Hepato-pancreato-biliary
Ryan C. Bynum, MD
Resident
The University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Ryan C. Bynum, MD
Resident
The University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Tereza Husarova, MD
Resident
Military University Hospital Prague, United States
Emma Sanderson, n/a
Student
The University of Oklahoma Health Sciences Center, United States
Ajay Jain, MD, FACS
Professor
The University of Oklahoma Health Sciences Center, United States
Lacey McNally, PhD
Professor
The University of Oklahoma Health Sciences Center, United States
Barish Edil, MD, FACS
Professor
The University of Oklahoma Health Sciences Center, United States
While serum markers such as CA19-9 and CEA are useful biomarkers in diagnosing pancreatic cancer, they can be discordant with imaging findings. We hypothesized that tissue pH could be used as a marker for pancreatic cancer. As such we assessed intraoperative pH measurements of pancreatic human tumors and used a pH probe to image pancreatic cancer in pathological specimens and an orthotopic murine model using multispectral optoacoustic imaging (MSOT).
Methods:
A radiologically guidance microelectrode was placed intraoperatively to measure pH of human pancreatic cancer specimens and grossly uninvolved tissue immediately following resection in 20 patients. Then a pH probe (V7) was selected and synthesized with microwave chemistry. V7 was conjugated to 750 dye and uptake measured in vitro in pancreatic cancer cell lines (S2VP10 and S2013) grown in pH specific media (7.4, 6.8, 6.6). Specificity of V7-750 was then measured in human pathological specimens using fluorescence imaging. MSOT was then used to image female athymic mice with 3mm sized tumors following orthotopic implantation with S2VP10 or S2013 cells using intravenously injected V7-750. Accumulation on probe in tumor was confirmed with near infrared imaging. Statistical analysis was performed using ANOVA and the Wilcoxon test.
Results:
Intraoperative pH of pancreatic tumors was significantly more acidic than uninvolved pancreatic tissue (Figure 1A), pH 6.18-6.65 vs pH 7.17-7.27 (p< 0.01). In vitro, greater fluorescence was demonstrated by V7-750 at more acidic pH, centered at pH 6.6 (p=0.015). In ex vivo human surgical specimens, tumor specific uptake of V7-750 was greater at pH 6.6 vs 7.2 (p=0.01) (Figure 1B). In orthotopic murine models, V7-750 demonstrated specificity for tumor over uninvolved tissue (kidneys and liver) in both S2VP10 (p=0.011) and S2013 (p=0.021) orthotopic murine models of pancreatic cancer (Figure 1C).
Conclusions:
Human pancreatic tumor has significantly more acidic pH compared to uninvolved surrounding tissue. As such the V7 can be effective in imaging of pancreatic tumors based on pH using MSOT. This imaging modality is currently undergoing translation into large animal models, a promising next step in its translation from preclinical to clinical use.