The Use of Contrast Enhanced Ultrasound (CEUS) In Post-Surgical Pancreatic Cancer Patients to Evaluate Local Disease Recurrence

The sensitivity and specificity of ultrasound imaging can be improved by intravenous (IV) injection of gas microbubbles as vascular contrast agents, which can enhance both Doppler and grayscale signals by up to 27 dB. These contrast agents not only enhance the backscattered ultrasound signals, but at sufficient acoustic pressures they also act as nonlinear oscillators. These oscillations generate significant energy components in the received echo signals, which span the range of possible frequency emissions from subharmonics through ultraharmonics. These nonlinear bubble echoes can be separated from tissue echoes and used to create contrast sensitive imaging modalities such as harmonic imaging (HI), which is commercially available on most state-of-the-art ultrasound scanners.

CEUS has been one of the most important advances in ultrasonography over the last two decades. One example is the rapid success in detection and characterization of focal liver lesions, where CEUS in many studies have demonstrated the same value as Computer Tomography (CT) and Magnetic Resonance Imaging (MRI). Transabdominal ultrasonography with CEUS in the pancreas may have the same potential and has in some centers been established in diagnostic routine. Ultrasound contrast agents have minimal side effects compared to CT or MRI contrast agents. They are not toxic, and do not influence the metabolism of the thyroid gland. The most serious adverse event is anaphylactic reaction. The frequency of anaphylaxis using registered ultrasound contrast agents is very low (0.001 % for ultrasound contrast agents versus 0.07 % for X-ray contrast agents).

Given the excellent safety profile of ultrasound contrast agents and the established benefits of CEUS, this study will investigate the feasibility of using CEUS imaging to evaluate local PDAC recurrence. As a secondary objective we will also explore how imaging of the surgical site may differ with CEUS and with standard of care CT imaging.

CEUS provides vascular information which will help determine potential recurrence by determining the presence or absence to vascularity and therefore viability.

Endpoints 2.2.1 Primary CEUS image quality compared to standard ultrasound imaging as evaluated qualitatively by radiologists 2.2.2. Secondary

• The surgical site area/volume with/without enhancement from CEUS
• The surgical site area/volume with/without enhancement from CT imaging
• Presence or absence of recurrence 2.2.3. Tertiary
• Determine patient experience with CEUS examination.

This is an open-label, non-randomized, single center, clinical study that will be conducted at TJU. Patients that underwent surgical resection of PDAC located in the head or body of the pancreas and are being followed for recurrence with CT imaging as part of their SoC are eligible to participate in this pilot study.

The results from the SoC imaging will be available for the research team including the personnel performing the CEUS examination, this is not a blinded study the potential cases will be selected based on the results of their SoC imaging. The patients are expected to undergo CT imaging as their SoC imaging.

There is not a specific timepoint after the surgery where the patient will be identified and consent will be obtained. Patients will be identified after a standard of care CT that will be performed after the surgery that will be ordered by the patient's clinical team without the research team input on the timeline.

The CEUS study examination will be performed up to 4 weeks after the patient's SoC CT imaging.

The imaging procedure that the patient will undergo as part of their participation in the study is one CEUS examination. Patients' participation in the study will be one CEUS examination; no other imaging modalities examinations will be performed during the patients' participation in the study. Any other imaging modalities examinations that the patients may undergo will be part of the patient's standard of care by the discretion of the patient's clinical team, which the research study team having no participation in the patient's clinical care.

This trial will consist of 10 adults (18 years of age or older), that underwent surgical resection of PDAC located in the head or body of the pancreas and are being followed for recurrence with CT imaging as part of their SoC. This will not be a randomized study; the plan is to enroll 5 patients with local recurrence and 5 patients without recurrence based on the results of their follow-up imaging.

Lumason (sulfur hexafluoride lipid-type A microspheres) is an ultrasound contrast agent for injectable administration. This product is marketed under the name "Lumason" in the United States and "SonoVue" in Europe and Canada. Lumason is sulfur hexafluoride lipid microspheres that are composed of SF6 gas in the core surrounded by an outer shell monolayer of phospholipids consisting of distearoylphosphatidylcholine (DSPC) and dipalmitoylphosphatidylglycerol sodium (DPPG-Na) with palmitic acid as a stabilizer.

The single-patient use kit contains the following three items:

• one clear glass 10 mL vial containing 25 mg of white lyophilized powder lipid-type A, 60.7 mg of sulfur hexafluoride gas and capped with a blue flip-cap
• one prefilled syringe containing 5 mL Sodium Chloride 0.9% Injection, USP (Diluent)
• one Mini-Spike Each vial is formulated as a 25 mg sterile, pyrogen-free lyophilized powder containing 24.56 mg of polyethylene glycol 4000, 0.19 mg of DSPC, 0.19 mg of DPPG-Na and 0.04 mg of palmitic acid. The headspace of each vial contains 6.07 mg/mL (±2%) sulfur hexafluoride, SF6, or 60.7 mg per vial. Each prefilled syringe with 5 mL of diluent 0.9% Sodium Chloride Injection is sterile, nonpyrogenic, preservative free containing 9 mg sodium chloride per mL. Upon reconstitution with 5 mL diluent, Lumason is a milky white, homogeneous suspension containing sulfur hexafluoride lipid-type A microspheres. The suspension is isotonic and has a pH of 4.5 to 7.5.

Lumason will be stored in a secure cabinet, with only the study investigators and research personnel having access. New vials must be prepared for each subject's contrast administration. Unused drug and empty vials will be properly disposed of after reconciling in the log of study drug.