1. INTRA-TUMORAL METABOLIC HETEROGENEITY OF CERVICAL CANCER Perry Grigsby

2. Tumor Heterogeneity Definition

3. Pre-Treatment

12. Heterogeniety = d(V)/d(T)

14. Chemo-IMRT Timeline 7-8 weeks (~55 days) Pre-tx FDG-PET & MR PlanIMRT Post-tx Evaluateresponse ADC-MR to guide brachytherapy 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDRIMRT

15. Change in Heterogeneity During Treatment

16. Cu-ATSM Hypoxia

17. A B C AxialCoronalSagittal

19. ThresholdMean ± SEM 40%0.773 ± 0.013 50%0.536 ± 0.023 60%0.357 ± 0.024 70%0.202 ± 0.018 80%0.087 ± 0.010 Fraction of 64 Cu-ATSM Threshold Volume Within the FDG Defined Tumor Volume

20. 64 Cu-ATSM Heterogeneity 0 0.2 0.4 0.6 0.8 1 051015202530354045 p=0.04 Hetero > -1.7 Hetero ≤ -1.7 Time (Months) Progression Free Survival

21. Non-Spatial

22. Other Measures of Heterogeneity Texture & Shape of Metabolism

23. A toy example for demonstration of constructing the co-occurrence matrix. (a) Test image of size 4x4 and 4 intensity levels (M=4). The corresponding co-occurrence matrix assuming single pixel distance in: (b) East direction and (c) all directions. The matrix is converted into a probability mass function by normalization so that the sum is equal to unity.

28. Texture Features EnergyEnergy ContrastContrast Local HomogeneityLocal Homogeneity EntropyEntropy

29. Shape-based Features EccentricityEccentricity Euler NumberEuler Number SoliditySolidity ExtentExtent

30. 30 Volumetric run length type texture FeatureDefinitionDescription Short Run Emphasis Measures the distribution of short runs. The SRE is highly dependent on the occurrence of short runs and is expected large for fine textures. Long Run Emphasis Measures distribution of long runs. The LRE is highly dependent on the occurrence of long runs and is expected large for coarse structural textures. Low Gray-Level Run Emphasis Measures the distribution of low gray level values. The LGRE is expected large for the image with low gray level values. High Gray-Level Run Emphasis Measures the distribution of high gray level values. The HGRE is expected large for the image with high gray level values. Short Run Low Gray-Level Emphasis Measures the joint distribution of short runs and low gray level values. The SRLGE is expected large for the image with many short runs and lower gray level values. Short Run High Gray-Level Emphasis Measures the joint distribution of short runs and high gray level values. The SRHGE is expected large for the image with many short runs and high gray level values. Long Run Low Gray-Level Emphasis Measures the joint distribution of long runs and low gray level values. The LRLGE is expected large for the image with many long runs and low gray level values. Long Run High Gray-Level Emphasis Measures the joint distribution of long runs and high gray level values. The LRHGE is expected large for images with many long runs and high gray level values. Gray-Level Non-uniformity Measures the similarity of gray level values through out the image. The GLNU is expected small if the gray level values are alike through out the image. Run Length Non-uniformity Measures the similarity of the length of runs through out the image. The RLNU is expected small if the run lengths are alike through out the image. Run Percentage Measures the homogeneity and the distribution of runs of an image in a specific direction. The RP is the largest when the length of runs is 1 for all gray levels in specific direction.

31. Volumetric run length type texture 31

32. 32 Volumetric zone length type texture FeatureDefinition Short Zones Emphasis (SZE) Long Zones Emphasis (LZE) Low Grey-Level Zone Emphasis (LGZE) High Grey-Level Zone Emphasis (HGZE) Short Zone Low Gray-Level Emphasis (SZLGE) Short Zone High Gray-Level Emphasis (SZHGE) Long Zone Low Gray-Level Emphasis (LZLGE) Long Zone High Gray-Level Emphasis (LZHGE) Gray Level Non-Uniformity (GLNU) Zone Length Non-Uniformity (ZLNU) Zone Percentage (ZP)

33. Volumetric zone length type texture 33

34. Chemo-IMRT Timeline 7-8 weeks (~55 days) Pre-tx FDG-PET & MR PlanIMRT Post-tx Evaluateresponse ADC-MR to guide brachytherapy 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDR 4 days IMRT 1 day HDRIMRT

37. Diffusion Weighted Imaging T2WADC

39. Week 1 Week 3 Week 5 Patient 2 Patient 1 Olsen JR, et al. ASTRO 2011.

41. Tumor Volume Comparison

42. Tumor Sub-Volume Comparison

45. ADC Diffusion Weighted Imaging

46. Segmentation

47. DTI

48. DTI

49. Goals Identify Biologic TargetsIdentify Biologic Targets Improve Image Guided TherapyImprove Image Guided Therapy

50. Improve Survival with IMRT/IGRT External RT & Brachytherapy

51. Decrease Complications with IMRT/IGRT External RT & Brachytherapy

52. Future Directions Spatial Heterogeneity Pre-TreatmentIntra-TreatmentPost-Treatment

53. Future Directions

54. Whole-Body PET/MR Hybrid Imaging