Distinct cerebral cortical perfusion patterns in idiopathic normal-pressure hydrocephalus.

The aims of the study are to evaluate idiopathic normal-pressure hydrocephalus (INPH)-related cerebral blood flow (CBF) abnormalities and to investigate their relation to cortical thickness in INPH patients. We investigated cortical CBF utilizing surface-based early-phase 18 F-florbetaben (E-FBB) PET analysis in two groups: INPH patients and healthy controls. All 39 INPH patients and 20 healthy controls were imaged with MRI, including three-dimensional volumetric images, for automated surface-based cortical thickness analysis across the entire brain. A subgroup with 37 participants (22 INPH patients and 15 healthy controls) that also underwent 18 F-fluorodeoxyglucose (FDG) PET imaging was further analyzed. Compared with age- and gender-matched healthy controls, INPH patients showed statistically significant hyperperfusion in the high convexity of the frontal and parietal cortical regions. Importantly, within the INPH group, increased perfusion correlated with cortical thickening in these regions. Additionally, significant hypoperfusion mainly in the ventrolateral frontal cortex, supramarginal gyrus, and temporal cortical regions was observed in the INPH group relative to the control group. However, this hypoperfusion was not associated with cortical thinning. A subgroup analysis of participants that also underwent FDG PET imaging showed that increased (or decreased) cerebral perfusion was associated with increased (or decreased) glucose metabolism in INPH. A distinctive regional relationship between cerebral cortical perfusion and cortical thickness was shown in INPH patients. Our findings suggest distinct pathophysiologic mechanisms of hyperperfusion and hypoperfusion in INPH patients.

Incidence rate and factors associated with the development of secondary cancers after radioiodine therapy in differentiated thyroid cancer: a multicenter retrospective study.

PURPOSE: The objective of this study was to estimate the incidence of secondary cancers and the factors associated with their development among patients who underwent radioiodine therapy (RIT) with differentiated thyroid cancer. METHODS: We retrospectively collected medical records for patients who underwent first RIT between January 1, 2000, and December 31, 2005, from seven tertiary hospitals in South Korea after total thyroidectomy for differentiated thyroid cancer. Cancer incidence and calculated standardized rate ratio were compared with Korean cancer incidence data. The association between the development of secondary cancers and various parameters was analyzed by Cox-proportional hazard regression. RESULTS: A total of 3106 patients were included in this study. Mean age at the time of diagnosis of thyroid cancer was 45.7 ± 13.3 years old, and 2669 (85.9%) patients were female. The follow-up period was 11.9 ± 4.6 (range, 1.2-19.6) years. A total of 183 secondary cancers, which included 162 solid and 21 hematologic cancers, occurred in 173 patients (5.6%). There was no significant difference between solid cancer incidence in our study population who underwent RIT and the overall Korean population, but the incidence of hematologic cancers and total cancer in our study was significantly higher compared with that of the Korean population. A multivariate analysis identified independent prognostic factors for the development of secondary cancer including age at 1st RIT, male, and total cumulative dose over 200 mCi. CONCLUSION: We need to assess the risk benefit for patients who receive over 200 mCi of a total cumulative dose.

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.

Extracellular vesicles derived from macrophage promote angiogenesis In vitro and accelerate new vasculature formation In vivo.

BACKGROUND: Ischemia is the partial or complete blockage of blood supply to tissues. Extracellular vesicles (EVs) are emerging as a therapeutic tool for ischemic diseases. Most EV-based ischemia therapies are based on various stem cells. Here, we propose an alternative cell source for the isolation of pro-angiogenic EVs. METHODS: EVs were isolated from a mouse macrophage cell line (Raw 264.7). The characteristic features of the macrophage-derived EVs (MAC-EVs) were assessed using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting (WB) analysis. WB and qRT-PCR were performed to identify the pro-angiogenic VEGF and Wnt3a proteins and microRNAs (miR-210, miR-126, and miR-130a) in the MAC-EVs. In vitro and in vivo Matrigel plug assays were performed to investigate the capacity of the MAC-EVs for tube (blood vessel-like) formation and new blood vessel formation and assessed by histology. RESULTS: The MAC-EVs was positive for ALIX and negative for calnexin, with a round shape and an average size of 189 ± 65.1 nm. WB and qRT-PCR results revealed that VEGF, Wnt3a and miR-130a were more abundant in the MAC-EVs than cells. MAC-EVs treatment resulted in increased endothelial cellular proliferation, migration, and tube formation in vitro. In vivo assay results revealed that MAC-EVs increased the formation of new and larger blood vessels in the Matrigel plug of mice compared to the formation in the control group. CONCLUSION: Our results suggest that MAC-EVs have the potential to induce angiogenesis in vitro and in vivo, could serve as a pro-angiogenic alternative for ischemic diseases.

White blood cell labeling with Technetium-99m (99mTc) using red blood cell extracellular vesicles-mimetics.

BACKGROUND: Extracellular vesicles, have gained increasing attention for their application in drug delivery. Here, we developed a novel method for radiolabeling WBCs with 99mTc using RBC-derived extracellular vesicles -mimetics (EVMs), and monitored in vivo inflammation tracking of 99mTc-WBC using gamma camera in acute inflammation mouse model. METHODS: Engineered EVMs from RBCs were produced by a one-step extrusion method. RBC-EVMs were analyzed by NTA and TEM. Cells were labeled with 99mTc by using 99mTc-RBC-EVMs. Inflammation mice model was prepared and confirmed by 18F-FDG PET/CT. 99mTc-WBCs were injected in mice, and their biodistribution was analyzed by gamma camera. FINDING: The radiochemical purity of 99mTc-RBC-EVMs was 100%. The 99mTc-labeling did't affect the size and morphology. The 99mTc in the cytoplasm of RBC-EVMs was successfully confirmed by high angle annular dark field STEM (scanning transmission electron microscope). Cells were successfully labeled with 99mTc using 99mTc-RBC-EVMs, and the counts per minute was increased in dose- and time-dependent manners. The 18F-FDG PET/CT images confirmed establishment of acute inflammation (left mouse foot). 99mTc-WBCs showed higher uptake in the inflamed foot than non-inflamed foot. INTERPRETATION: This novel method for radiolabeling WBCs using RBC-EVMs. 99mTc labeling may be a feasible method to monitor the in vivo biodistribution of cells.

Utility of 18F-FDG PET/CT for predicting pathologic complete response in hormone receptor-positive, HER2-negative breast cancer patients receiving neoadjuvant chemotherapy.

BACKGROUND: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) is a predictor of improved outcomes in breast cancer. In patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2) -negative breast cancer, the response to NAC is variable and mostly limited. This study was an investigation of the predictive relevance of parameters of 18F-FDG PET/CT for the pCR to NAC in patients with HR-positive, HER2-negative breast cancer. METHODS: AH total of 109 consecutive HR-positive and HER2-negative breast cancer patients who were treated with NAC were enrolled in this prospective cohort study. The relationships between pretreatment 18F-FDG PET/CT and clinical outcomes including pathologic response to NAC were evaluated. RESULTS: All patients finished their planned NAC cycles and eight patients (7.3%) achieved pCR. In the receiver operating characteristic (ROC) curve analysis, pSUVmax exhibited high sensitivity and specificity for predicting pCR. Furthermore, multivariate logistic regression analysis revealed pSUVmax as a predictive factor for pCR (hazard ratio = 17.452; 95% CI = 1.847-164.892; p = 0.013). CONCLUSION: The results of this study suggest that 18F-FDG PET/CT pSUVmax is a predictive factor for pCR of HR-positive, HER2-negative breast cancer to NAC.

A systematic review and meta-analysis of 18F-fluorodeoxyglucose positron emission tomography or positron emission tomography/computed tomography for detection of infected prosthetic vascular grafts.

OBJECTIVE: The purpose of this investigation was to evaluate the diagnostic accuracy of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or PET/computed tomography (PET/CT) for the detection of vascular prosthetic graft infection (VPGI) using a diagnostic accuracy test. METHODS: The MEDLINE/PubMed and Embase databases, from the earliest available date of indexing through March 31, 2018, were searched for results investigating the diagnostic accuracy of 18F-FDG PET or PET/CT for the detection of VPGI. We calculated the pooled sensitivities and specificities of included studies, calculated positive and negative likelihood ratios, and obtained summary receiver operating characteristic curves. RESULTS: Across 10 studies (286 patients), the pooled sensitivity was 0.96 (95% confidence interval [CI], 0.89-0.98) without heterogeneity (I2 = 40.2; 95% CI, 0.0-84.4; P = .09), and pooled specificity was 0.74 (95% CI, 0.67-0.81) without heterogeneity (I2 = 39.9; 95% CI, 0.0-84.3; P = .09). Likelihood ratio syntheses showed an overall positive likelihood ratio of 3.7 (95% CI, 2.9-4.9) and negative likelihood ratio of 0.06 (95% CI, 0.02-0.15). The pooled diagnostic odds ratio was 63 (95% CI, 23-173). The hierarchical summary receiver operating characteristic curve showed the area under the curve to be 0.87 (95% CI, 0.83-0.89). CONCLUSIONS: This study showed the high sensitivity and moderate specificity of 18F-FDG PET or PET/CT for the detection of VPGI. The clinical usefulness of 18F-FDG PET or PET/CT for detection of VPGI should be validated through further large multicenter studies.

F-18 FDG PET for assessment of disease activity of large vessel vasculitis: A systematic review and meta-analysis.

BACKGROUND: The aim of this study is to investigate the performance of F-18 fluorodeoxyglucose positron emission tomography (F-18 FDG PET) or positron emission tomography/computed tomography (PET/CT) for the assessment of disease activity in patients with large vessel vasculitis (LVV) through a meta-analysis. METHODS: The MEDLINE via PubMed and EMBASE were searched for the studies evaluating the performance of F-18 FDG PET or PET/CT in the assessment of disease activity in patients with LVV. Pooled sensitivity, specificity, diagnostic odds ratios (DORs), and summary receiver-operating characteristic (sROC) curve were estimated across the included studies. Possible publication bias was assessed by Deek's funnel plot asymmetry tests. RESULTS: A total of 439 PET images from 298 patients pooled from nine studies showed that the pooled sensitivity was 0.88 [95% confidence interval (CI) 0.79-0.93] without heterogeneity (χ2 = 14.42, P = .07) and the pooled specificity was 0.81 (95% CI 0.64-0.91) with heterogeneity (χ2 = 63.72, P = .00) for the detection of active LVV. The pooled DOR was 30 (95% CI 8-107). Hierarchical sROC curve indicates that the area under the curve was 0.91 (95% CI 0.89-0.94). There was no significant publication bias (P = .42), and meta-regression analysis revealed that none of the variables was the source of the study heterogeneity. CONCLUSIONS: F-18 FDG PET has a good performance for the detection of active disease status in patients with LVV. Revised criteria for the assessment of disease activity incorporated with F-18 FDG PET or PET/CT should be introduced and validated. Further studies are warranted to determine if PET-based treatment of LVV can improve outcomes.

PROGNOSTIC VALUE OF LYMPH NODE UPTAKE ON PRETREATMENT F-18 FDG PET/CT IN PATIENTS WITH N1B PAPILLARY THYROID CARCINOMA.

Objective: The aim of this study was to investigate the prognostic value of metabolic characteristics of metastatic lymph node (LN) using pretreatment F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for patients with papillary thyroid carcinoma (PTC) and metastatic lateral LN (N1b). Methods: Ninety-six PTC patients (female:male = 72:24; median age, 44.5 years) with pathologic N1b who underwent pretreatment FDG PET/CT, total thyroidectomy, and radioactive iodine ablation were retrospectively reviewed. To predict responses to initial therapy and recurrence, clinicopathologic factors and metabolic parameters were reviewed, such as sex, age, tumor size, extranodal extension, number and ratio of metastatic LNs, serum thyroglobulin, and maximum standardized uptake value (SUVmax). Results: Among the 96 PTC patients, 81 (84.4%) were classified into the acceptable response (58 excellent; 23 indeterminate) and 15 (15.6%) into the incomplete response (8 biochemical incomplete; 7 structural incomplete) by the 2015 American Thyroid Association management guideline for differentiated thyroid carcinoma. The multivariate analysis showed that SUVmax of N1b (P = .018), pre-ablation stimulated thyroglobulin level (P = .006), and the ratio of metastatic LNs (P = .018) were related to incomplete response. The cutoff value of each variable was determined by receiver operating characteristic analysis. Nine (9.4%) patients experienced recurrences (median follow-up: 50 months). The Kaplan-Meier analysis revealed that SUVmax of N1b (cutoff value: 2.3; P = .025) and ratio of metastatic LNs (cutoff value: 0.218; P = .037) were significant prognostic factors for recurrence. Conclusion: High SUVmax of N1b cervical LN on pretreatment FDG PET/CT could predict incomplete responses to initial therapy and recurrence in patients with N1b PTC. Abbreviations: ATA = American Thyroid Association; DTC = well-differentiated thyroid carcinoma; FDG = F-18 fluorodeoxyglucose; IQR = interquartile range; LN = lymph node; N1b = metastatic lateral cervical lymph node; PET/CT = positron emission tomography/computed tomography; PTC = papillary thyroid carcinoma; RAI = radioactive iodine; ROC = receiver operating characteristic; SUVmax = maximum standardized uptake value; Tg = thyroglobulin; USG = ultrasonography.

Susceptibility of the Index Urinary Tract Infection to Prophylactic Antibiotics Is a Predictive Factor of Breakthrough Urinary Tract Infection in Children with Primary Vesicoureteral Reflux Receiving Continuous Antibiotic Prophylaxis.

BACKGROUND: Few studies have reported on breakthrough urinary tract infection (UTI) associated with the susceptibility of index UTI to prophylactic antibiotics in children with primary vesicoureteral reflux (VUR) receiving continuous antibiotic prophylaxis (CAP). We assessed the impact of the susceptibility of index UTI to prophylactic antibiotics in breakthrough UTIs in children with primary VUR receiving CAP. METHODS: We retrospectively reviewed the medical records of 81 children with primary VUR who were diagnosed after febrile or symptomatic UTI and subsequently received trimethoprim-sulfamethoxazole (TMP-SMX) as CAP between January 2010 and December 2013. We allocated children to a susceptible group or a resistant group based on the susceptibility of index UTI to TMP-SMX. We evaluated patient demographics and clinical outcomes after CAP according to the susceptibility of index UTI to TMP-SMX. Multivariate analysis was used to identify the predictive factors for breakthrough UTI. RESULTS: Of the 81 children, 42 were classified into the susceptible group and 39 into the resistant group. The proportion of breakthrough UTI was 31.0% (13/42) in the susceptible group and 53.8% (21/39) in the resistant group (P = 0.037). Progression of renal scarring was observed in 0% of children in the susceptible group and 15% in the resistant group (P = 0.053). Multivariate analysis showed that TMP-SMX resistance and initial renal scarring were significant predictors of breakthrough UTI. CONCLUSION: Susceptibility of index UTI to prophylactic antibiotics is a risk factor of breakthrough UTI and is associated with poor clinical outcomes in children with primary VUR receiving CAP.

Diagnostic performance of HMGA2 gene expression for differentiation of malignant thyroid nodules: A systematic review and meta-analysis.

OBJECTIVE: The purpose of the current study was to investigate the diagnostic performance of high mobility group A2 (HMGA2) gene expression for differentiation of malignant thyroid nodules through a systematic review and meta-analysis. DESIGN: The MEDLINE/PubMed and EMBASE database, from the earliest available date of indexing through 10 April 2018, were searched for studies evaluating the diagnostic performance of HMGA2 expression for differentiation of thyroid nodules. METHODS: We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic (ROC) curves. RESULTS: Across 7 studies, the pooled sensitivity for HMGA2 expression was 0.78 (95% CI; 0.67-0.86) with heterogeneity (I2  = 86.6) and a pooled specificity of 0.94 (95% CI: 0.85-0.98) with heterogeneity (I2  = 94.7). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 12.6 (95% CI: 5.1-31.3) and negative likelihood ratio (LR-) of 0.24 (95% CI: 0.15-0.36). The pooled diagnostic odds ratio (DOR) was 53 (95% CI: 18-159). Hierarchical summary ROC curve indicates that the areas under the curve were 0.92 (95% CI: 0.89-0.94). In meta-regression analysis, no definite variable was the source of the study heterogeneity. CONCLUSION: The current meta-analysis showed the moderate sensitivity and high specificity of HMGA2 expression for differentiation of malignant thyroid nodules. The likelihood ratio scatter-gram suggested that HMGA2 expression analysis could be useful for confirmation of the presence of malignant thyroid nodules. Considering the heterogeneity of included studies, further large prospective studies are necessary to confirm these results.

Prognostic significance of residual lymph node status after definitive chemoradiotherapy in patients with node-positive cervical cancer.

OBJECTIVE: Lymph node involvement is an important prognostic factor in patients with cervical cancer. However, the prognostic significance of lymph node response to chemoradiotherapy remains unclear. We retrospectively analyzed the relationship between residual lymph node status after definitive chemoradiotherapy and survival. METHODS: We enrolled 117 patients with node-positive cervical cancer. All patients were treated with definitive chemoradiotherapy in our institution, from 2006 to 2016. The median follow-up period was 41months (range, 6-128months). The criterion for a positive lymph node was defined as a maximum short axis diameter of ≥8mm on pretreatment magnetic resonance imaging (MRI)/computed tomography (CT) scans. Posttreatment pelvic MRI was obtained 3months after the completion of chemoradiotherapy. Residual primary tumor was defined as any residual lesion identified upon clinical examination and/or MRI. Residual lymph node was defined as any lymph node with a short axis diameter of ≥8mm posttreatment, according to MRI/CT. RESULTS: At follow-up, 3months after chemoradiotherapy, we observed residual primary tumor in 30 patients (25.6%), and residual lymph node in 31 patients (26.5%). The presence of residual lymph node was associated with worse overall survival according to multivariate analysis (hazard ratio, 3.04; 95% confidence interval, 1.43-6.44; p=0.004). In the 5-year time-dependent ROC analysis of survival prediction, the presence of residual lymph node showed an AUC value of 0.72. CONCLUSIONS: The presence of residual lymph node after chemoradiotherapy was associated with worse survival in patients with node-positive cervical cancer.

Migration of mesenchymal stem cells to tumor xenograft models and in vitro drug delivery by doxorubicin.

Mesenchymal stem cells (MSCs) show therapeutic effects in various types of diseases. MSCs have been shown to migrate towards inflamed or cancerous tissues, and visualized after sacrificing the animal. MSCs are able to deliver drugs to target cells, and are an ideal candidate for cancer therapy. The purpose of this study was to track the migration of MSCs in tumor-bearing mice; MSCs were also used as drug delivery vehicles. Human breast cancer cells (MDA-MB-231) and anaplastic thyroid cancer cells (CAL62) were transduced with lentiviral particles, to express the Renilla luciferase and mCherry (mCherry-Rluc) reporter genes. Human bone marrow-derived MSCs were transduced with lentiviral particles, to express the firefly luciferase and enhanced green fluorescence protein (Fluc2-eGFP) reporter genes (MSC/Fluc). Luciferase activity of the transduced cells was measured by bioluminescence imaging (BLI). Further in vitro migration assays were performed to confirm cancer cells conditioned medium dependent MSC and doxorubicin (DOX) treated MSC migration. MSCs were loaded with DOX, and their therapeutic effects against the cancer cells were studied in vitro. In vivo MSC/Fluc migration in mice having thyroid or breast cancer xenografts was evaluated after systemic injection. Rluc activity of CAL62/Rluc (R2=0.911), MDA-MB-231/Rluc (R2=0.934) cells and Fluc activity of MSC/Fluc (R2=0.91) cells increased with increasing cell numbers, as seen by BLI. eGFP expression of MSC/Fluc was confirmed by confocal microscopy. Similar migration potential was observed between MSC/Fluc and naïve MSCs in migration assay. DOX treated MSCs migration was not decreased compared than MSCs. Migration of the systemically injected MSC/Fluc cells into tumor xenografts (thyroid and breast cancer) was visualized in animal models (p<0.05) and confirmed by ex vivo (p<0.05) BLI. Additionally, MSCs delivered DOX to CAL62/Rluc and MDA-MB-231/Rluc cells, thereby decreasing their Rluc activities. In this study, we confirmed the migration of MSCs to tumor sites in cancer xenograft models using both in vivo and ex vivo BLI imaging. DOX-pretreated MSCs showed enhanced cytotoxic effects. Therefore, this noninvasive reporter gene (Fluc2)-based BLI may be useful for visualizing in vivo tracking of MSCs, which can be used as a drug delivery vehicle for cancer therapy.

PEGylated crushed gold shell-radiolabeled core nanoballs for in vivo tumor imaging with dual positron emission tomography and Cerenkov luminescent imaging.

BACKGROUND: Radioactive isotope-labeled gold nanomaterials have potential biomedical applications. Here, we report the synthesis and characterization of PEGylated crushed gold shell-radioactive iodide-124-labeled gold core nanoballs (PEG-124I-Au@AuCBs) for in vivo tumor imaging applications through combined positron emission tomography and Cerenkov luminescent imaging (PET/CLI). RESULTS: PEG-124I-Au@AuCBs showed high stability and sensitivity in various pH solutions, serum, and in vivo conditions and were not toxic to tested cells. Combined PET/CLI clearly revealed tumor lesions at 1 h after injection of particles, and both signals remained visible in tumor lesions at 24 h, consistent with the biodistribution results. CONCLUSION: Taken together, the data provided strong evidence for the application of PEG-124I-Au@AuCBs as promising imaging agents in nuclear medicine imaging of various biological systems, particularly in cancer diagnosis.

Amyloid Deposits and Idiopathic Normal-Pressure Hydrocephalus: An 18F-Florbetaben Study.

BACKGROUND: The first aim of our study was to determine whether cortical 18F-florbetaben retention was different between healthy controls and idiopathic normal-pressure hydrocephalus (INPH) patients. Our second aim was to investigate whether there were any relationships between 18F-florbetaben retention and either hippocampal volume or clinical symptoms in INPH patients. METHODS: Seventeen patients diagnosed with INPH and 8 healthy controls underwent studies with magnetic resonance imaging and 18F-florbetaben positron emission tomography imaging. RESULTS: Automated region-of-interest analysis showed significant increases in 18F-florbetaben uptake in several brain regions in INPH patients compared to control subjects, with especially remarkable increases in the frontal (bilateral), parietal (bilateral), and occipital (bilateral) cortices. In the INPH group, right hippocampal volume was found to be negatively correlated with right frontal 18F-florbetaben retention. Korean-Mini Mental State Examination scores negatively correlated with right occipital 18F-florbetaben retention. Higher 18F-florbetaben retention correlated significantly with a higher Clinical Dementia Rating Scale score in the right occipital cortex. CONCLUSIONS: Our results indicate that INPH might be a disease exhibiting a characteristic pattern of cortical 18F-florbetaben retention. 18F-florbetaben retention in the frontal cortex may be related to hippocampal neuronal degeneration. Our findings may also help us understand the potential pathophysiology of cognitive impairments associated with INPH.

Regulated Mesenchymal Stem Cells Mediated Colon Cancer Therapy Assessed by Reporter Gene Based Optical Imaging.

Colorectal cancer is the most common cancer in both men and women and the second most common cause of cancer-related deaths. Suicide gene-based therapy with suicide gene-transduced mesenchymal stem cells (MSCs) is a promising therapeutic strategy. A tetracycline-controlled Tet-On inducible system used to regulate gene expression may be a useful tool for gene-based therapies. The aim of this study was to develop therapeutic MSCs with a suicide gene that is induced by an artificial stimulus, to validate therapeutic gene expression, and to monitor the MSC therapy for colon cancer using optical molecular imaging. For our study, we designed the Tet-On system using a retroviral vector and developed a response plasmid RetroX-TRE (tetracycline response element) expressing a mutant form of herpes simplex virus thymidine kinase (HSV1-sr39TK) with dual reporters (eGFP-Fluc2). Bone marrow-derived MSCs were transduced using a RetroX-Tet3G (Clontech, CA, USA) regulatory plasmid and RetroX-TRE-HSV1-sr39TK-eGFP-IRES-Fluc2, for a system with a Tet-On (MSC-Tet-TK/Fluc2 or MSC-Tet-TK) or without a Tet-On (MSC-TK/Fluc2 or MSC-TK) function. Suicide gene engineered MSCs were co-cultured with colon cancer cells (CT26/Rluc) in the presence of the prodrug ganciclovir (GCV) after stimulation with or without doxycycline (DOX). Treatment efficiency was monitored by assessing Rluc (CT26/Rluc) and Fluc (MSC-Tet-TK and MSC-TK) activity using optical imaging. The bystander effect of therapeutic MSCs was confirmed in CT26/Rluc cells after GCV treatment. Rluc activity in CT26/Rluc cells decreased significantly with GCV treatment of DOX(+) cells (p < 0.05 and 0.01) whereas no significant changes were observed in DOX(-) cells. In addition, Fluc activity in also decreased significantly with DOX(+) MSC-Tet-TK cells, but no signal was observed in DOX(-) cells. In addition, an MSC-TK bystander effect was also confirmed. We assessed therapy with this system in a colon cancer xenograft model (CT26/Rluc). We successfully transduced cells and developed a Tet-On system with the suicide gene HSV1-sr39TK. Our results confirmed the therapeutic efficiency of a suicide gene with the Tet-On system for colon cancer. In addition, our results provide an innovative therapeutic approach using the Tet-On system to eradicate tumors by administration of MSC-Tet-TK cells with DOX and GCV.

Role of pulmonary macrophages in initiation of lung metastasis in anaplastic thyroid cancer.

Several clinical studies have demonstrated that increased macrophage infiltration into tumors confers metastatic potential and poor prognosis in cancer. Preclinical studies are needed to develop new strategies for countering metastasis. Our study was designed to investigate the impact of pulmonary macrophages on lung metastasis of anaplastic thyroid cancer (ATC). ATC (CAL-62) and macrophage (Raw264.7) were transfected with the effluc (CAL-62/effluc, Raw264.7/effluc). Coculture and migration assays were used to assess the effect of Raw264.7 or THP1 (human macrophage) (or conditioned medium) on the proliferation and/or migration of CAL-62/effluc cells in vitro. The effect of clodro-lipo or PBS-lipo on macrophage depletion was confirmed in vitro and in vivo. CAL-62/effluc cells (1 × 10(6) ) were intravenously injected into nude mice 24 h after clodro-lipo or PBS-lipo administration. Effect of clodro-lipo on the lung metastasis of CAL-62/effluc was assessed by bioluminescence imaging (BLI). Micro computed tomography (micro-CT) and histology. BLI signals of CAL-62/effluc and Raw264.7/effluc increased to cell number. Raw264.7 cells and THP1 cells promoted CAL-62/effluc proliferation, and conditioned medium of Raw264.7 cells promoted CAL-62/effluc migration. Clodro-lipo significantly depleted pulmonary macrophages in vitro and in vivo. Intensity of BLI signals in ATC lung metastasis was weaker in the clodro-lipo group than PBS-lipo control. Micro-CT imaging and hematoxylin/eosin staining revealed smaller tumor masses in the clodro-lipo group than PBS-lipo control. Our findings indicate that pulmonary macrophages have an important role in initiation of lung metastasis of ATC. New therapeutic strategies that preclude initiation of pulmonary metastasis could potentially be developed by targeting pulmonary macrophages.

Combined Positron Emission Tomography and Cerenkov Luminescence Imaging of Sentinel Lymph Nodes Using PEGylated Radionuclide-Embedded Gold Nanoparticles.

New imaging probes with high sensitivity and stability are urgently needed to accurately detect sentinel lymph nodes (SLNs) for successful cancer diagnosis. Herein, the use of highly sensitive and stable PEGylated radionuclide-embedded gold nanoparticles (PEG-RIe-AuNPs) is reported for the detection of SLNs by combined positron emission tomography and Cerenkov luminescence imaging (PET/CLI). PEG-RIe-AuNPs show high sensitivity and stability both in vitro and in vivo, and are not toxic to normal ovarian and immune cells. In vivo PET/CLI imaging clearly reveals SLNs as early as 1 h post PEG-RIe-AuNP-injection, with peak signals achieved at 6 h postinjection, which is consistent with the biodistribution results. Taken together, the data provide strong evidence that PEG-RIe-AuNPs are promising as potential lymphatic tracers in biomedical imaging for pre and intraoperative surgical guidance.

Quantitative metabolic parameters measured on F-18 FDG PET/CT predict survival after relapse in patients with relapsed epithelial ovarian cancer.

OBJECTIVE: This study aimed to evaluate the prognostic value of quantitative metabolic parameters measured on F-18 FDG PET/CT (FDG PET/CT) at the time of the first relapse in patients with relapsed epithelial ovarian cancer (EOC). METHODS: Fifty-six relapsed EOC patients were retrospectively included. Quantitative metabolic parameters including maximum standardized uptake value (SUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) were measured on FDG PET/CT at the time of the first relapse. Post-relapse survival (PRS) was calculated from the date of diagnosis of relapsed disease to the date of death or last follow-up. Univariate and multivariate analyses for PRS were performed using clinical and quantitative metabolic parameters. RESULTS: Thirty-two patients died from the disease during the follow-up period (median: 46.2 months). On univariate and multivariate analyses, the platinum-free interval, type of second-line treatment, WBMTV, and WBTLG were all significant prognostic factors for PRS. The subgroup of patients who were platinum-sensitive with low WBMTV and low WBTLG showed better prognosis, when compared with other subgroups (log-rank test, p<0.001). Patients treated with secondary cytoreductive surgery (SCS) followed by second-line chemotherapy showed significantly longer duration of PRS than patients treated with second-line chemotherapy only (mean PRS=61 vs. 36 months, χ(2)=8.68, p=0.032). CONCLUSION: Our results suggest that quantitative metabolic parameters measured on FDG PET/CT at the time of the first relapse have significant predictive values for PRS. Incorporating quantitative metabolic parameters and conventional clinical parameters has a superior prognostic discrimination compared with conventional clinical parameters alone.

Whole-Body Metabolic Tumor Volume, as Determined by (18)F-FDG PET/CT, as a Prognostic Factor of Outcome for Patients With Breast Cancer Who Have Distant Metastasis.

OBJECTIVE: This study was performed to evaluate the prognostic relevance of PET parameters measured by (18)F-FDG PET/CT in patients with invasive ductal carcinoma of the breast (IDC) who had distant metastasis at the time of initial diagnosis. MATERIALS AND METHODS: Forty women with IDC who had distant metastasis at the time of initial diagnosis and who underwent FDG PET/CT before receiving treatment were enrolled in the study. Clinicopathologic parameters and metabolic PET parameters, including the maximum standardized uptake value (SUVmax) of the primary tumor (pSUVmax), the SUVmax of the axillary lymph node (nSUVmax), the highest SUVmax of whole malignant lesions (wSUVmax), the whole-body (WB) metabolic tumor volume (MTV), and WB total lesion glycolysis (TLG), were analyzed to determine their usefulness in predicting overall survival (OS). Univariate and multivariate analyses were performed with the use of Kaplan-Meier and Cox proportional hazards models. RESULTS: Twenty-one of the 40 patients (52.5%) died during follow-up (mean follow-up, 36.4 months; range, 0.8-71.4 months). Nonsurvivors had a statistically significantly higher mean (± SD) WB MTV than did survivors (424.0 ± 683.9 vs 92.1 ± 96.3 cm(3); p = 0.0430). T category, performance of palliative surgery, presence of visceral metastasis, wSUVmax, WB MTV, and WB TLG were identified by univariate analysis as prognostic factors for OS, whereas age, N category, hormone receptor status, status, triple-negative breast cancer status (defined as a tumor for which estrogen receptor, progesterone receptor, and ERBB2 statuses were all negative), pSUVmax, and nSUVmax were not. Multivariate analysis revealed that only WB MTV independently predicted OS (hazard ratio, 4.10; 95% CI, 1.17-14.31; p = 0.0280). CONCLUSION: The WB MTV value, as determined by FDG PET/CT performed before treatment, was found to be an independent prognostic factor for OS in patients with IDC who had distant metastasis at the time of initial diagnosis.