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Ionizing radiation kills tumor cells or inhibits the cell cycle mainly by damaging DNA in the cell nucleus. Patient-specific dose response may be influenced by inter-patient variation in cell/nucleus . This project investigates the relation between the pre-treatment patient-specific nuclei distribution obtained from digitized histopathology images and tumor recurrence outcomes for gynecological patients treated with radiotherapy.

Thirty-six gynecological cancer patients who underwent a combination of external beam radiotherapy, brachytherapy, and concurrent chemotherapy were included in this analysis, 25% of which experienced post radiotherapy recurrence. Median age at diagnosis was 59.5 years with a median follow-up time of 25.7 months. Patient-specific nuclei and cell spacing distributions from cancerous and non-tumoral regions of diagnostic pre-treatment hematoxylin and eosin-stained digital histopathology whole slide images were extracted. Each gigapixel histopathology whole slide (WSI) image was separated into patches. For each patient's WSI, the nuclei center was automatically detected by a blob detection algorithm where each nuclear content area was computed generating a nuclei radius distribution, a Voronoi cell diagram was constructed to estimate cell distributions. Probability of post radiotherapy recurrence given a pre-treatment patient-specific nuclei distribution mean was computed, as well as student t-tests for clinical variables such as stage, cancer type, and age at diagnosis between patients who had opposite post radiotherapy recurrence outcomes.  

Across all patients, inter-patient variability in nuclei distribution mean was observed for the both non-tumoral and cancerous regions with a median of 1.729 microns and 2.837 microns respectively, as presented in Figure 1. On a patient-level, a decrease in the probability of post radiotherapy recurrence given a larger patient-specific nuclei distribution mean was observed for both cancerous and non-tumoral region features as shown in Figure 2. Similarly in radiobiology experiments, Behmand et.al (Behmand et al 2021) showed a strong positive correlation between nuclei of HeLa and PC3 cell line with the number of γ-H2AX foci at an absorbed dose of 1, 2, and 4 Gy following irradiation with 225 kV x-rays and iridium 192 high dose rate brachytherapy. This offers a quantitative radiobiological explanation for the decreased likelihood in post radiotherapy probability for patients with larger nuclei.

Larger patient specific nuclei may cause more DNA damage on a radiobiological standpoint, which translated to lowered probability of post radiotherapy recurrence on a patient level. The results illustrate the importance of multiscale dosimetry where variation in patient specific nuclei were taken into account to enable personalized dose prescriptions and achieve optimal treatment prognosis in the clinic.