Detection of Pancreatic Carcinomas by Imaging Lactose-Binding Protein Expression in Peritumoral Pancreas Using [18F]Fluoroethyl-Deoxylactose PET/CT

Abstract

BackgroundEarly diagnosis of pancreatic carcinoma with highly sensitive diagnostic imaging methods could save lives of many thousands of patients, because early detection increases resectability and survival rates. Current non-invasive diagnostic imaging techniques have inadequate resolution and sensitivity for detection of small size (∼2–3 mm) early pancreatic carcinoma lesions. Therefore, we have assessed the efficacy of positron emission tomography and computer tomography (PET/CT) imaging with β-O-D-galactopyranosyl-(1,4′)-2′-deoxy-2′-[18F]fluoroethyl-D-glucopyranose ([18F]FEDL) for detection of less than 3 mm orthotopic xenografts of L3.6pl pancreatic carcinomas in mice. [18F]FEDL is a novel radioligand of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), which is overexpressed in peritumoral pancreatic acinar cells.Methodology/Principal FindingsDynamic PET/CT imaging demonstrated rapid accumulation of [18F]FEDL in peritumoral pancreatic tissue (4.04±2.06%ID/g), bi-exponential blood clearance with half-lives of 1.65±0.50 min and 14.14±3.60 min, and rapid elimination from other organs and tissues, predominantly by renal clearance. Using model-independent graphical analysis of dynamic PET data, the average distribution volume ratio (DVR) for [18F]FEDL in peritumoral pancreatic tissue was estimated as 3.57±0.60 and 0.94±0.72 in sham-operated control pancreas. Comparative analysis of quantitative autoradiographic images and densitometry of immunohistochemically stained and co-registered adjacent tissue sections demonstrated a strong linear correlation between the magnitude of [18F]FEDL binding and HIP/PAP expression in corresponding regions (r = 0.88). The in situ analysis demonstrated that at least a 2–4 fold apparent lesion size amplification was achieved for submillimeter tumors and to nearly half a murine pancreas for tumors larger than 3 mm.Conclusion/SignificanceWe have demonstrated the feasibility of detection of early pancreatic tumors by non-invasive imaging with [18F]FEDL PET/CT of tumor biomarker HIP/PAP over-expressed in peritumoral pancreatic tissue. Non-invasive non-invasive detection of early pancreatic carcinomas with [18F]FEDL PET/CT imaging should aid the guidance of biopsies and additional imaging procedures, facilitate the resectability and improve the overall prognosis.

Detection of pancreatic cancer tumours and precursor lesions by cathepsin E activity in mouse models

“…Furthermore, micro single-photon emission CT/CT is already used in the clinic, so that this plectin probe may be quickly adapted for human use. In another approach, it was shown that it is possible to image increased levels of pancreatitis-associated protein (PAP), which is expressed in pancreatic acinar cells surrounding foci of pancreatic cancer or pancreatic inflammation, using ( 18 F)-fluoroethyl-deoxylactose (FDG) positron emission tomography 37. The localisation of PAP has the advantage that the area occupied by cells expressing this molecule is much greater than the volume of the cancer cells themselves.…”

Preliminary evaluation of 1′-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for detection of pancreatic cancer in nude mouse orthotopic xenografts

“…To establish pancreatic tumor xenografts in nude mice, human L3.6pl pancreatic cancer cells were stably transduced with a retroviral vector bearing dual reporter gene GL, a tandem fusion of the green fluorescence protein and firefly luciferase genes, as previously reported [18]. Transduced L3.6pl-GL + cells were selected by fluorescence-activated cell sorting and their fluorescence and bioluminescence properties were characterised as previously described [22].…”

“…Tumor implantation was performed as previously described [18]. Briefly, 4- to 6-week-old athymic nude mice (n=15, Charles River Laboratories) were anaesthetised by isoflurane inhalation (2–2.5% in oxygen).…”

“…The final product was synthesized by radiofluorination of a precursor, which was synthesized through a 12-step process. [ 18 F]FEDL demonstrated efficacy in the micro-PET/CT detection of early microscopic pancreatic carcinoma lesions in an orthotopic xenograft model of L3.6pl pancreatic carcinoma in mice [18]. …”

Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions

“…In a recent study, Zhao et al (139) reported earlier detection of pancreatic cancer xenografts with 11 C-acetate PET than with FDG PET, but the ratio of radiotracer accumulation between tumor and nontumor in 11 C-acetate PET was lower than that in FDG PET during the same period. Another radiotracer, 18 F-FEDL, which is overexpressed in peritumoral pancreatic acinar cells, was reported to be helpful for detection of small pancreatic cancer lesions (140). Additional studies are needed to evaluate the performance of new radiotracers for detecting and characterizing pancreatic cancer specifically.…”