title: Early detection of chemotherapy-refractory patients by monitoring textural alterations in diffuse optical spectroscopic images.
abstract: OBJECTIVE
  Changes in textural characteristics of diffuse optical spectroscopic (DOS) functional images, accompanied by alterations in their mean values, are demonstrated here for the first time as early surrogates of ultimate treatment response in locally advanced breast cancer (LABC) patients receiving neoadjuvant chemotherapy (NAC). NAC, as a standard component of treatment for LABC patient, induces measurable heterogeneous changes in tumor metabolism which were evaluated using DOS-based metabolic maps. This study characterizes such inhomogeneous nature of response development, by determining alterations in textural properties of DOS images apparent at early stages of therapy, followed later by gross changes in mean values of these functional metabolic maps.
  
  
  METHODS
  Twelve LABC patients undergoing NAC were scanned before and at four times after treatment initiation, and tomographic DOS images were reconstructed at each time. Ultimate responses of patients were determined clinically and pathologically, based on a reduction in tumor size and assessment of residual tumor cellularity. The mean-value parameters and textural features were extracted from volumetric DOS images for several functional and metabolic parameters prior to the treatment initiation. Changes in these DOS-based biomarkers were also monitored over the course of treatment. The measured biomarkers were applied to differentiate patient responses noninvasively and compared to clinical and pathologic responses.
  
  
  RESULTS
  Responding and nonresponding patients demonstrated different changes in DOS-based textural and mean-value parameters during chemotherapy. Whereas none of the biomarkers measured prior the start of therapy demonstrated a significant difference between the two patient populations, statistically significant differences were observed at week one after treatment initiation using the relative change in contrast/homogeneity of seven functional maps (0.001<p<0.049), and mean value of water content in tissue (p=0.010). The cross-validated sensitivity and specificity of these parameters at week one of therapy ranged between 80%-100% and 67%-100%, respectively. Higher levels of statistically significant differences were exhibited at week four after start of treatment, with cross-validated sensitivities and specificities ranging between 80% and 100% for three textural and three mean-value parameters. The combination of the textural and mean-value parameters in a "hybrid" profile could better separate the two patient populations early on during a course of treatment, with cross-validated sensitivities and specificities of up to 100% (p=0.001).
  
  
  CONCLUSIONS
  The results of this study suggest that alterations in textural characteristics of DOS images, in conjunction with changes in their mean values, can classify noninvasively the ultimate clinical and pathologic response of LABC patients to chemotherapy, as early as one week after start of their treatment. This provides a basis for using DOS imaging as a tool for therapy personalization.
authors.affiliation: Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Sadeghi-Naini
authors.affiliation: Department of Medical Physics, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Physics, Ryerson University, Toronto, Ontario M5B 2K3, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Vorauer
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Ontario M4N 3M5, Canada; Department of Medical Physics, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Department of Physics, Ryerson University, Toronto, Ontario M5B 2K3, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Chin
authors.affiliation: Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Omar
authors.initials: O
authors.lastname: Falou
authors.affiliation: Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: William T
authors.initials: WT
authors.lastname: Tran
authors.affiliation: Division of General Surgery, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Surgery, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Frances C
authors.initials: FC
authors.lastname: Wright
authors.affiliation: Division of Medical Oncology, Sunnybrook Health Sciences Centre, and Faculty of Medicine, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Sonal
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Yaffe
authors.affiliation: Physical Sciences, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M4N 3M5, Canada; Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario M4N 3M5, Canada; and Department of Radiation Oncology, University of Toronto, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Czarnota
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000188:drug therapy*; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D006801:Humans; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013057:Spectrum Analysis / Q000379:methods*; D041622:Tomography, Optical / Q000379:methods; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor