Clinical utility of endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling of pancreatic cancer

Background/Aims@#Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is essential for the diagnosis of pancreatic cancer. The feasibility of comprehensive genomic profiling (CGP) using samples obtained by EUS-TA has been under recent discussion. This study aimed to evaluate the utility of EUS-TA for CGP in a clinical setting. @*Methods@#CGP was attempted in 178 samples obtained from 151 consecutive patients with pancreatic cancer at the Aichi Cancer Center between October 2019 and September 2021. We evaluated the adequacy of the samples for CGP and determined the factors associated with the adequacy of the samples obtained by EUS-TA retrospectively. @*Results@#The overall adequacy for CGP was 65.2% (116/178), which was significantly different among the four sampling methods (EUS-TA vs. surgical specimen vs. percutaneous biopsy vs. duodenal biopsy, 56.0% [61/109] vs. 80.4% [41/51] vs. 76.5% [13/17] vs. 100.0% [1/1], respectively; p=0.022). In a univariate analysis, needle gauge/type was associated with adequacy (22 G fine-needle aspiration vs. 22 G fine-needle biopsy [FNB] vs. 19 G-FNB, 33.3% (5/15) vs. 53.5% (23/43) vs. 72.5% (29/40); p=0.022). The sample adequacy of 19 G-FNB for CGP was 72.5% (29/40), and there was no significant difference between 19 G-FNB and surgical specimens (p=0.375). @*Conclusions@#To obtain adequate samples for CGP with EUS-TA, 19 G-FNB was shown to be the best in clinical practice. However, 19 G-FNB was not still sufficient, so further efforts are required to improve adequacy for CGP.

Safety and feasibility of opening window fistulotomy as a new precutting technique for primary biliary access in endoscopic retrograde cholangiopancreatography

Background/Aims@#Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is the most common and serious complication of endoscopic retrograde cholangiopancreatography. To prevent this event, a unique precutting method, termed opening window fistulotomy, was performed in patients with a large infundibulum as the primary procedure for biliary cannulation, whereby a suprapapillary laid-down H-shaped incision was made without touching the orifice. This study aimed to assess the safety and feasibility of this novel technique. @*Methods@#One hundred and ten patients were prospectively enrolled in this study. Patients with a papillary roof size ≥10 mm underwent opening window fistulotomy for primary biliary access. In addition, the incidence of complications and success rate of biliary cannulation were evaluated. @*Results@#The median size of the papillary roof was 6 mm (range, 3–20 mm). Opening window fistulotomy was performed in 30 patients (27.3%), none of whom displayed PEP. Duodenal perforation was recorded in one patient (3.3%), which was resolved by conservative treatment. The cannulation rate was high (96.7%, 29/30 patients). The median duration of biliary access was 8 minutes (range, 3–15 minutes). @*Conclusions@#Opening window fistulotomy demonstrated its feasibility for primary biliary access by achieving great safety with no PEP complications and a high success rate for biliary cannulation.

Endoscopic ultrasound-guided portal vein coiling: troubleshooting interventional endoscopic ultrasonography

Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (HGS) is widely performed not only as an alternative to transpapillary biliary drainage, but also as primary drainage for malignant biliary obstruction. For anatomical reasons, this technique carries an unavoidable risk of mispuncturing intrahepatic vessels. We report a technique for troubleshooting EUS-guided portal vein coiling to prevent bleeding from the intrahepatic portal vein after mispuncture during interventional EUS. EUS-HGS was planned for a 59-year-old male patient with unresectable pancreatic cancer. The dilated bile duct (lumen diameter, 2.8 mm) was punctured with a 19-gauge needle, and a guidewire was inserted. After bougie dilation, the guidewire was found to be inside the intrahepatic portal vein. Embolizing coils were placed to prevent bleeding. Embolization coils were successfully inserted under stabilization of the catheter using a double-lumen cannula with a guidewire. Following these procedures, the patient was asymptomatic. Computed tomography performed the next day revealed no complications.

Outcomes of Endoscopic Ultrasound-Guided Biliary Drainage in Patients Undergoing Antithrombotic Therapy

Background/Aims@#The Japan Gastroenterological Endoscopy Society (JGES) has published guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. These guidelines classify endoscopic ultrasound-guided biliary drainage (EUS-BD) as a high-risk procedure. Nevertheless, the bleeding risk of EUS-BD in patients undergoing antithrombotic therapy is uncertain. Therefore, this study aimed to assess the bleeding risk in patients undergoing antithrombotic therapy. @*Methods@#This single-center retrospective study included 220 consecutive patients who underwent EUS-BD between January 2013 and December 2018. We managed the withdrawal and continuation of antithrombotic agents according to the JGES guidelines. We compared the bleeding event rates among patients who received and those who did not receive antithrombotic agents. @*Results@#A total of 18 patients (8.1%) received antithrombotic agents and 202 patients (91.8%) did not. Three patients experienced bleeding events, with an overall bleeding event rate of 1.3% (3/220): one patient was in the antithrombotic group (5.5%) and two patients were in the non-antithrombotic group (0.9%) (p=0.10). All cases were moderate. The sole thromboembolic event (0.4%) was a cerebral infarction in a patient in the non-antithrombotic group. @*Conclusions@#The rate of EUS-BD-related bleeding events was low. Even in patients receiving antithrombotic therapy, the bleeding event rates were not significantly different from those in patients not receiving antithrombotic therapy.

Outcomes of Endoscopic Ultrasound-Guided Biliary Drainage in Patients Undergoing Antithrombotic Therapy

Background/Aims@#The Japan Gastroenterological Endoscopy Society (JGES) has published guidelines for gastroenterological endoscopy in patients undergoing antithrombotic treatment. These guidelines classify endoscopic ultrasound-guided biliary drainage (EUS-BD) as a high-risk procedure. Nevertheless, the bleeding risk of EUS-BD in patients undergoing antithrombotic therapy is uncertain. Therefore, this study aimed to assess the bleeding risk in patients undergoing antithrombotic therapy. @*Methods@#This single-center retrospective study included 220 consecutive patients who underwent EUS-BD between January 2013 and December 2018. We managed the withdrawal and continuation of antithrombotic agents according to the JGES guidelines. We compared the bleeding event rates among patients who received and those who did not receive antithrombotic agents. @*Results@#A total of 18 patients (8.1%) received antithrombotic agents and 202 patients (91.8%) did not. Three patients experienced bleeding events, with an overall bleeding event rate of 1.3% (3/220): one patient was in the antithrombotic group (5.5%) and two patients were in the non-antithrombotic group (0.9%) (p=0.10). All cases were moderate. The sole thromboembolic event (0.4%) was a cerebral infarction in a patient in the non-antithrombotic group. @*Conclusions@#The rate of EUS-BD-related bleeding events was low. Even in patients receiving antithrombotic therapy, the bleeding event rates were not significantly different from those in patients not receiving antithrombotic therapy.

Utility of Forward-View Echoendoscopy for Transcolonic Fine-Needle Aspiration of Extracolonic Lesions: An Institutional Experience

Background/Aims@#Non-invasive tissue sampling from the lower intra-abdominal and pelvic cavity is challenging. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) in this situation is not well-established because of the limitations of the curved linear-array echoendoscopy-EUS for colonic insertion. The aim of this study was to report our institutional experience of transcolonic EUS-FNA using forward-viewing therapeutic linear echoendoscopy-EUS (FV-EUS) in combination with fluoroscopic guidance. @*Methods@#Medical records of 13 patients who underwent transcolonic EUS-FNA of extracolonic lesions using FV-EUS in combination with fluoroscopic guidance at Aichi Cancer Center Hospital, Nagoya, Japan from June 2015 to November 2018 were retrospectively reviewed. @*Results@#Using FV-EUS under fluoroscopic guidance, the FNA procedure could be performed successfully in all patients (100% technical success), with a median procedure time of 31 minutes. The sensitivity, specificity, and accuracy of EUS-FNA for detecting malignant lesions in this study were 91%, 100%, and 92%, respectively. There were no adverse events associated with the EUS-FNA procedure. @*Conclusions@#FV-EUS in combination with fluoroscopic guidance is an easy, safe, and effective technique for FNA of extracolonic lesions in the lower abdomen.

Infectious peritonitis after endoscopic ultrasound-guided biliary drainage in a patient with ascites

SUMMARY OF EVENT: Bacterial, mycotic peritonitis and Candida fungemia developed in a patient with moderate ascites who had undergone endoscopic ultrasound-guided biliary drainage (EUS-BD). Antibiotics and antifungal agent were administered and ascites drainage was performed. Although the infection improved, the patient's general condition gradually deteriorated due to aggravation of the primary cancer and he died. TEACHING POINT: This is the first report to describe infectious peritonitis after EUS-BD. Ascites carries the potential risk of severe complications. As such, in patients with ascites, endoscopic retrograde cholangiopancreatography (ERCP) is typically preferred over EUS-BD or percutaneous drainage to prevent bile leakage. However, ERCP may not be possible in some patients with tumor invasion of the duodenum or with surgically altered anatomy. Thus, in patients with ascites who require EUS-BD, we recommend inserting the drainage tube percutaneously and draining the ascites before and after the intervention in order to prevent severe infection.

Risks of transesophageal endoscopic ultrasonography-guided biliary drainage

SUMMARY OF EVENT: Pneumoderma, mediastinal emphysema, and bilateral pneumothorax were developed in the patient who had undergone transesophageal endoscopic ultrasonography-guided rendezvous technique. Chest drainage was performed immediately. TEACHING POINT: Transesophageal approach carries the potential risks of severe complications such as mediastinal emphysema, mediastinitis, and pneumothorax. To prevent puncturing through the esophagus, clipping the esophagogastric junction using a forward-viewing scope before procedure is very useful. In cases of inadvertent transesophageal puncture, devices other than the needle should not be passed through the site.

Development of a new reagent for endoscopic ultrasound-guided celiac plexus neurolysis and tumor ablation therapy

BACKGROUND: Both endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) and tumor ablation using ethanol are very common procedures, and the utility of these therapies has already been reported in prominent journals. However, their effectiveness appears temporary and insufficient, especially EUS-CPN. We therefore have to consider new reagents for improving the results. The present study examined the best concentration of ethanol and povidone iodine mixed with atelocollagen for more effective therapies. METHODS: The effects of the new reagents were confirmed in three live pigs. At first, we injected three kinds of reagents (including indigo carmine) in three separate areas of para-aortic tissue under EUS guidance in one pig. At more than 4 hours after injection, we checked ethanol injection sites after dissection. In next study, we performed EUS-guided injection of a total of six kinds of reagents (two kinds of ethanol, three kinds of povidone iodine, and control atelocollagen) into the livers of two living pigs. After 2 weeks, we examined tissue damage to the liver in the two pigs. RESULTS: The 75% ethanol (absolute ethanol 3.75 mL + 1% atelocollagen 1.25 mL + a very small amount of indigo carmine) was seen like blue gel, and still remained in the para-aortic tissue. Brownish areas of povidone iodine mixed with 3% atelocollagen exhibited clear, regular borders with greatly reduced infiltration into surrounding tissue compared to others. CONCLUSION: We concluded that 75% ethanol mixed with 1% atelocollagen appears optimal for EUS-CPN. Povidone iodine mixed with 3% atelocollagen may be suitable for small tumor ablation therapy.

Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? / Шинэ санаа Шинэ нээлт

Background: The WHO classified pancreatic neuroendocrine neoplasms (pNEN) in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. Methods: We retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated (WDNEC) and poorlydifferentiated NEC (PDNEC), the latter further subdivided into large and small cell type. Results: The median Ki67 LI was 69.1% (range, 40% - 95%) and the median tumor size was 35 mm. 11 WHO-NECs were subclassified 4 WDNEC and 7 PDNEC, and further separated PDNEC into 3 large cell and 4 small cell subtypes. Comparisons of WDNEC vs. PDNEC revealed hypervascularity on CT, 50% (2/4) vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40% - 53%) vs. 85% (54% - 95%) (P = 0.001); KRAS mutations, 0% (0/4) vs. 85.7% (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0% (0/2) vs.100% (4/4) (P = 0.067) and median survival, 227 vs. 186 days (P = 0.227). Conclusions: The WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing Ki67 and KRAS mutation profiles, and distinct response to chemotherapy. Further studies for the re-evaluation of the current WHO 2010 classification is warranted.

Diagnosis of pancreatic ductal carcinoma / Шинэ санаа Шинэ нээлт

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of gastrointestinal cancer, with a 5-year survival rate of 5%; it remains a significant, unresolved therapeutic challenge. Its aggressive features include insidious presentation, unresectability due to early involvement of major vessels, debilitating symptoms at the late stage and de novo chemoresistance. However, according to the Japan Pancreatic Cancer Registry, the 5-year survival of UICC Stages 0 and 1a are 85.8% and 68.7%, respectively. Early diagnosis plays an important role in improving the overall survival of patients with PDAC; therefore, efforts should focus on early diagnosis and the reliable identification of patients who will most likely benefit from major surgical intervention. Patients with risk factors, including family history, accompanying disease, diabetes mellitus, chronic pancreatitis and intraductal papillary mucinous neoplasms (IPMN), should be followed up for early detection of PDAC. In Japan, a national team has undertaken such surveillance of patients with IPMN. The protocol comprises a semi-annual follow up using various modalities to detect not only IPMN carcinoma, but also PDAC concomitant with IPMN. I will address this protocol in detail. The most accurate imaging technique for PDAC diagnosis and staging is considered to be contrast-enhanced computed tomography (CECT). Whereas CT should be the first choice in patients with suspected PDAC, endoscopic ultrasound (EUS) is the most accurate, particularly for detecting small lesions (< 10 mm). EUS combines the potential of endoscopy, which enables visualization of the mucosal surface of the gastrointestinal (GI) tract, with ultrasonography. Thus, EUS is able to provide detailed, high-resolution images of the pancreas. However, whether a lesion is malignant or benign is unable to be discriminated solely from EUS imaging features. Obtaining samples from suspicious lesions or lymph nodes using EUS-guided fine-needle aspiration (FNA), offers the potential for cytological or histological diagnoses of pancreatic lesions with high sensitivity and specificity. Since accurate preoperative evaluation is essential to select the appropriate management strategy, the roles of EUS and EUS-FNA are crucial. Stage 0 PDAC (carcinoma in situ) has recently been discovered. This stage of PDAC is unable to be diagnosed using EUS-FNA, because EUS-FNA is only applicable after PDAC forms a cancerous mass (worse than stage1). Thus, diagnostic methods other than imaging require development. Presently, endoscopic retrograde pancreatography (ERP) combined with cytology is able to detect Stage 0 PDAC, and in Japan, nasopancreatic drainage tubes have recently been used to collect pancreatic juice for cytodiagnosis. I would also like to introduce this method.

Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? / Шинэ санаа Шинэ нээлт

Background: The WHO classified pancreatic neuroendocrine neoplasms (pNEN)in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to Ki67labeling index (LI). However, the clinical behavior of NEC is still not fully studied.We aimed to clarify the clinicopathological and molecular characteristics ofNECs.Methods: We retrospectively evaluated the clinicopathological characteristics,KRAS mutation status, treatment response, and the overall survival of elevenpNEC patients diagnosed between 2001 and 2014 according to the WHO 2010.We subclassified WHO-NECs into well-differentiated (WDNEC) and poorlydifferentiatedNEC (PDNEC), the latter further subdivided into large and smallcell type.Results: The median Ki67 LI was 69.1% (range, 40% - 95%) and the mediantumor size was 35 mm. 11 WHO-NECs were subclassified 4 WDNEC and 7PDNEC, and further separated PDNEC into 3 large cell and 4 small cell subtypes.Comparisons of WDNEC vs. PDNEC revealed hypervascularity on CT, 50% (2/4)vs. 0% (0/7) (P = 0.109); median Ki67 LI, 46.3% (40% - 53%) vs. 85% (54% -95%) (P = 0.001); KRAS mutations, 0% (0/4) vs. 85.7% (6/7) (P = 0.015); responserates to platinum-based chemotherapy, 0% (0/2) vs.100% (4/4) (P = 0.067) andmedian survival, 227 vs. 186 days (P = 0.227).Conclusions: The WHO-NEC category may be composed of heterogeneousdisease entities, namely WDNEC and PDNEC. These subgroups tended to exhibitdiffering Ki67 and KRAS mutation profiles, and distinct response to chemotherapy.Further studies for the re-evaluation of the current WHO 2010 classification iswarranted.

Diagnosis of pancreatic ductal carcinoma / Шинэ санаа Шинэ нээлт

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal type of gastrointestinalcancer, with a 5-year survival rate of 5%; it remains a significant, unresolvedtherapeutic challenge. Its aggressive features include insidious presentation,unresectability due to early involvement of major vessels, debilitating symptomsat the late stage and de novo chemoresistance.However, according to the Japan Pancreatic Cancer Registry, the 5-year survivalof UICC Stages 0 and 1a are 85.8% and 68.7%, respectively.Early diagnosis plays an important role in improving the overall survival ofpatients with PDAC; therefore, efforts should focus on early diagnosis and thereliable identification of patients who will most likely benefit from major surgicalintervention.Patients with risk factors, including family history, accompanying disease,diabetes mellitus, chronic pancreatitis and intraductal papillary mucinousneoplasms (IPMN), should be followed up for early detection of PDAC. In Japan,a national team has undertaken such surveillance of patients with IPMN. Theprotocol comprises a semi-annual follow up using various modalities to detectnot only IPMN carcinoma, but also PDAC concomitant with IPMN. I will addressthis protocol in detail.The most accurate imaging technique for PDAC diagnosis and staging isconsidered to be contrast-enhanced computed tomography (CECT). WhereasCT should be the first choice in patients with suspected PDAC, endoscopicultrasound (EUS) is the most accurate, particularly for detecting small lesions (<10 mm). EUS combines the potential of endoscopy, which enables visualizationof the mucosal surface of the gastrointestinal (GI) tract, with ultrasonography.Thus, EUS is able to provide detailed, high-resolution images of the pancreas.However, whether a lesion is malignant or benign is unable to be discriminatedsolely from EUS imaging features. Obtaining samples from suspicious lesions orlymph nodes using EUS-guided fine-needle aspiration (FNA), offers the potentialfor cytological or histological diagnoses of pancreatic lesions with high sensitivityand specificity. Since accurate preoperative evaluation is essential to select theappropriate management strategy, the roles of EUS and EUS-FNA are crucial.Stage 0 PDAC (carcinoma in situ) has recently been discovered. This stage of PDACis unable to be diagnosed using EUS-FNA, because EUS-FNA is only applicableafter PDAC forms a cancerous mass (worse than stage1). Thus, diagnostic methodsother than imaging require development. Presently, endoscopic retrogradepancreatography (ERP) combined with cytology is able to detect Stage 0 PDAC,and in Japan, nasopancreatic drainage tubes have recently been used to collectpancreatic juice for cytodiagnosis. I would also like to introduce this method.

EUS-Guided Biliary Drainage

Endoscopic ultrasonography (EUS) combines endoscopy and intraluminal ultrasonography, and allows imaging with a high-frequency transducer over a short distance to generate high-resolution ultrasonographic images. EUS is now a widely accepted modality for diagnosing pancreatobiliary diseases. EUS-guided fine-needle aspiration (EUS-FNA) using a curved linear-array echoendoscope was initially described more than 20 years ago, and since then many researchers have expanded its indications to sample diverse lesions and have also used it for various therapeutic purposes. EUS-guided biliary drainage (EUS-BD) is one of the therapeutic procedures that has been developed using a curved linear-array echoendoscope. Technically, EUS-BD includes rendezvous techniques via transesophageal, transgastric, and transduodenal routes, EUS-guided choledochoduodenostomy (EUS-CDS), and EUS-guided hepaticogastrostomy (EUS-HGS). Published data have demonstrated a high success rate, albeit with a comparatively high rate of nonfatal complications for EUS-CDS and EUS-HGS, and a comparatively low success rate with a low complication rate for the rendezvous technique. At present, these procedures represent an alternative to surgery or percutaneous transhepatic biliary drainage (PTBD) for patients with obstructive jaundice when endoscopic biliary drainage (EBD) has failed. However, these procedures should be performed in centers with extensive experience in linear EUS and therapeutic biliary ERCP. Large prospective studies are needed in the near future to establish standardized EUS-BD procedures as well as to perform controlled comparative trials between EUS-BD and PTBD, between rendezvous techniques and direct-access techniques (EUS-CDS and EUS-HGS), and between EBD and EUS-BD.