Benjamin Lewis Franc

All Publications

• Estrogen Receptor-targeted PET Imaging for Breast Cancer. Radiology Zhou, W., Franc, B. L., DeMartini, W. B., Rosen, E. L. 2024; 312 (2): e240315

  Abstract

  Two complementary patient cases are presented to highlight the importance of estrogen receptor (ER)-targeting imaging in treatment planning and selection for endocrine therapy in breast cancer patients. This article will discuss the radiopharmaceuticals and biology, imaging interpretation, and current clinical applications of ER-targeting imaging using fluorine 18 fluoroestradiol PET.

  View details for DOI 10.1148/radiol.240315

  View details for PubMedID 39136565

• Frequent Amplification and Overexpression of PSMA in Basallike Breast Cancer from Analysis of The Cancer Genome Atlas. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Zhou, W., Halder, S., Herwald, S., Ghijsen, M., Shafi, G., Uttarwar, M., Rosen, E., Franc, B., Kishore, S. 2024

  Abstract

  Prostate-specific membrane antigen (PSMA) is frequently overexpressed in nonprostate malignancies. This preclinical study investigated the molecular basis of the application of PMSA-targeting radiopharmaceuticals in breast cancer subtypes. Methods: The somatic copy number status and the transcriptomic and protein expressions of FOLH1 (gene name of PSMA) were analyzed across breast cancer subtypes in 998 patients from The Cancer Genome Atlas dataset. Results: FOLH1 was frequently amplified in basallike breast cancer (BLBC) (32%) compared with luminal and human epidermal growth factor receptor 2-positive subtypes (16% and 17%, respectively; P < 0.01). FOLH1 expression was higher in BLBC (P < 0.001) and was negatively correlated with estrogen-receptor and progesterone-receptor expressions. Consistently, the PSMA protein level was higher in BLBC (P < 0.05). Interestingly, FOLH1 expression was associated with relapse-free and distant metastasis-free survival in patients with BLBC. Conclusion: The BLBC subtype exhibited frequent amplification and overexpression of PSMA, supporting the exploration of PSMA-targeting radiopharmaceuticals in this aggressive breast cancer subtype.

  View details for DOI 10.2967/jnumed.123.266659

  View details for PubMedID 38664014

• Same-day post-therapy imaging with a new generation whole-body digital SPECT/CT in assessing treatment response to [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer. European journal of nuclear medicine and molecular imaging Song, H., Leonio, M. I., Ferri, V., Duan, H., Aparici, C. M., Davidzon, G., Franc, B. L., Moradi, F., Shah, J., Bergstrom, C. P., Fan, A. C., Shah, S., Khaki, A. R., Srinivas, S., Iagaru, A. 2024

  Abstract

  PURPOSE: Lutetium-177 [177Lu]Lu-PSMA-617 radioligand therapy (RLT) represents a significant advancement for metastatic castration-resistant prostate cancer (mCRPC), demonstrating improvements in radiographic progression free survival (rPFS) and overall survival (OS) with a low rate of associated side effects. Currently, most post-therapy SPECT/CT is conducted at 24h after infusion. This study examines the clinical utility of a next-generation multi-detector Cadmium-Zinc-Telluride (CZT) SPECT/CT system (StarGuide) in same-day post-infusion assessment and early treatment response to [177Lu]Lu-PSMA-617.METHODS: In this retrospective study, 68 men with progressive mCRPC treated with [177Lu]Lu-PSMA-617 at our center from June 2022 to June 2023 were evaluated. Digital whole-body SPECT/CT imaging was performed after [177Lu]Lu-PSMA-617infusion (mean±SD: 1.8±0.6h, range 1.1-4.9h). Quantitative analysis of [177Lu]Lu-PSMA-617 positive lesions was performed in patients who underwent at least 2 post-therapy SPECT/CT, using liver parenchyma uptake as reference. Metrics including [177Lu]Lu-PSMA-617 positive total tumor volume (Lu-TTV), SUVmax and SUVmean were calculated. These quantitative metrics on post-infusion SPECT/CT images after cycles 1, 2 and 3 were correlated with overall survival (OS), prostate specific antigen-progression free survival (PSA-PFS) as defined by prostate cancer working group 3 (PCWG3), and PSA decrease over 50% (PSA50) response rates.RESULTS: 56 patients (means age 76.2±8.1 years, range: 60-93) who underwent at least 2 post-therapy SPECT/CT were included in the image analysis. The whole-body SPECT/CT scans (~12min per scan) were well tolerated, with 221 same-day scans performed (89%). At a median of 10-months follow-up, 33 (58.9%) patients achieved PSA50 after [177Lu]Lu-PSMA-617 treatment and median PSA-PFS was 5.0 months (range: 1.0-15 months) while median OS was not reached. Quantitative analysis of SPECT/CT images showed that 37 patients (66%) had>30% reduction in Lu-TTV, associated with significantly improved overall survival (median not reached vs. 6 months, P=0.008) and PSA-PFS (median 6 months vs. 1 months, P<0.001). However, changes in SUVmax or SUVmean did not correlate with PSA-PFS or OS.CONCLUSION: We successfully implemented same-day post-therapy SPECT/CT after [177Lu]Lu-PSMA-617 infusions. Quantitation of 1-2h post-therapy SPECT/CT images is a promising method for assessing treatment response. However, the approach is currently limited by its suboptimal detection of small tumor lesions and the necessity of incorporating a third-cycle SPECT/CT to mitigate the effects of any potential treatment-related flare-up. Further investigation in a larger patient cohort and prospective validation is essential to confirm these findings and to explore the role of SPECT/CT as a potential adjunct to PSMA PET/CT in managing mCRPC.

  View details for DOI 10.1007/s00259-024-06718-6

  View details for PubMedID 38635050

• Total and anatomically contextualized quantitative <SUP>18</SUP>F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression-free survival in patients with prostate cancer. Song, H., Anand, A., Sjostrand, K., Ferri, V., Duan, H., Shah, J., Moradi, F., Aparici, C., Franc, B., Davidzon, G., Bergstrom, C. P., Fan, A. C., Shah, S., Khaki, A., Srinivas, S., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 33

  View details for DOI 10.1200/JCO.2024.42.4_suppl.33

  View details for Web of Science ID 001266676900393

• Assessing the clinical utility of rapid post-therapy whole-body digital SPECT/CT in evaluating early treatment response of <SUP>177</SUP>Lu-PSMA-617 treatment. Leonio, M., Ferri, V., Duan, H., Shah, J., Moradi, F., Mari Aparici, C., Franc, B., Davidzon, G., Bergstrom, C. P., Fan, A. C., Shah, S., Khaki, A., Srinivas, S., Iagaru, A., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 32

  View details for DOI 10.1200/JCO.2024.42.4_suppl.32

  View details for Web of Science ID 001266676900643

• Total and anatomically contextualized quantitative 18F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression free survival in patients with prostate cancer Song, H., Sjostrand, K., Duan, H., Ferri, V., Aparici, C., Davidzon, G., Franc, B., Moradi, F., Anand, A., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2023

  View details for Web of Science ID 001053772002474

• Rapid dynamic reconstruction using list mode data for monitoring PET image quality accurately predicts final image noise and perceived quality Moradi, F., Khalighi, M., Su, K., Zhang, X., Wollenweber, S., Spangler-Bickell, M., Bharathi, P., Franc, B., Davidzon, G., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2023

  View details for Web of Science ID 001109210200126

• A Case-Based Primer on FDG PET/CT for Imaging Cardiovascular Infections: Protocol, Interpretation, and Pitfalls. Zhou, W., Moradi, F., Davidzon, G., Song, H., Grady, E., Nguyen, J., Franc, B., Aparici, C., Iagaru, A., Shah, J. SOC NUCLEAR MEDICINE INC. 2023

  View details for Web of Science ID 001109210201036

• Total and Anatomically Contextualized Quantitative 18F-DCFPyL PET at biochemical recurrence predicts subsequent biochemical progression free survival in prostate cancer patients Song, H., Duan, H., Ferri, V., Na, S., Davidzon, G., Franc, B., Aparici, C., Moradi, F., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2023

  View details for Web of Science ID 001109210201271

• Case Series of Precision Delivery of Methylprednisolone in Pediatric Inflammatory Bowel Disease: Feasibility, Clinical Outcomes, and Identification of a Vasculitic Transcriptional Program. Journal of clinical medicine Levitte, S., Yarani, R., Ganguly, A., Martin, L., Gubatan, J., Nadel, H. R., Franc, B., Gugig, R., Syed, A., Goyal, A., Park, K. T., Thakor, A. S. 2023; 12 (6)

  Abstract

  Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn's disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn's disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term "bridge" between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy.

  View details for DOI 10.3390/jcm12062386

  View details for PubMedID 36983386

• SPECT at the speed of PET: a feasibility study of CZT-based whole-body SPECT/CT in the post 177Lu-DOTATATE and 177Lu-PSMA617 setting. European journal of nuclear medicine and molecular imaging Song, H., Ferri, V., Duan, H., Aparici, C. M., Davidzon, G., Franc, B. L., Moradi, F., Nguyen, J., Shah, J., Iagaru, A. 2023

  Abstract

  To evaluate the feasibility of using the StarGuide (General Electric Healthcare, Haifa, Israel), a new generation multi-detector cadmium-zinc-telluride (CZT)-based SPECT/CT, for whole-body imaging in the setting of post-therapy imaging of 177Lu-labeled radiopharmaceuticals.Thirty-one patients (34-89 years old; mean ± SD, 65.5 ± 12.1) who were treated with either 177Lu-DOTATATE (n=17) or 177Lu-PSMA617 (n=14) as part of standard of care were scanned post-therapy with the StarGuide; some were also scanned with the standard GE Discovery 670 Pro SPECT/CT. All patients had either 64Cu-DOTATATE or 18F-DCFPyL PET/CT prior to first cycle of therapy for eligibility check. The detection/targeting rate (lesion uptake greater than blood pool uptake) of large lesions meeting RECIST 1.1 size criteria on post-therapy StarGuide SPECT/CT was evaluated and compared to the standard design GE Discovery 670 Pro SPECT/CT (when available) and pre-therapy PET by two nuclear medicine physicians with consensus read.This retrospective analysis identified a total of 50 post-therapy scans performed with the new imaging protocol from November 2021 to August 2022. The StarGuide system acquired vertex to mid-thighs post-therapy SPECT/CT scans with 4 bed positions, 3 min/bed and a total scan time of 12 min. In comparison, the standard GE Discovery 670 Pro SPECT/CT system typically acquires images in 2 bed positions covering the chest, abdomen, and pelvis with a total scan time of 32 min. The pre-therapy 64Cu-DOTATATE PET takes 20 min with 4 bed positions on GE Discovery MI PET/CT, and 18F-DCFPyL PET takes 8-10 min with 4-5 bed positions on GE Discovery MI PET/CT. This preliminary evaluation showed that the post-therapy scans acquired with faster scanning time using StarGuide system had comparable detection/targeting rate compared to the Discovery 670 Pro SPECT/CT system and detected large lesions defined by RECIST criteria on the pre-therapy PET scans.Fast acquisition of whole-body post-therapy SPECT/CT is feasible with the new StarGuide system. Short scanning time improves the patients' clinical experience and compliance which may lead to increased adoption of post-therapy SPECT. This opens the possibility to offer imaged-based treatment response assessment and personalized dosimetry to patients referred for targeted radionuclide therapies.

  View details for DOI 10.1007/s00259-023-06176-6

  View details for PubMedID 36869177

  View details for PubMedCentralID 6667427

• Retroperitoneal Inflammation Detected on FDG PET/CT in Patient on Long-Term Immunotherapy. Clinical nuclear medicine Khessib, T., Franc, B., Yang, E., Moradi, F. 2023

  Abstract

  ABSTRACT: A 68-year-old man with a history of pulmonary adenocarcinoma on maintenance pembrolizumab presented for surveillance imaging. 18F-FDG PET/CT demonstrated new ill-defined right retroperitoneal and presacral soft tissue stranding with associated FDG uptake suggestive of inflammation. Biopsy results revealed fibroadipose tissue with extensive lymphoplasmacytic inflammation concerning for immunotherapy-related toxicity. The patient was subsequently taken off pembrolizumab, which he had been on for approximately 3 years. Recognition of immunotherapy-related adverse effects and how they can manifest on 18F-FDG PET/CT is important for prompt cessation of treatment.

  View details for DOI 10.1097/RLU.0000000000004513

  View details for PubMedID 36728374

• Hong Song, Heying Duan, Caitlyn Harrison, Kip Guja, Negin Hatami, Judy Nguyen, Benjamin Franc, Farshad Moradi, Carina Mari Aparici, Guido Davidzon, Sandy Srinivas and Andrei lagaru Song, H., Duan, H., Harrison, C., Guja, K., Hatami, N., Nguyen, J., Franc, B., Moradi, F., Aparici, C., Davidzon, G., Srinivas, S., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2022

  View details for Web of Science ID 000893739700240

• Prediction of future healthcare expenses of patients from chest radiographs using deep learning: a pilot study. Scientific reports Sohn, J. H., Chen, Y., Lituiev, D., Yang, J., Ordovas, K., Hadley, D., Vu, T. H., Franc, B. L., Seo, Y. 2022; 12 (1): 8344

  Abstract

  Our objective was to develop deep learning models with chest radiograph data to predict healthcare costs and classify top-50% spenders. 21,872 frontal chest radiographs were retrospectively collected from 19,524 patients with at least 1-year spending data. Among the patients, 11,003 patients had 3years of cost data, and 1678 patients had 5years of cost data. Model performances were measured with area under the receiver operating characteristic curve (ROC-AUC) for classification of top-50% spenders and Spearman rho for prediction of healthcare cost. The best model predicting 1-year (N=21,872) expenditure achieved ROC-AUC of 0.806 [95% CI 0.793-0.819] for top-50% spender classification and rho of 0.561 [0.536-0.586] for regression. Similarly, for predicting 3-year (N=12,395) expenditure, ROC-AUC of 0.771 [0.750-0.794] and rho of 0.524 [0.489-0.559]; for predicting 5-year (N=1779) expenditure ROC-AUC of 0.729 [0.667-0.729] and rho of 0.424 [0.324-0.529]. Our deep learning model demonstrated the feasibility of predicting health care expenditure as well as classifying top 50% healthcare spenders at 1, 3, and 5year(s), implying the feasibility of combining deep learning with information-rich imaging data to uncover hidden associations that may allude to physicians. Such a model can be a starting point of making an accurate budget in reimbursement models in healthcare industries.

  View details for DOI 10.1038/s41598-022-12551-4

  View details for PubMedID 35585177

• First-in-human immunoPET imaging of HIV-1 infection using 89Zr-labeled VRC01 broadly neutralizing antibody. Nature communications Beckford-Vera, D. R., Flavell, R. R., Seo, Y., Martinez-Ortiz, E., Aslam, M., Thanh, C., Fehrman, E., Pardons, M., Kumar, S., Deitchman, A. N., Ravanfar, V., Schulte, B., Wu, I. K., Pan, T., Reeves, J. D., Nixon, C. C., Iyer, N. S., Torres, L., Munter, S. E., Hyunh, T., Petropoulos, C. J., Hoh, R., Franc, B. L., Gama, L., Koup, R. A., Mascola, J. R., Chomont, N., Deeks, S. G., VanBrocklin, H. F., Henrich, T. J. 2022; 13 (1): 1219

  Abstract

  A major obstacle to achieving long-term antiretroviral (ART) free remission or functional cure of HIV infection is the presence of persistently infected cells that establish a long-lived viral reservoir. HIV largely resides in anatomical regions that are inaccessible to routine sampling, however, and non-invasive methods to understand the longitudinal tissue-wide burden of HIV persistence are urgently needed. Positron emission tomography (PET) imaging is a promising strategy to identify and characterize the tissue-wide burden of HIV. Here, we assess the efficacy of using immunoPET imaging to characterize HIV reservoirs and identify anatomical foci of persistent viral transcriptional activity using a radiolabeled HIV Env-specific broadly neutralizing antibody, 89Zr-VRC01, in HIV-infected individuals with detectable viremia and on suppressive ART compared to uninfected controls (NCT03729752). We also assess the relationship between PET tracer uptake in tissues and timing of ART initiation and direct HIV protein expression in CD4 T cells obtained from lymph node biopsies. We observe significant increases in 89Zr-VRC01 uptake in various tissues (including lymph nodes and gut) in HIV-infected individuals with detectable viremia (N=5) and on suppressive ART (N=5) compared to uninfected controls (N=5). Importantly, PET tracer uptake in inguinal lymph nodes in viremic and ART-suppressed participants significantly and positively correlates with HIV protein expression measured directly in tissue. Our strategy may allow non-invasive longitudinal characterization of residual HIV infection and lays the framework for the development of immunoPET imaging in a variety of other infectious diseases.

  View details for DOI 10.1038/s41467-022-28727-5

  View details for PubMedID 35264559

• Peptide Receptor Radionuclide Therapy (PRRT) in Advanced Pheochromocytoma and Paraganglioma From a Single Institution Experience Duan, H., Ferri, V., Fisher, G. A., Shaheen, S., Davidzon, G. A., Moradi, F., Nguyen, J., Franc, B. L., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2022: E42-E43

  View details for Web of Science ID 000819123700057

• Phantom study of SPECT/CT augmented reality for intraoperative localization of sentinel lymph nodes in head and neck melanoma. Oral oncology Nakamoto, R., Zhuo, J., Guja, K. E., Duan, H., Perkins, S. L., Leuze, C., Daniel, B. L., Franc, B. L. 1800; 125: 105702

  Abstract

  OBJECTIVE: To show that augmented reality (AR) visualization of single-photon emission computed tomography (SPECT)/computed tomography (CT) data in 3D can be used to accurately localize targets in the head and neck region.MATERIALS AND METHODS: Eight head and neck styrofoam phantoms were painted with a mixture of radioactive solution (Tc-99m) detectable with a handheld gamma probe and fluorescent ink visible only under ultraviolet (UV) light to create 10-20 simulated lymph nodes on their surface. After obtaining SPECT/CT images of these phantoms, virtual renderings of the nodes were generated from the SPECT/CT data and displayed using a commercially available AR headset. For each of three physician evaluators, the time required to localize lymph node targets was recorded (1) using the gamma probe alone and (2) using the gamma probe while wearing the AR headset. In addition, the surface localization accuracy when using the AR headset was evaluated by measuring the misalignment between the locations visually marked by the evaluators and the ground truth locations identified using UV stimulation of the ink at the site of the nodes.RESULTS: For all three evaluators, using the AR headset significantly reduced the time to detect targets (P=0.012, respectively) compared to using the gamma probe alone. The average misalignment between the location marked by the evaluators and the ground truth location was 8.6mm.CONCLUSION: AR visualization of SPECT/CT data in 3D allows for accurate localization of targets in the head and neck region, and may reduce the localization time of targets.

  View details for DOI 10.1016/j.oraloncology.2021.105702

  View details for PubMedID 34991004

• PROSPECTIVE EVALUATION OF F-18-DCFPYL PET/CT IN BIOCHEMICALLY RECURRENT PROSTATE CANCER: ANALYSIS OF F-18-DCFPYL UPTAKE IN POSSIBLE EXTRA-PELVIC OLIGOMETASTASES Song, H., Nguyen, J., Moradi, F., Aparici, C., Franc, B., Davidzon, G., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: E1177-E1178

  View details for Web of Science ID 000693689000847

• Perfusion Only Scans with and without SPECT/CT in the Era of COVID-19 Zhang, R., Moradi, F., Aparici, C., Davidzon, G., Nguyen, J., Iagaru, A., Franc, B. SOC NUCLEAR MEDICINE INC. 2021

  View details for Web of Science ID 000713713600506

• Prognostic value of bone marrow metabolism on pretreatment 18F-FDG PET/CT in patients with metastatic melanoma treated with anti-PD-1 therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Nakamoto, R., Zaba, L. C., Liang, T., Reddy, S. A., Davidzon, G., Aparici, C. M., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. L. 2021

  Abstract

  Purpose: To investigate the prognostic value of 18F-FDG PET/CT parameters in melanoma patients before beginning anti-PD-1 therapy. Methods: Imaging parameters including SUVmax, metabolic tumor volume (MTV), and bone marrow to liver SUVmean ratio (BLR) were measured from baseline PET/CT in 92 patients before the start of anti-PD-1 therapy. Association with survival and imaging parameters combined with clinical factors was evaluated. Clinical and laboratory data between high (> median) and low (≤ median) BLR groups were compared. Results: Multivariate analyses demonstrated that BLR was an independent prognostic factor for PFS and OS (P = 0.017, P = 0.011, respectively). The high BLR group had higher levels of white blood cell count/neutrophil count and C-Reactive Protein than the low BLR group (P < 0.05). Conclusion: Patients with high BLR were associated with poor PFS and OS, potentially explained by evidence of systemic inflammation known to be associated with immunosuppression.

  View details for DOI 10.2967/jnumed.120.254482

  View details for PubMedID 33547210

• The Clinical Utility of 18F-Fluciclovine PET/CT in Biochemically Recurrent Prostate Cancer: an Academic Center Experience Post FDA Approval. Molecular imaging and biology Nakamoto, R. n., Harrison, C. n., Song, H. n., Guja, K. E., Hatami, N. n., Nguyen, J. n., Moradi, F. n., Franc, B. L., Aparici, C. M., Davidzon, G. n., Iagaru, A. n. 2021

  Abstract

  To evaluate the diagnostic performance and clinical utility of 18F-fluciclovine PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC).18F-Fluciclovine scans of 165 consecutive men with BCR after primary definitive treatment with prostatectomy (n = 102) or radiotherapy (n = 63) were retrospectively evaluated. Seventy patients had concurrent imaging with at least one other conventional modality (CT (n = 31), MRI (n = 31), or bone scan (n = 26)). Findings from 18F-fluciclovine PET were compared with those from conventional imaging modalities. The positivity rate and impact of 18F-fluciclovine PET on patient management were recorded. In 33 patients who underwent at least one other PET imaging (18F-NaF PET/CT (n = 12), 68Ga-PSMA11 PET/CT (n = 5), 18F-DCFPyL PET/CT (n = 20), and 68Ga-RM2 PET/MRI (n = 5)), additional findings were evaluated.The overall positivity rate of 18F-fluciclovine PET was 67 %, which, as expected, increased with higher prostate-specific antigen (PSA) levels (ng/ml): 15 % (PSA < 0.5), 50 % (0.5 ≤ PSA < 1), 56 % (1 ≤ PSA < 2), 68 % (2 ≤ PSA < 5), and 94 % (PSA ≥ 5), respectively. One hundred and two patients (62 %) had changes in clinical management based on 18F-fluciclovine PET findings. Twelve of these patients (12 %) had lesion localization on 18F-fluciclovine PET, despite negative conventional imaging. Treatment plans of 14 patients with negative 18F-fluciclovine PET were changed based on additional PET imaging with a different radiopharmaceutical.18F-Fluciclovine PET/CT remains a useful diagnostic tool in the workup of patients with BCR PC, changing clinical management in 62 % of participants in our cohort.

  View details for DOI 10.1007/s11307-021-01583-3

  View details for PubMedID 33469884

• Disparities in PET Imaging of Prostate Cancer at a Tertiary Academic Medical Center JOURNAL OF NUCLEAR MEDICINE Iagaru, A., Franc, B. 2021; 62 (5): 747-748

  View details for DOI 10.2967/jnumed.121.262029

  View details for Web of Science ID 000755623900036

• Evaluation of primary breast cancers using dedicated breast PET and whole-body PET. Scientific reports Hathi, D. K., Li, W., Seo, Y., Flavell, R. R., Kornak, J., Franc, B. L., Joe, B. N., Esserman, L. J., Hylton, N. M., Jones, E. F. 2020; 10 (1): 21930

  Abstract

  Metabolic imaging of the primary breast tumor with 18F-fluorodeoxyglucose ([18F]FDG) PET may assist in predicting treatment response in the neoadjuvant chemotherapy (NAC) setting. Dedicated breast PET (dbPET) is a high-resolution imaging modality with demonstrated ability in highlighting intratumoral heterogeneity and identifying small lesions in the breast volume. In this study, we characterized similarities and differences in the uptake of [18F]FDG in dbPET compared to whole-body PET (wbPET) in a cohort of tenpatients with biopsy-confirmed, locally advanced breast cancer at the pre-treatment timepoint. Patients received bilateral dbPET and wbPET following administration of 186MBq and 307MBq [18F]FDG on separate days, respectively. [18F]FDG uptake measurements and 20 radiomic features based on morphology, tumor intensity, and texture were calculated and compared. There was a fivefold increase in SULpeak for dbPET (median difference (95% CI): 4.0mL-1 (1.8-6.4mL-1), p=0.006). Additionally, spatial heterogeneity features showed statistically significant differences between dbPET and wbPET. The higher [18F]FDG uptake in dbPET highlighted the dynamic range of this breast-specific imaging modality. Combining with the higher spatial resolution, dbPET may be able to detect treatment response in the primary tumor during NAC, and future studies with larger cohorts are warranted.

  View details for DOI 10.1038/s41598-020-78865-3

  View details for PubMedID 33318514

• Positron Emission Tomography Imaging of Functional TGFbeta Activity and Benefit of TGFbeta Inhibition in Irradiated Intracranial Tumors. International journal of radiation oncology, biology, physics Gonzalez-Junca, A., Reiners, O., Borrero-Garcia, L. D., Beckford-Vera, D., Lazar, A. A., Chou, W., Braunstein, S., VanBrocklin, H., Franc, B. L., Barcellos-Hoff, M. H. 2020

  Abstract

  INTRODUCTION: Transforming growth factor beta (TGFbeta) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFbeta activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed.METHODS: & Materials: We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFbeta neutralizing monoclonal antibody, as means to detect TGFbeta activation in intracranial tumor models. TGFbeta pathway activity was validated by immunodetection of phosphorylated SMAD2 and TGFbeta target, tenascin. The contribution of TGFbeta to radiation response was assessed by Kaplan Meier survival analysis of mice bearing intracranial murine tumor models, GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFbeta neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy).RESULTS: 89Zr-fresolimumab PET imaging detected engineered, physiological and radiation-induced TGFbeta activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had more PET signal compared to similar sized SB28 glioblastoma tumors, whereas widespread PET signal of 4T1-BrA intracranial tumors is consistent with its highly dispersed histological distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of combination of radiation and 1D11 was associated with the degree of TGFbeta activity detected by PET.CONCLUSIONS: This study demonstrates that 89Zr -fresolimumab PET imaging detects radiation-induced TGFbeta activation in tumors. Functional imaging indicated a range of TGFbeta activity in intracranial tumors, but TGFbeta blockade provided survival benefit only in the context of radiation treatment. These studies are further evidence that radiation-induced TGFbeta activity opposes therapeutic response to radiation.

  View details for DOI 10.1016/j.ijrobp.2020.09.043

  View details for PubMedID 33007434

• Obituary for Sanjiv Sam Gambhir, MD, PhD. Clinical nuclear medicine Davidzon, G., Franc, B., Mari Aparici, C., Moradi, F., Nguyen, J., Iagaru, A. 2020

  View details for DOI 10.1097/RLU.0000000000003284

  View details for PubMedID 32956118

• Prospective evaluation of F-18-DCFPyL PET/CT in biochemically recurrent prostate cancer: Analysis of lesion localization and distribution. Song, H., Duan, H., Harrison, C., Guja, K., Hatami, N., Franc, B., Moradi, F., Aparici, C., Davidzon, G., Srinivas, S., Iagaru, A. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000560368302399

• Extrahepatic Ga-68-DOTATATE-Avid Tumor Volume and serum Chromogranin A Predict Short-Term Outcome of Lu-177-DOTATATE in Late-Stage Metastatic Gastroenteropancreatic Neuroendocrine Tumors Song, H., Kunz, P., Franc, B., Moradi, F., Fisher, G., Aparici, C., Iagaru, A., Davidzon, G. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500275

• PSMA-and GRPR-targeted PET: Preliminary Results in Patients with Biochemically Recurrent Prostate Cancer Baratto, L., Duan, H., Hatami, N., Song, H., Davidzon, G., Franc, B., Aparici, C., Moradi, F., Nguyen, J., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501184

• Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy Nakamoto, R., Zaba, L., Rosenberg, J., Reddy, S., Nobashi, T., Davidzon, G., Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500428

• Imaging characteristics and diagnostic performance of F-18-FDG PET/CT for melanoma patients who demonstrate hyperprogressive disease when treated with immunotherapy Nakamoto, R., Zaba, L., Rosenberg, J., Reddy, S., Nobashi, T., Davidzon, G., Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Franc, B. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500424

• Toxicity identification and evaluation of peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors (NETs) Duan, H., Girod, B., Ninatti, G., Ferri, V., Kunz, P., Fisher, G., Moradi, F., Davidzon, G., Franc, B., Iagaru, A., Aparici, C. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501378

• Fungal endocarditis resembling primary cardiac malignancy in a patient with B-cell ALL with culture confirmation. Radiology case reports Girod, B. J., Guja, K. E., Davidzon, G., Chan, F., Zucker, E., Franc, B. L., Moradi, F., Iagaru, A., Aparici, C. M. 2020; 15 (2): 117–19

  Abstract

  Fungal endocarditis is a rare subtype of infective endocarditis that often presents with nonspecific symptoms in patients with complex medical histories, making diagnosis challenging. Patients with a history of ALL may present with congestive heart failure, chemo-induced cardiomyopathy, acute coronary syndrome, cardiac lymphomatous metastasis, or infections. We present the case of a patient with a history of ALL who presented with acute coronary syndrome and imaging concerning for primary cardiac lymphoma, when in fact the patient ended up suffering from culture proven fungal endocarditis.

  View details for DOI 10.1016/j.radcr.2019.10.022

  View details for PubMedID 31768196

• Single institution experience with peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) Duan, H., Ninatti, G., Girod, B., Ferri, V., Kunz, P. L., Fisher, G. A., Moradi, F., Davidzon, G., Franc, B., Iagaru, A., Mari, C. AMER SOC CLINICAL ONCOLOGY. 2020

  View details for Web of Science ID 000530922700601

• Using diagnosis codes in claims data to identify cohorts of breast cancer patients following initial treatment. The breast journal Franc, B. L., Thombley, R., Luo, Y., John Boscardin, W., Rugo, H. S., Seidenwurm, D., Adams Dudley, R. 2020

  View details for DOI 10.1111/tbj.13758

  View details for PubMedID 31960541

• Letter to the Editor: "Disparities in PET imaging for prostate cancer at a tertiary academic medical center". Journal of nuclear medicine : official publication, Society of Nuclear Medicine Franc, B. L., Iagaru, A. n. 2020

  View details for DOI 10.2967/jnumed.120.258160

  View details for PubMedID 33127623

• Preclinical SPECT and SPECT-CT in Oncology. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer Franc, B. L., Seo, Y., Flavell, R., Aparici, C. M. 2020; 216: 359–404

  Abstract

  Molecular imaging enables both spatial and temporal understanding of the complex biologic systems underlying carcinogenesis and malignant spread. Single-photon emission tomography (SPECT) is a versatile nuclear imaging-based technique with ideal properties to study these processes in vivo in small animal models, as well as to identify potential drug candidates and characterize their antitumor action and potential adverse effects. Small animal SPECT and SPECT-CT (single-photon emission tomography combined with computer tomography) systems continue to evolve, as do the numerous SPECT radiopharmaceutical agents, allowing unprecedented sensitivity and quantitative molecular imaging capabilities. Several of these advances, their specific applications in oncology as well as new areas of exploration are highlighted in this chapter.

  View details for DOI 10.1007/978-3-030-42618-7_11

  View details for PubMedID 32594393

• Deep learning detection of prostate cancer recurrence with 18F-FACBC (fluciclovine, Axumin®) positron emission tomography. European journal of nuclear medicine and molecular imaging Lee, J. J., Yang, H. n., Franc, B. L., Iagaru, A. n., Davidzon, G. A. 2020

  Abstract

  To evaluate the performance of deep learning (DL) classifiers in discriminating normal and abnormal 18F-FACBC (fluciclovine, Axumin®) PET scans based on the presence of tumor recurrence and/or metastases in patients with prostate cancer (PC) and biochemical recurrence (BCR).A total of 251 consecutive 18F-fluciclovine PET scans were acquired between September 2017 and June 2019 in 233 PC patients with BCR (18 patients had 2 scans). PET images were labeled as normal or abnormal using clinical reports as the ground truth. Convolutional neural network (CNN) models were trained using two different architectures, a 2D-CNN (ResNet-50) using single slices (slice-based approach) and the same 2D-CNN and a 3D-CNN (ResNet-14) using a hundred slices per PET image (case-based approach). Models' performances were evaluated on independent test datasets.For the 2D-CNN slice-based approach, 6800 and 536 slices were used for training and test datasets, respectively. The sensitivity and specificity of this model were 90.7% and 95.1%, and the area under the curve (AUC) of receiver operating characteristic curve was 0.971 (p < 0.001). For the case-based approaches using both 2D-CNN and 3D-CNN architectures, a training dataset of 100 images and a test dataset of 28 images were randomly allocated. The sensitivity, specificity, and AUC to discriminate abnormal images by the 2D-CNN and 3D-CNN case-based approaches were 85.7%, 71.4%, and 0.750 (p = 0.013) and 71.4%, 71.4%, and 0.699 (p = 0.053), respectively.DL accurately classifies abnormal 18F-fluciclovine PET images of the pelvis in patients with BCR of PC. A DL classifier using single slice prediction had superior performance over case-based prediction.

  View details for DOI 10.1007/s00259-020-04912-w

  View details for PubMedID 32556481

• An unusual presentation of recurrent T cell lymphoma: angiocentric pattern of cutaneous uptake on [18F]FDG PET/CT. European journal of nuclear medicine and molecular imaging Guja, K. E., Brown, R. n., Girod, B. n., Song, H. n., Harrison, C. n., Franc, B. L., Moradi, F. n., Davidzon, G. n., Iagaru, A. n., Aparici, C. M. 2020

  View details for DOI 10.1007/s00259-020-05026-z

  View details for PubMedID 32918110

• Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy. European journal of nuclear medicine and molecular imaging Nakamoto, R. n., Zaba, L. C., Rosenberg, J. n., Reddy, S. A., Nobashi, T. W., Davidzon, G. n., Aparici, C. M., Nguyen, J. n., Moradi, F. n., Iagaru, A. n., Franc, B. L. 2020

  Abstract

  The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs).Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated.The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group.Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

  View details for DOI 10.1007/s00259-020-04792-0

  View details for PubMedID 32296882

• Identifying tests related to breast cancer care in claims data. The breast journal Franc, B. L., Thombley, R., Luo, Y., Boscardin, W. J., Rugo, H. S., Seidenwurm, D., Dudley, R. A. 2019

  Abstract

  To develop a method for calculating rates of testing for breast cancer recurrence in patients who have already undergone initial treatment for breast cancer, we calculated rates in a cohort of Medicare breast cancer patients and an age-matched noncancer cohort. We first used only tests with claims including diagnosis codes indicating invasive breast cancer and then used all tests regardless of diagnosis code. For each method, we calculated testing rates in the breast cancer cohort above the background rate in the noncancer population. The two methods provided similar estimates of testing prevalence and frequency, with exception of prevalence of CT.

  View details for DOI 10.1111/tbj.13691

  View details for PubMedID 31736191

• Prospective Evaluation in an Academic Center of 18F-DCFPyL PET/CT in Biochemically Recurrent Prostate Cancer: A Focus on Localizing Disease and Changes in Management. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Song, H., Harrison, C., Duan, H., Guja, K., Hatami, N., Franc, B., Moradi, F., Mari Aparici, C., Davidzon, G., Iagaru, A. 2019

  Abstract

  18F-DCFPyL is a promising PET radiopharmaceutical targeting prostate specific membrane antigen (PSMA). We present our experience in this single academic center prospective study evaluating the positivity rate of 18F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52-91 years old, mean±SD: 71.5±7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by two independent readers. Fifty-nine patients had concurrent scans with at least one other conventional scan: bone scan (24), CT (21), MR (20), 18F-Fluciclovine PET/CT (18) and/or 18F-NaF PET (14). Findings from 18F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on 18F-DCFPyL PET/CT was recorded from clinical chart review. Results: 18F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate specific antigen (PSA) levels (ng/mL): 50% (PSA<0.5), 69% (0.5≤PSA<1), 100% (1≤PSA<2), 91% (2≤PSA<5) and 96% (PSA≥5), respectively. 18F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20/41 (49%) CT/MRI had congruent findings with 18F-DCFPyL, while 18F-DCFPyL PET was positive in 17/41 (41%) cases with negative CT/MRI. For bone imaging, 26/38 (68%) bone scan/18F-NaF PET were congruent with 18F-DCFPyL PET, while 18F-DCFPyL PET localized bone lesions in 8/38 (21%) patients with negative bone scan/18F-NaF PET. In 8/18 (44%) patients, 18F-Fluciclovine PET had located the same lesions as the 18F-DCFPyL PET, while 5/18 (28%) patients with negative 18F-Fluciclovine had positive 18F-DCFPyL PET findings and 1/18 (6%) patient with negative 18F-DCFPyL had uptake in the prostate bed on 18F-Fluciclovine PET. In the remaining 4/18 (22%) patients, 18F-DCFPyL and 18F-Fluciclovine scans showed different lesions. Lastly, 43/72 (60%) patients had treatment changes after 18F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on 18F-DCFPyL PET, despite negative conventional imaging. Conclusion: 18F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent prostate cancer given the high positivity rate as compared to FDA-approved currently available imaging modalities and its impact on clinical management in 60% of patients.

  View details for DOI 10.2967/jnumed.119.231654

  View details for PubMedID 31628216

• PET/CT Imaging of Human TNFα Using [89Zr]Certolizumab Pegol in a Transgenic Preclinical Model of Rheumatoid Arthritis. Molecular imaging and biology Beckford-Vera, D. R., Gonzalez-Junca, A., Janneck, J. S., Huynh, T. L., Blecha, J. E., Seo, Y., Li, X., VanBrocklin, H. F., Franc, B. L. 2019

  Abstract

  Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice.CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats.[89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP.The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.

  View details for DOI 10.1007/s11307-019-01363-0

  View details for PubMedID 31065895

• Prospective Evaluation of F-18-DCFPyL PET/CT and Conventional Imaging in Patients with Biochemically Recurrent Prostate Cancer Song, H., Harrison, C., Guja, K., Franc, B., Moradi, F., Davidzon, G., Aparici, C., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116801016

• Prospective evaluation of F-18- DCFPyL in Patients with Biochemically Recurrent Prostate Cancer: Positivity Rate and Correlation with PSA levels Harrison, C., Song, H., Franc, B. L., Guja, K., Moradi, F., Davidzon, G., Aparici, C., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116801610

• Prospective Comparison of F-18-DCFPyL PET/CT with F-18-NaF PET/CT for Detection of Skeletal Metastases in Biochemically Recurrent Prostate Cancer Duan, H., Song, H., Baratto, L., Khalaf, M., Hatami, N., Franc, B., Moradi, F., Davidzon, G., Aparici, C., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116801621

• Initial experience of dedicated breast PET imaging of ER+ breast cancers using [F-18]fluoroestradiol. NPJ breast cancer Jones, E. F., Ray, K. M., Li, W., Chien, A. J., Mukhtar, R. A., Esserman, L. J., Franc, B. L., Seo, Y., Pampaloni, M. H., Joe, B. N., Hylton, N. M. 2019; 5: 12

  Abstract

  Dedicated breast positron emission tomography (dbPET) is an emerging technology with high sensitivity and spatial resolution that enables detection of sub-centimeter lesions and depiction of intratumoral heterogeneity. In this study, we report our initial experience with dbPET using [F-18]fluoroestradiol (FES) in assessing ER+ primary breast cancers. Six patients with >90% ER+ and HER2- breast cancers were imaged with dbPET and breast MRI. Two patients had ILC, three had IDC, and one had an unknown primary tumor. One ILC patient was treated with letrozole, and another patient with IDC was treated with neoadjuvant chemotherapy without endocrine treatment. In this small cohort, we observed FES uptake in ER+ primary breast tumors with specificity to ER demonstrated in a case with tamoxifen blockade. FES uptake in ILC had a diffused pattern compared to the distinct circumscribed pattern in IDC. In evaluating treatment response, the reduction of SUVmax was observed with residual disease in an ILC patient treated with letrozole, and an IDC patient treated with chemotherapy. Future study is critical to understand the change in FES SUVmax after endocrine therapy and to consider other tracer uptake metrics with SUVmax to describe ER-rich breast cancer. Limitations include variations of FES uptake in different ER+ breast cancer diseases and exclusion of posterior tissues and axillary regions. However, FES-dbPET has a high potential for clinical utility, especially in measuring response to neoadjuvant endocrine treatment. Further development to improve the field of view and studies with a larger cohort of ER+ breast cancer patients are warranted.

  View details for DOI 10.1038/s41523-019-0107-9

  View details for PubMedID 31016232

  View details for PubMedCentralID PMC6467896

• Large Scale Semi-Automated Labeling of Routine Free-Text Clinical Records for Deep Learning. Journal of digital imaging Trivedi, H. M., Panahiazar, M., Liang, A., Lituiev, D., Chang, P., Sohn, J. H., Chen, Y. Y., Franc, B. L., Joe, B., Hadley, D. 2019; 32 (1): 30-37

  Abstract

  Breast cancer is a leading cause of cancer death among women in the USA. Screening mammography is effective in reducing mortality, but has a high rate of unnecessary recalls and biopsies. While deep learning can be applied to mammography, large-scale labeled datasets, which are difficult to obtain, are required. We aim to remove many barriers of dataset development by automatically harvesting data from existing clinical records using a hybrid framework combining traditional NLP and IBM Watson. An expert reviewer manually annotated 3521 breast pathology reports with one of four outcomes: left positive, right positive, bilateral positive, negative. Traditional NLP techniques using seven different machine learning classifiers were compared to IBM Watson's automated natural language classifier. Techniques were evaluated using precision, recall, and F-measure. Logistic regression outperformed all other traditional machine learning classifiers and was used for subsequent comparisons. Both traditional NLP and Watson's NLC performed well for cases under 1024 characters with weighted average F-measures above 0.96 across all classes. Performance of traditional NLP was lower for cases over 1024 characters with an F-measure of 0.83. We demonstrate a hybrid framework using traditional NLP techniques combined with IBM Watson to annotate over 10,000 breast pathology reports for development of a large-scale database to be used for deep learning in mammography. Our work shows that traditional NLP and IBM Watson perform extremely well for cases under 1024 characters and can accelerate the rate of data annotation.

  View details for DOI 10.1007/s10278-018-0105-8

  View details for PubMedID 30128778

  View details for PubMedCentralID PMC6382632

• A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F-FDG PET of the Brain. Radiology Ding, Y., Sohn, J. H., Kawczynski, M. G., Trivedi, H., Harnish, R., Jenkins, N. W., Lituiev, D., Copeland, T. P., Aboian, M. S., Mari Aparici, C., Behr, S. C., Flavell, R. R., Huang, S. Y., Zalocusky, K. A., Nardo, L., Seo, Y., Hawkins, R. A., Hernandez Pampaloni, M., Hadley, D., Franc, B. L. 2019; 290 (2): 456-464

  Abstract

  Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (18F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective 18F-FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t-distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue.

  View details for DOI 10.1148/radiol.2018180958

  View details for PubMedID 30398430

  View details for PubMedCentralID PMC6358051

• Performance Comparison of Individual and Ensemble CNN Models for the Classification of Brain 18F-FDG-PET Scans. Journal of digital imaging Nobashi, T. n., Zacharias, C. n., Ellis, J. K., Ferri, V. n., Koran, M. E., Franc, B. L., Iagaru, A. n., Davidzon, G. A. 2019

  Abstract

  The high-background glucose metabolism of normal gray matter on [18F]-fluoro-2-D-deoxyglucose (FDG) positron emission tomography (PET) of the brain results in a low signal-to-background ratio, potentially increasing the possibility of missing important findings in patients with intracranial malignancies. To explore the strategy of using a deep learning classifier to aid in distinguishing normal versus abnormal findings on PET brain images, this study evaluated the performance of a two-dimensional convolutional neural network (2D-CNN) to classify FDG PET brain scans as normal (N) or abnormal (A).Two hundred eighty-nine brain FDG-PET scans (N; n = 150, A; n = 139) resulting in a total of 68,260 images were included. Nine individual 2D-CNN models with three different window settings for axial, coronal, and sagittal axes were trained and validated. The performance of these individual and ensemble models was evaluated and compared using a test dataset. Odds ratio, Akaike's information criterion (AIC), and area under curve (AUC) on receiver-operative-characteristic curve, accuracy, and standard deviation (SD) were calculated.An optimal window setting to classify normal and abnormal scans was different for each axis of the individual models. An ensembled model using different axes with an optimized window setting (window-triad) showed better performance than ensembled models using the same axis and different windows settings (axis-triad). Increase in odds ratio and decrease in SD were observed in both axis-triad and window-triad models compared with individual models, whereas improvements of AUC and AIC were seen in window-triad models. An overall model averaging the probabilities of all individual models showed the best accuracy of 82.0%.Data ensemble using different window settings and axes was effective to improve 2D-CNN performance parameters for the classification of brain FDG-PET scans. If prospectively validated with a larger cohort of patients, similar models could provide decision support in a clinical setting.

  View details for DOI 10.1007/s10278-019-00289-x

  View details for PubMedID 31659587

• Delayed Fluorodeoxyglucose Positron Emission Tomography Imaging in the Differentiation of Tumor Recurrence and Radiation Necrosis in Pediatric Central Nervous System Tumors: Case Report and Review of the Literature. Cureus Wadhwa, E. L., Franc, B. L., Aboian, M., Kim, J. Y., Pampaloni, M., Nicolaides, T. 2018; 10 (9): e3364

  Abstract

  Malignant central nervous system (CNS) tumors are often treated with radiation therapy, after which clinical and radiographic sequelae can lead to difficulties differentiating tumor recurrence from treatment effect. Magnetic resonance imaging (MRI) is often unable to distinguish between these two entities. The improved ability to delineate concerning foci could lead to earlier tumor detection with quicker access to new therapies and/or clinical trials; conversely, it could alleviate patient concerns in the case of radiation necrosis as the etiology. The utility of positron emission tomography with computed tomography (PET/CT) imaging with fluorodeoxyglucose (FDG) has been explored in CNS tumors in the past, as this imaging modality is widely used in oncologic practices. As there are concerns with false positive imaging in the case of cells with a high metabolic uptake due to causes other than malignancy (i.e. infection, inflammation), delayed FDG PET imaging has been proposed as a mechanism to reduce this confusion. Delayed FDG PET imaging has been explored in several adult and pediatric malignancies, including adult CNS tumors, though there are no current publications applying its use in pediatric CNS tumors. We present two cases of pediatric CNS tumors, where delayed FDG PET imaging helped in the early diagnosis of a recurrence through a distinguishing tumor from the treatment effect.

  View details for DOI 10.7759/cureus.3364

  View details for PubMedID 30510874

  View details for PubMedCentralID PMC6257469

• Exploration of PET and MRI radiomic features for decoding breast cancer phenotypes and prognosis. NPJ breast cancer Huang, S. Y., Franc, B. L., Harnish, R. J., Liu, G., Mitra, D., Copeland, T. P., Arasu, V. A., Kornak, J., Jones, E. F., Behr, S. C., Hylton, N. M., Price, E. R., Esserman, L., Seo, Y. 2018; 4: 24

  Abstract

  Radiomics is an emerging technology for imaging biomarker discovery and disease-specific personalized treatment management. This paper aims to determine the benefit of using multi-modality radiomics data from PET and MR images in the characterization breast cancer phenotype and prognosis. Eighty-four features were extracted from PET and MR images of 113 breast cancer patients. Unsupervised clustering based on PET and MRI radiomic features created three subgroups. These derived subgroups were statistically significantly associated with tumor grade (p = 2.0 × 10-6), tumor overall stage (p = 0.037), breast cancer subtypes (p = 0.0085), and disease recurrence status (p = 0.0053). The PET-derived first-order statistics and gray level co-occurrence matrix (GLCM) textural features were discriminative of breast cancer tumor grade, which was confirmed by the results of L2-regularization logistic regression (with repeated nested cross-validation) with an estimated area under the receiver operating characteristic curve (AUC) of 0.76 (95% confidence interval (CI) = [0.62, 0.83]). The results of ElasticNet logistic regression indicated that PET and MR radiomics distinguished recurrence-free survival, with a mean AUC of 0.75 (95% CI = [0.62, 0.88]) and 0.68 (95% CI = [0.58, 0.81]) for 1 and 2 years, respectively. The MRI-derived GLCM inverse difference moment normalized (IDMN) and the PET-derived GLCM cluster prominence were among the key features in the predictive models for recurrence-free survival. In conclusion, radiomic features from PET and MR images could be helpful in deciphering breast cancer phenotypes and may have potential as imaging biomarkers for prediction of breast cancer recurrence-free survival.

  View details for DOI 10.1038/s41523-018-0078-2

  View details for PubMedID 30131973

  View details for PubMedCentralID PMC6095872

• Geographic Variation in Postoperative Imaging for Low-Risk Breast Cancer. Journal of the National Comprehensive Cancer Network : JNCCN Franc, B. L., Copeland, T. P., Thombley, R., Park, M., Marafino, B., Dean, M. L., Boscardin, W. J., Rugo, H. S., Seidenwurm, D., Sharma, B., Johnston, S. R., Dudley, R. A. 2018; 16 (7): 829-837

  Abstract

  Background: The objective of this study was to examine the presence and magnitude of US geographic variation in use rates of both recommended and high-cost imaging in young patients with early-stage breast cancer during the 18 month period after surgical treatment of their primary tumor. Methods: Using the Truven Health MarketScan Commercial Database, a descriptive analysis was conducted of geographic variation in annual rates of dedicated breast imaging and high-cost body imaging of 36,045 women aged 18 to 64 years treated with surgery for invasive unilateral breast cancer between 2010 and 2012. Multivariate hierarchical analysis examined the relationship between likelihood of imaging and patient characteristics, with metropolitan statistical area (MSA) serving as a random effect. Patient characteristics included age group, BRCA1/2 carrier status, family history of breast cancer, combination of breast surgery type and radiation therapy, drug therapy, and payer type. All MSAs in the United States were included, with areas outside MSAs within a given state aggregated into a single area for analytic purposes. Results: Descriptive analysis of rates of imaging use and intensity within MSA regions revealed wide geographic variation, irrespective of treatment cohort or age group. Increased probability of recommended postoperative dedicated breast imaging was primarily associated with age and treatment including both surgery and radiation therapy, followed by MSA region (odds ratio, 1.42). Increased probability of PET use-a high-cost imaging modality for which postoperative routine use is not recommended in the absence of specific clinical findings-was primarily associated with surgery type followed by MSA region (odds ratio, 1.82). Conclusions: In patients with breast cancer treated for low-risk disease, geography has effects on the rates of posttreatment imaging, suggesting that some patients are not receiving beneficial dedicated breast imaging, and high-cost nonbreast imaging may not be targeted to those groups most likely to benefit.

  View details for DOI 10.6004/jnccn.2018.7024

  View details for PubMedID 30006425

• Translational Radiomics: Defining the Strategy Pipeline and Considerations for Application-Part 2: From Clinical Implementation to Enterprise JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Shaikh, F., Franc, B., Allen, E., Sala, E., Awan, O., Hendrata, K., Halabi, S., Mohiuddin, S., Malik, S., Hadley, D., Shrestha, R. 2018; 15 (3): 543–49

  Abstract

  Enterprise imaging has channeled various technological innovations to the field of clinical radiology, ranging from advanced imaging equipment and postacquisition iterative reconstruction tools to image analysis and computer-aided detection tools. More recently, the advancement in the field of quantitative image analysis coupled with machine learning-based data analytics, classification, and integration has ushered in the era of radiomics, a paradigm shift that holds tremendous potential in clinical decision support as well as drug discovery. However, there are important issues to consider to incorporate radiomics into a clinically applicable system and a commercially viable solution. In this two-part series, we offer insights into the development of the translational pipeline for radiomics from methodology to clinical implementation (Part 1) and from that point to enterprise development (Part 2). In Part 2 of this two-part series, we study the components of the strategy pipeline, from clinical implementation to building enterprise solutions.

  View details for PubMedID 29366598

• Translational Radiomics: Defining the Strategy Pipeline and Considerations for Application-Part 1: From Methodology to Clinical Implementation JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Shaikh, F., Franc, B., Allen, E., Sala, E., Awan, O., Hendrata, K., Halabi, S., Mohiuddin, S., Malik, S., Hadley, D., Shrestha, R. 2018; 15 (3): 538–42

  Abstract

  Enterprise imaging has channeled various technological innovations to the field of clinical radiology, ranging from advanced imaging equipment and postacquisition iterative reconstruction tools to image analysis and computer-aided detection tools. More recently, the advancements in the field of quantitative image analysis coupled with machine learning-based data analytics, classification, and integration have ushered us into the era of radiomics, which has tremendous potential in clinical decision support as well as drug discovery. There are important issues to consider to incorporate radiomics as a clinically applicable system and a commercially viable solution. In this two-part series, we offer insights into the development of the translational pipeline for radiomics from methodology to clinical implementation (Part 1) and from that to enterprise development (Part 2).

  View details for PubMedID 29366600

• Contextualizing Oncologic Imaging Utilization Through End-of-Life Spending Patterns JOURNAL OF THE AMERICAN COLLEGE OF RADIOLOGY Copeland, T. P., Hillman, J., Franc, B. L. 2017; 14 (10): 1269–78

  Abstract

  The aim of this study was to assess the effect of spending patterns during the final year of life on high-cost imaging utilization in the final 3 months of life.An academic comprehensive cancer center's radiology, cancer registry, and claims records were matched to identify decedents with dates of death from April 2013 through June 2014. Spending patterns in the final year of life were identified using group-based trajectory modeling. Descriptive analysis of CT, MRI, and PET utilization across trajectories was conducted. Multivariate logistic regressions modeled the likelihood of imaging utilization in the final 3 months of life, and a sensitivity analysis assessed the impact of spending trajectories on model fit.Six spending trajectories were identified. Membership in the late rising trajectory was the strongest predictor of high-cost imaging in the final 3 months of life (odds ratio, 11.61; P = .000), followed by diagnosis 12 to 6 months premortem (odds ratio, 7.49; P = .000). The likelihood of imaging the final 3 months of life was no different between high persistent and low persistent trajectory patients, despite the heterogeneity between the two patient groups. Sensitivity analysis indicated that spending trajectory improved the prediction of imaging in the final 3 months of life to a greater extent than temporal proximity to death at the time of diagnosis, which may serve as a proxy for severity and/or complexity.Clinical measures of severity and patients' utilization histories should be considered by hospital administrators in estimations of aggregate and individual oncologic imaging utilization. This analytic approach may aid in evaluating participation in advanced payment models.

  View details for DOI 10.1016/j.jacr.2017.06.004

  View details for Web of Science ID 000412625400007

  View details for PubMedID 28709782

• In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis MOLECULAR IMAGING Franc, B. L., Goth, S., MacKenzie, J., Li, X., Blecha, J., Lam, T., Jivan, S., Hawkins, R. A., VanBrocklin, H. 2017; 16: 1536012117712638

  Abstract

  Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-β-d-arabinofuranosylguanine ([18F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model.Using positron emission tomography-computed tomography imaging, uptake of [18F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry.Differential uptake of [18F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry.[18F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.

  View details for DOI 10.1177/1536012117712638

  View details for Web of Science ID 000403887800001

  View details for PubMedID 28625080

  View details for PubMedCentralID PMC5480631

• A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. Cancer research Ronald, J. A., Kim, B., Gowrishankar, G., Namavari, M., Alam, I. S., D'Souza, A., Nishikii, H., Chuang, H., Ilovich, O., Lin, C., Reeves, R., Shuhendler, A., Hoehne, A., Chan, C. T., Baker, J., Yaghoubi, S. S., VanBrocklin, H. F., Hawkins, R., Franc, B. L., Jivan, S., Slater, J. B., Verdin, E. F., Gao, K. T., Benjamin, J., Negrin, R., Gambhir, S. S. 2017; 77 (11): 2893-2902

  Abstract

  A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR.

  View details for DOI 10.1158/0008-5472.CAN-16-2953

  View details for PubMedID 28572504

• Dedicated Breast Positron Emission Tomography for the Evaluation of Early Response to Neoadjuvant Chemotherapy in Breast Cancer. Clinical breast cancer Jones, E. F., Ray, K. M., Li, W., Seo, Y., Franc, B. L., Chien, A. J., Esserman, L. J., Pampaloni, M. H., Joe, B. N., Hylton, N. M. 2017; 17 (3): e155-e159

  View details for DOI 10.1016/j.clbc.2016.12.008

  View details for PubMedID 28110902

• Contextualizing the use of oncologic imaging within treatment phases: imaging trends and modality preferences, 2000-2014 CURRENT ONCOLOGY Copeland, T. P., Creasman, J. M., Seidenwurm, D. J., Franc, B. L. 2017; 24 (2): E99–E105

  Abstract

  In the present study, we retrospectively evaluated the use of tomographic imaging in adult cancer patients to clarify how recent growth plateaus in the use of tomographic imaging in the United States might have affected oncologic imaging during the same period.At a U.S. academic cancer centre, 12,059 patients with dates of death from January 2000 through December 2014 were identified. Imaging was restricted to brain and body computed tomography (ct), brain and body magnetic resonance (mr), and body positron-emission tomography (pet) with and without superimposed ct. Trends during the staging (1 year after diagnosis), monitoring (18-6 months before death), and end-of-life (final 6 months before death) phases were analyzed.Comparing the 2005-2009 with the 2010-2014 period, mean intensity of pet imaging increased 21% during staging (p = 0.0000) and 27% during end of life (p = 0.0019). In the monitoring phase, mean intensity for ct brain, ct body, and mr body imaging decreased by 26% (p = 0.0133), 11% (p = 0.0118), and 26% (p = 0.0008), respectively. Aggregate mean intensity of imaging increased in the 13%-27% range every 3 months from 18 months before death to death, reaching 1.43 images in the final 3 months of life. Patients diagnosed in the final 18 months of life had an average of 1 additional image during both the 3 months after diagnosis (p = 0.0000) and the final 3 months before death (p = 0.0000).Imaging increased as temporal proximity to death decreased, and patients diagnosed near death received more staging imaging, suggesting that imaging guidelines should consider imaging intensity within the context of treatment phase. Despite the development, by multiple organizations, of appropriateness criteria to reduce imaging utilization, aggregate per-patient imaging showed insignificant changes. Simultaneous fluctuations in the intensity of imaging by modality suggest recent changes in the modalities preferred by providers.

  View details for DOI 10.3747/co.24.3216

  View details for Web of Science ID 000401830000004

  View details for PubMedID 28490932

  View details for PubMedCentralID PMC5407885

• Imaging Bone-Cartilage Interactions in Osteoarthritis Using [F-18]-NaF PET-MRI MOLECULAR IMAGING Savic, D., Pedoia, V., Seo, Y., Yang, J., Bucknor, M., Franc, B. L., Majumdar, S. 2016; 15: 1–12

  Abstract

  Simultaneous positron emission tomography-magnetic resonance imaging (PET-MRI) is an emerging technology providing both anatomical and functional images without increasing the scan time. Compared to the traditional PET/computed tomography imaging, it also exposes the patient to significantly less radiation and provides better anatomical images as MRI provides superior soft tissue characterization. Using PET-MRI, we aim to study interactions between cartilage composition and bone function simultaneously, in knee osteoarthritis (OA).In this article, bone turnover and remodeling was studied using [18F]-sodium fluoride (NaF) PET data. Quantitative MR-derived T1ρ relaxation times characterized the biochemical cartilage degeneration. Sixteen participants with early signs of OA of the knee received intravenous injections of [18F]-NaF at the onset of PET-MR image acquisition. Regions of interest were identified, and kinetic analysis of dynamic PET data provided the rate of uptake ( Ki) and the normalized uptake (standardized uptake value) of [18F]-NaF in the bone. Morphological MR images and quantitative voxel-based T1ρ maps of cartilage were obtained using an atlas-based registration technique to segment cartilage automatically. Voxel-by-voxel statistical parameter mapping was used to investigate the relationship between bone and cartilage.Increases in cartilage T1ρ, indicating degenerative changes, were associated with increased turnover in the adjoining bone but reduced turnover in the nonadjoining compartments. Associations between pain and increased bone uptake were seen in the absence of morphological lesions in cartilage, but the relationship was reversed in the presence of incident cartilage lesions.This study shows significant cartilage and bone interactions in OA of the knee joint using simultaneous [18F]-NaF PET-MR, the first in human study. These observations highlight the complex biomechanical and biochemical interactions in the whole knee joint in OA, which potentially could help assess therapeutic targets in treating OA.

  View details for DOI 10.1177/1536012116683597

  View details for Web of Science ID 000394789100001

  View details for PubMedID 28654417

  View details for PubMedCentralID PMC5470142

• ACR Practice Parameter for the Performance of Therapy With Unsealed Radiopharmaceutical Sources CLINICAL NUCLEAR MEDICINE Spratt, D. E., Zaki, B. I., Franc, B. L., Hartford, A. C., Osborne, J. R. 2016; 41 (2): 106–17

  Abstract

  This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with unsealed radiopharmaceutical sources. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this practice parameter should help to maximize the efficacious use of these procedures, maintain safe conditions, and ensure compliance with applicable regulations. The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or effective palliation of disease while minimizing untoward side effects and complications.

  View details for DOI 10.1097/RLU.0000000000001036

  View details for Web of Science ID 000368629600017

  View details for PubMedID 26646993

• Overall and disease-free survival outcomes of patients receiving intensity-modulated radiation therapy (IMRT) with PET-CT-based planning for cancers of the head and neck JOURNAL OF RADIOTHERAPY IN PRACTICE Franc, B. L., DeLemos, C., Jones, C. 2015; 14 (3): 285–95

  View details for DOI 10.1017/S1460396915000187

  View details for Web of Science ID 000212297800010

• Detection of Recurrent Non-Hodgkin Lymphoma on In-111 Capromab Pendetide Imaging CLINICAL NUCLEAR MEDICINE Franc, B. L., Lin, H. 2015; 40 (7): 585–88

  Abstract

  A 73-year-old man presented with a rising prostate-specific antigen (PSA) level 5 years following brachytherapy for prostate cancer. In-111 capromab pendetide (ProstaScint) whole-body planar imaging revealed abnormal uptake in the right knee, localizing to a mass in the popliteal fossa on SPECT/CT. MRI showed a mass encasing the popliteal artery and vein, subsequently found to be non-Hodgkin lymphoma on biopsy. Response of the mass to chemotherapy was documented on ¹⁸F-FDG PET/CT. Elevated In-111 capromab pendetide uptake in soft tissue can be important but unrelated to prostate cancer, as demonstrated in this case.

  View details for DOI 10.1097/RLU.0000000000000782

  View details for Web of Science ID 000356375000013

  View details for PubMedID 25899589

• Preclinical SPECT and SPECT/CT. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer Seo, Y., Jiang, H., Franc, B. L. 2013; 187: 193-220

  Abstract

  The molecular processes underlying carcinogenesis and malignant spread are the foundation of future drug development for the treatment of cancer. Understanding these processes requires study of the interaction of complex biologic systems in a way that spatially and temporally recapitulates that seen in humans. Likewise, once an anticancer agent is developed, its intended antitumor action and its unintended side-effects must be studied in a rigorous and reproducible manner prior to its introduction into the clinic, a process that can benefit from methods that elucidate specific molecular processes and that can be performed serially. Recent advances in small-animal models of cancer, radiochemistry of single photon emitting radionuclides, single photon emission tomography systems, and image reconstruction techniques have set the stage for an ever-increasing use of SPECT and SPECT/CT in preclinical oncology-related applications. Several of these advances as well as several specific applications in oncology are highlighted and areas needing further improvement are identified.

  View details for DOI 10.1007/978-3-642-10853-2_6

  View details for PubMedID 23179882

• Detection and localization of carcinoma within the prostate using high resolution transrectal gamma imaging (TRGI) of monoclonal antibody directed at prostate specific membrane antigen (PSMA)-Proof of concept and initial imaging results EUROPEAN JOURNAL OF RADIOLOGY Franc, B. L., Cho, S. Y., Rosenthal, S. A., Cui, Y., Tsui, B., Vandewalker, K. N., Holz, A. L., Poonamallee, U., Pomper, M. G., James, R. B. 2013; 82 (11): 1877–84

  Abstract

  Molecular imaging methods may identify primary prostate cancer foci and potentially guide biopsy and optimal management approaches. In this exploratory study, safety and first human imaging experience of a novel solid state endocavity transrectal gamma-imaging (TRGI) device was evaluated.Twelve patients received 5 ± 0.5 mCi In-111 capromab pendetide (ProstaScint) intravenously and the prostate of each was imaged 4 days later transrectally using an endoluminal cadmium zinc telluride (CZT)-based compact gamma camera (ProxiScan™, Hybridyne Imaging Technologies, Inc.). Immediate and 5-7-day post imaging safety assessments were performed. In those patients with a prostate cancer diagnosis (N=10), single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) of the pelvis were also acquired. Images were reviewed and sites of suspected cancer were localized by prostate quadrant by consensus of two nuclear medicine physicians. Pathology from TRUS biopsy, or surgical pathology following prostatectomy (N=3) when available, served as the gold standard.There were no serious adverse events associated with TRGI. No focal signal was detected in patients without a diagnosis of prostate cancer (N=2). Of 40 quadrants evaluated in the cancer cohort (N=10), 22 contained malignancy. In 8 of these 10 patients, the most focal site of uptake on TRGI corresponded to a prostatic quadrant with biopsy-proven malignancy. In 6 cancer-containing quadrants, TRGI was positive where SPECT-CT was negative; MRI showed a detectable abnormality in only 1 of these 6 quadrants. Qualitative image review of the planar TRGI images for prostate cancer localization was severely limited in some cases by scatter artifact within the vicinity of the prostate gland arising from physiologic urine and blood pool activity from nearby structures.TRGI is a safe imaging method that can potentially detect radiopharmaceutical uptake of primary prostate cancer and facilitate prostatic quadrant - localization of cancer. Further investigation of this technology is warranted.

  View details for DOI 10.1016/j.ejrad.2013.07.025

  View details for Web of Science ID 000325484600026

  View details for PubMedID 23993140

• Improved techniques to localize foci of carcinoma within the prostate using high-resolution transrectal gamma imaging (TRGI) of monoclonal antibody directed at prostate specific membrane antigen (PSMA). Franc, B. L., Cui, Y., Rosenthal, S. A., Johnston, T., Poonamallee, U., Wiesner, J. B., Vandewalker, K. N., Seo, Y., Lall, T., James, R. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for Web of Science ID 000318009803664

• Clinical Utility of SPECT-(Low-Dose)CT Versus SPECT Alone in Patients Presenting for Bone Scintigraphy CLINICAL NUCLEAR MEDICINE Franc, B. L., Myers, R., Pounds, T. R., Bolton, G., Conte, F., Bartheld, M., Da Silva, A. J. 2012; 37 (1): 26–34

  Abstract

  This prospective study evaluated the contribution of single-photon emission computed tomography (SPECT)-(low-dose)CT (SPECT-ldCT) over SPECT alone in all-comers referred for bone scintigraphy for any indication.In this prospective study, imaging was performed on 100 consecutive patients who presented for bone scintigraphy using a combined SPECT-ldCT single-gantry system (Brightview XCT, Philips Medical Systems Inc., Cleveland, OH). SPECT images were reconstructed with (AC) and without (NAC) attenuation and scatter correction. SPECT (NAC), SPECT-ldCT (NAC), and SPECT-ldCT (AC) were reviewed independently and in a blinded manner. Reader interpretation of images was compared with the final clinical diagnosis.Subjects were referred for oncologic (28%) and nononcologic (72%) indications. Attenuation correction significantly improved perceived image quality (P = 0.012), but did not significantly alter diagnostic confidence (P = 0.96). Availability of ldCT data during interpretation of the SPECT images yielded a significant increase in the level of diagnostic confidence (P < 0.001). When the ldCT data were available, 18 of 200 bone SPECT reads recommended additional diagnostic CT imaging, compared with 70 when ldCT data were unavailable at the time of reading (P < 0.001). The sensitivity, specificity, and accuracy of SPECT-ldCT (with or without attenuation and scatter correction) in the diagnosis of osseous processes were 90.9%, 85.9%, and 87.0%, respectively, and these values did not differ significantly from those obtained with SPECT alone.Bone SPECT-ldCT provides interpreting physicians a significantly greater level of diagnostic confidence and reduces additional diagnostic imaging studies, but the overall diagnostic accuracy of SPECT-ldCT was not affected when compared with SPECT alone, suggesting that SPECT-ldCT should be used on a patient-by-patient basis.

  View details for DOI 10.1097/RLU.0b013e3182392bd0

  View details for Web of Science ID 000298146300013

  View details for PubMedID 22157024

• Patient-Specific Method of Generating Parametric Maps of Patlak K(i) without Blood Sampling or Metabolite Correction: A Feasibility Study. International journal of molecular imaging Sayre, G. A., Franc, B. L., Seo, Y. 2011; 2011: 185083

  Abstract

  Currently, kinetic analyses using dynamic positron emission tomography (PET) experience very limited use despite their potential for improving quantitative accuracy in several clinical and research applications. For targeted volume applications, such as radiation treatment planning, treatment monitoring, and cerebral metabolic studies, the key to implementation of these methods is the determination of an arterial input function, which can include time-consuming analysis of blood samples for metabolite correction. Targeted kinetic applications would become practical for the clinic if blood sampling and metabolite correction could be avoided. To this end, we developed a novel method (Patlak-P) of generating parametric maps that is identical to Patlak K(i) (within a global scalar multiple) but does not require the determination of the arterial input function or metabolite correction. In this initial study, we show that Patlak-P (a) mimics Patlak K(i) images in terms of visual assessment and target-to-background (TB) ratios of regions of elevated uptake, (b) has higher visual contrast and (generally) better image quality than SUV, and (c) may have an important role in improving radiotherapy planning, therapy monitoring, and neurometabolism studies.

  View details for DOI 10.1155/2011/185083

  View details for PubMedID 21912742

  View details for PubMedCentralID PMC3168784

• Thyroid and Hepatic Function After High-Dose I-131-Metaiodobenzylguanidine (I-131-MIBG) Therapy for Neuroblastoma PEDIATRIC BLOOD & CANCER Quach, A., Ji, L., Mishra, V., Sznewajs, A., Veatch, J., Huberty, J., Franc, B., Sposto, R., Groshen, S., Wei, D., Fitzgerald, P., Maris, J. M., Yanik, G., Hawkins, R. A., Villablanca, J. G., Matthay, K. K. 2011; 56 (2): 191–201

  Abstract

  (131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function.Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined.In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12  ±  4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76  ±  4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23  ±  5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies.The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction.

  View details for DOI 10.1002/pbc.22767

  View details for Web of Science ID 000286017500005

  View details for PubMedID 20830775

  View details for PubMedCentralID PMC3006009

• Biodistributions of Lu-177- and In-111-Labeled 7E11 Antibodies to Prostate-Specific Membrane Antigen in Xenograft Model of Prostate Cancer and Potential Use of In-111-7E11 as a Pre-therapeutic Agent for Lu-177-7E11 Radioimmunotherapy MOLECULAR IMAGING AND BIOLOGY Pan, M., Gao, D., Feng, J., He, J., Seo, Y., Tedesco, J., Wolodzko, J. G., Hasegawa, B. H., Franc, B. L. 2009; 11 (3): 159–66

  Abstract

  Prostate-specific membrane antigen is a transmembrane glycoprotein highly expressed in many prostate cancers and can be targeted with radiolabeled antibodies for diagnosis and treatment of this disease. To serve as a radioimmunotherapeutic agent, a kinetically inert conjugate is desired to maximize tumor uptake and tumor radiation dose with minimal nonspecific exposure to bone marrow and other major organs.In this study, we assessed the pharmacokinetics and biodistribution of the 7E11 monoclonal antibody (MAb) radiolabeled with the lutetium-177 ((177)Lu)-tetraazacyclododecanetetraacetic acid conjugate system ((177)Lu-7E11) versus those of the 7E11 MAb radiolabeled with the indium-111 ((111)In)/glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)/lysine hydrochloride conjugate system ((111)In-7E11, also known as ProstaScint) to determine the feasibility of using (111)In-7E11 as a pre-therapeutic agent for (177)Lu-7E11 radioimmunotherapy. Pharmacokinetic and biodistribution studies of (177)Lu-7E11 in lymph node cancer of the prostate (LNCaP) xenograft mice were performed at 2, 8, 12, 24, 72, and 168 h after radiopharmaceutical administration. For (111)In-7E11, pharmacokinetic and biodistribution studies were performed at 8, 24, and 72 h. Parallel studies of (177)Lu-7E11 in non-tumor-bearing mice at 8, 24, and 72 h post-injection served as controls. Gamma scintigraphy was performed, followed by autoradiography and tissue counting, to demonstrate and quantify the distributions of radioconjugated MAb in the tumor and normal tissues.Both (177)Lu- and (111)In-7E11 conjugates demonstrated an early blood pool phase in which uptake was dominated by the blood, lung, spleen and liver, followed by uptake and retention of the radiolabeled antibody in the tumor which was most prominent at 24 h. Total accumulation of radioconjugated MAb in tumor at 24 h was greater in the case of (177)Lu-7E11 in comparison to that of (111)In-7E11. Continued accumulation in tumor was observed for the entire time course studied for both (177)Lu-7E11 and (111)In-7E11. The liver was the only major organ demonstrating a significant difference in accumulation between the two conjugates. In conclusion, pharmacokinetic and biodistribution studies of (177)Lu-7E11 in LNCaP xenograft mouse models support its potential application as a radioimmunotherapeutic agent targeting prostate cancer, and the distribution and tumor uptake of (111)In-7E11 appear to be similar to those of (177)Lu-7E11, supporting its use as a pre-therapeutic tool to assess the potential accumulation of (177)Lu-7E11 radioimmunotherapeutic at sites of prostate cancer. However, the different accumulation patterns of the (111)In and (177)Lu immunoconjugates in liver will likely prevent the use of (111)In-7E11 as a true dosimetry tool for (177)Lu-7E11 radioimmunotherapy.

  View details for DOI 10.1007/s11307-008-0185-9

  View details for Web of Science ID 000265686900003

  View details for PubMedID 19034582

  View details for PubMedCentralID PMC2841328

• Iodine-131-Metaiodobenzylguanidine Double Infusion With Autologous Stem-Cell Rescue for Neuroblastoma: A New Approaches to Neuroblastoma Therapy Phase I Study JOURNAL OF CLINICAL ONCOLOGY Matthay, K. K., Quach, A., Huberty, J., Franc, B. L., Hawkins, R. A., Jackson, H., Groshen, S., Shusterman, S., Yanik, G., Veatch, J., Brophy, P., Villablanca, J. G., Maris, J. M. 2009; 27 (7): 1020–25

  Abstract

  Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy with more than 30% response rate in refractory neuroblastoma, but activity infused is limited by radiation safety and hematologic toxicity. The goal was to determine the maximum-tolerated dose of (131)I-MIBG in two consecutive infusions at a 2-week interval, supported by autologous stem-cell rescue (ASCR) 2 weeks after the second dose.The (131)I-MIBG dose was escalated using a 3 + 3 phase I trial design, with levels calculated by cumulative red marrow radiation index (RMI) from both infusions. Using dosimetry, the second infusion was adjusted to achieve the target RMI, except at level 4, where the second infusion was capped at 21 mCi/kg.Twenty-one patients were enrolled onto the study at levels 1 to 4, with 18 patients assessable for toxicity and 20 patients assessable for response. Cumulative (131)I-MIBG given to achieve the target RMI ranged from 22 to 50 mCi/kg, with cumulative RMI of 3.2 to 8.92 Gy. No patient had a dose-limiting toxicity. Reversible grade 3 nonhematologic toxicity occurred in six patients at level 4, establishing the recommended cumulative dose as 36 mCi/kg. The median time to absolute neutrophil count more than 500/microL after ASCR was 13 days (4 to 27 days) and to platelet independence was 17 days (6 to 47 days). Responses included two partial responses, eight mixed responses, three stable disease, and seven progressive disease. Responses by semiquantitative MIBG score occurred in eight patients, soft tissue responses occurred in five of 11 patients, but bone marrow responses occurred in only two of 13 patients.The lack of toxicity with this approach allowed dramatic dose intensification of (131)I-MIBG, with minimal toxicity and promising activity.

  View details for DOI 10.1200/JCO.2007.15.7628

  View details for Web of Science ID 000266193500005

  View details for PubMedID 19171714

  View details for PubMedCentralID PMC2738616

• Identification of MCAM/CD146 as the Target Antigen of a Human Monoclonal Antibody that Recognizes Both Epithelioid and Sarcomatoid Types of Mesothelioma CANCER RESEARCH Bidlingmaier, S., He, J., Wang, Y., An, F., Feng, J., Barbone, D., Gao, D., Franc, B., Broaddus, V., Liu, B. 2009; 69 (4): 1570–77

  Abstract

  The prognosis for patients diagnosed with mesothelioma is generally poor, and currently available treatments are usually ineffective. Therapies that specifically target tumor cells hold much promise for the treatment of cancers that are resistant to current approaches. We have previously selected phage antibody display libraries on mesothelioma cell lines to identify a panel of internalizing human single chain (scFv) antibodies that target mesothelioma-associated, clinically represented cell surface antigens and further exploited the internalizing function of these scFvs to specifically deliver lethal doses of liposome-encapsulated small molecule drugs to both epithelioid and sarcomatous subtypes of mesothelioma cells. Here, we report the identification of MCAM/MUC18/CD146 as the surface antigen bound by one of the mesothelioma-targeting scFvs using a novel cloning strategy based on yeast surface human proteome display. Immunohistochemical analysis of mesothelioma tissue microarrays confirmed that MCAM is widely expressed by both epithelioid and sarcomatous types of mesothelioma tumor cells in situ but not by normal mesothelial cells. In addition, quantum dot-labeled anti-MCAM scFv targets primary meosthelioma cells in tumor fragment spheroids cultured ex vivo. As the first step in evaluating the therapeutic potential of MCAM-targeting antibodies, we performed single-photon emission computed tomography studies using the anti-MCAM scFv and found that it recognizes mesothelioma organotypic xenografts in vivo. The combination of phage antibody library selection on tumor cells and rapid target antigen identification by screening the yeast surface-displayed human proteome could be a powerful method for mapping the targetable tumor cell surface epitope space.

  View details for DOI 10.1158/0008-5472.CAN-08-1363

  View details for Web of Science ID 000263399100042

  View details for PubMedID 19221091

  View details for PubMedCentralID PMC2752656

• CAN POSITRON EMISSION TOMOGRAPHY (PET) OR PET/COMPUTED TOMOGRAPHY (CT) ACQUIRED IN A NONTREATMENT POSITION BE ACCURATELY REGISTERED TO A HEAD-AND-NECK RADIOTHERAPY PLANNING CT? INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Hwang, A. B., Bacharach, S. L., Yom, S. S., Weinberg, V. K., Quivey, J. M., Franc, B. L., Xia, P. 2009; 73 (2): 578–84

  Abstract

  To quantify the uncertainties associated with incorporating diagnostic positron emission tomography/CT (PET/CT) and PET into the radiotherapy treatment-planning process using different image registration tools, including automated and manual rigid body registration methods, as well as deformable image registration.The PET/CTs and treatment-planning CTs from 12 patients were used to evaluate image registration accuracy. The PET/CTs also were used without the contemporaneously acquired CTs to evaluate the registration accuracy of stand-alone PET. Registration accuracy for relevant normal structures was quantified using an overlap index and differences in the center of mass (COM) positions. For tumor volumes, the registration accuracy was measured using COM positions only.Registration accuracy was better with PET/CT than with PET alone. The COM displacements ranged from 3.2 +/- 0.6 mm (mean +/- 95% confidence interval, for brain) to 8.4 +/- 2.6 mm (spinal cord) for registration with PET/CT data, compared with 4.8 +/- 1.7 mm (brain) and 9.9 +/- 3.1 mm (spinal cord) with PET alone. Deformable registration improved accuracy, with minimum and maximum errors of 1.1 +/- 0.8 mm (brain) and 5.4 +/- 1.4 mm (mandible), respectively.It is possible to incorporate PET and/or PET/CT acquired in diagnostic positions into the treatment-planning process through the use of advanced image registration algorithms, but precautions must be taken, particularly when delineating tumor volumes in the neck. Acquisition of PET/CT in the treatment-planning position would be the ideal method to minimize registration errors.

  View details for DOI 10.1016/j.ijrobp.2008.09.041

  View details for Web of Science ID 000262543800036

  View details for PubMedID 19084350

• Development of an optimized activatable MMP-14 targeted SPECT imaging probe BIOORGANIC & MEDICINAL CHEMISTRY Watkins, G. A., Jones, E. F., Shell, M. S., VanBrocklin, H. F., Pan, M., Hanrahan, S. M., Feng, J. J., He, J., Sounni, N. E., Dill, K. A., Contag, C. H., Coussens, L. M., Franc, B. L. 2009; 17 (2): 653-659

  Abstract

  Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r(8)) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two-fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity.

  View details for DOI 10.1016/j.bmc.2008.11.078

  View details for Web of Science ID 000262708300027

  View details for PubMedID 19109023

  View details for PubMedCentralID PMC2639212

• Multiple Scalp Lesions in a Patient with Keratitis, Ichthyosis and Deafness Syndrome Mimicking Metastatic Squamous Cell Carcinoma on 18F-FDG PET/CT. Radiology case reports Kleis, M. A., Daldrup-Link, H., Goldsby, R., Hawkins, R. A., Franc, B. L. 2009; 4 (2): 218-?

  Abstract

  We report the case of a 17-year-old girl with keratitis, ichthyosis, and deafness (KID) syndrome. As a complication of her KID syndrome she developed squamous cell carcinoma at the left index finger. Additional clinical features were multiple soft tissue lesions over the scalp mimicking metastatic disease on 18F-FDG PET/CT. To our knowledge, this is the first case report about the uptake pattern of KID syndrome associated skin lesions on whole body PET/CT with 18F-FDG.

  View details for DOI 10.2484/rcr.v4i2.218

  View details for PubMedID 27307799

• Diagnostic value of PET/CT for the staging and restaging of pediatric tumors EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Kleis, M., Daldrup-Link, H., Matthay, K., Goldsby, R., Lu, Y., Schuster, T., Schreck, C., Chu, P. W., Hawkins, R. A., Franc, B. L. 2009; 36 (1): 23-36

  Abstract

  The objective of this retrospective study was to compare the diagnostic value of 2-[(18)F]fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET)/CT versus (18)F-FDG PET and CT alone for staging and restaging of pediatric solid tumors.Forty-three children and adolescents (19 females and 24 males; mean age, 15.2 years; age range, 6-20 years) with osteosarcoma (n = 1), squamous cell carcinoma (n = 1), synovial sarcoma (n = 2), germ cell tumor (n = 2), neuroblastoma (n = 2), desmoid tumor (n = 2), melanoma (n = 3), rhabdomyosarcoma (n = 5), Hodgkin's lymphoma (n = 7), non-Hodgkin-lymphoma (n = 9), and Ewing's sarcoma (n = 9) who had undergone (18)F-FDG PET/CT imaging for primary staging or follow-up of metastases were included in this study. The presence, location, and size of primary tumors was determined separately for PET/CT, PET, and CT by two experienced reviewers. The diagnosis of the primary tumor was confirmed by histopathology. The presence or absence of metastases was confirmed by histopathology (n = 62) or clinical and imaging follow-up (n = 238).The sensitivities for the detection of solid primary tumors using integrated (18)F-FDG PET/CT (95%), (18)F-FDG PET alone (73%), and CT alone (93%) were not significantly different (p > 0.05). Seventeen patients showed a total of 153 distant metastases. Integrated PET/CT had a significantly higher sensitivity for the detection of these metastases (91%) than PET alone (37%; p < 0.05), but not CT alone (83%; p > 0.05). When lesions with a diameter of less than 0.5 cm were excluded, PET/CT (89%) showed a significantly higher specificity compared to PET (45%; p < 0.05) and CT (55%; p < 0.05). In a sub-analysis of pulmonary metastases, the values for sensitivity and specificity were 90%, 14%, 82% and 63%, 78%, 65%, respectively, for integrated PET/CT, stand-alone PET, and stand-alone CT. For the detection of regional lymph node metastases, (18)F-FDG PET/CT, (18)F-FDG PET alone, and CT alone were diagnostically correct in 83%, 61%, and 42%. A sub-analysis focusing on the ability of PET/CT, PET, and CT to detect osseous metastases showed no statistically significant difference between the three imaging modalities (p > 0.05).Our study showed a significantly increased sensitivity of PET/CT over that of PET for the detection of distant metastases but not over that of CT alone. However, the specificity of PET/CT for the characterization of pulmonary metastases with a diameter > 0.5 cm and lymph node metastases with a diameter of <1 cm was significantly increased over that of CT alone.

  View details for DOI 10.1007/s00259-008-0911-1

  View details for Web of Science ID 000261422600004

  View details for PubMedID 18719909

• Role of IV Iodinated Contrast Material in F-18-FDG PET/CT of Liver Metastases AMERICAN JOURNAL OF ROENTGENOLOGY Badiee, S., Franc, B. L., Webb, E. M., Chu, B., Hawkins, R. A., Coakley, F. 2008; 191 (5): 1436–39

  Abstract

  The purpose of our study was to investigate the role of IV iodinated contrast material in the evaluation of hepatic metastases at (18)F-FDG PET/CT.We retrospectively identified 39 patients (25 men and 14 women) with suspected isolated hepatic metastases from colorectal cancer who underwent FDG PET/CT. The CT protocol included acquisition of unenhanced and multiphase contrast-enhanced CT images through the liver. At two separate sittings, four readers (two radiologists and two nuclear medicine physicians) noted and characterized all hepatic lesions in consensus, first based on PET and unenhanced CT images and later based on PET and contrast-enhanced CT images. The nature of detected lesions was established by histopathologic or clinicoradiologic correlation.A total of 178 hepatic lesions were identified, consisting of 137 metastases and 41 benign lesions. Using lesion-based analyses with Obuchowski's method for paired observations, 172 of 178 lesions (97%) were detected at PET/contrast-enhanced CT compared with only 135 of 178 (76%) at PET/unenhanced CT (p = 0.0004). Specifically, 114 of 137 (83%) hepatic metastases were detected on PET/contrast-enhanced CT compared with 92 of 137 (67%) on PET/unenhanced CT (p = 0.012). One hundred thirty-one of 178 lesions (73%) were accurately characterized at PET/contrast-enhanced CT compared with 101 of 178 (57%) at PET/unenhanced CT (p = 0.004).IV iodinated contrast material administration improves the detection of hepatic metastases and the characterization of focal hepatic lesions at PET/CT.

  View details for DOI 10.2214/AJR.07.3750

  View details for Web of Science ID 000260246700024

  View details for PubMedID 18941082

• Small-Animal SPECT and SPECT/CT: Important Tools for Preclinical Investigation JOURNAL OF NUCLEAR MEDICINE Franc, B. L., Acton, P. D., Mari, C., Hasegawa, B. H. 2008; 49 (10): 1651–63

  Abstract

  The need to study dynamic biologic processes in intact small-animal models of disease has stimulated the development of high-resolution nuclear imaging methods. These methods are capable of clarifying molecular interactions important in the onset and progression of disease, assessing the biologic relevance of drug candidates and potential imaging agents, and monitoring therapeutic effectiveness of pharmaceuticals serially within a single-model system. Single-photon-emitting radionuclides have many advantages in these applications, and SPECT can provide 3-dimensional spatial distributions of gamma- (and x-) ray-emitting radionuclide imaging agents or therapeutics. Furthermore, combining SPECT with CT in a SPECT/CT system can assist in defining the anatomic context of biochemical processes and improve the quantitative accuracy of the SPECT data. Over the past decade, dedicated small-animal SPECT and SPECT/CT systems have been developed in academia and industry. Although significant progress in this arena has been realized through system development and biologic application, further innovation continues to address challenges in camera sensitivity, spatial resolution, and image reconstruction and quantification. The innumerable applications of small-animal SPECT and SPECT/CT in drug development, cardiology, neurology, and oncology are stimulating further investment in education, research, and development of these dedicated small-animal imaging modalities.

  View details for DOI 10.2967/jnumed.108.055442

  View details for Web of Science ID 000260229900044

  View details for PubMedID 18794275

• Assessment of the sources of error affecting the quantitative accuracy of SPECT imaging in small animals PHYSICS IN MEDICINE AND BIOLOGY Hwang, A. B., Franc, B. L., Gullberg, G. T., Hasegawa, B. H. 2008; 53 (9): 2233–52

  Abstract

  Small animal SPECT imaging systems have multiple potential applications in biomedical research. Whereas SPECT data are commonly interpreted qualitatively in a clinical setting, the ability to accurately quantify measurements will increase the utility of the SPECT data for laboratory measurements involving small animals. In this work, we assess the effect of photon attenuation, scatter and partial volume errors on the quantitative accuracy of small animal SPECT measurements, first with Monte Carlo simulation and then confirmed with experimental measurements. The simulations modeled the imaging geometry of a commercially available small animal SPECT system. We simulated the imaging of a radioactive source within a cylinder of water, and reconstructed the projection data using iterative reconstruction algorithms. The size of the source and the size of the surrounding cylinder were varied to evaluate the effects of photon attenuation and scatter on quantitative accuracy. We found that photon attenuation can reduce the measured concentration of radioactivity in a volume of interest in the center of a rat-sized cylinder of water by up to 50% when imaging with iodine-125, and up to 25% when imaging with technetium-99m. When imaging with iodine-125, the scatter-to-primary ratio can reach up to approximately 30%, and can cause overestimation of the radioactivity concentration when reconstructing data with attenuation correction. We varied the size of the source to evaluate partial volume errors, which we found to be a strong function of the size of the volume of interest and the spatial resolution. These errors can result in large (>50%) changes in the measured amount of radioactivity. The simulation results were compared with and found to agree with experimental measurements. The inclusion of attenuation correction in the reconstruction algorithm improved quantitative accuracy. We also found that an improvement of the spatial resolution through the use of resolution recovery techniques (i.e. modeling the finite collimator spatial resolution in iterative reconstruction algorithms) can significantly reduce the partial volume errors.

  View details for DOI 10.1088/0031-9155/53/9/002

  View details for Web of Science ID 000255120100003

  View details for PubMedID 18401059

  View details for PubMedCentralID PMC2871254

• Nuclear medicine in the assessment of differentiated thyroid cancer CLINICAL RADIOLOGY Rutherford, G., Franc, B., O'Connor, A. 2008; 63 (4): 453–63

  Abstract

  Despite modern multi-modality treatment, 10-30% of patients treated for differentiated thyroid cancer (DTC) ultimately develop local recurrence or metastatic disease. These malignancies are frequently slow-growing and secondary surgical resection is often undertaken along with radioactive iodine treatment. Correlation of radiological imaging with nuclear medicine studies is essential for individualized treatment planning, and to optimize this management. Radiologists should be familiar with the interpretation of various nuclear medicine studies used to image differentiated thyroid neoplasms.

  View details for DOI 10.1016/j.crad.2007.08.002

  View details for Web of Science ID 000254516900015

  View details for PubMedID 18325367

• Correcting tumour SUV for enhanced bone marrow uptake: retrospective F-18-FDG PET/CT studies NUCLEAR MEDICINE COMMUNICATIONS Teo, B., Badiee, S., Hadi, M., Lam, T., Johnson, L., Seo, Y., Bacharach, S. L., Hasegawa, B. H., Franc, B. L. 2008; 29 (4): 359-366

  Abstract

  The concentration of F-FDG in the bone marrow is usually low. One common cause of high uptake is due to bone marrow stimulating drugs administered in conjunction with chemotherapy or radiation therapy. It has been hypothesized that the sequestration of F-FDG to the bone marrow may reduce the standardized uptake value (SUV) of a tumour. We tested this hypothesis by quantifying total F-FDG uptake in the bone marrow of patients with visibly enhanced bone marrow uptake and computing its effect on tumour SUV.Total F-FDG in bone marrow was measured in two groups of PET/CT studies: one (n=19) with visibly enhanced bone marrow, the other (n=5), a baseline group with 'normal' levels of uptake. To measure the F-FDG in bone marrow, the entire skeleton in the CT was segmented from surrounding tissue, and the resulting volume applied to the PET image. Using kinetic analysis we show that the predicted correction factor to tumour SUV is given by (1-q0/Q)/(1-q/Q), where Q is the injected dose, and q and q0 are enhanced and baseline bone marrow uptake (MBq).The enhanced bone marrow uptake averaged 8.9+/-3.2% of injected dose (15.2% max) vs. 4.2+/-0.4% (4.6% max) at baseline. This resulted in a predicted artificial decrease in tumour SUV of up to 11.5% (4.9+/-4.3%, on average).Enhanced bone marrow uptake is predicted to reduce tumour SUVs by as much as 11.5% in our patient group and is a potential confounding factor in using SUV for monitoring tumour response to therapy.

  View details for Web of Science ID 000254261300010

  View details for PubMedID 18317301

• Nanoprobes for medical diagnosis: Current status of nanotechnology in molecular imaging CURRENT NANOSCIENCE He, J., VanBrocklin, H. F., Franc, B. L., Seo, Y., Jones, E. 2008; 4 (1): 17–29

  View details for Web of Science ID 000254019100002

• In vivo imaging of mucosal CD4(+) T cells using single photon emission computed tomography in a murine model of colitis JOURNAL OF IMMUNOLOGICAL METHODS Kanwar, B., Gao, D., Hwang, A. B., Grenert, J. P., Williams, S. P., Franc, B., McCune, J. M. 2008; 329 (1-2): 21–30

  Abstract

  Immune responses that occur in the context of human infectious and inflammatory diseases are usually studied by sampling cells from peripheral blood, from biopsies, or by end-point harvests at necropsy. These approaches are likely to yield information that is incomplete and/or non-representative. Here, we report the development and validation of a non-invasive method to localize and to quantitate the disposition of specific subpopulations of cells in vivo. In a murine model of dextran sulfate sodium (DSS)-induced colitis, CD4+ T cells were visualized in the colon by single photon emission computed tomography (SPECT-CT) after injection of monoclonal, non-depleting, indium-111 (111In) labeled anti-CD4+ antibodies. The SPECT-CT colon uptake ratio (CUR) was found to correlate (p<0.01) with the number of total CD4+ T cells and with standard measures of pathology (colon length, cell counts, and histopathologic evidence of apoptosis, edema, and cellular infiltrates) as assessed by direct examination of diseased colon. Each of these parameters, including the SPECT-CT signal uptake, increased as a function of DSS dose (p<0.05). We conclude that CT-SPECT imaging using an 111In-labeled anti-CD4+ antibody is reflective of traditional parameters of pathology in this experimental model of murine colitis. This approach should be readily applicable to the imaging of discrete cell subpopulations in non-human primates and in humans, thus augmenting our understanding of infectious diseases and inflammation in vivo.

  View details for DOI 10.1016/j.jim.2007.09.008

  View details for Web of Science ID 000253124100003

  View details for PubMedID 17964595

  View details for PubMedCentralID PMC2683264

• Positron emission tomography, positron emission tomography-computed tomography, and molecular imaging of the breast cancer patient SEMINARS IN ROENTGENOLOGY Franc, B. L., Hawkins, R. A. 2007; 42 (4): 265–79

  View details for DOI 10.1053/j.ro.2007.06.005

  View details for Web of Science ID 000250240100010

  View details for PubMedID 17919529

• Anterior layering of excreted F-18-FDG in the bladder on PET/CT: Frequency and cause AMERICAN JOURNAL OF ROENTGENOLOGY Purcell, D. D., Coakley, F. V., Franc, B. L., Hawkins, R. A., Boddington, S. E., Yeh, B. M. 2007; 189 (2): W96–W99

  Abstract

  The objective of our study was to determine the frequency and cause of anterior layering of excreted 18F-FDG in the bladder on PET/CT.Anterior layering of excreted FDG in the bladder is commonly seen on PET/CT scans obtained with i.v. iodinated contrast material and is due to displacement of FDG by excreted iodinated contrast material; this phenomenon may unmask FDG-avid bladder disease.

  View details for DOI 10.2214/AJR.07.2175

  View details for Web of Science ID 000248624400045

  View details for PubMedID 17646448

• An automatic method to delineate 18F-FDG PET tumor volumes for radiation treatment planning Teo, B., Seo, Y., Xia, P., Bacharach, S. L., Franc, B. L., Hasegawa, B. H. AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS. 2007: 2397–98

  View details for DOI 10.1118/1.2760633

  View details for Web of Science ID 000247479600347

• Calciphylaxis and bone scintigraphy: case report with histological confirmation and review of the literature ANNALS OF NUCLEAR MEDICINE Han, M. M., Pang, J., Shinkai, K., Franc, B., Hawkins, R., Aparici, C. M. 2007; 21 (4): 235–38

  Abstract

  We present a patient with a history of end-stage renal disease, who developed skin lesions in the bilateral calves a month after the initiation of hemodialysis. The lesions were biopsied, and the histological findings were consistent with a diagnosis of calciphylaxis. The patient had a baseline pretreatment bone scan that showed extensive systemic disease. The patient died 20 days after the imaging study. A review of the literature on bone scans and calciphylaxis is presented.

  View details for DOI 10.1007/s12149-007-0013-3

  View details for Web of Science ID 000248096500007

  View details for PubMedID 17581723

• Partial-volume correction in PET: Validation of an iterative postreconstruction method with phantom and patient data JOURNAL OF NUCLEAR MEDICINE Teo, B., Seo, Y., Bacharach, S. L., Carrasquillo, J. A., Libutti, S. K., Shukla, H., Hasegawa, B. H., Hawkins, R. A., Franc, B. L. 2007; 48 (5): 802–10

  Abstract

  Partial-volume errors (PVEs) in PET can cause incorrect estimation of radiopharmaceutical uptake in small tumors. An iterative postreconstruction method was evaluated that corrects for PVEs without a priori knowledge of tumor size or background.Volumes of interest (VOIs) were drawn on uncorrected PET images. PVE-corrected images were produced using an iterative 3-dimensional deconvolution algorithm and a local point spread function. The VOIs were projected on the corrected image to estimate the PVE-corrected mean activity concentration. These corrected mean values were compared with uncorrected maximum and mean values. Simulated data were generated as a first test of the correction algorithm. Phantom measurements were made using (18)F-FDG-filled spheres in a scattering medium. Clinical validation used 154 surrogate tumors from 9 patients. The surrogate tumors were blood-pool images of the descending aorta as well as mesenteric and iliac arteries and veins. Surrogate tumors ranged in diameter from 5 to 25 mm. Analysis used (18)F-FDG and (11)C-CO datasets (both dynamic and static). Values representing "truth" were derived from imaging the blood pool in large structures (e.g., the left ventricle, left atrium, or sections of the aorta) where PVEs were negligible. Surrogate tumor sizes were measured from contrast CT.The PVE-correction technique, when applied to the mean value in spheric phantoms, yielded recovery coefficients of 87% for an 8-mm-diameter sphere and between 100% and 103% for spheres between 13 and 29 mm. For the human studies, PVE-corrected data recovered a large fraction of the true activity concentration (86% +/- 7% for an 8-mm-diameter tumor and 98% +/- 8% for tumors between 10 and 24 mm). For tumors smaller than 18 mm, the PVE-corrected mean values were less biased (P<0.05) than the uncorrected maximum or mean values.Iterative postreconstruction PVE correction generated more accurate uptake measurements in subcentimeter tumors for both phantoms and patients than the uncorrected values. The method eliminates the requirement for segmenting anatomic data and estimating tumor metabolic size or tumor background level. This technique applies a PVE correction to the mean voxel value within a VOI, yielding a more accurate estimate of uptake than the maximum voxel value.

  View details for DOI 10.2967/jnumed.106.035576

  View details for Web of Science ID 000246326100027

  View details for PubMedID 17475970

• Interpretation, accuracy and management implications of FDG PET/CT in cutaneous malignant melanoma NUCLEAR MEDICINE COMMUNICATIONS Falk, M. S., Truitt, A. K., Coakley, F. V., Kashani-Sabet, M., Hawkins, R. A., Franc, B. 2007; 28 (4): 273–80

  Abstract

  To investigate the accuracy of different interpretative approaches and to evaluate the management implications of fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in cutaneous malignant melanoma.We retrospectively identified 60 consecutive patients who underwent 76 PET/CT scans for cutaneous malignant melanoma. PET/CT reports were classified as positive, negative, or equivocal for regional and distant disease. Scan indication (staging, restaging, surveillance, or therapeutic monitoring), tumour stage, presence or absence of regional or distant disease, and post-scan management changes were determined by review of all available medical records. Maximum standardized uptake values (SUV(max)) of all findings were noted. Diagnostic accuracy of PET/CT was compared using either a high or low threshold interpretation (i.e. subtle, but indeterminate findings coded negative or positive, respectively). The frequency of management changes was compared between patient subgroups (stratified by tumour stage or indication).Using a high threshold interpretative approach, the overall accuracy of PET/CT for disease was 72.4% (55/76), which was significantly (P<0.05) greater than the accuracy of 53.9% (41/76) seen when using a low threshold approach. Per scan accuracy by staging site was 92.1% (70/76) for regional and 76.3% (58/76) for distant disease. PET/CT changed management in 21 of 76 studies (27.6%). When stratified by stage and indication, management changes occurred in all patient subgroups, except for stage I patients (0 of 5).When interpreted with a high threshold approach, PET/CT demonstrates high accuracy for the diagnosis of both regional and distant disease in cutaneous malignant melanoma and frequently changes management in patients with stage II-IV disease referred for a variety of indications.

  View details for DOI 10.1097/MNM.0b013e3280708ecf

  View details for Web of Science ID 000245373900008

  View details for PubMedID 17325590

• Case 110: Nonossifying fibroma. Radiology Hetts, S. W., Hilchey, S. D., Wilson, R., Franc, B. 2007; 243 (1): 288-92

  View details for DOI 10.1148/radiol.2431040427

  View details for PubMedID 17392261

• Rodent brain imaging with SPECT/CT MEDICAL PHYSICS Seo, Y., Gao, D., Hasegawa, B. H., Dae, M. W., Franc, B. L. 2007; 34 (4): 1217–20

  Abstract

  We evaluated methods of imaging rat models of stroke in vivo using a single photon emission computed tomography (SPECT) system dedicated to small animal imaging (X-SPECT, Gamma Medica-Ideas, Northridge, CA). An animal model of ischemic stroke was developed for in vivo SPECT/CT imaging using the middle cerebral artery occlusion (MCAO) technique. The presence of cerebral ischemia was verified in ex vivo studies using triphenyltetrazolium chloride (TTC) staining. In vivo radionuclide imaging of cerebral blood flow was performed in rats following MCAO using dynamic planar imaging of 99mTc-exametazime with parallel hole collimation. This was followed immediately by in vivo radionuclide imaging of cerebral blood flow with 99mTc-exametazime in the same animals using 1-mm pinhole SPECT. Correlated computed tomography imaging was performed to localize radiopharmaceutical uptake. The animals were allowed to recover and ex vivo autoradiography was performed with separate administration of 99mTc-exametazime. Time activity curve of 99mTc-exametazime showed that the radiopharmaceutical uptake could be maintained for over 9 min. The activity would be expected to be relatively stable for a much longer period, although the data were only obtained for 9 min. TTC staining revealed sizable infarcts by visual observation of inexistence of TTC stain in infracted tissues of MCAO rat brains. In vivo SPECT imaging showed cerebral blood flow deficit in the MCAO model, and the in vivo imaging result was confirmed with ex vivo autoradiography. We have demonstrated a capability of imaging regions of cerebral blood flow deficit in MCAO rat brains in vivo using a pinhole SPECT dedicated to small animal imaging.

  View details for DOI 10.1118/1.2710950

  View details for Web of Science ID 000245842500010

  View details for PubMedID 17500453

• Telomeric transgenes are silenced in adult mouse tissues and embryo fibroblasts but are expressed in embryonic stem cells STEM CELLS Gao, Q., Reynolds, G. E., Innes, L., Pedram, M., Jones, E., Junabi, M., Gao, D., Ricoul, M., Sabatier, L., Van Brocklin, H., Franc, B. L., Murnane, J. P. 2007; 25 (12): 3085–92

  Abstract

  In addition to their role in protecting the ends of chromosomes, telomeres also influence the expression of adjacent genes, a process called telomere-position effect. We previously reported that the neo and HSV-tk transgenes located adjacent to telomeres in mouse embryonic stem cells are initially expressed at low levels and then become gradually silenced upon passage in culture through a process involving DNA methylation. We also reported extensive DNA methylation in these telomeric transgenes in three different tissues isolated from mice generated from one of these embryonic stem cell clones. In the present study, we demonstrate that embryo fibroblasts isolated from two different mouse strains show extensive DNA methylation and silencing of the telomeric transgenes. Consistent with this observation, we also demonstrate little or no detectable expression of the HSV-tk telomeric transgene in somatic tissues using whole body imaging. In contrast, both telomeric transgenes are expressed at low levels and have little DNA methylation in embryonic stem cell lines isolated from these same mouse strains. Our results demonstrate that telomere-position effect in mammalian cells can be observed either as a low level of expression in embryonic stem cells in the preimplantation embryo or as complete silencing and DNA methylation in differentiated cells and somatic tissues. This pattern of expression of the telomeric transgenes demonstrates that subtelomeric regions, like much of the genome, are epigenetically reprogrammed in the preimplantation embryo, a process that has been proposed to be important in early embryonic development. Disclosure of potential conflicts of interest is found at the end of this article.

  View details for DOI 10.1634/stemcells.2007-0478

  View details for Web of Science ID 000251707200013

  View details for PubMedID 17823235

• Evaluation of semi-quantitative scoring system for metaiodobenzylguanidine (mIBG) scans in patients with relapsed neuroblastoma PEDIATRIC BLOOD & CANCER Messina, J. A., Cheng, S., Franc, B. L., Charron, M., Shulkin, B., To, B., Maris, J. M., Yanik, G., Hawkins, R. A., Matthay, K. K. 2006; 47 (7): 865–74

  Abstract

  The purpose of this study was to determine the accuracy of two semi-quantitative scoring systems to assess response to (131)I-metaiodobenzylguanidine (mIBG) therapy in recurrent neuroblastoma.Diagnostic mIBG scan pairs (n = 57) were collected for patients who underwent (131)I-mIBG therapy for relapsed neuroblastoma. Two scoring systems were designated: Method 1, which divided the body into nine segments to view osteomedullary lesions with an additional tenth segment to assess soft tissue involvement; and Method 2, which divided the body into seven segments without a corresponding compartment for soft tissue involvement. Four nuclear medicine physicians independently assigned extension and intensity scores utilizing both methods, and separately recorded their impression of whether the post-therapy scan had improved, not changed, or worsened. Inter- and intra-observer concordance and correlation with overall response and progression-free survival (PFS) were performed.Method 1 produced the highest inter-observer concordance and was used to calculate the relative extension scores (post-therapy score divided by pre-therapy score), which correlated significantly with overall response. Patients who achieved complete response (CR) or partial response (PR) (n = 21) had lower relative extension scores, compared to those without response (P < 0.001). The readers' overall impression associated highly (P < 0.001) with the relative extension scores though results were less quantitative. Concordance was higher if initial scores were >5. Relative extension score did not predict PFS.Semi-quantitative scoring of mIBG scans provides a more reliable method of assessing response in patients with relapsed neuroblastoma than qualitative impression. The reproducibility and high inter-observer concordance makes mIBG score an important component of overall response criteria in patients with recurrent neuroblastoma.

  View details for DOI 10.1002/pbc.20777

  View details for Web of Science ID 000241803700002

  View details for PubMedID 16444675

• Tumor fluoro-2-deoxy-D-glucose avidity on positron emission tomographic scan predicts mortality in patients with early-stage pure and mixed bronchioloalveolar carcinoma Raz, D. J., Odisho, A. Y., Franc, B. L., Jablons, D. M. MOSBY, INC. 2006: 1189–95

  Abstract

  Bronchioloalveolar carcinoma is a clinically heterogeneous subtype of non-small cell lung carcinoma that frequently has low 2-[18F]fluoro-D-glucose (FDG) uptake on positron emission tomographic scanning. We investigated whether tumor FDG avidity was associated with worse survival among patients with completely resected node-negative pure and mixed bronchioloalveolar carcinoma.We performed a cohort study of 36 patients who had completely resected pure and mixed bronchioloalveolar carcinoma between 1998 and 2004, who had no hilar or mediastinal lymph node metastases, and who had undergone a preoperative positron emission tomographic scan. Tumor FDG avidity was defined as a standardized uptake value of 2.5 or greater. Survival analysis was performed with a proportional hazards model.Of 36 patients studied, 26 patients (72%) were alive and 10 patients (28%) were dead after a median follow-up of 31 months (interquartile range 17-41 months). Seventeen patients (47%) had FDG-avid tumors, and 19 patients (53%) had non-avid tumors. Three-year survival was 49% in the FDG-avid group and 95% in the non-avid group (P = .005). FDG avidity had a hazard ratio of death of 8.6 (95% confidence interval 1.4-244.7, P = .02) after adjusting for tumor size, the presence of multifocal bronchioloalveolar carcinoma, and the presence of histologically mixed bronchioloalveolar carcinoma.Preoperative tumor FDG standardized uptake value of 2.5 or greater on positron emission tomography is a powerful predictor of long-term mortality in patients with lymph node-negative pure and mixed bronchioloalveolar carcinoma who undergo complete surgical resection. Patients with a high level of FDG uptake (standardized uptake value > or = 2.5) may benefit from adjuvant chemotherapy or more frequent clinical follow-up.

  View details for DOI 10.1016/j.jtcvs.2006.06.033

  View details for Web of Science ID 000241497500028

  View details for PubMedID 17059942

• Progress in SPECT/CT imaging of prostate cancer TECHNOLOGY IN CANCER RESEARCH & TREATMENT Seo, Y., Franc, B. L., Hawkins, R. A., Wong, K. H., Hasegawa, B. H. 2006; 5 (4): 329–36

  Abstract

  Prostate cancer is the most common type of cancer (other than skin cancer) among men in the United States. Although prostate cancer is one of the few cancers that grow so slowly that it may never threaten the lives of some patients, it can be lethal once metastasized. Indium-111 capromab pendetide (ProstaScint, Cytogen Corporation, Princeton, NJ) imaging is indicated for staging and recurrence detection of the disease, and is particularly useful to determine whether or not the disease has spread to distant metastatic sites. However, the interpretation of 111In-capromab pendetide is challenging without correlated structural information mostly because the radiopharmaceutical demonstrates nonspecific uptake in the normal vasculature, bowel, bone marrow, and the prostate gland. We developed an improved method of imaging and localizing 111In-Capromab pendetide using a SPECT/CT imaging system. The specific goals included: i) development and application of a novel iterative SPECT reconstruction algorithm that utilizes a priori information from coregistered CT; and ii) assessment of clinical impact of adding SPECT/CT for prostate cancer imaging with capromab pendetide utilizing the standard and novel reconstruction techniques. Patient imaging studies with capromab pendetide were performed from 1999 to 2004 using two different SPECT/CT scanners, a prototype SPECT/CT system and a commercial SPECT/CT system (Discovery VH, GE Healthcare, Waukesha, WI). SPECT projection data from both systems were reconstructed using an experimental iterative algorithm that compensates for both photon attenuation and collimator blurring. In addition, the data obtained from the commercial system were reconstructed with attenuation correction using an OSEM reconstruction supplied by the camera manufacturer for routine clinical interpretation. For 12 sets of patient data, SPECT images reconstructed using the experimental algorithm were interpreted separately and compared with interpretation of images obtained using the standard reconstruction technique. The experimental reconstruction algorithm improved spatial resolution, reduced streak artifacts, and yielded a better correlation with anatomic details of CT in comparison to conventional reconstruction methods (e.g., filtered back-projection or OSEM with attenuation correction only). Images produced with the experimental algorithm produced a subjective improvement in the confidence of interpretation for 11 of 12 studies. There were also changes in interpretations for 4 of 12 studies although the changes were not sufficient to alter prognosis or the patient treatment plan.

  View details for DOI 10.1177/153303460600500404

  View details for Web of Science ID 000240089900005

  View details for PubMedID 16866563

• Intracellular cargo delivery by an octaarginine transporter adapted to target prostate cancer cells through cell surface protease activation BIOCONJUGATE CHEMISTRY Goun, E. A., Shinde, R., Dehnert, K. W., Adams-Bond, A., Wender, P. A., Contag, C. H., Franc, B. L. 2006; 17 (3): 787-796

  Abstract

  Delivery of therapeutics and imaging agents to target tissues requires localization and activation strategies with molecular specificity. Cell-associated proteases can be used for these purposes in a number of pathologic conditions, and their enzymatic activities can be exploited for activation strategies. Here, molecules based on the d-arginine octamer (r8) protein-transduction domain (PTD, also referred to as molecular transporters) have been adapted for selective uptake into cells only after proteolytic cleavage of a PTD-attenuating sequence by the prostate-specific antigen (PSA), an extracellular protease associated with the surface and microenvironment of certain prostate cancer cells. Convergent syntheses of these activatable PTDs (APTDs) are described, and the most effective r8 PTD-attenuating sequence is identified. The conjugates are shown to be stable in serum, cleaved by PSA, and taken up into Jurkat (human T cells) and PC3M prostate cancer cell lines only after cleavage by PSA. These APTD peptide-based molecules may facilitate targeted delivery of therapeutics or imaging agents to PSA-expressing prostate cancers.

  View details for DOI 10.1021/bc0503216

  View details for PubMedID 16704219

• Lymphatic drainage patterns of head and neck cutaneous melanoma observed on lymphoscintigraphy and sentinel lymph node biopsy Lin, D., Franc, B. L., Kashani-Sabet, M., Singer, M. I. WILEY. 2006: 249–55

  Abstract

  The purpose of this study was to evaluate lymphatic drainage patterns of head and neck cutaneous melanoma observed on preoperative lymphoscintigraphy and sentinel lymph node biopsy (SLNB) and determine discordancy from clinically predicted lymphatic drainage patterns.We conducted a retrospective chart review of 114 patients with head and neck cutaneous melanomas evaluated with preoperative lymphoscintigraphy and SLNB from January 2001 through July 2004.At least one sentinel lymph node (SLN) was identified in 97% of cases. On preoperative lymphoscintigraphy, an SLN was identified in an area not clinically predicted in 49 cases (43%). The most common sites of discordancy were in areas not typically dissected in standard neck dissections, such as the postauricular region, or in areas of more distant drainage than described previously, such as the inferior or posterior neck. Their percentages of discordant cases were 51%, 27%, and 22%, respectively. The sites of regional recurrence occurred in two cases not predicted on preoperative lymphoscintigraphy and in two cases of failed SLNB.On the basis of preoperative lymphoscintigraphy and the results of SLNB, head and neck cutaneous melanomas do have expected lymphatic drainage patterns despite perceived discordancy with previously clinically predicted drainage patterns that are based on standard neck dissection specimens. These "discordant" sites can still harbor melanoma, and all sites predicted on preoperative lymphoscintigraphy still need to be explored. The four cases of recurrences underscore the importance of close follow-up for all patients regardless of the SLNB result.

  View details for DOI 10.1002/hed.20328

  View details for Web of Science ID 000235599600009

  View details for PubMedID 16470744

• Phase I dose escalation of iodine-131-metaiodobenzylguanidine with myeloablative chemotherapy and autologous stem-cell transplantation in refractory neuroblastoma: A new approaches to neuroblastoma therapy consortium study Matthay, K. K., Tan, J. C., Villablanca, J. G., Yanik, G. A., Veatch, J., Franc, B., Twomey, E., Horn, B., Reynolds, C. P., Groshen, S., Seeger, R. C., Maris, J. M. AMER SOC CLINICAL ONCOLOGY. 2006: 500–506

  Abstract

  To determine the maximum-tolerated dose (MTD) and toxicity of iodine-131-metaiodobenzylguanidine ((131)I-MIBG) with carboplatin, etoposide, melphalan (CEM) and autologous stem-cell transplantation (ASCT) in refractory neuroblastoma.Twenty-four children with primary refractory neuroblastoma and no prior ASCT were entered; 22 were assessable for toxicity and response. (131)I-MIBG was administered on day -21, CEM was administered on days -7 to -4, and ASCT was performed on day 0, followed by 13-cis-retinoic acid. (131)I-MIBG was escalated in groups of three to six patients, stratified by corrected glomerular filtration rate (GFR).The MTD for patients with normal GFR (> or = 100 mL/min/1.73 m2) was 131I-MIBG 12 mCi/kg, carboplatin 1,500 mg/m2, etoposide 1,200 mg/m2, and melphalan 210 mg/m2. In the low-GFR cohort, at the initial dose level using 12 mCi/kg of 131I-MIBG and reduced chemotherapy, one in six patients had dose limiting toxicity (DLT), including veno-occlusive disease (VOD). Three more patients in this group had grade 3 or 4 hepatotoxicity, and two had VOD, without meeting DLT criteria. There was only one death as a result of toxicity among all 24 patients. All assessable patients engrafted, with median time for neutrophils > or = 500/microL of 10 days and median time for platelets > or = 20,000/microL of 26 days. Six of 22 assessable patients had complete or partial response, and 15 patients had mixed response or stable disease. The estimated probability of event-free survival and survival from the day of MIBG infusion for all patients at 3 years was 0.31 +/- 0.10 and 0.58 +/- 0.10, respectively.131I-MIBG with myeloablative chemotherapy is feasible and effective for patients with neuroblastoma exhibiting de novo resistance to chemotherapy.

  View details for DOI 10.1200/JCO.2005.03.6400

  View details for Web of Science ID 000234776300028

  View details for PubMedID 16421427

• Rodent Brain Imaging with SPECT and CT Seo, Y., Gao, D., Hashimoto, T., Franc, B. L., Dae, M. W., Hasegawa, B. H., IEEE IEEE. 2006: 3526-+

  View details for Web of Science ID 000288875603130

• FDG PET imaging in the evaluation of post-transplant lymphoproliferative disorder following renal transplantation NUCLEAR MEDICINE COMMUNICATIONS O'Conner, A. R., Franc, B. L. 2005; 26 (12): 1107–11

  Abstract

  To assess the usefulness of fluorodeoxyglucose positron emission tomography (FDG PET) in the evaluation of post-transplant lymphoproliferative disorder (PTLD) following renal transplantation.Staging FDG PET examinations were reviewed in five patients with biopsy proven post-renal allograft PTLD and compared with conventional imaging. Follow-up PET examinations of three patients at various points during their therapy for PTLD were also reviewed and compared with clinical outcome.PET imaging identified all disease sites seen at cross-sectional imaging, clarified sites of uncertain significance and detected additional disease in two out of five patients. Early follow-up imaging impacted PTLD management in two of three patients.In this limited series FDG PET was an effective imaging modality in the staging and follow-up of PTLD.

  View details for DOI 10.1097/00006231-200512000-00010

  View details for Web of Science ID 000233546000010

  View details for PubMedID 16264358

• The role of a positron- and high-energy gamma photon probe in intraoperative localization of recurrent melanoma CLINICAL NUCLEAR MEDICINE Franc, B. L., Mari, C., Johnson, D., Leong, S. P. 2005; 30 (12): 787-791

  Abstract

  This preliminary study retrospectively evaluated the ability of intraoperative localization of recurrent melanoma using F-18 fluorodeoxyglucose (FDG) and a probe sensitive to both high-energy gamma rays and positrons to enable complete tumor resection and improved patient outcome.Three hours before surgery for resection of recurrent melanoma, 5 patients (mean age, 52 +/- 22 years) with a history of local surgery, radiation therapy, and/or large habitus received 14.6 +/- 3.2 mCi of F-18 FDG. Intraoperative tumor localization was performed with a radiation probe (PET-Probe; IntraMedical Imaging LLC, Los Angeles, CA). Intraoperative tumor tissue activities, background tissue activities, pathology results, and patient follow up (clinical/imaging) were recorded.Eight of the 19 surgical specimens were identified by the probe as having increased FDG uptake when compared with the surrounding tissues before resection. All 8 specimens contained melanoma. Of the 11 specimens that were not identified using the probe, one contained melanoma, yielding a sensitivity of 89% (8 of 9) and a specificity of 100% (10 of 10). In 3 of the 5 cases, the probe allowed the identification of nonvisualized and nonpalpable tumor foci that were later confirmed pathologic. At an average follow up of 210 days (range, 30-515 days), 2 of 5 patients had no evidence of recurrent melanoma by clinical or radiographic evaluations.In the setting of recurrent melanoma, there appear to be potential benefits to intraoperative detection with FDG and a positron-detecting probe, particularly in cases with challenging or altered anatomy.

  View details for Web of Science ID 000233455500003

  View details for PubMedID 16319633

• Improved prostate cancer imaging with SPECT/CT and MRI/MRSI IEEE TRANSACTIONS ON NUCLEAR SCIENCE Seo, Y., Kurhanewicz, J., Franc, B. L., Hawkins, R. A., Hasegawa, B. H. 2005; 52 (5): 1316–20

  View details for DOI 10.1109/TNS.2005.858241

  View details for Web of Science ID 000233780800015

• Correction of photon attenuation and collimator response for a body-contouring SPECT/CT imaging system JOURNAL OF NUCLEAR MEDICINE Seo, Y., Wong, K. H., Sun, M. S., Franc, B. L., Hawkins, R. A., Hasegawa, B. H. 2005; 46 (5): 868–77

  Abstract

  (111)In-Capromab pendetide imaging is indicated for postprostatectomy patients at risk for residual or recurrent disease. However, this study is complicated by relatively long times for tumor uptake and background washout that require imaging to be performed several days after radiopharmaceutical administration. In addition, (111)In-capromab pendetide demonstrates uptake in normal structures that produce images that are interpreted best using correlation with anatomic imaging. Finally, the visual quality of radionuclide imaging can be improved with corrections for photon attenuation and for the geometric response of the radionuclide collimator. Therefore, we have evaluated the advantages of using a commercially available dual-modality SPECT/CT system. In this article, we evaluate a novel iterative reconstruction algorithm using the SPECT/CT data obtained from phantoms and (111)In-capromab pendetide patient studies.Phantom data acquired with the dual-head SPECT camera were reconstructed using both filtered backprojection (FBP) and an iterative maximum-likelihood expectation maximization (MLEM) algorithm incorporating corrections for (a) attenuation coefficient at the effective energy of the radionuclide (either (99m)Tc or (111)In) and (b) collimator response based on experimentally measured depth-dependent spatial resolution of the camera. The collimator response model used the coregistered CT image to estimate the source-target distances produced by the patient-contouring logic of the SPECT camera. Spatial resolution was measured using SPECT images of 2 line sources and uniformity from a uniform cylindric tank. Clinical (111)In-capromab pendetide SPECT/CT data were acquired according to the radiopharmaceutical manufacturer's protocol. Region-of-interest (ROI) analysis of a transverse slice at the level of the sacral base produced mean, median, maximum, and minimum counts per pixel for bone marrow and surrounding soft-tissue ROIs. Ratios of the mean capromab pendetide uptake within marrow to uptake within soft tissue were compared for images reconstructed with FBP versus that obtained from the MLEM method with photon attenuation and collimator response corrections.The source-target distances reconstructed from the patient-specific CT image agreed well with the corresponding values recorded manually from the camera display unit. This information was incorporated into the iterative reconstruction algorithms and improved the quality of SPECT images from phantoms and patients versus SPECT images reconstructed without the depth-dependent collimator response model. Qualitatively, SPECT images reconstructed with corrections for photon attenuation and collimator response showed less background activity and improved target contrast compared with those images reconstructed with FBP. The target-to-background ratio (marrow uptake-to-soft-tissue uptake) was significantly better using MLEM reconstruction than with FBP when mean uptake values were measured.A priori anatomic data can be used to enhance the quality of the SPECT image when reconstructed using iterative techniques (e.g., MLEM) that use the CT data to produce a patient-specific attenuation map and a collimator response model based on the body contour produced during the SPECT acquisition.

  View details for Web of Science ID 000228952400029

  View details for PubMedID 15872362

• Pericardial lymph node involvement in lymphoma as identified on PET CLINICAL NUCLEAR MEDICINE Franc, B., Yoshida, E., Herfkens, R., Goris, M. 2004; 29 (11): 741-742

  View details for PubMedID 15483497

• Apoptosis in a rodent model of cranial suture fusion: In situ imaging and gene expression analysis PLASTIC AND RECONSTRUCTIVE SURGERY Fong, K. D., Song, H. M., Nacamuli, R. P., Franc, B. L., Mari, C., Fang, T. D., Warren, S. M., Contag, C. H., Blankenberg, F. G., Longaker, M. T. 2004; 113 (7): 2037-2047

  Abstract

  Craniosynostosis, the premature fusion of cranial sutures, is one of the most common craniofacial anomalies, with a reported incidence of up to one in 2500 live births. Despite its prevalence, the cause of craniosynostosis remains unknown. Previously, apoptosis has been postulated to be a contributing factor in the pathogenesis of craniosynostosis, although the role of programmed cell death in cranial sutures is poorly understood. To address this problem, the authors used an established rodent model of posterior-frontal suture fusion and sagittal suture patency to globally examine apoptosis in cranial sutures. Apoptosis was evaluated by systemically coinjecting Sprague-Dawley rats with both fluorescent and technetium-99m-labeled annexin V at time points before, during, and after the period of predicted posterior-frontal suture fusion to determine the magnitude and time course of overall apoptotic activity in both fusing and patent sutures. Using these novel in situ imaging techniques, the authors observed a significant increase in the overall levels of apoptosis in both the posterior-frontal and sagittal suture complexes during the period of predicted posterior-frontal suture fusion. To further explore this increase in apoptotic activity, they used microarray technology to study apoptosis-related genes within the suture complex. Interestingly, there was activation of distinct apoptotic pathways in the posterior-frontal and sagittal sutures during the period of predicted posterior-frontal suture fusion. Whereas increased transcription of genes associated with the mitochondria-mediated apoptotic pathway occurred in the posterior-frontal suture during fusion, activation of genes associated with the death receptor-mediated apoptotic pathway predominated in the patent sagittal suture during the same time period. These data suggest that although overall apoptotic activity in rat patent and fusing sutures is similar, the pathways mediating apoptosis within each suture are distinct.

  View details for DOI 10.1097/01.prs.000012118201199.c1

  View details for PubMedID 15253194

• Potential role for antiangiogenic proteins in the myocardial infarction repair process JOURNAL OF SURGICAL RESEARCH Thompson, J. L., Ryan, J. A., Barr, M. L., Franc, B., Starnes, V. A., Schwarz, M. A. 2004; 116 (1): 156–64

  Abstract

  Although angiogenic proteins have been identified as positive modulators of myocardial revascularization following acute myocardial infarction, little if anything is known regarding the role that antiangiogenic proteins have in myocardial revascularization. We explored the temporospatial distribution of endothelial-monocyte activating polypeptide (EMAP) II to determine whether antiangiogenic proteins have a role in the repair of myocardial tissue following infarction.A rat model of myocardial infarction was utilized to examine EMAP II distribution (in situ hybridization) and protein expression (Western analysis) over a 6-week period.At baseline, EMAP II protein and mRNA are minimally expressed with transcription products localizing predominately to the perivascular stroma region in the normal rat myocardium. Six hours following myocardial infarction, EMAP II changes its distribution from the perivascular stroma to an invading inflammatory cell population. This is associated with a 2-fold (P < 0.0009) increase in EMAP II protein and its transcription primarily localized to the infarct region. EMAP II protein expression remains elevated throughout the weeks following the infarction with transcription limited to the infarct region and a notable decrease in EMAP II transcription products noted in the viable vasculature surrounding the infarct zone. Six weeks following myocardial infarction, EMAP II protein is elevated above control, changes its location of transcription from the inflammatory cell population to that of the fibroblasts located in the relative avascular scar tissue, and has resumed its perivascular stromal distribution in the viable periinfarct tissue.Thus, the temporospatial distribution of this antiangiogenic protein suggests that negative vascular modulators may have a function in the revascularization process following acute myocardial infarction.

  View details for DOI 10.1016/j.jss.2003.06.001

  View details for Web of Science ID 000188368900022

  View details for PubMedID 14732363

• Breaching biological barriers: protein translocation domains as tools for molecular imaging and therapy. Molecular imaging Franc, B. L., Mandl, S. J., Siprashvili, Z., Wender, P., Contag, C. H. 2003; 2 (4): 313-323

  Abstract

  The lipid bilayer of a cell presents a significant barrier for the delivery of many molecular imaging reagents into cells at target sites in the body. Protein translocation domains (PTDs) are peptides that breach this barrier. Conjugation of PTDs to imaging agents can be utilized to facilitate the delivery of these agents through the cell wall, and in some cases, into the cell nucleus, and have potential for in vitro and in vivo applications. PTD imaging conjugates have included small molecules, peptides, proteins, DNA, metal chelates, and magnetic nanoparticles. The full potential of the use of PTDs in novel in vivo molecular probes is currently under investigation. Cells have been labeled in culture using magnetic nanoparticles derivatized with a PTD and monitored in vivo to assess trafficking patterns relative to cells expressing a target antigen. In vivo imaging of PTD-mediated gene transfer to cells of the skin has been demonstrated in living animals. Here we review several natural and synthetic PTDs that have evolved in the quest for easier translocation across biological barriers and the application of these peptide domains to in vivo delivery of imaging agents.

  View details for PubMedID 14717330

• Oral administration of F-18FDG to evaluate a single pulmonary nodule by positron emission tomography in a patient with poor intravenous access CLINICAL NUCLEAR MEDICINE Franc, B., Carlisle, M. R., Segall, G. 2003; 28 (7): 541-544

  Abstract

  F-18 fluorodeoxyglucose (FDG) is typically administered intravenously for positron emission tomography. The authors present a case of oral administration of FDG for evaluation of a pulmonary nodule and review the limited literature on this subject. Oral administration of FDG is a useful alternative to intravenous administration in patients with difficult intravenous access when the alimentary tract is not involved in the clinical diagnosis.

  View details for Web of Science ID 000183782800001

  View details for PubMedID 12819404

• Low uptake of Tc-99m tetrofosmin in lung cancer - A case report CLINICAL NUCLEAR MEDICINE Franc, B., Goris, M. 2002; 27 (10): 698-700

  Abstract

  Technetium-99m tetrofosmin has been used as a tumor-imaging agent in cases of lung cancer. The authors present a case showing a lung tumor that concentrated Tl-201 distinctly more than Tc-99m tetrofosmin during a dual-isotope cardiac examination. A brief review of the literature is provided and possible explanations for this difference in tracer uptake are discussed.

  View details for DOI 10.1097/01.RLU.0000027801.86894.5D

  View details for PubMedID 12352109