Analysis of the intra- and intertumoral heterogeneity of hypoxia in pancreatic cancer patients receiving the nitroimidazole tracer pimonidazole.
BACKGROUND
Hypoxia is thought to be an adverse feature of pancreatic cancer, but direct measurement in patients is technically challenging. To address this, we characterised the intra/interpatient heterogeneity of hypoxia in surgical specimens from patients who received the 2-nitroimidazole tracer pimonidazole pre-operatively.


METHODS
Pimondazole was given intravenously 16-20 h before pancreatectomy, and the extent and intratumoral heterogeneity of hypoxia determined by image analysis applied to multiple tissue blocks stained by immunohistochemistry. Intra/interpatient heterogeneity was estimated by variance component analysis.


RESULTS
Pimonidazole staining was analysed in 10 tumours. The extent of labelling varied amongst patients (0-26%), with a broader range of hypoxia in the epithelial (1-39%) compared with the stromal (1-13%) compartments. Variance component analysis demonstrated greater inter- than intrapatient variability of hypoxia, and that multiple (4-5) tumour sections are required to provide a consistent evaluation of its extent in individual tumours.


CONCLUSIONS
There is significant intra- and intertumoral heterogeneity of hypoxia in pancreatic cancers, and these do not appear to be generally more hypoxic than other cancer types. This study establishes the feasibility to assess hypoxia in pancreatic cancer patients using pimonidazole, but questions the reliability of measurements made using a single tissue section.
Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Dhani
Department of Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Serra
Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, M5G 2M9.
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Pintilie
Department of Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Schwock
Applied Molecular Profiling Laboratory, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Xu
Division of Hepato-biliary Pancreatic Surgical Oncology, University Health Network and Mount Sinai Hospital, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Gallinger
Radiation Medicine Program, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Hill
Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9.
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Hedley
D000328:Adult; D000704:Analysis of Variance; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D015687:Cell Hypoxia; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011292:Premedication; D015983:Selection Bias
D007202:Indicators and Reagents; D009593:Nitroimidazoles; C033815:pimonidazole