Neoplasms

All Conditions

Digestive System Diseases

Symptoms and General Pathology

Rare Diseases

Adenocarcinoma

Pancreatitis

Pancreatitis, Chronic

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pancreatic Diseases

Gastrointestinal Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Patients diagnosed with solid pancreatic adenocarcinoma masses, with cytological / histological confirmation

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

Adrian Saftoiu, Professor

The aim of the study is to assess elastography during EUS examinations of focal pancreatic masses, and to consequently differentiate benign versus malignant pancreatic masses in a prospective multi-center design.

Ultrasound elastography is a recent ultrasound method used for the calculation of tissue elasticity distribution in real-time. The method allows the reconstruction of tissue elasticity (i.e. the elasticity modulus) and reveals directly the physical properties of the tissue, consequently showing different tissue hardness patterns that are determined by diseases. Tissue elastography can be easily performed real-time with conventional probes, including the linear EUS probes used for the examination of the pancreas. The calculation of tissue elasticity distribution is performed in real-time and the examination results are represented as transparent overlay colour images overimposed on the conventional gray-scale B-mode images.

Ultrasound elastography was previously used for the diagnosis of breast lesions, prostate cancer and thyroid nodules. However, the value of endoscopic ultrasound elastography for the diagnosis of pancreatic focal masses is not clear for the current moment, as some authors couldn't differentiate benign and malignant pancreatic tumors. Moreover, the intense fibrotic reaction and calcifications in chronic pancreatitis induce strain differences, and it is not clear if elastography is sensitive enough to detect them.

The study protocol is based on a semi-quantitative approach of EUS elastography data (movies) consisting of characterization of manually user-defined regions of interest, based on the hue histograms of the individual focal masses. Due to the inherent bias induced by selection of images from a dynamic sequence of EUS elastography, we have previously reported on the utility of using computer-aided diagnosis by averaging images from a dynamic sequence of EUS elastography. A special plugin (based on the ImageJ software, NIH, Bethesda, MD, USA) is used to compute hue histograms on average EUS elastography images, while the hue histograms values for each patient (0 to 255 values) are further used to classify the patients with benign and malignant lesions.

Ultrasound elastography will be performed during an usual EUS examination (7.5 MHz frequency), with two movies of 10 seconds recorded on the embedded HDD in order to minimize variability and to increase repeatability of acquisition. A two panel image with the usual conventional gray-scale B-mode EUS image on the right side and with the elastography image on the left side will be used. The region of interest will be preferably larger than the focal mass, in order to include the surrounding structures. In order to minimize the human bias, all the post-processing and computer analysis of digital movies will be performed within the IT Center in Craiova, with all programmers and statisticians being blinded to the clinical, pathological and imaging data, with the exception of the average hue histogram values calculated from a second region of interest manually traced around the focal mass.

The study design is prospective, blinded and multi-center, comparing endoscopic ultrasound elastography (EUS-EG) results for the detection and characterization of focal pancreatic masses by using artificial intelligence techniques, 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.

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

Endoscopic Ultrasound Elastography in Pancreatic Masses

Computer-aided Diagnosis of Endoscopic Ultrasound Elastography Used in the Differentiation of Focal Pancreatic Masses

University Hospital, Gentofte, Copenhagen

Odense University Hospital

Institut Paoli-Calmettes

San Raffaele University Hospital, Italy

UCL (Univ), Brussels, Belgium

Glasgow Royal Infirmary

Caritas-Krankenhaus Bad Mergentheim

University of Bergen

University of Witten/Herdecke

Newcastle-upon-Tyne Hospitals NHS Trust

University of Medicine and Pharmacy Craiova

Adrian Saftoiu

Gland and Hormone Related Diseases

Pancreatic Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Endocrine System Diseases

Pancreatic Cancer

Gastrointestinal Agents

All Drugs and Chemicals

Pancrelipase

Pancreatin

All patients with a suspicion of pancreatic masses will undergo EUS (including EUS-FNA for confirmation of diagnosis). 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 during a clinical follow-up of at least 6 months.

Both pancreatic adenocarcinomas and pancreatic neuroendocrine tumors will be included.

Endoscopic ultrasound (including fine needle aspiration for confirmation of diagnosis) with sequential contrast-enhanced endoscopic ultrasound and elastography endoscopic ultrasound and contrast-enhanced computed tomography will be performed before and 2 months after the first course of treatment

EUS will be performed before (including EUS-FNA for confirmation of diagnosis) and 2 months after the first course of treatment.

* 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 four passes.

Endoscopic ultrasound (including fine needle aspiration)

CE-EUS will be performed during usual EUS examination before and 2 months after the first course of chemotherapy.

* The starting point of the timer will be considered the moment of intravenous contrast injection (Sonovue 4.8 mL).
* The whole movie (T0-T120s) will be recorded in a DICOM format on the embedded HDD of the ultrasound system, for later analysis.
* All post-processing and computer analysis of digital movies will be performed within the coordinating IT Center using Vue-Box

Contrast-enhanced endoscopic ultrasound (CE-EUS)

EUS-EG will be performed during usual EUS examinations, before and 2-months after the first course of chemotherapy, with two movies of 10 seconds recorded on the embedded HDD

* The region of interest for EUS-EG will be preferably larger than the focal mass. If the focal mass is larger than 3 cm, part of the mass will be included in the ROI, as well as the surrounding structures. Very large ROI for the elastography calculations will be avoided
* The following pre-settings will be used in all centers: elastography color map 1, frame rejection 2, noise rejection 2, persistence 3, dynamic rage 4, smoothing 2, blend 50%.
* SR and SH will be measured; with three measurements made and recorded on the embedded HDD.

Endoscopic ultrasound elastography (EG-EUS)

* Contrast-enhanced computed tomography will be obtained before treatment to assess the local extension of the tumor, and presence of lymph nodes and distant metastases.
* A template will be used to report the imaging results.
* The template includes morphologic, arterial, venous, and extrapancreatic evaluations.
* Contrast-enhanced computed tomography will be performed 2 months after the first course of chemotherapy, using the same template, in order to evaluate the tumor response. Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST).

Contrast-enhanced computed tomography (CT)

Adrian Saftoiu, MD PhD FASGE

Irina Cazacu, MD

Patients with non-resectable pancreatic cancer have a poor prognosis.The analysis of prognostic factors before treatment may be helpful in selecting appropriate candidates for chemotherapy and determining treatment strategies.

The aim of the PEACE study is to assess the vascularity of pancreatic malignant tumors using contrast-enhanced endoscopic ultrasonography and to clarify the prognostic value of tumor vascularity in patients with locally advanced and metastatic pancreatic cancer.

Introduction and rationale:

Pancreatic cancer (PC) is one of the most lethal and therapeutically resistant malignancies, with a grim prognosis that is attributed to the late clinical presentation and the relative chemoresistance of the disease.

Even with identical chemotherapy regimens, some patients experience improvements in survival and tumor response, whereas other patients only experience inconvenience and increased toxicity. It has been suggested that the burden of treatment should not be added to the suffering of those with advanced pancreatic cancer. Therefore, understanding prognostic factors before treating patients with antitumoral agents may be helpful in selecting those patients predicted to have an improved survival and tumor response after treatment.

Studies have shown that angiogenesis is an important factor that influences the prognostic of solid tumors, including pancreatic tumors. Contrast-enhanced imaging methods can offer detailed information on tumor vascularity. Contrast-enhanced endoscopic ultrasound (CE-EUS) is a new method which allows detailed characterization of focal pancreatic masses. CE-EUS offers high-resolution images of the pancreas that far surpass those achieved by computed tomography, ultrasound, or magnetic resonance imaging. CE-EUS can detect intratumoral vessels in the pancreatic lesions. One of the fluoro-gas-containing contrast agents used in CE-EUS is Sonovue®, which 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 European Union countries.

The hypothesis that tumors with intratumoral vessels are chemosensitive appears to be reasonable because drugs penetrate tumors through vessels. Therefore, it is possible that hypoxic condition in tumor tissue leads to chemoresistance and poor prognosis in patients with pancreatic carcinoma who received systemic chemotherapy. However, whether low vascularized tumors correlate with the chemoresistance and poor prognosis is still unclear. Patients with non-resectable pancreatic cancer have an especially poor prognosis and have many severe symptoms.The analysis of prognostic factors before treatment may be helpful in selecting appropriate candidates for chemotherapy and determining treatment strategies. For example, patients who have a poor prognosis may be treated best with only supportive care because of their short survival. Consequently, the aim of the PEACE study is to assess the vascularity of pancreatic malignant tumors with CE-EUS and to clarify the prognostic value of tumor vascularity in patients with advanced PC.

Moreover, studies have shown that angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumor blood vessels. Chauchan et al. demonstrated that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production. Consequently, losartan reduces solid stress in tumors resulting in increased vascular perfusion. Through this physical mechanism, it can improve drug and oxygen delivery to tumors, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Accordingly, another aim of our study will be to examine the correlation between tumor vascularity and angiotensin inhibitors use in patients using these drugs to control arterial hypertension.

Objectives:

Primary Objective:

• to register time-intensity curve (TIC) analysis-derived parameters, obtained from post-processing of CE-EUS recordings with a commercially available software, before and after chemotherapy and to describe tumor changes in vascularity after treatment.

Secondary Objectives:

* to prospectively determine whether the CE-EUS parameters can be used to predict response to treatment in patients with locally advanced and metastatic pancreatic cancer. Tumor response will be assessed by contrast-enhanced computed tomography, according to the Response Evaluation Criteria in Solid Tumors (RECIST)
* to determine the correlation between CE-EUS parameters before treatment and overall survival and progression-free survival
* to determine the correlation between changes in tumor vascularity and progression-free survival and overall survival
* to assess quantitative elastography parameters during EUS, before and after systemic treatment and determine their correlation with overall survival and progression-free survival
* to examine the correlation between tumor vascularity and angiotensin inhibitors use.

Study design:

This is a prospective, non-randomized, single-arm, observational, multicenter study aiming to assess changes in tumor vascularity using CE-EUS before and after systemic treatment in patients with locally advanced and metastatic pancreatic cancer and to examine the correlation between vascular changes and treatment response, progression-free survival and overall survival.

All patients with a suspicion of pancreatic masses will undergo EUS (including endoscopic ultrasound-fine needle aspiration for confirmation of diagnosis), with sequential elastography EUS (EG-EUS) and CE-EUS. A positive cytological diagnosis will be taken as a final proof of malignancy of the pancreas mass. The diagnoses obtained by EUS-fine needle aspiration will be further verified during a clinical follow-up of at least 6 months. Contrast-enhanced computed tomography (CT) will be performed as pretreatment staging study to assess the diagnosis of pancreatic cancer, local extension of the tumor, and presence of distant and lymph node metastasis.

Patients with a confirmed diagnosis of pancreatic cancer (both adenocarcinomas and neuroendocrine tumors will be included) will undergo systemic treatment. Selection of the specific treatment regimen will be according to individual physicians' choice.

Two months after the first course of systemic chemotherapy, CT and EUS (with sequential EG-EUS and CE-EUS) will be repeated. CT will be performed in order to evaluate the tumor response. Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST).

CE-EUS will be performed during usual EUS examinations, with the whole movie (T0-T120s) recorded in a DICOM format 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. Off-line analysis of time-intensity curves will be performed using Vue-Box, which yields the following quantitative parameters: Peak Enhancement (PE), Wash-in Area Under the Curve (Wi-AUC), Rise Time (RT), mean Transit Time (mTT), Time To Peak (TTP), Wash-in Rate (WiR) and Wash-in Perfusion Index (WiPI). The software also provides referenced values (expressed in percentages), aligning the set of values for the tumor Region of interest (ROI) to the parenchymal ones.

EUS-EG will also be performed during usual EUS examinations, with two movies of 10 seconds recorded on the embedded Hard Disk Drive (HDD) in order to minimize variability and to increase repeatability of acquisition. Strain Ratio (SR) and SH (Strain Histogram) will be measured; with three measurements made and recorded on the embedded HDD.

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.

For each patient, the following information will be recorded and uploaded to http://oncobase.umfcv.ro/ (this website aims to provide hosting and support for multicentric studies; all registered users can access the project and submit the data or upload files through a form defined and controlled by the project's coordinator):

* Age
* Gender
* Primary tumor location (pancreatic head or pancreatic body and tail)
* Primary tumor size
* Tumor status (metastatic or locally advanced)
* Site of metastasis
* Histologic grade
* Serum carcinoembryonic antigen (CEA) level
* Serum carbohydrate antigen 19-9 (CA19-9) level
* Prior biliary drainage (presence or absence).
* Antitumoral agent (chemotherapy regimen).
* Angiotensin inhibitors (drug, dose).
* Parameters of the pancreatic cancer CT reporting template
* EUS, CE-EUS, EG-EUS parameters (echogenicity, echostructure, size, presence/absence of power Doppler signals, Strain Ratio, Strain Histogram, Peak Enhancement (PE), Wash-in Area Under the Curve (Wi-AUC), Rise Time (RT), mean Transit Time (mTT), Time To Peak (TTP), Wash-in Rate (WiR) and Wash-in Perfusion Index (WiPI)).

Perfusion Assessment With Contrast-Enhanced EUS in Locally Advanced and Metastatic Pancreatic Cancer

Changes in Tumor Vascularity Depicted by Contrast-Enhanced Endoscopic Ultrasonography as a Predictor of Treatment Efficacy in Patients With Locally Advanced and Metastatic Pancreatic Cancer (PEACE)

PE represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

Wi-AUC represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

RT represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

mTT represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

TTP represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

Wir represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

WiPI represents a TIC analysis-derived parameter, obtained from post-processing of CE-EUS recordings with a commercially available software

The overall survival (OS) will be measured from the first day of chemotherapy to the date of death

The progression-free survival (PFS) will be measured from the first day of chemotherapy to the date of progressive disease.

Contrast-enhanced computed tomography will be performed 2 months after the first course of chemotherapy in order to evaluate the tumor response.

Tumor response will be assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST). According to RECIST guidelines,complete response (CR) is defined as the complete disappearance of the tumor, partial response (PR) as ≥30% decrease in longest diameter (LD), progressive disease (PD) as ≥20% increase in LD, and stable disease (SD) as a decrease or increase less than PR or PD based on anatomic assessment. Patients with CR or PR will be defined as responders, whereas those with PD or SD are defined as non-responders.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Endoscopic Ultrasound Elastography in Pancreatic Masses	NCT00909103	Pancreatic Aden... Chronic Pancrea...		18 Years - 80 Years	University of Medicine and Pharmacy Craiova
Perfusion Assessment With Contrast-Enhanced EUS in Locally Advanced and Metastatic Pancreatic Cancer	NCT03513198	Pancreas Cancer	Endoscopic ultr... Contrast-enhanc... Endoscopic ultr... Contrast-enhanc...	18 Years - 90 Years	University of Medicine and Pharmacy Craiova
Endoscopic Ultrasound Elastography in Pancreatic Masses	NCT00909103	Pancreatic Aden... Chronic Pancrea...		18 Years - 80 Years	University of Medicine and Pharmacy Craiova

Spots Global Cancer Trial Database for endoscopic ultrasound elastography