullary carcinoma, and clinicopathologically analyzed 23 cases of medullary carcinomas and 38 cases of non-medullary carcinomas. The medullary carcinomas less frequently displayed lymphatic invasion, venous invasion, and lymph node metastasis, compared with the non-medullary carcinoma (P < 0.001, P = 0.002, and P < 0.001, respectively). The patients with medullary carcinomas significantly showed better disease-free survival (P = 0.017). This is the first study to demonstrate that poorly differentiated adenocarcinoma of solid type can be subclassified into tumors with low and high malignant potentials. Gastric poorly differentiated medullary carcinoma is considered to be a novel histological type predicting good patients' prognosis.

Effects of orexins/hypocretins on neuronal activity in the paraventricular nucleus of the thalamus in rats in vitro.

Orexin-A (ORX-A) and orexin-B (ORX-B), also called hypocretin-1 and hypocretin-2, respectively, act upon orexin 1 (OX1R) and orexin 2 (OX2R) receptors, and are involved in the regulation of sleep-wakefulness and energy homeostasis. Orexin neurons in the lateral hypothalamic perifornical region project heavily to the paraventricular nucleus of the thalamus (PVT), which is deeply involved in the control of motivated behaviors. In the present study, electrophysiological and cytosolic Ca2+ concentration ([Ca2+]i) imaging studies on the effects of ORX-A and ORX-B on neurons in the PVT were carried out in rat brain slice preparations. ORX-A and/or ORX-B were applied extracellularly in the perfusate. Extracellular recordings showed that about 80% of the PVT neurons were excited dose-dependently by both ORX-A and ORX-B at concentrations of 10(-8) to 10(-6)M, and the increase in firing rate was about three times larger for ORX-B than for ORX-A at 10(-7)M. When both ORX-A and ORX-B were applied simultaneously at 10(-7)M, the increase in firing rate was almost equal to that of ORX-B at 10(-7)M, suggesting that the PVT neurons do not show a high affinity to ORX-A which is expected if they have OX1R receptors. The excitatory effect of ORX-B was seen in low Ca2+ and high Mg2+ ACSF as well as in normal ACSF, and the increase in firing rate was greater in low Ca2+ and high Mg2+ ACSF than in normal ACSF. [Ca2+]i imaging studies demonstrated that [Ca2+]i was increased in about 50% of the PVT neurons by both 10(-7)M ORX-A and ORX-B with a stronger effect for ORX-B, and the increase in [Ca2+]i induced by ORX-B was abolished in Ca2+-free ACSF, suggesting that ORX-B does not release Ca2+ from intracellular Ca2+ stores. Subsequent whole cell patch clamp recordings revealed that an after hyperpolarization seen following each action potential in normal ACSF disappeared in Ca2+-free ACSF, and the mean magnitude of the depolarization induced by ORX-B was same in normal, Ca2+-free and TTX-containing Ca2+-free ACSFs. Furthermore, ORX-B-induced depolarization was reversed to hyperpolarization when membrane potential was lowered to about -97 mV, and an increase of extracellular K+ concentration from 4.25 to 13.25 mM abolished the ORX-B-induced depolarization, indicating that the ORX-B-induced depolarization is associated with an increase in the membrane resistance resulting from a closure of K+ channels. These results suggest that orexins depolarize and excite post-synaptically PVT neurons via OX2R receptors, and that orexin-activated PVT neurons play a role in the integration of sleep-wakefulness and energy homeostasis, and in the control of motivated behaviors.