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.

Efficacy of endoscopic submucosal resection with a ligation device for small rectal neuroendocrine tumor: study protocol of a multicenter open-label randomized control trial (BANDIT trial).

BACKGROUND: Endoscopic resection is widely accepted as a local treatment for rectal neuroendocrine tumors sized ≤ 10 mm. However, there is no consensus on the best method for the endoscopic resection of rectal neuroendocrine tumors. As a simplified endoscopic procedure, endoscopic submucosal resection with a ligation device (ESMR-L) indicates a histologically complete resection rate comparable to that of endoscopic submucosal dissection (ESD). We hypothesized that ESMR-L than ESD would be preferred for rectal neuroendocrine tumors. Hence, this trial aimed to verify whether ESMR-L is non-inferior to ESD in terms of histologically complete resection rate. METHODS: This is a prospective, open-label, multicenter, non-inferiority, randomized controlled trial of two parallel groups, conducted at the Shizuoka Cancer Center and 31 other institutions in Japan. Patients with a lesion endoscopically diagnosed as a rectal neuroendocrine tumor ≤ 10 mm are eligible for inclusion. A total of 266 patients will be recruited and randomized to undergo either ESD or ESMR-L. The primary endpoint is the rate of en bloc resection with histologically tumor-free margins (R0 resection). Secondary endpoints include en bloc resection rate, procedure time, adverse events, hospitalization days, total devices and agents cost, adverse event rate between groups with and without resection site closure, outcomes between expert and non-expert endoscopists, and factors associated with R0 resection failure. The sample size is determined based on the assumption that the R0 resection rate will be 95.2% in the ESD group and 95.3% in the ESMR-L group, with a non-inferiority margin of 8%. With a one-sided significance level of 0.05 and a power of 80%, 226 participants are required. Assuming a dropout rate of 15%, 266 patients will be included in this study. DISCUSSION: This is the first multicenter randomized controlled trial comparing ESD and ESMR-L for the R0 resection of rectal neuroendocrine tumors ≤ 10 mm. This will provide valuable information for standardizing endoscopic resection methods for rectal neuroendocrine tumors. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs042210124. Registered on Jan 6, 2022.

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.

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (Tmax), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs. METHODS: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and Tmax. RESULTS: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and Tmax varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and Tmax (OR, 6.056; 95% CI, 1.094-33.529; P = .039). CONCLUSIONS: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.

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.

l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.

Hypothalamic neurons regulate body homeostasis by sensing and integrating changes in the levels of key hormones and primary nutrients (amino acids, glucose, and lipids). However, the molecular mechanisms that enable hypothalamic neurons to detect primary nutrients remain elusive. Here, we identified l-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor-expressing (LepR-expressing) neurons as being important for systemic energy and bone homeostasis. We observed LAT1-dependent amino acid uptake in the hypothalamus, which was compromised in a mouse model of obesity and diabetes. Mice lacking LAT1 (encoded by solute carrier transporter 7a5, Slc7a5) in LepR-expressing neurons exhibited obesity-related phenotypes and higher bone mass. Slc7a5 deficiency caused sympathetic dysfunction and leptin insensitivity in LepR-expressing neurons before obesity onset. Importantly, restoring Slc7a5 expression selectively in LepR-expressing ventromedial hypothalamus neurons rescued energy and bone homeostasis in mice deficient for Slc7a5 in LepR-expressing cells. Mechanistic target of rapamycin complex-1 (mTORC1) was found to be a crucial mediator of LAT1-dependent regulation of energy and bone homeostasis. These results suggest that the LAT1/mTORC1 axis in LepR-expressing neurons controls energy and bone homeostasis by fine-tuning sympathetic outflow, thus providing in vivo evidence of the implications of amino acid sensing by hypothalamic neurons in body homeostasis.

[A fatal case intra-abdominal hemorrhage following self-removal of a percutaneous transhepatic gallbladder drainage tube].

A 92-year-old woman with gallstone pancreatitis and acute cholangitis was admitted to our hospital where endoscopic retrograde cholangiopancreatography was performed for emergency biliary drainage. Biliary cannulation was unsuccessful. Consequently, percutaneous transhepatic gallbladder drainage (PTGBD) was performed, and her symptoms improved. The PTGBD tube was removed by the patient on the third day of admission resulting in cardiopulmonary arrest two hours later. Cardiopulmonary resuscitation restored spontaneous circulation. Contrast computed tomography revealed intra-abdominal hemorrhage from the right hepatic artery by the removed part of the PTGBD tube. The patient died despite hemostasis by transcatheter artery embolization. PTGBD is generally effective and safe;however, it can cause fatal hemorrhage, especially if PTGBD tubes are removed by the patient. Thus, self-removal should be strictly prevented.

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.

The role of CDK8 in mesenchymal stem cells in controlling osteoclastogenesis and bone homeostasis.

Bone marrow mesenchymal stem cells (MSCs) are critical regulators of postnatal bone homeostasis. Osteoporosis is characterized by bone volume and strength deterioration, partly due to MSC dysfunction. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Here, CDK8 in MSCs was identified as important for bone homeostasis. CDK8 level was increased in aged MSCs along with the association with aging-related signals. Mouse genetic studies revealed that CDK8 in MSCs plays a crucial role in bone resorption and homeostasis. Mechanistically, CDK8 in MSCs extrinsically controls osteoclastogenesis through the signal transducer and transcription 1 (STAT1)-receptor activator of the nuclear factor κ Β ligand (RANKL) axis. Moreover, aged MSCs have high osteoclastogenesis-supporting activity, partly through a CDK8-dependent manner. Finally, pharmacological inhibition of CDK8 effectively repressed MSC-dependent osteoclastogenesis and prevented ovariectomy-induced osteoclastic activation and bone loss. These findings highlight that the CDK8-STAT1-RANKL axis in MSCs could play a crucial role in bone resorption and homeostasis.

Persistent γ-H2AX Formation and Expression of Stem Cell Markers in N-Butyl-N-(4-Hydroxybutyl)Nitrosamine-Induced Bladder Carcinogenesis in Rats.

We investigated γ-H2AX formation, a biomarker of DNA damage, and expression of stem cell markers (SCMs), including cytokeratin 14, aldehyde dehydrogenase 1A1 (ALDH1A1), and CD44, in the development of rat bladder tumors induced by short-term administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Histopathological examination showed that diffuse simple hyperplasia of the bladder urothelium induced by BBN recovered to the normal-appearing urothelium after withdrawal, whereas focal proliferative lesions were newly developed and subsequently progressed to benign papilloma and carcinoma. Immunohistochemical analysis revealed that BBN-induced γ-H2AX formation and ALDH1A1 and CD44 expression persisted at higher levels in the normal-appearing urothelium than those in the control group for long periods after withdrawal. Since persistent chronic inflammation was observed even after withdrawal, targeted gene expression analysis of inflammation-related factors revealed 101 genes, including Stat3 and Myc, that showed persistent high expression. Pathway analysis suggested that Stat3 and/or Myc activation may be associated with SCM expression. We focused on hepatocyte growth factor (Hgf), one of the genes predicted in relation to Stat3/Myc, and confirmed that HGF-positive cells increased by BBN persisted in the normal-appearing urothelium after withdrawal and colocalized with γ-H2AX and SCMs. These results suggested that the long-term persistence of γ-H2AX formation and SCM expression, which occurred during the early stages of bladder tumorigenesis, is not a transient response to exposure and might contribute to bladder tumorigenesis. Although further studies are needed, BBN-induced rat bladder tumors may originate from focal hyperplasia arising from SCM-positive cells via activation of the STAT3/MYC pathway after DNA damage involving γ-H2AX formation.

Erk5 in Bone Marrow Mesenchymal Stem Cells Regulates Bone Homeostasis by Preventing Osteogenesis in Adulthood.

Extracellular signal-regulated kinase 5 (Erk5) belongs to the mitogen-activated protein kinase (MAPK) family. Previously, we demonstrated that Erk5 directly phosphorylates Smad-specific E3 ubiquitin protein ligase 2 (Smurf2) at Thr249 (Smurf2Thr249) to activate its E3 ubiquitin ligase activity. Although we have clarified the importance of Erk5 in embryonic mesenchymal stem cells (MSCs) on skeletogenesis, its role in adult bone marrow (BM)-MSCs on bone homeostasis remains unknown. Leptin receptor-positive (LepR+) BM-MSCs represent a major source of bone in adult bone marrow and are critical regulators of postnatal bone homeostasis. Here, we identified Erk5 in BM-MSCs as an important regulator of bone homeostasis in adulthood. Bone marrow tissue was progressively osteosclerotic in mice lacking Erk5 in LepR+ BM-MSCs with age, accompanied by increased bone formation and normal bone resorption in vivo. Erk5 deficiency increased the osteogenic differentiation of BM-MSCs along with a higher expression of Runx2 and Osterix, essential transcription factors for osteogenic differentiation, without affecting their stemness in vitro. Erk5 deficiency decreased Smurf2Thr249 phosphorylation and subsequently increased Smad1/5/8-dependent signaling in BM-MSCs. The genetic introduction of the Smurf2T249E mutant (a phosphomimetic mutant) suppressed the osteosclerotic phenotype in Erk5-deficient mice. These findings suggest that the Erk5-Smurf2Thr249 axis in BM-MSCs plays a critical role in the maintenance of proper bone homeostasis by preventing excessive osteogenesis in adult bone marrow.

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.

In vivo mutagenicity and tumor-promoting activity of 1,3-dichloro-2-propanol in the liver and kidneys of gpt delta rats.

1,3-Dichloro-2-propanol (1,3-DCP), a food contaminant, exerts carcinogenic effects in multiple organs, including the liver and kidneys, in rats. However, the underlying mechanisms of 1,3-DCP-induced carcinogenesis remain unclear. Here, the in vivo mutagenicity and tumor-promoting activity of 1,3-DCP in the liver and kidneys were evaluated using medium-term gpt delta rat models previously established in our laboratory (GPG and GNP models). Six-week-old male F344 gpt delta rats were treated with 0 or 50 mg/kg body weight/day 1,3-DCP by gavage for 4 weeks. After 2 weeks of cessation, partial hepatectomy or unilateral nephrectomy was performed to collect samples for in vivo mutation assays, followed by single administration of diethylnitrosamine (DEN) for tumor initiation. One week after DEN injection, 1,3-DCP treatment was resumed, and tumor-promoting activity was evaluated in the residual liver or kidneys by histopathological analysis of preneoplastic lesions. gpt mutant frequencies increased in excised liver and kidney tissues following 1,3-DCP treatment. 1,3-DCP did not affect the development of glutathione S-transferase placental form-positive foci in residual liver tissues, but enhanced atypical tubule hyperplasia in residual kidney tissues. Detailed histopathological analyses revealed glomerular injury and increased cell proliferation of renal tubular cells in residual kidney tissues of rats treated with 1,3-DCP. These results suggested possible involvement of genotoxic mechanisms in 1,3-DCP-induced carcinogenesis in the liver and kidneys. In addition, we found that 1,3-DCP exhibited limited tumor-promoting activity in the liver, but enhanced clonal expansion in renal carcinogenesis via proliferation of renal tubular cells following glomerular injury.

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.

CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway.

Glioblastoma (GBM) is the most malignant form of glioma. Glioma stem cells (GSCs) contribute to the initiation, progression, and recurrence of GBM as a result of their self-renewal potential and tumorigenicity. Cyclin-dependent kinase 8 (CDK8) belongs to the transcription-related CDK family. Although CDK8 has been shown to be implicated in the malignancy of several types of cancer, its functional role and mechanism in gliomagenesis remain largely unknown. Here, we demonstrate how CDK8 plays an essential role in maintaining stemness and tumorigenicity in GSCs. The genetic inhibition of CDK8 by shRNA or CRISPR interference resulted in an abrogation of the self-renewal potential and tumorigenicity of patient-derived GSCs, which could be significantly rescued by the ectopic expression of c-MYC, a stem cell transcription factor. Moreover, we demonstrated that the pharmacological inhibition of CDK8 significantly attenuated the self-renewal potential and tumorigenicity of GSCs. CDK8 expression was significantly higher in human GBM tissues than in normal brain tissues, and its expression was positively correlated with stem cell markers including c-MYC and SOX2 in human GBM specimens. Additionally, CDK8 expression is associated with poor survival in GBM patients. Collectively, these findings highlight the importance of the CDK8-c-MYC axis in maintaining stemness and tumorigenicity in GSCs; these findings also identify the CDK8-c-MYC axis as a potential target for GSC-directed therapy.

Neuromuscular and vascular hamartoma of the small intestine in an F344 rat.

An intestinal mass was found in the border area of the jejunum and ileum of a 110-week-old male F344 rat. Histopathologically, the mass protruded into the lumen and was covered with intestinal epithelium, exhibiting a normal architecture. The lesion was located in the submucosa and consisted of loose connective tissue, smooth muscle, scattered ganglion cells, and blood vessels of various sizes. Although these components showed an irregular and disordered structure, no cellular atypia, increased proliferation activity, or invasive growth to adjacent tissues were detected. Immunohistochemical analyses revealed that smooth muscle, ganglion, and endothelial cells were positive for α-smooth muscle actin and vimentin, S-100, and CD34 and von Willebrand factor, respectively, indicating maturation of these cells. Thus, the mass was diagnosed as a neuromuscular and vascular hamartoma of the small intestine. To the best of our knowledge, this is the first report of this type of lesion in rodents.