Monitoring Acute Changes in Pancreatic Tumor Perfusion with Contrast-Enhanced Ultrasound and Photoacoustic Imaging Following Targeted Hyaluronic Acid Treatment




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Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related deaths. Early diagnosis is crucial for treating PDAC but is unlikely due to the asymptomatic nature of the tumor in early stages. PDAC is usually diagnosed in late stages when it cannot be resected and is not responsive to chemotherapy (chemoresistance). The chemoresistance and late symptoms are mostly due to the presence of hyaluronan (HA, glycosaminoglycan) in the extracellular matrix (ECM). HA is a marker of tumor aggression and is hydrophilic. It retains water molecules and forms a gel-fluid phase which increases the tumor interstitial pressure, collapses the tumor microvasculature, and causes chemoresistance. HA can be degraded by an enzyme, pegylated pancreatic hyaluronidase (PEGPH20; targeted HA treatment), into its subunits. The aim of this study was to monitor the acute changes in tumor perfusion with contrast enhanced ultrasound and photoacoustic imaging following HA removal by PEGPH20. Athymic nude mice (N=18) were implanted subcutaneously in the peri-tibial region of the right leg with 2 million pancreatic cancer cells. Contrast enhanced ultrasound (CEUS) and photoacoustic (PA) imaging studies were conducted at baseline (0 h) and at 6 h. A single dose of PEGPH20 (treatment) or saline (control) was injected at baseline. After the targeted removal of HA by PEGPH20, the tumor microvasculature expanded and an increase in tumor perfusion parameters; peak enhancement (PE) and wash-in rate (WiR) measured by CEUS, and total hemoglobin signal (HbT) and oxygen saturation (sO2) measured by PA was seen. These changes in CEUS and PA measures were confirmed by histological analysis of the excised tumor tissue. In conclusion, we saw a 50% increase in perfusion parameters at 6 h post treatment as compared to the control group. These acute changes in pancreatic tumor tissue can be monitored noninvasively by CEUS and PA imaging within 6 h of HA removal by PEGPH20.



Contrast-enhanced ultrasound, Diagnostic imaging, Pancreas -- Cancer, Pancreatic duct


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