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Chronic Graft Versus Host Disease

Patients diagnosed with solid pancreatic adenocarcinoma masses, with cytological / histologicalconfirmation

Patients diagnosed with solid pancreatic tumor masses with all the criteria fulfilled to exclude pancreatic cancer

Adrian Săftoiu, Professor

The aim of the study is to assess the accuracy of real-time perfusion imaging pattern of pancreatic focal lesions visualized by contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) for the differential diagnosis between chronic pseudotumoral pancreatitis and pancreatic cancer in a prospective multicenter design.

The study will include patients with focal pancreatic masses evaluated by CEH-EUS and EUS-FNA. The diagnosis is usually unknown in the moment of the initial evaluation, the patients being included based on a suspicion of focal pancreatic masses after transabdominal ultrasound, CT or MR examinations. However, after a complete evaluation, a final diagnosis will be reached based on the combination of EUS-FNA cytology/pathology, surgical pathology and minimum 12 months follow-up.

Ultrasound contrast agents in conjunction with contrast specific imaging techniques are increasingly accepted in clinical use for diagnostic imaging. The study of the pancreas is a new and promising application of contrast-enhanced ultrasound (CE-US), including contrast-enhanced endoscopic ultrasound (CE-EUS). The technique is not indicated to improve the detection of pancreatic lesions, but to improve the delineation and differential diagnosis of pancreatic lesions. One of the fluoro-gas-containing contrast agents used in CE-US and CE-EUS is Sonovue®, which consists of phospholipids-stabilized bubbles of sulfurhexafluoride (SF6). Sonovue® is isotonic, stable and resistant to pressure, with a viscosity similar to blood. It does not diffuse into the extravascular compartment remaining within the blood vessels until the gas dissolves and is eliminated in the expired air (blood pool contrast agent). The safety profile of SonoVue showed a very low incidence of side effects; it is not nephrotoxic and the incidence of severe hypersensitivity is similar to other magnetic resonance imaging contrast agents. Moreover, Sono-Vue is approved for clinical use in EU countries. The blood supply of the pancreas is entirely arterial, making contrast-enhanced examinations feasible and readily available. Based on the European Federation Societies of Ultrasound in Medicine and Biology guidelines and recommendations, updated in 2008, two phases were defined for CE-US and CE-EUS of the pancreas: an early/arterial phase (starting from 10 to 30 seconds) and a venous/late phase (from 30 to 120 seconds).

Distinguishing pancreatic adenocarcinoma from other pancreatic masses remains challenging with current imaging techniques. The specificity of the discrimination between benign and malignant focal pancreatic lesions was found to be 93.3% using power Doppler contrast-enhanced EUS (PD-CE-EUS) compared with 83.3% for conventional EUS. The hypovascular aspect of lesions under PD-CE-EUS seemed highly sensitive and specific (higher than 90%) for adenocarcinoma in several published studies. During PD-CE-EUS examinations the ultrasound frequency returned to the transducer is the same with that transmitted, but the method is associated with artifacts resulting from turbulent flow (flash and overpainting). At CE-EUS, ductal adenocarcinoma is typically hypoenhanced compared to the adjacent pancreatic tissue in all phases. Furthermore, the lesion size and margins are better visualized, as well as the relationship with peripancreatic arteries and veins. Focal lesions in chronic pancreatitis are reported to have similar or hyper enhancement features as compared to the normal pancreatic parenchyma.

Dedicated contrast-enhanced harmonic EUS techniques (based on a low mechanical index) are recently available in new EUS systems. The harmonic frequencies returned during CEH-EUS are different from those transmitted by the transducer and are the result of non-linear oscillations of the microbubbles. The image obtained is an addition of the signal created by the distortion of the microbubbles and the tissue-derived signal. This can be optimized by using low MI, which allows minimum bubble destruction and complete "subtraction" of the tissue derived signal, obtaining a high resolution continuous real-time assessment of the microvascularization during the contrast uptake period (real-time perfusion imaging). CEH-EUS allows a more precise location of vascular structures within the parenchyma and focal abnormalities, with better delineation of pancreatic lesions than EUS, especially in the cases where air or fat causes artifacts and insufficient visualization of the pancreatic parenchyma. An initial pilot study described an experimental technique of CEH-EUS based on a linear prototype EUS scope, a low mechanical index (0.08 - 0.25) and a 2nd generation contrast agent (Sono-Vue), which allowed the visualization of early arterial phase and late parenchymal phase enhancement of the pancreas. Another pilot study demonstrated both real-time continuous images of finely branching vessels of the pancreas and intermittent homogenous parenchymal perfusion images, by using a radial prototype EUS scope, a low mechanical index (0.4) and a 2nd generation contrast agent (Sono-Vue). Several other research groups already reported the feasibility of CEH-EUS with low mechanical index. The sensitivity, specificity and accuracy for diagnosing pancreatic adenocarcinoma were 88%, 89%, and 88.5% in one study and 80%, 91.7%, and 86% in the other study. However, the data is still limited and a prospective, multicentric blinded study would certainly be necessary.

The study design is prospective, blinded and multi-center, comparing contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) results for the detection and characterization of focal pancreatic masses, in comparison with the gold standard represented by pathology. The study will be performed with the approval of the institutional board review of each center. The study protocol will be uploaded on ClinicalTrials.gov, the registry of federally and privately supported clinical trials conducted in the United States and around the world.

The study is already approved by the ethical committee of the University of Medicine and Pharmacy Craiova, Romania (attached). According to EFSUMB (European Federation Societies for Ultrasound in Medicine and Biology) guidelines published in 2008, second-generation contrast agents are also approved in the E.U. for ultrasound examinations, including liver and pancreas examinations.

All patients with a suspicion (clinical, US, CT/MR) of pancreatic masses should undergo EUS, contrast-enhanced harmonic EUS and EUS-elastography, as well as EUS-FNA

EUS with EUS-guided FNA

* Protocol of EUS with EUS-FNA should include linear EUS instruments with complete examinations of the pancreas.
* Tumor characteristics (echogenicity, echostructure, size) will be described as well as presence / absence of power Doppler signals.
* EUS-FNA will be performed in all pancreatic masses with at least three passes
* All examiners should be blinded for the results of pathology

CEH-EUS procedure

* A two panel image with the usual conventional gray-scale B-mode EUS image on the right side and with the contrast harmonic image on the left side will be used, according to pre-established presets.
* A low mechanical index procedure (dynamic wide-band contrast harmonic imaging mode) will be used, with a mechanical index of 0.08-0.25 and corresponding powers.
* The starting point of the timer will be considered the moment of intravenous contrast injection (Sonovue 4.8 mL).
* CEH-EUS will be performed during usual EUS examinations, with the whole movie (T0-T120s) recorded on the embedded HDD of the ultrasound system, for later analysis.
* In order to minimize human bias, all post-processing and computer analysis of digital movies will be performed within the coordinating IT Center, with all programmers and statisticians being blinded to the clinical, imaging and pathological data.

EUS-elastography procedures

* An additional EUS elastography movie of 30 seconds should be saved on the embedded HDD.
* The following settings will be used for EUS elastography: examination frequency is usually set at 7.5 MHz, while preinstalled system settings are used in all patients: reject (2), E-smoothing (2), persistence (3), and E-dynamic range (4).

Final diagnosis The diagnosis of chronic pancreatitis will be based on the clinical information (history of alcohol abuse, previous diagnosis of chronic pancreatitis or diabetes mellitus), as well as a combination of imaging methods (ultrasound, CT and EUS). At least four criteria of chronic pancreatitis during EUS will be considered for the positive diagnosis. The diagnosis of chronic pseudotumoral pancreatitis will always be confirmed by surgery or by a follow-up of at least six months used to exclude malignancy in the patients that will not be operated on.

A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-FNA will be further verified either by surgery or during a clinical follow-up of at least 6 months.

Pathology samples obtained from duodeno-pancreatectomies or caudal pancreatectomies done with curative intent, as well as microhistological fragments obtained through EUS-FNA biopsy will be processed by paraffin embedding with usual colorations (haematoxylin-eosin), with subsequent immune-histochemistry at the discretion of the participating centers pathologists in order to exclude neuroendocrine tumors / pancreatic metastases.

The patients will be followed-up for at least six months through clinical examination, biological exams and transabdominal ultrasound, eventually with a repeat spiral CT / EUS after six months.

Statistical analysis All results will be expressed as mean ± standard deviation (SD). Differences between the patients with pancreatic cancer and chronic pancreatitis will performed by the two-sample t-test (two independent samples). Since this parametric method makes assumptions about normality and similar variances, we will initially perform both the Kolmogorov-Smirnov and Shapiro-Wilk W normality tests and verify the equality of variances assumption with the F test. In the case of the two-sample t-test, we will also perform the non-parametric alternative given by the Mann-Whitney U test, since in some instances it may even offer greater power to reject the null hypothesis than the t-test.

Since with more than two groups of observations it is far better to use a single analysis that enables us to look at all the data in the same time, we will also perform the one-way analysis of variance (ANOVA) method with the same baseline assumptions. A p-value less than 0.05 will be considered as statistically significant.

Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CEH-EUS +/- will be determined in comparison with the final diagnosis.

The estimated number of patients included is at least 210, based on at least 10 centers with at least 20 patients each, which will be enrolled in an 18 months period. The power analysis was based on the following assumption: in order to use the powerful t-test for independent samples, a sample size equaling 105 patients in each group is sufficient to provide 95% statistical power to detect a difference of 5% in mean, for a type I error alpha = 0.05, and the population standard deviation = 10%. The difference in mean was based on previously published data which report an accuracy of approximately 80-85% for EUS-FNA, and 90% for contrast-enhanced EUS.

Pathology samples obtained from duodeno-pancreatectomies or caudal pancreatectomies done with curative intent, as well as microhistological fragments obtained through EUS-FNA biopsy processed by paraffin embedding

Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) in Focal Pancreatic Masses

Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) Used in the Differentiation of Focal Pancreatic Masses

Value of contrast enhanced harmonic endoscopic ultrasound for the differential diagnoses of pancreatic masses.

Copenhagen University Hospital, Denmark

Caritas-Krankenhaus Bad Mergentheim

Institut Paoli-Calmettes

University of Witten/Herdecke

Hospital Meiningen Germany

Odense University Hospital

University of Santiago de Compostela

Università Vita-Salute San Raffaele

SRH Wald-Klinikum Gera GmbH

University of Bergen

Institutul Clinic Fundeni

Glasgow Royal Infirmary

University College, London

University of Medicine and Pharmacy Craiova

Cysts

Pancreatic Cyst

Pathological Conditions, Anatomical

Pharmaceutical Solutions

All Drugs and Chemicals

Gastrointestinal Agents

Pancrelipase

Pancreatin

After a careful endoscopic ultrasound examination in B mode of the entire pancreas, contrast enhancement was administrated to the participants. The uptake and the wash-out of the agent were followed and then a morphological diagnose was established. EUS-fine needle aspiration of the cyst wall, septa or solid components was guided by the enhancing pattern.

During the echoendoscopy the image was fixed on the region of interest (pancreatic cyst) and the extended pure harmonic detection mode was selected. 2,4ml contrast enhancement (Sonovue-Bracco Italy) was injected in the right antecubital vein of the participants followed by a flush of 5ml 0.9% saline solution to ensure that the entire quantity of the agent goes in to the blood flow.

After the administration the pancreatic cyst was observed for at least 120 seconds.We followed the enhancing behavior of the cyst wall, the septa and the solid components. Arterial enhancement (contrast uptake) was considered the first 25-30 seconds after injection and the venous phase (wah-out) 30-45 seconds after injection.

EUS-FNA was performed in all patients without contraindications

Contrast enhanced harmonic endoscopic ultrasound

Andrada Seicean, MD,PhD

The study evaluates the role of contrast-enhanced harmonic endoscopic ultrasound (CH-EUS) for the differentiation of the pancreatic cysts and their malignant potential.

Due to the increase use of cross-sectional imaging techniques for varied medical conditions more and more pancreatic cysts are incidentally found. Magnetic resonance imaging revealed a prevalence of incidental pancreatic cystic neoplasm (PCN) in adults between 2,4-49,1% and autopsy studies showed that half of the individuals had pancreatic cysts.

There is a great variety of pancreatic cysts, they are mainly divided in neoplastic or non-neoplastic (i.e pseudocyst). Pseudocysts appear after acute or chronic pancreatitis and represent only 20% of all pancreatic cysts.. PCN include a diverse group of pancreatic cysts including mucin-producing (Intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN)) and nonmucin-producing lesions (Serous cystadenoma (SCN), Solid pseudopapillary neoplasm(SPN) cystic neuroendocrine tumor(cNET)) with different morphology and progression to malignancy. SPN's,cNET are considered premalignant or malignant conditions and require surveillance or surgical resection. SCN instead are benign and surveillance is not necessary. Resection is considered only if symptoms are present.

The discrimination between the different cyst types is crucial for the therapeutic approach. Their morphology can be similar and sometimes it's a challenge to diagnose them.There are many tools but none is good enough to be used alone.

Contrast-enhanced harmonic endoscopic ultrasound using low mechanical index (0.12-0.4) is an additional test to assess the vascularization of the cystic wall and the septa and solid component for the differential diagnosis of PCN.

Our aim was to identify specific imaging characteristics using CH-EUS in order to increase the diagnostic accuracy for potential malignant pancreatic cysts.

Patients diagnosed with unclear cystic lesions who underwent CH-EUS at our Institute

Usefulness of Contrast Enhanced Harmonic Endoscopic Ultrasound for Pancreatic Cysts

Usefulness of Contrast-enhanced Harmonic Endoscopic Ultrasound (CH-EUS) for the Differentiation of the Pancreatic Cysts and for Guiding Endoscopic Ultrasound Guided Fine Needle Aspiration (EUS-FNA) From Murale Nodules.

To identify specific imaging characteristics using CH-EUS ( the contrast uptake pattern) in order to increase the diagnostic accuracy for the different type of the pancreatic cysts

The role of CH-EUS for the identification of true mural nodules

To asses the improvement of the EUS-FNA results if the lesions are targeted through the enhancement pattern

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Contrast Enhanced Harmonic Endoscopic Ultrasound (CEH-EUS) in Focal Pancreatic Masses	NCT01315548	Adenocarcinoma ... Chronic Pancrea...		18 Years - 90 Years	University of Medicine and Pharmacy Craiova
Usefulness of Contrast Enhanced Harmonic Endoscopic Ultrasound for Pancreatic Cysts	NCT04389892	Pancreatic Cyst	Contrast enhanc...	18 Years -	Iuliu Hatieganu University of Medicine and Pharmacy
Usefulness of Contrast Enhanced Harmonic Endoscopic Ultrasound for Pancreatic Cysts	NCT04389892	Pancreatic Cyst	Contrast enhanc...	18 Years -	Iuliu Hatieganu University of Medicine and Pharmacy

Spots Global Cancer Trial Database for contrast enhanced harmonic endoscopic ultrasound