Molecular Imaging Program

Recent Accomplishments


snmmi

June 7-11, 2014
Members of CQCI recently presented lectures and educational courses in the Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging held in St. Louis, Missouri.

John Hoffman, MD, presented lectures on “Challenges of Response to Therapy in Brain Tumors” and “Amyloid PET Imaging.” Dr. Hoffman was also the Co-Moderator for a Continuing Education session on “The Status of DOTA Agents in Molecular Imaging. “

Jeffrey Yap, PhD, presented lectures on “Metrics of Response Assessment” and “Imaging Response Assessment Criteria for Cancer Clinical Trials.” Dr. Yap was also the Moderator for a Continuing Education session on “The Status of DOTA Agents in Molecular Imaging” and the Co-Moderator for a Continuing Education session on “Molecular Imaging for Assessing Response to Therapy.”

Lance Burrell, MS, presented a lecture on “A Comparison of Three PET Phantoms for Evaluating Spatial Resolution” and received an award and $500 prize for the “2nd PLACE Technologist Best Oral Abstract.”


SARC May 30, 2014

Jeffrey Yap, PhD, Presented a lecture on “Development of quantitative imaging biomarkers for assessing response to sarcoma therapy” at the Semiannual meeting of the Sarcoma Alliance for Research through Collaboration (SARC) held in Chicago, IL during the annual meeting of the American Society of Clinical Oncology (ASCO).

Jeffrey Yap


Investigational and Clinical PET Imaging Radiopharmaceuticals

Imaging in both humans and pre-clinical applications continue to expand within the Center for Quantitative Cancer Imaging (CQCI). This center has incorporated the assets of the former HCI Molecular Imaging Program, including two dedicated research PET/CT scanners, and a new state-of-the-art time of flight PET/CT. The HCI CQCI  supports integration of PET imaging into HCI investigator initiated trials (IIT) using the numerous PET imaging agents and radiopharmaceuticals produced in our GMP compliant cyclotron facility and will ensure that any IIT wishing to use this important imaging technology has the ability to do so.

Filing and obtaining FDA IND approval for the use of various investigational PET imaging agents at HCI has been a priority and accomplishment over the past several years. The following table summarizes the recent IND approvals.  In addition, ANDA’s for both FDG (ANDA # 204498) and NaF (ANDA # 204497) have been filed to be in compliance with the cGMP for PET Drugs (21 CFR 212), which took effect on 12/12/11. We have made it possible for this cadre of PET imaging agents to be available to the clinical and research communities and will continue to do so.

IND#

Investigational Radiopharmaceutical

Date of Approval

109.760

18F-39-F-6-OH-BTA1 also known as 18FGE067 (Flutemetamol) or 18F-PIB

9/17/2010

111,064

1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole [18F]-fluoromisonidazole, [18F]FMISO, FMISO

2/11/2011

113,183 

11C-Acetate or [C-11] Sodium Acetate

9/22/2011

113,529  

H215O ([O-15] Water)

11/3/2011

113,858 

2-deoxy-2-[18F]fluoro-D-glucose (FDG)

12/8/2011

120,130  

[18F] Fluciclatide (GE [18F]AH111585)

11/27/2013


Research Accomplishments from Center for Quantitative Cancer Imaging Members

Multi-Tracer PET Imaging:

One of the greatest strengths of PET is the ability to image any of a number of molecular or physiologic targets using different radiotracers. The clinical utility of PET is well- established for cancer detection and staging. Validated PET radiopharmaceuticals provide the ability to assess several of the most important biologic parameters of cancer (metabolism, proliferation, and blood flow).  However, much of this potential remains unrealized because current technology permits only one PET tracer to be imaged at a time over. This requires multiple scanning sessions to be scheduled, often on different days, resulting in high costs, image alignment issues, and a long and onerous experience for the patient. Recent advances have shown that it is technically feasible to image 2-3 PET tracers in a single scan using staggered injections and dynamic imaging. Measures of each tracer can be recovered using "signal-separation" algorithms based on kinetic constraints for each tracer. The development of such rapid multi-tracer imaging technologies, with emphasis on developing specific methods of immediate value and translation to clinical patient imaging are critically important. Four tracers have INDs in place to be studied: 18F-fluorodeoxyglucose (FDG) as a marker for glucose metabolism; 18F-fluorothymidine (FLT) for proliferation; 11C-acetate (ACE) for lipid synthesis and related growth; and 15O-water (H2O) for blood flow and volume of distribution.

A NCI-funded study (5R01CA135556-04, Kadrmas, PI) supported Dan Kadrmas, PhD; Dr. Hoffman; Randy Jensen, MD, PhD; and Howard Colman, MD, PhD, in a novel research project using multi-tracer PET techniques to assess tumor treatment in patients with primary brain tumors.  Since the last CCSG funding the development of strategies and kinetic modeling techniques have been developed to evaluate tumors with multiple PET tracers, using a small animal PET/CT system. In addition, human multi-tracer studies continue in an investigator-initiated clinical trial. The goal of these studies is to use a cadre of PET imaging techniques to improve early assessment of the biologic response of tumors. Several publications have shown the promise of this promising technique.

  • Kadrmas DJ, Rust TC, Hoffman JM. Single-Scan Dual-Tracer FLT+FDG PET Tumor Characterization. Phys Med Biol. 7;58(3):429-49, 2013
  • Kadrmas, Hoffman JM.  Methodology for Quantitative Rapid Multi-Tracer PET Tumor Characterizations. Theranostics. 3(10):757-773, 2013
  • Kadrmas DJ, Oktay MB. Generalized separable parameter space techniques for fitting 1K-5K serial compartment models. Med Phys. 2013 Jul;40(7):072502. doi: 10.1118/1.4810937.
  • Zeng GL, Kadrmas DJ, Gullberg GT. Fourier domain closed-form formulas for estimation of kinetic parameters in reversible multi-compartment models. Biomed Eng Online. 2012 Sep 20;11:70

A Molecular Imaging Profile of Early Response and Resistance to Targeted Chemotherapy:

Drs. Hoffman, PI; Kathryn Morton, MD, Co-PI; Dr. Kadrmas, and Dr. Sharma used Experimental Therapeutics Program developmental funds to obtain pilot data that resulted in a grant titled, Multi-Tracer PET Assessment of Response to Novel Targeted Chemotherapy (1 R21 CA167795-01) in response to NCI PAR-11-216: Early-Phase Clinical Trials in Imaging and Image-Guided Interventions (R21). This grant was funded in late 2012 so results are not currently available, however the clinical trial is recruiting patients and initial results are expected soon. The goal of the project is to develop a molecular imaging profile of early response and resistance in patients with advanced cancer enrolled in early-phase therapeutic trials or in patients receiving recently approved drugs. This study tests the efficacy of novel single agent targeted chemotherapies. PET imaging is obtained at baseline (before treatment) and after one cycle of treatment. Three separate PET/CT scans will be performed utilizing 18F-FDG (metabolism), 18F-FLT (proliferation), and 15O-H2O (blood flow). The initial molecular imaging profile and the changes that occur during the first cycle of therapy will be compared to anatomic RECIST measurements, molecular signatures, and patient outcome. The proposal will extend and apply rapid (single-scan) multi-tracer PET tumor imaging techniques to dual-tracer FDG+FLT imaging of early response and resistance in this patient population, evaluating the feasibility and accuracy of the methods using the clinical scan data obtained in the initial individual PET studies.

Diagnosis of Occult Malignancy Using Whole-Body 18F-FDG-PET/CT:

The association between blood clot formation, inflammation and cancer is strong. Cancer predisposes patients to the development of blood clots, which may complicate therapy and has a higher risk of morbidity and death than in non-cancer patients. The converse is also true, nearly 50% of patients who develop unprovoked venothromboembolic disease (VTE) may harbor an occult cancer, yet a search for cancer in these patients is not considered standard of practice. The diagnosis of blood clot formation is compromised when the clot is in the abdomen or pelvis, and/or the patient has a containdication to iodinated contrast. In cancer patients, multiple anatomic abnormalities associated with the cancer or its treatment, and a heightened propensity for intraabdominal or pelvic clot may further complicate the diagnosis of VTE. Further, no current methods exist to identify patients at particularly high risk for cancer-related thrombosis, a critical step in thrombo-prevention. The link between clot, cancer and inflammation may be due to a host response to cancer resulting in expression of both local and systemic inflammatory cytokines and tissue factors that act on platelets and myeloid leukocytes to produce a cascade of events culminating in blood clot formation. FDG PET imaging has emerged as a powerful tool in the diagnosis, staging, and therapeutic assessment of malignancy. Based on preliminary data and personal observation, we hypothesized that FDG PET may be a useful adjunct in the diagnosis of complicated cases of VTE, in identifying patients with unprovoked VTE that harbor an occult malignancy, and in identifying the systemic state that predisposes many cancer patients to VTE.

The results from a funded NCI R01 (R01 CA121003-01, FDG PET in Cancer-Associated Venothromboembolic Disease) Dr. Morton – PI and Dr. Hoffman - Co-Investigator have recently published the results of this study  and made presentations at national and international meetings.

  • Rondina MT, Wanner N, Pendleton TG, Kraiss LW, Vinik, Zimmerman GA. Heilbrun M, Hoffman JM, Morton KA.  A pilot study utilizing whole body 18 F-FDG-PET/CT as a comprehensive screening strategy for occult malignancy in patients with unprovoked venous thromboembolism. Thrombosis Research. 129(1): 22-27, 2012 
  • Rondina MT, Lam UT, Pendleton RC, Kraiss LW, Wanner N, Zimmerman GA, Hanrahan C, Boucher K,  Hoffman JM, Morton KA.  A Prospective Comparative Study Using 18Fluorine-Fluorodeoxyglucose Positron Emission Tomography for the Evaluation of Acute Deep Vein Thrombosis. Clin Nucl Med. 37(12):1139-45,2012
  •    Rondina MT, Wanner N, Pendleton TG, Kraiss LW, Vinik, Zimmerman GA. Heilbrun M, Hoffman JM, Morton KA. The utility of 18F-FDG-PET/CT for the diagnosis of occult malignancy in patients with acute, unprovoked venous thromboembolism. Society for Vascular Medicine (Poster 32). Presented at the Society of Vascular Medicine National Meeting
  • Rondina MT, Wanner N, Pendleton RC, Kraiss LW, Vinik R, Zimmerman GA, Heilbrun M, Hoffman JM, Morton KA. A pilot study utilizing whole body FDG-PET/CT as a comprehensive screening strategy for occult malignancy in patients with unprovoked VTE. Oral Presentation as the Jay D. Coffman Young Investigator Award Finalist at the Society of Vascular Medicine Meeting
  • Hoffman JM, Wang LM, Wu Q, Morton K (2011) Uptake of 2-deoxyglucose analogs by thrombotically activated cells. J Nucl Med 52:327. Presented at Society of Nuclear Medicine 2011 Annual Meeting
  • Hoffman JM, Butterfield RI, Christian PE, Heilbrun M, Morton K (2011) The utility of FDG PET-CT for the diagnosis of occult malignancy in patients with acute, unprovoked venous thromboembolism. J Nucl Med 52:1922. Presented at Society of Nuclear Medicine 2011 Annual Meeting

Optimized PET Reconstruction for Cancer Detection:

PET has become one of the most valuable imaging technologies available for the detection, staging, and response monitoring of patients with cancer.  Image reconstruction in PET is reaching a maturing stage where the main algorithmic classes (e.g. analytical vs. iterative) are largely delineated, modeling of the main physics processes (e.g. attenuation, scatter, randoms, and more recently the point spread function) is well established, and more complex issues such as respiratory motion compensation and direct kinetic parameter estimation are aggressively being pursued. One of the greatest challenges when investigating new PET algorithms and technologies is the need for efficacious assessment of image quality. The most widely accepted method for objective assessment of PET image quality relies upon measuring performance for specific clinical tasks (or surrogates thereof), which requires significant expertise and challenging development of test datasets and methodologies. Dr Kadrmas has had ongoing funding 5R03EB014454-02) and 5R03EB014454-02 to study optimized PET reconstruction techniques for cancer detection.  Building on his previous experience in image reconstruction technique development and validation, Dr Kadrmas is creating a database of PET imaging data designed and tuned for evaluating observer performance in detecting focal warm lesions, modeling the clinical task of cancer detection and staging. This database will be comprised of existing datasets acquired under a prior R01 project and via research relationships with two major PET tomograph manufacturers. The database will include scans from four PET tomographs from two vendors operated in 2D, fully-3D, and 3D + time-of-flight (TOF) acquisition modes. The database is intended to provide a collaborative shared resource enabling the broad PET research community to easily assess lesion-detection performance improvements for their own developmental algorithms and technologies. As such, the database will be designed with portable data formats, plus include collaborative access to research reconstruction software and observer study tools. To date several manuscripts have been published describing the efforts and science behind this important project.

  • Kadrmas DJ, Oktay MB, Casey ME, Hamill JJ Effect of Scan Time on Oncologic Lesion Detection in Whole-Body PET. IEEE Trans Nucl Sci. 2012 Oct;59(5):1940-1947.
  • Lois C, Jakoby BW, Long MJ, Hubner KF, Barker DW, Casey ME, Conti M, Panin VY, Kadrmas DJ, Townsend DW. An assessment of the impact of incorporating time-of-flight information into clinical PET/CT imaging. J Nucl Med. 2010 Feb;51(2):237-45
  • Kadrmas DJ, Casey ME, Conti M, Jakoby BW, Lois C, Townsend DW. Impact of time-of-flight on PET tumor detection. J Nucl Med. 2009 Aug;50(8):1315-2317