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Pancreatin

Patients with high suspicion of solid pancreas neoplasia: carcinoma, intrapapillary mucinous neoplasia (IPMN), neuroendocrine tumor, lymphoma, or intrapancreatic metastasis; based on CT/MR.

Patients with high suspicion of solid inflammatory lesions: acute, chronic, or autoimmune pancreatitis; based on CT/MR.

Patients without a history of any type of solid or hematologic malignancy, hepato-pancreato-biliary disease (including fatty liver and pancreas disease), tobacco/alcohol habits, or morbid obesity with bariatric surgery criteria; who require EUS evaluation (e.g., suspicious of a subepithelial lesion in the context of chronic dyspepsia).

EUS Shear wave elastography (SWE) is a form of ultrasound elastography used in transabdominal ultrasonography. It measures tissue elasticity by generating shear waves inside the organ using the acoustic radiation force impulse (ARFI). The ultrasound machine monitors shear wave propagation and measures the velocity. The shear wave velocity, displayed in kilopascals \[kPa\] or meters per second. Also, the dispersion slope or ultrasound shear wave dispersion (SWD) will be recorded. It is the measure of viscosity \[(m/sec)/kHz\] using SWE.

A first endoscopist will perform EUS over pancreas tissue. Without any elastography assessment (strain ratio/histogram) , the endoscopist will take ten shear wave measurements of pancreas tissue elasticity by generating shear waves inside the pancreas using the ARFI.

Pancreas EUS shear wave

Pancreas EUS-elastography measures the pancreatic tissue stiffness through strain ratio (SR) and strain histogram (SH).

A second endoscopist blind to pancreas tissue shear wave findings will perform EUS-elastography with corresponding SR and SH measurements. The SR/SH will be measured and documented. Finally, a pancreas tissue biopsy will be performed. The impossibility of biopsy is an exclusion criterion (except in control patients). Due to ethical purposes, a biopsy will not be performed on patients from the control group.

Pancreas EUS-elastography and EUS-guided biopsy

Carlos Robles-Medranda, MD FASGE

The diagnosis of pancreas diseases is based on a combination of clinical signs, symptoms, and laboratory tests, but mainly on imaging techniques such as computed tomography (CT) and magnetic resonance (MR). However, CT/MR have variable sensitivity and specificity, with certain disadvantages. Endoscopic ultrasound with elastography is an important resource with higher diagnostic accuracy in assessing solid pancreas lesions. Shear wave velocities of healthy parenchyma, acute, chronic and autoimmune pancreatitis, neoplastic lesions of the pancreas must be evaluated and compared.

The pancreas is a retroperitoneal organ that can cause inflammatory and neoplastic diseases, significantly impacting the quality of life to survival. Acute pancreatitis is one of the most frequent gastrointestinal causes for hospital admission in industrialized countries. Chronic pancreatitis, although lower in incidence, significantly reduces patients' quality of life. Pancreas cancer is one of the neoplastic diseases with high mortality worldwide. Those diseases have been associated with significant morbidity, mortality, and hospitalization costs

The diagnosis of pancreas diseases is based on a combination of clinical signs, symptoms, and laboratory tests, but mainly on imaging techniques such as computed tomography (CT) and magnetic resonance (MR). Imaging provides a significant contribution to the diagnosis of pancreatic diseases and severity estimation or staging for inflammatory and neoplastic lesions, respectively. However, CT/MR have variable sensitivity and specificity, with certain disadvantages.

Endoscopic ultrasound with elastography is an important resource with higher diagnostic accuracy in assessing solid pancreas lesions. Shear wave elastography is a novel technique that can measure tissue elasticity by generating shear waves inside the organ using the acoustic radiation force impulse.

EUS Shear wave velocities of healthy parenchyma and solid pancreas lesions as acute, chronic, autoimmune pancreatitis and neoplasia are under described and must be evaluated and contrasted. Therefore, the present study pursues to estimate the diagnostic accuracy of EUS Shear wave for neoplasia assessment among solid pancreas lesions.

EUS Shear Wave for Solid Pancreatic Lesions.

Endoscopic Ultrasound Shear Wave for Neoplasia and Inflammation Assessment Among Solid Pancreas Lesions: a Case-control Observational Trial.

The median of ten SWE/SWD measures will be calculated to represent the final pancreas tissue shear wave measure per case. The higher the median, the more suspicious for neoplasia.

The SR/SH measures will be recorded per case. A SR\>15 kPa and a SH≤45 will be considered as highly suspicious for neoplasia.

The pathologist will have access to all the clinical data of each patient, including EUS-elastography findings, except shear wave measurements, to determine if the assessed pancreas lesion was neoplasia or inflammatory. In addition, a preliminary diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of pancreas EUS shear wave measurements and pancreas EUS-elastography will be calculated using histopathology results as gold standard.

A gastroenterologist will follow patients for one year after the procedure. During this follow-up, there will record cases who undergo exploratory or onco-specific surgery (histopathology) and the number of patients who undergo onco-specific treatment (radiotherapy, radiosurgery, chemotherapy, and biological therapy) or clinical management/surveillance. Survival and cause of death will also be recorded when corresponding. This follow-up purposes of determining definitively if the assessed pancreas lesion was neoplasia or inflammatory. A definitive diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of pancreas EUS shear wave measurements and pancreas EUS-elastography will be calculated using a one-year follow-up as the gold standard.

Instituto Ecuatoriano de Enfermedades Digestivas

Necrosis

Pancreatic Pseudocyst

Cysts

Pancreatic Cyst

Endoscopic necrosectomy will be conducted in the same session of EUS-guided drainage (or at least within 72 hours of randomization) and be repeated until clinical success.

Step-up treatment will be conducted if a patient's condition does not improve after EUS-guided drainage. The step-up approach includes increasing the number of stents, adding another EUS-guided drainage, and performing percutaneous drainage after 72-96 hours of the initial drainage. Endoscopic necrosectomy is considered when clinical improvement is not observed even after two times of step-up treatment.

Endoscopic ultrasonography (EUS)-guided drainage will be conducted within 72 hours from randomization. A convex-type echoendoscope is advanced to the stomach or duodenum, and the walled-off necrosis (WON) is visualized and punctured under EUS guidance. A lumen-apposing metal stent (LAMS), such as Hot AXIOS system (Boston Scientific Japan, Tokyo, Japan), is recommended for the initial EUS-guided drainage.

For the immediate necrosectomy group, endoscopic necrosectomy (EN) will be performed in the same session of EUS-guided drainage using a gastroscope. The endoscope is inserted into the WON cavity through the LAMS, and necrotic tissue is removed using biopsy forceps, snare, or basket catheter. The EN procedures will be repeated until clinical improvement.

Immediate necrosectomy

Endoscopic ultrasonography (EUS)-guided drainage will be conducted within 72 hours from randomization. A convex-type echoendoscope is advanced to the stomach or duodenum, and the walled-off necrosis (WON) is visualized and punctured under EUS guidance. A lumen-apposing metal stent (LAMS), such as Hot AXIOS system (Boston Scientific Japan, Tokyo, Japan), is recommended for the initial EUS-guided drainage.

For the step-up approach group, an additional interventional procedure will be withheld for 72-96 hours after initial EUS-guided drainage. In cases without clinical improvement after 72-96 hours, additional drainage will be permitted, which includes increasing the number of stents, additional EUS-guided drainage, and performing percutaneous drainage (step-up treatment). Insufficient improvement even after two times of step-up treatment allows subsequent endoscopic necrosectomy (EN).

Step-up approach

Yousuke Nakai

Tomotaka Saito

Hiroyuki Isayama

Toshio Fujisawa

Sho Takahashi

Tadahisa Inoue

Hiroshi Ohyama

Koji Takahashi

Keisuke Iwata

Mitsuru Okuno

Akinori Maruta

Kensaku Yoshida

Takuji Iwashita

Shinya Uemura

Hideyuki Shiomi

Shogo Ota

Ryota Nakano

Hideki Kamada

Daisuke Namima

Shinichi Hashimoto

Makoto Hinokuchi

Toshiyasu Shiratori

So Nakaji

Tsuyoshi Mukai

Saburo Matsubara

Keito Nakagawa

Shinpei Doi

Nobuhiro Katsukura

Atsuhiro Masuda

Masahiro Tsujimae

Kenji Chinen

Takeshi Ogura

Atsushi Okuda

Masaki Kuwatani

Hirofumi Kogure

Kei Saito

Ichiro Yasuda

Nobuhiko Hayashi

Mamoru Takenaka

Shunsuke Omoto

Walled-off necrosis (WON) is a pancreatic fluid collection, which contains necrotic tissue after four weeks of the onset of acute pancreatitis. Interventions are required to manage patients with infected WON, for which endoscopic ultrasonography (EUS)-guided drainage has become a first-line treatment modality. For patients who are refractory to EUS-guided drainage, the step-up treatment including endoscopic necrosectomy (EN) and/or additional drainage is considered to subside the infection. Recent evidence suggests that EN immediately after EUS-guided drainage may shorten treatment duration without increasing adverse events. In this randomized trial, the investigators will compare treatment duration between EN immediately after EUS-guided drainage versus the step-up approach in patients with symptomatic WON.

Pancreatic fluid collection is a late complication of severe acute pancreatitis. According to the revised Atlanta classification, walled-off necrosis (WON) is defined as an encapsulated collection of necrotic tissue that is observed after four weeks of the onset of acute pancreatitis. Infected WON is associated with high morbidity and mortality; therefore, an appropriate treatment, including antibiotics and drainage, is mandatory. With the development of endoscopic equipment, endoscopic ultrasonography (EUS)-guided drainage has become a first-line treatment modality for infected WON. For patients who are refractory to EUS-guided drainage, endoscopic necrosectomy (EN) is a treatment option to facilitate direct removal of infected necrotic tissue within the WON. However, due to potentially lethal adverse events of EN, such as bleeding, perforation, and peritonitis, EN is usually withheld for several days after EUS-guided drainage. This strategy is known as "the step-up approach." Recently, with the accumulated evidence supporting the safety of EN, especially with the use of a dedicated lumen-apposing metal stent, it has been reported that EN immediately after EUS-guided drainage can shorten the treatment duration without increasing adverse events. Given these lines of evidence, the investigators hypothesized that immediate EN following EUS-guided drainage of WON might shorten time to clinical success compared to the step-up approach. To examine this hypothesis, the investigators planned to conduct a multicenter randomized controlled trial comparing treatment duration between EN immediately after EUS-guided drainage versus the step-up approach in patients with symptomatic WON.

Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis

Immediate Necrosectomy vs. Step-up Approach After EUS-guided Drainage of Walled-off Necrosis: a Multicenter Randomized Controlled Trial (WONDER-01)

Clinical success is defined as 1) a decrease in the WON size to 3 cm or less and 2) an improvement of more than two out of the three following inflammatory markers; body temperature, white blood cell count, and C-reactive protein.

All procedure-related adverse events including bleeding, perforation, peritonitis, etc.

Successful placement of EUS-guided drainage including a lumen-apposing metal stent and plastic stents

Inflammatory-induced obstruction of bile duct and gastrointestinal tract

Total number of interventions and total procedure time

Indwelling period of stents and drainage tube

Success rate of surgeries associated with WON and total operation time

Total hospitalization days and total ICU stay

Total cost of interventions and total cost of hospitalization

Time from clinical success to recurrence of WON

Incidence of new-onset pancreatic pseudocyst

Total treatment period for new-onset pancreatic pseudocyst

New-onset diabetes mellitus, pancreatic cancer, and clinical symptoms associated with pancreatic exocrine insufficiency, such as steatorrhea , constipation, diarrhea, maldigestion, flatulence, and tenesmus

The start of medications for pancreatic exocrine insufficiency and the date

The presence of sarcopenia and the date of diagnosis

Change in the morphology and the volume of pancreas

Tokyo University

Associate professor, Department of Endoscopy and Endoscopic Surgery, The University of Tokyo Hospital

The group of participants with post-inflammatory pancreatic and peripancreatic fluid collections with double pigtail plastic stents introduced through the LAMS during endoscopic transmural drainage.

The group of participants with post-inflammatory pancreatic and peripancreatic fluid collections without double pigtail plastic stents introduced through the LAMS during endoscopic transmural drainage.

During endoscopic procedure of endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections the operator introduces double pigtail plastic stents through the LAMS.

Introduction of double pigtail plastic stents through the LAMS during endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections

During endoscopic procedure of transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections the operator introduces transmurally the LAMS only, without the double pigtail plastic stents.

Endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections with use of LAMS only

Mateusz Jagielski, Prof.

The goal of this clinical trial is to learn about clinical usefulness of double pigtail plastic stents during endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections with use of lumen-apposing metal stents (LAMS).

The main question it aims to answer is:

Does introduction of double pigtail plastic stents through the LAMS increases efficacy and safety of endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections?

Acute pancreatitis (AP) of moderate-to-severe clinical course is associated with a high risk of local complications and organ failure leading to increased mortality. Pancreatic and peripancreatic fluid collections (PPFCs) that can appear in the late phase of pancreatitis can take the form of pancreatic pseudocysts and walled-off pancreatic necrosis (WOPN). These types of PPFCs are the most common local complications of acute and chronic pancreatitis. For many years, the traditional treatment of post-inflammatory PPFCs in the late phase of pancreatitis relied on surgical methods. However, there has been a recent dynamic development of minimally invasive techniques, including endoscopic transluminal methods. While endoscopic treatment is an established method of managing these complications, some aspects of endotherapy are still a source of much controversy. One of the most debated issues in interventional endoscopy of local complications in pancreatitis is the use of transmural self-expanding metallic stents (SEMSs).

Endoscopic transmural drainage consists of creating a fistula between the lumen of the PPFC and gastrointestinal tract to allow for a free outflow of fluid out of the PPFC and into the gastrointestinal tract. During an endoscopic ultrasound (EUS)-guided procedure of endoscopic transmural drainage of post-inflammatory PPFCs, this can be visualized in the endosonographic image through the wall of the upper gastrointestinal tract. Afterwards, a transmural puncture of the PPFC is performed under EUS guidance and widened with a cystotome to a diameter of 10 Fr using coagulation. This forms a transmural cystostomy, which joins the gastrointestinal tract and the lumen of the PPFC. The next step of the endoscopic procedure is mechanical (with a dilator) or pneumatic (with a high-pressure balloon) dilation of the pancreaticocystogastrostomy or pancreaticocystoduodenostomy. Once dilated, a transmural SEMS or plastic stent(s) is introduced through the cystostomy to facilitate free passive transmural drainage of the collection contents into the gastrointestinal tract. Passive transmural drainage is an effective method of endoscopic treatment of pancreatic pseudocysts, whose contents are entirely liquid. In the case of necrotic PPFCs that contain both liquefied necrotic material and tissue fragments, it is necessary to use active transmural drainage, which consists of inserting an additional nasal drain through the transmural cystostomy to enable flushing of the collection cavity in the postoperative period.

The development of advanced endoscopic techniques has led to rapid advancements in biomedical materials, including polymers for manufacturing endoscopic devices. Currently, there is a wide variety of transmural endoprostheses of different sizes, shapes, and designs for endoscopic treatment of post-inflammatory PPFCs. These endoprostheses were divided into two groups. The first group includes plastic stents, usually made of Teflon or polyethylene. The second group is SEMSs, often referred to as "lumen-apposing metal stents" (LAMSs), that are used in the treatment of post-inflammatory pancreatic local complications. For many years, the only type of endoprosthesis available for use in transmural drainage was plastic double-pigtail stents. However, LAMSs have been attracting increasing interest as a relatively new option in endoscopy. LAMSs are a special type of SEMS used in a variety of gastrointestinal endoscopic procedures. They are made of nitinol wire and are fully covered with a silicone membrane.

However, the role of LAMSs in transmural drainage remains unclear. Many authors believe that use of LAMS during endoscopic transmural drainage increases risk of complications in form of bleeding. Despite the development of advanced endoscopic techniques and devices, the high rates of bleeding into the PPFC lumen remain a major challenge in transmural drainage treatment. This type of complication is often caused by blood vessels adjacent to the fluid collection being damaged by the distal flange of the LAMS. It seems that inserting a plastic double-pigtail stent through the LAMS limits the risk of this kind of complication by moving the back wall of the PPFC away from the distal flange, PPFC cavity bleeding during transmural drainage is still a major complication associated with a high risk of fatal outcomes.

In this trial the participants with post-inflammatory PPFCs will be divided into two arms.

The first arm will consist of participants who underwent traditional transmural drainage procedure with use of LAMS only.

The second arm will consist of participants with PPFCs who underwent endoscopic transmural drainage with use of LAMS and during the procedure double pigtail plastic stents will be introduced through the LAMS in order to prevent bleeding.

Each arm will consist of at least 50 participants with post-inflammatory PPFCs.

The Role of Double Pigtail Plastic Stents During Endoscopic Transmural Drainage of Pancreatic Fluid Collections.

The Assessment of Effectiveness and Safety of Double Pigtail Plastic Stents During Endoscopic Transmural Drainage of Post-inflammatory Pancreatic and Peripancreatic Fluid Collections With Use of Lumen-apposing Metal Stents (LAMS).

Evaluation of efficacy based on clinical picture and results of imaging examinations.

Evaluation of safety based on clinical picture and results of imaging examinations.

Evaluation of early complications within thirty days from onset of endoscopic drainage.

Evaluation of late complications of endoscopic drainage.

Assessment of clinical results of endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections with use of double pigtail plastic stents introduced through the LAMS.

Assessment of long-term results of endoscopic transmural drainage of post-inflammatory pancreatic and peripancreatic fluid collections with use of double pigtail plastic stents introduced through the LAMS.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
EUS Shear Wave for Solid Pancreatic Lesions.	NCT05095831	Pancreas Neopla... Pancreatitis Pancreatitis, A... Pancreatitis, C... Pancreatitis, A...	Pancreas EUS sh... Pancreas EUS-el...	18 Years - 79 Years	Instituto Ecuatoriano de Enfermedades Digestivas
Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis	NCT05451901	Pancreatic Flui... Walled-off Necr... Pancreatitis, A... Pancreatic Pseu...	Immediate necro... Step-up approac...	18 Years -	Tokyo University
The Role of Double Pigtail Plastic Stents During Endoscopic Transmural Drainage of Pancreatic Fluid Collections.	NCT06134024	Pancreatitis, A... Pancreatitis, A... Pancreatic Pseu... Pancreatic Necr... Pancreatitis, C...	Introduction of... Endoscopic tran...	18 Years -	Nicolaus Copernicus University
Immediate Necrosectomy vs. Step-up Approach for Walled-off Necrosis	NCT05451901	Pancreatic Flui... Walled-off Necr... Pancreatitis, A... Pancreatic Pseu...	Immediate necro... Step-up approac...	18 Years -	Tokyo University

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