Karen Kurdziel | National Institutes of Health (original) (raw)

Papers by Karen Kurdziel

Journal of translational science, 2018

Introduction: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplifi... more Introduction: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Using trastuzumab and/or other HER2 targeted therapies can increase overall survival in patients with HER2(+) tumors making it critical to accurately identify patients who may benefit. We report on a Phase 0 study of the imaging agent, 111 In-CHX-A"-DTPA trastuzumab, in patients with known HER2 status to evaluate its safety and biodistribution and to obtain preliminary data regarding its ability to provide an accurate, whole-body, non-invasive means to determine HER2 status. Methods: 111 In-CHX-A"-DTPA trastuzumab was radiolabeled on-site and slowly infused into 11 patients who underwent single (n=5) or multiple (n=6) ɣ-camera (n=6) and/or SPECT (n=8) imaging sessions. Results: No safety issues were identified. Visual and semi-quantitative imaging data were concordant with tissue HER2 expression profiling in all but 1 patient. The biodistribution showed intense peak liver activity at the initial imaging timepoint (3.3h) and a single-phase clearance fit of the average time-activity curve (TAC) estimated t 1/2 =46.9h (R 2 =0.97; 95%CI 41.8 to 53h). This was followed by high gastrointestinal (GI) tract activity peaking by 52h. Linear regression predicted GI clearance by 201.2h (R 2 =0.96; 95%CI 188.5to 216.9h). Blood pool had lower activity with its maximum on the initial images. Non-linear regression fit projected a t 1/2 =34.2h (R 2 =0.96; 95%CI 25.3 to 46.3h). Assuming linear whole-body clearance, linear regression projected complete elimination (x-intercept) at 256.5hr (R 2 =0.96; 95%CI 186.1 to 489.2h). Conclusion: 111 In-CHX-A"-DTPA trastuzumab can be safely imaged in humans. The biodistribution allowed for visual and semiquantitative analysis with results concordant with tissue expression profiling in 10 of 11 patients. Advances in Knowledge and Implications for Patient Care Using readily available components and on-site radiolabeling 111 In-CHX-A"-DTPA trastuzumab SPECT imaging may provide an economical, non-invasive means to detect HER2 over-expression.

Radiology, Mar 1, 2014

To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (18 F FACBC) ... more To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (18 F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging.

Journal of Clinical Oncology, May 20, 2013

Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. A... more Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999. GENITOURINARY (NONPROSTATE) CANCER

The Journal of Nuclear Medicine, Jun 22, 2012

The Journal of Nuclear Medicine, Feb 17, 2012

The Journal of Nuclear Medicine, Jan 21, 2016

This prospective pilot study evaluated the ability of Na 18 F PET/CT to detect and monitor bone m... more This prospective pilot study evaluated the ability of Na 18 F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. Methods: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na 18 F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. Results: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P 5 0.014) and 12 mo (P 5 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P 5 0.0147) and 6-12 mo (P 5 0.0053); SUV change at 6 mo and overall survival (P 5 0.018); number of lesions on Na 18 F PET/CT and clinical impression at baseline (P , 0.0001), 6 mo (P 5 0.0078), and 12 mo (P 5 0.0029); and number of lesions on Na 18 F PET/CT per patient at baseline and overall survival (P 5 0.017). In an exploratory analysis, paired 99m Tc-methylene diphosphonate bone scans (99m Tc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na 18 F PET/CT (n 5 57) were classified on 99m Tc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na 18 F PET/CT than on 99m Tc-BS. Conclusion: The baseline number of malignant lesions and changes in SUV on follow-up Na 18 F PET/CT significantly correlate with clinical impression and overall survival. Na 18 F PET/CT detects more bone metastases earlier than 99m Tc-BS and enhances detection of new bone disease in high-risk patients.

The Journal of Nuclear Medicine, 2015

1440 Objectives Current methods of imaging advanced prostate cancer are nonspecific and better mo... more 1440 Objectives Current methods of imaging advanced prostate cancer are nonspecific and better molecular imaging probes are sought. 18F DCFBC is a radiolabeled PET agent that binds with high affinity to PSMA, which is highly expressed in almost all prostate cancers. Identifying disease in soft tissue and bone with one tracer is appealing. We preliminarily compare the uptake of 18F DCFBC in bone with 18F NaF in prostate cancer patients with metastatic disease. Methods Subjects undergo 2 separate 18F DCFBC imaging sessions, one at baseline, and then at 4-6 months. PET/CT images are performed at 1 and 2 hours after IV injection of 8 mCi 18F DCFBC. Patients also undergo a whole body 18F NaF scan within 3 weeks of each 18F DCFBC. Patients receive 3 mCi 18F NaF IV bolus and undergo whole body imaging 1 hour post injection. PSA levels are obtained at the time of 18F DCFBC imaging. Results 6 patients with known bone metastasis were imaged. 13 bone lesions with focal 18F NaF uptake were comp...

Journal of Clinical Oncology, 2014

329 Background: 18F-NaF has shown improved sensitivity for bone imaging when compared to conventi... more 329 Background: 18F-NaF has shown improved sensitivity for bone imaging when compared to conventional planar imaging or SPECT/CT using 99mTc-MDP. We compared the number of bone lesions detected on 18F-NaF versus 18F-FDG in urothelial cancer pts with known bone metastases undergoing treatment. Methods: Pts enrolled in a prospective single-arm phase II study of cabozantinib underwent 18F-NaF and 18F-FDG scans at baseline and at 8 weeks of therapy. In a lesion-based analysis independently confirmed by a nuclear medicine physician, abnormal foci of radiotracer uptake were categorized by location (skull, spine, pelvis, thorax, or long bones) and by disease state (benign, malignant, or indeterminate). A patient-based analysis was performed to determine if findings indicated disease progression, stable disease, or improvement of disease, based on the number of lesions and standardized uptake values (SUVs). Results: 294 total bone lesions were identified at baseline in 10 pts (8 male and 2 ...

Journal of Clinical Oncology, Feb 20, 2013

103 Background: We performed a prospective study of 18F-NaF PET/CT bone scan (NaF) in the detecti... more 103 Background: We performed a prospective study of 18F-NaF PET/CT bone scan (NaF) in the detection of bone metastases in men with prostate cancer. We previously reported that NaF identified more malignant lesions than Technetium-99m MDP bone scan (TcBS) (ASCO 2012 10589). This study evaluates the ability of NaF to detect bone metastasis in men with normal TcBS and also explores the change in NaF over 6 and 12 months compared to PSA changes. Methods: In a prospective 2-arm study, 60 men with prostate cancer (30 with and 30 without bone metastases by TcBS) were studied (ages 51-79). All had NaF and TcBS at baseline, followed by repeat NaF at 6 and 12 months. TcBS and NaF were reviewed by experienced nuclear medicine physicians. Abnormal foci of uptake on TcBS and NaF were classified as benign, malignant or indeterminate. Malignant uptake on NaF was confirmed by characteristic osteoblastic features on CT. Scan results were categorized as “positive” if any malignant lesion was present. In the 6 and 12 months follow up NaF, results were categorized as progression of disease (PD) = any new lesions or SUV increase > 30% in known lesions; stable disease (SD) = no new lesions or SUV changes < 30% in known lesions; and improvement of disease (ID) = resolution of known lesions or decrease SUV > 30% in known lesions. Results: 60 men have enrolled on study, 58 and 34 completed 6 and 12 month follow-up respectively. At baseline, 14 of 30 (47%) men with negative TcBS showed evidence of bone metastases in NaF (PSA mean 45); 7/14 had 2 baseline NaF and showed positive results in both, demonstrating reproducibility; 13/14 and 7/14 had follow up NaF at 6 and 12 months, respectively, all of which remained positive. In follow-up, 13/58 men at 6 months and 8/34 men at 12 months had PD from baseline on NaF, of whom 5/13 (38%) at 6 months and 5/8 (63%) at 12 months also had a PSA increase > 50%. All men who had PD on NaF at 6 months and had a follow-up scan at 12 months remained positive. 15 men at 6 months and 7 men at 12 months had ID on follow-up NaF, of which 11/15 (73%) and 6/7 (86%) had PSA decrease > 50% at 6 and 12 months, respectively. Conclusions: Early results of this ongoing NaF study are encouraging and suggest NaF identifies metastatic bone disease earlier than TcBS and correlates with changes in PSA. Clinical trial information: NCT01240551.

The Journal of Nuclear Medicine, 2016

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2007

Cancer Drug Discovery and Development, 2013

The challenge of drug development in oncology is to achieve optimum delivery of active drug to th... more The challenge of drug development in oncology is to achieve optimum delivery of active drug to the tumor with minimal exposure to normal tissue. Newer, highly specific targeted drugs require careful evaluation of these parameters as these agents often leave alternative signaling pathways unblocked, thus providing a mechanism for resistance. Determining these characteristics early in the drug development cycle can reduce the human and monetary costs. Imaging provides a potential means of approximating the fate of a drug throughout the body (whole body imaging) and over time (dynamic imaging) in a noninvasive manner. There are many promising imaging technologies that could be applied to drug development. Among these, radionuclide tagging provides the most sensitive method. This chapter will focus on positron emission tomography (PET), as the most sensitive and quantitative among existing imaging modalities.

Journal of Nuclear Medicine, 2012

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the... more Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18 F-fluorobenzyl-Lcysteine (18 F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18 F-DCFBC in men with metastatic PCa. Methods: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18 F-DCFBC. Serial PET was performed until 2 h after administration. Timeactivity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Results: Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (mGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 6 1.34 mSv/MBq (mean 6 SD). Conclusion: Although further studies are needed for validation, our findings demonstrate the potential of 18 F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18 F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18 F-FDG.

Journal of Nuclear Medicine, 2012

Expert Review of Molecular Diagnostics, 2013

As personalized medicine becomes a reality, there is a need for specific imaging agents that refl... more As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent.

Drug Resistance Updates, 2012

This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR... more This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.

Journal of translational science, 2018

Introduction: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplifi... more Introduction: Tumors over-expressing the human epithelial receptor 2 (HER2) or exhibiting amplification or mutation of its proto-oncogene have a poorer prognosis. Using trastuzumab and/or other HER2 targeted therapies can increase overall survival in patients with HER2(+) tumors making it critical to accurately identify patients who may benefit. We report on a Phase 0 study of the imaging agent, 111 In-CHX-A"-DTPA trastuzumab, in patients with known HER2 status to evaluate its safety and biodistribution and to obtain preliminary data regarding its ability to provide an accurate, whole-body, non-invasive means to determine HER2 status. Methods: 111 In-CHX-A"-DTPA trastuzumab was radiolabeled on-site and slowly infused into 11 patients who underwent single (n=5) or multiple (n=6) ɣ-camera (n=6) and/or SPECT (n=8) imaging sessions. Results: No safety issues were identified. Visual and semi-quantitative imaging data were concordant with tissue HER2 expression profiling in all but 1 patient. The biodistribution showed intense peak liver activity at the initial imaging timepoint (3.3h) and a single-phase clearance fit of the average time-activity curve (TAC) estimated t 1/2 =46.9h (R 2 =0.97; 95%CI 41.8 to 53h). This was followed by high gastrointestinal (GI) tract activity peaking by 52h. Linear regression predicted GI clearance by 201.2h (R 2 =0.96; 95%CI 188.5to 216.9h). Blood pool had lower activity with its maximum on the initial images. Non-linear regression fit projected a t 1/2 =34.2h (R 2 =0.96; 95%CI 25.3 to 46.3h). Assuming linear whole-body clearance, linear regression projected complete elimination (x-intercept) at 256.5hr (R 2 =0.96; 95%CI 186.1 to 489.2h). Conclusion: 111 In-CHX-A"-DTPA trastuzumab can be safely imaged in humans. The biodistribution allowed for visual and semiquantitative analysis with results concordant with tissue expression profiling in 10 of 11 patients. Advances in Knowledge and Implications for Patient Care Using readily available components and on-site radiolabeling 111 In-CHX-A"-DTPA trastuzumab SPECT imaging may provide an economical, non-invasive means to detect HER2 over-expression.

Radiology, Mar 1, 2014

To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (18 F FACBC) ... more To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid (18 F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging.

Journal of Clinical Oncology, May 20, 2013

Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. A... more Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999. GENITOURINARY (NONPROSTATE) CANCER

The Journal of Nuclear Medicine, Jun 22, 2012

The Journal of Nuclear Medicine, Feb 17, 2012

The Journal of Nuclear Medicine, Jan 21, 2016

This prospective pilot study evaluated the ability of Na 18 F PET/CT to detect and monitor bone m... more This prospective pilot study evaluated the ability of Na 18 F PET/CT to detect and monitor bone metastases over time and its correlation with clinical outcomes and survival in advanced prostate cancer. Methods: Sixty prostate cancer patients, including 30 with and 30 without known bone metastases by conventional imaging, underwent Na 18 F PET/CT at baseline, 6 mo, and 12 mo. Positive lesions were verified on follow-up scans. Changes in SUVs and lesion number were correlated with prostate-specific antigen change, clinical impression, and overall survival. Results: Significant associations included the following: SUV and prostate-specific antigen percentage change at 6 mo (P 5 0.014) and 12 mo (P 5 0.0005); SUV maximal percentage change from baseline and clinical impression at 6 mo (P 5 0.0147) and 6-12 mo (P 5 0.0053); SUV change at 6 mo and overall survival (P 5 0.018); number of lesions on Na 18 F PET/CT and clinical impression at baseline (P , 0.0001), 6 mo (P 5 0.0078), and 12 mo (P 5 0.0029); and number of lesions on Na 18 F PET/CT per patient at baseline and overall survival (P 5 0.017). In an exploratory analysis, paired 99m Tc-methylene diphosphonate bone scans (99m Tc-BS) were available for 35 patients at baseline, 19 at 6 mo, and 14 at 12 mo (68 scans). Malignant lesions on Na 18 F PET/CT (n 5 57) were classified on 99m Tc-BS as malignant 65% of the time, indeterminate 25% of the time, and negative 10% of the time. Additionally, 69% of paired scans showed more lesions on Na 18 F PET/CT than on 99m Tc-BS. Conclusion: The baseline number of malignant lesions and changes in SUV on follow-up Na 18 F PET/CT significantly correlate with clinical impression and overall survival. Na 18 F PET/CT detects more bone metastases earlier than 99m Tc-BS and enhances detection of new bone disease in high-risk patients.

The Journal of Nuclear Medicine, 2015

1440 Objectives Current methods of imaging advanced prostate cancer are nonspecific and better mo... more 1440 Objectives Current methods of imaging advanced prostate cancer are nonspecific and better molecular imaging probes are sought. 18F DCFBC is a radiolabeled PET agent that binds with high affinity to PSMA, which is highly expressed in almost all prostate cancers. Identifying disease in soft tissue and bone with one tracer is appealing. We preliminarily compare the uptake of 18F DCFBC in bone with 18F NaF in prostate cancer patients with metastatic disease. Methods Subjects undergo 2 separate 18F DCFBC imaging sessions, one at baseline, and then at 4-6 months. PET/CT images are performed at 1 and 2 hours after IV injection of 8 mCi 18F DCFBC. Patients also undergo a whole body 18F NaF scan within 3 weeks of each 18F DCFBC. Patients receive 3 mCi 18F NaF IV bolus and undergo whole body imaging 1 hour post injection. PSA levels are obtained at the time of 18F DCFBC imaging. Results 6 patients with known bone metastasis were imaged. 13 bone lesions with focal 18F NaF uptake were comp...

Journal of Clinical Oncology, 2014

329 Background: 18F-NaF has shown improved sensitivity for bone imaging when compared to conventi... more 329 Background: 18F-NaF has shown improved sensitivity for bone imaging when compared to conventional planar imaging or SPECT/CT using 99mTc-MDP. We compared the number of bone lesions detected on 18F-NaF versus 18F-FDG in urothelial cancer pts with known bone metastases undergoing treatment. Methods: Pts enrolled in a prospective single-arm phase II study of cabozantinib underwent 18F-NaF and 18F-FDG scans at baseline and at 8 weeks of therapy. In a lesion-based analysis independently confirmed by a nuclear medicine physician, abnormal foci of radiotracer uptake were categorized by location (skull, spine, pelvis, thorax, or long bones) and by disease state (benign, malignant, or indeterminate). A patient-based analysis was performed to determine if findings indicated disease progression, stable disease, or improvement of disease, based on the number of lesions and standardized uptake values (SUVs). Results: 294 total bone lesions were identified at baseline in 10 pts (8 male and 2 ...

Journal of Clinical Oncology, Feb 20, 2013

103 Background: We performed a prospective study of 18F-NaF PET/CT bone scan (NaF) in the detecti... more 103 Background: We performed a prospective study of 18F-NaF PET/CT bone scan (NaF) in the detection of bone metastases in men with prostate cancer. We previously reported that NaF identified more malignant lesions than Technetium-99m MDP bone scan (TcBS) (ASCO 2012 10589). This study evaluates the ability of NaF to detect bone metastasis in men with normal TcBS and also explores the change in NaF over 6 and 12 months compared to PSA changes. Methods: In a prospective 2-arm study, 60 men with prostate cancer (30 with and 30 without bone metastases by TcBS) were studied (ages 51-79). All had NaF and TcBS at baseline, followed by repeat NaF at 6 and 12 months. TcBS and NaF were reviewed by experienced nuclear medicine physicians. Abnormal foci of uptake on TcBS and NaF were classified as benign, malignant or indeterminate. Malignant uptake on NaF was confirmed by characteristic osteoblastic features on CT. Scan results were categorized as “positive” if any malignant lesion was present. In the 6 and 12 months follow up NaF, results were categorized as progression of disease (PD) = any new lesions or SUV increase > 30% in known lesions; stable disease (SD) = no new lesions or SUV changes < 30% in known lesions; and improvement of disease (ID) = resolution of known lesions or decrease SUV > 30% in known lesions. Results: 60 men have enrolled on study, 58 and 34 completed 6 and 12 month follow-up respectively. At baseline, 14 of 30 (47%) men with negative TcBS showed evidence of bone metastases in NaF (PSA mean 45); 7/14 had 2 baseline NaF and showed positive results in both, demonstrating reproducibility; 13/14 and 7/14 had follow up NaF at 6 and 12 months, respectively, all of which remained positive. In follow-up, 13/58 men at 6 months and 8/34 men at 12 months had PD from baseline on NaF, of whom 5/13 (38%) at 6 months and 5/8 (63%) at 12 months also had a PSA increase > 50%. All men who had PD on NaF at 6 months and had a follow-up scan at 12 months remained positive. 15 men at 6 months and 7 men at 12 months had ID on follow-up NaF, of which 11/15 (73%) and 6/7 (86%) had PSA decrease > 50% at 6 and 12 months, respectively. Conclusions: Early results of this ongoing NaF study are encouraging and suggest NaF identifies metastatic bone disease earlier than TcBS and correlates with changes in PSA. Clinical trial information: NCT01240551.

The Journal of Nuclear Medicine, 2016

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2007

Cancer Drug Discovery and Development, 2013

The challenge of drug development in oncology is to achieve optimum delivery of active drug to th... more The challenge of drug development in oncology is to achieve optimum delivery of active drug to the tumor with minimal exposure to normal tissue. Newer, highly specific targeted drugs require careful evaluation of these parameters as these agents often leave alternative signaling pathways unblocked, thus providing a mechanism for resistance. Determining these characteristics early in the drug development cycle can reduce the human and monetary costs. Imaging provides a potential means of approximating the fate of a drug throughout the body (whole body imaging) and over time (dynamic imaging) in a noninvasive manner. There are many promising imaging technologies that could be applied to drug development. Among these, radionuclide tagging provides the most sensitive method. This chapter will focus on positron emission tomography (PET), as the most sensitive and quantitative among existing imaging modalities.

Journal of Nuclear Medicine, 2012

Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the... more Prostate-specific membrane antigen (PSMA) is a type II integral membrane protein expressed on the surface of prostate cancer (PCa) cells, particularly in androgen-independent, advanced, and metastatic disease. Previously, we demonstrated that N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18 F-fluorobenzyl-Lcysteine (18 F-DCFBC) could image an experimental model of PSMA-positive PCa using PET. Here, we describe the initial clinical experience and radiation dosimetry of 18 F-DCFBC in men with metastatic PCa. Methods: Five patients with radiologic evidence of metastatic PCa were studied after the intravenous administration of 370 MBq (10 mCi) of 18 F-DCFBC. Serial PET was performed until 2 h after administration. Timeactivity curves were generated for selected normal tissues and metastatic foci. Radiation dose estimates were calculated using OLINDA/EXM 1.1. Results: Most vascular organs demonstrated a slow decrease in radioactivity concentration over time consistent with clearance from the blood pool, with primarily urinary radiotracer excretion. Thirty-two PET-positive suspected metastatic sites were identified, with 21 concordant on both PET and conventional imaging for abnormal findings compatible with metastatic disease. Of the 11 PET-positive sites not identified on conventional imaging, most were within the bone and could be considered suggestive for the detection of early bone metastases, although further validation is needed. The highest mean absorbed dose per unit administered radioactivity (mGy/MBq) was in the bladder wall (32.4), and the resultant effective dose was 19.9 6 1.34 mSv/MBq (mean 6 SD). Conclusion: Although further studies are needed for validation, our findings demonstrate the potential of 18 F-DCFBC as a new positron-emitting imaging agent for the detection of metastatic PCa. This study also provides dose estimates for 18 F-DCFBC that are comparable to those of other PET radiopharmaceuticals such as 18 F-FDG.

Journal of Nuclear Medicine, 2012

Expert Review of Molecular Diagnostics, 2013

As personalized medicine becomes a reality, there is a need for specific imaging agents that refl... more As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody-antibody fragments and drug-drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent.

Drug Resistance Updates, 2012

This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR... more This special issue of Drug Resistance Updates is dedicated to multidrug resistance protein 1 (MDR-1), 35 years after its discovery. While enormous progress has been made and our understanding of drug resistance has become more sophisticated and nuanced, after 35 years the role of MDR-1 in clinical oncology remains a work in progress. Despite clear in vitro evidence that P-glycoprotein (Pgp), encoded by MDR-1, is able to dramatically reduce drug concentrations in cultured cells, and that drug accumulation can be increased by small molecule inhibitors, clinical trials testing this paradigm have mostly failed. Some have argued that it is no longer worthy of study. However, repeated analyses have demonstrated MDR-1 expression in a tumor is a poor prognostic indicator leading some to conclude MDR-1 is a marker of a more aggressive phenotype, rather than a mechanism of drug resistance. In this review we will re-evaluate the MDR-1 story in light of our new understanding of molecular targeted therapy, using breast and lung cancer as examples. In the end we will reconcile the data available and the knowledge gained in support of a thesis that we understand far more than we realize, and that we can use this knowledge to improve future therapies.