Faculty Bibliography

Purpose: There is limited data regarding how many cycles of chemotherapy are optimal prior to debulking surgery in metastatic ovarian cancer. Furthermore, early identification of non-responders would prompt discontinuation of chemotherapy and earlier surgical management. The purpose of our study was to investigate the performance of FDG PET, dynamic contrast-enhanced (DCE) and intra-voxel incoherent motion (IVIM) MR as early predictors of treatment response in ovarian cancer. Parametric images of molecular diffusion restriction (D), tissue perfusion (D[asterisk]), vascular volume fraction (F), blood->interstitium constant of transfer (Ktrans), interstitum->plasma constant of transfer (Kep), extravascular/extracellular volume % (Ve) and plasma volume % (Ve) were investigated along with routine measures of SUV and ADC. Materials & Methods: Five subjects with a new diagnosis of epithelial ovarian cancer enrolled in the study. All subjects underwent 3 cycles of standardized chemotherapy followed by cytoreduction (debulking surgery). FDG PET/MR including DCE and IVIM was performed at baseline (T1), after cycle 1 (T2) and after cycle 3 (T3) of chemotherapy. Final responses were categorized at T3 by RECIST 1.1. Olea 3.0 software was used to generate parametric images from the multi-B-value DWI and DCE-MR datasets at all three timepoints. Parametric DICOM images were then coregistered to anatomical datasets using MIMvista and fusion was manually adjusted to optimize co-registration of tumor lesions across the multiple datasets. VOIs were manually drawn on clearly visible solid tumor deposits on PET, DCE-MR and DWI MR images. The parametric images derived from IVIM and DCE-MR at T2 were analyzed as early predictors of final response. Results: Five subjects completed FDG PET and IVIM-MR, three of which underwent DCE-MR. All subjects were partial responders by RECIST at T3. SUV values were only available for 4/5 patients due to technical difficulties and DCE-MR was only available for 3/5. All 5 subjects had good IVIM data. At T2, the SUVmax decreased on average by -39% across all subjects (p<0.001) and the SUVmean decreased on average by -43% across all subjects (p<0.001). At T2, the ADCmean increased on average by +25% across all subjects (p<0.05). At T2, the molecular diffusion restriction (D) increased on average by +43% across all subjects, approaching statistical significance (p=0.058). Furthermore, D[asterisk], F, Kep, Ktrans, and Vp increased in some subjects and decreased in others, without any recognizable pattern. Ve decreased in 3/3 patients, however, not reaching statistical significance. Conclusions: In this current FDG PET/MR study of ovarian cancer, SUVmax and ADCmean values obtained after one cycle of chemotherapy were consistently associated with partial anatomical treatment responses at end of therapy. These findings are in agreement with pre-existing literature studying the value of SUV and ADC in early treatment response assessment. Only one of seven advanced perfusion/diffusion metrics (D; molecular diffusion restriction) was reliably associated with treatment response. This finding that D is associated with treatment response is not surprising given that it is based on ADC without the contribution of intravascular diffusion. Our current small dataset does not yet demonstrate the value of the remaining analyzed advanced DCE-MR and DWI parameters. Further study is required to determine the utility of DCE- and IVIM-derived parameters in early response assessment. Voxelwise correlative studies and other advanced data processing methods are underway to determine if these advanced quantitative parameters may provide further information in the early assessment of chemotherapy treatment response. (Table Presented)

BACKGROUND: Targeted therapies in HER2-positive metastatic breast cancer significantly improve outcomes but efficacy is limited by therapeutic resistance. HER2 is an acutely sensitive Heat Shock Protein 90 (HSP90) client and HSP90 inhibition can overcome trastuzumab resistance. Preclinical data suggest that HSP90 inhibition is synergistic with taxanes with the potential for significant clinical activity. We therefore tested ganetespib, a HSP90 inhibitor, in combination with paclitaxel and trastuzumab in patients with trastuzumab-refractory HER2-positive metastatic breast cancer. METHODS: In this phase I dose-escalation study, patients with trastuzumab-resistant HER2-positive metastatic breast cancer received weekly trastuzumab (2 mg/kg) and paclitaxel (80 mg/m2) on days 1, 8, 15, and 22 of a 28-day cycle with escalating doses of ganetespib (100 mg/m2, 150 mg/m2, and a third cohort of 125 mg/m2 if needed) on days 1, 8, and 15. Therapy was continued until disease progression or toxicity. The primary objective was to establish the safety and maximum tolerated dose and/or recommended phase II dose (RP2D) of this therapy. The secondary objectives included evaluation of the effects of ganetespib on the pharmacokinetics of paclitaxel, and to make a preliminary assessment of the efficacy of the combination therapy. RESULTS: Dose escalation was completed for the two main cohorts without any observed dose-limiting toxicities. Nine patients received treatment. The median prior lines of anti-HER2 therapy numbered three (range 2-4), including prior pertuzumab in 9/9 patients and ado-trastuzumab emtansine (T-DM1) in 8/9 patients. The most common grade 1/2 adverse events (AEs) were diarrhea, fatigue, anemia, and rash. There were no grade 4 AEs related to ganetespib. The overall response rate was 22% (2/9 patients had partial response) and stable disease was seen in 56% (5/9 patients). The clinical benefit rate was 44% (4/9 patients). The median progression-free survival was 20 weeks (range 8-55). CONCLUSION: The RP2D of ganetespib is 150 mg/m2 in combination with weekly paclitaxel plus trastuzumab. The combination was safe and well tolerated. Despite prior taxanes, pertuzumab, and T-DM1, clinical activity of this triplet regimen in this heavily pretreated cohort is promising and warrants further study in HER2-positive metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT02060253 . Registered 30 January 2014.

Interpretation of iodine I whole-body scintigraphy can be challenging, as there are many nonpathologic findings that may present with increased radiotracer uptake. Radiotracer uptake has been reported in the literature involving the salivary glands, thymus, renal cysts, skin contamination, and other benign etiologies. We present the case of an incidental right wrist ganglion cyst demonstrating persistent increased uptake on I whole-body scintigraphy.

PURPOSE: The aim of this study was to conduct a prospective pilot study comparing the diagnostic performance of MRI alone and F-FDG simultaneous PET/MRI using a diuresis protocol in bladder cancer patients. METHODS: Twenty-two bladder cancer patients underwent F-FDG PET/MRI, using intravenous furosemide and oral hydration for bladder clearance. A radiologist scored probability of tumor in 3 locations (urinary bladder, pelvic lymph nodes, nonnodal pelvis) using 1- to 3-point scale (1 = negative, 2 = equivocal, 3 = definite tumor). A nuclear medicine physician reviewed fused PET/MRI images, after which scores were reassigned based on combined findings. Follow-up pathologic and imaging data served as reference. Performances of MRI alone and PET/MRI were compared. RESULTS: Of these patients, 82%, 38%, and 18% were positive for bladder, pelvic nodal, and nonnodal pelvic tumor, respectively. At a score of 3, PET/MRI exhibited greater accuracy for detection of bladder tumor (86% vs 77%), metastatic pelvic lymph nodes (95% vs 76%), and nonnodal pelvic malignancy (100% vs 91%). In the bladder, PET changed the level of suspicion in 36% of patients (50% increased suspicion, 50% decreased suspicion), with 75% of these changes deemed correct based on reference standard. For pelvic lymph nodes, PET changed suspicion in 52% (36% increase, 64% decrease), with 95% of changes deemed correct. For nonnodal pelvis, PET changed suspicion in 9% (100% increase), with 100% deemed correct. CONCLUSIONS: Additional PET information helped to appropriately determine level of suspicion in multiple anatomic sites for otherwise equivocal findings on MRI alone. Although requiring larger studies, findings suggest a possible role for simultaneous PET/MRI to assist bladder cancer management.

Besides amyloid deposition, white matter (WM) changes are involved in the early pathogenesis of Alzheimer's Disease (AD), including inflammation, demyelination and axonal loss. Using simultaneous PET and MRI, we investigated differences in WM microstructural integrity, measured with Diffusion Kurtosis Imaging (DKI), with respect to beta amyloid (Aa) deposition as measured with18F-Florbetapir PET. DKI is a clinically feasible diffusion MRI method that extends beyond Diffusion Tensor Imaging and probes non-Gaussian diffusion properties of nervous tissue, and allows for quantifying the microstructural index for the axonal water fraction (AWF), a specific marker for axonal degeneration and demyelination. Methods: 34 subjects were scanned on a 3T integrated PET-MRI system (Siemens Biograph mMR, VB20). 18FFlorbetapir (9 mCi, Eli Lilly) was injected intravenously and a static 20-minute PET image was reconstructed starting at 40 min post-injection using a UTE-based attenuation map. An anatomical MP-RAGE was acquired for cortical and sub-cortical segmentation using Freesurfer. Hippocampal volume was normalized to the estimated total intracranial volume. The standardized uptake values (SUV) in 5 cortical regions known for pathological uptake of Florbetapir (anterior and posterior cingulate, medial orbito-frontal, parietal and temporal), normalized to the cerebellum, yielded mean cortical relative SUV (SUVr). DKI provided parametric maps for the radial diffusivity (RD), radial kurtosis (RK), and the AWF. Using a lower and higher mean SUVr threshold of 1.0 and 1.1, age- and gender-controlled subjects were categorized into Aa negative (Aa-) (n = 13, 5 females, age = 69.8 +/- 5.1 yrs), Aa intermediate (Aai) (n = 13, 8 females, age = 68.9 +/- 4.8 yrs), or Aa positive (Aa+) (n = 8, 4 females, age = 70.6 +/- 5.3 yrs). Using Tract-Based Spatial Statistics (TBSS), skeletonized voxel-wise analysis was performed to identify areas of differences in the diffusion metrics while covarying for age. Separately, WM regions of interests (ROIs) were automatically segmented using atlas registration over which mean values were extracted. Analysis of covariance covarying for age was used to compare diffusion metrics and hippocampal volume among groups. Results: See figure. Results from both TBSS and ROI analysis demonstrated changes in the fornix and the genu of the corpus callosum. Between the Aa- and Aai groups, RD decreased while RK and AWF increased. Conversely, between the Aai and Aa+ groups, RD increased RD while RK and AWF decreased. A trend towards significantly higher hippocampal volume in the Aai group was observed. Conclusions: We report changes in RD, RK and AWF in opposite directions between Aa- and Aa~, and between Aa~ and Aa+, respectively, suggesting that different mechanisms affect the microstructure during different stages of AD. Early on, mechanisms including microglial activation may restrict diffusion, resulting in the observed decrease in RD and increase in RK and AWF. Later on, neurodegenerative effects such as demyelination and axonal loss may outweigh inflammation, resulting in the observed increase in RD and decrease in RK and AWF. [IMAGE PRESENTED]

Hybrid imaging systems have dramatically improved thoracic oncology patient care over the past 2 decades. PET-MR imaging systems have the potential to further improve imaging of thoracic neoplasms, resulting in diagnostic and therapeutic advantages compared with current MR imaging and PET-computed tomography systems. Increasing soft tissue contrast and lesion sensitivity, improved image registration, reduced radiation exposure, and improved patient convenience are immediate clinical advantages. Multiparametric quantitative imaging capabilities of PET-MR imaging have the potential to improve understanding of the molecular mechanisms of cancer and treatment effects, potentially guiding improvements in diagnosis and therapy.

OBJECTIVE: This article explores recent developments in PET and MRI, separately or combined, for assessing metastatic lymph nodes in patients with head and neck cancer. CONCLUSION: The synergistic role of PET and MRI for imaging metastatic lymph nodes has not been fully explored. To facilitate the understanding of the areas that need further investigation, we discuss potential mechanisms and evidence reported so far, as well as future directions and challenges for continued development and clinical research.

PURPOSE: There is considerable controversy over the treatment of medication-related osteonecrosis of the jaw (MRONJ) and growing interest and debate related to the timing, type, technique, and goals of surgical intervention. The specific aim was to evaluate the predictive value of fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT) on healing outcomes in patients undergoing surgery for MRONJ of the mandible. MATERIALS AND METHODS: A retrospective cohort study of 31 patients with 33 MRONJ lesions of the mandible who had undergone surgery using FDG PET-CT was conducted. Data were collected on FDG uptake patterns, healing, follow-up, demographics, lesion characteristics, antiresorptive therapy, and adjunctive therapy. Panoramic and periapical radiographs were used to identify non-restorable teeth and PET-CT images were used to identify sequestra and FDG uptake. Above the mandibular canal, surgery consisted of marginal resection or debridement of clinically involved bone and exposure of clinically uninvolved bone identified by FDG uptake. Below the mandibular canal, mobile segments of bony sequestra were removed, but areas of clinically uninvolved bone with FDG uptake were not. Patients who did not heal underwent segmental resection and reconstruction with rigid fixation and a local or regional soft tissue flap or free fibular flap. The primary predictor variable was the FDG uptake pattern for each patient. The outcome variable was postoperative healing defined by mucosal closure without signs of infection or exposed bone at the time of evaluation. RESULTS: Two risk groups were identified based on FDG uptake pattern. The low-risk group, type A, included 22 patients with activity limited to the alveolus, torus, and basal bone superior to the mandibular canal. The high-risk group, type B, included 11 patients with type A FDG activity with extension inferior to the mandibular canal. Treatment of type A MRONJ lesions was more successful than treatment of type B MRONJ lesions (100 vs 27%; P < .001). Seven of the type B failures were successfully retreated by segmental resection and reconstruction (1 patient refused further treatment). CONCLUSION: These results showed that low-risk FDG PET-CT findings predicted successful healing with surgery above the mandibular canal. In contrast, high-risk FDG findings were associated with a greater than 50% risk of failure for treatment that extended below the mandibular canal. Although these failures suggest that FDG uptake indicates infected tissue, further research is needed to identify which high-risk patients are most likely to benefit from a conservative treatment protocol.

Objectives Learning objectives: 1. To review morphologic and functional imaging changes on PET/CT following various lymphoma treatment regimens. 2. To evaluate various circumstances under which the morphologic and functional imaging changes are concordant or discordant. The World Health Organization International Classification of Disease (2008) identifies numerous types of lymphoma based on histopathologic, immunohistochemical, cytogenetic, and molecular analyses. Practically, only a few subtypes of lymphoma account for the majority of cases such as diffuse large B cell lymphoma. Many of the lymphomas are potentially curable when treated with chemotherapy alone or in combination with radiation therapy; remainder are only potentially curable with stem cell transplantation. Nowadays PET/CT imaging is crucial in staging and treatment response assessment for most of these lymphomas. On PET/CT there are multiple imaging patterns of the treatment response. Additionally, there have been continuing efforts to establish the response criteria on PET/CT to help aid optimal treatment decisions. This exhibit is designed to review and understand the various imaging patterns observed on the PET/CT on treatment of the lymphoma following simple and complex treatment regimens