Research ArticleBasic (Radiobiology/Dosimetry/Safety)
Open Access

Dosimetric Evaluation of the Effect of Receptor Heterogeneity on the Therapeutic Efficacy of Peptide Receptor Radionuclide Therapy: Correlation with DNA Damage Induction and In Vivo Survival

Giulia Tamborino, Julie Nonnekens, Marijke De Saint-Hubert, Lara Struelens, Danny Feijtel, Marion de Jong and Mark W. Konijnenberg
Journal of Nuclear Medicine January 2022, 63 (1) 100-107; DOI: https://doi.org/10.2967/jnumed.121.262122

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  • FIGURE 1.
    FIGURE 1.

    Schematic representation of methodology used to model in vivo survival distribution starting from immunofluorescent SSTR2 stainings used to define activity map (source) and functional volumes (tumor cells). Dose rate in each tumor voxel and radiobiologic information are then integrated in linear quadratic model to evaluate in vivo survival distribution within time intervals E(Ti). Probability density function of survival (gray histogram) is approximated by gaussian distribution (blue histogram) and reported with box plots to simplify representation. Volumetric absorbed dose computed over tumor cells is alternatively reported in 2 dimensions by means of cumulative dose–volume histograms (cDVH).

  • FIGURE 2.
    FIGURE 2.

    Absorbed dose response. (A) Correlation between average absorbed dose delivered to cancer cells and total number of DSBs measured by γHA2X foci formation. Highlighted area indicates 95% CI. (B) Representative tile-scan of SSTR2 stainings thresholded to identify areas of low and high SSTR2 expression. (C) Absorbed dose distribution map contoured for isodose levels, with color bar in grays. (D) Zoom of SSTR2 (red) and γH2AX (green) immunofluorescent stainings corresponding to high and low levels of SSTR2 expression, indicated by 1 and 2, respectively.

  • FIGURE 3.
    FIGURE 3.

    Template-matching technique. (A) Small tissue section used as template. (B) Large tissue section used as test image. (C) Color map indicating similarity score based on χ2 value overlaid on top of large tissue section. Color bars indicate pixel intensities of tile scans (grayscale) or similarity map (red-yellow). (D) Absorbed dose map with color bar in grays.

  • FIGURE 4.
    FIGURE 4.

    Box plots indicating in vivo survival distribution over time on different excised tissue sections. Whiskers correspond to 1.5 times interquartile range. Corresponding tissue section nomenclature is reported in Supplemental Table 1.

  • FIGURE 5.
    FIGURE 5.

    In vivo survival correlations. (A) Radiosensitivity parameter analysis for modeled heterogeneous survival (het). (B) Comparison with experimental data (TUNEL assay; 0 h = time of injection), including modeled results for average approach (avg) (i.e., 1 average S value). α and α/β are reported in Gy-1 and Gy, respectively. Error bars indicate 1 SD. (C) Cell survival correlation with and without regrowth for average calculation approach together with fitted relative tumor volume curve (0 h = onset of shrinkage shifted of 3 d) normalized to volume at time of injection (green triangles).

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