Molecular Imaging Theme 2 Accomplishments

Molecular Imaging Theme 2 Accomplishments

Ultrasound tomography (UST) has been developed by Drs. Duric and Littrup to address the limitations of mammography in breast imaging.  This technology was cleared by the FDA for clinical use in December 2013.  UST has been used by Drs. Duric and Littrup to perform the following studies:

1. Characterize lesions on the basis of their biomechanical properties.  In a study of 162 patients they measured biomechanical properties of lesions to estimate the ability to differentiate cancer, fibroadenomas and cysts, the three most common pathologies in the breast. Figure 1 shows the distinct groupings of these lesions based on these properties.  Using a cut line that yields 100 NPV they found a PPV of 80%.  The corresponding PPV for conventional ultrasound was found to be 55%.  This work is being carried out under an SBIR grant from the NCI.  These studies are being extended to multiple sites including Royal Marsden Hospital, UK, University of Michigan and University of Iowa.
   
   
   

   Figure . Lesions were characterized Using the measured properties of speed of sound, attenuation and reflectivity. The corresponding values were plotted in parametric form to produce the graph. Biopsy results (assumed truth) were used to identify the type of lesion.
2. Assess treatment response on the basis of breast density changes (e.g chemoprevention) and/or biomechanical properties of tumors (e.g. Neoadjuvant chemotherapy).  Drs. Littrup and Duric, together with their collaborators, Drs. Sherman and Gierach (NCI), and Dr. Boyd (University of Toronto), are carrying out a study measuring changes in breast density as a marker of response to the chemo-preventive agent Tamoxifen.  Preliminary results are shown in Figure 2.  This work is being carried out under an NCI contract.  Results suggest that changes, as early as two months after onset of treatment, can be discerned.  In parallel with this effort, Drs. Littrup and Duric are collaborating with Drs. Albrecht and Simon of the Population Studies and Disparities Research Program to quantify changes in tumor properties in patients undergoing neoadjuvant chemotherapy.  Preliminary results suggest that changes in properties of tumors may predict pCR as early as 1 to 2 weeks after the onset of chemotherapy (Figure 3).
   
   
   

   Figure 2. Patients undergoing Tamoxifen treatment (N=45) were scanned using UST to quantify their breast density at baseline (before onset of treatment) and on three follow-up visit spanning 1 year. The data were binned according to changes relative to baseline.
   

   Figure 3. Patients undergoing Neoadjuvant chemotherapy were imaged with UST at each treatment visit (N=25). The tumor stiffness and volume were parameterized into a single biomechanical marker and tracked for each patient showing how the marker changes, on average, among partial or non-responders (red) vs complete responders (blue).
3. Investigate the use of the whole-breast sound speed measurement as a marker of breast density (BD), a known risk factor for breast cancer. In a study of 249 patients the volume averaged sound speeds (VASS) of the breast for each patient were compared to the corresponding mammograms to calculate mammographic percent density (MPD).  The Spearman correlation coefficient (rS) between VASS and MPD was found to be 0.71 and 0.77 for digital and film mammography, respectively.  This result sets the stage for future work that will focus on directly testing the association of UST measured density with breast cancer risk.  Work with Dr. Maev may be able to extend UST to imaging the brain.  He has developed methods to measure both sound velocity and thickness of the human skull bone, which will be needed to reconstruct brain images for tumor imaging.

Under the second scientific theme, the use of susceptibility weighted imaging (SWI) and diffuse weighted imaging (DWI) with MRI has been used in the evaluation of patients with cancer.  In a study of 37 patients with renal cell carcinoma using SWI, more dominant vascular structures and less hemorrhage were seen in low-grade tumors (2.15±1.05) compared to high-grade tumors (1.27±0.47) (P<0.005).  The ratio of intratumoral susceptibility signal intensity area to tumor area was also significantly higher for the high-grade group (1.55±0.52) than that for the low-grade group (0.88±0.43) on SWI (P<0.005).   Since grade is important in deciding appropriate treatment, this approach may find clinical utility.  Researchers completed the meta-analysis of the diagnostic performance of DWI and 18F-FDG PET/CT in the mediastinal and hillar nodes of patients with N stage non-small cell lung cancer. This study of 2845 pathologically confirmed patients found no significant difference in the pooled sensitivity estimate of DWI and PET/CT.  However, the pooled specificity estimate for DWI (0.95, 95% CI 0.85-0.98) was significantly greater than for 18F-FDG PET/CT (0.89, 95% CI 0.85-0.91; P = 0.02). This demonstrates the utility of DWI MRI in routine lung cancer staging.

• Lead researcher - Dr. Haacke

Program members have worked to extend the use of the PET tracers through national studies, including FDG to assess metabolism, 18F-sodium fluoride (NaF) for bone imaging, and 18F-FLT for proliferation.  He has served has co-chair of the National Oncology PET Registry (NOPR) and in collaboration with the Centers for Medicare and Medicaid Services (CMS) prospective data has been collected from Medicare recipients who have undergone PET assessment with FDG and NaF for cancers and indications not previously eligible for Medicare reimbursement.  The primary scientific objective of the NOPR was to measure the impact of PET on the referring physician’s intended patient management by collecting questionnaire data before PET and again after the PET results were available for decision making.  Results were collected and analyzed from over 341,000 FDG and 27,000 NaF PET scans.  For FDG-PET for restaging or suspected recurrence, comparing the total change in intended management ranged by cancer type 31%–41%.  PET for chemotherapy monitoring was associated with a 25% increase in plans to continue therapy and a complementary decline in plans to adjust therapy.  Based on these results CMS approved expanded use of FDG-PET for all cancers and many more indications, with exceptions for staging some early cancers and surveillance.  More recently, similar analyses have been conducted with NaF PET, where 75% of scans were done for prostate cancer, 10% for breast cancer, 5% for lung cancer, and 10% for other cancers.  In prostate cancer patients after NaF PET, the post-imaging plan was revised to treatment in 77% of patients imaged as part of initial staging, 52% done for suspected first osseous metastases, and 71% for suspected progression.  For non-prostate cancers, the change in intended management averaged 48.3%.  This work has recently been submitted to CMS with a request to approve all oncologic indications for 18F-sodium fluoride (NaF) PET imaging.

• Lead researcher - Dr. Shields