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Nrf2 is essential for cytoprotection against carcinogens, and through systemic Nrf2 knockout mice, Nrf2-deficient cells were shown to be susceptible to chemical carcinogens and prone to developing cancers. However, the oncogenic potential of Nrf2-deficient epithelial cells surrounded by normal cells in the esophagus could not be assessed by previous models, and the fate of Nrf2-deficient cells in such situations remains elusive. In this study, therefore, we generated mice that harbor almost equal levels of cells with Nrf2 deleted and those with Nrf2 intact in the basal layer of the esophageal epithelium, utilizing inducible Cre-mediated recombination of Nrf2 alleles in adults through moderate use of tamoxifen. In this mouse model, epithelial cells with Nrf2 deleted were maintained with no obvious decrease or phenotypic changes for 12 weeks under unstressed conditions. Upon exposure to the carcinogen 4-nitroquinoline-1-oxide (4NQO), the cells with Nrf2 deleted accumulated DNA damage and selectively disappeared from the epithelium, so almost all 4NQO-induced tumors originated from cells with Nrf2 intact and not from those with Nrf2 deleted. We propose that cells with Nrf2 deleted do not undergo carcinogenesis due to selective elimination upon exposure to 4NQO, indicating that cellular Nrf2 abundance and the epithelial environment determine the cell fate or oncogenic potential of esophageal epithelial cells in 4NQO-induced carcinogenesis.

BACKGROUND AND AIM Endoscopic nasobiliary drainage (ENBD) is often recommended in preoperative biliary drainage (PBD) for hilar malignant biliary obstruction (MBO), but endoscopic biliary stent (EBS) is also used in the clinical practice. We conducted this large-scale multicenter study to compare ENBD and EBS in this setting. METHODS A total of 374 cases undergoing PBD including 281 ENBD and 76 EBS for hilar MBO in 29 centers were retrospectively studied. RESULTS Extrahepatic cholangiocarcinoma (ECC) accounted for 69.8% and Bismuth-Corlette classification was III or more in 58.8% of the study population. Endoscopic PBD was technically successful in 94.6%, and adverse event rate was 21.9%. The rate of post-endoscopic retrograde cholangiopancreatography pancreatitis was 16.0%, and non-endoscopic sphincterotomy was the only risk factor (odds ratio [OR] 2.51). Preoperative re-intervention was performed in 61.5%: planned re-interventions in 48.4% and unplanned re-interventions in 31.0%. Percutaneous transhepatic biliary drainage was placed in 6.4% at the time of surgery. The risk factors for unplanned procedures were ECC (OR 2.64) and total bilirubin ≥ 10 mg/dL (OR 2.18). In surgically resected cases, prognostic factors were ECC (hazard ratio [HR] 0.57), predraiange magnetic resonance cholangiopancreatography (HR 1.62) and unplanned re-interventions (HR 1.81). EBS was not associated with increased adverse events, unplanned re-interventions, or a poor prognosis. CONCLUSIONS Our retrospective analysis did not demonstrate the advantage of ENBD over EBS as the initial PBD for resectable hilar MBO. Although the technical success rate of endoscopic PBD was high, its re-intervention rate was not negligible, and unplanned re-intervention was associated with a poor prognosis in resected hilar MBO.

A 78-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric adenocarcinoma twice in 2009 and 2014. Between the procedures, he successfully completed Helicobacter pylori eradication therapy. In May 2015, upper endoscopy screening showed two elevated lesions on the gastric fundus, and en bloc resection by ESD was performed. We histopathologically diagnosed the patient to have gastric adenocarcinoma of the fundic gland type. In this case, the two lesions of gastric adenocarcinoma of the fundic gland type multifocally developed after ESD for metachronous gastric tubular adenocarcinoma. Furthermore, they appeared in the gastric fundus, where atrophy had been improved due to eradication therapy.

While immunomodulators (IMs) are used as key drugs in remission maintenance treatment for ulcerative colitis (UC), there has been no evidence to date for determining monitoring methods and drug withdrawal. Therefore, we examined if a decrease in white blood cell count (WBC) and an elevation in mean cell volume (MCV) could be used as optimization indices and if mucosal healing (MH) could be a rationale for determining the time of IM withdrawal. Subjects were 89 UC patients who were using IMs and for whom clinical remission had been maintained. Those with a Rachmilewitz Clinical Activity Index score of 4 or lower and those with a Mayo endoscopic subscore (MES) of 0 or 1 were defined as MH. The remission maintenance rates of the following comparative groups were examined: an IM continuation group and an IM withdrawal group; an IM continuation group with a WBC of less than 3000 or a MCV of 100 or greater and an IM continuation group with a WBC of 3000 or greater and a MCV of 99 or lower; an IM continuation group of patients for whom MH had been achieved and an IM continuation group of patients for whom MH had not been achieved; and an IM withdrawal group with a MES of 0 and an IM withdrawal group with a MES of 1. A significantly higher remission maintenance rate was observed in the IM continuation group compared to the withdrawal group (p

A patient was diagnosed with ulcerative colitis (UC) in 2010. In March 2015, she had abdominal pain, diarrhea, bloody stool, and UC has relapsed. In June 2015, pain and sensory disturbance of both lower limbs appeared. Blood flow at the distal femoral artery was not confirmed with magnetic resonance angiography, and it was diagnosed as bilateral acute inferior limb ischemia. Arterial thrombolectomy with Fogarty’s balloon catheter was performed and blood flow was improved. The severity of UC was moderate with Mayo score 8. Thrombosis is considered to be a complication with a high incidence in inflammatory bowel disease. Reports of arterial thrombosis are very rare. It is important to evaluate the risk of bleeding and thrombosis in active or severe cases in UC and need to do thrombotic prophylactic treatment simultaneously with UC treatment.

Rationale: There is currently no consensus on the ideal method for obtaining deep tissue biopsy material of advanced gastric LP. EUS-FNA has potential as a useful diagnostic method. Thus, we report the case of a 46-year-old male with advanced gastric linitis plastica (LP) who was diagnosed using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Patient concerns: The patient underwent esophagogastroduodenoscopy (EGD) because of epigastric pain at a local clinic. The gastric fold swelling was pointed out by the EGD and despite the suspected advanced gastric LP, biopsy indicated Group 1. Repeat biopsy did not suggest malignancy. The patient was referred to our institution. Diagnoses: Endoscopic ultrasound indicated gastric wall thickening mainly in the greater curvature of the gastric corpus. Low-level echoes were detected throughout the entire gastric wall, and gastric wall layers had been disappeared. EUS-FNA of the gastric wall indicated signet ring cell carcinoma. Interventions: As a result of EUS - FNA, it became a policy to administer chemotherapy. In accordance with the patient's wishes, he was referred to another institution for chemotherapy. Outcomes: Normal biopsy did not give a definitive pathological diagnosis, and final diagnosis of LP was obtained with EUS-FNA. Lessons: We expect that EUS-FNA can be utilized as a relatively non-invasive, highly sensitive, and specific pathological diagnostic procedure for advanced gastric LP. EUS-FNA should be considered as one way to obtain a deep tissue biopsy of advanced gastric LP.

Extension of inflammation into the scrotum is rare in acute pancreatitis. If inflammation spreads in the scrotum, it may become severe. Clinicians should be aware of this condition as a possible complication. Proactive imaging testing is recommended when complaining of cyst swelling or testicular pain.

Background and study aims Endoscopic submucosal dissection (ESD) is a technically advanced procedure for colorectal tumors. Hayashi et al. invented the “pocket-creation method (PCM),” and reported that Is-type lesions with fibrosis could be efficaciously and safely resected. However, only case studies have been published, and there are no previous reports on the usefulness of PCM in colorectal ESD for all lesions, as compared with the conventional method. This study aimed to evaluate the effectiveness and safety of PCM in colorectal ESD. Patients and methods Ninety-six colorectal tumors were treated: 47 using the PCM and the other 49, considered the control group, using the conventional method. Therapeutic effectiveness and safety were retrospectively assessed. Results The comparison between the PCM and control groups revealed higher rates of en bloc resection (100 % vs. 88 %, P = 0.015) and curative endoscopic resection (100 % vs. 84 %, P = 0.0030) with PCM. There was no significant difference in perforation as an adverse event (AE) between the two groups, though perforation was observed in only 6 % of the control group and none of the PCM group. Compared with the control group, the PCM group had lower incidences of perforation and post-ESD coagulation syndrome, and both AEs were associated with excessive thermal denaturation of the muscle layer (2 % vs. 16 %, P = 0.018). Conclusions This study demonstrated the effectiveness and safety of ESD with PCM for colorectal tumors. Although there is a possible learning curve, PCM enables the endoscopist to safely perform ESD in most cases without encountering the difficulties associated with conventional ESD.

A 53-year-old man presented with diarrhoea and hypokalaemia and was diagnosed with a neuroendocrine tumour of unknown origin with multiple liver metastases. Somatostatin analogues led to a reduction in the size of the tumours and improvement of his symptoms. However, after several years, the tumours grew in size, and the patient's clinical symptoms recurred. The patient underwent transcatheter arterial embolization (TAE) of the hepatic artery to treat the liver metastases. Immediately after embolization, the symptoms disappeared. Although the patient had an unresectable vasoactive intestinal polypeptide-producing neuroendocrine tumour, the endocrine symptoms were able to be controlled with chemotherapy and TAE, resulting in a long-term survival.

The KEAP1-NRF2 system regulates the cellular defence against oxidative and xenobiotic stresses. NRF2 is a transcription factor that activates the expression of cytoprotective genes encoding antioxidative, detoxifying and metabolic enzymes as well as transporters. Under normal conditions, KEAP1 represses NRF2 activity by degrading the NRF2 protein. When cells are exposed to stresses, KEAP1 stops promoting NRF2 degradation, and NRF2 rapidly accumulates and activates the transcription of target genes. Constitutive accumulation of NRF2 via a variety of mechanisms that disrupt KEAP1-mediated NRF2 degradation has been observed in various cancer types. Constitutive NRF2 accumulation confers cancer cells with a proliferative advantage as well as resistance to anti-cancer drugs and radiotherapies. To suppress the chemo- and radio-resistance of cancer cells caused by NRF2 accumulation, we conducted high-throughput chemical library screening for NRF2 inhibitors and identified febrifugine derivatives. We found that application of the less-toxic derivative halofuginone in a low dose range rapidly reduced NRF2 protein levels. Halofuginone induced a cellular amino acid starvation response that repressed global protein synthesis and rapidly depleted NRF2. Halofuginone treatment ameliorated the resistance of NRF2-addicted cancer cells to anti-cancer drugs both in vitro and in vivo. These results provide preclinical proof-of-concept evidence for halofuginone as an NRF2 inhibitor applicable to treatment of chemo- and radio-resistant forms of cancer.