Seong Young Kwon

High total metabolic tumor volume in PET/CT predicts worse prognosis in diffuse large B cell lymphoma patients with bone marrow involvement in rituximab era.

Bone marrow involvement (BMI) in diffuse large B cell lymphoma (DLBCL) was naively regarded as an adverse clinical factor. However, it has been unknown which factor would separate clinical outcomes in DLBCL patients with BMI. Recently, metabolic tumor volume (MTV) on positron emission tomography/computed tomography (PET/CT) was suggested to predict prognosis in several lymphoma types. Therefore, we investigated whether MTV would separate the outcomes in DLBCL patients with BMI. MTV on PET/CT was defined as an initial tumor burden as target lesion ≥ standard uptake value, 2.5 in 107 patients with BMI. Intramedullary (IM) MTV was defined as extent of BMI and total MTV was as whole tumor burden. 260.5 cm(3) and 601.2 cm(3) were ideal cut-off values for dividing high and low MTV status in the IM and total lymphoma lesions in Receiver Operating Curve analysis. High risk NCCN-IPI (p<0.001, p<0.001), bulky disease (p=0.011, p=0.005), concordant subtype (p=0.025, p=0.029), high IM MTV status (p<0.001, p<0.001), high total MTV status (p<0.001, p<0.001), and ≥ 2CAs in BM (p=0.037, p=0.033) were significantly associated with progression-free survival (PFS) and overall survival (OS) than other groups. In multivariate analysis, high risk NCCN-IPI (PFS, p=0.006; OS, p=0.013), concordant subtype (PFS, p=0.005; OS, p=0.007), and high total MTV status (PFS, p<0.001; OS, p<0.001) had independent clinical impacts. MTV had prognostic significances for survivals in DLBCL with BMI.

CT and PET-CT of a Dog with Multiple Pulmonary Adenocarcinoma

ABSTRACT A 10-year-old, intact female Yorkshire terrier had multiple pulmonary nodules on thoracic radiography and ultrasonography with no lesions elsewhere. Computed tomography (CT) and positron emission tomography and computed tomography (PET-CT) using 18F-fluorodeoxyglucose (FDG) were performed to identify metastasis and undetected primary tumors. On CT examination, pulmonary nodules had a hypoattenuating center with thin peripheral enhancement, suggesting ischemic or necrotizing lesion. In PET-CT at 47 min after intravenous injection of 11.1 MBq/kg of FDG, the maximum standardized uptake value of each pulmonary nodule was about from 3.8 to 6.4. There were no abnormal lesions except for four pulmonary nodules on the CT and PET-CT. Primary lung tumor was tentatively diagnosed, and palliative therapy using 2 mg/kg tramadol and 2.2 mg/kg carprofen twice per day was applied. After the dog’s euthanasia due to deteriorated clinical signs and poor prognosis, undifferentiated pulmonary adenocarcinoma was diagnosed through histopathologic and immunochemistry examination. To the best of the authors’ knowledge, this is the first study of CT and PET-CT features of canine pulmonary adenocarcinoma. In this case, multiple pulmonary adenocarcinoma could be determined on the basis of FDG PET-CT through screening the obvious distant metastasis and/or lymph node invasions and excluding unknown primary tumors.

Congenital lymphangiomatosis and an enteric duplication cyst in a young dog.

A two-year-old female poodle with abdominal distention was diagnosed with concurrent enteric duplication cyst and lymphangiomatosis. Both lesions were shown as cystic structures, but some characteristic features of enteric duplication cyst were identified including a thick cyst wall and shared blood supply with the duodenum. Although it was challenging to discriminate between the types of cyst based on diagnostic imaging, this report describes the characteristics of each type of lesion using several different imaging modalities.

A High-Affinity Repebody for Molecular Imaging of EGFR-Expressing Malignant Tumors

The accurate detection of disease-related biomarkers is crucial for the early diagnosis and management of disease in personalized medicine. Here, we present a molecular imaging of human epidermal growth factor receptor (EGFR)-expressing malignant tumors using an EGFR-specific repebody composed of leucine-rich repeat (LRR) modules. The repebody was labeled with either a fluorescent dye or radioisotope, and used for imaging of EGFR-expressing malignant tumors using an optical method and positron emission tomography. Our approach enabled visualization of the status of EGFR expression, allowing quantitative evaluation in whole tumors, which correlated well with the EGFR expression levels in mouse or patients-derived colon cancers. The present approach can be effectively used for the accurate detection of EGFR-expressing cancers, assisting in the development of a tool for detecting other disease biomarkers.

Impact of Lymphoid Follicles and Histiocytes on the False-Positive FDG Uptake of Lymph Nodes in Non-Small Cell Lung Cancer

PurposeAlthough 18F-fluorodeoxyglucose (FDG) PET/CT has improved the accuracy of evaluating lymph node (LN) staging in non-small cell lung cancer (NSCLC), false-positive results remain a problem. The reason why benign LNs show high FDG uptake is still unclear. The aim of this study was to identify molecular and pathological characteristics of benign LNs showing high FDG uptake.Materials and MethodsWe studied 108 mediastinal LNs of pathologically benign nature obtained from 43 patients with NSCLC who underwent FDG PET/CT and surgery. We measured the following parameters in each LN: maximum standardized uptake value (maxSUV), short diameter, maximum Hounsfield unit (maxHU) value, occupied proportions of lymphoid follicles, histiocytes in extrafollicular space and the degree of glucose transporter 1 (Glut1) expression. We compared the parameters between two LN groups according to maxSUV.ResultsThere were 74 LNs showing maxSUV≥3.0 (group 1) and 34 LNs with maxSUV<3.0 (group 2). The size of LN (p < 0.001) and maxHU (p = 0.003) in group 1 was higher than that in group 2. Histologically, the occupied proportions of lymphoid follicles (p = 0.031) or histiocytes (p = 0.004) were higher in group 1. The Glut1 expression of lymphoid follicles (p = 0.035) or histiocytes (p = 0.005) was also higher in group 1.ConclusionLymphoid follicular hyperplasia and histiocyte infiltration associated with Glut1 overexpression are important molecular and pathological mechanisms for false-positive FDG uptake in benign mediastinal LNs in patients with NSCLC.

64Cu-Labeled Repebody Molecules for Imaging of Epidermal Growth Factor Receptor–Expressing Tumors

The epidermal growth factor receptor (EGFR) is a member of the erbB family of receptors and is overexpressed in many tumor types. A repebody is a newly designed nonantibody protein scaffold for tumor targeting that contains leucine-rich repeat modules. In this study, 3 64Cu-labeled anti-EGFR repebodies with different chelators were synthesized, and their biologic characteristics were assessed in cultured cells and tumor-bearing mice. Methods: Repebodies were synthesized with the chelators 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-N,N′,N,″-triacetic acid trihydrochloride ([p-SCN-Bn]-NOTA), 2,2′,2″-(10-(2-(2,5-dioxopyrrolidin-1-yloxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DOTA-N-hydroxysuccinimide ester), or 1-(p-isothiocyanatobenzyl)diethylenetriamine pentaacetic acid trihydrochloride ([p-SCN-Bn]-DTPA) in 1.0 M NaHCO3 buffer (pH 9.2) for 24 h. Purified NOTA-, DOTA-, and DTPA-conjugated repebody were radiolabeled with 64Cu in 0.1 M NH4OAc buffer (pH 5.5). To compare the EGFR-binding affinities of the repebodies, cellular uptake studies were performed with the human non–small cell lung cancer cell line H1650 (high expression of EGFR) and the human colon adenocarcinoma cell line SW620 (low expression of EGFR). Biodistribution and small-animal PET imaging studies were performed using H1650 tumor–bearing mice. Results: Radiochemical yields of the 64Cu-labeled repebodies were approximately 70%–80%. Cellular uptake of the NOTA-, DOTA-, and DTPA-repebodies was over 4-fold higher in H1650 cells than in SW620 cells at 1 h. The 3 repebodies had accumulated specifically in H1650 tumor–bearing nude mice by 1 h after intravenous injection and were retained for over 24 h, as measured by the percentage injected dose per gram of tissue (%ID/g). Tumor uptake of all repebodies increased from 1 to 6 h (at 1 h, 6.28, 8.46, and 6.91 %ID/g for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 9.4, 8.28, and 10.1 %ID/g, respectively). H1650 tumors were clearly visible after injection of each repebody, with high tumor-to-background ratios (at 1 h, 3.43, 4.89, and 2.38 for NOTA-, DOTA-, and DTPA-repebody, respectively; at 6 h, 3.05, 4.36, and 2.08; at 24 h, 3.81, 4.58, and 2.86). Conclusion: The 3 64Cu-repebody complexes demonstrated specific and rapid uptake in EGFR-expressing tumors within 1 h and may have potential as novel EGFR imaging agents for PET.

Characteristics of anginal patients with high resting myocardial blood flow measured with N-13 ammonia PET/CT.

ObjectivesWe hypothesized that anginal patients with low coronary flow reserve (CFR) could have variable clinical features according to resting myocardial blood flow (MBF). Therefore, we analyzed the clinical and imaging characteristics according to resting MBF in anginal patients. MethodsWe enrolled 70 patients who underwent N-13 ammonia PET–computed tomography (CT) for evaluation of angina. Resting and stress MBF values were obtained and resting MBF was corrected with rate–pressure product to exclude the effect of heart rate and blood pressure on resting MBF. Clinical and imaging characteristics were compared on the basis of MBF and CFR. ResultsAmong patients with CFR less than 2.0, those with high resting MBF (≥1.0 ml/min/g) had significantly fewer number of smokers, were younger, had lower Agatston calcium scores, and had less coronary stenosis compared with those with low resting MBF (<1.0 ml/min/g). In contrast, there was no significant difference in clinical or imaging findings according to resting MBF when compared among all patients or within those with CFR greater than or equal to 2.0. The subgroup analysis of patients with CFR less than 2.0 revealed lower Agatston calcium score and less coronary stenosis in patients with high resting MBF regardless of stress MBF. ConclusionHigh resting MBF is associated with a lower rate of smoking, younger age, less coronary calcium burden, and less coronary stenosis compared with low resting MBF in anginal patients with low CFR. Moreover, in these patients, favorable angiographic features were mainly associated with high resting MBF, irrespective of stress MBF. Therefore, resting MBF should be reviewed to validate the clinical significance of low CFR measured by N-13 ammonia PET/CT especially in anginal patients showing low CFR.

Rhodobacter sphaeroides, a novel tumor-targeting bacteria that emits natural near-infrared fluorescence

Several optical imaging techniques have been used to monitor bacterial tropisms for cancer. Most such techniques require genetic engineering of the bacteria to express optical reporter genes. This study investigated a novel tumor‐targeting strain of bacteria, Rhodobacter sphaeroides 2.4.1 (R. sphaeroides), which naturally emits near‐infrared fluorescence, thereby facilitating the visualization of bacterial tropisms for cancer. To determine the penetration depth of bacterial fluorescence, various numbers of cells (from 108 to 1010 CFU) of R. sphaeroides and two types of Escherichia coli, which stably express green fluorescent protein (GFP) or red fluorescent protein (RFP), were injected s.c. or i.m. into mice. Bacterial tropism for cancer was determined after i.v. injection of R. sphaeroides (108 CFU) into mice implanted s.c. with eight types of tumors. The intensity of the fluorescence signal in deep tissue (muscle) from R. sphaeroides was much stronger than from E. coli‐expressing GFP or RFP. The near‐infrared fluorescence signal from R. sphaeroides was visualized clearly in all types of human or murine tumors via accumulation of bacteria. Analyses of C‐reactive protein and procalcitonin concentrations and body weights indicated that i.v. injection of R. sphaeroides does not induce serious systemic immune reactions. This study suggests that R. sphaeroides could be used as a tumor‐targeting microorganism for the selective delivery of drugs to tumor tissues without eliciting a systemic immune reaction and for visualizing tumors.

Ultrasound, CT and FDG PET-CT of a duodenal granuloma in a dog.

ABSTRACT A 12-year-old spayed female Yorkshire Terrier with intermittent vomiting was diagnosed with regional granulomatous enteritis through histopathological examination. On ultrasonography and computed tomography, a focal thickened duodenal wall showed a mass-like appearance with indistinct wall layers. Marked uptake of 18F-fluorodeoxyglucose was observed from the mass on positron emission tomography-computed tomography. Regional granulomatous enteritis is a rare form of inflammatory bowel disease and may have imaging features similar to intestinal tumors. This is the first study describing the diagnostic imaging features of ultrasonography, computed tomography and positron emission tomography-computed tomography for regional granulomatous enteritis in a dog.

Variations in findings on 18F-FDG PET/CT, Tc-99m HDP bone scan and WBC scan in chronic multifocal osteomyelitis

Dear Editor, Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition the true incidence of which is unknown. CRMO is associated with several autoimmune diseases, including inflammatory bowel diseases, such as ulcerative colitis (as in the patient in this study), Wegener’s granulomatosis and psoriasis. In addition, CRMO has been reported to be associated with a pediatric variant of SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome. CRMO may be solitary ormultifocal. The diagnosis of CRMO is based on clinical symptoms, scans and pathologic findings. Until now, there have been no reports of the results of white blood cell (WBC) scans in CRMO. This is a case study of a patient with CRMO who underwent Tc-99m hydroxymethylene diphosphonate (HDP) bone scan, Tc-99m hexamethylpropyleneamine oxime (HMPAO)WBC scan and F-18 fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomo-graphy (F-FDG PET/CT), and showed different scan findings with each lesion with different degrees of inflammation. A 41-year-old man with known ulcerative colitis and an abscess on the right zygoma underwent a Tc-99m HDP bone scan for pain in the lower back, right knee, left ankle, left anterior chest wall and sternum. An anterior view of the Tc-99m HDP bone scan (Fig. 1a) showed hot uptakes not only in the lesions associated with pain (right zygmotic bone, sternum, right patella, left third rib, spinous process of T11) but also in the lesions without pain (skull and right cuboid bone). However, the Tc-99m HMPAO WBC scan (Fig. 1b) was negative for all lesions. The F-18 FDG PET/CT (Fig. 1c, maximum intensity projection [MIP]; d, lateral MIP; e, sagittal image of CT portion; f, sagittal image of PET portion) showed hypermetabolism only in the sternum and T11–L2 vertebrae. Note that the sternum (blank arrow in Fig. 1a,c,d) showed hot uptake and hypermetabolism on the bone scan and the PET/CT but not on the WBC scan. Also note that spinal processes of vertebrae showed hypermetabolism in much broader lesions on the PET/CT (white arrow in Fig. 1d,f) than on the bone scan (arrow in Fig. 1e). A biopsy of the sternum of this patient was done; acute and chronic inflammation with edematous soft tissue change was revealed on microscopy. The diagnosis of CRMO was thus confirmed. In this patient, the discrepancy between the findings of the WBC scan and the F-18 FDG PET/CT in the vertebrae and sternum might be due to the ‘chronicity’ of the inflammation. In WBC scans, false-negatives are known to occur with chronic infection. In addition, this patient was taking antibiotics at the time of the WBC scan. The antibiotics might alter leukocyte function in this patient as well. Among the three scans (bone scan, WBC scan and F-18 FDG PET/CT), the bone scan showed greatest numbers of lesions. It has been previously reported that a bone scan is able to detect many asymptomatic lesions (even radiographically obscure foci of the disease). However, not only can a bone scan be positive in active disease, it can also be positive where there are recovering lesions. Otherwise, the FDG PET is highly effective in excluding osteomyelitis, according to Zhuang et al. FDG uptake is not the same thing as bone turn-over, which is shown by a bone scan. In this patient, bone scan-positive and FDG PET/CT-negative lesions (skull and right cuboid bone) were asymptomatic both initially and after 18 months of follow-up, suggesting they were recovering lesions. This might account for the discrepancy in findings between the bone scan and the F-18 FDG PET/CT in this case. Based on the scan findings in this case and other previous reports, it would be helpful to have a bone scan performed in the beginning of evaluation of CRMO to detect all lesions, followed by F-18 FDG PET/ CT to detect only active lesions.