Faculty Bibliography

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 1. Review the existing literature on radio-guided surgery using conventional nuclear medicine and PET radiopharmaceuticals, gamma cameras and PET/CT scanners. 2. Learn about a new technique using PET/MR in the pre-operative localization of lesions prior to radio-guided surgery. Background: Radiopharmaceuticals have been used in conjunction with gamma cameras and PET scanners to localize tumor deposits prior to radio-guided surgery using intra-operative probes, often assisted by portable cameras. One disadvantage of PET/CT scanners is that pre-operative lesion localization may require multiple CT acquisitions, thus increasing radiation exposure to the patient. This exhibit will briefly review conventional techniques to localize non-palpable tumor deposits before surgery using nuclear medicine techniques, and will demonstrate in detail a new method of FDG PET/MR-guided pre-operative lesion localization prior to radio-guided surgery. A major focus of this review will be on case examples of patients with non-palpable subcutaneous FDG-avid tumor deposits for which surgical resection is the gold standard for management. After confirming uptake on whole-body PET/CT, patients are referred to the PET/MR Department on the day of surgery. FDG is injected and lesions are imaged on a Siemens Biograph mMR PET/MR scanner using conventional static PET and STIR MR sequences. A vitamin E marker is used in conjunction with an FDG point source to mark the tumor location on the skin, and the best orientation for surgical dissection and patient positioning is reviewed. A PET probe is used intra-operatively to assist in identification of tumor deposits. (Figure Presented)

Objectives PET/MR may be used in the evaluation of cognitively impaired patients. There are known quantitative differences between PET images obtained on PET/MR scanners when reconstructed with Dixon-MR, CT-based or atlas-based attenuation correction (AC) maps. This study seeks to assess the impact, if any, of these three-different AC methods on the blinded visual interpretation of regional hypometabolism in patients with cognitive impairment. Methods Forty-five minutes following injection of 10 mCi of FDG, 15 patients with cognitive impairment underwent brain PET/CT. PET/MR scanning with a 10 minute PET acquisition and Dixon MR imaging was subsequently performed on a Siemens Biograph mMR scanner under an IRB-approved protocol, at approximately two hours post-injection. A manufacturer-provided non-product offline reconstruction tool was used to reconstruct PET data obtained from PET/MR with AC based on the patient's own CT images, a Dixon-MR derived AC map and an atlas-based AC map that combined Dixon-MR with a segmentation of bony skull structures. Two nuclear medicine physicians blindly scored brain regions (frontal, temporal, parietal, occipital, precuneus) as normal versus hypometabolic using 2D and 3D images generated by MIM software. Abnormal regions were scored as mild, moderate, or severely hypometabolic (score of 0, 1, 2 or 3 respectively). The hypometabolism scores obtained using the different methods of AC were compared and reader agreement assessed. All statistical tests were conducted at the two-sided 5% significance level using SAS 9.3 (SAS Institute, Cary, NC). Results Regional hypometabolism versus normal metabolism was correctly classified (accuracy) for 150 regions in 15 patients by two readers on atlas- and Dixon-based AC map PET reconstructions (versus CT reference AC) for 94% (90 - 96% c.i.) and 93% (89 - 96% c.i.) of all regions. The averaged sensitivity/specificity for detection of any regional hypometabolism was 95%/94% and 90%/91% for atlas-based and Dixon-based AC maps, respectively, compared to the reference standard CT images. The mean absolute error of regional hypometabolism scores for atlas- and Dixon-based PET reconstructions (versus CT) was 0.25 +/- 0.44 and 0.21 +/- 0.42 . There were no statistically significant differences between the visual assessments. Intra-reader agreement for detection of regional hypometabolism was high, with similar outcome assessments when using atlas- and Dixon-corrected PET data in 93% and 93% of scored regions, respectively. The simple kappa coefficient to assess reader agreement in terms of hypometabolism versus normal regions was 0.82 for atlas- and 0.84 for Dixon-based AC. The weighted kappa coefficient to assess reader agreement in terms of the hypometabolism score was 0.75 for atlas- and 0.77 for Dixon-AC. Conclusions Despite the more accurate FDG SUV quantification with CT-based and atlas-based attenuation correction in brain PET/MR compared to Dixon AC, there were no measureable differences between the three AC methods with respect to visual identification of regional hypometabolism in the evaluation of cognitively impaired patients