Phase II study comparing nasal pressure monitoring with capnography during invasive endoscopic procedures: a single-center, single-arm trial.

Nasal pressure signal is commonly used to evaluate obstructive sleep apnea. This study aimed to assess its safety for respiratory monitoring during sedation. A total of 45 adult patients undergoing sedation with propofol and fentanyl for invasive endoscopic procedures were enrolled. While both nasal pressure and capnograph signals were continuously recorded, only the nasal pressure signal was displayed. The primary outcome was the incidence of oxygen desaturation below 90%. The secondary outcomes were the ability to predict the desaturation and incidence of harmful events and false alarms, defined as an apnea waveform lasting more than 3 min without desaturation. Of the 45 participants, 43 completed the study. At least one desaturation event occurred in 12 patients (27.9%; 95% confidence interval 15.3-43.7%). In these 12 patients, more than half of the desaturation events were predictable in 9 patients by capnography and 11 patients by nasal pressure monitoring (p = 0.59). In the 43 patients, false alarms were detected in 7 patients with capnography and 11 patients with nasal pressure monitoring (p = 0.427). Harmful events unrelated to nasal pressure monitoring occurred in 2 patients. Nasal pressure monitoring is safe and possibly useful for respiratory monitoring despite false alarms during sedation.

Thirty-two years' experience of treating fulminant hepatitis in a Japanese single center.

AIM: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late-onset hepatic failure (LOHF) admitted to our unit over a 32-year period to clarify the nature of Japanese patients with FH and LOHF. METHODS: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. RESULTS: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. CONCLUSIONS: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult-to-treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT.

Liver cirrhosis is a risk factor for poor prognosis of acute cholangitis caused by choledocholithiasis.

INTRODUCTION AND OBJECTIVES: Acute cholangitis, which is characterized by biliary infection and acute liver injury, may impact cirrhosis prognosis. However, the prognosis itself remains unclear. MATERIALS AND METHODS: This multicenter retrospective cohort study compared the mortality and liver function change between patients with and without cirrhosis who underwent endoscopic treatment for acute cholangitis caused by choledocholithiasis between January 2004 and December 2019. RESULTS: We analyzed 699 patients, 44 of whom had cirrhosis. The cirrhotic group had a significantly higher 30-day mortality rate than the noncirrhotic group (14% vs. 1%; P < 0.001). The cirrhotic group also had significantly lower total bilirubin and albumin recovery. However, all patients with cirrhosis who survived achieved total-bilirubin recovery, and 91% achieved albumin recovery within 90 days. In multivariable Cox regression analysis, the independent risk factors for total-bilirubin recovery included cirrhosis (hazard ratio, 0.37; 95%CI, 0.24‒0.58; P < 0.001) and high total-bilirubin level (0.46; 95%CI, 0.34‒0.60; P < 0.001), whereas those for albumin recovery were cirrhosis (0.51; 95%CI, 0.33‒0.79; P = 0.002), high age (0.62; 95%CI, 0.47‒0.82; P < 0.001), organ dysfunction (0.62; 95%CI, 0.39‒0.96; P = 0.03), low albumin level (0.57; 95%CI, 0.36‒0.91; P = 0.02), and high C-reactive protein level (0.73; 95%CI, 0.56‒0.95; P = 0.02). CONCLUSIONS: Patients with cirrhosis complicated with acute cholangitis had poor prognosis. Recovery of liver function after endoscopic treatment was slow; nevertheless, most patients who survived could recover within 90 days.

Diagnostic value of peroral cholangioscopy in addition to computed tomography for indeterminate biliary strictures.

BACKGROUND: Peroral cholangioscopy (POCS) has been used to overcome the difficulty in diagnosing indeterminate biliary stricture or tumor spread. However, the value of adding POCS to computed tomography (CT) remains unclear. Our aim was to evaluate the diagnostic value of adding POCS to CT for indeterminate biliary stricture and tumor spread by interpretation of images focusing on the high diagnostic accuracy of visual findings in POCS. METHODS: We retrospectively identified 52 patients with biliary stricture who underwent endoscopic retrograde cholangiography (ERC) at our institution between January 2013 and December 2018. Two teams, each composed of an expert endoscopist and surgeon, performed the interpretation independently, referring to the CT findings of the radiologist. The CT + ERC + POCS images (POCS group) were evaluated 4 weeks after the evaluation of CT + ERC images (CT group). A 5-point scale (1: definitely benign to 5: definitely malignant) was used to determine the confident diagnosis rate, which was defined as an evaluation value of 1 or 5. Tumor spread was also evaluated. RESULTS: In the evaluation of 45 malignant diagnoses, the score was significantly closer to 5 in the POCS group than in the CT group in both teams (P < 0.001). The confident diagnosis rate was significantly higher for the POCS group (92% and 73%) than for the CT group (25% and 12%) in teams 1 and 2, respectively (P < 0.001). We found no significant difference in diagnostic accuracy for tumor spread between the groups. CONCLUSION: Visual POCS findings confirmed the diagnosis of biliary strictures. POCS was useful in cases of indefinite diagnosis of biliary strictures by CT.

EZH1/2 inhibition augments the anti-tumor effects of sorafenib in hepatocellular carcinoma.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.

Long-term effects of endoscopic papillary large balloon dilation in patients with challenging bile duct calculi: A retrospective observational study.

ABSTRACT: Endoscopic papillary large balloon dilation (EPLBD) can be used to treat challenging common bile duct stones. No previous studies have reported intractable cases treated either by EPLBD or mechanical lithotripter use. We aimed to evaluate and compare the long-term effects of EPLBD with mechanical lithotripter use.This retrospective cohort study reviewed data from 153 patients admitted to the Eastern Chiba Medical Center from April 2014 to March 2020, presenting with common bile duct calculi that could not be removed using a basket or balloon catheter. Patients were divided into groups depending on whether the treatment was performed using a mechanical lithotripter or EPLBD. The primary outcome was the recurrence rate of common bile duct calculi, and the secondary outcome was the rate of postoperative adverse events. The Wilcoxon test was used to compare the 2 groups. Statistical significance was set at P < .05.The median age of patients included in the lithotripter and EPLBD groups were 73 years and 83 years, respectively (P = .006), while the sex ratio (male:female) in the groups was 18:13 and 55:67, respectively. The EPLBD group showed a statistically larger median bile duct diameter (13 mm [range: 8-24 mm] vs 11 mm [range: 5-16 mm]; P < .001), larger maximal calculus diameter (median, 13.5 mm [range: 8-25 mm] vs 11 mm [range: 7-16 mm]; P < .001), and shorter median cumulative treatment time after reaching the duodenal papilla (35.5 minutes [range: 10-176 minutes] vs 47 minutes [range: 22-321 minutes]; P = .026) in comparison to the lithotripter group. There was no significant difference in the rate of adverse events between the EPLBD and the mechanical lithotripter groups. The recurrence rate was significantly lower (P = .014) in the EPLBD group.EPLBD increases therapeutic efficacy and reduces treatment duration for patients in whom calculus removal is difficult, without increasing the frequency of adverse events. No serious adverse events were observed. Additionally, EPLBD appears to reduce the risk of long-term recurrence. Future studies are needed to evaluate long-term outcomes in younger patients.

Diagnostic value of IMP3 and p53 immunohistochemical staining in EUS-guided fine-needle aspiration for solid pancreatic tumors.

We previously identified insulin-like growth factor-II messenger ribonucleic acid-binding protein 3 (IMP3) as a valuable marker to distinguish malignant from benign lesions in pancreatic solid masses. The aim of this prospective study was to evaluate the usefulness of IMP3 and p53 immunohistochemical staining in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples for pancreatic solid masses. The study recruited 90 consecutive patients with pancreatic masses, including 62 pancreatic ductal adenocarcinomas (PDACs), 11 benign tumors, and 17 other tumors, who underwent EUS-FNA, and conducted IMP3 and p53 immunohistochemical staining. The main outcome measurement was improved diagnostic utility using IMP3 and p53 immunohistochemical staining. IMP3 and p53 expressions were detected in 60.8% and 49.4% of malignant lesions, 69.4% and 58.1% of PDACs, and 0% of benign lesions, respectively. In PDAC and benign tumors, the use of IMP3 and/or p53 immunostaining increased the sensitivity of cytohistological analysis from 88.7 to 93.5%, although the difference was not statistically significant. The sensitivity of histological analysis combined with that of IMP3 staining was 91.9%, which was significantly greater than that of histology alone (80.6%). The use of IMP3 and p53 immunohistochemical staining did not significantly improve the sensitivity of cytohistological analysis; however, IMP3 staining may be helpful for the histological analysis of malignant pancreatic tumors.

Current status of diagnosis and therapy for intraductal papillary neoplasm of the bile duct.

Bile duct epithelial tumours showing papillary neoplasm in the bile duct lumen are present in the intrahepatic and extrahepatic bile ducts. Clinicopathological images of these tumours are distinctive and diverse, including histological images with a low to high grade dysplasia, infiltrating and noninfiltrating characteristics, excessive mucus production, and similarity to intraductal papillary mucinous neoplasm (IPMN) of the pancreas. The World Health Organization Classification of Tumours of the Digestive System in 2010 named these features, intraductal papillary neoplasm of the bile duct (IPNB), as precancerous lesion of biliary carcinoma. IPNB is currently classified into type 1 that is similar to IPMN, and type 2 that is not similar to IPMN. Many of IPNB spreads superficially, and diagnosis with cholangioscopy is considered mandatory to identify accurate localization and progression. Prognosis of IPNB is said to be better than normal bile duct cancer.

Analysis of circulating cell-free DNA after endoscopic ultrasound-guided fine needle aspiration in pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Recently, increase in cell-free DNA (cfDNA) concentration or newly detected KRAS mutation after endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy were reported to be related to the occurrence of new distant metastasis. In this study, we investigated whether cfDNA concentration increased with the release of tumor components into the blood after EUS-FNA and whether its increase was related to prognosis. METHODS: Sixty-eight patients underwent EUS-FNA and were pathologically confirmed as having pancreatic ductal adenocarcinoma (PDAC). We measured plasma cfDNA concentration and the copy number of KRAS mutation in 68 patients and circulating tumor cells in 8 before and after EUS-FNA. RESULTS: The average cfDNA concentration after EUS-FNA (672.5 ± 919.6 ng/mL) was significantly higher than that before EUS-FNA (527.7 ± 827.3 ng/mL) (P < 0.001). KRAS mutation in plasma was detected in 8 patients (11.8%), however a significant increase in cfDNA concentration after EUS-FNA was not related to the change in KRAS-mutant copy number. Minimal increase in circulating tumor cells was observed in 3 of 8 patients. New distant metastasis was observed within 286 days to initial metastasis detection in 6 of 12 patients with ≥2-fold increase in cfDNA concentration and 26 of 56 patients with <2-fold increase within 185 days. In 32 patients who underwent surgery, ≥2-fold increase in cfDNA did not affect early recurrence. CONCLUSIONS: The increase in cfDNA concentration after EUS-FNA was not caused by tumor cell components released into blood vessels. Hence, the risk of seeding via the blood stream after EUS-FNA may need not be considered.

Percutaneous Two-Dimensional Shear Wave Elastography for Diagnosis of Pancreatic Tumor.

BACKGROUND: To investigate the efficacy of two-dimensional shear wave elastography (2D-SWE) for the diagnosis of pancreatic mass lesions. METHODS: This ethics committee-approved cross-sectional study included 52 patients with histologically-proven pancreatic tumors (pancreatic ductal adenocarcinoma (PDAC), 36; tumor-forming pancreatitis (TFP), 15; neuroendocrine tumor, 1) and 33 control subjects. The 2D-SWE was performed for the tumor/non-tumor tissues, and SWE-mapping patterns and propagation quality were assessed. RESULTS: Three mapping patterns were detected based on the size and distribution of the coloring areas. Pattern A (whole coloring) was detected in all non-tumor tissues and TFP, whereas pattern C (multiple small coloring spots) was detected in PDAC only. Pattern B (partial coloring with smaller spots) was detected in other lesions. The specificity and positive predictive value of pattern A for non-PDAC and those of pattern C for PDAC were 100%. The SWE value was higher in tumor lesions than in the non-tumor tissues (38.1 vs. 9.8 kPa; p < 0.001) in patients with PDAC. The SWE value in the non-tumor lesion was higher in patients with PDAC than in control (9.8 vs. 7.5 kPa; p < 0.001). CONCLUSIONS: 2D-SWE may play a role as a novel diagnostic tool for PDAC to detect a specific mapping pattern with quantitative assessment.

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.

FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

BACKGROUND: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden. AIMS: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs. METHODS: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC. RESULTS: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC. CONCLUSIONS: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.

Diverse transitions in diabetes status during the clinical course of patients with resectable pancreatic cancer.

OBJECTIVE: Pancreatic cancer and diabetes status have complex bilateral interactions; therefore, understanding their clinical features is essential for the clinical management of pancreatic cancer patients. We aimed to evaluate the diabetes status before diagnosis, after resection and until the time of recurrence in patients with resectable pancreatic cancer and to clarify the correlations among the clinical course of pancreatic cancer, operative procedure and diabetes status. METHODS: Between 2011 and 2016, we retrospectively identified 189 pancreatic cancer patients who underwent pancreatoduodenectomy or distal pancreatectomy at our institution. The entire clinical course of each patient was retrieved from the medical records, and the diabetes status in the longest possible duration was assessed. RESULTS: Among 115 pancreatic cancer patients who had normal glucose tolerance at the time of resection, 22 (19.1%) developed type 2 diabetes after resection. In a multivariate analysis, distal pancreatectomy was strongly associated with the development of postoperative diabetes. On the other hand, 74 pancreatic cancer patients had already been diagnosed with type 2 diabetes at the time of resection. During the follow-up period, 15 patients were noted to have diabetes resolution after resection; interestingly, the majority of these patients had newly diagnosed diabetes, which was defined as the diagnosis of diabetes within 3 months before resection. Moreover, newly diagnosed diabetes was an independent factor for diabetes resolution after resection. CONCLUSIONS: In pancreatic cancer patients who underwent pancreatectomy, distal pancreatectomy was correlated with postoperative diabetes, and newly diagnosed diabetes had a high probability of resolution after resection.

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.

Endoscopic Ultrasound Criteria for Arterial Invasion in Pancreatic Cancer of the Body and Tail.

OBJECTIVES: We aimed to determine the difference in endoscopic ultrasonography (EUS) images between portal vein (PV) and arterial invasion of pancreatic cancer and to develop criteria for arterial involvement. METHODS: We reviewed EUS data of consecutive patients who underwent distal pancreatectomy from December 2010 to May 2017. We categorized the tumor-vessel relationship into 4 and 5 types, respectively, for the PV and arteries: (a) clear separation between tumor and vessel; (b) tumor border at vessel, echo-rich vessel wall uninterrupted; (c) echo-rich vessel wall interrupted; (d) vessel contour irregularity; and (e) arterial wall thickening or echogenic band surrounding the artery. We compared EUS outcomes with surgical and pathological results. RESULTS: Overall, 56 patients underwent distal pancreatectomy, of whom 22 received en bloc celiac axis resection. The pathological invasion rates of PVs and arteries were 46.2% and 0% in (c), and 72.5% and 42.4% in (d) (P = 0.046, P = 0.016), respectively. The overall sensitivity and specificity were 92.1% and 83.2%, respectively, for diagnosing venous invasion and 70.0% and 84.4%, respectively, for arterial invasion. CONCLUSIONS: Different EUS criteria may be necessary for diagnosing arterial and portal venous invasions. Criterion (d) might be appropriate for diagnosing arterial invasion.

Sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a multicenter retrospective study in Japan.

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.