A Novel Dual-labeled Peptide for Multimodal Imaging of EGFR with L858R Mutation.

BACKGROUND: The development of molecular imaging agents targeting epidermal growth factor receptor (EGFR) with L858R mutation may help with the selection of non-small cell lung carcinoma (NSCLCL) patients who may benefit from EFGR tyrosine kinase inhibitor (TKI) therapy. OBJECTIVE: In this study, we developed 99mTc STHHYYP-GHEG-ECGK-tetramethylrhodamine (STHHYYP-ECGK-TAMRA) to target EGFR with L858R mutation in NSCLC tumors and verified its probability as a molecular imaging agent. METHODS: Fmoc solid-phase peptide synthesis was used to synthesize STHHYYP-ECGKTAMRA. 99mTc labelled STHHYYP-ECGK-TAMRA was prepared. Gamma imaging, fluorescent imaging and biodistribution were performed in murine models bearing NCI-H1975 and NCI-H1650 tumors. RESULTS: The binding affinity value (Kd) of 99mTc STHHYYP-ECGK-TAMRA was estimated to be 130.6 ± 29.2 nM in NCI-H1975 cells. The gamma camera images showed a substantial uptake of 99mTc STHHYYP-ECGK-TAMRA in the NCI-H1975 tumor. The % injected dose/gram of the NCI-H1975 tumor tissue was 2.77 ± 0.70 and 3.48 ± 1.01 at 1 and 3 h, respectively. CONCLUSION: Specific binding of 99mTc STHHYYP-ECGK-TAMRA to L858R-mutated EGFRpositive NCI-H1975 cells and tumors was demonstrated in in vivo and in vitro studies. The results suggest that 99mTc STHHYYP-ECGK-TAMRA is a good candidate agent for dualmodality imaging targeting EGFR with L858R mutation.

The utility of F-18 FDG PET/CT for diagnosis and response evaluation of hepatosplenic tuberculosis.

A 77-year-old woman underwent F-18 FDG PET/CT for evaluation of fever focus. Diffuse and intense hepatosplenic uptake was noted and lymphoma or tuberculosis was proposed. Liver biopsy revealed chronic granulomatous inflammation with Langerhans-type giant cells and necrosis. A follow-up PET/CT after anti-tuberculosis treatment revealed that the hepatosplenic uptake had resolved.

A novel dual-labeled small peptide as a multimodal imaging agent for targeting wild-type EGFR in tumors.

The epidermal growth factor receptor (EGFR) is over-expressed in various human cancer. The over-expression of EGFR in tumors is an excellent target for the development of cancer imaging agents. In the present study, we developed Tc-99m SYPIPDT-GHEG-ECG-K-tetramethylrhodamine (SYPIPDT-ECG-TAMRA) as a molecular imaging agent targeting wild-type EFGR (wtEGFR)-positive tumor cells, and verified its feasibility as molecular imaging agent. SYPIPDT-ECG-TAMRA was synthesized using Fmoc solid-phase peptide synthesis. The radiolabeling of SYPIPDT-ECG-TAMRA with Tc-99m was accomplished using ligand exchange via tartrate. Cellular uptake and binding affinity studies were performed. In vivo gamma camera imaging, ex vivo imaging and biodistribution studies were performed using NCI-H460 and SW620 tumor-bearing murine models. After radiolabeling procedures with Tc-99m, Tc-99m SYPIPDT-ECG-TAMRA complexes were prepared at high yield (> 95%). The binding affinity value (Kd) of Tc-99m SYPIPDT-ECG-TAMRA for NCI-H460 cells was estimated to be 76.5 ± 15.8 nM. In gamma camera imaging, the tumor to normal muscle uptake ratios of Tc-99m SYPIPDT-ECG-TAMRA increased with time (2.7 ± 0.6, 4.0 ± 0.9, and 6.2 ± 1.0 at 1, 2, and 3 h, respectively). The percentage injected dose per gram of wet tissue for the NCI-H460 tumor was 1.91 ± 0.11 and 1.70 ± 0.22 at 1 and 3 h, respectively. We developed Tc-99m SYPIPDT-ECG-TAMRA, which is dual-labeled with both radioisotope and fluorescence. In vivo and in vitro studies demonstrated specific uptake of Tc-99m SYPIPDT-ECG-TAMRA into wtEGFR-positive NCI-H460 cells and tumors. Thus, the results of the present study suggest that Tc-99m SYPIPDT-ECG-TAMRA is a potential dual-modality imaging agent targeting wtEGFR.

KSNM60 in Non-thyroidal Radionuclide Therapy: Leaping into the Future.

This year, the Korean Society of Nuclear Medicine (KSNM) is celebrating its 60th anniversary. Treatment, as well as diagnosis, has played a very important role in the development of nuclear medicine. Since I-131 was used for thyroid therapy in 1959, other radionuclide therapy is still being used, and attempts to use new radionuclide are increasing. In this review, we briefly summarize and introduce the therapies such as radioimmunotherapy, transarterial radioembolization, radionuclide therapy for neuroendocrine tumors, peptide receptor radionuclide therapy, control of metastatic bone pain, radiation synovectomy, radionuclide brachytherapy, alpha particle therapy, and boron neutron capture therapy, which has been being attempted so far in the field of nuclear medicine.

Clinical impact of radioactive iodine dose selection based on the number of metastatic lymph nodes in patients with papillary thyroid carcinoma: A multicenter retrospective cohort study.

OBJECTIVE: The aim of this study is to investigate whether the number of metastatic lymph nodes (LNs) could be used as a basis in the radioactive iodine (RAI) dose selection for patients with papillary thyroid carcinoma (PTC). PATIENTS: A total of 595 patients with PTC who received first RAI therapy after total or near-total thyroidectomy and had no evidence of disease in treatment response assessment were retrospectively enroled from five hospitals. The patients were classified into two subgroups based on the number of metastatic LNs (>5). The multivariate Cox-proportional hazard model was performed to identify the significant factors for recurrence prediction in each group as well as all enroled patients. RESULTS: Overall, 22 (3.7%) out of 595 patients had the recurrent disease during the follow-up period. The number of metastatic LNs (>5) was only a significant factor for recurrence prediction in all enroled patients (odds ratio: 7.834, p < .001). In the subgroup with ≤5 metastatic LNs, the presence of extrathyroidal extension was only associated with recurrence (odds ratio: 7.333, p = .024) in multivariate analysis. RAI dose was significantly associated with recurrence rate in which the patients with high-dose RAI (3.7 GBq or higher) had less incidence of recurrence than those with low-dose RAI (1.11 GBq) in the subgroup with more than five metastatic LNs (odds ratio: 6.533, p = .026). CONCLUSIONS: High-dose RAI (≥3.7 GBq) therapy significantly lowered the recurrence rate in patients with more than five metastatic LNs. Therefore, RAI dose should be determined based on the number of metastatic LNs as well as conventional risk factors.

Dual-labeled prostate-specific membrane antigen (PSMA)-targeting agent for preoperative molecular imaging and fluorescence-guided surgery for prostate cancer.

The objective of this study was to report the synthesis and characteristics of a dual modality imaging agent, Tc-99m GRFLTGGTGRLLRIS-GHEG-ECG-K(-5-carboxy-X-rhodamine)-NH2 (GRFLT-ECG-ROX), and to verify its feasibility as both molecular imaging and intraoperative guidance agent. GRFLT-ECG-ROX was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of GRFLT-ECG-ROX with Tc-99m was accomplished using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed using LNCaP and PC-3 tumor-bearing murine models. Surgical removal of tumor nodules in murine models with peritoneal carcinomatosis was performed under a fluorescence imaging system. After radiolabeling procedures with Tc-99m, Tc-99m GRFLT-ECG-ROX complexes were prepared in high yield (>96%). The binding affinity value (Kd ) of Tc-99m GRFLT-ECG-ROX for LNCaP cells was estimated to be 9.5 ± 1.3 nM. In gamma camera imaging, the tumor to normal muscle uptake ratios of Tc-99m GRFLT-ECG-ROX increased with time (3.1 ± 0.2, 4.0 ± 0.4, and 6.3 ± 0.9 at 1, 2, and 3 h, respectively). Under real-time optical imaging, the removal of visible nodules was successfully performed. Thus, Tc-99m GRFLT-ECG-ROX could provide both preoperative molecular imaging and fluorescence imaging guidance for tumor removal.

Incidental Detection of Iliac Artery Occlusion on 3-Phase Bone Scintigraphy.

Our patient was a 72-year-old man with absent activity of the right femoral artery and mildly decreased Tc-DPD activity on the right leg as indicated on the blood pool and delayed images, respectively. Subsequent peripheral angiography revealed a total occlusion of the right external iliac artery with good collateral flow. Careful review of blood flow and blood pool images of 3-phase bone scintigraphy could provide additional information about peripheral vascular disease.

A novel dual-modality imaging agent targeting folate receptor of tumor for molecular imaging and fluorescence-guided surgery.

OBJECTIVE: Folate receptor (FR) is an ideal target for cancer imaging because it is frequently overexpressed in major types of human tumor, whereas its expression in normal organs is highly limited. Combining nuclear and fluorescence-imaging techniques provides a novel approach for cancer imaging and monitoring the surgery. The objective of this study was to report the synthesis and characteristics of a dual-modality imaging agent, Tc-99m Folate-Gly-His-Glu-Gly-Glu-Cys-Gly-Lys(-5-carboxy-X-rhodamine)-NH2 (Folate-ECG-ROX), and verify its feasibility as both molecular imaging agent and intra-operative guidance. METHODS: Folate-ECG-ROX was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of Folate-ECG-ROX with Tc-99m was done using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed using KB and HT-1080 tumor-bearing murine models. Tumor tissue slides were prepared and analyzed with immunohistochemistry staining and confocal microscopy. Surgical removal of tumor nodules in murine models with peritoneal carcinomatosis was performed under the fluorescence-imaging system. RESULTS: After radiolabeling procedures with Tc-99m, Tc-99m Folate-ECG-ROX complexes were prepared in high yield (> 97%). The binding affinity value (Kd) of Tc-99m Folate-ECG-ROX for KB cells was estimated to be 6.9 ± 0.9 nM. In gamma camera imaging, tumor to normal muscle uptake ratio of Tc-99m Folate-ECG-ROX increased with time (3.4 ± 0.4, 4.4 ± 0.7, and 6.6 ± 0.8 at 1, 2, and 3 h, respectively). In biodistribution study, %IA/g for KB tumor was 2.50 ± 0.80 and 4.08 ± 1.16 at 1 and 3 h, respectively. Confocal microscopy with immunohistochemistry staining detected strong Tc-99m Folate-ECG-ROX fluorescence within KB tumor tissue which is correlating with the fluorescent activity of anti-FR antibody. Under real-time optical imaging, the removal of visible nodules was successfully performed. CONCLUSIONS: In vivo and in vitro studies revealed substantial and specific uptake of Tc-99m Folate-ECG-ROX in FR-positive tumors. Thus, Tc-99m Folate-ECG-ROX could provide both pre-operative molecular imaging and fluorescence image-guidance for tumor.

Tc-99m and Fluorescence-Labeled Anti-Flt1 Peptide as a Multimodal Tumor Imaging Agent Targeting Vascular Endothelial Growth Factor-Receptor 1.

PURPOSE: We developed a Tc-99m and fluorescence-labeled peptide, Tc-99m TAMRA-GHEG-ECG-GNQWFI, to target tumor cells, and evaluated the diagnostic performance as a dual-modality imaging agent for tumor in a murine model. METHODS: TAMRA-GHEG-ECG-GNQWFI was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-GNQWFI with Tc-99m was done using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with U87MG tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry using confocal microscopy. RESULTS: After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-GNQWFI complexes were prepared in high yield (> 95%). The K d of Tc-99m TAMRA-GHEG-ECG-GNQWFI determined by saturation binding was 29.5 ± 4.5 nM. Confocal microscopy images of U87MG cells incubated with TAMRA-GHEG-ECG-GNQWFI showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-GNQWFI in tumors. Tumor uptake was effectively blocked by the co-injection of an excess concentration of GNQWFI. Specific uptake of Tc-99m TAMRA-GHEG-ECG-GNQWFI was assessed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. CONCLUSIONS: In vivo and in vitro studies revealed substantial and specific uptake of Tc-99m TAMRA-GHEG-ECG-GNQWFI in tumor cells. Tc-99m TAMRA-GHEG-ECG-GNQWFI could be a good candidate dual-modality imaging agent for tumors.

Incidental Detection of Peri-Renal Hemorrhage on F-18 FDG PET/CT Imaging in a Patient with Polycystic Kidney Disease.

A 72-year-old male patient with a history of polycystic kidney disease and lung malignancy underwent F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for the evaluation of tumor recurrence. The FDG PET/CT and subsequent non-enhanced CT scans revealed a hemorrhage in the peri-renal space of the left original kidney. Interesting in this case was the incidental detection of unexpected peri-renal hemorrhage during an oncologic assessment with FDG PET/CT.

A novel Tc-99m and fluorescence-labeled arginine-arginine-leucine-containing peptide as a multimodal tumor imaging agent in a murine tumor model.

We developed a Tc-99m and TAMRA-labeled peptide, Tc-99m arginine-arginine-leucine (RRL) peptide (TAMRA-GHEG-ECG-RRL), to target tumor cells and evaluated the diagnostic performance of Tc-99m TAMRA-GHEG-ECG-RRL as a dual-modality imaging agent for tumor in a murine model. TAMRA-GHEG-ECG-RRL was synthesized using Fmoc solid-phase peptide synthesis. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with PC-3 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry using confocal microscopy. After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-RRL complexes were prepared in high yield (>96%). The Kd of Tc-99m TAMRA-GHEG-ECG-RRL determined by saturation binding was 41.7 ± 7.8 nM. Confocal microscopy images of PC-3 cells incubated with TAMRA-GHEG-ECG-RRL showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-RRL in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of RRL. Specific uptake of Tc-99m TAMRA-GHEG-ECG-RRL was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In conclusion, in vivo and in vitro studies revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-RRL in tumors. Tc-99m TAMRA-GHEG-ECG-RRL has potential as a dual-modality tumor imaging agent.

Crossed Cerebellar Diaschisis: Risk Factors and Correlation to Functional Recovery in Intracerebral Hemorrhage.

OBJECTIVE: The purpose of this study is to investigate predictors of crossed cerebellar diaschisis (CCD), and the effects of CCD on functional outcomes including motor function, activities of daily living, cognitive function, and ambulation 6 months after onset in patients with intracerebral hemorrhage (ICH). METHODS: A total of 74 patients experiencing their first ICH were recruited. If the asymmetric index was more than 10% using single photon emission computed tomography (SPECT), a diagnosis of CCD was confirmed. Clinical factors were retrospectively assessed by reviewing medical records. Radiologic factors encompassed the concomitance of intraventricular hemorrhage, side and location of the lesion, and hemorrhage volume. Functional outcomes were evaluated using the Fugl-Meyer Assessment, the Korean version of the Mini-Mental State Examination, the Korean version of the Modified Barthel Index, and measurement of the Functional Ambulatory Category at the time of SPECT measurement and 6 months post-ICH. RESULTS: Lesion location, especially in the basal ganglia (odds ratio [OR]=6.138, p=0.011), and hemorrhagic volume (OR=1.055, p=0.046) were independent predictors for CCD according to multivariate logistic regression analysis. In addition, the presence of CCD was significantly related to the improvement in Fugl-Meyer Assessment score after 6 months (adjusted R2=0.152, p=0.036). CONCLUSION: Lesion location and hemorrhagic volume were the predisposing factors for CCD, and the CCD was associated with poor motor recovery over 6 months in patients with hemorrhagic stroke.

Transiently Altered Distribution of F-18 FDG in a Patient with Subacute Thyroiditis.

F-18 fluorodeoxyglucose (FDG) is a highly influential radiotracer that provides valuable information in many cancer types. However, the normal biodistribution of F-18 FDG is often variable and can be altered by intrinsic or iatrogenic factors. We report a case of diffuse symmetrically increased skeletal muscle uptake and relatively decreased hepatic uptake on F-18 FDG PET/CT in a 57-year-old female with pulmonary adenocarcinoma. Detailed clinical evaluation and retrospective radiologic evaluation revealed that she had been diagnosed with subacute thyroiditis 2 weeks ago. After 6 weeks, F-18 FDG distribution was normalized at the follow-up PET/CT study.

Usefulness of Tc-99m Pertechnetate SPECT/CT in the Diagnosis of Testicular Infarction After Inguinal Herniorrhaphy.

A 77-year-old male underwent open repair for a right indirect inguinal hernia and complained of right scrotal pain on the third postoperative day. Color Doppler imaging revealed decreased blood flow with heterogeneous hypoechogenicity in the right testis. A Tc-99m pertechnetate testicular scan showed diffuse hyperemia and increased uptake in the right scrotum. Additional SPECT/CT revealed a photon defect in the right testicle with increased uptake in the peri-testicular area. A subsequent operation revealed a large hematoma in the right spermatic cord and consequent right testicular infarction, and right orchiectomy was performed.

Synthesis and evaluation of Tc-99m and fluorescence-labeled elastin-derived peptide, VAPG for multimodal tumor imaging in murine tumor model.

We developed a Tc-99m and fluorescence-labeled peptide, Tc-99m TAMRA-GHEG-ECG-VAPG to target tumor cells and evaluated the diagnostic performance as a dual-modality imaging agent for tumor in a murine model. TAMRA-GHEG-ECG-VAPG was synthesized by using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-VAPG with Tc-99m was done by using ligand exchange via tartrate. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with SW620 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry by using confocal microscopy. After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-VAPG complexes were prepared in high yield (>96%). The Kd of Tc-99m TAMRA-GHEG-ECG-VAPG determined by saturation binding was 16.8 ± 3.6 nM. Confocal microscopy images of SW620 cells incubated with TAMRA-GHEG-ECG-VAPG showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of VAPG. Specific uptake of Tc-99m TAMRA-GHEG-ECG-VAPG was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In vivo and in vitro studies revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-VAPG in tumor cells. Tc-99m TAMRA-GHEG-ECG-VAPG has potential as a dual-modality tumor imaging agent.

Neural Correlates of Motor Recovery Measured by SPECT at Six Months After Basal Ganglia Stroke.

OBJECTIVE: To investigate neural correlates associated with recovery of motor function over 6 months in patients with basal ganglia (BG) stroke using acetazolamide (ACZ) stress brain-perfusion single-photon emission computed tomography (SPECT). METHODS: Medical records of 22 patients presenting first-ever BG stroke were retrospectively reviewed. Regional cerebral blood flow (CBF) and cerebrovascular reserve (CVR) were measured for 9 regions in each cerebral hemisphere (primary motor cortex, supplementary motor area, premotor cortex, prefrontal cortex, temporal lobe, parietal lobe, occipital lobe, BG, and thalamus). The Fugl-Meyer Assessment (FMA) motor score was used to assess motor function. RESULTS: After ACZ injection, CBF of all regions of interest (ROIs) increased compared with baseline. Baseline CBF of all ROIs was not significantly correlated with changes in FMA upper or lower motor score. However, multivariate analysis revealed CVR was significantly associated with change in FMA upper score in the ipsilateral primary motor cortex (R2=0.216, p=0.017), the ipsilateral parietal lobe (R2=0.135, p=0.029), and the contralateral primary motor cortex (R2=0.210, p=0.041). CONCLUSION: CVR in the bilateral primary motor cortex and ipsilateral parietal lobe was associated with restoration of upper motor function 6 months after BG stroke. SPECT is a readily available imaging modality useful in studying brain residual function in patients with BG stroke.

Extrathyroidal Radioiodine Accumulation in a Fibroadenoma of the Breast.

A 45-year-old woman with a differentiated thyroid carcinoma received adjuvant radioiodine therapy following total thyroidectomy and left modified radical neck dissection. A posttherapy planar radioiodine scan showed multifocal uptake in the thyroid bed and left chest. SPECT/CT revealed a fibroadenoma in the left breast. Six months later, an I scan showed no iodine avidity in the breast fibroadenoma, whereas ultrasonography showed no significant change in the size of the fibroadenoma. Altered radioiodine uptake of a breast fibroadenoma can be observed on follow-up scans after cytotoxic radioiodide treatment in patients with differentiated thyroid carcinoma.

Fibrous dysplasia of the maxilla in an elderly female: Case report on a 14-year quiescent phase.

Fibrous dysplasia (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Mainly, FD is found in children, and by adulthood it usually becomes quiescent. Our case showed FD of more than 14-year duration in the left maxilla. Our evaluation was that growth ceased in adulthood and had achieved the static stage. Because FD cases in elderly patients are rarely reported, we hereby present a monostotic FD case in a 65-year-old female. We presented sequential radiographic images and scintigraphic images of this case, and combined them with a literature review that emphasized the progression of the disease.

Tc­99m Ser­Asp­Val­Glu­Cys­Gly: A novel Tc­99m labeled hexapeptide for molecular and non­invasive tumor imaging.

In a ProteoChip­based screening system and subsequent studies, serine­aspartic acid­valine (SDV) was demonstrated to specifically bind to integrin αvß3. An SDV­containing peptide could target the tumor vessel and it may be an effective replacement for molecular imaging of the tumor. In the present study, a hexapeptide, SDV­glutamic acid­cysteine­glycine (ECG), was developed and evaluated its diagnostic performance as a tumor imaging agent in tumor­bearing mice. The hexapeptide SDV­ECG was synthesized using Fmoc solid­phase peptide synthesis. Following radiolabeling procedures with technetium­99m, the Tc­99m SDV­ECG complexes were prepared at high yields (>97%). The uptake of Tc­99m SDV­ECG within HT­1080 tumor cells (integrin αvß3­positive) was confirmed by in vitro studies. γ­camera imaging revealed substantial uptake of Tc­99m SDV­ECG in the HT­1080 cell line tumor murine model. With the co­injection of excess SDV, tumoral uptake was blocked. Furthermore, HT­29 tumor cells (integrin αvß3­negative) and inflammatory lesions demonstrated minimal uptake of Tc­99m SDV­ECG. In the present study, Tc­99m SDV­ECG was developed as a novel Tc­99m agent for tumor imaging. The current in vitro and in vivo studies demonstrated specific functions of Tc­99m SDV­ECG in tumor imaging.