Clinical Focus

  • Nuclear Radiology

Academic Appointments

Professional Education

  • Residency: Stanford University Nuclear Medicine Residency (2005) CA
  • Board Certification: American Board of Nuclear Medicine, Nuclear Medicine (2005)
  • Medical Education: Universitat de Valencia (1992) Spain

Clinical Trials

  • 18F-FSPG PET/CT in Diagnosing Early Lung Cancer in Patients With Lung Nodules Recruiting

    This phase II trial studies how well 18F-FSPG positron emission tomography (PET)/computed tomography (CT) work in diagnosing early lung cancer in patients with lung nodules. PET imaging with an imaging agent called 18F-FDG is often used in combination with a PET/CT scanner to evaluate cancers. Giving 18F-FSPG before a PET/CT scan may work better in helping researchers diagnose early lung cancer in patients with lung nodules.

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  • Lutetium 177Lu-Edotreotide Versus Best Standard of Care in Well-differentiated Aggressive Grade-2 and Grade-3 GastroEnteroPancreatic NeuroEndocrine Tumors (GEP-NETs) - COMPOSE Recruiting

    The purpose of the study is to evaluate the efficacy, safety & patient-reported outcomes of peptide receptor radionuclide therapy (PRRT) with 177Lu-Edotreotide as 1st or 2nd line of treatment compared to best standard of care in patients with well-differentiated aggressive grade 2 and grade 3, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin.

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  • A Study to Evaluate Safety, Tolerability, Dosimetry, and Preliminary Efficacy of the HER2 Directed Radioligand CAM-H2 in Patients With Advanced/Metastatic HER2-Positive Breast, Gastric, and Gastro-Esophageal Junction (GEJ) Cancer Not Recruiting

    This is a Phase 1/2 multi-center, open label, dose escalation and dose expansion study to evaluate safety, tolerability, dosimetry, pharmacodynamics (PD), and efficacy of the targeted radionuclide therapeutic CAM-H2 in patients with progressive, advanced/metastatic HER2-positive breast, gastric, and GEJ cancer with disease progression following anti-HER2 standard of care treatment. The study duration for each phase will be up to 18 months. The study is comprised of a Treatment Period, consisting of a maximum of 4 cycles (12 weeks per cycle) of study drug, and a 12-month Long-Term Follow-Up Period.

    Stanford is currently not accepting patients for this trial. For more information, please contact Carina Mari Aparici, 650-736-4183.

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  • Efficacy and Safety of 177Lu-edotreotide PRRT in GEP-NET Patients Not Recruiting

    The purpose of the study is to evaluate efficacy and safety of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-Edotreotide compared to targeted molecular therapy with Everolimus in patients with inoperable, progressive, somatostatin receptor-positive (SSTR+), neuroendocrine tumours of gastroenteric or pancreatic origin (GEP-NET).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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All Publications

  • Definitive Treatment of Brain Metastases From a Neuroendocrine Tumor With Peptide Receptor Radionuclide Therapy With 177Lutetium DOTATATE: A Case Report. Cureus Zhang, V., Taparra, K., Fisher, G., Aparici, C., Soltys, S. G. 2023; 15 (9): e45327


    Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare malignancies that arise from secretory endocrine cells of the gastroenteropancreatic system. Clinical outcomes have improved for patients with GEP-NETs due to the development and recent FDA approval of 177Lutetium DOTATATE. However, the response of brain metastases from GEP-NETs from 177Lutetium DOTATATE is unreported. We present the case of an 81-year-old man with low-grade small bowel GEP-NET with liver and brain metastases treated with a total of six cycles of 177Lutetium DOTATATE. With over three years of follow-up from his initial treatment, his brain metastases have had complete or partial responses, with no need for brain radiotherapy or radiosurgery.

    View details for DOI 10.7759/cureus.45327

    View details for PubMedID 37849592

    View details for PubMedCentralID PMC10577096

  • 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
  • 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


    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

  • A Pilot Study of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for Biopsy Guidance in Patients with Suspected Prostate Cancer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Duan, H., Ghanouni, P., Daniel, B., Rosenberg, J., Thong, A., Kunder, C., Mari Aparici, C., Davidzon, G. A., Moradi, F., Sonn, G. A., Iagaru, A. 2022


    Purpose: Targeting of lesions seen on multiparametric MRI (mpMRI) improves prostate cancer (PC) detection at biopsy. However, 20-65% of highly suspicious lesions on mpMRI (PI-RADS 4 or 5) are false positives (FP), while 5-10% of clinically significant PC (csPC) are missed. Prostate specific membrane antigen (PSMA) and gastrin-releasing peptide receptors (GRPR) are both overexpressed in PC. We therefore aimed to evaluate the potential of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for biopsy guidance in patients with suspected PC. Methods: A highly selective cohort of 13 men, aged 58.0±7.1 years, with suspected PC (persistently high prostate-specific antigen [PSA] and PSA density) but negative or equivocal mpMRI and/or negative biopsy were prospectively enrolled to undergo 68Ga-PSMA11 and 68Ga-RM2 PET/MRI. PET/MRI included whole-body and dedicated pelvic imaging after a delay of 20 minutes. All patients had targeted biopsy of any lesions seen on PET followed by standard 12-core biopsy. Maximum standardized uptake values (SUVmax) of suspected PC lesions were collected and compared to gold standard biopsy. Results: PSA and PSA density at enrollment were 9.8±6.0 (1.5-25.5) ng/mL and 0.20±0.18 (0.06-0.68) ng/mL2, respectively. Standardized systematic biopsy revealed a total of 14 PC in 8 participants: 7 were csPC and 7 were non-clinically significant PC (ncsPC). 68Ga-PSMA11 identified 25 lesions, of which 11 (44%) were true positive (TP) (5 csPC). 68Ga-RM2 showed 27 lesions, of which 14 (52%) were TP, identifying all 7 csPC and also 7 ncsPC. There were 17 concordant lesions in 11 patients vs. 14 discordant lesions in 7 patients between 68Ga-PSMA11 and 68Ga-RM2 PET. Incongruent lesions had the highest rate of FP (12 FP vs. 2 TP). SUVmax was significantly higher for TP than FP lesions in delayed pelvic imaging for 68Ga-PSMA11 (6.49±4.14 vs. 4.05±1.55, P = 0.023) but not for whole-body images, nor for 68Ga-RM2. Conclusion: Our results show that 68Ga-PSMA11 and 68Ga-RM2 PET/MRI are feasible for biopsy guidance in suspected PC. Both radiopharmaceuticals detected additional clinically significant cancers not seen on mpMRI in this selective cohort. 68Ga-RM2 PET/MRI identified all csPC confirmed at biopsy.

    View details for DOI 10.2967/jnumed.122.264448

    View details for PubMedID 36396456

  • A Pilot Study of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for Evaluation of Prostate Cancer Response to High Intensity Focused Ultrasound (HIFU) Therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Duan, H., Ghanouni, P., Daniel, B., Rosenberg, J., Davidzon, G. A., Mari Aparici, C., Kunder, C., Sonn, G., Iagaru, A. 2022


    Rationale: Focal therapy for localized prostate cancer (PC) using high intensity focused ultrasound (HIFU) is gaining in popularity as it is non-invasive and associated with fewer side effects than standard whole-gland treatments. However, better methods to evaluate response to HIFU ablation are an unmet need. Prostate specific membrane antigen (PSMA) and gastrin-releasing peptide receptors (GRPR) are both overexpressed in PC. In this study, we evaluated a novel approach of using both 68Ga-RM2 and 68Ga-PSMA11 PET/MRI in each patient before and after HIFU to assess accuracy of target tumor localization and response to treatment. Methods: Fourteen men, 64.5 ± 8.0 (range 48-78) years-old, with newly diagnosed PC were prospectively enrolled. Pre-HIFU, patients underwent prostate biopsy, multiparametric MRI (mpMRI), 68Ga-PSMA11, and 68Ga-RM2 PET/MRI. Response to treatment was assessed at a minimum of 6 months after HIFU with prostate biopsy (n = 13), as well as 68Ga-PSMA11 and 68Ga-RM2 PET/MRI (n = 14). Maximum and peak standardized uptake values (SUVmax and SUVpeak) of known or suspected PC lesions were collected. Results: Pre-HIFU biopsy revealed 18 cancers of which 14 were clinically significant (Gleason score ≥3+4). mpMRI identified 18 lesions; 14 of them were ≥PI-RADS 4. 68Ga-PSMA11 and 68Ga-RM2 PET/MRI each showed 23 positive intraprostatic lesions; 21 were congruent in 13 patients and five were incongruent in 5 patients. Pre-HIFU, 68Ga-PSMA11 identified all target tumors while 68Ga-RM2 PET/MRI missed two tumors. Post-HIFU, 68Ga-RM2 and 68Ga-PSMA11 PET/MRI both identified clinically significant residual disease in one patient. Three significant ipsilateral recurrent lesions were identified, whereas one was missed by 68Ga-PSMA11. Pre-treatment prostate specific antigen (PSA) decreased significantly after HIFU by 66%. Concordantly, pre-treatment SUVmax decreased significantly after HIFU for 68Ga-PSMA11 (P = 0.001) and 68Ga-RM2 (P = 0.005). Conclusion: The results of this pilot study show that 68Ga-PSMA11 and 68Ga-RM2 PET/MRI identified the target tumor for HIFU in 100% and 86%, respectively, and accurately verified response to treatment. PET might be a useful tool in the guidance and monitoring of treatment success in patients receiving focal therapy for PC. These preliminary findings warrant larger studies for validation.

    View details for DOI 10.2967/jnumed.122.264783

    View details for PubMedID 36328488

  • A Pilot Study of Ga-68-PSMA11 and Ga-68-RM2 PET/MRI for Evaluation of Prostate Cancer Response to High Intensity Focused Ultrasound (HIFU) Therapy Duan, H., Ghanouni, P., Daniel, B., Rosenberg, J., Davidzon, G. A., Aparici, C., Thong, A., Sonn, G. A., Kunder, C., Iagaru, A. SPRINGER. 2022: S497-S498
  • Head-to-head Comparison of a Conventional or CZT-based SPECT/CT with a Next Generation Multidetector CZT-based SPECT/CT System Duan, H., Ferri, V., Castaneda, P., Visser, T., Luong, K., Davidzon, G. A., Aparici, C., Iagaru, A. SPRINGER. 2022: S263
  • A Pilot Study of Ga-68-PSMA11 and 68Ga-RM2 PET/MRI for Biopsy Guidance in Patients with Suspected Prostate Cancer Duan, H., Ghanouni, P., Daniel, B., Rosenberg, J., Thong, A., Sonn, G. A., Kunder, C., Davidzon, G. A., Aparici, C., Moradi, F., Iagaru, A. SPRINGER. 2022: S484
  • Striking Size Reduction of Rapidly Growing Pancreatic Neuroendocrine Carcinoma Metastatic Nodal Conglomerate After Only 2 Cycles of 177Lu-DOTATATE. Clinical nuclear medicine Somoza, E. A., Duan, H., Shaheen, S., Fischer, G. A., Aparici, C. M. 2022


    ABSTRACT: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE has shown great treatment efficacy in patients with well-differentiated metastatic neuroendocrine tumors and a metastatic size reduction of ~20% for metastatic lesions <3 cm in size. We present a 66-year-old man with pancreatic neuroendocrine carcinoma, who had a rapidly growing metastatic nodal conglomerate, which measured close to 10 cm in size. After only 2 cycles of PRRT with 177Lu-DOTATATE, the nodal conglomerate had a striking size reduction greater than 75%. This case highlights the potential efficacy of PRRT with 177Lu-DOTATATE for treatment of aggressive neuroendocrine neoplasms.

    View details for DOI 10.1097/RLU.0000000000004262

    View details for PubMedID 35695695

  • 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
  • Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up. The oncologist Duan, H., Ferri, V., Fisher, G. A., Shaheen, S., Davidzon, G. A., Iagaru, A., Mari Aparici, C. 2022


    Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin receptor (SSR) analogs is now an established systemic treatment for neuroendocrine tumors (NET). However, more short- and long-term data about renal and hepatotoxicity is needed. Here we present our experience in this clinical scenario.Eighty-six patients with progressive SSR-expressing malignancies underwent PRRT with Lu-177 Dotatate and were followed up for up to 2 years. Laboratory tests were done 1 week before each cycle and every 2 months at follow-up. Hepatic and renal toxicity was determined based on NCI CTCAE V5.0.55/86 (64%) patients completed all 4 cycles of PRRT; 18/86 (20.9%) are currently being treated; 13/86 (15.1%) had to discontinue PRRT: 4/13 (31%) due to hematologic toxicity, 9/13 (69%) due to non-PRRT-related comorbidities. Out of the patients who finished treatment, only transient grade 2 toxicities were observed during PRRT: hypoalbuminemia in 5.5% (3/55), and renal toxicity (serum creatinine and estimated glomerular filtration rate) in 1.8% (1/55). No grade 3 or 4 liver and renal toxicity occurred. Patients presenting with impaired liver or renal function prior to PRRT, either improved or had stable findings. No deterioration was observed.Peptide receptor radionuclide therapy does not have a negative impact on liver and renal function, even in patients with pre-existing impaired parameters. No grade 3 or 4 hepatic or renal toxicity was identified. Only transient grade 2 hypoalbuminemia in 5.5% and nephrotoxicity in 1.8% of patients were seen during PRRT.

    View details for DOI 10.1093/oncolo/oyab072

    View details for PubMedID 35641196

  • Evaluation of Liver and Renal Toxicity in Peptide Receptor Radionuclide Therapy for Somatostatin Receptor Expressing Tumors: A 2-Year Follow-Up ONCOLOGIST Duan, H., Ferri, V., Fisher, G., Shaheen, S., Davidzon, G., Iagaru, A., Aparici, C. 2022
  • 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
  • Response to Letter to Editor re: "Combined Quantification of 18F-FDG and 68Ga-DOTATATE PET/CT for Prognosis in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms". Academic radiology Lee, H., Nakamoto, R., Moore, S. E., Pantel, A. R., Eads, J. R., Aparici, C. M., Pryma, D. A. 2022

    View details for DOI 10.1016/j.acra.2022.02.001

    View details for PubMedID 35227613

  • Radiotheranostics - Precision Medicine in Nuclear Medicine and Molecular Imaging. Nanotheranostics Duan, H., Iagaru, A., Aparici, C. M. 1800; 6 (1): 103-117


    'See what you treat and treat what you see, at a molecular level', could be the motto of theranostics. The concept implies diagnosis (imaging) and treatment of cells (usually cancer) using the same molecule, thus guaranteeing a targeted cytotoxic approach of the imaged tumor cells while sparing healthy tissues. As the brilliant late Sam Gambhir would say, the imaging agent acts like a 'molecular spy' and reveals where the tumoral cells are located and the extent of disease burden (diagnosis). For treatment, the same 'molecular spy' docks to the same tumor cells, this time delivering cytotoxic doses of radiation (treatment). This duality represents the concept of a 'theranostic pair', which follows the scope and fundamental principles of targeted precision and personalized medicine. Although the term theranostic was noted in medical literature in the early 2000s, the principle is not at all new to nuclear medicine. The first example of theranostic dates back to 1941 when Dr. Saul Hertz first applied radioiodine for radionuclide treatment of thyroid cells in patients with hyperthyroidism. Ever since, theranostics has been an integral element of nuclear medicine and molecular imaging. The more we understand tumor biology and molecular pathology of carcinogenesis, including specific mutations and receptor expression profiles, the more specific these 'molecular spies' can be developed for diagnostic molecular imaging and subsequent radionuclide targeted therapy (radiotheranostics). The appropriate selection of the diagnostic and therapeutic radionuclide for the 'theranostic pair' is critical and takes into account not only the type of cytotoxic radiation emission, but also the linear energy transfer (LET), and the physical half-lives. Advances in radiochemistry and radiopharmacy with new radiolabeling techniques and chelators are revolutionizing the field. The landscape of cytotoxic systemic radionuclide treatments has dramatically expanded through the past decades thanks to all these advancements. This article discusses present and promising future theranostic applications for various types of diseases such as thyroid disorders, neuroendocrine tumors (NET), pediatric malignancies, and prostate cancer (PC), and provides an outlook for future perspectives.

    View details for DOI 10.7150/ntno.64141

    View details for PubMedID 34976584

  • Multi-tracer PET Imaging Using Deep Learning: Applications in Patients with High-Grade Gliomas Wardak, M., Hooper, S. M., Schiepers, C., Chen, W., Aparici, C., Davidzon, G. A., Vermesh, O., Cloughesy, T. F., Huang, S., Gambhir, S., Rekik, Adeli, E., Park, S. H., Cintas, C. SPRINGER INTERNATIONAL PUBLISHING AG. 2022: 24-35
  • Combined Quantification of 18F-FDG and 68Ga-DOTATATE PET/CT for Prognosis in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms. Academic radiology Lee, H., Nakamoto, R., Moore, S. E., Pantel, A. R., Eads, J. R., Aparici, C. M., Pryma, D. A. 2021


    RATIONALE AND OBJECTIVES: High-grade gastroenteropancreatic neuroendocrine neoplasms (G3 GEP-NENs) are pathologically classified into well differentiated neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (G3 NECs). Using a novel parameter, we examined the prognostic value of 18F-FDG and 68Ga-DOTATATE PET/CT quantification in comparison to pathologic assessment in G3 GEP-NENs.MATERIALS AND METHODS: A total of 31 patients with G3 GEP-NENs were reviewed. For each patient, the SUVmax on 18F-FDG and 68Ga-DOTATATE PET/CT were used to calculate the FDG-DOTATATE-Z (FDZ) score: a continuous parameter that increases with 68Ga-DOTATATE uptake and decreases with 18F-FDG uptake. The variation in the FDZ score with respect to pathologic variables was examined. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of FDZ score on overall survival. An external cohort of 21 patients was used for validation.RESULTS: The FDZ score was significantly higher in G3 NETs compared to G3 NECs (p<0.001), and was inversely correlated with Ki67 index (R2=0.33, p<0.001). Patients in the FDZ>0.05 group showed significantly longer survival compared to those in the FDZ≤0.05 group, with median of 34.9 vs. 12.0 months (p<0.001). On univariate regression, FDZ>0.05 (p=0.005), well differentiated disease (p=0.044), and lower Ki67 index (p=0.042) were predictors of survival. On multivariate regression, only FDZ>0.05 could independently predict longer survival with HR=0.16 (p=0.018), which was reproduced in the external validation cohort.CONCLUSION: Combined quantification of 18F-FDG and 68Ga-DOTATATE PET/CT into a novel parameter, the FDZ score, reflects the pathologic characteristics of G3 GEP-NENs and is a prognostic indicator of overall survival independent of differentiation.

    View details for DOI 10.1016/j.acra.2021.10.004

    View details for PubMedID 34836776

  • 68Ga-PSMA11 PET/CT for biochemically recurrent prostate cancer: Influence of dual-time and PMT- vs SiPM-based detectors. Translational oncology Duan, H., Baratto, L., Hatami, N., Liang, T., Mari Aparici, C., Davidzon, G. A., Iagaru, A. 2021; 15 (1): 101293


    OBJECTIVES: 68Ga-PSMA11 PET/CT is excellent for evaluating biochemically recurrent prostate cancer (BCR PC). Here, we compared the positivity rates of dual-time point imaging using a PET/CT scanner (DMI) with silicon photomultiplier (SiPM) detectors and a PET/CT scanner (D690) with photomultiplier tubes (PMT), in patients with BCR PC.METHODS: Fifty-eight patients were prospectively recruited and randomized to receive scans on DMI followed by D690 or vice-versa. Images from DMI were reconstructed using the block sequential regularized expectation maximization (BSREM) algorithm and images from D690 were reconstructed using ordered subset expectation maximization (OSEM), according to the vendor's recommendations. Two readers independently reviewed all images in randomized order, recorded the number and location of lesions, as well as standardized uptake value (SUV) measurements.RESULTS: Twenty-eight patients (group A) had DMI as first scanner followed by D690, while 30 patients (group B) underwent scans in reversed order. Mean PSA was 30±112.9 (range 0.3-600.66)ng/mL for group A and 41.5±213.2 (range 0.21-1170) ng/mL for group B (P=0.796). The positivity rate in group A was 78.6% (22/28 patients) vs. 73.3% (22/30 patients) in group B. Although the performance of the two scanners was equivalent on a per-patient basis, DMI identified 5 additional sites of suspected recurrent disease when used as first scanner. The second scan time point did not reveal additional abnormal uptake.CONCLUSIONS: The delayed time point in 68Ga-PSMA11 PET/CT did not show a higher positivity rate. SiPM-based PET/CT identified additional lesions. Further studies with larger cohorts are needed to confirm these results.

    View details for DOI 10.1016/j.tranon.2021.101293

    View details for PubMedID 34823095

  • A Pilot Study of 68Ga-PSMA11 and 68Ga-RM2 PET/MRI for Biopsy Guidance in Patients with Suspected Prostate Cancer Duan, H., Ferri, V., Ghanouni, P., Daniel, B., Hatami, N., Davidzon, G. A., Aparici, C., Thong, A., Sonn, G. A., Iagaru, A. SPRINGER. 2021: S204
  • A Pilot Study of Ga-68-PSMA11 and Ga-68-RM2 PET/MRI for Evaluation of Prostate Cancer Response to High Intensity Focused Ultrasound (HIFU) Therapy Duan, H., Ghanouni, P., Hatami, N., Davidzon, G. A., Aparici, C., Thong, A., Sonn, G. A., Iagaru, A. SPRINGER. 2021: S205-S206
  • COMPETE Phase III Trial - Peptide Receptor Radionuclide Therapy (PRRT) with Lu-177-Edotreotide vs. Everolimus in Progressive GEP-NET. Wahba, M. M., Strosberg, J., Avram, A., Aparici, C. AMER ASSOC CANCER RESEARCH. 2021
  • Results of a Prospective Trial to Compare 68Ga-DOTA-TATE with SiPM-Based PET/CT vs. Conventional PET/CT in Patients with Neuroendocrine Tumors. Diagnostics (Basel, Switzerland) Baratto, L., Toriihara, A., Hatami, N., Aparici, C. M., Davidzon, G., Levin, C. S., Iagaru, A. 2021; 11 (6)


    We prospectively enrolled patients with neuroendocrine tumors (NETs). They underwent a single 68Ga-DOTA-TATE injection followed by dual imaging and were randomly scanned using first either the conventional or the silicon photomultiplier (SiPM) positron emission tomography/computed tomography (PET/CT), followed by imaging using the other system. A total of 94 patients, 44 men and 50 women, between 35 and 91 years old (mean ± SD: 63 ± 11.2), were enrolled. Fifty-two out of ninety-four participants underwent SiPM PET/CT first and a total of 162 lesions were detected using both scanners. Forty-two out of ninety-four participants underwent conventional PET/CT first and a total of 108 lesions were detected using both scanners. Regardless of whether SiPM-based PET/CT was used first or second, maximum standardized uptake value (SUVmax) of lesions measured on SiPM was on average 20% higher when comparing two scanners with all enrolled patients, and the difference was statistically significant. SiPM-based PET/CT detected 19 more lesions in 13 patients compared with conventional PET/CT. No lesions were only identified by conventional PET/CT. In conclusion, we observed higher SUVmax for lesions measured from SiPM PET/CT compared with conventional PET/CT regardless of the order of the scans. SiPM PET/CT allowed for identification of more lesions than conventional PET/CT. While delayed imaging can lead to higher SUVmax in cancer lesions, in the series of lesions identified when SiPM PET/CT was used first, this was not the case; therefore, the data suggest superior performance of the SiPM PET/CT scanner in visualizing and quantifying lesions.

    View details for DOI 10.3390/diagnostics11060992

    View details for PubMedID 34070751

  • A Pilot Study of68Ga-PSMA11 PET/MRI and68GaRM2 PET/MRI for Biopsy Guidance in Patients with Suspected Prostate Cancer Duan, H., Ferri, V., Ghanouni, P., Daniel, B., Hatami, N., Davidzon, G., Aparici, C., Moradi, F., Thong, A., Sonn, G., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2021
  • 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
  • High-specific-activity 131I-MIBG vs 177Lu-DOTATATE targeted radionuclide therapy for metastatic pheochromocytoma and paraganglioma. Clinical cancer research : an official journal of the American Association for Cancer Research Jha, A., Taieb, D., Carrasquillo, J. A., Pryma, D. A., Patel, M., Millo, C., de Herder, W. W., Del Rivero, J., Crona, J., Shulkin, B. L., Virgolini, I., Chen, A. P., Mittal, B. R., Basu, S., Dillon, J. S., Hope, T. A., Mari Aparici, C., Iagaru, A., Hicks, R. J., Avram, A. M., Strosberg, J. R., Civelek, A. C., Lin, F. I., Pandit-Taskar, N., Pacak, K. 2021


    Targeted radionuclide therapies using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic or inoperable pheochromocytoma and/or paraganglioma (PPGL). Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of metastatic PPGL. However, a clinical dilemma often arises in the selection of targeted radionuclide therapy, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatostatin receptor imaging. In order to address this problem, we assembled a group of international experts including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with targeted radionuclide therapies in order to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic PPGL. This manuscript aims to summarize the survival outcomes of the available targeted radionuclide therapies, discuss personalized treatment strategies based on functional imaging scans, address practical issues including regulatory approvals, and compare toxicities and risk factors across treatments. Further, it discusses the emerging targeted radionuclide therapies.

    View details for DOI 10.1158/1078-0432.CCR-20-3703

    View details for PubMedID 33685867

  • Renal and Hepatotoxicity of Peptide Receptor Radionuclide Therapy (PRRT) - A Single Institution Experience Duan, H., Ferri, V., Kunz, P., Davidzon, G., Nguyen, J., Moradi, F., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456-457
  • Single Institution Experience With Peptide Receptor Radionuclide Therapy (PRRT) in Neuroendocrine Tumors (NET) Duan, H., Ferri, V., Kunz, P., Davidzon, G., Nguyen, J., Moradi, F., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456
  • Renal and Hepatotoxicity of Peptide Receptor Radionuclide Therapy (PRRT) - A Single Institution Experience Duan, H., Ferri, V., Kunz, P., Davidzon, G., Nguyen, J., Moradi, F., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456-457
  • Hematotoxicity of Peptide Receptor Radionuclide Therapy (PRRT) - A Single Institution Experience Duan, H., Ferri, V., Kunz, P., Davidzon, G., Moradi, F., Nguyen, J., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456
  • Hematotoxicity of Peptide Receptor Radionuclide Therapy (PRRT) - A Single Institution Experience Duan, H., Ferri, V., Kunz, P., Davidzon, G., Moradi, F., Nguyen, J., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456
  • Single Institution Experience With Peptide Receptor Radionuclide Therapy (PRRT) in Neuroendocrine Tumors (NET) Duan, H., Ferri, V., Kunz, P., Davidzon, G., Nguyen, J., Moradi, F., Franc, B., Iagaru, A., Aparici, C. LIPPINCOTT WILLIAMS & WILKINS. 2021: 456
  • Diagnostic Performance of 18F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase 3, Multicenter Study. Clinical cancer research : an official journal of the American Association for Cancer Research Morris, M. J., Rowe, S. P., Gorin, M. A., Saperstein, L., Pouliot, F., Josephson, D. Y., Wong, J. Y., Pantel, A. R., Cho, S. Y., Gage, K. L., Piert, M. R., Iagaru, A., Pollard, J. H., Wong, V., Jensen, J., Lin, T., Stambler, N., Carroll, P., Siegel, B. A., Wibmer, A. G., Durack, J. C., Solomon, S. B., Harb, R., Pucar, D., Sprenkle, P., Beauregard, J., Beaulieu, A., Buteau, F., Yamauchi, D., Glaser, S., Dorff, T. B., Narayan, V., Fillare, M. A., Schubert, E., Cooley, G., Morris, Z. S., Langeland, M., Pow-Sang, J. M., Yamoah, K., Alva, A. S., Reichert, Z., Spratt, D., Davidzon, G., Mari Aparici, C., Moradi, F., Tracy, C., Behr, S., Nguyen, H. G., Simko, J. P., Jennings, J. W., Michalski, J. M., Pachynski, R. K. 2021


    PURPOSE: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). 18F-DCFPyL is a highly selective, small-molecule PSMA-targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of 18F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.METHODS: Men with rising PSA {greater than or equal to}0.2 ng/mL after prostatectomy or {greater than or equal to}2 ng/mL above nadir after radiation therapy were eligible. The primary endpoint was correct localization rate (CLR) defined as positive predictive value with an additional requirement of anatomic lesion co-localization between 18F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority: 1) histopathology, 2) subsequent correlative imaging findings, or 3) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval for CLR exceeded 20% for 2 of 3 18F‑DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.RESULTS: 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2-98.4 ng/mL) underwent 18F-DCFPyL-PET/CT. The CLR was 84.8%-87.0% (lower bound of 95% CI: 77.8%-80.4%). 63.9% of evaluable patients had a change in intended management after 18F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by 18F-DCFPyL-PET/CT by central readers).CONCLUSION: Performance of 18F-DCFPyL-PET/CT achieved the study's primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of 18F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer.

    View details for DOI 10.1158/1078-0432.CCR-20-4573

    View details for PubMedID 33622706

  • 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


    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


    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

  • Sigma-1 Receptor Changes Observed in Chronic Pelvic Pain Patients: A Pilot PET/MRI Study. Frontiers in pain research (Lausanne, Switzerland) Yoon, D., Fast, A. M., Cipriano, P., Shen, B., Castillo, J. B., McCurdy, C. R., Mari Aparici, C., Lum, D., Biswal, S. 2021; 2: 711748


    Introduction: Chronic pelvic pain is a highly prevalent pain condition among women, but identifying the exact cause of pelvic pain remains a significant diagnostic challenge. In this study, we explored a new diagnostic approach with PET/MRI of the sigma-1 receptor, a chaperone protein modulating ion channels for activating nociceptive processes. Methods: Our approach is implemented by a simultaneous PET/MRI scan with a novel radioligand [18F]FTC-146, which is highly specific to the sigma-1 receptor. We recruited 5 chronic pelvic pain patients and 5 healthy volunteers and compared our PET/MRI findings between these two groups. Results: All five patients showed abnormally increased radioligand uptake on PET compared to healthy controls at various organs, including the uterus, vagina, pelvic bowel, gluteus maximus muscle, and liver. However, on MRI, only 2 patients showed abnormalities that could be potentially associated with the pain symptoms. For a subset of patients, the association of pain and the abnormally increased radioligand uptake was further validated by successful pain relief outcomes following surgery or trigger point injections to the identified abnormalities. Conclusion: In this preliminary study, sigma-1 receptor PET/MRI demonstrated potential for identifying abnormalities associated with chronic pelvic pain. Future studies will need to correlate samples with imaging findings to further validate the correlation between S1R distribution and pathologies of chronic pelvic pain. Trial Registration: The clinical trial registration date is June 2, 2018, and the registration number of the study is NCT03195270 (

    View details for DOI 10.3389/fpain.2021.711748

    View details for PubMedID 35295458

  • Neurovascular, muscle, and skin changes on [18F]FDG PET/MRI in complex regional pain syndrome of the foot: A Prospective Clinical Study. Pain medicine (Malden, Mass.) Yoon, D., Xu, Y., Cipriano, P. W., Alam, I. S., Mari Aparici, C. A., Tawfik, V. L., Curtin, C. M., Carroll, I. R., Biswal, S. 2021


    The goal of this study is to demonstrate the feasibility of simultaneous [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) for non-invasive visualization of muscular, neurovascular, and skin changes secondary to complex regional pain syndrome (CRPS).Seven adult patients with CRPS of the foot and seven healthy adult controls participated in our [18F]FDG PET/MRI study.All participants received whole-body PET/MRI scans one hour after the injection of 370MBq [18F]FDG. Resulting PET/MRI images were reviewed by two radiologists. Metabolic and anatomic abnormalities identified, were grouped into muscular, neurovascular, and skin lesions. The [18F]FDG uptake of each lesion was compared with that of corresponding areas in controls using a Mann-Whitney U-test.On PET images, muscular abnormalities were found in five patients, neurovascular abnormalities in four patients, and skin abnormalities in two patients. However, on MRI images, no muscular abnormalities were detected. Neurovascular abnormalities and skin abnormalities in the affected limb were identified on MRI in one and two patients, respectively. The difference in [18F]FDG uptake between the patients and the controls was significant in muscle (p = 0.018) and neurovascular bundle (p = 0.0005).The increased uptake of [18F]FDG in the symptomatic areas likely reflects the increased metabolism due to the inflammatory response causing pain. Therefore, our approach combining metabolic [18F]FDG PET and anatomic MR imaging may offer non-invasive monitoring of the distribution and progression of inflammatory changes associated with CRPS.

    View details for DOI 10.1093/pm/pnab315

    View details for PubMedID 34718774

  • Pulmonary large cell neuroendocrine carcinoma (LCNEC) with confirmed liver metastases negative on 18F-FDG and 68Ga-DOTATATE PET. Radiology case reports Ninatti, G., Duan, H., Ferri, V., Martin, B. A., Aparici, C. M. 2020; 15 (12): 2698–2700


    Lung neuroendocrine neoplasms (NENs) encompass the low-, intermediate-, and high-grade entities. Differentiated NENs overexpress somatostatin receptors, which are targeted by 68Ga-DOTA-conjugated peptides in molecular imaging with positron emission tomography. Less differentiated NENs may have lost their expression of somatostatin receptors and thus show lower uptake of 68Ga-DOTA-peptides; however, these tumors express GLUT-1 and can be imaged with (18)F-fluordeoxyglucose (FDG). We report the case of a 72-year-old patient with a poorly differentiated, high grade lung NEN, which was 18F-FDG-positive at initial diagnosis. After treatment and remission, the patient had histologically confirmed relapse in the liver. Interestingly, these hepatic metastases did not demonstrated radiopharmaceutical uptake at neither 18F-FDG nor 68Ga-DOTATATE positron emission tomography/computed tomography.

    View details for DOI 10.1016/j.radcr.2020.10.023

    View details for PubMedID 33117470

  • 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

  • Imaging Characteristics and Diagnostic Performance of 2-deoxy-2-[18F]fluoro-D-Glucose PET/CT for Melanoma Patients Who Demonstrate Hyperprogressive Disease When Treated with Immunotherapy. Molecular imaging and biology Nakamoto, R., C Zaba, L., Rosenberg, J., Arani Reddy, S., W Nobashi, T., Ferri, V., Davidzon, G., Mari Aparici, C., Nguyen, J., Moradi, F., Iagaru, A., Lewis Franc, B. 2020


    PURPOSE: We investigated the ability of baseline 2-deoxy-2-[18F]fluoro-D-glucose PET/CT parameters, acquired before the start of immunotherapy, to predict development of hyperprogressive disease (HPD) in melanoma patients. We also evaluated the diagnostic performances of ratios of baseline and first restaging PET/CT parameters to diagnose HPD without information of the tumor growth kinetic ratio (TGKR) that requires pre-baseline imaging before baseline imaging (3 timepoint imaging).PROCEDURES: Seventy-six patients who underwent PET/CT before and approximately 3months following initiation of immunotherapy were included. PET/CT parameters, including metabolic tumor volume (MTV) for all melanoma lesions and total measured tumor burden (TMTB) based on irRECIST, were measured from baseline PET/CT (MTVbase and TMTBbase) and first restaging PET/CT (MTVpost and TMTBpost). The ratios of MTV (MTVpost/MTVbase, MTVr) and TMTB (TMTBpost/TMTBbase, TMTBr) were calculated.RESULTS: MTVbase of HPD patients (n=9, TGKR ≥2) was larger than that of non-HPD (n=67, TGKR <2) patients (P<0.05), and HPD patients demonstrated shorter median overall survival (7 vs. more than 60months, P<0.05). The area under the curve (AUC) of MTVbase (≥155.5ml) to predict the risk of HPD was 0.703, with a sensitivity of 66.7% and specificity of 81.2%. The AUCs of MTVr (≥1.25) and TMTBr (≥1.27) to diagnose HPD without information of TGKR were 0.875 and 0.977 with both sensitivities of 100%, and specificities of 79% and 83.9%, respectively.CONCLUSIONS: Patients at high risk of developing HPD could not be accurately identified based on baseline PET/CT parameters. The ratios of baseline and first restaging PET/CT parameters may be helpful to diagnose HPD, when patients do not undergo pre-baseline imaging.

    View details for DOI 10.1007/s11307-020-01526-4

    View details for PubMedID 32789649

  • Evaluation of Toxicity in Peptide Receptor Radionuclide Therapy (PRRT) for Neuroendocrine Tumors (NET) Duan, H., Girod, B., Ninatti, G., Ferri, Kunz, P., Fisher, G., Moradi, F., Davidzon, G., Franc, B., Lagaru, A., Aparici, M. C. KARGER. 2020: 252
  • Extrahepatic 68Ga-DOTATATE-Avid Tumor Volume and Serum Chromogranin A Predict Short-Term Outcome of 177Lu-DOTATATE in Late-Stage Metastatic Gastroenteropancreatic Neuroendocrine Tumors Song, H., Kunz, P., Franc, B., Moradi, F., Fisher, G., Aparici, M. C., Lagaru, A., Davidzon, G. KARGER. 2020: 274
  • 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


    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
  • 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

  • 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


    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

  • 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


    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

  • 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


    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

  • Evaluating the Role of Theranostics in Grade 3 Neuroendocrine Neoplasms JOURNAL OF NUCLEAR MEDICINE Waseem, N., Aparici, C., Kunz, P. L. 2019; 60 (7): 882–91
  • 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
  • Comparison of three interpretation criteria of Ga-68-PS A PET based on in er and intra-reader agreement Toriihara, A., Nobashi, T., Baratto, L., Park, S., Hatami, N., Duan, H., Aparici, C., Davidzon, G., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019
  • Preliminary Results of a Prospective Study of Ga-68-RM2 PET/MRI for Detection of Recurrent Prostate Cancer in Patients with Negative Conventional Imaging Baratto, L., Duan, H., Harrison, C., Hatami, N., Aparici, C., Davidzon, G., Yohannan, T., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019
  • 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
  • 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
  • Quantification of uptake in Ga-68-DOTATATE PET: Correlation between standardized uptake values and patient factors Moradi, F., Guja, K., Aparici, C., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2019
  • State of the Art: Evaluating the Role of Theranostics in G3 Neuroendocrine Neoplasms. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Waseem, N. L., Aparici, C. M., Kunz, P. L. 2019


    The diagnosis and subsequent therapy of neuroendocrine neoplasms (NENs) have long-relied on somatostatin receptor (SSTR) expression. The field of theranostics now uses newer SSTR based Positron Emission Tomography (SSTR-PET) imaging with 68Ga-DOTA0-Tyr3-Octreotate (68Ga-DOTATATE) or 68Ga-DOTA0-Tyr3-Octreotide (68Ga-DOTATOC), as a prerequisite for the administration of peptide receptor radionuclide therapy (PRRT). In the US, 177Lu-Dotatate, a form of PRRT, gained FDA approval in 2018 for use in gastroenteropancreatic NENs and was based on prolonged progression-free survival (PFS) vs. high dose Octreotide LAR in a phase III clinical trial of well-differentiated midgut NENs. Well-differentiated, grade 1 and grade 2 NENs have a low proliferation index (Ki-67 < 20%) and longer overall survival > 10 years while higher grade (grade 3) NENs have a high Ki-67 > 20% and shorter overall survival < 1 year. Here, we present a review on the newest histologic classification of NENs and the role of both SSTR-based imaging and PRRT in grade 3 (G3) NENs. Some studies suggest that G3 disease is less likely to be positive on SSTR-based imaging (but more likely in FDG PET) as compared to low grade disease, but these data are limited. Additionally, we found only eleven studies mentioning the use of PRRT in G3 NENs and a total of only forty-nine patients across these studies in which radiologic response was measured. Out of these forty-nine patients, twenty-seven (55%) demonstrated at least stable disease or a partial response, indicating that some G3 NENs can be responsive to PRRT. We suggest that patients with G3 NENs should receive both 18F-FDG PET and SSTR-based imaging to aide in both diagnosis and treatment selection. However, prospective studies are needed to understand the role of PRRT in G3 NENs, especially in well- versus poorly-differentiated G3 disease.

    View details for PubMedID 30850504

  • Comparison of three interpretation criteria of 68Ga-PSMA11 PET based on inter- and intra-reader agreement. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Toriihara, A. n., Nobashi, T. n., Baratto, L. n., Duan, H. n., Moradi, F. n., Park, S. n., Hatami, N. n., Aparici, C. n., Davidzon, G. n., Iagaru, A. n. 2019


    Positron emission tomography (PET) using radiolabeled prostate specific membrane antigen (PSMA) is now more and more widely adopted as a valuable tool to evaluate patients with prostate cancer (PC). Recently, three different criteria for interpretation of PSMA PET were published: European Association of Nuclear Medicine (EANM) criteria, prostate cancer molecular imaging standardized evaluation (PROMISE) criteria, and PSMA-reporting and data system (PSMA-RADS). We compared these three criteria in terms of inter-reader, intra-reader, and inter-criteria agreement. Methods: Data from 104 patients prospectively enrolled in research protocols at our institution were retrospectively reviewed. The cohort consisted of two groups: 47 patients (mean age: 64.2 years old) who underwent Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA11) PET/magnetic resonance imaging (MRI) for initial staging of biopsy-proven intermediate- or high-risk PC, and 57 patients (mean age: 70.5 years old) who underwent 68Ga-PSMA11 PET/computed tomography (CT) due to biochemically recurrent (BCR) PC. Three nuclear medicine physicians independently evaluated all 68Ga-PSMA11 PET/MRI and PET/CT studies according to the three interpretation criteria. Two of them reevaluated all studies 6 months later in the same manner and blinded to the initial reading. Gwet's AC was calculated to evaluate inter- and intra-reader, and inter-criteria agreement based on the following sites: local lesion (primary tumor or prostate bed after radical prostatectomy), lymph node metastases, and other metastases. Results: In the PET/MRI group, inter-reader, intra-reader, and inter-criteria agreements were substantial to almost perfect in any sites according to all of the three criteria. In the PET/CT group, inter-reader agreement was substantial to almost perfect except judgement of distant metastases based on PSMA-RADS (Gwet's AC = 0.57, moderate agreement), in which the most frequent cause of disagreement was lung nodules. Intra-reader agreements were substantial to almost perfect in any sites according to all of the three criteria. Inter-criteria agreements of each site were also substantial to almost perfect. Conclusion: Although the three published criteria have good inter-reader and intra-reader reproducibility in evaluating 68Ga-PSMA11 PET, there are factors bringing inter-reader disagreement. This indicates that further work is needed to address the issue.

    View details for DOI 10.2967/jnumed.119.232504

    View details for PubMedID 31562226

  • Correction: shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients. Molecular pain Tzabazis, A., Aparici, C. M., Rowbotham, M. C., Schneider, M. B., Etkin, A., Yeomans, D. C. 2014; 10: 16-?

    View details for DOI 10.1186/1744-8069-10-16

    View details for PubMedID 24594349

    View details for PubMedCentralID PMC3942267

  • Correction: Shaped Magnetic Field Pulses by Multi-Coil Repetitive Transcranial Magnetic Stimulation (rTMS) Differentially Modulate Anterior Cingulate Cortex Responses and Pain in Volunteers and Fibromyalgia Patients. Molecular pain Tzabazis, A., Aparici, C. M., Rowbotham, M. C., Schneider, M. B., Etkin, A., Yeomans, D. C. 2014; 10: 174480691016

    View details for DOI 10.1186/1744-8069-10-16

    View details for PubMedID 30110879

    View details for PubMedCentralID PMC3942267

  • Shaped magnetic field pulses by multi-coil repetitive transcranial magnetic stimulation (rTMS) differentially modulate anterior cingulate cortex responses and pain in volunteers and fibromyalgia patients MOLECULAR PAIN Tzabazis, A., Aparici, C. M., Rowbotham, M. C., Schneider, M. B., Etkin, A., Yeomans, D. C. 2013; 9


    Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients.Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H215O positron emission tomography -- computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRSTMS-NRSplacebo) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded.A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session.Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.

    View details for DOI 10.1186/1744-8069-9-33

    View details for Web of Science ID 000323054600001

  • Steerable Electrical Currents using Multi-coil rTMS: Clinical Effects of Modifying Current Direction Schneider, M., Yang, S., Aparici, C., VanBrocklin, H., Seo, Y., Etkin, A., Patrick, K., Yeomans, D. C. ELSEVIER SCIENCE INC. 2012: 282S
  • Pattern of 18F-FDG Uptake in the Spinal Cord in Patients With Non-Central Nervous System Malignancy SPINE Do, B. H., Mari, C., Tseng, J. R., Quon, A., Rosenberg, J., Biswal, S. 2011; 36 (21): E1395-E1401


    Retrospective review.To (1) propose a standard method to quantitate 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake in the spinal cord and (2) use this methodology to retrospectively characterize the pattern of uptake within the entire spinal cord using whole-body positron emission tomography/computed tomography (PET/CT) imaging.A physiologic understanding of glucose metabolism within the spinal cord may provide insight regarding infectious, inflammatory, vascular, and neoplastic spinal cord diseases.Institutional review board approval was obtained. A total of 131 consecutive whole-body PET/CT studies from July to August 2004 were reviewed, and using exclusionary criteria of: (1) severe spinal arthropathy or curvature, (2) motion artifact, (3) canal hardware, (4) spinal tumor, and (5) marrow hyperplasia, 92 studies of neurologically intact patients (49 men and 43 women) were selected for a retrospective review of spinal cord 18F-FDG activity. The transaxial CT was used to define the canal and circular regions of interests were placed within the canal at the level of the vertebral body midpoint from C1 to L3. Region of interest total count, area, and maximum standardized uptake value (SUVmax) were recorded. Measurements at L5 served as an internal control. For comparative analysis, the cord-to-background (CTB) ratio was defined as spinal cord SUVmax to L5 SUVmax.Mean CTB decreased along each spinal level from cranial to caudal (P < 0.001). Significant relative increases were observed at the T11-T12 vertebral body levels (P < 0.001). Although insignificant, a relative increase was observed at C4. No significant interactions of age or sex on CTB were observed.The pattern of 18F-FDG uptake within the spinal cord, observed in patients with non-central nervous system malignancy, may be helpful in understanding glucose physiology of spinal cord diseases and warrants further research.

    View details for DOI 10.1097/BRS.0b013e31820a7df8

    View details for Web of Science ID 000295318000005

    View details for PubMedID 21311407

  • F-18-FDG-PET/CT evaluation of response to treatment in lymphoma: when is the optimal time for the first re-evaluation scan? HELLENIC JOURNAL OF NUCLEAR MEDICINE Iagaru, A., Wang, Y., Mari, C., Quon, A., Goris, M. L., Horning, S., Gambhir, S. S. 2008; 11 (3): 153-156


    Assessing the response to treatment as soon after treatment initiation is one of the key reasons for imaging lymphoma patients. The optimal time after initiating treatment for assessing response to treatment has yet to be determined. Therefore, we were prompted to review our experience with serial (18)F-FDG PET/CT in patients undergoing treatment for Hodgkin's disease (HD) and non Hodgkin's lymphoma (NHL). This is a retrospective study (Feb 2003 - Oct 2004) of 20 patients, 11 men and 9 women, with age range of 7-75 years with diagnosis of HD (10) and NHL (10), who had PET/CT at our institution prior, during and at the completion of therapy. Restaging PET/CT was done after 2 cycles of chemotherapy in 10 patients (group A) and after 4 cycles of chemotherapy in 10 pts (group B). A total of 60 scans were reviewed. The DeltaSUV from baseline to first PET/CT was on average 67.6% in group A and 75.1% in group B. This had no statistical significance (P value: 0.31). The DeltaSUV from baseline to post-therapy PET/CT was on average 72.9% in group A and 79.8% in group B. This difference also had no statistical significance (P value: 0.24). The correlation coefficient was 0.98 in group A and 0.80 in group B. Results of PET/CT after 2 cycles of chemotherapy did not statistically differ from the results of PET/CT after 4 cycles of chemotherapy. These results need to be confirmed in larger, prospective, randomized trials.

    View details for Web of Science ID 000262093600003

    View details for PubMedID 19081857

  • [Introduction to the molecular imaging]. Revista espanola de medicina nuclear Mari Aparici, C. 2006; 25 (6): 394-409

    View details for PubMedID 17173791

  • F-18FDG PET evaluation of bronchial plasmacytoma with CT and MRI correlation CLINICAL NUCLEAR MEDICINE Iagaru, A., Mari, C., Segall, G. 2006; 31 (5): 279-280

    View details for PubMedID 16622337

  • 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


    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

  • Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover TISSUE ENGINEERING Cowan, C. M., Aalami, O. O., Shi, Y. Y., Chou, Y. F., Mari, C., Thomas, R., Quarto, N., Nacamuli, R. P., Contag, C. H., Wu, B., Longaker, M. T. 2005; 11 (3-4): 645-658


    Reconstruction of craniofacial defects presents a substantial biomedical burden, and requires complex surgery. Interestingly, children after age 2 years and adults are unable to heal large skull defects. This nonhealing paradigm provides an excellent model system for craniofacial skeletal tissueengineering strategies. Previous studies have documented the in vivo osteogenic potential of adipose-derived stromal (ADS) cells and bone marrow-derived stromal (BMS) cells. This study investigates the ability to accelerate in vivo osteogenesis on ex vivo recombinant human bone morphogenetic protein 2 (BMP-2) and retinoic acid stimulation. Mouse osteoblasts, ADS cells, and BMS cells were seeded onto apatite-coated PLGA scaffolds, stimulated with rhBMP-2 and retinoic acid ex vivo for 4 weeks, and subsequently implanted into critically sized (4 mm) calvarial defects. Samples were harvested after 2, 4, 8, and 12 weeks. Areas of complete bony bridging were noted as early as 2 weeks in vivo; however, osteoclasts were attracted to the scaffold as identified by calcitonin receptor staining and tartrate-resistant acid phosphatase activity staining. Although the optimal method of in vitro osteogenic priming for mesenchymal cells remains unknown, these results provide evidence that BMP-2 and retinoic acid stimulation of multipotent cells ex vivo can subsequently induce significant quantities of bone formation within a short time period in vivo.

    View details for PubMedID 15869441

  • Tumor imaging using a standardized radiolabeled adapter protein docked to vascular endothelial growth factor JOURNAL OF NUCLEAR MEDICINE Blankenberg, F. G., Mandl, S., Cao, Y. A., O'Connell-Rodwell, C., Contag, C., Mari, C., Gaynutdinov, T. I., Vanderheyden, J. L., Backer, M. V., Backer, J. M. 2004; 45 (8): 1373-1380


    Direct radiolabeling of proteins can result in the loss of targeting activity, requires highly customized procedures, and yields heterogeneous products. Here we describe a novel imaging complex comprised of a standardized (99m)Tc-radiolabeled adapter protein noncovalently bound to a "Docking tag" fused to a "Targeting protein". The assembly of this complex is based on interactions between human 109-amino acid (HuS) and 15-amino acid (Hu-tag) fragments of ribonuclease I, which serve as an "Adapter protein" and a Docking tag, respectively.HuS modified with hydrazinonicotinamide (HYNIC) was radiolabeled using (99m)Tc-tricine to a specific activity of 3.4-7.4 MBq/microg. Protein complexes were then formed by mixing (99m)Tc-HuS with equimolar amounts of either Hu-tagged VEGF(121) (Hu-VEGF [vascular endothelial growth factor]) or Hu-tagged anti-VEGFR-2 single-chain antibody (Hu-P4G7) and incubating on ice for 15 min. 4T1 luc/gfp luciferase-expressing murine mammary adenocarcinoma cells (1 x 10(4)) were implanted subcutaneously or injected intravenously into BALB/c mice. Bioluminescent imaging (BLI) was performed 10 d later. Immediately after BLI visualization of tumor, 18.5-37 MBq of tracer (5-10 microg of protein) were injected via tail vein. One hour later planar or SPECT images were obtained, followed by killing the mice.There was significantly (P = 0.0128) increased uptake of (99m)Tc-HuS/Hu-VEGF (n = 10) within subcutaneous tumor as compared with (99m)Tc-HuS/Hu-P4G7 (n = 5) at biodistribution assay (2.68 +/- 0.75 vs. 1.8 +/- 0.21; tumor-to-subcutaneous tissue [ratio of specific activities], respectively), despite similar molecular weights. The focal (99m)Tc-HuS/Hu-VEGF uptake seen on planar images (3.44 +/- 1.16 [tumor to soft-tissue background]) corresponded directly to the locations of tumor observed by BLI. Region of interest analyses of SPECT images revealed a significant increase of (99m)Tc-HuS/Hu-VEGF (n = 5) within the lungs with BLI-detectable pulmonary tumor nodules as compared with controls (n = 4) (right: 4.47 +/- 2.07 vs. 1.79 +/- 0.56; left: 3.66 +/- 1.65 vs. 1.62 +/- 0.45, tumor lung [counts/pixel]/normal lung [counts/pixel], respectively).(99m)Tc-HuS/Hu-VEGF complex is stable for at least 1 h in vivo and can be effectively used to image mouse tumor neovasculature in lesions as small as several millimeters in soft tissue. We expect that a similar approach can be adapted for in vivo delivery of other targeting proteins of interest without affecting their bioactivity.

    View details for PubMedID 15299064

  • 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


    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

  • Detection of focal hypoxic-ischemic injury and neuronal stress in a rodent model of unilateral MCA occlusion/reperfusion using radiolabeled annexin V EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Mari, C., Karabiyikoglu, M., Goris, M. L., Tait, J. F., Yenari, M. A., Blankenberg, F. G. 2004; 31 (5): 733-739


    In this study we wished to determine whether technetium-99m annexin V, an in vivo marker of cellular injury and death, could be used to noninvasively monitor neuronal injury following focal middle cerebral artery (MCA) occlusion/reperfusion injury. Sixteen adult male Sprague-Dawley rats (along with four controls) underwent left (unilateral) MCA intraluminal beaded thread occlusion for 2 h followed by reperfusion. One hour following tail vein injection of 5-10 mCi of (99m)Tc-annexin V, animals underwent either single-photon emission computerized tomography (SPECT) or autoradiography followed by immunohistochemical analyses. There was abnormal, bilateral, multifocal uptake of (99m)Tc-annexin V in each cerebral hemisphere as seen by both SPECT and autoradiography at 4 h and 1, 3, and 7 days after initiation of occlusion. The average maximal annexin V uptake at 4 h was 310%+/-85% and 365%+/-151% above control values (P<0.006) within the right and left hemispheres, respectively, peaking on day 3 with values of 925%+/-734% and 1,194%+/-643% (P<0.03) that decreased by day 7 to 489%+/-233% and 785%+/-225% (P<0.01). Total lesional volume of the left hemisphere was 226%, 261%, and 451% ( P<0.03) larger than the right at 4, 24, and 72 h after injury, respectively. Annexin V localized to the cytoplasm of injured neurons ipsilateral to the site of injury as well as to otherwise normal-appearing neurons of the contralateral hemisphere as confirmed by dual fluorescent microscopy. It is concluded that there is abnormal bilateral, multifocal annexin V uptake, greater on the left than on the right side, within 4 h of unilateral left MCA ischemic injury and that the uptake peaks at 3 days and decreases by 7 days after injury. This pattern suggests that neuronal stress may play a role in the response of the brain to focal injury and be responsible for annexin V uptake outside the region of ischemic insult.

    View details for DOI 10.1007/s00259-004-1473-5

    View details for PubMedID 14985868

  • Adipose-derived adult stromal cells heal critical-size mouse calvarial defects NATURE BIOTECHNOLOGY Cowan, C. M., Shi, Y. Y., Aalami, O. O., Chou, Y. F., Mari, C., Thomas, R., Quarto, N., Contag, C. H., Wu, B., Longaker, M. T. 2004; 22 (5): 560-567


    In adults and children over two years of age, large cranial defects do not reossify successfully, posing a substantial biomedical burden. The osteogenic potential of bone marrow stromal (BMS) cells has been documented. This study investigates the in vivo osteogenic capability of adipose-derived adult stromal (ADAS) cells, BMS cells, calvarial-derived osteoblasts and dura mater cells to heal critical-size mouse calvarial defects. Implanted, apatite-coated, PLGA scaffolds seeded with ADAS or BMS cells produced significant intramembranous bone formation by 2 weeks and areas of complete bony bridging by 12 weeks as shown by X-ray analysis, histology and live micromolecular imaging. The contribution of implanted cells to new bone formation was 84-99% by chromosomal detection. These data show that ADAS cells heal critical-size skeletal defects without genetic manipulation or the addition of exogenous growth factors.

    View details for DOI 10.1038/nbt958

    View details for PubMedID 15077117

  • Multi-modality imaging identifies key times for annexin V imaging as an early predictor of therapeutic outcome. Molecular imaging Mandl, S. J., Mari, C., Edinger, M., Negrin, R. S., Tait, J. F., Contag, C. H., Blankenberg, F. G. 2004; 3 (1): 1-8


    Radiolabeled annexin V may provide an early indication of the success or failure of anticancer therapy on a patient-by-patient basis as an in vivo marker of tumor cell killing. An important question that remains is when, after initiation of treatment, should annexin V imaging be performed. To address this issue, we obtained simultaneous in vivo measurements of tumor burden and uptake of radiolabeled annexin V in the syngeneic orthotopic murine BCL1 lymphoma model using in vivo bioluminescence imaging (BLI) and small animal single-photon emission computed tomography (SPECT). BCL1 cells labeled for fluorescence and bioluminescence assays (BCL1-gfp/luc) were injected into mice at a dose that leads to progressive disease within two to three weeks. Tumor response was followed by BLI and SPECT before and after treatment with a single dose of 10 mg/kg doxorubicin. Biodistribution analyses revealed a biphasic increase of annexin V uptake within the tumor-bearing tissues of mice. An early peak occurring before actual tumor cells loss was observed between 1 and 5 hr after treatment, and a second longer sustained rise from 9 to 24 hr after therapy, which heralds the onset of tumor cell loss as confirmed by BLI. Multimodality imaging revealed the temporal patterns of tumor cell loss and annexin V uptake revealing a better understanding of the timing of radiolabeled annexin V uptake for its development as a marker of therapeutic efficacy.

    View details for PubMedID 15142407

  • The use of (99m)Technetium-labeled MCP-1 to assess, graft coronary artery disease in rat cardiac allografts JOURNAL OF HEART AND LUNG TRANSPLANTATION Kown, M. H., Jahncke, C. L., Lijkwan, M. A., Koransky, M. L., Mari, C., Berry, G. J., Blankenberg, F. G., Strauss, H. W., Robbins, R. C. 2002; 21 (9): 1009-1015


    Monocyte chemoattractant protein-1 (MCP-1) is associated with the development of graft coronary artery disease (GCAD) following cardiac transplantation. This study assessed whether technetium 99m ((99m)Tc)-labeled MCP-1 binds its receptors in chronic cardiac transplants and thereby provides a potential modality to assess GCAD.Allogeneic (PVG-->ACI, n = 9) and syngeneic (ACI-->ACI, n = 9) rat heterotopic heart transplants were performed. Allograft recipients were treated with 7.5 mg/kg per day of Cyclosporin A for 10 days until tolerance was achieved. After 90 days, animals were injected intravenously with (99m)Tc-MCP-1 and killed after 1 hour. Radioactivity of heart tissues was measured and standardized to uptake in the overall blood pool. Two-dimensional (99m)Tc-MCP-1 uptake (autoradiographs) was imaged by exposing 50-microm sections on a phosphoimager overnight. ED-1 staining of monocyte/macrophages was performed on serial sections. Additional sections were stained with elastin von Gieson and hematoxylin. Hearts were scored for luminal narrowing and intima/media ratio (I/M) with computerized image analysis.Allografts exhibited significantly more luminal narrowing (22.5 +/- 10.7% vs 2.6 +/- 4.6, p = 0.0005) and higher I/M (0.173 +/- 0.151 vs 0.015 +/- 0.029, p = 0.0088) than isografts. The ratio of (99m)Tc-MCP-1 uptake in allografts (1.04 +/- 0.4) was greater than that of isograft controls (0.72 +/- 0.11, p = 0.03). Pixel counts of autoradiographs and ED-1-stained sections demonstrated a modest correlation between the two (R(2) = 0.50). No significant differences were seen in acute rejection scores.(99m)Tc-MCP-1 uptake was higher in allografts vs isografts and was consistent with a greater degree of GCAD. These data demonstrating increased radiopharmaceutical uptake in hearts with GCAD provide a foundation for the development of a potentially non-invasive imaging assay of this disease process in heart transplantation.

    View details for PubMedID 12231372

  • Radiotracer characterization of coronary artery lesions NUCLEAR MEDICINE COMMUNICATIONS Mari, C., Strauss, H. W. 2002; 23 (8): 703–6
  • Zinc chloride-mediated reduction of apoptosis as an adjunct immunosuppressive modality in cardiac transplantation JOURNAL OF HEART AND LUNG TRANSPLANTATION Kown, M. H., van der Steenhoven, T. J., Jahncke, C. L., Mari, C., Lijkwan, M. A., Koransky, M. L., Blankenberg, F. G., Strauss, H. W., Robbins, R. C. 2002; 21 (3): 360-365


    Zinc (Zn) blocks caspase-3 activation in cardiac allografts and therefore may synergistically decrease apoptosis along with cyclosporine (CsA), which inhibits mitochondrial release of cytochrome c. Simultaneous treatment of rat recipients of heterotopic heart transplants with zinc chloride (ZnCl(2)) thus may allow lower doses of CsA for immunosuppression.PVG (RT1(c)) rat hearts were transplanted heterotopically into the abdomen of ACI (RT1(a)) rats. Group 1 (n = 15) rats received no treatment. Group 2 rats (n = 8) received 2 mg/kg/day CsA (sub-therapeutic dose) by oral gavage. Group 3 rats (n = 9) received 2 mg/kg/day oral CsA in addition to 1 mg/kg/day sub-cutaneous ZnCl(2) delivered by osmotic pump. All rats were imaged using Annexin V-bound (99m)Technetium ((99m)Tc-Annexin V) on post-operative Day 4 and subsequently killed. Annexin V avidly binds apoptotic cells in vivo. Region of interest per whole body (WB) data were calculated using the images. The allograft survival study was conducted with n = 11, 6, and 5 in control, CsA, and CsA+Zn groups, respectively. Finally, percentages of allografts that reached tolerance were measured in both CsA-only and CsA+Zn groups (n = 8 each).Zinc chloride had an additive effect with CsA on apoptotic blockade and graft survival. The regions of interest per WB uptake of (99m)Tc-Annexin V were 2.43% +/- 0.37%, 2.08% +/- 0.52%, and 1.49% +/- 0.29%*, and acute survivals were 6.4 +/- 1.7, 7.2 +/- 2.1, and 11.2 +/- 2.5* days for control, CsA, and CsA+Zn groups, respectively (*p < 0.001 vs controls). In addition, 87.5% of allografts became tolerant and survived for 90 days in the CsA+Zn group compared with only 37.5% in the CsA-only group (p = 0.049).Zinc-mediated reduction of apoptosis served as an effective adjunct immunosuppressive therapy to CsA in a rat model of cardiac transplantation.

    View details for PubMedID 11897525

  • Development of radiocontrast agents for vascular imaging: progress to date. American journal of cardiovascular drugs Blankenberg, F. G., Mari, C., Strauss, H. W. 2002; 2 (6): 357-365


    The revolution in molecular imaging techniques is profoundly changing the understanding of the pathophysiology and treatment of atherosclerosis. With these rapid changes there is an increasing demand for development of sensitive and well tolerated novel imaging agents that can be rapidly translated from small animal models into patients with atherosclerosis. Nuclear medicine and positron emission tomography techniques have the ability to detect and serially monitor a variety of biologic and pathophysiologic processes usually with tracer quantities of radiolabeled peptides, drugs, and other molecules at dosages free of pharmacologic adverse effects unlike the current generation of intravenous agents required for magnetic resonance imaging (MRI) and computed axial tomography (CT) scanning. A representative sampling of the wide array of radiopharmaceuticals developed specifically for radionuclide imaging of atherosclerosis, that have been approved for clinical use and those in pre-clinical trials, have been reviewed in this article. The presence of an inflammatory stimulus increases expression of CC (cysteine-cysteine motif) chemokine receptor (CCR)-2 on monocytes and macrophages, and somatostatin receptors on T lymphocytes. Radiolabeled monocyte chemoattractant protein (MCP)-1 binds with high affinity to CCR-2 and can be used to detect subacute and chronic inflammatory lesions. Similarly, radiolabeled octreotide or depreotide can be used to detect activated T lymphocytes which may identify the vulnerable plaque. Animal models indicate that (99m)Tc-annexin V, (125)I-MCP-1 and [(18)F]-fluoro-2-deoxyglucose are effective in identifying apoptotic cell death, macrophage infiltration and metabolic activity in atheromatous lesions, respectively. Expression of alpha(v)beta(3) integrin is increased in activated endothelial cells and vascular smooth muscle cells after vascular injury, and alpha(v)beta(3) integrin is minimally expressed on smooth muscle cells and is not expressed on quiescent epithelial cells. Radiolabeled high-affinity peptides can be used to target the alpha(v)beta(3) integrin and visualize areas of vascular damage. Advances in technology such as the micro-single photon emission computed tomography (microSPECT) have the potential to overcome the drawbacks of older CT and MRI methodologies, such as lack of biologically relevant ligands and compatible blood pool contrast agents for imaging. Despite these advances in imaging technology, the small size of atheromatous lesions makes it difficult to detect using external imaging techniques. Therefore, recently there has been renewed interest in the use of intravascular catheter-based radiation detectors.

    View details for PubMedID 14727951