Evidence of Nrf2/Keap1 Signaling Regulation by Mitochodria-Generated Reactive Oxygen Species in RGK1 Cells.

It has been known that reactive oxygen species (ROS) are generated from the mitochondrial electron transport chain (ETC). Majima et al. proved that mitochondrial ROS (mtROS) caused apoptosis for the first time in 1998 (Majima et al. J Biol Chem, 1998). It is speculated that mtROS can move out of the mitochondria and initiate cellular signals in the nucleus. This paper aims to prove this phenomenon by assessing the change in the amount of manganese superoxide dismutase (MnSOD) by MnSOD transfection. Two cell lines of the same genetic background, of which generation of mtROS are different, i.e., the mtROS are more produced in RGK1, than in that of RGM1, were compared to analyze the cellular signals. The results of immunocytochemistry staining showed increase of Nrf2, Keap1, HO-1 and 2, MnSOD, GCL, GST, NQO1, GATA1, GATA3, GATA4, and GATA5 in RGK1 compared to those in RGM1. Transfection of human MnSOD in RGK1 cells showed a decrease of those signal proteins, suggesting mtROS play a role in cellular signals in nucleus.

Risk factors for postoperative bleeding and early death in percutaneous endoscopic gastrostomy: A multicenter retrospective study.

BACKGROUND AND AIM: Comprehensive reports on the risk factors for bleeding and early death after percutaneous endoscopic gastrostomy (PEG) are limited. In this multicenter study, we retrospectively investigated the risk factors for bleeding and early death after PEG. METHODS: Patients (n = 1234) who underwent PEG between 2015 and 2020 at Osaka Medical and Pharmaceutical University and its affiliated hospitals (11 institutions in total) were evaluated for postoperative bleeding and early death (within 60 days) after PEG according to patient characteristics, construction method, medical history, medications, preoperative hematological findings, and perioperative adverse events. Multivariate logistic regression was performed to identify independent predictors of bleeding and early death after PEG. RESULTS: The risk factors for bleeding after PEG were PEG tube insertion using the modified introducer method (odds ratio [OR], 4.37; P = 0.0003), low platelet count (OR, 0.99; P = 0.014), antiplatelet therapy (OR, 2.11; P = 0.036), and heparinization (OR, 4.50; P = 0.007). Risk factors for early death were low body mass index (BMI) (OR, 0.89; P = 0.015), low serum albumin levels (OR, 0.50; P = 0.035), and comorbidity of active cancer (OR, 4.03; P < 0.0001). There was no significant association between bleeding and early death after PEG. CONCLUSIONS: We identified several risk factors for bleeding and early death after PEG. Risk factors for bleeding were PEG tube insertion using the modified introducer method, low platelet count, antiplatelet therapy, and heparinization. Risk factors for early death were low BMI, low serum albumin levels, and comorbidity of active cancer.

EUS-guided versus percutaneous biliary access in patients with obstructive jaundice due to gastric cancer.

BACKGROUND: Gastric cancer is sometimes complicated by obstructive jaundice. However, ERCP may be challenging in patients who have advanced gastric cancer, or recurrent gastric cancer after surgical resection that is complicated by obstructive jaundice. In such cases, percutaneous transhepatic biliary drainage (PTBD) is considered. Recently, EUS-guided biliary drainage (EUS-BD) has been developed. We conducted a retrospective study to compare the efficacy of EUS-BD and PTBD in patients with obstructive jaundice due to gastric cancer. METHODS: Patients with gastric cancer complicated with obstructive jaundice who were contraindicated for standard ERCP were enrolled. RESULTS: A total of 47 consecutive patients were enrolled during the study period. The technical success rates of PTBD and EUS-BD were 88.9% (16/18) and 96.7% (29/30), respectively (P = 0.64). The stent patency period, including patient death was equivalent between the two groups (EUS-BD vs. PTBD: 188.4 days vs. 200.9 days, P = 0.974). Time to stent dysfunction in the EUS-BD group (391.1 days) was not significantly different as compared to that in the PTBD group (398.1 days) (P = 0.78). Adverse events were relatively severe in the PTBD group. CONCLUSIONS: Given the relative severity of adverse events in the PTBD group, EUS-BD might be the procedure of choice for gastric cancer patients with contraindications by inability to perform ERCP.

Analysis of Prognostic Factors in Pancreatic Metastases: A Multicenter Retrospective Analysis.

OBJECTIVES: Pancreatic metastases (PMs) account for 1% to 2% of pancreatic tumors, and their prognostic significance is poorly defined. We evaluated the incidence and clinical characteristics of primary tumors and defined prognostic factors. METHODS: This retrospective study of 39 Japanese tertiary referral hospitals (January 2005 to August 2015) analyzed patient and tumor characteristics and survival time. Kaplan-Meier analysis and Cox proportional hazards models were applied to evaluate overall survival and prognostic factors, respectively. RESULTS: We enrolled 159 patients with a pathologic diagnosis of PM. The most common primary tumor was renal cell carcinoma (38.4%), followed by lung cancer (24.5%), colorectal cancer (11.3%), and sarcoma (6.3%). Eight patients were lost during follow-up, and 151 patients were included for statistical analysis. Median overall survival was 43.0 months, and the 5-year survival rate was 42.6%. Multivariate analysis identified 3 independent prognostic factors: extrapancreatic metastasis (hazard ratio, 2.13; 95% confidence interval, 1.11-4.07; P = 0.02), tumor-related symptoms at diagnosis (hazard ratio, 5.39; 95% confidence interval, 2.92-9.91; P < 0.001), and pathologic diagnosis of primary tumors (P < 0.001). CONCLUSIONS: Treatment strategies and prognoses for PMs completely differ according to the primary tumor type. A definitive pathologic diagnosis of PMs is essential for selecting the appropriate treatment.

Prospective evaluation of digital single-operator cholangioscope for diagnostic and therapeutic procedures (with videos).

BACKGROUND AND AIM: Recently, the digital single-operator cholangioscope (SPY-DS) has become available. This system may allow diagnosis by direct visualization and allow performance of various therapeutic procedures. The aim of the present study was to prospectively evaluate the clinical utility of DSOCS for diagnostic and therapeutic procedures for biliary disease. METHODS: Technical success was defined as successful visualization of target lesions in the biliary tract and carrying out forceps biopsy as a diagnostic procedure, and successfully carrying out treatment such as guidewire insertion for the area of interest, electrohydraulic lithotripsy (EHL), or migrated stent removal. Also, the present study aimed at investigating diagnostic yield of the cholangioscopic findings and biopsy specimens. RESULTS: A total of 55 consecutive patients were prospectively enrolled in this study; a diagnostic procedure was done in 33 patients, and a therapeutic procedure was done in 22 patients. Overall accuracy of visual findings was 93%, with a sensitivity of 83%, a specificity of 89%, positive predictive value (PPV) of 83%, and negative predictive value (NPV) of 100%. However, the overall accuracy of forceps biopsy was 89%, with a sensitivity, specificity, and PPV of 100%, and NPV of 90%. Overall technical success rate of therapeutic procedures such as selective guidewire insertion, EHL or migrated stent removal was 91% (20/22). Finally, adverse events were seen in two cases in the diagnostic group, but were not seen in the therapeutic group. CONCLUSION: Although additional cases and a randomized, controlled study with another cholangioscope are needed, diagnostic and therapeutic procedures using SPY-DS appear to be feasible and safe.

Lymphatic invasion is a significant indicator of poor patient prognosis in lung squamous cell carcinoma.

Pathological stage is the most important prognostic factor in patients with lung cancer, and is defined according to the tumor node metastasis classification system. The present study aimed to investigate the clinicopathological significance of lymphatic invasion in 103 patients who underwent surgical resection of lung squamous cell carcinoma (SqCC). The patients were divided into two groups, according to the degree of lymphatic invasion: Those with no or mild lymphatic invasion (ly0­1) and those with moderate or severe lymphatic invasion (ly2­3). Ly2­3 was associated with tumor size (P=0.028), lymph node metastasis (P<0.001), venous invasion (P=0.001) and histological differentiation (P=0.047). Statistical analysis using the Kaplan­Meier method and the log­rank test indicated that overall survival was significantly reduced in patients with ly2­3 compared with those with ly0­1 (P<0.001). Multivariate analysis identified ly2­3 as an independent predictor of mortality (hazard ratio, 2.580; 95% confidence interval, 1.376­4.839). In conclusion, moderate or severe lymphatic invasion (ly2­3) indicated a high malignant potential and may be considered an independent predictor of poor prognosis in patients with SqCC of the lung.

Evaluation of the safety of endoscopic radiofrequency ablation for malignant biliary stricture using a digital peroral cholangioscope (with videos).

BACKGROUND AND AIM: The clinical impact of catheter-based radiofrequency ablation (RFA) under endoscopic retrograde cholangiopancreatography (ERCP) guidance has recently been reported; however, severe adverse events have also been noted. If tumor is not present in the biliary tract, severe adverse events such as perforation or bleeding as a result of vessel injury around the biliary tract may occur. In addition, the effectiveness of RFA may not be sufficient based solely on radiographic guidance. The aim of the present study was to evaluate the actual feasibility of intraductal RFA by peroral cholangioscope (POCS) evaluation before/after RFA. METHODS: In this retrospective study carried out between July and September 2016, consecutive patients who underwent RFA for malignant biliary stricture and POCS evaluation before/after RFA were enrolled. Primary endpoint of this study was technical feasibility of RFA, which was evaluated by POCS. Secondary endpoints were rates and types of adverse event. RESULTS: A total of 12 consecutive patients were retrospectively enrolled in this study. Stent placement using uncovered metal stents had been previously done in six patients before RFA. Tumor was seen in the biliary tract in all patients. RFA was technically successful in all patients, and clinical success was confirmed in all patients by POCS imaging. Adverse events were seen in only one patient. Median stent patency was 154 days. CONCLUSIONS: RFA for malignant biliary stricture may be safe. To confirm the feasibility and efficacy of RFA, additional cases, prospective studies, and a comparison study between with and without endobiliary RFA are needed.

Prospective clinical study of endoscopic ultrasound-guided biliary drainage using novel balloon catheter (with video).

BACKGROUND AND AIM: On endoscopic ultrasound (EUS)-guided biliary drainage, fistula dilation may be accompanied by leakage of bile juice, potentially along with bacteria or air, so this procedure should be kept as simple and short as possible. To date, various techniques to dilate the fistula have been reported. This prospective, single-center, single-arm study evaluated the technical feasibility and safety of EUS-guided biliary drainage using novel balloon catheters. METHODS: Tip of novel balloon catheters is only 3 Fr and tapered, and the catheters also show favorable push ability. First, biliary tract was punctured using 19-G fine needle aspiration needle. Next, we immediately inserted the novel balloon catheter, and the biliary tract and intestinal wall were dilated. Then, we performed metallic stent placement without any dilation fistula. RESULTS: A total of 20 patients were prospectively enrolled in this study. Technical success rate was 100%. Eleven patients underwent EUS-guided choledochoduodenostomy, and nine patients underwent EUS-guided hepaticogastrostomy. Median procedure time was only 11 min (range, 8-16 min) for EUS-guided choledochoduodenostomy and 14 min (range, 11-18 min) for EUS-guided hepaticogastrostomy. Adverse events were seen in 15% (3/20; self-limited abdominal pain n = 2, peritonitis n = 1). CONCLUSIONS: Although additional cases and a randomized controlled comparison with another dilation technique such as the graded dilation or cystotome dilation technique are needed, our technique may be helpful for EUS-guided biliary drainage.

Clinical utility of endoscopic ultrasound-guided biliary drainage as a rescue of re-intervention procedure for high-grade hilar stricture.

BACKGROUND AND AIM: Re-intervention after stent placement for malignant hepatic hilum obstruction (HBO) is challenging. endoscopic ultrasound-guided biliary drainage (EUS-BD) has been developed as an alternative method for failed endoscopic retrograde cholangiopancreatography (ERCP). In this retrospective study, the clinical utility of EUS-BD as a rescue drainage technique for HBO patients who failed re-intervention under ERCP guidance was evaluated. METHODS: Between April 2012 and August 2015, patients with HBO were enrolled. Patients' characteristics, kinds of metallic stents, configuration of stent placement, overall survival, stent patency, and results of re-intervention were reviewed, along with the re-intervention technical success rate. RESULTS: The biliary stricture type was Bismuth type IV in 59% (23/39) and types IIIa and b in 20.5% (8/39) each. Biliary metallic stent placement was bilateral in 38.5% (15/39), and unilateral in 61.5% (24/39). Primary stent dysfunction was observed in 71.8% (28/39) of cases. Planned re-intervention under ERCP guidance was attempted in 26 patients. The technical success rate was 62% (16/26). For the 10 patients who failed re-intervention under ERCP guidance, EUS-BD was planned. The technical success rate was 100% (10/10). The procedure time was 25.8 min. Adverse events were not seen in any patients. Stent patency after re-intervention was not significantly different between ERCP (165 days) guidance and EUS-BD (152 days) guidance (P = 0.463) CONCLUSIONS: In conclusion, EUS-BD as a re-intervention method for metallic stent obstruction was safe and feasible. If ERCP was failed, EUS-BD may be one of option as re-intervention method for high-grade hilar stricture.

Choledochoduodenal Fistula after the Placement of a Partially Covered Metal Stent for Unresectable Pancreatic Cancer.

A 75-year-old Japanese man with type 2 diabetes mellitus suffered from unresectable pancreatic head cancer and was admitted to our institution due to acute cholangitis. A partially covered metal stent was placed at that time. 11 months later, he was readmitted for acute cholangitis. Upper endoscopy revealed complete stent distal migration and a small hole on the oral side of the ampulla. While attempting cannulation into the hole, an upstream biliary tract was revealed. Accordingly, we diagnosed the patient to have a choledochoduodenal fistula. After metal stent removal and balloon dilation, we placed two 7 Fr plastic stents, which successfully relieved the patient's cholangitis.

EUS-guided FNA for biliary disease as first-line modality to obtain histological evidence.

BACKGROUND: Few reports have described endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) for biliary lesions. In addition, adverse events were not completely examined in previous reports, due to the inclusion of cases in which biliary stents had already been placed. The present study aimed to investigate the diagnostic yield and adverse events of EUS-FNA for biliary lesions as the first-line diagnostic modality for consecutive prospectively registered patients. METHODS: Inclusion criteria were as follows: (1) patients with suspected cholangiocarcinoma (CCA) based on computed tomography or other imaging modalities; (2) patients who had not previously undergone endoscopic retrograde cholangiopancreatography or EUS-FNA; (3) absence of surgically altered anatomy, such as Roux-en-Y anastomosis or duodenal obstruction caused by tumor invasion, through which an endoscope could not pass; and (4) provision of written informed consent to all procedures associated with the study. RESULTS: A total of 47 consecutive patients with suspected CCA were registered to this study. Sensitivity and accuracy were 89% and 87%, respectively. On multivariate analysis, puncture site was the only factor associated with reduced diagnostic yield (hazard ration, 6.879; 95% confidence interval, 1.172-40.374; P = 0.033). Remarkably, no adverse events such as bleeding or bile leakage were associated with EUS-FNA in any of the 47 patients. CONCLUSIONS: Our results suggest that EUS-FNA can be safely performed for biliary disease without biliary stenting. Furthermore, this procedure may warrant use as the first-line diagnostic method, although our results need to be validated in future prospective studies.

EUS-guided cholecystoduodenostomy for acute cholecystitis with an anti-stent migration and anti-food impaction system; a pilot study.

BACKGROUND: Recently, endoscopic ultrasound-guided gall bladder drainage (EUS-GBD) has been reported using a self-expandable metallic stent. To prevent stent migration and food flowing into the common bile duct through the cystic duct, we perform a novel EUS-guided cholecystoduodenostomy. The aim of our study was to evaluate the safety and feasibility of EUS-guided cholecystoduodenostomy with an anti-stent migration and anti-food impaction system. METHODS: A total of 16 consecutive patients who underwent EUS-guided cholecystoduodenostomy for acute cholecystitis were included in this study. RESULTS: Technical and clinical success was obtained in all patients. The median procedure time was 26.9 min (range 19-42 min). Median follow-up time was 181.5 days (range 18-604 days), and in this time, recurrence of acute cholecystitis was not seen in all patients. Adverse events such as stent migration and cholangitis were not seen in any patients, although pneumoperitoneum was seen in one patient. CONCLUSION: Our technique may be favorable and effective for the prevention of adverse events on EUS-GBD.

Recurrence in regional pulmonary lymph nodes after surgery for isolated pulmonary metastasis from hepatocellular carcinoma.

Hepatocellular carcinoma occasionally metastasizes to extrahepatic organs, rarely to the mediastinal lymph nodes. We present the case of a 64-year-old man who presented with nodules in the upper and right lower lobes of the lung 4 years after undergoing resection of a hepatocellular carcinoma. We performed wedge resection of both lesions. Pathological examination showed that the lesion in the right upper lobe was non-small cell lung cancer and that in the right lower lobe hepatocellular carcinoma. We accordingly performed right upper lobectomy with lymph node dissection. Nine months later, enlarged subcarinal and segmental lymph nodes were detected and mediastinal lymph node metastases from the hepatocellular carcinoma diagnosed by transbronchial needle aspiration.

Comparison of the clinical impact of endoscopic ultrasound-guided choledochoduodenostomy and hepaticogastrostomy for bile duct obstruction with duodenal obstruction.

BACKGROUND AND STUDY AIM: To date, only a few reports with small numbers of patients have described double stenting (biliary and duodenal), in particular endoscopic ultrasound (EUS)-guided biliary drainage, for patients with obstructive jaundice. In addition, no reports have sought to determine which EUS-guided biliary drainage route has better outcomes. The aim of the current study was to investigate adverse events and stent patency in patients who underwent EUS-guided biliary drainage and duodenal stenting. PATIENTS AND METHODS: Patients who were admitted to the Osaka Medical College with obstructive jaundice caused by lower biliary obstruction and duodenal obstruction due to malignant tumor between June 2012 and April 2014 were retrospectively enrolled in the study. RESULTS: A total of 39 patients were enrolled in the study; 13 underwent EUS-guided choledochoduodenostomy (EUS-CDS), and 26 underwent EUS-guided hepaticogastrostomy (EUS-HGS). Adjusted analyses for covariates using propensity scores showed that the EUS-HGS group had significantly longer stent patency than the EUS-CDS group (duodenal stent patency: median 113 vs. 34 days; hazard ratio [HR] 0.415, 95 % confidence interval [CI] 0.175 - 0.984; P = 0.046; biliary stent patency: median 133 vs. 37 days; HR 0.391, 95 %CI 0.156 - 0.981; P = 0.045). On logistic regression analysis, only EUS-CDS was associated with adverse events, in particular reflux cholangitis (OR 10.285, 95 %CI 1.686 - 62.733; P = 0.012). CONCLUSION: In cases of obstructive jaundice with duodenal obstruction, EUS-HGS may be better than EUS-CDS, with longer stent patency and fewer adverse events.

Yield of endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography for solid pancreatic neoplasms.

OBJECTIVE: Both endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) cytology may provide tissue diagnoses in solid pancreatic neoplasms. However, there are scant data comparing these two methods. This study aims at retrospectively comparing EUS-FNA and ERCP tissue sampling and ability of cytopathological diagnosis in solid pancreatic neoplasms and to determine usefulness and adverse events of combining both procedures. MATERIAL AND METHODS: Two hundred and thirty four patients suspected to have solid pancreatic mass on abdominal ultrasound and/or computed tomography (CT) were enrolled. EUS-FNA (group A), ERCP cytology (group B) and combined procedures (Group C) performed in 105, 91 and 38 cases, respectively. RESULTS: Sensitivity, specificity and accuracy were 98.9%, 93.3% and 98.1% for group A, and 72.1%, 60% and 71.4% for group B. Those for group C were all 100%. Sensitivity for malignancy in the pancreas head was 100% for group A and 82.4% for group B, and in the pancreas body and tail, 97.6% for group A and 57.1% for group B. EUS-FNA was more sensitive than ERCP cytology in diagnosing malignant pancreatic neoplasms 21-30 mm in size (p = 0.0068), 31-40 mm (p = 0.028) and ≥ 41 mm (p < 0.0001). Sensitivity for pancreatic malignancy with group C was 100% regardless of mass location or size. Adverse events were 1.9%, 6.6% and 2.6% following EUS-FNA, ERCP and combined procedures, respectively. CONCLUSIONS: EUS-FNA is superior to ERCP cytology for diagnosis of solid pancreatic neoplasms. Although combination of both procedures provide efficient tissue diagnosis and with a minimal adverse events rate, a prospective study including larger number of patients is required.

Clinical Outcome of Endoscopic Ultrasound-Guided Liver Abscess Drainage Using Self-Expandable Covered Metallic Stent (with Video).

BACKGROUND: Percutaneous drainage (PCD) is now the first-line drainage method for liver abscess because of its minimal invasiveness and high technical success rate. However, this procedure has several disadvantages, such as extra-drainage and self-tube removal. Recently, EUS-guided liver abscess drainage (EUS-AD) has been developed. However, only a few reports of EUS-AD have been reported. In addition, the clinical benefits of PCD and EUS-AD have not been reported. AIMS: In the present study, the safety and feasibility of EUS-AD using fully covered SEMS (FCSEMS) and the clinical outcomes of EUS-AD and PCD were examined retrospectively. METHODS: Twenty-seven consecutive patients who underwent PCD or EUS-AD between April 2012 and April 2015 were included in this study. EUS-AD was performed using FCSEMS. In addition, to prevent stent migration, 7-Fr pig tail plastic stent was placed within FCSEMS. RESULTS: Technical success was achieved in all patients of both groups. Clinical success was 100 % in the EUS-AD group although it was 89 % in PCD group (P = 034). Three adverse events were seen in the PCD group (self-tube removal n = 1, tube migration n = 2), but no adverse events were seen in the EUS-AD group. The median hospital stay was significantly shorter in the EUS-AD group than in the PCD group (21 vs 41 days, P = 0.03). CONCLUSION: Because of the short hospital stay, the high clinical success rate, and the low adverse event rate compared to PCD, EUS-AD has potential as a first-line treatment for liver abscess.