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.

Tc-99m DMSA SPECT for Follow-Up of Non-Operative Treatments in Renal Injuries: A Prospective Single-Center Study.

OBJECTIVE: The assessment of cortical integrity following renal injuries with planar Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy depends on measuring relatively decreased cortical uptake (i.e., split renal function [SRF]). We analyzed the additive values of the volumetric and quantitative analyses of the residual cortical integrity using single-photon emission computed tomography (SPECT) compared to the planar scintigraphy. MATERIALS AND METHODS: This prospective study included 47 patients (male:female, 32:15; age, 47 ± 22 years) who had non-operatively managed renal injuries and underwent DMSA planar and SPECT imaging 3-6 months after the index injury. In addition to planar SRF, SPECT SRF, cortical volume, and absolute cortical uptake were measured for the injured kidney and both kidneys together. The correlations of planar SRF with SPECT SRF and those of SRF with volumetric/quantitative parameters obtained with SPECT were analyzed. The association of SPECT parameters with renal function, grades of renal injuries, and the risk of renal failure was also analyzed. RESULTS: SPECT SRF was significantly lower than planar SRF, with particularly higher biases in severe renal injuries. Planar and SPECT SRF (dichotomized with a cutoff of 45%) showed 19%-36% of discrepancies with volumetric and quantitative DMSA indices (when dichotomized as either high or low). Absolute cortical uptake of the injured kidney best correlated with glomerular filtration rate (GFR) at follow-up (ρ = 0.687, P < 0.001) with significant stepwise decreases by GFR strata (90 and 60 mL/min/1.73 m²). Total renal cortical uptake was significantly lower in patients with moderate-to-high risk of renal failure than those with low risk. However, SRF did not reflect GFR decrease below 60 mL/min/1.73 m² or the risk of renal failure, regardless of planar or SPECT (count- or volume-based SRF) imaging. CONCLUSION: Quantitative measurements of renal cortical integrity assessed with DMSA SPECT can provide more clinically relevant and comprehensive information than planar imaging or SRF alone.

Applying Pix2pix to Translate Hyperemia in Blood Pool Image into Corresponding Increased Bone Uptake in Delayed Image in Three-Phase Bone Scintigraphy.

Purpose: Delayed images may not be acquired due to severe pain, drowsiness, or worsening vital signs while waiting after blood pool imaging in three-phase bone scintigraphy. If the hyperemia in the blood pool image contains information from which increased uptake on the delayed images can be inferred, the generative adversarial network (GAN) can generate the increased uptake from the hyperemia. We attempted to apply pix2pix, a type of conditional GAN, to transform hyperemia into increased bone uptake. Methods: We enrolled 1464 patients who underwent three-phase bone scintigraphy for inflammatory arthritis, osteomyelitis, complex regional pain syndrome (CRPS), cellulitis, and recent bone injury. Blood pool images were acquired 10 min after intravenous injection of Tc-99 m hydroxymethylene diphosphonate, and delayed bone images were obtained after 3 h. The model was based on the open-source code of the pix2pix model with perceptual loss. Increased uptake in the delayed images generated by the model was evaluated using lesion-based analysis by a nuclear radiologist in areas consistent with hyperemia in the blood pool images. Results: The model showed sensitivities of 77.8% and 87.5% for inflammatory arthritis and CRPS, respectively. In osteomyelitis and cellulitis, their sensitivities of about 44% were observed. However, in cases of recent bone injury, the sensitivity was only 6.3% in areas consistent with focal hyperemia. Conclusion: The model based on pix2pix generated increased uptake in delayed images matching the hyperemia in the blood pool image in inflammatory arthritis and CRPS.

Evaluation of Non-infarct-Related Arteries Using C-11 Acetate PET in STEMI With Multivessel Disease.

BACKGROUND: We analyzed whether C-11 acetate positron emission tomography (PET) can be used for the evaluation of non-infarct-related artery (NIRA) in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease. METHODS: We prospectively enrolled 31 patients with STEMI and at least one NIRA stenosis (diameter stenosis [DS] ≥ 50%). C-11 acetate PET was performed after successful revascularization for the infarct-related artery (IRA). Myocardial blood flow (MBF) and oxidative metabolism (kmono) were measured and compared between NIRA vs. IRA, stenotic (DS ≥ 50%) vs. non-stenotic (DS < 50%) NIRAs, and NIRAs with significant stenosis (DS ≥ 70% or fractional flow reserve [FFR] ≤ 0.80) vs. those without (neither DS ≥ 70% nor FFR ≤ 0.80). The correlations between PET and angiographic parameters were also analyzed. RESULTS: MBF and kmono were significantly higher in NIRAs than those in IRAs. Stenotic NIRAs showed significantly reduced stress MBF, myocardial flow reserve (MFR), relative flow reserve (RFR) (0.72 ± 0.12 vs. 0.82 ± 0.14; p = 0.001), and stress kmono, as compared to those in non-stenotic NIRAs. NIRAs with significant stenosis had significantly lower stress MBF, MFR, and RFR (0.70 ± 0.10 vs. 0.80 ± 0.14; p = 0.001). RFR showed the best, but modest linear correlation with DS of NIRA stenosis (r = -0.429, p = 0.001). RFR > 0.81 could effectively exclude the presence of significant NIRA stenosis. CONCLUSIONS: C-11 acetate PET could be a feasible alternative noninvasive modality in patients with STEMI and multivessel disease, by excluding the presence of significant NIRA stenosis.

Multimodal Imaging-Based Potential Visualization of the Tumor Microenvironment in Bone Metastasis.

Bone metastasis (BM) is the most common malignant bone tumor and a significant cause of morbidity and mortality for patients with cancer. Compared to other metastatic organs, bone has unique characteristics in terms of the tumor microenvironment (TME). Precise assessments of the TME in BM could be an important step for developing an optimized management plan for patient care. Imaging approaches for BM have several advantages, such as biopsy not being required, multiple site evaluation, and serial assessment in the same sites. Owing to the developments of new imaging tracers or imaging modalities, bone TME could be visualized using multimodal imaging techniques. In this review, we describe the BM pathophysiology, diagnostic principles of major imaging modalities, and clinically available imaging modalities to visualize the TME in BM. We also discuss how the interactions between various factors affecting the TME could be visualized using multimodal imaging techniques.

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.

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.

Deceased vs. living donor kidney transplantation in prediction of acute renal allograft rejection using Tc-99m DTPA renal scan.

OBJECTIVES: No data are available regarding different prognostic values of Tc-99m diethylenetriaminepentaacetic acid (DTPA) renal scan in kidney transplantation (KT) recipients according to two distinct donor types: deceased donor KT (DDKT) and living donor KT (LDKT). We evaluated whether the interpretation of Tc-99m DTPA renal scan should be different by the donor type in predicting acute renal allograft rejection (AR). METHODS: One hundred and seven KT recipients (61 DDKT and 46 LDKT) were included in this study. Tc-99m DTPA renal scan was performed 1 week after KT. AR was defined as pathological evidence of renal allograft rejection during the first 6 months of KT. Clinical factors and Tc-99m DTPA renal scan findings were compared between patients with and without AR. To further analyze the effect of the donor type, they were again compared within DDKT and LDKT recipients, respectively. RESULTS: AR occurred in 15 patients (7 DDKT and 8 LDKT recipients). Among all patients, time to peak uptake (TTP) of the cortex (TTPCX) measured by Tc-99m DTPA renal scan was independently predictive of AR. Moreover, TTPKD (TTP of the whole transplanted kidney) and TTPCX were the only predictors of AR among DDKT recipients. The most accurate predictors were TTPCX and kidney area on renal scan for DDKT and LDKT, respectively. However, these parameters could not predict AR for the opposite donor type. CONCLUSIONS: AR could be effectively predicted by Tc-99m DTPA renal scan obtained at 1 week post-KT. Different parameters should be applied according to the donor type in the prediction of AR.

MicroRNA-155 as a proinflammatory regulator via SHIP-1 down-regulation in acute gouty arthritis.

INTRODUCTION: Gout is characterized by episodes of intense joint inflammation in response to intra-articular monosodium urate monohydrate (MSU) crystals. miR-155 is crucial for the proinflammatory activation of human myeloid cells and antigen-driven inflammatory arthritis. The functional role of miR-155 in acute gouty arthritis has not been defined. Therefore, the aim of this study was to examine the role of miR-155 in pathogenesis of acute gouty arthritis. METHODS: Samples from 14 patients with acute gouty arthritis and 10 healthy controls (HCs) were obtained. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were cultured in vitro with MSU crystals, and gene expression (human miR-155 and SHIP-1) were assessed by real-time PCR. THP-1 cells were stimulated by MSU crystals and/or miR-155 transfection and then subjected to Western blot analysis. Levels of human tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1ß in cell culture supernatants were measured by Luminex. Immunohistochemistry was performed on formalin-fixed gout tissues with anti-SHIP-1 antibody. A C57BL/6 J male mouse model of gout was used to analyze the expressions of miR-155, SHIP-1, and inflammatory cytokines. RESULTS: The samples from gouty arthritis were highly enriched in miR-155, with levels of expression being higher than those found in PBMC from HC. Treatment of the cells with MSU crystals strongly induced miR-155. In addition, overexpression of miR-155 in the cells decreased levels of SHIP-1 and promoted production of MSU-induced proinflammatory cytokines, such as TNF-α and IL-1ß. Consistent with in vitro observations, miR-155 expression was elevated in the mouse model of gout. The production of inflammatory cytokines was markedly increased in MSU crystal induced peritonitis mice. CONCLUSIONS: Overexpression of miR-155 in the gouty SFMC leads to suppress SHIP-1 levels and enhance proinflammatory cytokines.

SLAT negatively regulates RANKL-induced osteoclast differentiation.

RANKL induces the formation of osteoclasts, which are responsible for bone resorption. Herein, we investigated the role of SWAP-70-like adapter of T cells (SLAT) in RANKL-induced osteoclastogenesis. Expression levels of SLAT were reduced during RANKL-induced osteoclastogenesis. Overexpression of SLAT in BMMs inhibited TRAP-positive multinuclear osteoclast formation and attenuated the expression of NFATc1, which is an important modulator in osteoclastogenesis. Furthermore, silencing of SLAT by RNA interference enhanced osteoclast formation as well as NFATc1 expression. In addition, SLAT was involved in RANKL-induced JNK activation in osteoclasts. Taken together, our data suggest that SLAT acts as a negative modulator of RANKL-induced osteoclastogenesis.

The transmembrane adaptor protein, linker for activation of T cells (LAT), regulates RANKL-induced osteoclast differentiation.

RANKL induces the formation of osteoclasts, which are responsible for bone resorption. Herein we investigate the role of the transmembrane adaptor proteins in RANKL-induced osteoclastogenesis. LAT positively regulates osteoclast differentiation and is up-regulated by RANKL via c-Fos and NFATc1, whereas LAB and LIME act as negative modulators of osteoclastogenesis. In addition, silencing of LAT by RNA interference or overexpression of a LAT dominant negative in bone marrow-derived macrophage cells attenuates RANKL-induced osteoclast formation. Furthermore, LAT is involved in RANKL-induced PLC(γ) activation and NFATc1 induction. Thus, our data suggest that LAT acts as a positive regulator of RANKL-induced osteoclastogenesis.

Akt induces osteoclast differentiation through regulating the GSK3ß/NFATc1 signaling cascade.

SHIP is an SH2-containing inositol-5-phosphatase expressed in hematopoietic cells. It hydrolyzes the PI3K product PI(3,4,5)P(3) and blunts the PI3K-initiated signaling pathway. Although the PI3K/Akt pathway has been shown to be important for osteoclastogenesis, the molecular events involved in osteoclast differentiation have not been revealed. We demonstrate that Akt induces osteoclast differentiation through regulating the GSK3ß/NFATc1 signaling cascade. Inhibition of the PI3K by LY294002 reduces formation of osteoclasts and attenuates the expression of NFATc1, but not that of c-Fos. Conversely, overexpression of Akt in bone marrow-derived macrophages (BMMs) strongly induced NFATc1 expression without affecting c-Fos expression, suggesting that PI3K/Akt-mediated NFATc1 induction is independent of c-Fos during RANKL-induced osteoclastogenesis. In addition, we found that overexpression of Akt enhances formation of an inactive form of GSK3ß (phospho-GSK3ß) and nuclear localization of NFATc1, and that overexpression of a constitutively active form of GSK3ß attenuates osteoclast formation through downregulation of NFATc1. Furthermore, BMMs from SHIP knockout mice show the increased expression levels of phospho-Akt and phospho-GSK3ß, as well as the enhanced osteoclastogenesis, compared with wild type. However, overexpression of a constitutively active form of GSK3ß attenuates RANKL-induced osteoclast differentiation from SHIP-deficient BMMs. Our data suggest that the PI3K/Akt/GSK3ß/NFATc1 signaling axis plays an important role in RANKL-induced osteoclastogenesis.

RANKL induces NFATc1 acetylation and stability via histone acetyltransferases during osteoclast differentiation.

NFATc1 (nuclear factor of activated T-cells c1), a key transcription factor, plays a role in regulating expression of osteoclast-specific downstream target genes such as TRAP (tartrate-resistant acid phosphatase) and OSCAR (osteoclast-associated receptor). It has been shown that RANKL [receptor activator of NF-κB (nuclear factor κB) ligand] induces NFATc1 expression during osteoclastogenesis at a transcriptional level. In the present study, we demonstrate that RANKL increases NFATc1 protein levels by post-translational modification. RANKL stimulates NFATc1 acetylation via HATs (histone acetyltransferases), such as p300 and PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor], thereby stabilizing NFATc1 proteins. PCAF physically interacts with NFATc1 and directly induces NFATc1 acetylation and stability, subsequently increasing the transcriptional activity of NFATc1. In addition, RANKL-mediated NFATc1 acetylation is increased by the HDAC (histone deacetylase) inhibitors sodium butyrate and scriptaid. Overexpression of HDAC5 reduces RANKL- or PCAF-mediated NFATc1 acetylation, stability and transactivation activity, suggesting that the balance between HAT and HDAC activities might play a role in the regulation of NFATc1 levels. Furthermore, RANKL and p300 induce PCAF acetylation and stability, thereby enhancing the transcriptional activity of NFATc1. Down-regulation of PCAF by siRNA (small interfering RNA) decreases NFATc1 acetylation and stability, as well as RANKL-induced osteoclastogenesis. Taken together, the results of the present study demonstrate that RANKL induces HAT-mediated NFATc1 acetylation and stability, and subsequently increases the transcriptional activity of NFATc1 during osteoclast differentiation.