title: Heterogeneity in intratumor correlations of 18F-FDG, 18F-FLT, and 61Cu-ATSM PET in canine sinonasal tumors.
abstract: Intratumor heterogeneity in biologic properties and in relationships between various phenotypes may present a challenge for biologically targeted therapies. Understanding the relationships between different phenotypes in individual tumor types could help inform treatment selection. The goal of this study was to characterize spatial correlations of glucose metabolism, proliferation, and hypoxia in 2 histologic types of tumors.
  
  
  METHODS
  Twenty canine veterinary patients with spontaneously occurring sinonasal tumors (13 carcinomas and 7 sarcomas) were imaged with (18)F-FDG, (18)F-labeled 3'-deoxy-3'-fluorothymidine ((18)F-FLT), and (61)Cu-labeled diacetyl-bis(N(4)-methylthiosemicarbazone) ((61)Cu-ATSM) PET/CT on 3 consecutive days. Precise positioning and immobilization techniques coupled with anesthesia enabled motionless scans with repeatable positioning. Standardized uptake values (SUVs) of gross sarcoma and carcinoma volumes were compared by use of Mann-Whitney U tests. Patient images were rigidly registered together, and intratumor tracer uptake distributions were compared. Voxel-based Spearman correlation coefficients were used to quantify intertracer correlations, and the correlation coefficients of sarcomas and carcinomas were compared. The relative overlap of the highest uptake volumes of the 3 tracers was quantified, and the values were compared for sarcomas and carcinomas.
  
  
  RESULTS
  Large degrees of heterogeneity in SUV measures and phenotype correlations were observed. Carcinoma and sarcoma tumors differed significantly in SUV measures, with carcinoma tumors having significantly higher (18)F-FDG maximum SUVs than sarcoma tumors (11.1 vs. 5.0; P = 0.01) as well as higher (61)Cu-ATSM mean SUVs (2.6 vs. 1.2; P = 0.02). Carcinomas had significantly higher population-averaged Spearman correlation coefficients than sarcomas in comparisons of (18)F-FDG and (18)F-FLT (0.80 vs. 0.61; P = 0.02), (18)F-FLT and (61)Cu-ATSM (0.83 vs. 0.38; P < 0.0001), and (18)F-FDG and (61)Cu-ATSM (0.82 vs. 0.69; P = 0.04). Additionally, the highest uptake volumes of the 3 tracers had significantly greater overlap in carcinomas than in sarcomas.
  
  
  CONCLUSIONS
  The relationships of glucose metabolism, proliferation, and hypoxia were heterogeneous across different tumors, with carcinomas tending to have high correlations and sarcomas having low correlations. Consequently, canine carcinoma tumors are robust targets for therapies that target a single biologic property, whereas sarcoma tumors may not be well suited for such therapies. Histology-specific PET correlations have far-reaching implications for the robustness of biologic target definition.
authors.affiliation: Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Bradshaw
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bowen
authors.forename: Ngoneh
authors.initials: N
authors.lastname: Jallow
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Forrest
authors.forename: Robert
authors.initials: R
authors.lastname: Jeraj
mesh_terms: D000818:Animals; D001692:Biological Transport; D015687:Cell Hypoxia; D049109:Cell Proliferation; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D015224:Dideoxynucleosides / Q000378:metabolism; D004283:Dog Diseases / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology*; D004285:Dogs; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D009367:Neoplasm Staging; D009669:Nose Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000662:veterinary*; D009942:Organometallic Compounds / Q000378:metabolism; D049268:Positron-Emission Tomography; D013882:Thiosemicarbazones / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D056831:Coordination Complexes; D003301:Copper Radioisotopes; D015224:Dideoxynucleosides; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D019788:Fluorodeoxyglucose F18; D005947:Glucose; C002854:alovudine
keywords: 18F-FDG; 18F-FLT; 61Cu-ATSM; dose painting; heterogeneity
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