Tumor Pre-Targeting System Using Streptavidin-Expressing Bacteria.

PURPOSE: A major obstacle to targeted cancer therapy is identifying suitable targets that are specifically and abundantly expressed by solid tumors. Certain bacterial strains selectively colonize solid tumors and can deliver genetically encoded cargo molecules to the tumor cells. Here, we engineered bacteria to express monomeric streptavidin (mSA) in tumors, and developed a novel tumor pre-targeting system by visualizing the presence of tumor-associated mSA using a biotinylated imaging probe. PROCEDURES: We constructed a plasmid expressing mSA fused to maltose-binding protein and optimized the ribosome binding site sequence to increase solubility and expression levels. E. coli MG1655 was transformed with the recombinant plasmid, expression of which is driven by the pBAD promotor. Expression of mSA was induced by L-arabinose 4 days after injection of bacteria into mice bearing CT26 mouse colon carcinoma cells. Selective accumulation of mSA in tumor tissues was visualized by optical imaging after administration of a biotinylated fluorescent dye. Counting of viable bacterial cells was also performed. RESULTS: Compared with a conventional system, the novel expression system resulted in significantly higher expression of mSA and sustained binding to biotin. Imaging signals in tumor tissues were significantly stronger in the mSA-expressing group than in non-expressing group (P = 0.0005). Furthermore, the fluorescent signal in tumor tissues became detectable again after multiple inductions with L-arabinose. The bacterial counts in tumor tissues showed no significant differences between conditions with and without L-arabinose (P = 0.45). Western blot analysis of tumor tissues confirmed expression and binding of mSA to biotin. CONCLUSIONS: We successfully engineered tumor-targeting bacteria carrying a recombinant plasmid expressing mSA, which was targeted to, and expressed in, tumor tissues. These data demonstrate the potential of this novel tumor pre-targeting system when combined with biotinylated imaging probes or therapeutic agents.

Prognostic Significance Of Sequential 18f-fdg Pet/Ct During Frontline Treatment Of Peripheral T Cell Lymphomas.

BACKGROUND/AIMS: The prognostic significance of 18F-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET/CT) in peripheral T-cell lymphomas (PTCLs) are controversial. We explored the prognostic impact of sequential 18F-FDG PET/CT during frontline chemotherapy of patients with PTCLs. METHODS: In total, 143 patients with newly diagnosed PTCLs were included. Sequential 18F-FDG PET/CTs were performed at the time of diagnosis, during chemotherapy, and at the end of chemotherapy. The baseline total metabolic tumor volume (TMTV) was calculated using the the standard uptake value with a threshold method of 2.5. RESULTS: A baseline TMTV of 457.0 cm3 was used to categorize patients into high and low TMTV groups. Patients with a requirehigh TMTV had shorter progression-free survival (PFS) and overall survival (OS) than those with a low TMTV (PFS, 9.8 vs. 26.5 mo, p = 0.043; OS, 18.9 vs. 71.2 mo, p = 0.004). The interim 18F-FDG PET/CT response score was recorded as 1, 2-3, and 4-5 according to the Deauville criteria. The PFS and OS showed significant differences according to the interim 18F-FDG PET/CT response score (PFS, 120.7 vs. 34.1 vs. 5.1 mo, p < 0.001; OS, not reached vs. 61.1 mo vs. 12.1 mo, p < 0.001). CONCLUSION: The interim PET/CT response based on visual assessment predicts disease progression and survival outcome in PTCLs. A high baseline TMTV is associated with a poor response to anthracycline-based chemotherapy in PTCLs. However, TMTV was not an independent predictor for PFS in the multivariate analysis.

Injuries and Illness during the 2019 Gwangju FINA and Masters World Championships in Elite and Amateur Athletes.

Comparative analysis of injury and illness prevalence in elite and amateur athletes provides the basis for the development of tailored prevention programs. The authors analyzed the differences in frequency and characteristics of injuries and illnesses which occurred in elite and amateur athletes during the 2019 Gwangju Federation Internationale de Natation (FINA) and Masters World Championships. The 2019 FINA World Championships hosted 3095 athletes in the disciplines of swimming, diving, high diving, artistic swimming, water polo, and open water swimming. While the 2019 Masters World Championships hosted 4032 athletes in swimming, diving, artistic swimming, water polo, and open water swimming. All medical records were electrically recorded in every venue as well as the central medical center located at the athlete's village. More elite athletes visited clinics than amateur athletes during the events (15.0 vs 8.6%, p<0.05) despite the ages of amateur athletes being higher than elite athletes (41.0±15.0 vs 22.4±5.6 years, p<0.01). Elite athletes complained mainly of musculoskeletal problems (69%), while amateur athletes complained of both musculoskeletal (38%) and cardiovascular (8%) problems. The most frequent injury in elite athletes was due to overuse in the shoulder joints, while that of amateur athletes was traumatic injuries involving feet and hands. The most common illness was respiratory infection in both elite and amateur athletes, while cardiovascular events occured only in amateur athletes. As the risk of injury varies in elite and amateur athletes, tailored preventive measures should be prepared. Furthermore, preventive measures of cardiovascular events should focus on amateur sports events.

Precise characterization of a solitary pulmonary nodule using tumor shadow disappearance rate-corrected F-18 FDG PET and enhanced CT.

ABSTRACT: We aimed to characterize solitary pulmonary nodule (SPN) using imaging parameters for F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) or enhanced CT corrected by tumor shadow disappearance rate (TDR) to reflect the tissue density.We enrolled 51 patients with an SPN who underwent PET/CT and chest CT with enhancement. The FDG uptake of SPN was evaluated using maximum standardized uptake value (SUVmax) on PET/CT. The mean Hounsfield unit (HU) for each SPN was evaluated over the region of interest on nonenhanced and enhanced CT images. The change in mean HU (HUpeak-pre) was quantified by subtracting the mean HU of the preenhanced CT from that of the post-enhanced CT. TDR was defined as the ratio of the tumor area, which disappears at a mediastinal window, to the tumor area of the lung window. We investigated which parameters (SUVmax or HUpeak-pre) could contribute to the characterization of SPN classified by TDR value and whether diagnostic performance could be improved using TDR-corrected imaging parameters.For SPN with higher tissue density (TDR <42%, n = 22), high value of SUVmax (≥3.1) was a significant factor to predict malignancy (P = .006). High value of HUpeak-pre (≥38) was a significant factor to characterize SPN (P = .002) with lower tissue density (TDR ≥42%, n = 29). The combined approach using TDR-corrected parameters had better predictive performance to characterize SPN than SUVmax only (P = .031).Applying imaging parameters such as SUVmax or HUpeak-pre in consideration of tissue density calculated with TDR could contribute to accurate characterization of SPN.

Prediction of cardiac events following concurrent chemoradiation therapy for non-small-cell lung cancer using FDG PET.

OBJECTIVE: No imaging biomarkers are available for the prediction of cardiac events following concurrent chemoradiation therapy (CCRT) for non-small-cell lung cancer (NSCLC). We evaluated whether F-18 fluorodeoxyglucose positron emission tomography (FDG PET) early after CCRT, in addition to cardiac dosimetry, could predict late cardiac events in NSCLC. METHODS: We retrospectively enrolled 133 consecutive patients with locally advanced, unresectable stage III NSCLC, who underwent FDG PET early after CCRT and survived at least 6 months. The primary endpoint was cardiac event ≥ grade 2 according to the Common Terminology Criteria for Adverse Events (version 5.0). Myocardial FDG uptake was measured and its association with the risk of cardiac events was evaluated. RESULTS: FDG PET was performed after a median interval of 11 days of completing CCRT. Overall, 42 (32%) patients experienced cardiac events during a median follow-up of 45 months. The mean heart dose, maximum left ventricular (LV) standardized uptake value (SUV), changes in maximum and mean LV SUV, right ventricular uptake, tumor stage, white blood cell count, and diabetes were associated with cardiac events in univariable analysis. In multivariable analysis, maximum LV SUV (cutoff > 12.84; hazard ratio [95% confidence interval] = 2.140 [1.140-4.016]; p = 0.018) was an independent predictor of cardiac events along with the mean heart dose (> 11.1 Gy; 3.646 [1.792-7.417]; p < 0.001) and tumor stage (IIIB; 1.986 [1.056-3.734]; p = 0.033). It remained predictive of cardiac events in those with higher mean heart dose but not in those with lower mean heart dose. CONCLUSIONS: Early FDG PET after CCRT for NSCLC could aid in predicting late cardiac events, especially in patients with higher mean heart dose.

Clinically viable myocardial CCTA segmentation for measuring vessel-specific myocardial blood flow from dynamic PET/CCTA hybrid fusion.

BACKGROUND: Positron emission tomography (PET)-derived LV MBF quantification is usually measured in standard anatomical vascular territories potentially averaging flow from normally perfused tissue with those from areas with abnormal flow supply. Previously we reported on an image-based tool to noninvasively measure absolute myocardial blood flow at locations just below individual epicardial vessel to help guide revascularization. The aim of this work is to determine the robustness of vessel-specific flow measurements (MBFvs) extracted from the fusion of dynamic PET (dPET) with coronary computed tomography angiography (CCTA) myocardial segmentations, using flow measured from the fusion with CCTA manual segmentation as the reference standard. METHODS: Forty-three patients' 13NH3 dPET, CCTA image datasets were used to measure the agreement of the MBFvs profiles after the fusion of dPET data with three CCTA anatomical models: (1) a manual model, (2) a fully automated segmented model and (3) a corrected model, where major inaccuracies in the automated segmentation were briefly edited. Pairwise accuracy of the normality/abnormality agreement of flow values along differently extracted vessels was determined by comparing, on a point-by-point basis, each vessel's flow to corresponding vessels' normal limits using Dice coefficients (DC) as the metric. RESULTS: Of the 43 patients CCTA fully automated mask models, 27 patients' borders required manual correction before dPET/CCTA image fusion, but this editing process was brief (2-3 min) allowing a 100% success rate of extracting MBFvs in clinically acceptable times. In total, 124 vessels were analyzed after dPET fusion with the manual and corrected CCTA mask models yielding 2225 stress and 2122 rest flow values. Forty-seven vessels were analyzed after fusion with the fully automatic masks producing 840 stress and 825 rest flow samples. All DC coefficients computed globally or by territory were ≥ 0.93. No statistical differences were found in the normal/abnormal flow classifications between manual and corrected or manual and fully automated CCTA masks. CONCLUSION: Fully automated and manually corrected myocardial CCTA segmentation provides anatomical masks in clinically acceptable times for vessel-specific myocardial blood flow measurements using dynamic PET/CCTA image fusion which are not significantly different in flow accuracy and within clinically acceptable processing times compared to fully manually segmented CCTA myocardial masks.

Determination of [N-13]-ammonia extraction fraction in patients with coronary artery disease by calibration to invasive coronary and fractional flow reserve.

BACKGROUND: This study presents a new extraction fraction (EF) model based on physiological measures of invasive coronary flow reserve (CFR) and fractional flow reserve (FFR) in patients with suspected coronary artery disease (CAD) and normal index microcirculatory resistance (IMR). To ascertain the clinical relevance of the new EFs, flow measurements using the newly patient-determined EFs were compared to flow measurements using traditional animal-determined EFs. METHODS: 39 patients were retrospectively selected that included a total of 91 vascular territories with invasive coronary angiography physiological measures. [N-13]-ammonia dynamic rest/adenosine-stress PET imaging was conducted in all patients and absolute myocardial flow was estimated using four published compartmental models. The extraction fraction during hyperemic flow was iteratively estimated by maximizing the agreement between invasive CFR and FFR with the non-invasive analogs myocardial flow reserve (MFR) and relative flow reserve (RFR) at similar physiological states, respectively. RESULTS: Using the new patient-determined EFs, agreement between CFR vs MFR for Model 1 and 2 was moderate and poor for Model 3 and 4. All models showed moderate agreement for FFR vs RFR. When using published models of animal-determined EFs, agreement between CFR vs MFR remained moderate for Model 1 and 2, and poor for Model 3 and 4. Similarly, all models showed moderate agreement for FFR vs RFR using animal-determined EF values. None of the observed differences were statistically significant. CONCLUSIONS: Flow measurements using extraction fraction correction for [N-13]-ammonia based on calibration to invasive intracoronary angiography physiological measures in patients with CAD were not discordant from those reported in the literature. Either patient-determined or traditional animal-determined EF correction, when used with the appropriate flow model, yields moderate agreement with invasive measurements of coronary flow reserve and fractional flow reserve.

Impact of COVID-19 on Nuclear Medicine in Asia.

Coronavirus disease 2019 (COVID-19) was first detected in China in late 2019 and rapidly spread to nearby Asian countries in early 2020. Outbreaks occurred differently in each country and affected nuclear medicine (NM) practice significantly even before the COVID-19 pandemic. The Asian NM community has worked together from the beginning of the pandemic. Fortunately, the Asian Regional Cooperative Council for Nuclear Medicine annual general meeting and Asia Nuclear Medicine Board examination was held in Manila from January 28 to February 2, 2020; these were the last face-to-face events of these organizations to date. Members shared information about COVID-19 at the conference, and through online means afterwards. Web-based surveys performed from March to April 2020 for the Asian Regional Cooperative Council for Nuclear Medicine and Asia Nuclear Medicine Board communities showed a significant reduction of NM practice and supply of radioisotopes (RI) at the beginning of the COVID-19 pandemic. A follow-up survey in March to April 2021 clearly showed the recovery of both NM practice and RI supplies. The pattern of recovery is variable according to institutions and countries. Herein, we have reported the case-in-point operational histories of four representative institutions in the East, Southeast, South, and West Asia. The second outbreak in India is ongoing on a worrisome scale. Various communications and educational sessions were actively performed online in the Asian NM community during the pandemic.

KSNM60 in Cardiology: Regrowth After a Long Pause.

The Korean Society of Nuclear Medicine (KSNM) is celebrating its 60th anniversary in honor of the nuclear medicine professionals who have dedicated their efforts towards research, academics, and the more comprehensive clinical applications and uses of nuclear imaging modalities. Nuclear cardiology in Korea was at its prime time in the 1990s, but its growth was interrupted by a long pause. Despite the academic and practical challenges, nuclear cardiology in Korea now meets the second leap, attributed to the growth in molecular imaging tailored for many non-coronary diseases and the genuine values of nuclear myocardial perfusion imaging. In this review, we describe the trends, achievements, challenges, and perspectives of nuclear cardiology throughout the 60-year history of the KSNM.

A Stepwise Approach Using Metastatic Lymph Node Ratio-Combined Thyroglobulin for Customization of [18F]FDG-PET/CT Indication to Detect Persistent Disease in Patients with Papillary Thyroid Cancer.

We investigated whether an indication for [18F]FDG-PET/CT to detect FDG-avid persistent disease (PD) could be identified precisely using the extent of metastatic lymph nodes (MLNs) and serum thyroglobulin (Tg) in papillary thyroid cancer (PTC) patients. This retrospective study included 429 PTC patients who underwent surgery and radioactive iodine (RAI) therapy. [18F]FDG-PET/CT and serum Tg were evaluated just before RAI therapy. The MLN ratio (LNR) was defined as the ratio of the number of MLNs to the number of removed LNs. To derive the LNR-combined criteria, different Tg cut-off values for identifying the PET/CT-indicated group for PD detection were applied individually to subgroups initially classified based on LNR cut-off values. The cut-off values for serum Tg, the number of MLNs, and LNR for a PET/CT indication were 6.0 ng/mL, 5, and 0.51, respectively. Compared to a single parameter (serum Tg, total number of MLNs, and LNR), the LNR-combined criteria showed significantly superior diagnostic performance in detecting FDG-avid PD (p < 0.001). The diagnostic performance of PET/CT in detecting FDG-avid PD was significantly improved when the PET/CT-indicated group was identified through the LNR-combined criteria in a stepwise manner; this can contribute to a customized PET/CT indication in PTC patients.

Dynamic cardiac PET motion correction using 3D normalized gradient fields in patients and phantom simulations.

This work expands on the implementation of three-dimensional (3D) normalized gradient fields to correct for whole-body motion and cardiac creep in [N-13]-ammonia patient studies and evaluates its accuracy using a dynamic phantom simulation model. METHODS: A full rigid-body algorithm was developed using 3D normalized gradient fields including a multi-resolution step and sampling off the voxel grid to reduce interpolation artifacts. Optimization was performed using a weighted similarity metric that accounts for opposing gradients between images of blood pool and perfused tissue without the need for segmentation. Forty-three retrospective dynamic [N-13]-ammonia PET/CT rest/adenosine-stress patient studies were motion corrected and the mean motion parameters plotted at each frame time point. Motion correction accuracy was assessed using a comprehensive dynamic XCAT simulation incorporating published physiologic parameters of the heart's trajectory following adenosine infusion as well as corrupted attenuation correction commonly observed in clinical studies. Accuracy of the algorithm was assessed objectively by comparing the errors between isosurfaces and centers of mass of the motion corrected XCAT simulations. RESULTS: In the patient studies, the overall mean cranial-to-caudal translation was 7 mm at stress over the duration of the adenosine infusion. Noninvasive clinical measures of relative flow reserve and myocardial flow reserve were highly correlated with their invasive analogues. Motion correction accuracy assessed with the XCAT simulations showed an error of <1 mm in late perfusion frames that broadened gradually to <3 mm in earlier frames containing blood pool. CONCLUSION: This work demonstrates that patients undergoing [N-13]-ammonia dynamic PET/CT exhibit a large cranial-to-caudal translation related to cardiac creep primarily at stress and to a lesser extent at rest, which can be accurately corrected by optimizing their 3D normalized gradient fields. Our approach provides a solution to the challenging condition where the image intensity and its gradients are opposed without the need for segmentation and remains robust in the presence of PET-CT mismatch.

Increasing Use of Cardiac PET/CT for Inflammatory and Infiltrative Heart Diseases in Korea.

Recently the incidence of inflammatory and infiltrative heart diseases is increasing in Korea. Cardiac PET/CT is a useful technology evaluating inflammatory and infiltrative heart diseases. This study analyzed trends in the use of cardiac PET/CT for evaluating inflammatory and infiltrative heart diseases in the Chonnam National University Hospital and Chonnam National University Hwasun Hospital. The general trend in Korea was also assessed based on the domestic nuclear medicine database. There was a common increasing trend in the number of F-18 FDG PET/CT for the evaluation of inflammatory and infiltrative heart diseases. A representative case with cardiac sarcoidosis is illustrated.

Change of Therapeutic Response Classification According to Recombinant Human Thyrotropin-Stimulated Thyroglobulin Measured at Different Time Points in Papillary Thyroid Carcinoma.

PURPOSE: We investigated whether response classification after total thyroidectomy and radioactive iodine (RAI) therapy could be affected by serum levels of recombinant human thyrotropin (rhTSH)-stimulated thyroglobulin (Tg) measured at different time points in a follow-up of patients with papillary thyroid carcinoma (PTC). METHODS: A total of 147 PTC patients underwent serum Tg measurement for response assessment 6 to 24 months after the first RAI therapy. Serum Tg levels were measured at 24 h (D1Tg) and 48-72 h (D2-3Tg) after the 2nd injection of rhTSH. Responses were classified into three categories based on serum Tg corresponding to the excellent response (ER-Tg), indeterminate response (IR-Tg), and biochemical incomplete response (BIR-Tg). The distribution pattern of response classification based on serum Tg at different time points (D1Tg vs. D2-3Tg) was compared. RESULTS: Serum D2-3Tg level was higher than D1Tg level (0.339 ng/mL vs. 0.239 ng/mL, P < 0.001). The distribution of response categories was not significantly different between D1Tg-based and D2-3Tg-based classification. However, 8 of 103 (7.8%) patients and 3 of 40 (7.5%) patients initially categorized as ER-Tg and IR-Tg based on D1Tg, respectively, were reclassified to IR-Tg and BIR-Tg based on D2-3Tg, respectively. The optimal cutoff values of D1Tg for the change of response categories were 0.557 ng/mL (from ER-Tg to IR-Tg) and 6.845 ng/mL (from IR-Tg to BIR-Tg). CONCLUSION: D1Tg measurement was sufficient to assess the therapeutic response in most patients with low level of D1Tg. Nevertheless, D2-3Tg measurement was still necessary in the patients with D1Tg higher than a certain level as response classification based on D2-3Tg could change.

Differences in diagnostic impact of dual-tracer PET/computed tomography according to the extrahepatic metastatic site in patients with hepatocellular carcinoma.

OBJECTIVES: We compared the diagnostic performance of C-11 acetate and F-18 fluorodeoxyglucose (FDG) PET/computed tomography (CT) for the detection of extrahepatic metastasis in patients with hepatocellular carcinoma (HCC) and evaluated whether the improvement in the diagnostic performance of dual tracer PET/CT differs by the metastatic site. METHODS: Fifty-eight patients who had extrahepatic metastasis on either C-11 acetate or F-18 FDG PET/CT were enrolled, and 193 metastatic lesions were analyzed in this retrospective study. The metastatic lesions were categorized based on six sites of involvement. According to each involved site, the tracer avidity of the metastatic lesions was compared using the maximum standardized uptake value (SUVmax). RESULTS: Bone was the most frequent categorized metastatic site (44.8%), followed by lymph node (39.7%), lung (34.5%), soft tissue (27.6%), adrenal gland (6.9%), and vascular category (3.4%). C-11 acetate PET/CT showed a higher SUVmax than F-18 FDG PET/CT in metastatic bone lesions (P = 0.003). F-18 FDG uptake was significantly higher than C-11 acetate uptake in metastatic lymph node lesions (P < 0.001). The detection rate of dual tracer PET/CT was significantly higher in the metastatic lung (93.6%) and soft tissue (100%) lesions. However, the diagnostic performance of dual tracer PET/CT was limited in the metastatic bone and lymph node lesions because each tracer's detection rate was very high (bone: 94.6% in C-11 acetate, lymph node: 94.1% in F-18 FDG). CONCLUSIONS: The tracer avidity of metastatic lesions differed according to the involved site. This difference affected the complementary role of dual tracer PET/CT in the diagnosis of extrahepatic metastases in patients with HCC.