Clinical Focus

  • Nuclear Medicine
  • PET/CT
  • Radioisotope Therapy
  • Molecular Imaging

Academic Appointments

Boards, Advisory Committees, Professional Organizations

  • CME Committee Chair-Elect, International Society of Clinical Densitometry (2015 - Present)
  • PET Center of Excellence Board Member, Society of Nuclear Medicine and Molecular Imaging (2013 - Present)
  • Correlative Imaging Council Board Member, Society of Nuclear Medicine and Molecular Imaging (2013 - Present)
  • Board Member, Northern California Chapter of the Society of Nuclear Medicine and Molecular Imaging (2013 - Present)
  • Targeted Radiotherapy Working Group Member, Society of Nuclear Medicine and Molecular Imaging (2012 - Present)

Professional Education

  • CCD, International Society of Clinical Densitometry (2015)
  • Fellowship:Stanford University School of Medicine (2009) CA
  • Residency:Stanford University School of Medicine (2008) CA
  • Internship:Stony Brook Univ Hospital (2006) NY
  • Professional Education:SUNY @ Stony Brook (2004) NY
  • Board Certification: Nuclear Medicine, American Board of Nuclear Medicine (2008)
  • Medical Education:SUNY - Stony Brook (2005) NY
  • N/A, Stanford University, PET/CT Fellowship (2009)
  • N/A, Stanford University, Nuclear Medicine Residency (2008)
  • N/A, Stony Brook University, Internal Medicine Internship (2006)
  • MD, Stony Brook University, Medicine (2005)
  • PhD, Stony Brook University, Biomedical Engineering (2004)
  • MS, Stony Brook University, Anatomical Sciences (2000)
  • BS, UC Berkeley, Molecular Biology (1996)
  • BA, UC Berkeley, Physical Anthropology (1996)

Research & Scholarship

Current Research and Scholarly Interests

Nuclear Medicine, Positron Emission Tomography (PET), Radioimmunotherapy

Clinical Trials

  • 4D-CT-based Ventilation Imaging for Adaptive Functional Guidance in Radiotherapy Recruiting

    To develop and investigate a novel radiotherapy technique for preserving lung function based on a map of lung function.

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  • A Study Comparing Treatment With 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in Patients With Inoperable, Progressive, Somatostatin Receptor Positive Midgut Carcinoid Tumours Recruiting

    The purpose of this study is to - compare Progression Free Survival (PFS) after treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, progressive (as determined by Response Evaluation Criteria in Solid Tumors [RECIST] Criteria), somatostatin receptor positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours). - compare the Objective Response Rate (ORR) between the two study arms - compare the Overall Survival (OS) between the two study arms - compare the Time to Tumour Progression (TTP) between the two study arms - evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate - evaluate the health related quality of life (QoL) as measured by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-G.I.NET21 questionnaire - explore the correlation of toxicity outcomes and administered radiation doses corrected for body weight and body surface area - explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine - evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20 patients - explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score - explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP)

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  • Radium-223 Dichloride (BAY88-8223) in Castration-Resistant (Hormone-Refractory) Prostate Cancer Patients With Bone Metastases Not Recruiting

    This study is a prospective, interventional, open-label, multi-center early access program for the use of Ra-223 Cl2 in HRPC/CRPC patients diagnosed with symptomatic bone metastasis and to collect additional short and long term safety data on the product.

    Stanford is currently not accepting patients for this trial. For more information, please contact Elizabeth Chitouras, 650-498-0623.

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  • PET/CT and Whole-Body MRI for Detection of Skeletal and Soft Tissue Metastases Recruiting

    Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool for cancer detection and monitoring response to therapy. However, not all cancers are identified reliably due to variable rates of glucose metabolism. Whole-body MRI emerges currently as an excellent modality for morphological characterization of soft tissue and skeletal lesions. Sodium Fluorine-18 (F-18) was used in the 1970's for bone scanning and can be used as a skeletal tracer in current PET/CT scanners. The direct comparison of F-18/F-18 FDG PET/CT and whole-body MRI for skeletal metastases detection was not attempted to date. However, such an approach has the potential to improve cancer diagnosis, staging, prognosis, and therapy monitoring. The combination of these technologies may also allow for improved screening or earlier cancer detection. We will attempt a pilot study with 10 patients to acquire the preliminary results needed to proceed with additional 90 subjects.

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  • 18F FPPRGD2 PET/CT or PET/MRI in Predicting Early Response in Patients With Cancer Receiving Anti-Angiogenesis Therapy Recruiting

    The purpose of the study is to conduct research of a new PET radiopharmaceutical in cancer patients. We will assess the uptake of this novel radiopharmaceutical in subjects with breast cancer, lung cancer, glioblastoma multiforme (GBM) and other cancers requiring antiangiogenesis treatment.

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  • Combined F18 and F18 FDG PET/CT for Evaluation of Malignancy Recruiting

    Fluorine-18 Fluorodeoxyglucose (F-18 FDG) PET/CT is established as a powerful imaging tool for cancer detection and monitoring response to therapy. Sodium Fluorine-18 (F-18) was used in the 1970s for bone scanning and can be used as a skeletal tracer in current PET/CT scanners. The combined administration of F-18 and F-18 FDG in a single PET/CT scan for cancer detection was not attempted to date. We hope to learn what is the best approach for detection of cancer and thus to improve cancer treatment.

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  • 68Ga DOTA-TATE PET/CT in Somatostatin Receptor Positive Tumors Recruiting

    The primary objective of the study is to evaluate 68Ga-DOTA TATE PET/CT for staging and monitoring response to chemotherapy in patients with carcinoid, neuroendocrine tumors, medullary thyroid cancer and other cancers expressing somatostatin receptors.

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  • Assessing Response to Treatment in Non-Hodgkin's Lymphoma Patients Using 64Cu-DOTA-Rituximab PET/CT Not Recruiting

    Rituximab is an antibody targeted against the CD20 antigen found primarily on B-cells. Therefore, an imaging agent targeting CD20 expression may provide a more accurate evaluation of extent of disease and response to therapy than the current standard of care, F-18 FDG PET/CT. The main purpose of the study is to investigate a new PET/CT imaging probe for detection and follow up of lymphoma. Following are the 3 aims of the study: a) Phase I testing in lymphoma patients of Cu-64 labelled Rituxan for defining normal tracer biodistribution, stability, pharmacokinetics and radiation dosimetry; b) comparison of Cu-64 Rituxan and F-18 FDG PET/CT in lymphoma patients; c) evaluation of changes in uptake of Cu-64 Rituxan in response to rituximab-based treatment in CD20-positive B-cell NHL

    Stanford is currently not accepting patients for this trial. For more information, please contact Elizabeth Chitouras, (650) 498 - 0623.

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2014-15 Courses


Journal Articles

  • Detection of Osseous Metastasis by 18F-NaF/18F-FDG PET/CT Versus CT Alone. Clinical nuclear medicine Sampath, S. C., Sampath, S. C., Mosci, C., Lutz, A. M., Willmann, J. K., Mittra, E. S., Gambhir, S. S., Iagaru, A. 2015; 40 (3): e173-7


    Sodium fluoride PET (F-NaF) has recently reemerged as a valuable method for detection of osseous metastasis, with recent work highlighting the potential of coadministered F-NaF and F-FDG PET/CT in a single combined imaging examination. We further examined the potential of such combined examinations by comparing dual tracer F-NaF/F-FDG PET/CT with CT alone for detection of osseous metastasis.Seventy-five participants with biopsy-proven malignancy were consecutively enrolled from a single center and underwent combined F-NaF/F-FDG PET/CT and diagnostic CT scans. PET/CT as well as CT only images were reviewed in blinded fashion and compared with the results of clinical, imaging, or histological follow-up as a truth standard.Sensitivity of the combined F-NaF/F-FDG PET/CT was higher than that of CT alone (97.4% vs 66.7%). CT and F-NaF/F-FDG PET/CT were concordant in 73% of studies. Of 20 discordant cases, F-NaF/F-FDG PET/CT was correct in 19 (95%). Three cases were interpreted concordantly but incorrectly, and all 3 were false positives. A single case of osseous metastasis was detected by CT alone, but not by F-NaF/F-FDG PET/CT.Combined F-NaF/F-FDG PET/CT outperforms CT alone and is highly sensitive and specific for detection of osseous metastases. The concordantly interpreted false-positive cases demonstrate the difficulty of distinguishing degenerative from malignant disease, whereas the single case of metastasis seen on CT but not PET highlights the need for careful review of CT images in multimodality studies.

    View details for DOI 10.1097/RLU.0000000000000560

    View details for PubMedID 25140557

  • Simultaneous Whole-Body Time-of-Flight F-18-FDG PET/MRI A Pilot Study Comparing SUVmax With PET/CT and Assessment of MR Image Quality CLINICAL NUCLEAR MEDICINE Iagaru, A., Mittra, E., Minamimoto, R., Jamali, M., Levin, C., Quon, A., Gold, G., Herfkens, R., Vasanawala, S., Gambhir, S. S., Zaharchuk, G. 2015; 14 (1): 1-8
  • F-18-FPPRGD2 PET/CT: Pilot Phase Evaluation of Breast Cancer Patients RADIOLOGY Lagaru, A., Mosci, C., Shen, B., Chin, F. T., Mittra, E., Telli, M. L., Gambhir, S. S. 2014; 273 (2): 549-559
  • (18)F-FPPRGD2 PET/CT: pilot phase evaluation of breast cancer patients. Radiology Iagaru, A., Mosci, C., Shen, B., Chin, F. T., Mittra, E., Telli, M. L., Gambhir, S. S. 2014; 273 (2): 549-559


    Purpose To present data from the first prospective pilot phase trial of breast cancer participants imaged with fluorine 18 ((18)F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) (FPPRGD2), a radiopharmaceutical agent used in positron emission tomographic (PET) imaging. Materials and Methods The local institutional review board approved the HIPAA-compliant protocol. Written informed consent was obtained from each patient. Eight women (age range, 44-67 years; mean age, 54.3 years ± 8.8 [standard deviation]) with newly diagnosed or recurrent breast cancer were recruited between November 2010 and February 2011. (18)F-FPPRGD2 PET/computed tomographic (CT) and (18)F-fluorodeoxyglucose (FDG) PET/CT examinations were performed within 3 weeks of each other. Dynamic (18)F-FPPRGD2 PET and two whole-body static (18)F-FPPRGD2 PET/CT scans were obtained. During this time, vital signs and electrocardiograms were recorded at regular intervals. Blood samples were obtained before the injection of (18)F-FPPRGD2 and at 24 hours and 1 week after injection to evaluate for toxicity. A nonparametric version of multivariate analysis of variance was used to assess the safety outcome measures simultaneously across time points. A paired two-sample t test was performed to compare the maximum standardized uptake values (SUVmax). Results (18)F-FPPRGD2 was well tolerated, without noticeable changes in vital signs, on electrocardiograms, or in laboratory values. A total of 30 lesions were evaluated at (18)F-FDG PET/CT and (18)F-FPPRGD2 PET/CT. The primary breast lesions had (18)F-FPPRGD2 uptake with SUVmax of 2.4-9.4 (mean, 5.6 ± 2.8) 60 minutes after injection, compared with (18)F-FDG uptake with SUVmax of 2.8-18.6 (mean, 10.4 ± 7.2). Metastatic lesions also showed (18)F-FPPRGD2 uptake, with SUVmax of 2.4-9.7 (mean, 5.0 ± 2.3) at 60 minutes, compared with (18)F-FDG uptake with SUVmax of 2.2-14.6 (mean, 6.6 ± 4.2). Conclusion Data from this pilot phase study suggest that (18)F-FPPRGD2 is a safe PET radiopharmaceutical agent. Evaluation of (18)F-FPPRGD2 in participants with breast cancer demonstrated significant uptake in the primary lesion and in the metastases. Larger cohorts are required to confirm these preliminary findings. © RSNA, 2014.

    View details for DOI 10.1148/radiol.14140028

    View details for PubMedID 25033190

  • Pulmonary Ventilation Imaging Based on 4-Dimensional Computed Tomography: Comparison With Pulmonary Function Tests and SPECT Ventilation Images INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Yamamoto, T., Kabus, S., Lorenz, C., Mittra, E., Hong, J. C., Chung, M., Eclov, N., To, J., Diehn, M., Loo, B. W., Keall, P. J. 2014; 90 (2): 414-422
  • Case 207: hodgkin lymphoma with paraneoplastic hypercalcemic pancreatitis. Radiology Mittra, E. S., Davidzon, G. 2014; 272 (1): 296-300


    A 15-year-old girl presented with a 2-month history of 30-lb (13.6 kg) weight loss, chest and abdominal pain, nausea, bilious emesis, cough, and shortness of breath. Initial blood count (performed at an outside hospital) showed elevated white blood cell and platelet counts but low hemoglobin and hematocrit levels. On examination, she had adenopathy in the left axillary and supraclavicular regions, fullness in the left chest, and abdominal guarding. Ultrasonography (US)-guided fine-needle aspiration biopsy of the left anterior chest wall mass was nondiagnostic, and lumbar puncture and bone marrow biopsies were negative. At that time, the patient underwent several imaging studies-including chest radiography; bone scanning; contrast material-enhanced computed tomography (CT) of the chest, abdomen, and pelvis; and fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT-all performed within 1 week of each other. Pertinent serum laboratory values at the time of these tests were as follows: calcium level, 17 mg/dL (4.25 mmol/L) (normal range, 8.5-10.5 mg/dL [2.1-2.6 mmol/L]); ionized calcium level, 2.3 mmol/L (normal range, 1.1-1.3 mmol/L); lipase level, 2423 U/L (normal level, <300 U/L); amylase level, 1435 U/L (normal level, <140 U/L); lactate dehydrogenase level, 253 U/L (normal level, <240 U/L), albumin level, 2.6 g/dL (26 g/L) (normal level, 3.5-5.0 g/dL [35-50 g/L]), and creatinine level, 1.7 mg/dL (150.3 μmol/L) (normal level, <1.2 mg/dL [<106.1 μmol/L]). A follow-up PET/CT scan was performed approximately 2 months later after initial therapy.

    View details for DOI 10.1148/radiol.14120419

    View details for PubMedID 24956051

  • Clinical evaluation of a novel intraoperative handheld gamma camera for sentinel lymph node biopsy PHYSICA MEDICA-EUROPEAN JOURNAL OF MEDICAL PHYSICS Olcott, P., Pratx, G., Johnson, D., Mittra, E., Niederkohr, R., Levin, C. S. 2014; 30 (3): 340-345


    Preoperative lymphoscintigraphy (PLS) combined with intraoperative gamma probe (GP) localization is standard procedure for localizing the sentinel lymph nodes (SLN) in melanoma and breast cancer. In this study, we evaluated the ability of a novel intraoperative handheld gamma camera (IHGC) to image SLNs during surgery.The IHGC is a small-field-of-view camera optimized for real-time imaging of lymphatic drainage patterns. Unlike conventional cameras, the IHGC can acquire useful images in a few seconds in a free-running fashion and be moved manually around the patient to find a suitable view of the node. Thirty-nine melanoma and eleven breast cancer patients underwent a modified SLN biopsy protocol in which nodes localized with the GP were imaged with the IHGC. The IHGC was also used to localize additional nodes that could not be found with the GP.The removal of 104 radioactive SLNs was confirmed ex vivo by GP counting. In vivo, the relative node detection sensitivity was 88.5 (82.3, 94.6)% for the IHGC (used in conjunction with the GP) and 94.2 (89.7, 98.7)% for the GP alone, a difference not found to be statistically significant (McNemar test, p = 0.24).Small radioactive SLNs can be visualized intraoperatively using the IHGC with exposure time of 20 s or less, with no significant difference in node detection sensitivity compared to a GP. The IHGC is a useful complement to the GP, especially for SLNs that are difficult to locate with the GP alone.

    View details for DOI 10.1016/j.ejmp.2013.10.005

    View details for Web of Science ID 000334094200012

  • F-18-FDG PET/CT in the management of patients with post-transplant lymphoproliferative disorder NUCLEAR MEDICINE COMMUNICATIONS Takehana, C. S., Twist, C. J., Mosci, C., Quon, A., Mittra, E., Iagaru, A. 2014; 35 (3): 276-281


    Post-transplant lymphoproliferative disorder (PTLD) is a rare but serious complication in transplant patients. Although fluorine-18 2-fluoro-2-deoxyglucose PET and computed tomography (F-FDG PET/CT) has been used for the evaluation and management of patients with PTLD, its utility has yet to be documented. We were therefore prompted to review our experience with F-FDG PET/CT in PTLD.We retrospectively reviewed the records of consecutive patients who had undergone F-FDG PET/CT for evaluation of PTLD from January 2004 to June 2012 at our institution. F-FDG PET/CT scans were compared with other imaging modalities performed concurrently. A chart review of pertinent clinical information was also conducted.A total of 30 patients were identified (14 female and 16 male; 1.7-76.7 years of age, average: 23.8 years). Twenty-seven participants had biopsy-proven PTLD and another three had been treated for PTLD because of high clinical suspicion of disease and positive F-FDG PET/CT findings in the absence of histological diagnosis. Eighty-three percent of these PTLD patients had extranodal involvement. In 57% of the cases, F-FDG PET/CT detected occult lesions not identified on other imaging modalities or suggested PTLD in equivocal lesions. The more aggressive PTLD histological subtypes demonstrated higher SUVmax compared with the less aggressive subtypes.F-FDG PET/CT is beneficial in the diagnostic evaluation of patients with PTLD. F-FDG PET/CT has the ability to detect occult lesions not identified on other imaging modalities, particularly extranodal lesions. In addition, F-FDG PET/CT may predict the PTLD subtype, as the lesions with higher pathologic grade presented with significantly higher SUVmax compared with the less aggressive forms.

    View details for DOI 10.1097/MNM.0000000000000050

    View details for Web of Science ID 000331291000008

  • Case 207. Radiology Mittra, E. S., Davidzon, G. 2014; 270 (3): 929-930

    View details for DOI 10.1148/radiol.13112741

    View details for PubMedID 24568707

  • Prognostic Utility of Y-90 Radioembolization Dosimetry Based on Fusion Tc-99m-Macroaggregated Albumin-Tc-99m-Sulfur Colloid SPECT JOURNAL OF NUCLEAR MEDICINE Lam, M. G., Goris, M. L., Iagaru, A. H., Mittra, E. S., Louie, J. D., Sze, D. Y. 2013; 54 (12): 2055-2061
  • Prognostic utility of 90Y radioembolization dosimetry based on fusion 99mTc-macroaggregated albumin-99mTc-sulfur colloid SPECT. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Lam, M. G., Goris, M. L., Iagaru, A. H., Mittra, E. S., Louie, J. D., Sze, D. Y. 2013; 54 (12): 2055-2061


    Planning hepatic (90)Y radioembolization activity requires balancing toxicity with efficacy. We developed a dual-tracer SPECT fusion imaging protocol that merges data on radioactivity distribution with physiologic liver mapping.Twenty-five patients with colorectal carcinoma and bilobar liver metastases received whole-liver radioembolization with resin microspheres prescribed as per convention (mean administered activity, 1.69 GBq). As part of standard treatment planning, all patients underwent SPECT imaging after intraarterial injection of 37 MBq of (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) to simulate subsequent (90)Y distribution. Immediately afterward, patients received 185 MBq of labeled sulfur colloid ((99m)Tc-SC) intravenously as a biomarker for normal hepatic reticuloendothelial function and SPECT was repeated. The SPECT images were coregistered and fused. A region-based method was used to predict the (90)Y radiation absorbed dose to functional liver tissue (DFL) by calculation of (99m)Tc-MAA activity in regions with (99m)Tc-SC uptake. Similarly, the absorbed dose to tumor (DT) was predicted by calculation of (99m)Tc-MAA activity in voxels without (99m)Tc-SC uptake. Laboratory data and radiographic response were measured for 3 mo, and the survival of patients was recorded. SPECT-based DT and DFL were correlated with parameters of toxicity and efficacy.Toxicity, as measured by increase in serum liver enzymes, correlated significantly with SPECT-based calculation of DFL at all time points (P < 0.05) (mean DFL, 27.9 Gy). Broad biochemical toxicity (>50% increase in all liver enzymes) occurred at a DFL of 24.5 Gy and above. In addition, in uni- and multivariate analysis, SPECT-based calculation of DT (mean DT, 44.2 Gy) correlated with radiographic response (P < 0.001), decrease in serum carcinoembryonic antigen (P < 0.05), and overall survival (P < 0.01). The cutoff value of DT for prediction of 1-y survival was 55 Gy (area under the receiver-operating-characteristic curve = 0.86; P < 0.01). Patients who received a DT of more than 55 Gy had a median survival of 32.8 mo, compared with 7.2 mo in patients who received less (P < 0.05).Dual-tracer (99m)Tc-MAA-(99m)Tc-SC fusion SPECT offers a physiology-based imaging tool with significant prognostic power that may lead to improved personalized activity planning.

    View details for DOI 10.2967/jnumed.113.123257

    View details for PubMedID 24144563

  • Preclinical Efficacy of the Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab in a Mouse Brain Orthotopic Glioma Model Evaluated by Bioluminescence, PET, and MRI CLINICAL CANCER RESEARCH Mittra, E. S., Fan-Minogue, H., Lin, F. I., Karamchandani, J., Sriram, V., Han, M., Gambhir, S. S. 2013; 19 (20): 5711-5721


    Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma.Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 × 10(5) U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response.There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[(18)F]fluoro-2-deoxy-d-glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later.Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate.

    View details for DOI 10.1158/1078-0432.CCR-12-1015

    View details for Web of Science ID 000325797600019

  • Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases. Clinical nuclear medicine Iagaru, A., Young, P., Mittra, E., Dick, D. W., Herfkens, R., Gambhir, S. S. 2013; 38 (7): e290-6


    The aim of this study was to compare Tc-MDP bone scanning, F NaF PET/CT, F FDG PET/CT, and whole-body MRI (WBMRI) for detection of known osseous metastases.This prospective pilot trial (September 2007-April 2009) enrolled 10 participants (5 men, 5 women, 47-81 years old) diagnosed with cancer and known osseous metastases. F NaF PET/CT, F FDG PET/CT, and WBMRI were performed within 1 month for each participant.The image quality and evaluation of extent of disease were superior by F NaF PET/CT compared to Tc-MDP scintigraphy in all patients with skeletal lesions and compared to F FDG PET/CT in 3 of the patients with skeletal metastases. F NaF PET/CT showed osseous metastases where F FDG PET/CT was negative in another 3 participants. Extraskeletal metastases were identified by F FDG PET/CT in 6 participants. WBMRI with the combination of iterative decomposition of water and fat with echo asymmetry and least-squares estimation, short tau inversion recovery, and diffusion-weighted imaging pulse sequences showed fewer lesions than F NaF PET/CT in 5 patients, same number of lesions in 2 patients, and more lesions in 1 patient. WBMRI showed fewer lesions than F FDG in 3 patients and same lesions in 6 patients.Our pilot phase prospective trial demonstrated superior image quality and evaluation of skeletal disease extent with F NaF PET/CT compared to Tc-MDP scintigraphy and F FDG PET/CT, as well as the feasibility of multisequence WBMRI. In addition, F FDG PET/CT provided valuable soft-tissue information that can change disease management. Further evaluation of these findings using the recently introduced PET/MRI scanners is warranted.

    View details for DOI 10.1097/RLU.0b013e3182815f64

    View details for PubMedID 23455520

  • Pilot Prospective Evaluation of Tc-99m-MDP Scintigraphy, F-18 NaF PET/CT, F-18 FDG PET/CT and Whole-Body MRI for Detection of Skeletal Metastases CLINICAL NUCLEAR MEDICINE Iagaru, A., Young, P., Mittra, E., Dick, D. W., Herfkens, R., Gambhir, S. S. 2013; 38 (7): E290-E296
  • Combined F-18-Fluoride and F-18-FDG PET/CT Scanning for Evaluation of Malignancy: Results of an International Multicenter Trial JOURNAL OF NUCLEAR MEDICINE Iagaru, A., Mittra, E., Mosci, C., Dick, D. W., Sathekge, M., Prakash, V., Iyer, V., Lapa, P., Isidoro, J., de Lima, J. M., Gambhir, S. S. 2013; 54 (2): 176-183


    (18)F-FDG PET/CT is used in a variety of cancers, but because of variable rates of glucose metabolism, not all cancers are reliably identified. (18)F(-) PET/CT allows for the acquisition of highly sensitive and specific images of the skeleton. We prospectively evaluated combined (18)F(-)/(18)F-FDG as a single PET/CT examination for evaluation of cancer patients and compared it with separate (18)F(-) PET/CT and (18)F-FDG PET/CT scans.One hundred fifteen participants with cancer were prospectively enrolled in an international multicenter trial evaluating (18)F(-) PET/CT, (18)F-FDG PET/CT, and combined (18)F(-)/(18)F-FDG PET/CT. The 3 PET/CT scans were performed sequentially within 4 wk of one another for each patient.(18)F(-)/(18)F-FDG PET/CT allowed for accurate interpretation of radiotracer uptake outside the skeleton, with findings similar to those of (18)F-FDG PET/CT. In 19 participants, skeletal disease was more extensive on (18)F(-) PET/CT and (18)F(-)/(18)F-FDG PET/CT than on (18)F-FDG PET/CT. In another 29 participants, (18)F(-) PET/CT and (18)F(-)/(18)F-FDG PET/CT showed osseous metastases where (18)F-FDG PET/CT was negative. The extent of skeletal lesions was similar in 18 participants on all 3 scans.This trial demonstrated that combined (18)F(-)/(18)F-FDG PET/CT shows promising results when compared with separate (18)F(-) PET/CT and (18)F-FDG PET/CT for evaluation of cancer patients. This result opens the possibility for improved patient care and reduction in health-care costs, as will be further evaluated in future trials.

    View details for DOI 10.2967/jnumed.112.108803

    View details for Web of Science ID 000314691200016

  • A Brain Tumor Molecular Imaging Strategy using a New Triple-Modality MRI-Photoacoustic-Raman Nanoparticle PHOTONS PLUS ULTRASOUND: IMAGING AND SENSING 2013 de la Zerda, A., Kircher, M. F., Jokerst, J. V., Zavaleta, C. L., Kempen, P. J., Mittra, E., Pitter, K., Huang, R., Campos, C., Habte, F., Sinclair, R., Brennan, C. W., Mellinghoff, I. K., Holland, E. C., Gambhir, S. S. 2013; 8581

    View details for DOI 10.1117/12.2001719

    View details for Web of Science ID 000322832800007

  • Exploratory Clinical Trial of (4S)-4-(3-[F-18]fluoropropyl)-L-glutamate for Imaging x(C) Transporter Using Positron Emission Tomography in Patients with Non-Small Cell Lung or Breast Cancer CLINICAL CANCER RESEARCH Baek, S., Choi, C., Ahn, S. H., Lee, J. W., Gong, G., Ryu, J., Oh, S. J., Bacher-Stier, C., Fels, L., Koglin, N., Hultsch, C., Schatz, C. A., Dinkelborg, L. M., Mittra, E. S., Gambhir, S. S., Moon, D. H. 2012; 18 (19): 5427-5437


    (4S)-4-(3-[(18)F]fluoropropyl)-l-glutamate (BAY 94-9392, alias [(18)F]FSPG) is a new tracer to image x(C)(-) transporter activity with positron emission tomography (PET). We aimed to explore the tumor detection rate of [(18)F]FSPG in patients relative to 2-[(18)F]fluoro-2-deoxyglucose ([(18)F]FDG). The correlation of [(18)F]FSPG uptake with immunohistochemical expression of x(C)(-) transporter and CD44, which stabilizes the xCT subunit of system x(C)(-), was also analyzed.Patients with non-small cell lung cancer (NSCLC, n = 10) or breast cancer (n = 5) who had a positive [(18)F]FDG uptake were included in this exploratory study. PET images were acquired following injection of approximately 300 MBq [(18)F]FSPG. Immunohistochemistry was done using xCT- and CD44-specific antibody.[(18)F]FSPG PET showed high uptake in the kidney and pancreas with rapid blood clearance. [(18)F]FSPG identified all 10 NSCLC and three of the five breast cancer lesions that were confirmed by pathology. [(18)F]FSPG detected 59 of 67 (88%) [(18)F]FDG lesions in NSCLC, and 30 of 73 (41%) in breast cancer. Seven lesions were additionally detected only on [(18)F]FSPG in NSCLC. The tumor-to-blood pool standardized uptake value (SUV) ratio was not significantly different from that of [(18)F]FDG in NSCLC; however, in breast cancer, it was significantly lower (P < 0.05). The maximum SUV of [(18)F]FSPG correlated significantly with the intensity of immunohistochemical staining of x(C)(-) transporter and CD44 (P < 0.01).[(18)F]FSPG seems to be a promising tracer with a relatively high cancer detection rate in patients with NSCLC. [(18)F]FSPG PET may assess x(C)(-) transporter activity in patients with cancer.

    View details for DOI 10.1158/1078-0432.CCR-12-0214

    View details for Web of Science ID 000311906600027

    View details for PubMedID 22893629

  • A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle NATURE MEDICINE Kircher, M. F., de la Zerda, A., Jokerst, J. V., Zavaleta, C. L., Kempen, P. J., Mittra, E., Pitter, K., Huang, R., Campos, C., Habte, F., Sinclair, R., Brennan, C. W., Mellinghoff, I. K., Holland, E. C., Gambhir, S. S. 2012; 18 (5): 829-U235


    The difficulty in delineating brain tumor margins is a major obstacle in the path toward better outcomes for patients with brain tumors. Current imaging methods are often limited by inadequate sensitivity, specificity and spatial resolution. Here we show that a unique triple-modality magnetic resonance imaging-photoacoustic imaging-Raman imaging nanoparticle (termed here MPR nanoparticle) can accurately help delineate the margins of brain tumors in living mice both preoperatively and intraoperatively. The MPRs were detected by all three modalities with at least a picomolar sensitivity both in vitro and in living mice. Intravenous injection of MPRs into glioblastoma-bearing mice led to MPR accumulation and retention by the tumors, with no MPR accumulation in the surrounding healthy tissue, allowing for a noninvasive tumor delineation using all three modalities through the intact skull. Raman imaging allowed for guidance of intraoperative tumor resection, and a histological correlation validated that Raman imaging was accurately delineating the brain tumor margins. This new triple-modality-nanoparticle approach has promise for enabling more accurate brain tumor imaging and resection.

    View details for DOI 10.1038/nm.2721

    View details for Web of Science ID 000303763500053

    View details for PubMedID 22504484

  • Prospective Evaluation of Tc-99m MDP Scintigraphy, F-18 NaF PET/CT, and F-18 FDG PET/CT for Detection of Skeletal Metastases MOLECULAR IMAGING AND BIOLOGY Iagaru, A., Mittra, E., Dick, D. W., Gambhir, S. S. 2012; 14 (2): 252-259


    Technetium (Tc) methylene diphosphonate (MDP) has been the standard method for bone scintigraphy for three decades. (18)F sodium fluoride ((18)F NaF) positron emission tomography (PET)/computed tomography (CT) has better resolution and is considered superior. The role of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F FDG) PET/CT is proven in a variety of cancers, for which it has changed the practice of oncology. There are few prospective studies comparing these three methods of detection of skeletal metastases. Thus, we were prompted to initiate this prospective pilot trial.This is a prospective study (Sep 2007-Dec 2010) of 52 patients with proven malignancy referred for evaluation of skeletal metastases. There were 37 men and 15 women, 19-84 years old (average, 55.6?±?15.9). Technetium-99m ((99m)Tc) MDP bone scintigraphy, (18)F NaF PET/CT, and (18)F FDG PET/CT were subsequently performed within 1 month.Skeletal lesions were detected by (99m)Tc MDP bone scintigraphy in 22 of 52 patients, by (18)F NaF PET/CT in 24 of 52 patients, and by (18)F FDG PET/CT in 16 of 52 patients. The image quality and evaluation of extent of disease were superior by (18)F NaF PET/CT over (99m)Tc MDP scintigraphy in all 22 patients with skeletal lesions on both scans and over (18)F FDG PET/CT in 11 of 16 patients with skeletal metastases on (18)F FDG PET/CT. In two patients, (18)F NaF PET/CT showed skeletal metastases not seen on either of the other two scans. Extraskeletal lesions were identified by (18)F FDG PET/CT in 28 of 52 subjects.Our prospective pilot-phase trial demonstrates superior image quality and evaluation of skeletal disease extent with (18)F NaF PET/CT over (99m)Tc MDP scintigraphy and (18)F FDG PET/CT. At the same time, (18)F FDG PET detects extraskeletal disease that can significantly change disease management. As such, a combination of (18)F FDG PET/CT and (18)F NaF PET/CT may be necessary for cancer detection. Additional evaluation with larger cohorts is required to confirm these preliminary findings.

    View details for DOI 10.1007/s11307-011-0486-2

    View details for Web of Science ID 000301584100013

    View details for PubMedID 21479710

  • Prospective comparison of combined F-18-FDG and F-18-NaF PET/CT vs. F-18-FDG PET/CT imaging for detection of malignancy EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Lin, F. I., Rao, J. E., Mittra, E. S., Nallapareddy, K., Chengapa, A., Dick, D. W., Gambhir, S. S., Iagaru, A. 2012; 39 (2): 262-270


    Typically, (18)F-FDG PET/CT and (18)F-NaF PET/CT scans are done as two separate studies on different days to allow sufficient time for the radiopharmaceutical from the first study to decay. This is inconvenient for the patients and exposes them to two doses of radiation from the CT component of the examinations. In the current study, we compared the clinical usefulness of a combined (18)F-FDG/(18)F-NaF PET/CT scan with that of a separate (18)F-FDG-only PET/CT scan.There were 62 patients enrolled in this prospective trial. All had both an (18)F-FDG-alone PET/CT scan and a combined (18)F-FDG/(18)F-NaF PET/CT scan. Of the 62 patients, 53 (85%) received simultaneous tracer injections, while 9 (15%) received (18)F-NaF subsequent to the initial (18)F-FDG dose (average delay 2.2 h). Images were independently reviewed for PET findings by two Board-Certified nuclear medicine physicians, with discrepancies resolved by a third reader. Interpreters were instructed to only report findings that were concerning for malignancy. Reading the (18)F-FDG-only scan first for half of the patients controlled for order bias.In 15 of the 62 patients (24%) neither the (18)F-FDG-only PET/CT scan nor the combined (18)F-FDG/(18)F-NaF PET/CT scan identified malignancy. In the remaining 47 patients who had PET findings of malignancy, a greater number of lesions were detected in 16 of 47 patients (34%) using the combined (18)F-FDG/(18)F-NaF PET/CT scan compared to the (18)F-FDG-only PET/CT scan. In 2 of these 47 patients (4%), the (18)F-FDG-only scan demonstrated soft tissue lesions that were not prospectively identified on the combined study. In 29 of these 47 patients (62%), the combined scan detected an equal number of lesions compared to the (18)F-FDG-only scan. Overall, 60 of all the 62 patients (97%) showed an equal or greater number of lesions on the combined scan than on the (18)F-FDG-only scan.The current study demonstrated that (18)F-FDG and (18)F-NaF can be combined in a single PET/CT scan by administering the two radiopharmaceuticals simultaneously or in sequence on the same day. In addition to patient convenience and reduced radiation exposure from the CT component, the combined (18)F-FDG/(18)F-NaF PET/CT scan appeared to increase the sensitivity for detection of osseous lesions compared to the (18)F-FDG-only PET/CT scan in the studied population.

    View details for DOI 10.1007/s00259-011-1971-1

    View details for Web of Science ID 000302286600009

    View details for PubMedID 22065013

  • First Experience with Clinical-Grade [F-18]FPP(RGD)(2): An Automated Multi-step Radiosynthesis for Clinical PET Studies MOLECULAR IMAGING AND BIOLOGY Chin, F. T., Shen, B., Liu, S., Berganos, R. A., Chang, E., Mittra, E., Chen, X., Gambhir, S. S. 2012; 14 (1): 88-95


    A reliable and routine process to introduce a new ¹?F-labeled dimeric RGD-peptide tracer ([¹?F]FPP(RGD?) for noninvasive imaging of ?(v)?? expression in tumors needed to be developed so the tracer could be evaluated for the first time in man. Clinical-grade [¹?F]FPP(RGD)? was screened in mouse prior to our first pilot study in human.[¹?F]FPP(RGD)? was synthesized by coupling 4-nitrophenyl-2-[¹?F]fluoropropionate ([¹?F]NPE) with the dimeric RGD-peptide (PEG?-c(RGDyK)?). Imaging studies with [¹?F]FPP(RGD)? in normal mice and a healthy human volunteer were carried out using small animal and clinical PET scanners, respectively.Through optimization of each radiosynthetic step, [¹?F]FPP(RGD)? was obtained with RCYs of 16.9?±?2.7% (n?=?8, EOB) and specific radioactivity of 114?±?72 GBq/?mol (3.08?±?1.95 Ci/?mol; n?=?8, EOB) after 170 min of radiosynthesis. In our mouse studies, high radioactivity uptake was only observed in the kidneys and bladder with the clinical-grade tracer. Favorable [¹?F]FPP(RGD)? biodistribution in human studies, with low background signal in the head, neck, and thorax, showed the potential applications of this RGD-peptide tracer for detecting and monitoring tumor growth and metastasis.A reliable, routine, and automated radiosynthesis of clinical-grade [¹?F]FPP(RGD)? was established. PET imaging in a healthy human volunteer illustrates that [¹?F]FPP(RGD)? possesses desirable pharmacokinetic properties for clinical noninvasive imaging of ?(v)?? expression. Further imaging studies using [¹?F]FPP(RGD)? in patient volunteers are now under active investigation.

    View details for DOI 10.1007/s11307-011-0477-3

    View details for Web of Science ID 000301583900012

    View details for PubMedID 21400112

  • Pilot Pharmacokinetic and Dosimetric Studies of F-18-FPPRGD2: A PET Radiopharmaceutical Agent for Imaging alpha(v)beta(3) Integrin Levels RADIOLOGY Mittra, E. S., Goris, M. L., Iagaru, A. H., Kardan, A., Burton, L., Berganos, R., Chang, E., Liu, S., Shen, B., Chin, F. T., Chen, X., Gambhir, S. S. 2011; 260 (1): 182-191


    To assess the safety, biodistribution, and dosimetric properties of the positron emission tomography (PET) radiopharmaceutical agent fluorine 18 ((18)F) FPPRGD2 (2-fluoropropionyl labeled PEGylated dimeric RGD peptide [PEG3-E{c(RGDyk)}2]), which is based on the dimeric arginine-glycine-aspartic acid (RGD) peptide sequence and targets ?(v)?(3) integrin, in the first volunteers imaged with this tracer.The protocol was approved by the institutional review board, and written informed consent was obtained from all participants. Five healthy volunteers underwent whole-body combined PET-computed tomography 0.5, 1.0, 2.0, and 3.0 hours after tracer injection (mean dose, 9.5 mCi ± 3.4 [standard deviation] [351.5 MBq ± 125.8]; mean specific radioactivity, 1200 mCi/mmol ± 714 [44.4 GBq/mmol ± 26.4]). During this time, standard vital signs, electrocardiographic (ECG) readings, and blood sample values (for chemistry, hematologic, and liver function tests) were checked at regular intervals and 1 and 7 days after the injection. These data were used to evaluate tracer biodistribution and dosimetric properties, time-activity curves, and the stability of laboratory values. Significant changes in vital signs and laboratory values were evaluated by using a combination of population-averaged generalized estimating equation regression and exact paired Wilcoxon tests.The administration of (18)F-FPPRGD2 was well tolerated, with no marked effects on vital signs, ECG readings, or laboratory values. The tracer showed the same pattern of biodistribution in all volunteers: primary clearance through the kidneys (0.360 rem/mCi ± 0.185 [0.098 mSv/MBq ± 0.050]) and bladder (0.862 rem/mCi ± 0.436 [0.233 mSv/MBq ± 0.118], voiding model) and uptake in the spleen (0.250 rem/mCi ± 0.168 [0.068 mSv/MBq ± 0.046]) and large intestine (0.529 rem/mCi ± 0.236 [0.143 mSv/MBq ± 0.064]). The mean effective dose of (18)F-FPPRGD2 was 0.1462 rem/mCi ± 0.0669 (0.0396 mSv/MBq ± 0.0181). With an injected dose of 10 mCi (370 MBq) and a 1-hour voiding interval, a patient would be exposed to an effective radiation dose of 1.5 rem (15 mSv). Above the diaphragm, there was minimal uptake in the brain ventricles, salivary glands, and thyroid gland. Time-activity curves showed rapid clearance from the vasculature, with a mean 26% ± 17 of the tracer remaining in the circulation at 30 minutes and most of the activity occurring in the plasma relative to cells (mean whole blood-plasma ratio, 0.799 ± 0.096).(18)F-FPPRGD2 has desirable pharmacokinetic and biodistribution properties. The primary application is likely to be PET evaluation of oncologic patients-especially those with brain, breast, or lung cancer. Specific indications may include tumor staging, identifying patients who would benefit from antiangiogenesis therapy, and separating treatment responders from nonresponders early.

    View details for DOI 10.1148/radiol.11101139

    View details for Web of Science ID 000291932300021

    View details for PubMedID 21502381

  • FDG-PET/CT in Cancers of the Head and Neck: What is the Definition of Whole Body Scanning? MOLECULAR IMAGING AND BIOLOGY Iagaru, A., Mittra, E. S., Gambhir, S. S. 2011; 13 (2): 362-367


    The role of 2-deoxy-2-[F-18]fluoro-D-glucose-positron emission tomography (FDG-PET) was studied in a variety of cancers, including head and neck squamous cell carcinomas (HNSCC) and nasopharyngeal carcinomas (NPC), with several presentations indicating that for these clinical entities a "whole-body" (i.e., eyes to thighs) may yield little additional information. Therefore, we were prompted to review our experience with PET/computed tomography (CT) in the management of patients with HNSCC and NPC.This is a retrospective study of 133 patients with HNSCC, 23-90 years old (average: 58.2?±?12.7) and 26 patients with NPC, ages 16-75 (average: 47.3?±?17.1), who had whole body PET/CT at our institution from Jan 2003 to Nov 2006. Reinterpretation of the imaging studies for accuracy and data analysis from medical records was performed. Lesions identified on PET/CT below the level of the adrenal glands were recorded and tabulated.Lesions were identified below the adrenal glands in seven patients (5.2%) with HNSCC. These included hepatic and osseous metastases from HNSCC in two patients (1.5%), a new renal cancer (0.75%), a new pancreatic cancer (0.75%), a new colon cancer (0.75%) and findings proven benign on follow-up (focal colon uptake in one patient and an inflammatory inguinal lymph node in another patient; 1.5%). Lesions were identified below the adrenal glands in three patients (11.5%) with NPC. These included osseous metastases from NPC in two patients (7.7%) and findings proven benign on follow-up (focal colon uptake in one patient; 3.84%).This study suggests that whole body PET/CT imaging in HNSCC has a relatively low yield (3%, 95% CI: 1.33-8.42) of significant findings below the level of the adrenal glands. Therefore, implementing a more limited protocol (through the level of adrenal glands), especially in low-risk cases of HNSCC, may be considered. However, whole body PET/CT imaging in NPC may have a significant yield (7.7%, 95% CI: 1.02-25.26) of medically relevant findings below the level of the adrenal glands. Thus, the whole body (i.e., vertex to thighs) PET/CT scan of NPC patients appears to be the appropriate imaging protocol for this population. This recommendation requires further evaluation and validation in larger prospective studies.

    View details for DOI 10.1007/s11307-010-0343-8

    View details for Web of Science ID 000288177700021

    View details for PubMedID 20495879

  • Case 166: Metastatic Left Pulmonary Artery Sarcoma RADIOLOGY Mittra, E. S., Iagaru, A. H., Leung, A. N. 2011; 258 (2): 645-648

    View details for DOI 10.1148/radiol.10082169

    View details for Web of Science ID 000286653700037

    View details for PubMedID 21273527

  • I-131-Tositumomab (BexxarA (R)) vs. Y-90-Ibritumomab (ZevalinA (R)) Therapy of Low-Grade Refractory/Relapsed Non-Hodgkin Lymphoma MOLECULAR IMAGING AND BIOLOGY Iagaru, A., Mittra, E. S., Ganjoo, K., Knox, S. J., Goris, M. L. 2010; 12 (2): 198-203


    The American Cancer Society estimated 66,120 new cases of non-Hodgkin lymphoma (NHL) in the USA in 2008. Radioimmunotherapy has been shown in clinical trials to be an effective treatment for refractory/relapsed NHL. The available agents are Bexxar, a (131)I radiolabeled murine monoclonal antibody, and Zevalin, a (90)Y radiolabeled murine antibody. Both target CD20 receptors present on the surface of lymphocytes. We present our clinical experience with Bexxar and Zevalin in the management of low-grade refractory or relapsed NHL.This is a retrospective study (Jan 2000-Jul 2006) of 67 patients with NHL, who were treated with Bexxar (31 patients, group A) or Zevalin (36 patients, group B) for refractory/relapsed disease. Group A included 16 men and 15 women, 35-81 years old (average, 59.3 +/- 13.4). Group B included 27 men and nine women, 36-85 years old (average, 55.4 +/- 13.8). Therapeutic doses ranged 40-138 mCi (average, 78.1 +/- 28.2) for Bexxar and 17-34 mCi (average, 28.8 +/- 4.37) for Zevalin.Objective responses were induced in 22 of the 31 patients (70.9%) in group A and 28 of the 36 patients (77.8%) in group B. Complete response was noted in 11 patients (35.5%), partial response in seven patients (22.6%), and mixed response in four patients (12.9%) in group A. There were five patients (16.1%) with stable disease and four patients (12.9%) with disease progression in the same group. Complete response was noted in 15 patients (41.7%), partial response in nine patients (25%), and mixed response in four patients (11.1%) in group B. There were four patients (11.1%) with stable disease and another four patients (11.1%) with disease progression in the same group. The average decreases at posttherapy nadir were 36.9% +/- 0.33 (group A) and 52.6% +/- 0.32 (group B) for platelets, 27.8% +/- 0.27 (group A) and 34.2% +/- 0.38 (group B) for leukocytes, and 4.9% +/- 0.15 (group A) and 7.6% +/- 0.11 (group B) for hemoglobin. Grades 3 and 4 hematological toxicity occurred in 14 patients (45.2%) treated with Bexxar and 22 patients (61.1%) treated with Zevalin, but was reversible.Our study suggests that clinical practice of Bexxar and Zevalin radioimmunotherapy is an effective and safe adjunctive treatment for patients with NHL refractory/relapsed to conventional treatment. However, due to the small number of subjects, it was not possible to determine whether differences in the outcomes or toxicities from the two agents were statistically significant.

    View details for DOI 10.1007/s11307-009-0245-9

    View details for Web of Science ID 000275974900010

    View details for PubMedID 19543946

  • Efficacy of F-18-FDG PET/CT in the evaluation of patients with recurrent cervical carcinoma EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Mittra, E., El-Maghraby, T., Rodriguez, C. A., Quon, A., McDougall, I. R., Gambhir, S. S., Iagaru, A. 2009; 36 (12): 1952-1959


    Only a limited number of studies have evaluated the efficacy of 18F-FDG PET/CT for recurrent cervical carcinoma, which this study seeks to expand upon.This is a retrospective study of 30 women with cervical carcinoma who had a surveillance PET/CT after initial therapy. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated using a 2 × 2 contingency table with pathology results (76%) or clinical follow-up (24%) as the gold standard. The Wilson score method was used to perform 95% confidence interval estimations.The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT for the detection of local recurrence at the primary site were 93, 93, 93, 86, and 96%, respectively. The same values for the detection of distant metastases were 96, 95, 95, 96, and 95%, respectively. Seventy-one percent of the scans performed in symptomatic patients showed true-positive findings. In comparison, 44% of scans performed in asymptomatic patients showed true-positive findings. But, all patients subsequently had a change in their management based on the PET/CT findings such that the effect was notable. The maximum standardized uptake value ranged from 5 to 28 (average: 13 ± 7) in the primary site and 3 to 23 (average: 8 ± 4) in metastases which were significantly different (p = 0.04).This study demonstrates favorable efficacy of 18F-FDG PET/CT for identification of residual/recurrent cervical cancer, as well as for localization of distant metastases.

    View details for DOI 10.1007/s00259-009-1206-x

    View details for Web of Science ID 000271979300004

    View details for PubMedID 19585114

  • Cutaneous Graft-Versus-Host Disease on Tc-99m Leukocyte Scintigraphy CLINICAL NUCLEAR MEDICINE Mittra, E., McDougall, I. R. 2009; 34 (12): 894-895

    View details for Web of Science ID 000272363600012

    View details for PubMedID 20139825

  • Novel Strategy for a Cocktail F-18-Fluoride and F-18-FDG PET/CT Scan for Evaluation of Malignancy: Results of the Pilot-Phase Study JOURNAL OF NUCLEAR MEDICINE Iagaru, A., Mittra, E., Yaghoubi, S. S., Dick, D. W., Quon, A., Goris, M. L., Gambhir, S. S. 2009; 50 (4): 501-505


    (18)F-FDG PET/CT is used for detecting cancer and monitoring cancer response to therapy. However, because of the variable rates of glucose metabolism, not all cancers are identified reliably. Sodium (18)F was previously used for bone imaging and can be used as a PET/CT skeletal tracer. The combined administration of (18)F and (18)F-FDG in a single PET/CT study for cancer detection has not been reported to date.This is a prospective pilot study (November 2007-November 2008) of 14 patients with proven malignancy (6 sarcoma, 3 prostate cancer, 2 breast cancer, 1 colon cancer, 1 lung cancer, and 1 malignant paraganglioma) who underwent separate (18)F PET/CT and (18)F-FDG PET/CT and combined (18)F/(18)F-FDG PET/CT scans for the evaluation of malignancy (a total of 3 scans each). There were 11 men and 3 women (age range, 19-75 y; average, 50.4 y).Interpretation of the combined (18)F/(18)F-FDG PET/CT scans compared favorably with that of the (18)F-FDG PET/CT (no lesions missed) and the (18)F PET/CT scans (only 1 skull lesion seen on an (18)F PET/CT scan was missed on the corresponding combined scan). Through image processing, the combined (18)F/(18)F-FDG scan yielded results for bone radiotracer uptake comparable to those of the (18)F PET/CT scan performed separately.Our pilot-phase prospective trial demonstrates that the combined (18)F/(18)F-FDG administration followed by a single PET/CT scan is feasible for cancer detection. This combined method opens the possibility for improved patient care and reduction in health care costs.

    View details for DOI 10.2967/jnumed.108.058339

    View details for Web of Science ID 000272487200003

    View details for PubMedID 19289439

  • Positron Emission Tomography/Computed Tomography: The Current Technology and Applications RADIOLOGIC CLINICS OF NORTH AMERICA Mittra, E., Quon, A. 2009; 47 (1): 147-?


    Positron emission tomography (PET) and combined PET/CT provide powerful metabolic and anatomical information together in a single exam. This article reviews the fundamentals of PET physics, the state of the art and future directions in PET technology, and the current clinical applications of PET. The latter is quite diverse and includes oncology, cardiology, neurology, and infection and inflammation imaging, all with FDG as the tracer. Additionally, novel radiopharmeuticals are under development, many of which are target cellular processes that are more specific than glucose metabolism.

    View details for DOI 10.1016/j.rcl.2008.10.005

    View details for Web of Science ID 000263843900012

    View details for PubMedID 19195540

  • F-18-FDG PET/CT evaluation of patients with ovarian carcinoma NUCLEAR MEDICINE COMMUNICATIONS Iagaru, A. H., Mittra, E. S., McDougall, I. R., Quon, A., Gambhir, S. S. 2008; 29 (12): 1046-1051


    The role of F-FDG PET has been studied in ovarian carcinoma, but its sensitivity and specificity calculations are based on dedicated PET acquisition, not PET/CT in the majority of the published studies. Therefore, we were prompted to review our experience with PET/CT in the management of patients with ovarian carcinoma.This is a retrospective study of 43 women with ovarian carcinoma, 27-80 years old (average: 53.9+/-7.8), who had whole-body PET/CT at our institution from 1 January 2003 to 31 August 2006. We reviewed the patients' outcomes from medical records and compared them to the interpretation of the PET/CT scans. Sensitivity and specificity were calculated using a 2 x 2 table with pathology results (79.1% of the patients) or clinical follow-up (20.9% of the cases) as the 'gold standard'. Confidence interval (CI) estimations were performed using the Wilson score method.All patients had advanced stage ovarian cancer and the study was requested for re-staging. A total of 60 scans were performed: 30 patients had one scan, nine patients had two scans and four patients had three scans. The administered doses of F-FDG ranged from 381.1 to 769.6 MBq (average: 569.8+/-73.3). PET/CT had a sensitivity of 88.4% (95% CI: 75.1-95.4) and a specificity of 88.2% (95% CI: 64.4-97.9) for detection of ovarian cancer. The SUV max of the detected lesions ranged from 3 to 27 (average: 9.4+/-5.9). The CA-125 tumor marker ranged from 3 to 935 kU/ml (average: 265.2) in patients with positive scans and 4-139 kU/ml (average: 17.1) in patients with negative scans. This difference was statistically significant (P value: 0.0242).This study confirms the good results of F-FDG PET/CT for identification of residual/recurrent ovarian cancer, as well as for distant metastases localization. PET/CT should be an integral part in evaluation of patients with high-risk ovarian cancer or rising values of tumor markers (CA-125), prior to selection of the most appropriate therapy.

    View details for DOI 10.1097/MNM.0b013e32831089cb

    View details for Web of Science ID 000261164200004

    View details for PubMedID 18987524

  • Uncommon causes of thyrotoxicosis JOURNAL OF NUCLEAR MEDICINE Mittra, E. S., Niederkohr, R. D., Rodriguez, C., El-Maghraby, T., McDougall, I. R. 2008; 49 (2): 265-278


    Apart from the common causes of thyrotoxicosis, such as Graves' disease and functioning nodular goiters, there are more than 20 less common causes of elevated free thyroid hormones that produce the symptoms and signs of thyrotoxicosis. This review describes these rarer conditions and includes 14 illustrative patients. Thyrotropin and free thyroxine should be measured and, when the latter is normal, the free triiodothyronine level should be obtained. Measurement of the uptake of (123)I is recommended for most patients.

    View details for DOI 10.2967/jnumed.107.041202

    View details for Web of Science ID 000252866300035

    View details for PubMedID 18199610

  • Evaluation of trabecular mechanical and microstructural properties in human calcaneal bone of advanced age using mechanical testing, mu CT, and DXA JOURNAL OF BIOMECHANICS Mittra, E., Rubin, C., Gruber, B., Qin, Y. 2008; 41 (2): 368-375


    Early detection of fracture risk is important for initiating treatment and improving outcomes from both physiologic and pathologic causes of bone loss. While bone mineral density (a quantity measure) has traditionally been used for this purpose, alternative structural imaging parameters (quality measures) are proposed to better predict bone's true mechanical properties. To further elucidate this, trabecular bone from cadaveric human calcanei were used to evaluate the interrelationship of mechanical and structural parameters using mechanical testing, dual energy X-ray absorptiometry (DXA) scanning, and micro computed tomography (microCT) imaging. Directional specific structural properties were assessed in three-dimensional (3-D) and correlated to mechanical testing and DXA. The results demonstrated that microCT-derived indices of bone quality (i.e., volume fraction and structural model index) are better than DXA-derived bone mineral density for the prediction of the mechanical parameters of bone (i.e., elastic modulus, yield stress, and ultimate stress). Diagnostically, this implies that future work on the early prediction of fracture risk should focus as much on bone quality as on quantity. Furthermore, the results of this study show that a loss of bone primarily affects the connectedness and overall number of trabeculae. Ultimate stress, however, is better correlated with trabecular number than thickness. As such, primary prevention of osteoporosis may be more important than later countermeasures for bone loss.

    View details for DOI 10.1016/j.jbiomech.2007.09.003

    View details for Web of Science ID 000253219800016

    View details for PubMedID 17953972

  • Concurrent metabolic and osseous metastatic disease on a Tc99m-MDP bone scan EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING Mittra, E., Segall, G. 2007; 34 (12): 2150-2150

    View details for DOI 10.1007/s00259-007-0535-x

    View details for Web of Science ID 000251370400034

    View details for PubMedID 17874099

  • Comparative morphometrics of the primate apical tuft AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY Mittra, E. S., Smith, H. F., Lemelin, P., Jungers, W. L. 2007; 134 (4): 449-459


    The relationship between the structure and function of the primate apical tuft is poorly understood. This study addresses several hypotheses about apical tuft morphology using a large modern primate comparative sample. Two indices of tuft size are employed: expansion and robusticity. First, comparisons of relative apical tuft size were drawn among extant nonhuman primate groups in terms of locomotion and phylogenetic category. Both of these factors appear to play a role in apical tuft size among nonhuman primates. Suspensory primates and all platyrrhines had the smallest apical tufts, while terrestrial quadrupeds and all strepsirrhines (regardless of locomotor category) had the largest tufts. Similarly, hypotheses regarding the apical tufts of hominins, especially the large tufts of Neandertals were addressed using a comparison of modern warm- and cold-adapted humans. The results showed that cold-adapted populations possessed smaller apical tufts than did warm-adapted groups. Therefore, the cold-adaptation hypothesis for Neandertal distal phalangeal morphology is not supported. Also, early modern and Early Upper Paleolithic humans had apical tufts that were significantly less expanded and less robust than those of Neandertals. The hypothesis that a large apical tuft serves as support for an expanded digital pulp is supported by radiographic analysis of modern humans in that a significant correlation was discovered between the width of the apical tuft and the width of the pulp. The implications of these findings for hypotheses about the association of apical tuft size and tool making in the hominin fossil record are discussed.

    View details for DOI 10.1002/ajpa.20687

    View details for Web of Science ID 000251098500002

    View details for PubMedID 17657781

  • A case of three synchronous primary tumors demonstrated by F-18FDG PET CLINICAL NUCLEAR MEDICINE Mittra, E., Vasanawala, M., Niederkohr, R., Rodriguez, C., Segall, G. 2007; 32 (8): 666-667


    We present an F-18 FDG PET scan which demonstrates 3 synchronous primary malignancies. The patient is a 61-year-old man who presented with weight loss and dysphagia. He was initially diagnosed with squamous cell carcinoma of the midesophagus, and was then found to have an adenocarcinoma in the right lung. A staging PET scan additionally showed increased left tonsillar uptake. Subsequent biopsy confirmed squamous cell carcinoma of the left tonsil. The demonstration of 3 synchronous primaries by PET is probably rare.

    View details for Web of Science ID 000248382000022

    View details for PubMedID 17667450

  • Recurrent silent thyroiditis: A report of four patients and review of the literature THYROID Mittra, E. S., McDougall, I. R. 2007; 17 (7): 671-675


    Silent thyroiditis, excluding postpartum thyroiditis and destructive amiodarone thyroiditis, is a relatively uncommon cause of thyrotoxicosis and recurrent cases are even rarer. We present four patients with recurrent silent thyroiditis. The number of episodes ranged from two to nine. All four patients had episodes that were similar in duration (4-6 weeks) as well as in their clinical (no viral prodrome or neck pain), biochemical (high total triiodothyronine [T(3)], free thyroxine [T(4)], and low thyrotropin [TSH] presence of antibodies to thyroid antigens), and scintigraphic (low radioiodine uptake) findings. Individual symptoms and symptom-free duration (from 1 to 4 years) were more variable. No associations were found with regard to medications, pregnancies, or other disease states previously implicated in thyroiditis. One patient was unsuccessfully prescribed thyroid hormone to prevent recurrence. Three were treated with radioablative iodine therapy during the recovery phase of an episode; they became hypothyroid and take replacement l-thyroxine. They have remained symptom free.

    View details for DOI 10.1089/thy.2006.0335

    View details for Web of Science ID 000248742000011

    View details for PubMedID 17696838

  • The effects of embedding material, loading rate and magnitude, and penetration depth in nanoindentation of trabecular bone. Journal of biomedical materials research. Part A Mittra, E., Akella, S., Qin, Y. 2006; 79 (1): 86-93


    Understanding the pathophysiology of metabolic bone disease requires the characterization of both the quantity as well as the quality (i.e., microarchitecture and material properties) of the bone tissue. Nanoindentation provides a powerful yet simple method to measure the nano/micro mechanical properties of bone, but no uniform testing methodology exists. This study examines the effects of embedding materials, rate and depth of indentation, and storage time on the measured modulus. Nineteen trabecular bone samples were evaluated for the study. Although there was an 8-fold increase in the stiffness of the soft to hard epoxy, bone tissue modulus was not affected by the stiffness of the embedding materials, but hardness was affected by both the embedding material modulus, for example from 0.70 +/- 0.20 GPa (ME(low)) to 0.45 +/- 0.21 GPa (ME(Med)) (p < 0.01), and viscosity (p < 0.01). No significant differences were found with regard to the tested rates and depths of indentation for either elastic modulus or hardness. The tissue modulus tested at the 6-month time point was significantly greater in comparison with that tested at 0 or 3 months (p < 0.01). The hardness, however, did not significantly change over the span of 6 months. The results show that while nanoindentation is powerful, it is particularly sensitive to certain testing variables.

    View details for PubMedID 16758456

  • Determination of ultrasound phase velocity in trabecular bone using time dependent phase tracking technique JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Lin, W., Mittra, E., Qin, Y. X. 2006; 128 (1): 24-29


    Ultrasound velocity is one of the key acoustic parameters for noninvasive diagnosis of osteoporosis. Ultrasound phase velocity can be uniquely measured from the phase of the ultrasound signal at a specified frequency. Many previous studies used fast Fourier transform (FFT) to determine the phase velocity, which may cause errors due to the limitations of FFT. The new phase tracking technique applied an adaptive tracking algorithm to detect the time dependent phase and amplitude of the ultrasound signal at a specified frequency. This overcame the disadvantages of FFT to ensure the accuracy of the ultrasound phase velocity. As a result, the new method exhibited high accuracy in the measurement of ultrasound phase velocity of two phantom blocks with the error less than 0.4%. 41 cubic trabecular samples from sheep femoral condyles were used in the study. The phase velocity of the samples using the new method had significantly high correlation to the bulk stiffness of the samples (r = 0.84) compared to the phase velocity measured using fast Fourier transform FFT (r = 0.14). In conclusion, the new method provided an accurate measurement of the ultrasound phase velocity in bone.

    View details for DOI 10.1115/1.2132369

    View details for Web of Science ID 000235264700005

    View details for PubMedID 16532614

  • Interrelationship of trabecular mechanical and microstructural properties in sheep trabecular bone JOURNAL OF BIOMECHANICS Mittra, E., Rubin, C., Qin, Y. X. 2005; 38 (6): 1229-1237


    The ability to evaluate fracture risk at an early time point is essential for improved prognostics as well as enhanced treatment in cases of bone loss such as from osteoporosis. Improving the diagnostic ability is inherent upon both high-resolution non-invasive imaging, and a thorough understanding of how the derived indices of structure and density relate to its true mechanical behavior. Using sheep femoral trabecular bone with a range of strength, the interrelationship of mechanical and microstructural parameters was analyzed using multi-directional mechanical testing and micro-computed tomography. Forty-five cubic trabecular bone samples were harvested from 23 adult female sheep, some of whom had received hind-limb vibratory stimuli over the course of 2 years with consequently enhanced mechanical properties. These samples were pooled into a low, medium, or high strength group for further analysis. The findings show that microCT indices that are structural in nature, e.g., structural model index (SMI) (r2=0.85, p<0.0001) is as good as more density oriented indices like bone volume/total volume (BV/TV) (r2=0.81, p<0.0001) in predicting the ultimate strength of a region of trabecular bone. Additionally, those indices more related to global changes in trabecular structure such as connectivity density (ConnD) or degree of anisotropy (DA) are less able to predict the mechanical properties of bone. Interrelationships of trabecular indices such as trabecular number (TbN), thickness (TbTh), and spacing (TbSp) provide clues as to how the trabecular bone will remodel to ultimately achieve differences in the apparent mechanical properties. For instance, the analysis showed that a loss of bone primarily affects the connectedness and overall number of trabeculae, while increased strength results in an increase of the overall thickness of trabeculae while not improving the connectedness. Certainly, the microCT indices studied are able to predict the bulk mechanical properties of a trabecular ROI well, leaving unaccounted only about 15-20% of its inherent variability. Diagnostically, this implies that future work on the early prediction of fracture risk should continue to explore the role of bone quality as the key factors or as an adjuvant to bone quantity (e.g., apparent density).

    View details for DOI 10.1016/j.jbiomech.2004.06.007

    View details for Web of Science ID 000229453600005

    View details for PubMedID 15863107

  • Quantity and quality of trabecular bone in the femur are enhanced by a strongly anabolic, noninvasive mechanical intervention JOURNAL OF BONE AND MINERAL RESEARCH Rubin, C., TURNER, A. S., Muller, R., Mittra, E., McLeod, K., Lin, W., Qin, Y. X. 2002; 17 (2): 349-357


    The skeleton's sensitivity to mechanical stimuli represents a critical determinant of bone mass and morphology. We have proposed that the extremely low level (< 10 microstrain), high frequency (20-50 Hz) mechanical strains, continually present during even subtle activities such as standing are as important to defining the skeleton as the larger strains typically associated with vigorous activity (>2000 microstrain). If these low-level strains are indeed anabolic, then this sensitivity could serve as the basis for a biomechanically based intervention for osteoporosis. To evaluate this hypothesis, the hindlimbs of adult female sheep were stimulated for 20 minutes/day using a noninvasive 0.3g vertical oscillation sufficient to induce approximately 5 microstrain on the cortex of the tibia. After 1 year of stimulation, the physical properties of 10-mm cubes of trabecular bone from the distal femoral condyle of experimental animals (n = 8) were compared with controls (n = 9), as evaluated using microcomputed tomography (microCT) scanning and materials testing. Bone mineral content (BMC) was 10.6% greater (p < 0.05), and the trabecular number (Tb.N) was 8.3% higher in the experimental animals (p < 0.01), and trabecular spacing decreased by 11.3% (p < 0.01), indicating that bone quantity was increased both by the creation of new trabeculae and the thickening of existing trabeculae. The trabecular bone pattern factor (TBPf) decreased 24.2% (p < 0.03), indicating trabecular morphology adapting from rod shape to plate shape. Significant increases in stiffness and strength were observed in the longitudinal direction (12.1% and 26.7%, respectively; both, p < 0.05), indicating that the adaptation occurred primarily in the plane of weightbearing. These results show that extremely low level mechanical stimuli improve both the quantity and the quality of trabecular bone. That these deformations are several orders of magnitude below those peak strains which arise during vigorous activity indicates that this biomechanically based signal may serve as an effective intervention for osteoporosis.

    View details for Web of Science ID 000173380000019

    View details for PubMedID 11811566

  • Lack of hand preference in wild Hanuman langurs (Presbytis entellus) AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY Mittra, E. S., FUENTES, A., McGrew, W. C. 1997; 103 (4): 455-461


    Although there is a vast literature on laterality of hand-use in nonhuman primates, the Colobinae have been notably overlooked. Ten manual activities of differing complexity were studied in five male and five female adult Hanuman langurs (Presbytis entellus) from a well habituated, wild population at Ramnagar, in southern Nepal. The activities recorded were carry, eat, hit, hold, idle, manipulate, reach, retrieve, self-groom and social groom. This study aimed to examine handedness across tasks and across subjects in a natural population. The overall result was a lack of preference for subjects and patterns. Only in the eating activity did four individuals show significant hand preference, though they were not unidirectional. Eat seemed to be loosely associated with hold due to the requirements of the strata which the monkeys utilize. These results suggest that hand use is unlateralized in P. entellus. Those individuals exhibiting some hand preferences can be viewed as statistical exceptions or perhaps subject to experiential differences. The results are discussed in terms of their evolutionary significance and methodological implications.

    View details for Web of Science ID A1997XU60600003

    View details for PubMedID 9292163

Conference Proceedings

  • The Impact of Partial Volume Correction in the Evaluation of Solitary Pulmonary Nodules by FDG PET/CT in a Population at Intermediate Risk of Lung Cancer Keu, K., Nair, V. S., Mittra, E., Gambhir, S. S., Iagaru, A. SPRINGER. 2012: S455-S455
  • Efficacy of F-18-FDG PET/CT for Breast Cancer Mittra, E., Quon, A., Gambhir, S. S., Iagaru, A. SPRINGER. 2009: S176-S176

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