Fusion Imaging Objectively Demonstrates Improved Pancreas Visualization through Manipulation Techniques: A Prospective Interventional Study.

Objective Abdominal ultrasonography (AUS) is used to screen for abdominal diseases owing to its low cost, safety, and accessibility. However, the detection rate of pancreatic disease using AUS is unsatisfactory. We evaluated the visualization area of the pancreas and the efficacy of manipulation techniques for AUS with fusion imaging. Methods Magnetic resonance imaging (MRI) volume data were obtained from 20 healthy volunteers in supine and right lateral positions. The MRI volume data were transferred to an ultrasound machine equipped with a fusion imaging software program. We evaluated the visualization area of the pancreas before and after postural changes using AUS with fusion imaging and assessed the liquid-filled stomach method using 500 ml of de-aerated water in 10 randomly selected volunteers. Patients This study included 20 healthy volunteers (19 men and 1 woman) with a mean age of 33.0 (21-37.5) years old. Results Fusion imaging revealed that the visualization area of the entire pancreas using AUS was 55%, which significantly improved to 75% with a postural change and 90% when using the liquid-filled stomach method (p=0.043). Gastrointestinal gas is the main obstacle for visualization of the pancreas. Conclusion Fusion imaging objectively demonstrated that manipulation techniques can improve pancreatic visualization.

A Novel Monochromatic Light to Detect Target Specimens Within Endoscopic Ultrasonography-guided Fine-needle Aspiration Biopsy Samples.

BACKGROUND/AIM: Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNB) enhances the diagnostic capabilities of EUS by providing additional pathological samples. However, detecting the target specimens within the collected samples can be challenging. The aim of this study was to determine the optimal wavelength of light for detection of target specimens within EUS-FNB samples in an animal experiment. MATERIALS AND METHODS: EUS-FNB pancreatic tissue samples were collected from a male beagle (weight, 10 kg), and the samples were illuminated with monochromatic light ranging from 430 to 700 nm in 5-nm intervals. The intensities of the target specimen and blood samples were analyzed using the densitometry of the images obtained through irradiation. RESULTS: We found that transmitted monochromatic light of 605 nm most vividly enhanced the contrast between the target specimens and blood in the samples in the impression of appearance. CONCLUSION: Thus, microscopical observations under transmitted light of 605 nm are optimal for target tissue identification within EUS-FNB samples.

The fecal carriage rate of extended-spectrum ß-lactamase-producing or carbapenem-resistant Enterobacterales among Japanese infants in the community at the 4-month health examination in a rural city.

Background: Extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) is a great public health concern globally not only in hospitals but also in the community. To our knowledge, there have been few studies on the prevalence of ESBL-E and much less about carbapenem-resistant Enterobacterales (CRE) among children in the community, and there is no such study in Japan despite such situations. This study aimed to clarify their carriage status among Japanese infants in the community by taking the opportunity of the 4-month health checkup. Methods: This prospective analysis was conducted from April 2020 to March 2021 in Shimabara City, Nagasaki Prefecture, Japan. The research-related items were mailed to all subjects with official documents for the checkup. The fecal samples were obtained from the diaper by guardians beforehand and were collected with the questionnaire and then screened for ESBL-E and CRE by a clinical laboratory company with selective agars followed by identification and confirmation. Only the positive samples were analyzed about resistant genotypes. Results: One hundred fifty infants aged 4-5 months, over half of the subjects, participated in this study. The overall ESBL-E carriage rate was 19.3% (n = 29), and no CRE carrier was detected among them. All identified ESBL-E were E. coli except for one K. pneumoniae. A significantly higher carriage rate was recorded among the infants born at "Hospital A" (25.0%) than the others (11.3%). Enterobacterales producing CTX-M-9 ± TEM were broadly distributed among the positive samples (65.5%), whereas the CTX-M-1 group was exclusively detected among those from "Hospital A". Recursive partitioning analysis suggested that delivery facilities might be an important factor for ESBL-E colonization, although the effect could be decreased as they grow. In contrast, no significant effect was observed for other factors such as parent(s) as healthcare worker(s), having a sibling(s), and the mode of delivery. Conclusion: This study revealed the ESBL-E and CRE carriage status of Japanese infants in the community for the first time, although the setting is somewhat limited. Our findings indicated that environmental factors, especially delivery facilities, influenced ESBL-E colonization among infants aged 4-5 months, implying the need for strengthening countermeasures against antimicrobial resistance at delivery facilities and communities outside the hospitals.

Comparison between Target Sample Check Illuminator and White Light Observation in Discriminating the Presence of Target Specimen for Endoscopic Ultrasound-Guided Fine Needle Aspiration Sample.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is an essential endoscopic tissue sampling method for diagnosing pancreatobiliary diseases; however, determining the presence of target specimens mixed in the blood by conventional observation is challenging due to the small size of the obtained sample. This study investigated the usefulness of a target sample check illuminator (TSCI) that emits a specific wavelength of light to determine the presence of target specimens. Twenty-seven patients who underwent EUS-FNA at our hospital were included. Conventional white light observation was performed for the collected samples, followed by TSCI; six people evaluated the presence of the target specimen on a 5-point scale. The target specimen discrimination score using TSCI (median: 5) was significantly higher than that using conventional white light observation (median: 1) (p < 0.001). No significant difference was observed in the discrimination score between the evaluator (novice vs. expert, p = 0.162) and puncture needle (22G vs. 25G, p = 0.196). The discriminability of TSCI in the samples obtained using EUS-FNA was significantly higher than that of conventional observation. TSCI does not depend on the evaluator or puncture needle for the identification of the target specimen; hence, it can provide a good pathological specimen and may contribute to the improvement of the diagnostic ability.

Review on acute pancreatitis attributed to COVID-19 infection.

The coronavirus disease 2019 (COVID-19) is known to cause gastrointestinal symptoms. Recent studies have revealed COVID-19-attributed acute pancreatitis (AP). However, clinical characteristics of COVID-19-attributed AP remain unclear. We performed a narrative review to elucidate relation between COVID-19 and AP using the PubMed database. Some basic and pathological reports revealed expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, key proteins that aid in the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the pancreas. The experimental and pathological evaluation suggested that SARS-CoV-2 infects human endocrine and exocrine pancreas cells, and thus, SARS-CoV-2 may have a direct involvement in pancreatic disorders. Additionally, systemic inflammation, especially in children, may cause AP. Levels of immune mediators associated with AP, including interleukin (IL)-1ß, IL-10, interferon-γ, monocyte chemotactic protein 1, and tumor necrosis factor-α are higher in the plasma of patients with COVID-19, that suggests an indirect involvement of the pancreas. In real-world settings, some clinical features of AP complicate COVID-19, such as a high complication rate of pancreatic necrosis, severe AP, and high mortality. However, clinical features of COVID-19-attributed AP remain uncertain due to insufficient research on etiologies of AP. Therefore, high-quality clinical studies and case reports that specify methods for differential diagnoses of other etiologies of AP are needed.

Peroral Cholangioscopy-Guided Forceps Mapping Biopsy for Evaluation of the Lateral Extension of Biliary Tract Cancer.

BACKGROUND: Peroral cholangioscopy (POCS)-guided forceps mapping biopsy (FMB) is a method for the accurate preoperative identification of the extent of the disease of biliary tract cancer (BTC). However, the diagnostic value of POCS-FMB is still uncertain. OBJECTIVES: We evaluated the diagnostic utility of POCS-FMB for the identification of lateral extension-superficial intraductal spread longitudinally and continuously from the main lesion-of BTC. METHODS: In the retrospective study, patients who received POCS-FMB and surgery for curative resection of BTC between September 2016 and August 2019 at our medical institution were enrolled. The diagnostic accuracy of POCS-FMB for the identification of lateral extension of BTC was evaluated. Furthermore, we also evaluated the factors affecting the diagnostic accuracy of POCS-FMB. RESULTS: A total of 23 patients with BTC were enrolled, and 24 procedures of POCS-FMB from 96 sites of biliary tracts were performed. The sensitivity, specificity, and accuracy of POCS-FMB were 53.8%, 63.9%, and 63.1%, respectively. In the multivariate logistic regression analyses, the biopsy from the bifurcation of biliary tracts was a significant factor affecting the diagnostic accuracy of POCS-FMB (odds ratio 3.538, 95%; confidence interval 1.151-10.875, p = 0.027). CONCLUSIONS: The diagnostic accuracy of POCS-FMB for the identification of lateral extension of BTC was insufficient. The biopsy from the bifurcation of biliary tracts was a positive factor affecting the diagnostic accuracy of POCS-FMB.

Peroral cholangioscopy-guided forceps biopsy versus fluoroscopy-guided forceps biopsy for extrahepatic biliary lesions.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP)-related tissue acquisition, including fluoroscopy-guided forceps biopsy (F-FB), is a common technique in diagnosing indeterminate biliary lesions. Recently, peroral cholangioscopy (POCS) and POCS-guided forceps biopsy (POCS-FB) has also been used for the diagnosis of indeterminate biliary lesions. However, it is uncertain which of those techniques were superior for the diagnosis of extrahepatic cholangiocarcinoma (ECC). We aimed to evaluate the diagnostic yield and safety of F-FB for indeterminate biliary lesions compared with POCS-FB. METHODS: Patients who underwent F-FB or POCS-FB to evaluate indeterminate biliary lesions between October 2011 and August 2019 were enrolled retrospectively. We carried out propensity score matching to balance these clinical differences between the F-FB group and POCS-FB group. In the propensity score-matched cohort, we compared the diagnostic performance of F-FB with that of POCS-FB based on the pathological evaluation. We also evaluate adverse events associated with F-FB and POCS-FB. RESULTS: We enrolled 113 patients with biliary diseases, and 62 patients were analyzed in the propensity score-matched cohort. Sensitivity, specificity, and accuracy of F-FB were 82.4, 100, and 90.3%, and for POCS-FB, those values were 83.3, 100, and 90.3%, respectively. There were no significant differences in the diagnostic performance between F-FB and POCS-FB. There were also no significant differences in the occurrence of adverse events between F-FB and POCS-FB (41.9 vs 29.0%, P = 0.289). CONCLUSIONS: The diagnostic yield of F-FB for ECC is similar to that of POCS-FB. POCS-FB is not necessary for the initial pathological diagnosis of indeterminate biliary lesions.

Adequate tissue acquisition rate of peroral cholangioscopy-guided forceps biopsy.

BACKGROUND: Peroral cholangioscopy (POCS)-guided forceps biopsy is a method for diagnosing indeterminate biliary strictures and for the preoperative identification of the exact perihilar and distal margins of biliary tract cancer (BTC). However, POCS-guided forceps biopsy may result in an insufficient amount of specimen at times. Therefore, we evaluated the adequate tissue acquisition rate and the factors affecting the adequate tissue acquisition of POCS-guided forceps biopsy for the biliary tract. METHODS: Patients who underwent POCS-guided forceps biopsy for biliary disease between September 2016 and October 2018 at our hospital were enrolled retrospectively. We evaluated the adequate tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion and that for non-stenotic bile duct. In addition, the factors affecting the adequate tissue acquisition rate of POCS-guided forceps biopsy were evaluated. RESULTS: We enrolled 47 patients with biliary disease and performed POCS-guided forceps biopsy for biliary lesion and POCS-guided forceps mapping biopsy for non-stenotic bile duct in 40 and 36 patients, respectively. The adequate tissue acquisition rates of POCS-guided forceps biopsy for biliary lesions and that for non-stenotic bile duct were 86.4%, and 68.9%, respectively. In the multivariate logistic regression analyses, age, and previous biliary stenting before POCS were factors affecting the adequate tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion. For non-stenotic bile duct, the location of the biliary lesion, endoscopic sphincterotomy (EST), and procedure time of POCS were factors affecting the adequate tissue acquisition rate of POCS-guided forceps mapping biopsy. CONCLUSIONS: Previous biliary stenting was a factor affecting a low tissue acquisition rate of POCS-guided forceps biopsy for the biliary lesion. In the POCS-guided forceps mapping biopsy, the location of the biliary lesion, EST, and procedure time were factors affecting tissue acquisition rates.

Programmed cell death-1 inhibitor-related sclerosing cholangitis: A systematic review.

BACKGROUND: Programmed cell death-1 (PD-1) inhibitor has been indicated for many types of malignancies. However, these inhibitors also cause immune-related adverse events. Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%-4.5% of patients treated with PD-1 inhibitors. Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis (SC); however, the associated clinical and pathological features are unclear. AIM: To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature. METHODS: The review, conducted using electronic databases in PubMed, was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English. We scanned the references of the selected literature to identify any further relevant studies. Six cases previously studied by us, including three that have not yet been published, were included in this review. RESULTS: Thirty-one PD-1 inhibitor-related SC cases were evaluated. Median age of patients was 67 years (range, 43-89), with a male to female ratio of 21:10. The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer. Agents that caused PD-1 inhibitor-related SC were nivolumab (19 cases), pembrolizumab (10 cases), avelumab (1 case), and durvalumab (1 case). The median number of cycles until PD-1 inhibitor-related SC onset was 5.5 (range, 1-27). Abdominal pain or discomfort (35.5%, 11/31) was the most frequent symptom. Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, and a normal level of serum immunoglobulin G4. Biliary dilation without obstruction (76.9%, 20/26), diffuse hypertrophy of the extrahepatic biliary tract (90.5%, 19/21), and multiple strictures of the intrahepatic biliary tract (30.4%, 7/23) were noted. In 11/23 (47.8%) cases, pathological examination indicated that CD8+ T cells were the dominant inflammatory cells in the bile duct or peribiliary tract. Although corticosteroids were mainly used for PD inhibitor-related SC treatment, the response rate was 11.5% (3/26). CONCLUSION: Some clinical and pathological features of PD-1 inhibitor-related SC were revealed. To establish diagnostic criteria for PD-1 inhibitor-related SC, more cases need to be evaluated.

Endoscopic ultrasound-guided fine-needle aspiration biopsy - Recent topics and technical tips.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is a useful procedure that enables reliable pathological diagnoses of pancreatobiliary diseases, subepithelial lesions, and swollen lymph nodes. In recent years, a pathological diagnosis based on EUS-FNA has made it possible to provide accurate treatment methods not only in these fields, but also in respiratory organs and otorhinolaryngology. This review discusses the latest topics pertaining to EUS-FNA as well as procedural tips.

Peroral Cholangioscopy-Guided Forceps Biopsy and Endoscopic Scraper for the Diagnosis of Indeterminate Extrahepatic Biliary Stricture.

BACKGROUND: Peroral cholangioscopy (POCS) has become a widely-used technique in diagnosing indeterminate biliary strictures, enabling optical viewing of the biliary system and targeted biopsies under direct vision. The diagnostic utility of the new endoscopic scraper, Trefle®, for extrahepatic cholangiocarcinoma (ECC) has also been reported. However, the diagnostic utility of POCS-guided and Trefle®-assisted tissue acquisition for ECC has never been compared empirically. We evaluated the efficacy and safety of Trefle®-assisted tissue acquisition for diagnosing ECC compared with POCS-guided tissue sampling. METHODS: Patients who underwent Trefle®-assisted tissue acquisition or POCS-guided forceps biopsy to differentiate ECC from benign biliary disease between April 2014 and March 2018 were enrolled retrospectively. We evaluated the diagnostic performance of Trefle®-assisted tissue acquisition and POCS-guided forceps biopsy based on pathological evaluation. We also compared adverse events associated with Trefle®-assisted tissue acquisition with those of POCS-guided forceps biopsy. RESULTS: We enrolled 34 patients with biliary disease and performed Trefle®-assisted tissue acquisition and POCS-guided forceps biopsy in 14 and 20 patients, respectively. Sensitivity, specificity, and accuracy of Trefle®-assisted tissue acquisition were 87.5%, 83.3%, and 85.7%, respectively, and for POCS-guided forceps biopsy, these were 90.0% each. Statistical values of Trefle®-assisted tissue acquisition and POCS-guided tissue acquisition were not significantly different. There were no significant differences in the occurrence of adverse events between the Trefle®-assisted tissue acquisition and the POCS-guided forceps biopsy (35.7% vs. 25.0%, p = 0.770). Compared with patients who underwent POCS procedure, endoscopic sphincterotomy was performed for fewer patients who underwent Trefle®-assisted tissue acquisition (p < 0.001). CONCLUSIONS: The diagnostic ability of Trefle®-assisted tissue acquisition for ECC is similar to that of POCS-guided tissue acquisition. Trefle®-assisted tissue acquisition might also help to preserve the sphincter of Oddi and its digestive function.

Randomized Controlled Trial Comparing the Usefulness of Endoscopic Ultrasound Processor.

BACKGROUND: Although endoscopic ultrasonography (EUS) is a useful tool for diagnosing pancreatobiliary diseases, not many facilities perform this technique as it is difficult to master. Currently, two new EUS systems exist: EU-ME2/GF-UCT260, manufactured by Olympus, and SU-1/EG-580UT, manufactured by Fujifilm. Some reports have compared new EUS models to older versions, but the operability and image quality of these two latest systems have not been compared. Our study aimed to compare the usefulness of these two types of EUS. METHODS: Forty consecutive patients were recruited and randomized in a two-arm clinical trial; Arm 1: EU-ME2/GF-UCT260 was used only for observation and SU-1/EG-580UT for EUS-fine needle aspiration (FNA); Arm 2: SU-1/EG-580UT was used only for observation and EU-ME2/GF-UCT260 for EUS-FNA. Using a crossover design, we evaluated image findings, ease of scope insertion, and visibility of the gastrointestinal (GI) tract. Each procedure was scored using a 5-point scale (Clinical Trial ID: UMIN000031373). RESULTS: SU-1/EG-580UT was significantly better in terms of lesion-delineating capacity: lesion border (P < 0.001), internal echo (P < 0.001). Significantly easier scope insertion was observed with SU-1/EG-580UT with respect to any insertion into the piriform recess (P = 0.018), the pylorus ring (P < 0.001), and the superior duodenal angle (P < 0.001). Visibility during gastrointestinal observation was also significantly better with the SU-1/EG-580UT (P < 0.001) than with the EU-ME2/GF-UCT260. CONCLUSION: SU-1/EG-580UT EUS demonstrated superior performance during ultrasonic endoscopic GI observation, operability, and ultrasonic image quality. The result of the superior ultrasound imaging quality of SU-1/EG-580UT EUS will aid in the identification of small pancreatic malignancies with unclear borders and prove useful in evaluating mural nodules of IPMN in detail. These findings could result in an increased use of EUS and improve identification and prognosis of patients with pancreatobiliary diseases.

Endoscopic Ultrasonography-Guided Fine Needle Aspiration for Extrahepatic Cholangiocarcinoma: A Safe Tissue Sampling Modality.

Few studies have compared the diagnostic utility of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) and endoscopic retrograde cholangiopancreatography (ERCP) tissue sampling for extrahepatic cholangiocarcinoma (ECC). We evaluated the efficacy and safety of EUS-FNA for diagnosing ECC compared with ERCP tissue sampling. Patients who underwent EUS-FNA or ERCP tissue sampling to differentiate ECC from benign biliary disease were enrolled retrospectively between October 2011 and March 2017. We evaluated diagnostic performances of EUS-FNA and ERCP tissue sampling based on pathological evaluation. We compared adverse events in EUS-FNA and ERCP tissue sampling. We enrolled 73 patients with biliary disease and performed EUS-FNA and ERCP in 19 and 54 patients, respectively. Sensitivity, specificity, and accuracy of ERCP tissue sampling were 76.0%, 100%, and 88.9%, respectively, and for EUS-FNA these were 81.8%, 87.5%, and 84.2%, respectively. Statistical values of ERCP tissue sampling and EUS-FNA were not significantly different. The adverse event frequency of EUS-FNA was significantly lower than that of ERCP tissue sampling (0% vs. 25.9%, p = 0.033). The diagnostic ability of EUS-FNA for ECC is similar to that of ERCP tissue sampling. EUS-FNA is a safer tissue sampling modality than ERCP for evaluating biliary disease.

Efficacy and safety of pancreatic juice cytology by using synthetic secretin in the diagnosis of pancreatic ductal adenocarcinoma.

BACKGROUND AND AIM: Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect in its early stages with the poorest prognosis of all cancers. To improve the prognosis, a precise diagnosis is needed when we suspect PDAC. Although endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA) is a widely accepted modality for the diagnosis of PDAC, its sensitivity is 85-89%, and approximately 10% of PDAC cases cannot be diagnosed. The main causes that interrupt the diagnosis of PDAC by using EUS-FNA are tumor size, presence of a vessel or the main pancreatic duct along the puncture route, and difficulty in withdrawing anticoagulant. Pancreatic juice cytology (PJC), the sensitivity of which is 33.3-65.8%, is a method for the diagnosis of PDAC cases in which carrying out of EUS-FNA is difficult. To diagnose PDAC appropriately, we need to improve the diagnostic ability of PJC. METHODS: We examined PJC using synthetic secretin for 138 cases of pancreatic tumor and pancreatic non-cancerous diseases. RESULTS: Sensitivity of PJC improved from 50.9% to 74.0% as a result of synthetic secretin loading, and 13 PDAC cases that had not been able to be diagnosed with EUS-FNA could be diagnosed pathologically by PJC. Although there were 12 patients with mild pancreatitis (8.7%) as a complication, all were relieved with conservative treatment. CONCLUSION: Adding synthetic secretin to PJC is useful for cases in which it is difficult to carry out EUS-FNA for PDAC.

Diagnostic usefulness of KL-6 concentration of bile in biliary tract cancer.

The sensitivity of bile cytology for biliary tract cancer varies from 6-64%, and hence remains unsatisfactory. Sialylated carbohydrate antigen KL-6 mucin is positive in biliary tract cancer tissues and serum KL-6 levels are significantly increased in intrahepatic ductal adenocarcinoma patients compared with healthy individuals. The aim of the present study was to evaluate the usefulness of the KL-6 concentration of bile for the diagnosis of biliary tract cancer. Bile cytology and measurements of bile KL-6 concentration were conducted for 43 patients (25 biliary tract cancers and 18 benign biliary disease). The concentration of KL-6 in the bile of the biliary tract cancer group was compared with the benign biliary disease group. The diagnostic ability was assessed by using receiver operating characteristic curves (ROC). The mean KL-6 concentration of bile for biliary tract cancer (34.6±51.6 U/ml) was increased compared with benign biliary disease (5.2±3.9 U/ml, P<0.001). The area under the ROC for diagnosis of biliary tract cancer was 0.84 for benign biliary disease. When the cut-off level of the KL-6 concentration of bile was 8.6 U/ml, the sensitivity, specificity, and accuracy of the KL-6 concentration of bile alone for the diagnosis of biliary tract cancer were 72, 89, and 79%, respectively. Adding the bile KL-6 concentration to bile cytology measurements, the sensitivity for the diagnosis of biliary tract cancer was increased significantly (100%, P=0.0184). The KL-6 concentration of bile may strengthen the sensitivity of bile cytology for biliary tract cancer.

Protein expression of Fragile Histidine Triad and cyclooxgenase-2 in serrated neoplasia of the colorectum.

The adenoma-carcinoma sequence (ACS) and the serrated pathway are two distinct developmental routes leading to the formation of colorectal carcinoma (CRC). However, the mechanism triggered by the serrated pathway remains unclear. Therefore, to clarify the molecular and clinicopathological characteristics of the serrated tumorigenic pathway, immunohistochemistry was used to examine the expression of Fragile Histidine Triad (FHIT), cyclooxygenase-2 (COX-2), MutL homolog 1 (MLH1), MutS protein homolog 2 (MSH2) and P53 in endoscopically resected samples of 62 serrated polyps. These samples included 20 hyperplastic polyps (HPs), 16 traditional serrated adenomas (TSAs), 26 sessile serrated adenoma/polyps (SSA/Ps), 20 non-serrated adenomas, 20 carcinoma in adenomas (CIAs) and 18 early pure CRCs without any adenoma component (EPCs). FHIT expression was markedly reduced or absent in 50% of TSA samples, 92.3% of SSA/Ps and 44% of EPCs, but only rarely in HPs, non-serrated adenomas and CIAs. COX-2 expression was more common in non-serrated adenomas compared with in serrated polyps, and was present in 25 and 3.2% of the cases respectively (P<0.01). Furthermore, COX-2 expression was more frequent in CIAs (60%) compared with in EPCs (22.2%; P<0.05). The incidence of negative COX-2 expression was higher in FHIT-negative SSA/Ps compared with in FHIT-positive SSA/Ps (P=0.08). A total of 16.7% of EPC samples and 11.5% of SSA/Ps demonstrated a loss of MLH1/MSH2 expression, but none of the other tumor types did. P53 overexpression was significantly increased in EPC (77.8%) and CIA (60%) samples compared with in HP (0%), TSA (6.6%), SSA/P (0%) and non-serrated adenoma (10%) samples (P<0.01). These findings demonstrated that there are different expression patterns between the serrated pathway and ACS, indicating that aberrant FHIT and inhibited COX-2 expression may be associated with serrated tumorigenesis. In addition, this data indicated that EPC may contain tumors derived from the serrated pathway as well as ACS.

Frequent aberrant p53 and Fhit expression in endoscopically resected superficial hypopharyngeal cancer and esophageal cancer.

In the last decade, the incidence rate of detection rate of superficial head, neck and esophageal squamous cell carcinomas has increased with the development of endoscopic imaging techniques. These cancers are thought to arise independently subsequent to tissue exposure to a common carcinogen e.g. alcohol or tobacco. This phenomenon has been termed field cancerization. To determine the molecular background of the development of hypopharyngeal squamous cell carcinomas (HPSCCs) and double esophageal squamous cell carcinomas (DESCCs), the present study immunohistochemically assessed tumor-related protein expression [p53, Fhit (fragile histidine triad), E-cadherin and activation-induced cytidine deaminase (AID)], and subsequently determined the correlation between protein expression and clinicopathological data. Tumor specimens of 9 HPSCCs and 9 DESCCs were endoscopically obtained from 8 patients with HPSCC. The 9 DESCCs, including 5 synchronous and 4 metachronous lesions, were all obtained from four patients with HPSCC. The overexpression of p53 and loss of Fhit expression was immunohistochemically detected in 8 (88.9%) and 8 (88.9%) of the 9 HPSCCs and in 8 (88.9%) and 8 (88.9%) of the 9 DESCCs, respectively, which demonstrated the high frequency of such expression. Additionally, 7 out of 9 HPSCCs, and 7 out of 9 DESCCs demonstrated aberrant expression of p53 and Fhit. The rate of aberrant AID and E-cadherin expression was 67 and 44% in HPSCCs and 44 and 44% in DESCC, respectively. These results suggested that aberrant p53 and Fhit expression was involved in the development of HPSCC and their DESCC, and that their expression may be used for the prediction of DESCC development in patients with HPSCC, thereby acting as a biomarker of field cancerization.

Expression of methylation-modulated tumor-related genes in endoscopically resected early esophageal squamous neoplasia.

Smoking and alcohol consumption are major risk factors for the development of esophageal squamous cell carcinoma (ESCC). Recent studies have demonstrated that smoking and alcohol consumption may be associated with altered DNA methylation in human cancer development. The aim of the present study was to evaluate methylation-modulated protein expression of tumor-related genes (TRGs) in the early stages of esophageal squamous neoplasia (ESN). ESN tissue samples (n=141) comprising 19 cases of low-grade intraepithelial neoplasia (LGIN), 70 of high-grade intraepithelial neoplasia/carcinoma in situ (HGIN/CIS) and 52 of invasive cancer, were endoscopically resected. The methylation-modulated protein expression of 5 TRGs [fragile histidine triad (FHIT), E-cadherin, MutL homolog 1 (MLH1) /MutS homolog 2 (MSH2) and cyclooxygenase-2 (COX-2)] as well as p53 was examined with immunohistochemistry, and their expression was compared with patient clinicopathological characteristics. Reduced or loss of FHIT, E-cadherin, MLH1/MSH2 and COX-2 expression was detected in 26.3 (5/19), 5.3 (1/19), 0 (0/19) and 63.2% (12/19) of LGIN cases, 61.4 (43/70), 18.6 (13/70), 7.1 (5/70) and 65.7% (46/70) of HGIN/CIS cases, and 78.8 (41/52), 50.0 (26/52), 11.5 (6/52) and 59.6% (31/52) of invasive cancer cases, respectively. Reduced or absent expression of FHIT and E-cadherin was significantly associated with neoplastic progression (FHIT, P=0.0007; E-cadherin, P=0.00014). The mean number of TRGs (FHIT, E-cadherin, MLH1/MSH2, and COX-2) that exhibited reduced or absent expression in LGIN, HGIN/CIS and invasive cancer specimens was 1.12±0.61, 1.66±0.93 and 2.09±0.96, respectively, demonstrating a significant stepwise increment from LGIN to HGIN/CIS and then to invasive cancer (P<0.05). p53 overexpression was frequently detected in ESN with head and neck carcinomas. However p53 overexpression was not significantly associated with ESN progression. An increase in the number of the 5 TRG proteins with reduced or loss of expression in the early stages of esophageal tumorigenesis was demonstrated, and their decreased expression was observed to be associated with tumor progression. Therefore, smoking and alcohol drinking may be associated with not only carcinogenesis but also the progression of ESN.

Endoscopic treatment for distal malignant biliary obstruction.

Distal malignant biliary obstruction (MBO) leads to obstructive jaundice as a result of when the bile excretion from the liver is disturbed and induces hepatic failure and sepsis, which when complicated with cholangitis, it becomes necessary to perform drainage for the MBO. For biliary drainage, we can perform a surgical bypass operation, percutaneous transhepatic biliary drainage (PTBD), endoscopic biliary drainage (EBD) via duodenal papilla, or endoscopic ultrasound (EUS)-guided biliary drainage (EUS-BD), which is a transgastrointestinal biliary drainage. Although currently we usually perform EBD for distal MBO to begin with, the choice is different for biliary drainage in patients in whom EBD has failed in a preoperative case or an unresectable case. In other words, we choose PTBD for preoperative cases, and PTBD or EUS-BD according to the ability of the institution for their procedures when EBD has failed. It is desirable not to choose a plastic stent (PS) but a self-expandable metallic stent (SEMS), in particular for the unresectable cases of pancreatic cancer it is desirable not to choose an uncovered SEMS but a covered SEMS in EBD. Nevertheless, further examinations are expected to decide which, a covered or uncovered SEMS, we should choose in unresectable biliary tract cancer (BTC) and whether we should select PS, SEMS or ENBD in preoperative cases.