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Assessment of Proliferation in Vivo Using 2-[¹¹C]Thymidine Positron Emission Tomography in Advanced Intra-abdominal Malignancies¹

Department of Cancer Medicine [P. W., P. P.], MRC Cyclotron Unit [R. N. G., C. S., A. S. R., F. B., S. O., T. J.], and Department of Histopathology [M. A., M. G.], Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS, United Kingdom

The purpose of this study was to determine the relationship between 2-[¹¹C]thymidine positron emission tomography (PET) in vivo-derived parameters and the ex vivo Ki-67 index of proliferation in human tumors. The study comprised 17 treatment-naïve patients with advanced intra-abdominal malignancies. Tumor thymidine kinetics were measured using 2-[¹¹C]thymidine PET. Tissue data were analyzed to give the standardized uptake value, the area under the time activity curve, and the fractional retention of thymidine (FRT) obtained by kinetic modeling. For the latter, the contribution of labeled metabolites was accounted for by measuring thymidine metabolites in arterial plasma. To examine the influence of tumor blood flow on the thymidine PET data, a perfusion scan using inhaled [¹⁵O]CO₂ was carried out in a subset of 11 patients. Biopsies were stained with a MIB1 antibody to obtain a Ki-67 index, and correlations with the PET-derived parameters were investigated. There was no relationship between tumor blood flow and the thymidine PET data, showing that the retention of 2-[¹¹C]thymidine in tumors was independent of tumor perfusion. There was no correlation between the Ki-67 index and either standard uptake value or area under the curve. There was a correlation between the Ki-67 index and FRT (r = 0.58; P = 0.01). The correlation between the Ki-67 index and FRT in this dataset was not influenced by the interval between biopsy and imaging (0.1–126 weeks), the origin of the biopsy for Ki-67 staining (primary tumor or metastasis), or whether the biopsy was from an imaged or a nonimaged tumor. This is the first report in human tumors showing that 2-[¹¹C]thymidine PET-derived parameters correlate with the level of tumor proliferation measured using Ki-67 immunohistochemistry. The study shows that the in vivo measurement of 2-[¹¹C]thymidine in tumors using PET can provide a surrogate marker of proliferation and supports the potential use of the technique in the early assessment of response to antiproliferative cancer treatment.

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