Hong Song, MD, PhD

All Publications

• [18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue. Communications biology Levi, J., Guglielmetti, C., Henrich, T. J., Yoon, J. C., Gokhale, P. C., Reardon, D. A., Packiasamy, J., Huynh, L., Cabrera, H., Ruzevich, M., Blecha, J., Peluso, M. J., Huynh, T. L., An, S. M., Dornan, M., Belanger, A. P., Nguyen, Q. D., Seo, Y., Song, H., Chaumeil, M. M., VanBrocklin, H. F., Chae, H. D. 2024; 7 (1): 793

  Abstract

  Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

  View details for DOI 10.1038/s42003-024-06494-x

  View details for PubMedID 38951146

  View details for PubMedCentralID 7998027

• Alpha and Beta Radiation for Theragnostics. PET clinics Song, H., Sgouros, G. 2024

  Abstract

  Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials. Despite these advancements, the scope of TRT in treating diverse solid tumors and integration with other therapies like immunotherapy remains under investigation. The success of antibody-drug conjugates further complements treatments with TRT, though challenges in treatment optimization continue.

  View details for DOI 10.1016/j.cpet.2024.03.006

  View details for PubMedID 38688775

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

  Abstract

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

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

  View details for PubMedID 38635050

• 68Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial. The Lancet. Oncology Duan, H., Moradi, F., Davidzon, G. A., Liang, T., Song, H., Loening, A. M., Vasanawala, S., Srinivas, S., Brooks, J. D., Hancock, S., Iagaru, A. 2024

  Abstract

  National Comprehensive Cancer Network guidelines include prostate-specific membrane antigen (PSMA)-targeted PET for detection of biochemical recurrence of prostate cancer. However, targeting a single tumour characteristic might not be sufficient to reflect the full extent of disease. Gastrin releasing peptide receptors (GRPR) have been shown to be overexpressed in prostate cancer. In this study, we aimed to evaluate the diagnostic performance of the GRPR-targeting radiopharmaceutical 68Ga-RM2 in patients with biochemical recurrence of prostate cancer.This single-centre, single-arm, phase 2/3 trial was done at Stanford University (USA). Adult patients (aged ≥18 years) with biochemical recurrence of prostate cancer, a Karnofsky performance status of 50 or higher, increasing prostate-specific antigen concentration 0·2 ng/mL or more after prostatectomy or 2 ng/mL or more above nadir after radiotherapy, and non-contributory conventional imaging (negative CT or MRI, and bone scan) were eligible. All participants underwent 68Ga-RM2 PET-MRI. The primary outcome was the proportion of patients with PET-positive findings on 68Ga-RM2 PET-MRI compared with MRI alone after initial therapy, at a per-patient and per-lesion level. The primary outcome would be considered met if at least 30% of patients had one or more lesions detected by 68Ga-RM2 PET-MRI and the detection by 68Ga-RM2 PET-MRI was significantly greater than for MRI. Each PET scan was interpreted by three independent masked readers using a standardised evaluation criteria. This study is registered with ClinicalTrials.gov, NCT02624518, and is complete.Between Dec 12, 2015, and July 27, 2021, 209 men were screened for eligibility, of whom 100 were included in analyses. Median follow-up was 49·3 months (IQR 36·7-59·2). The primary endpoint was met; 68Ga-RM2 PET-MRI was positive in 69 (69%) patients and MRI alone was positive in 40 (40%) patients (p<0·0001). In the per-lesion analysis 68Ga-RM2 PET-MRI showed significantly higher detection rates than MRI alone (143 vs 96 lesions; p<0·0001). No grade 1 or worse events were reported.68Ga-RM2 PET-MRI showed better diagnostic performance than MRI alone in patients with biochemical recurrence of prostate cancer. Further prospective comparative studies with PSMA-targeted PET are needed to gain a better understanding of GRPR and PSMA expression patterns in these patients.The US Department of Defense.

  View details for DOI 10.1016/S1470-2045(24)00069-X

  View details for PubMedID 38423030

• Real world outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with lutetium-177-PSMA-vipivotide tetraxetan (Lu177-PVT) Bergstrom, C. P., Song, H., Ruiz, S., Chien, J., Moore, K., Parikh, D., Shah, S., Fan, A. C., Srinivas, S., Iagaru, A., Khaki, A. LIPPINCOTT WILLIAMS & WILKINS. 2024: 86

  View details for DOI 10.1200/JCO.2024.42.4_suppl.86

  View details for Web of Science ID 001266676900238

• COMBAT: A study of <SUP>64</SUP>Cu-SAR-BBN and <SUP>67</SUP>Cu-SAR-BBN for identification and treatment of GRPr-expressing metastatic castrate-resistant prostate cancer. Nordquist, L. T., Lengyelova, E., Almaguel, F., Mancini, B., Song, H., Armstrong, A. J., Zurita, A. J., Anderson, M., Parker, M., Miller, R. M., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2024: TPS247

  View details for DOI 10.1200/JCO.2024.42.4_suppl.TPS247

  View details for Web of Science ID 001266676900673

• Analysing the tumor transcriptome of prostate cancer to predict efficacy of Lu-PSMA therapy. Journal for immunotherapy of cancer Handke, A., Kesch, C., Fendler, W. P., Telli, T., Liu, Y., Hakansson, A., Davicioni, E., Hughes, J., Song, H., Lueckerath, K., Herrmann, K., Hadaschik, B., Seifert, R. 2023; 11 (10)

  Abstract

  177Lu-PSMA ([177Lu]Lutetium-PSMA-617) therapy is an effective treatment option for patients with prostate specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer, but still shows a non-responder rate of approximately 30%. Combination regimes of programmed death-ligand 1 (PD-L1) inhibition and concomitant 177Lu-PSMA therapy have been proposed to increase the response rate. However, the interplay of immune landscape and 177Lu-PSMA therapy efficacy is poorly understood.Between March 2018 and December 2021, a total of 168 patients were referred to 177Lu-PSMA therapy in our department and received a mean total dose of 21.9 GBq (three cycles in mean). All patients received baseline PSMA positron emission tomography to assess the PSMA uptake. The histopathological specimen of the primary prostate tumor was available with sufficient RNA passing quality control steps for genomic analysis in n=23 patients. In this subset of patients, tumor RNA transcriptomic analyses assessed 74 immune-related features in total, out of which n=24 signatures were not co-correlated and investigated further for outcome prognostication.In the subset of patients who received 177Lu-PSMA therapy, PD-L1 was not significantly associated with OS (HR per SD change (95% CI) 0.74 (0.42 to 1.30); SD: 0.18; p=0.29). In contrast, PD-L2 signature was positively associated with longer OS (HR per SD change 0.46 (95% CI 0.29 to 0.74); SD: 0.24; p=0.001; median OS 17.2 vs 5.7 months in higher vs lower PD-L2 patients). In addition, PD-L2 signature correlated with PSA-response (ϱ=-0.46; p=0.04). The PD-L2 signature association with OS was significantly moderated by L-Lactatdehydrogenase (LDH) levels (Cox model interaction p=0.01).Higher PD-L2 signature might be associated with a better response to 177Lu-PSMA therapy and warrants further studies investigating additional immunotherapy. In contrast, PD-L1 was not associated with outcome. The protective effect of PD-L2 signature might be present only in men with lower LDH levels.

  View details for DOI 10.1136/jitc-2023-007354

  View details for PubMedID 37857524

• Modified PROMISE criteria for standardized interpretation of gastrin-releasing peptide receptor (GRPR)-targeted PET. European journal of nuclear medicine and molecular imaging Duan, H., Davidzon, G. A., Moradi, F., Liang, T., Song, H., Iagaru, A. 2023

  Abstract

  There are image interpretation criteria to standardize reporting prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET). As up to 10% of prostate cancer (PC) do not express PSMA, other targets such as gastrin-releasing peptide receptor (GRPR) are evaluated. Research on GRPR-targeted imaging has been slowly increasing in usage at staging and biochemical recurrence (BCR) of PC. We therefore propose a modification of the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria (mPROMISE) for GRPR-targeted PET.[68 Ga]Ga-RM2 PET data from initially prospective studies performed at our institution were retrospectively reviewed: 44 patients were imaged for staging and 100 patients for BCR PC. Two nuclear medicine physicians independently evaluated PET according to the mPROMISE criteria. A third expert reader served as standard reference. Interreader reliability was computed for GRPR expression, prostate bed (T), lymph node (N), skeleton (Mb), organ (Mc) metastases, and final judgment of the scan.The interrater reliability for GRPR PET at staging was moderate for GRPR expression (0.59; 95% confidence interval [CI] 0.40, 0.78), substantial for T-stage (0.78; 95% CI 0.63, 0.94), and almost perfect for N-stage (0.97; 95% CI 0.92, 1.00) and final judgment (0.92; 95% CI 0.82, 1.00). The interreader agreement at BCR showed substantial agreement for GRPR expression (0.70; 95% CI 0.59, 0.81) and final judgment (0.65; 95% CI 0.53, 0.78), while almost perfect agreement was seen across the major categories (T, N, Mb, Mc). Acceptable performance of the mPROMISE criteria was found for all subsets when compared to the standard reference.Interpreting GRPR-targeted PET using the mPROMISE criteria showed its reliability with substantial or almost perfect interrater agreement across all major categories. The proposed modification of the PROMISE criteria will aid clinicians in decreasing the level of uncertainty, and clinical trials to achieve uniform evaluation, reporting, and comparability of GRPR-targeted PET.Clinicaltrials.gov Identifier: NCT03113617 and NCT02624518.

  View details for DOI 10.1007/s00259-023-06385-z

  View details for PubMedID 37555901

  View details for PubMedCentralID 9635676

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

  View details for Web of Science ID 001053772002474

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

  Abstract

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

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

  View details for PubMedID 36869177

  View details for PubMedCentralID 6667427

• 64Cu-DOTATATE Uptake in a Pulmonary Hamartoma. Clinical nuclear medicine Song, H., Guja, K. E., Yang, E. J., Guo, H. H. 2023; 48 (1): 58-60

  Abstract

  DOTATATE PET/CT is frequently used to evaluate indeterminant pulmonary nodules suspected to be pulmonary carcinoid. We report an unexpected case of pulmonary hamartoma demonstrating 64Cu-DOTATATE uptake in a 43-year-old woman with a slowly enlarging pulmonary nodule. Histopathological staining showed somatostatin receptor 2 expression on vascular endothelial cells and a proportion of cartilage and smooth muscle cells within the hamartoma.

  View details for DOI 10.1097/RLU.0000000000004390

  View details for PubMedID 36469060

• Biodistribution of a Mitochondrial Metabolic Tracer, [18F]F-AraG, in Healthy Volunteers. Molecular imaging Levi, J., Duan, H., Yaghoubi, S., Packiasamy, J., Huynh, L., Lam, T., Shaikh, F., Behera, D., Song, H., Blecha, J., Jivan, S., Seo, Y., VanBrocklin, H. F. 2022; 2022: 3667417

  Abstract

  [18F]F-AraG is a radiolabeled nucleoside analog that shows relative specificity for activated T cells. The aim of this study was to investigate the biodistribution of [18F]F-AraG in healthy volunteers and assess the preliminary safety and radiation dosimetry.Six healthy subjects (three female and three male) between the ages of 24 and 60 participated in the study. Each subject received a bolus venous injection of [18F]F-AraG (dose range: 244.2-329.3 MBq) prior to four consecutive PET/MR whole-body scans. Blood samples were collected at regular intervals and vital signs monitored before and after tracer administration. Regions of interest were delineated for multiple organs, and the area under the time-activity curves was calculated for each organ and used to derive time-integrated activity coefficient (TIAC). TIACs were input for absorbed dose and effective dose calculations using OLINDA.PET/MR examination was well tolerated, and no adverse effects to the administration of [18F]F-AraG were noted by the study participants. The biodistribution was generally reflective of the expression and activity profiles of the enzymes involved in [18F]F-AraG's cellular accumulation, mitochondrial kinase dGK, and SAMHD1. The highest uptake was observed in the kidneys and liver, while the brain, lung, bone marrow, and muscle showed low tracer uptake. The estimated effective dose for [18F]F-AraG was 0.0162 mSv/MBq (0.0167 mSv/MBq for females and 0.0157 mSv/MBq for males).Biodistribution of [18F]F-AraG in healthy volunteers was consistent with its association with mitochondrial metabolism. PET/MR [18F]F-AraG imaging was well tolerated, with a radiation dosimetry profile similar to other commonly used [18F]-labeled tracers. [18F]F-AraG's connection with mitochondrial biogenesis and favorable biodistribution characteristics make it an attractive tracer with a variety of potential applications.

  View details for DOI 10.1155/2022/3667417

  View details for PubMedID 36072652

  View details for PubMedCentralID PMC9400547

• Results of First Interim Analysis of 68Ga-NeoB and 68Ga-PSMA R2 PET/MRI in Patients with Biochemically Recurrent Prostate Cancer Duan, H., Song, H., Davidzon, G., Moradi, F., Iagaru, A. SOC NUCLEAR MEDICINE INC. 2022

  View details for Web of Science ID 000893739700242

• PSMA theragnostics for metastatic castration resistant prostate cancer. Translational oncology Song, H., Guja, K. E., Iagaru, A. 2022; 22: 101438

  Abstract

  There has been tremendous growth in the development of theragnostics for personalized cancer diagnosis and treatment over the past two decades. In prostate cancer, the new generation of prostate specific membrane antigen (PSMA) small molecular inhibitor-based imaging agents achieve extraordinary tumor to background ratios and allow their therapeutic counterparts to deliver effective tumor doses while minimizing normal tissue toxicity. The PSMA targeted small molecule positron emission tomography (PET) agents 18F-DCFPyL (2-(3-{1-carboxy-5-((6-(18)F-fluoro-pyridine-3-carbonyl)-amino)-pentyl}-ureido)-pentanedioic acid) and Gallium-68 (68Ga)-PSMA-11 have been approved by the United States Food and Drug Administration (FDA) for newly diagnosed high risk prostate cancer patients and for patients with biochemical recurrence. More recently, the Phase III VISION trial showed that Lutetium-177 (177Lu)-PSMA-617 treatment increases progression-free survival and overall survival in patients with heavily pre-treated advanced PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we review the PSMA targeted theragnostic pairs under clinical investigation for detection and treatment of metastatic prostate cancer.

  View details for DOI 10.1016/j.tranon.2022.101438

  View details for PubMedID 35659674

• The other immuno-PET: Metabolic tracers in evaluation of immune responses to immune checkpoint inhibitor therapy for solid tumors. Frontiers in immunology Levi, J., Song, H. 2022; 13: 1113924

  Abstract

  Unique patterns of response to immune checkpoint inhibitor therapy, discernable in the earliest clinical trials, demanded a reconsideration of the standard methods of radiological treatment assessment. Immunomonitoring, that characterizes immune responses, offers several significant advantages over the tumor-centric approach currently used in the clinical practice: 1) better understanding of the drugs' mechanism of action and treatment resistance, 2) earlier assessment of response to therapy, 3) patient/therapy selection, 4) evaluation of toxicity and 5) more accurate end-point in clinical trials. PET imaging in combination with the right agent offers non-invasive tracking of immune processes on a whole-body level and thus represents a method uniquely well-suited for immunomonitoring. Small molecule metabolic tracers, largely neglected in the immuno-PET discourse, offer a way to monitor immune responses by assessing cellular metabolism known to be intricately linked with immune cell function. In this review, we highlight the use of small molecule metabolic tracers in imaging immune responses, provide a view of their value in the clinic and discuss the importance of image analysis in the context of tracking a moving target.

  View details for DOI 10.3389/fimmu.2022.1113924

  View details for PubMedID 36700226

• 18F DCFPyL PET Acquisition, Interpretation and Reporting: Suggestions Post Food and Drug Administration Approval. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Song, H., Iagaru, A., Rowe, S. P. 2021

  Abstract

  18F-DCFPyL was recently approved by the FDA for evaluation prior to definitive therapy and for biochemical recurrence. Here we focus on the key data that justify the clinical use of 18F-DCFPyL, as well as those aspects of protocol implementation and image interpretation that are important to the nuclear medicine physicians and radiologists who will interpret 18F-DCFPyL PET/CT and PET/MR scans.

  View details for DOI 10.2967/jnumed.121.262989

  View details for PubMedID 34531266

• PROSPECTIVE STUDY OF (68)GA-RM2 PET/MRI IN PATIENTS WITH BIOCHEMICALLY RECURRENT PROSTATE CANCER AND NEGATIVE CONVENTIONAL IMAGING Baratto, L., Song, H., Duan, H., Moradi, F., Davidzon, G., Iagaru, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: E1178

  View details for Web of Science ID 000693689000848

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

  View details for Web of Science ID 000693689000847

• PSMA- and GRPR-targeted PET: Results from 50 Patients with Biochemically Recurrent Prostate Cancer. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Baratto, L., Song, H., Duan, H., Hatami, N., Bagshaw, H., Buyyounouski, M., Hancock, S., Shah, S. A., Srinivas, S., Swift, P., Moradi, F., Davidzon, G. A., Iagaru, A. 2021

  Abstract

  Rationale: Novel radiopharmaceuticals for positron emission tomography (PET) are evaluated for the diagnosis of biochemically recurrent prostate cancer (BCR PC). Here, we compare the gastrin releasing peptide receptors (GRPR) - targeting 68Ga-RM2 with the prostate specific membrane antigen (PSMA) - targeting 68Ga-PSMA11 and 18F-DCFPyL. Methods: Fifty patients had both 68Ga-RM2 PET/MRI and 68Ga-PSMA11 PET/CT (n = 23) or 18F-DCFPyL PET/CT (n = 27) at an interval ranging from 1 to 60 days (mean±SD: 15.8±17.7). Maximum standardized uptake values (SUVmax) were collected for all lesions. Results: RM2 PET was positive in 35 and negative in 15 of the 50 patients. PSMA PET was positive in 37 and negative in 13 of the 50 patients. Both scans detected 70 lesions in 32 patients. Forty-three lesions in 18 patients were identified only on one scan: 68Ga-RM2 detected 7 more lesions in 4 patients, while PSMA detected 36 more lesions in 13 patients. Conclusion: 68Ga-RM2 remains a valuable radiopharmaceutical even when compared with the more widely used 68Ga-PSMA11/18F-DCFPyL in the evaluation of BCR PC. Larger studies are needed to verify that identifying patients for whom these two classes of radiopharmaceuticals are complementary may ultimately allow for personalized medicine.

  View details for DOI 10.2967/jnumed.120.259630

  View details for PubMedID 33674398

• 18F-FDG PET/CT for Evaluation of Post-Transplant Lymphoproliferative Disorder (PTLD). Seminars in nuclear medicine Song, H., Guja, K. E., Iagaru, A. 2021

  Abstract

  Post-transplant lymphoproliferative disorders (PTLD) are a spectrum of heterogeneous lymphoproliferative conditions that are serious and possibly fatal complications after solid organ or allogenic hematopoietic stem cell transplantation. Most PTLD are attributed to Epstein-Barr virus reactivation in B-cells in the setting of immunosuppression after transplantation. Early diagnosis, accurate staging, and timely treatment are of vital importance to reduce morbidity and mortality. Given the often nonspecific clinical presentation and disease heterogeneity of PTLD, tissue biopsy and histopathological analysis are essential to establish diagnosis and most importantly, determine the subtype of PTLD, which guides treatment options. Advanced imaging modalities such as 18F-FDG PET/CT have played an increasingly important role and have shown high sensitivity and specificity in detection, staging, and assessing treatment response in multiple clinical studies over the last two decades. However, larger multicenter prospective validation is still needed to further establish the clinical utility of PET imaging in the management of PTLD. Significantly, new hybrid imaging modalities such as PET/MR may help reduce radiation exposure, which is especially important in pediatric transplant patients.

  View details for DOI 10.1053/j.semnuclmed.2020.12.009

  View details for PubMedID 33455722

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

  Abstract

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

  View details for DOI 10.2967/jnumed.119.231654

  View details for PubMedID 31628216

• Diagnostic 123I Whole Body Scan Prior to Ablation of Thyroid Remnant in Patients With Papillary Thyroid Cancer: Implications for Clinical Management CLINICAL NUCLEAR MEDICINE Song, H., Mosci, C., Akatsu, H., Basina, M., Dosiou, C., Iagaru, A. 2018; 43 (10): 705–9

  Abstract

  The use of I whole body scintigraphy (WBS) before I radioiodine ablation (RIA) of the post-surgical thyroid remnant in patients with papillary thyroid cancer (PTC) remains debated. The American Thyroid Association's guidelines state that WBS may be useful before RIA (rating C-expert opinion). Some institutions do not use I WBS before RIA in their routine clinical protocol. We were therefore prompted to evaluate the impact of I WBS prior to ablation of thyroid remnant in patients with PTC.We reviewed data from 152 consecutive patients with PTC who had total thyroidectomy and were referred for RIA between August 2007 and February 2009 at our institution. The group included 107 women and 45 men, 13-82 years old (mean ± SD: 45.5 ± 18.3). Three endocrinologists blinded to the results of the I WBS reviewed patients' data including sex, age, pathology, thyroglobulin (Tg) level, anti-Tg antibodies, thyroid stimulating hormone (TSH) level and ultrasound results. Each endocrinologist then returned a form with the recommended I dose for each participant, according to the following rules: 50-75 mCi (remnant ablation), 75-125 mCi (lymph nodes metastases), 150 mCi (lung metastases), and 200 mCi (bone metastases). We compared their recommended doses with the actual I doses prescribed after the pre-therapy I WBS.All three endocrinologists recommended the same dose in 98.7% of the cases. The dose prescribed by the endocrinologists matched the dose administered after analyzing the I WBS in 77 patients (51%). However, for 46 patients (30%) the endocrinologists would have given a lower dose, for 18 patients (12%) a higher dose than that administered based on the results of the I WBS, while 11 patients (7%) would have been treated unnecessarily (5/11 had no I uptake and 6/11 had I uptake in the breasts).Our study suggests a significant role of the pre-therapy I WBS in PTC patients referred for I ablation post-thyroidectomy. The actual I dose that was administered based on the I WBS differed from the dose recommended in the absence of the I WBS in 49% of the cases.

  View details for PubMedID 30153149

• Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer. Oncotarget Yoshida, T., Jin, K., Song, H., Park, S., Huso, D. L., Zhang, Z., Liangfeng, H., Zhu, C., Bruchertseifer, F., Morgenstern, A., Sgouros, G., Sukumar, S. 2016; 7 (22): 33306-15

  Abstract

  The standard treatment for ductal carcinoma in situ (DCIS) of the breast is surgical resection, followed by radiation. Here, we tested localized therapy of DCIS in mice using the immunoconjugate 225Ac linked-trastuzumab delivered through the intraductal (i.duc) route. Trastuzumab targets HER-2/neu, while the alpha-emitter 225Ac (half-life, 10 days) delivers highly cytotoxic, focused doses of radiation to tumors. Systemic 225Ac, however, elicits hematologic toxicity and at high doses free 213Bi, generated by its decay, causes renal toxicity. I.duc delivery of the radioimmunoconjugate could bypass its systemic toxicity. Bioluminescent imaging showed that the therapeutic efficacy of intraductal 225Ac-trastuzumab (10-40 nCi per mammary gland; 30-120 nCi per mouse) in a DCIS model of human SUM225 cancer cells in NSG mice was significantly higher (p<0.0003) than intravenous (120 nCi per mouse) administration, with no kidney toxicity or loss of body weight. Our findings suggest that i.duc radioimmunotherapy using 225Ac-trastuzumab deserves greater attention for future clinical development as a treatment modality for early breast cancer.

  View details for DOI 10.18632/oncotarget.8949

  View details for PubMedID 27119227

  View details for PubMedCentralID PMC5078096

• Redefining relative biological effectiveness in the context of the EQDX formalism: implications for alpha-particle emitter therapy. Radiation research Hobbs, R. F., Howell, R. W., Song, H., Baechler, S., Sgouros, G. 2014; 181 (1): 90-8

  Abstract

  Alpha-particle radiopharmaceutical therapy (αRPT) is currently enjoying increasing attention as a viable alternative to chemotherapy for targeting of disseminated micrometastatic disease. In theory, αRPT can be personalized through pre-therapeutic imaging and dosimetry. However, in practice, given the particularities of α-particle emissions, a dosimetric methodology that accurately predicts the thresholds for organ toxicity has not been reported. This is in part due to the fact that the biological effects caused by α-particle radiation differ markedly from the effects caused by traditional external beam (photon or electron) radiation or β-particle emitting radiopharmaceuticals. The concept of relative biological effectiveness (RBE) is used to quantify the ratio of absorbed doses required to achieve a given biological response with alpha particles versus a reference radiation (typically a beta emitter or external beam radiation). However, as conventionally defined, the RBE varies as a function of absorbed dose and therefore a single RBE value is limited in its utility because it cannot be used to predict response over a wide range of absorbed doses. Therefore, efforts are underway to standardize bioeffect modeling for different fractionation schemes and dose rates for both nuclear medicine and external beam radiotherapy. Given the preponderant use of external beams of radiation compared to nuclear medicine in cancer therapy, the more clinically relevant quantity, the 2 Gy equieffective dose, EQD2(α/β), has recently been proposed by the ICRU. In concert with EQD2(α/β), we introduce a new, redefined RBE quantity, named RBE2(α/β), as the ratio of the two linear coefficients that characterize the α particle absorbed dose-response curve and the low-LET megavoltage photon 2 Gy fraction equieffective dose-response curve. The theoretical framework for the proposed new formalism is presented along with its application to experimental data obtained from irradiation of a breast cancer cell line. Radiobiological parameters are obtained using the linear quadratic model to fit cell survival data for MDA-MB-231 human breast cancer cells that were irradiated with either α particles or a single fraction of low-LET (137)Cs γ rays. From these, the linear coefficient for both the biologically effective dose (BED) and the EQD2(α/β) response lines were derived for fractionated irradiation. The standard RBE calculation, using the traditional single fraction reference radiation, gave RBE values that ranged from 2.4 for a surviving fraction of 0.82-6.0 for a surviving fraction of 0.02, while the dose-independent RBE2(4.6) value was 4.5 for all surviving fraction values. Furthermore, bioeffect modeling with RBE2(α/β) and EQD2(α/β) demonstrated the capacity to predict the surviving fraction of cells irradiated with acute and fractionated low-LET radiation, α particles and chronic exponentially decreasing dose rates of low-LET radiation. RBE2(α/β) is independent of absorbed dose for α-particle emitters and it provides a more logical framework for data reporting and conversion to equieffective dose than the conventional dose-dependent definition of RBE. Moreover, it provides a much needed foundation for the ongoing development of an α-particle dosimetry paradigm and will facilitate the use of tolerance dose data available from external beam radiation therapy, thereby helping to develop αRPT as a single modality as well as for combination therapies.

  View details for DOI 10.1667/RR13483.1

  View details for PubMedID 24502376

  View details for PubMedCentralID PMC3984880

• Targeting aberrant DNA double-strand break repair in triple-negative breast cancer with alpha-particle emitter radiolabeled anti-EGFR antibody. Molecular cancer therapeutics Song, H., Hedayati, M., Hobbs, R. F., Shao, C., Bruchertseifer, F., Morgenstern, A., Deweese, T. L., Sgouros, G. 2013; 12 (10): 2043-54

  Abstract

  The higher potential efficacy of alpha-particle radiopharmaceutical therapy lies in the 3- to 8-fold greater relative biological effectiveness (RBE) of alpha particles relative to photon or beta-particle radiation. This greater RBE, however, also applies to normal tissue, thereby reducing the potential advantage of high RBE. As alpha particles typically cause DNA double-strand breaks (DSB), targeting tumors that are defective in DSB repair effectively increases the RBE, yielding a secondary, RBE-based differentiation between tumor and normal tissue that is complementary to conventional, receptor-mediated tumor targeting. In some triple-negative breast cancers (TNBC; ER(-)/PR(-)/HER-2(-)), germline mutation in BRCA-1, a key gene in homologous recombination DSB repair, predisposes patients to early onset of breast cancer. These patients have few treatment options once the cancer has metastasized. In this study, we investigated the efficacy of alpha-particle emitter, (213)Bi-labeled anti-EGF receptor antibody, cetuximab, in BRCA-1-defective TNBC. (213)Bi-cetuximab was found to be significantly more effective in the BRCA-1-mutated TNBC cell line HCC1937 than BRCA-1-competent TNBC cell MDA-MB-231. siRNA knockdown of BRCA-1 or DNA-dependent protein kinase, catalytic subunit (DNA-PKcs), a key gene in non-homologous end-joining DSB repair pathway, also sensitized TNBC cells to (213)Bi-cetuximab. Furthermore, the small-molecule inhibitor of DNA-PKcs, NU7441, sensitized BRCA-1-competent TNBC cells to alpha-particle radiation. Immunofluorescent staining of γ-H2AX foci and comet assay confirmed that enhanced RBE is caused by impaired DSB repair. These data offer a novel strategy for enhancing conventional receptor-mediated targeting with an additional, potentially synergistic radiobiological targeting that could be applied to TNBC.

  View details for DOI 10.1158/1535-7163.MCT-13-0108

  View details for PubMedID 23873849

  View details for PubMedCentralID PMC3804319

• Radiobiologic optimization of combination radiopharmaceutical therapy applied to myeloablative treatment of non-Hodgkin lymphoma. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Hobbs, R. F., Wahl, R. L., Frey, E. C., Kasamon, Y., Song, H., Huang, P., Jones, R. J., Sgouros, G. 2013; 54 (9): 1535-42

  Abstract

  Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid-1990s, such treatment strategies have only been implemented clinically recently and without a rigorous methodology for treatment optimization. Radiobiologic and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiologic normal-organ tolerance while optimizing the ratio of 2 different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-Hodgkin lymphoma (NHL) patients using (131)I-tositumomab and (90)Y-ibritumomab tiuxetan.The range of potential administered activities (AAs) is limited by the normal-organ maximum-tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose-limiting normal organs are expected to be the lungs for (131)I-tositumomab and the liver for (90)Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal-organ constraints as a function of the AAs and calculating tumor biologic effective dose (BED) along the normal-organ MTBED limits, we obtained the optimal combination of activities. The model was tested using previously acquired patient normal-organ and tumor kinetic data and MTBED values taken from the literature.The average AA value based solely on normal-organ constraints was 19.0 ± 8.2 GBq (range, 3.9-36.9 GBq) for (131)I-tositumomab and 2.77 ± 1.64 GBq (range, 0.42-7.54 GBq) for (90)Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal-organ kinetics for the 2 radiopharmaceuticals. Results included AA ranges that would deliver 95% of the maximum tumor BED, allowing for informed inclusion of clinical considerations, such as a maximum-allowable (131)I administration.A rational approach for combination radiopharmaceutical treatment has been developed within the framework of a proven 3-dimensional (3D) personalized dosimetry software, 3D-RD, and applied to the myeloablative treatment of NHL. We anticipate that combined radioisotope therapy will ultimately supplant single radioisotope therapy, much as combination chemotherapy has substantially replaced single-agent chemotherapy.

  View details for DOI 10.2967/jnumed.112.117952

  View details for PubMedID 23918734

  View details for PubMedCentralID PMC4142210

• A nephron-based model of the kidneys for macro-to-micro α-particle dosimetry. Physics in medicine and biology Hobbs, R. F., Song, H., Huso, D. L., Sundel, M. H., Sgouros, G. 2012; 57 (13): 4403-24

  Abstract

  Targeted α-particle therapy is a promising treatment modality for cancer. Due to the short path-length of α-particles, the potential efficacy and toxicity of these agents is best evaluated by microscale dosimetry calculations instead of whole-organ, absorbed fraction-based dosimetry. Yet time-integrated activity (TIA), the necessary input for dosimetry, can still only be quantified reliably at the organ or macroscopic level. We describe a nephron- and cellular-based kidney dosimetry model for α-particle radiopharmaceutical therapy, more suited to the short range and high linear energy transfer of α-particle emitters, which takes as input kidney or cortex TIA and through a macro to micro model-based methodology assigns TIA to micro-level kidney substructures. We apply a geometrical model to provide nephron-level S-values for a range of isotopes allowing for pre-clinical and clinical applications according to the medical internal radiation dosimetry (MIRD) schema. We assume that the relationship between whole-organ TIA and TIA apportioned to microscale substructures as measured in an appropriate pre-clinical mammalian model also applies to the human. In both, the pre-clinical and the human model, microscale substructures are described as a collection of simple geometrical shapes akin to those used in the Cristy-Eckerman phantoms for normal organs. Anatomical parameters are taken from the literature for a human model, while murine parameters are measured ex vivo. The murine histological slides also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus versus proximal tubule versus distal tubule. Monte Carlo simulations are run with activity placed in the different nephron compartments for several α-particle emitters currently under investigation in radiopharmaceutical therapy. The S-values were calculated for the α-emitters and their descendants between the different nephron compartments for both the human and murine models. The renal cortex and medulla S-values were also calculated and the results compared to traditional absorbed fraction calculations. The nephron model enables a more optimal implementation of treatment and is a critical step in understanding toxicity for human translation of targeted α-particle therapy. The S-values established here will enable a MIRD-type application of α-particle dosimetry for α-emitters, i.e. measuring the TIA in the kidney (or renal cortex) will provide meaningful and accurate nephron-level dosimetry.

  View details for DOI 10.1088/0031-9155/57/13/4403

  View details for PubMedID 22705986

  View details for PubMedCentralID PMC3640368

• A bone marrow toxicity model for ²²³Ra alpha-emitter radiopharmaceutical therapy. Physics in medicine and biology Hobbs, R. F., Song, H., Watchman, C. J., Bolch, W. E., Aksnes, A. K., Ramdahl, T., Flux, G. D., Sgouros, G. 2012; 57 (10): 3207-22

  Abstract

  Ra-223, an α-particle emitting bone-seeking radionuclide, has recently been used in clinical trials for osseous metastases of prostate cancer. We investigated the relationship between absorbed fraction-based red marrow dosimetry and cell level-dosimetry using a model that accounts for the expected localization of this agent relative to marrow cavity architecture. We show that cell level-based dosimetry is essential to understanding potential marrow toxicity. The GEANT4 software package was used to create simple spheres representing marrow cavities. Ra-223 was positioned on the trabecular bone surface or in the endosteal layer and simulated for decay, along with the descendants. The interior of the sphere was divided into cell-size voxels and the energy was collected in each voxel and interpreted as dose cell histograms. The average absorbed dose values and absorbed fractions were also calculated in order to compare those results with previously published values. The absorbed dose was predominantly deposited near the trabecular surface. The dose cell histogram results were used to plot the percentage of cells that received a potentially toxic absorbed dose (2 or 4 Gy) as a function of the average absorbed dose over the marrow cavity. The results show (1) a heterogeneous distribution of cellular absorbed dose, strongly dependent on the position of the cell within the marrow cavity; and (2) that increasing the average marrow cavity absorbed dose, or equivalently, increasing the administered activity resulted in only a small increase in potential marrow toxicity (i.e. the number of cells receiving more than 4 or 2 Gy), for a range of average marrow cavity absorbed doses from 1 to 20 Gy. The results from the trabecular model differ markedly from a standard absorbed fraction method while presenting comparable average dose values. These suggest that increasing the amount of radioactivity may not substantially increase the risk of toxicity, a result unavailable to the absorbed fraction method of dose calculation.

  View details for DOI 10.1088/0031-9155/57/10/3207

  View details for PubMedID 22546715

  View details for PubMedCentralID PMC3442928

• Trafficking of High Avidity HER-2/neu-Specific T Cells into HER-2/neu-Expressing Tumors after Depletion of Effector/Memory-Like Regulatory T Cells PLOS ONE Weiss, V. L., Lee, T. H., Song, H., Kouo, T. S., Black, C. M., Sgouros, G., Jaffee, E. M., Armstrong, T. D. 2012; 7 (2): e31962

  Abstract

  Cancer vaccines are designed to activate and enhance cancer-antigen-targeted T cells that are suppressed through multiple mechanisms of immune tolerance in cancer-bearing hosts. T regulatory cell (Treg) suppression of tumor-specific T cells is one barrier to effective immunization. A second mechanism is the deletion of high avidity tumor-specific T cells, which leaves a less effective low avidity tumor specific T cell repertoire available for activation by vaccines. Treg depleting agents including low dose cyclophosphamide (Cy) and antibodies that deplete CD25-expressing Tregs have been used with limited success to enhance the potency of tumor-specific vaccines. In addition, few studies have evaluated mechanisms that activate low avidity cancer antigen-specific T cells. Therefore, we developed high and low avidity HER-2/neu-specific TCR transgenic mouse colonies specific for the same HER-2/neu epitope to define the tolerance mechanisms that specifically affect high versus low avidity tumor-specific T cells.High and low avidity CD8(+) T cell receptor (TCR) transgenic mice specific for the breast cancer antigen HER-2/neu (neu) were developed to provide a purified source of naïve, tumor-specific T cells that can be used to study tolerance mechanisms. Adoptive transfer studies into tolerant FVB/N-derived HER-2/neu transgenic (neu-N) mice demonstrated that high avidity, but not low avidity, neu-specific T cells are inhibited by Tregs as the dominant tolerizing mechanism. High avidity T cells persisted, produced IFNγ, trafficked into tumors, and lysed tumors after adoptive transfer into mice treated with a neu-specific vaccine and low dose Cy to deplete Tregs. Analysis of Treg subsets revealed a Cy-sensitive CD4(+)Foxp3(+)CD25(low) tumor-seeking migratory phenotype, characteristic of effector/memory Tregs, and capable of high avidity T cell suppression.Depletion of CD25(low) Tregs allows activation of tumor-clearing high avidity T cells. Thus, the development of agents that specifically deplete Treg subsets should translate into more effective immunotherapies while avoiding autoimmunity.

  View details for DOI 10.1371/journal.pone.0031962

  View details for Web of Science ID 000302796200116

  View details for PubMedID 22359647

  View details for PubMedCentralID PMC3281086

• Tumor dosimetry and response for 153Sm-ethylenediamine tetramethylene phosphonic acid therapy of high-risk osteosarcoma. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Senthamizhchelvan, S., Hobbs, R. F., Song, H., Frey, E. C., Zhang, Z., Armour, E., Wahl, R. L., Loeb, D. M., Sgouros, G. 2012; 53 (2): 215-24

  Abstract

  (153)Sm-ethylenediamine tetramethylene phosphonic acid ((153)Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of (153)Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radiobiologic modeling and examined the relationship between tumor AD and response.Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of (153)Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of (153)Sm-EDTMP (37.0-51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after (153)Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates.On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose-treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48-14.6 and 0.98-3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93-59.3 and 1.89-12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively).The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low- and high-dose therapy, respectively. A dose-response relationship was observed for transient tumor volume shrinkage.

  View details for DOI 10.2967/jnumed.111.096677

  View details for PubMedID 22251554

  View details for PubMedCentralID PMC3291096

• Modelling and dosimetry for alpha-particle therapy. Current radiopharmaceuticals Sgouros, G., Hobbs, R. F., Song, H. 2011; 4 (3): 261-5

  Abstract

  As a consequence of the high potency and short range of alpha-particles, radiopharmaceutical therapy with alpha- particle emitting radionuclides is a promising treatment approach that is under active pre-clinical and clinical investigation. To understand and predict the biological effects of alpha-particle radiopharmaceuticals, dosimetry is required at the micro or multi-cellular scale level. At such a scale, highly non-uniform irradiation of the target volume may be expected and the utility of a single absorbed dose value to predict biological effects comes into question. It is not currently possible to measure the pharmacokinetic input required for micro scale dosimetry in humans. Accordingly, pre-clinical studies are required to provide the pharmacokinetic data for dosimetry calculations. The translation of animal data to the human requires a pharmacokinetic model that links macro- and micro-scale pharmacokinetics thereby enabling the extrapolation of micro-scale kinetics from macroscopic measurements. These considerations along with a discussion of the appropriate physical quantity and related units for alpha-particle radiopharmaceutical therapy are examined in this review.

  View details for DOI 10.2174/1874471011104030261

  View details for PubMedID 22201712

  View details for PubMedCentralID PMC4332831

• Radioimmunotherapy of solid tumors: searching for the right target. Current drug delivery Song, H., Sgouros, G. 2011; 8 (1): 26-44

  Abstract

  Radioimmunotherapy of solid tumors remains a challenge despite the tremendous success of ⁹⁰Y ibritumomab tiuxetan (Zevalin) and ¹³¹I Tositumomab (Bexxar) in treating non-Hodgkin's lymphoma. For a variety of reasons, clinical trials of radiolabeled antibodies against solid tumors have not led to responses equivalent to those seen against lymphoma. In contrast, promising responses have been observed with unlabeled antibodies that target solid tumor receptors associated with cellular signaling pathways. These observations suggest that anti-tumor efficacy of the carrier antibody might be critical to achieving clinical responses. Here, we review and compare tumor antigens targeted by radiolabeled antibodies and unlabeled antibodies used in immunotherapy. The review shows that the trend for radiolabeled antibodies under pre-clinical development is to also target antigens associated with signaling pathways that are essential for the growth and survival of the tumor.

  View details for DOI 10.2174/156720111793663651

  View details for PubMedID 21034423

  View details for PubMedCentralID PMC4337879

• Immunoliposomal delivery of 213Bi for alpha-emitter targeting of metastatic breast cancer. Cancer research Lingappa, M., Song, H., Thompson, S., Bruchertseifer, F., Morgenstern, A., Sgouros, G. 2010; 70 (17): 6815-23

  Abstract

  Current treatment for late-stage metastatic breast cancer is largely palliative. alpha-Particles are highly potent, short-range radiation emissions capable of sterilizing individual cells with one to three traversals of the cell nucleus. The alpha-emitter, (213)Bi (T(1/2) = 45.6 min), was conjugated to a 100-nm diameter liposomal-CHX-A''-DTPA construct, upon which the rat HER2/neu reactive antibody, 7.16.4, was grafted. A conjugation time of 10 minutes was achieved giving a specific activity corresponding to 0.1 (213)Bi atom per liposome; stability in vitro and in vivo was confirmed. Efficacy in a rat/neu transgenic mouse model of metastatic mammary carcinoma was investigated. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu-expressing syngeneic tumor cells, macrophage-depleted Neu-N mice were treated by i.v. injection with (a) 19.2 MBq (520 muCi) of liposome-CHX-A''-DTPA-(213)Bi, (b) 19.2 MBq of liposome-CHX-A''-DTPA-(213)Bi-7.16.4, (c) 4.44 MBq (120 muCi) of (213)Bi-7.16.4, and (d) cold (nonradioactive) liposome-CHX-A''-DTPA-7.16.4 as control. Treatment with (a) increased median survival time to 34 days compared with 29 days for the untreated controls (P = 0.013) and 27 days for treated cold controls. Treatment with the radiolabeled antibody-conjugated liposome (b) increased median survival time to 38 days (P = 0.0002 relative to untreated controls). The radiolabeled antibody-treated group (c) gave a median survival of 39 days, which was similar to that for the radiolabeled antibody-conjugated liposome-treated group (P = 0.5). We have shown that the (213)Bi radiolabeled immunoliposomes are effective in treating early-stage micrometastases, giving median survival times similar to those obtained with antibody-mediated delivery of (213)Bi in this animal model.

  View details for DOI 10.1158/0008-5472.CAN-09-4548

  View details for PubMedID 20651254

  View details for PubMedCentralID PMC2977986

• MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Sgouros, G., Roeske, J. C., McDevitt, M. R., Palm, S., Allen, B. J., Fisher, D. R., Brill, A. B., Song, H., Howell, R. W., Akabani, G., Bolch, W. E., Brill, A. B., Fisher, D. R., Howell, R. W., Meredith, R. F., Sgouros, G., Wessels, B. W., Zanzonico, P. B. 2010; 51 (2): 311-28

  Abstract

  The potential of alpha-particle emitters to treat cancer has been recognized since the early 1900s. Advances in the targeted delivery of radionuclides and radionuclide conjugation chemistry, and the increased availability of alpha-emitters appropriate for clinical use, have recently led to patient trials of radiopharmaceuticals labeled with alpha-particle emitters. Although alpha-emitters have been studied for many decades, their current use in humans for targeted therapy is an important milestone. The objective of this work is to review those aspects of the field that are pertinent to targeted alpha-particle emitter therapy and to provide guidance and recommendations for human alpha-particle emitter dosimetry.

  View details for DOI 10.2967/jnumed.108.058651

  View details for PubMedID 20080889

  View details for PubMedCentralID PMC5680544

• Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y. Cancer research Song, H., Hobbs, R. F., Vajravelu, R., Huso, D. L., Esaias, C., Apostolidis, C., Morgenstern, A., Sgouros, G. 2009; 69 (23): 8941-8

  Abstract

  alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients.

  View details for DOI 10.1158/0008-5472.CAN-09-1828

  View details for PubMedID 19920193

  View details for PubMedCentralID PMC2789180

• An immunotolerant HER-2/neu transgenic mouse model of metastatic breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research Song, H., Shahverdi, K., Huso, D. L., Wang, Y., Fox, J. J., Hobbs, R. F., Gimi, B., Gabrielson, K. L., Pomper, M. G., Tsui, B. M., Bhujwalla, Z., Reilly, R. T., Sgouros, G. 2008; 14 (19): 6116-24

  Abstract

  Animal models of breast cancer metastases that recapitulate the pattern of metastatic progression seen in patients are lacking; metastatic breast cancer models do not currently exist for evaluation of immune-mediated therapies. We have developed and characterized a preclinical model for the evaluation of immune-mediated metastatic breast cancer therapies.The NT2.5 mammary tumor cell line was injected into the left cardiac ventricle of immunotolerant transgenic neu-N mice and athymic nu/nu mice. Metastatic progression was monitored by bioluminescent, small-animal magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography/computed tomography imaging, and also by histopathology. Antigen expression in normal organs and tumor metastases was evaluated by Western blot analysis and flow cytometry.Left cardiac ventricle injection of NT2.5 cells yielded widespread metastases in bones, liver, and spleen. Three to four weeks after injection, mice exhibited hind limb paralysis and occasional abdominal enlargement. Bioluminescence imaging of metastatic progression was successful in nude mice but the bioluminescent cells were rejected in immunocompetent mice. Other imaging modalities allowed successful imaging of nonbioluminescent cells. Small-animal positron emission tomography imaging allowed visualization of disease, in vivo, in the bones and liver. Magnetic resonance imaging revealed initial dissemination of the tumor cells to the bone marrow. Small-animal single-photon emission computed tomography/computed tomography imaging identified metastatic bone lesions targeted by a radiolabeled antibody.The model closely recapitulates the pattern of metastatic spread in breast cancer. This immunotolerant metastatic model is a novel addition to existing breast cancer models and coupling the model with in vivo imaging greatly facilitates the evaluation of targeted immunotherapies of metastasis.

  View details for DOI 10.1158/1078-0432.CCR-07-4672

  View details for PubMedID 18829490

  View details for PubMedCentralID PMC2570093

• 213Bi (alpha-emitter)-antibody targeting of breast cancer metastases in the neu-N transgenic mouse model. Cancer research Song, H., Shahverdi, K., Huso, D. L., Esaias, C., Fox, J., Liedy, A., Zhang, Z., Reilly, R. T., Apostolidis, C., Morgenstern, A., Sgouros, G. 2008; 68 (10): 3873-80

  Abstract

  Treatment failure in breast cancer is largely the failure to control metastatic dissemination. In this study, we investigated the efficacy of an antibody against the rat variant of HER-2/neu, labeled with the alpha-particle emitter (213)Bi to treat widespread metastases in a rat/neu transgenic mouse model of metastatic mammary carcinoma. The model manifests wide-spread dissemination of tumor cells leading to osteolytic bone lesions and liver metastases, common sites of clinical metastases. The maximum tolerated dose was 120 muCi of (213)Bi-7.16.4. The kinetics of marrow suppression and subsequent recovery were determined. Three days after left cardiac ventricular injection of 10(5) rat HER-2/neu--expressing syngeneic tumor cells, neu-N mice were treated with (a) 120 muCi (213)Bi-7.16.4, (b) 90 muCi (213)Bi-7.16.4, (c) 120 muCi (213)Bi-Rituximab (unreactive control), and (d) unlabeled 7.16.4. Treatment with 120 muCi (213)Bi-7.16.4 increased median survival time to 41 days compared with 28 days for the untreated controls (P < 0.0001); corresponding median survival times for groups b, c, and d were 36 (P < 0.001), 31 (P < 0.01), and 33 (P = 0.05) days, respectively. Median survival relative to controls was not significantly improved in mice injected with 10-fold less cells or with multiple courses of treatment. We concluded that alpha-emitter (213)Bi-labeled monoclonal antibody targeting the HER-2/neu antigen was effective in treating early-stage HER-2/neu--expressing micrometastases. Analysis of the results suggests that further gains in efficacy may require higher specific activity constructs or target antigens that are more highly expressed on tumor cells.

  View details for DOI 10.1158/0008-5472.CAN-07-6308

  View details for PubMedID 18483272

  View details for PubMedCentralID PMC2981030

• Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. The Journal of clinical investigation Kim, P. S., Armstrong, T. D., Song, H., Wolpoe, M. E., Weiss, V., Manning, E. A., Huang, L. Q., Murata, S., Sgouros, G., Emens, L. A., Reilly, R. T., Jaffee, E. M. 2008; 118 (5): 1700-11

  Abstract

  The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8(+) neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8(+) T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.

  View details for DOI 10.1172/JCI34333

  View details for PubMedID 18398507

  View details for PubMedCentralID PMC2289797

• Cancer stem cell targeting using the alpha-particle emitter, 213Bi: mathematical modeling and feasibility analysis. Cancer biotherapy & radiopharmaceuticals Sgouros, G., Song, H. 2008; 23 (1): 74-81

  Abstract

  There is increasing recognition that treatment failure in cancer may be associated with the failure to sterilize a small subpopulation of tumor cells that have been characterized as tumor stem cells. Defined as cells that are able to self-renew and also to replenish a phenotypically diverse tumor-cell population, such cells are also considered resistant to chemotherapy. These characteristics are optimal for targeting by using alpha-particle-emitting radionuclides. Because of their high-energy deposition density per track, alpha-particles are capable of targeting single cells or small clusters of cells with minimal normal organ toxicity. The DNA damage induced by alpha-particles is largely irreparable and, therefore, alpha-particle-induced damage is minimally susceptible to resistance mechanisms. In this work, theoretical modeling was performed to examine the potential of alpha-emitter targeting of such small clusters of cancer stem cells. Critical parameters influencing efficacy and toxicity were identified and their relationship elucidated. The results identify specific activity, antigen site density, and number of target cells as critical parameters for effective cell killing and demonstrate substantial efficacy gains by targeting a smaller number of stem cells, as opposed to the entire tumor-cell population.

  View details for DOI 10.1089/cbr.2007.0408

  View details for PubMedID 18298331

  View details for PubMedCentralID PMC2977973

• Three-dimensional radiobiologic dosimetry: application of radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Prideaux, A. R., Song, H., Hobbs, R. F., He, B., Frey, E. C., Ladenson, P. W., Wahl, R. L., Sgouros, G. 2007; 48 (6): 1008-16

  Abstract

  Phantom-based and patient-specific imaging-based dosimetry methodologies have traditionally yielded mean organ-absorbed doses or spatial dose distributions over tumors and normal organs. In this work, radiobiologic modeling is introduced to convert the spatial distribution of absorbed dose into biologically effective dose and equivalent uniform dose parameters. The methodology is illustrated using data from a thyroid cancer patient treated with radioiodine.Three registered SPECT/CT scans were used to generate 3-dimensional images of radionuclide kinetics (clearance rate) and cumulated activity. The cumulated activity image and corresponding CT scan were provided as input into an EGSnrc-based Monte Carlo calculation: The cumulated activity image was used to define the distribution of decays, and an attenuation image derived from CT was used to define the corresponding spatial tissue density and composition distribution. The rate images were used to convert the spatial absorbed dose distribution to a biologically effective dose distribution, which was then used to estimate a single equivalent uniform dose for segmented volumes of interest. Equivalent uniform dose was also calculated from the absorbed dose distribution directly.We validate the method using simple models; compare the dose-volume histogram with a previously analyzed clinical case; and give the mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for an illustrative case of a pediatric thyroid cancer patient with diffuse lung metastases. The mean absorbed dose, mean biologically effective dose, and equivalent uniform dose for the tumor were 57.7, 58.5, and 25.0 Gy, respectively. Corresponding values for normal lung tissue were 9.5, 9.8, and 8.3 Gy, respectively.The analysis demonstrates the impact of radiobiologic modeling on response prediction. The 57% reduction in the equivalent dose value for the tumor reflects a high level of dose nonuniformity in the tumor and a corresponding reduced likelihood of achieving a tumor response. Such analyses are expected to be useful in treatment planning for radionuclide therapy.

  View details for DOI 10.2967/jnumed.106.038000

  View details for PubMedID 17504874

  View details for PubMedCentralID PMC2974276

• Therapeutic potential of 90Y- and 131I-labeled anti-CD20 monoclonal antibody in treating non-Hodgkin's lymphoma with pulmonary involvement: a Monte Carlo-based dosimetric analysis. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Song, H., Du, Y., Sgouros, G., Prideaux, A., Frey, E., Wahl, R. L. 2007; 48 (1): 150-7

  Abstract

  Pulmonary involvement is common in patients with non-Hodgkin's lymphoma (NHL). (90)Y- and (131)I-anti-CD20 antibodies (ibritumomab tiuxetan and tositumomab, respectively) have been approved for the treatment of refractory low-grade follicular NHL. In this work, we used Monte Carlo-based dosimetry to compare the potential of (90)Y and (131)I, based purely on their emission properties, in targeted therapy for NHL lung metastases of various nodule sizes and tumor burdens.Lung metastases were simulated as spheres, with radii ranging from 0.2 to 5.0 cm, which were randomly distributed in a voxelized adult male lung phantom. Total tumor burden was varied from 0.2 to 1,641 g. Tumor uptake and retention kinetics of the 2 radionuclides were assumed equivalent; a uniform distribution of activity within tumors was assumed. Absorbed dose to tumors and lung parenchyma per unit activity in lung tumors was calculated by a Monte Carlo-based system using the MCNP4B package. Therapeutic efficacy was defined as the ratio of mean absorbed dose in the tumor to that in normal lung. Dosimetric analysis was also performed for a lung-surface distribution of tumor nodules mimicking pleural metastatic disease.The therapeutic efficacy of both (90)Y and (131)I declined with increasing tumor burden. In treating tumors with radii less than 2.0 cm, (131)I targeting was more efficacious than (90)Y targeting. (90)Y yielded a broader distribution of tumor absorbed doses, with the minimum 54.1% lower than the average dose; for (131)I, the minimum absorbed dose was 33.3% lower than the average. The absorbed dose to normal lungs was reduced when the tumors were distributed on the lung surface. For surface tumors, the reductions in normal-lung absorbed dose were greater for (90)Y than for (131)I, but (131)I continued to provide a greater therapeutic ratio across different tumor burdens and sizes.Monte Carlo-based dosimetry was performed to compare the therapeutic potential of (90)Y and (131)I targeting of lung metastases in NHL patients. (131)I provided a therapeutic advantage over (90)Y, especially in tumors with radii less than 2.0 cm and at lower tumor burdens. For both (90)Y- and (131)I-labeled antibodies, treatment is more efficacious when applied to metastatic NHL cases with lower tumor burdens. (131)I has advantages over (90)Y in treating smaller lung metastases.

  View details for PubMedID 17204712

  View details for PubMedCentralID PMC2967041

• Lung dosimetry for radioiodine treatment planning in the case of diffuse lung metastases. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Song, H., He, B., Prideaux, A., Du, Y., Frey, E., Kasecamp, W., Ladenson, P. W., Wahl, R. L., Sgouros, G. 2006; 47 (12): 1985-94

  Abstract

  The lungs are the most frequent sites of distant metastasis in differentiated thyroid carcinoma. Radioiodine treatment planning for these patients is usually performed following the Benua-Leeper method, which constrains the administered activity to 2.96 GBq (80 mCi) whole-body retention at 48 h after administration to prevent lung toxicity in the presence of iodine-avid lung metastases. This limit was derived from clinical experience, and a dosimetric analysis of lung and tumor absorbed dose would be useful to understand the implications of this limit on toxicity and tumor control. Because of highly nonuniform lung density and composition as well as the nonuniform activity distribution when the lungs contain tumor nodules, Monte Carlo dosimetry is required to estimate tumor and normal lung absorbed dose. Reassessment of this toxicity limit is also appropriate in light of the contemporary use of recombinant thyrotropin (thyroid-stimulating hormone) (rTSH) to prepare patients for radioiodine therapy. In this work we demonstrated the use of MCNP, a Monte Carlo electron and photon transport code, in a 3-dimensional (3D) imaging-based absorbed dose calculation for tumor and normal lungs.A pediatric thyroid cancer patient with diffuse lung metastases was administered 37 MBq of (131)I after preparation with rTSH. SPECT/CT scans were performed over the chest at 27, 74, and 147 h after tracer administration. The time-activity curve for (131)I in the lungs was derived from the whole-body planar imaging and compared with that obtained from the quantitative SPECT methods. Reconstructed and coregistered SPECT/CT images were converted into 3D density and activity probability maps suitable for MCNP4b input. Absorbed dose maps were calculated using electron and photon transport in MCNP4b. Administered activity was estimated on the basis of the maximum tolerated dose (MTD) of 27.25 Gy to the normal lungs. Computational efficiency of the MCNP4b code was studied with a simple segmentation approach. In addition, the Benua-Leeper method was used to estimate the recommended administered activity. The standard dosing plan was modified to account for the weight of this pediatric patient, where the 2.96-GBq (80 mCi) whole-body retention was scaled to 2.44 GBq (66 mCi) to give the same dose rate of 43.6 rad/h in the lungs at 48 h.Using the MCNP4b code, both the spatial dose distribution and a dose-volume histogram were obtained for the lungs. An administered activity of 1.72 GBq (46.4 mCi) delivered the putative MTD of 27.25 Gy to the lungs with a tumor absorbed dose of 63.7 Gy. Directly applying the Benua-Leeper method, an administered activity of 3.89 GBq (105.0 mCi) was obtained, resulting in tumor and lung absorbed doses of 144.2 and 61.6 Gy, respectively, when the MCNP-based dosimetry was applied. The voxel-by-voxel calculation time of 4,642.3 h for photon transport was reduced to 16.8 h when the activity maps were segmented into 20 regions.MCNP4b-based, patient-specific 3D dosimetry is feasible and important in the dosimetry of thyroid cancer patients with avid lung metastases that exhibit prolonged retention in the lungs.

  View details for PubMedID 17138741

  View details for PubMedCentralID PMC2967027

• Lung toxicity in radioiodine therapy of thyroid carcinoma: development of a dose-rate method and dosimetric implications of the 80-mCi rule. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Sgouros, G., Song, H., Ladenson, P. W., Wahl, R. L. 2006; 47 (12): 1977-84

  Abstract

  Based on an extensive dataset analyzed by Benua et al., a whole-body retention threshold of 2.96 GBq (80 mCi) at 48 h has been used to limit the radioactivity of (131)I administered to thyroid cancer patients with diffuse pulmonary metastases. In this work, the 80-mCi activity retention limit is used to derive lung-absorbed doses and dose rates. The resulting dose-rate-based limits make it possible to account for patient-specific differences in lung geometry. This is particularly important, for example, in pediatric patients exhibiting diffuse lung metastases. The approach also highlights the impact of altered radioiodine kinetics as seen with recombinant human thyroid-stimulating hormone.The dose-rate constraint (DRC) was defined as the absorbed dose rate to the lungs of the adult female reference phantom when 80 mCi of (131)I are in the body and 90% of this is uniformly distributed in the lungs. With this definition, the 80-mCi rule was generalized by calculating the activity required to yield a dose rate equal to DRC using lung-to-lung S factor values corresponding to different reference phantoms.A DRC value of 43.6 cGy/h was obtained. Applying this DRC to the adult male phantom and to the phantom of a 15-y-old yields equivalent 48-h activity limits of 3.72 GBq (101 mCi) and 2.45 GBq (66.2 mCi), respectively. Depending on model parameters, the absorbed doses to lungs ranged from 57 to 112 Gy; the photon-only portion, which better reflects the dose to normal lung parenchyma, ranged from 4.9 to 55 Gy.A dose-rate-based version of the 80-mCi rule is derived and used to demonstrate application of this rule to pediatric patients and to adult male patients. The implications of the 80-mCi rule are also examined. The assumption of uniform energy deposition in the lungs leads to substantially overestimated absorbed doses. Severe radiation-induced lung toxicity, expected at normal lung absorbed doses of 25-27 Gy, is avoided, probably because most of the local electron dose is delivered to tumor tissue instead of to normal lung parenchyma. The possibility of using a DRC to adjust treatment for different clinical situations is illustrated. The analysis suggests that a dosimetry-based approach will be particularly important in the treatment of patients with lung metastases when a recombinant human thyroid-stimulating hormone protocol is used.

  View details for PubMedID 17138740

  View details for PubMedCentralID PMC2974326

• Liposome-mediated radiotherapeutics within avascular tumor spheroids: comparative dosimetry study for various radionuclides, liposome systems, and a targeting antibody. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Emfietzoglou, D., Kostarelos, K., Papakostas, A., Yang, W. H., Ballangrud, A., Song, H., Sgouros, G. 2005; 46 (1): 89-97

  Abstract

  Absorbed dose profiles within tumor spheroids simulating avascular micrometastases have been calculated for a variety of liposome- and antibody-radionuclide combinations to assess the anticipated therapeutic efficacy based on the intratumoral distribution of the carrier systems within the spheroid model.Experiments studying the targeting and diffusion capability of the most clinically relevant liposome systems and the anti-PSMA (prostate-specific membrane antigen) antibody J591 within spheroids of the prostate cancer cell line LNCaP (diameter, 150-200 mum) have been performed. The intratumoral biodistribution data were then used as the input to obtain absorbed dose profiles within the tumor spheroid mass. The dosimetric analysis was performed for a variety of medium- and high-energy beta-emitting radionuclides ((32)P, (90)Y, (188)Re, (67)Cu, (131)I) and 2 low-energy Auger or conversion electron emitters ((123)I, (125)I) following the point-kernel convolution method in the continuous slowing-down approximation.Relative absorbed dose distribution calculations as a function of the distance from the rim of the spheroids are presented. For all liposome systems studied, the SUV-DMPC-chol (small unilamellar vesicle-dimyristoyl-phosphatidylcholine-cholesterol) was most efficient in penetrating deeper within the spheroids. For the beta-emitters it delivered its maximum absorbed dose (D(max)) at 40- to 50-microm depth, exhibiting an almost flat absorbed dose profile beyond that point, as is evident by the high absorbed dose value at the center of the spheroid (D(core)), D(core)/D(max) > 0.9; the respective values for the J591 antibody were 20 mum and 0.85. The Auger or conversion emitters resulted in the most heterogeneous absorbed dose distribution; the ratio D(core)/D(max) fell to 0.4 for the SUV-DMPC-chol and to 0.4-0.5 for the antibody. In general, a 2- to 10-fold "cross-fire"-related increase of the core absorbed dose was observed. For liposomes exhibiting high binding capacity (3beta-[N-(N',N']-dimethylaminoethane)carbamoyl]cholesterol [DC-chol]), however, the low-energy emitters deliver up to a 40% higher D(max) relative to the beta-emitters. The surface characteristics of liposomes appear to have a noticeable influence on the absorbed dose profiles. The use of neutral (DMPC-chol) versus cationic (DC-chol) lipids resulted in up to a 10-fold increase of D(core)/D(max) depending on the radionuclide. Changing the cationic lipid used to N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl sulfate also had a notable influence (up to a 6-fold increase), whereas the effect of fusogenic lipids (dioleoylphosphatidylcholine) was found to be much smaller.It is possible to engineer liposome systems that are particularly effective in delivering an almost uniform absorbed dose profile at the central region of micrometastatic tumors, provided that conjugates with the appropriate radionuclides are constructed. In view of the passive means of diffusion of liposomes within solid tumors, it is suggested that they may effectively complement an antibody-based therapeutic regime against micrometastatic tumors, leading to cytotoxic absorbed dose levels throughout the entire tumor volume--thus, hindering tumor recurrence.

  View details for PubMedID 15632038

• Spatial composition of prostate cancer spheroids in mixed and static cultures. Tissue engineering Song, H., David, O., Clejan, S., Giordano, C. L., Pappas-Lebeau, H., Xu, L., O'Connor, K. C. 2004; 10 (7-8): 1266-76

  Abstract

  Aggregation of neoplastic cells produces multicellular spheroids resembling micrometastases. The objective of this study was to investigate the effects of mixing culture medium on the spatial composition of spheroids prepared from well (LNCaP) and poorly (DU 145) differentiated human prostate cancer cells. Spheroids were cultured in a mixed suspension within a high-aspect rotating wall vessel and static liquid-overlay plate. Results from this study demonstrate that mixed cultures consistently manifested differences in morphology and composition between DU 145 and LNCaP spheroids. For example, 40 +/- 12% of DU 145 cells were Ki-67 positive 100 microm from the surface within mixed spheroids versus 0% for LNCaP cells; there was no significant difference in this spatial profile for static cultures. The results suggest that poorly differentiated spheroids may be more likely to experience a change in composition from mixing culture medium than well-differentiated spheroids, due to low tissue density. Immunostaining for P-glycoprotein is representative of this trend; average staining intensity increased 50% for DU 145 spheroids on mixing but was unchanged for LNCaP spheroids. The effects of mixing on spheroid composition were attributed to faster interstitial mass transport. Applications include drug development and delivery, as well as basic research on drug action and resistance.

  View details for DOI 10.1089/ten.2004.10.1266

  View details for PubMedID 15363181

• Restructuring dynamics of DU 145 and LNCaP prostate cancer spheroids. In vitro cellular & developmental biology. Animal Song, H., Jain, S. K., Enmon, R. M., O'Connor, K. C. 2004; 40 (8-9): 262-7

  Abstract

  Neoplastic cells acquire multidrug resistance as they assemble into multicellular spheroids. Image analysis and Monte Carlo simulation provided an insight into the adhesion and motility events during spheroid restructuring in liquid-overlay culture of DU 145 and LNCaP human prostate cancer cells. Irregularly shaped, two-dimensional aggregates restructured through incremental cell movements into three-dimensional spheroids. Of the two cultures examined, restructuring was more pronounced for DU 145 aggregates. Motile DU 145 cells formed spheroids with a minimum cell overlay of 30% for 25-mers as estimated by simulation versus 5% for adhesive LNCaP cells in aggregates of the same size. Over 72 h, the texture ratio increased from 0.55 +/- 0.05 for DU 145 aggregates with projected areas exceeding 2000 microm2 to a value approaching 0.75 +/- 0.02 (P < 0.05). For LNCaP aggregates of comparable size, the increase in texture ratio was more modest, less than 15% during the same time period (P < 0.05). Combined, these data suggest that motility events govern the overall rate of spheroid restructuring. This information has application to the chemosensitization of solid tumors and kinetic modeling of spheroid production.

  View details for DOI 10.1290/0406038.1

  View details for PubMedID 15723561

• Monte Carlo simulation of LNCaP human prostate cancer cell aggregation in liquid-overlay culture. Biotechnology progress Song, H., O'Connor, K. C., Lacks, D. J., Enmon, R. M., Jain, S. K. 2003; 19 (6): 1742-9

  Abstract

  Neoplastic cells self-assemble in liquid-overlay cultures into multicellular spheroids that resemble micrometastases and avascular regions of larger tumors. A Monte Carlo simulation based on Meakin's cluster-cluster aggregation model resolved the physical mechanisms by which LNCaP human prostate cancer cells aggregate in this environment. The best-fit solution suggests that LNCaP cells aggregate with an adhesion probability of 0.5% when they migrate within a radius of influence between cell centers of 180 microm, 10 times the cell diameter. The sweeping radius of influence is indicative of cell tethering and/or chemotaxis and results in an intrinsic rate of self-aggregation that increases from k(11) = 1.5 h(-1) for single cells to k(1010) = 17.5 h(-1) for 10-mers. Similar rates are predicted by Smoluchowski's collision theory (1), suggesting that they are inherent properties of LNCaP liquid-overlay culture. Aggregates form more compact structures in culture than during simulation as measured by the fractal dimension: D(F) = 1.74 +/- 0.04 for 10-mers in culture vs D(F) = 1.25 +/- 0.10 for simulated 10-mers. Additional restructuring would further extend the radius of influence and diminish adhesion. Applications of this work include the production of highly viable spheroids for drug testing and basic oncological research.

  View details for DOI 10.1021/bp034061n

  View details for PubMedID 14656150

• Extracellular matrix substrata alter adipocyte yield and lipogenesis in primary cultures of stromal-vascular cells from human adipose. Biotechnology letters O'Connor, K. C., Song, H., Rosenzweig, N., Jansen, D. A. 2003; 25 (23): 1967-72

  Abstract

  The stromal-vascular fraction of human adipose was subjected to in vitro adipogenesis on different extracellular matrix substrata. Adipose tissue was harvested from the breast of 25 to 45 year-old female patients undergoing elective surgery. After 24 d, less than 5% of stromal-vascular cells had converted to adipocytes on fibronectin, 13% to 28% on tissue culture plastic and collagen I; and 59% +/- 7% on Matrigel. Lipid volume surpassed 4.5 x 10(3) microm3 cell(-1) for Matrigel and was 30% lower for the other substrata. Cell proliferation was evident for Matrigel and fibronectin, and cell spreading was most pronounced for fibronectin with a projected area exceeding 3 x 10(3) microm2 cell(-1). These results are relevant to the design of an adipose implant, providing insight into its feasibility and scaffold composition.

  View details for DOI 10.1023/b:bile.0000004386.08923.ab

  View details for PubMedID 14719807

• Aggregation kinetics of well and poorly differentiated human prostate cancer cells. Biotechnology and bioengineering Enmon, R. M., O'Connor, K. C., Song, H., Lacks, D. J., Schwartz, D. K. 2002; 80 (5): 580-8

  Abstract

  Aggregation of attachment-dependent animal cells represents a series of motility, collision, and adhesion events applicable to such diverse fields as tissue engineering, bioseparations, and drug testing. Aggregation of human prostate cancer cells in liquid-overlay culture was modeled using Smoluchowski's collision theory. Using well (LNCaP) and poorly differentiated (DU 145 and PC 3) cell lines, the biological relevance of the model was assessed by comparing aggregation rates with diffusive and adhesive properties. Diffusion coefficients ranged from 5 to 90 microm(2)/min for single LNCaP and PC 3 cells, respectively. Similar diffusivities were predicted by the persistent random walk model and Einstein relation, indicating random motion. LNCaP cells were the most adhesive in our study with reduced cell shedding, 100% adhesion probability, and enhanced expression of E-cadherin. There was an increase in DU 145 cells staining positive for E-cadherin from nearly 20% of single cells to uniform staining across the surface of all aggregates; under 30% of PC 3 aggregates stained positive. Aggregation rates were more consistent with adhesive properties than with motilities, suggesting that aggregation in our study was reaction-controlled. Relative to other assays employed here, aggregation rates were more sensitive to phenotypic differences in cell lines and described size-dependent changes in aggregation at a finer resolution. In particular, model results suggest similar aggregation rates for two-dimensional DU 145 and PC 3 aggregates and upwards of 4-fold higher rates for larger three-dimensional DU 145 spheroids, consistent with expression of E-cadherin. The kinetic model has application to spheroid production, to cell flocculation and as an adhesion assay.

  View details for DOI 10.1002/bit.10394

  View details for PubMedID 12355469