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Sevoflurane is a safe and well-known inhaled anesthetic. Given that sevoflurane can be delivered to developing fetuses through the mother, it is critical to determine whether this agent affects fetal neurodevelopment. Recent research has sought to determine whether sevoflurane affects fetal brain development when the mother is exposed during the second to third trimester of pregnancy, considered to be the crucial period for the development of nervous system. However, even though the first trimester is a critical period for fetal organogenesis and the most susceptible time to teratogen exposure, research regarding the effects of sevoflurane on organogenesis, especially on brain development, is insufficient. In the present study, human embryonic stem cells (hESC)-derived cerebral organoids were exposed to sevoflurane during the time corresponding to the first trimester to investigate the effect of early sevoflurane exposure on fetal brain development, specifically the processes of neuronal differentiation and maturation. Organoid size exposed to the intermediate concentration of sevoflurane did not differ from control, immunofluorescence demonstrated that sevoflurane temporarily decreased the size of SOX2 + /N-cad + ventricular zone structures only during the mid-time point, and upregulated expression of TUJ1 and MAP2 only during the early time point. However, all markers returned to normal levels, and organoids formed normal cortical structures at the late time point. Our results suggest that maternal sevoflurane exposure during the first trimester of pregnancy can cause abnormal neuronal differentiation in the fetal brain. However, considering the recovery observed in later periods, sevoflurane exposure might not have lasting impacts on fetal brain development.

Pancreatic cancer is a devastating disease and is highly resistant to anticancer drugs because of its complex microenvironment. Cancer-associated fibroblasts (CAFs) are an important source of extracellular matrix (ECM) components, which alter the physical and chemical properties of pancreatic tissue, thus impairing effective intratumoral drug delivery and resulting in resistance to conventional chemotherapy. The objective of this study was to develop a new cancer organoid model, including a fibrous tumor microenvironment (TME) using CAFs. The CAF-integrated pancreatic cancer organoid (CIPCO) model developed in this study histologically mimicked human pancreatic cancer and included ECM production by CAFs. The cancer cell–CAF interaction in the CIPCO promoted epithelial–mesenchymal transition of cancer cells, which was reversed by CAF inhibition using all-trans retinoic acid. Deposition of newly synthesized collagen I in the CIPCO disturbed the delivery of gemcitabine to cancer cells, and treatment with collagenase increased the cytotoxic effect of gemcitabine. This model may lead to the development of next-generation cancer organoid models recapitulating the fibrous TME.

Aim To investigate predictive and prognostic role of metabolic parameters using [18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG PET) in patients with locally advanced non-small cell lung cancer (NSCLC) treated with docetaxel-platinum induction chemotherapy (IC). Methods Medical records of 31 patients with pre- and post-IC 18 F-FDG PET were reviewed. Using 18 F-FDG PET, metabolic parameters, including metabolic tumor response, adjusted peak standardized uptake values using lean body mass at baseline (pre-SULpeak ) and after IC (post-SULpeak ), and percentage change of pre- and post-SULpeak (ΔSULpeak ), were assessed. Results Response rate (RR) was 71%, with a metabolic RR of 83.9%. Nineteen (61.3%) patients underwent surgery, R0 resection was achieved for 17 (89.5%) patients. Median relapse-free survival (RFS) and overall survival (OS) were 8.9 months (95% CI: 4.5-12.1) and 24.1 months (95% CI: 17.1-34.1), respectively. Post-SULpeak 1.4 could predict recurrence with a sensitivity of 84% and a specificity of 100%. Conclusion In patients with locally advanced NSCLC receiving IC, post-SULpeak and ΔSULpeak showed clinical significance for survival outcome.

PURPOSE: Bone single-photon emission computed tomography/computed tomography (SPECT/CT) has been widely used for evaluation of femoral head viability in patients with femoral neck fracture. The current study aimed to investigate utility of standardized uptake value (SUV) from quantitative bone SPECT/CT for assessment of femoral head viability. METHODS: From March 2015 to November 2018, quantitative bone SPECT/CT was performed in 9 patients with non-viable femoral head post femoral neck fracture and in 31 controls. Maximum (SUVmax), mean (SUVmean), and minimum standardized uptake values (SUVmin) were measured over femoral head and neck. Mann-Whitney U test with Bonferroni correction was used to compare SUVs of ipsilateral and contralateral femurs from femoral neck fracture patients with those of control femurs. RESULTS: As for femoral head viability, SUVmax and SUVmean were not significantly decreased in non-viable femoral heads compared to those in controls. Only the SUVmin was significantly reduced in non-viable femoral heads (mean ± standard deviation, 0.57 ± 0.38) than in controls (0.95 ± 0.26, p = 0.006) and contralateral femoral heads (1.36 ± 0.59, p = 0.008). The cutoff SUVmin of 0.61 (g/mL) yielded a sensitivity of 77.8% and specificity of 87.1% for detection of non-viable femoral heads (p = 0.006). Contralateral femoral necks of the femoral neck fracture patients showed significantly higher SUVmean and SUVmin (3.17 ± 1.20 and 1.64 ± 0.63) than those of controls (2.32 ± 0.53 and 1.04 ± 0.27; p = 0.021 and p = 0.002, respectively), which seemed to reflect weight bearing effect or metabolic derangement. CONCLUSIONS: The non-viable femoral heads from the femoral neck fracture showed significantly reduced SUVmin. Quantitative bone SPECT/CT holds promise for objective evaluation of femoral head viability. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13139-019-00600-2) contains supplementary material, which is available to authorized users.

We have previously reported human fetal cartilage progenitor cells (hFCPCs) as a novel source of therapeutic cells showing high proliferation and stem cell properties superior to those of adult mesenchymal stem cells (MSCs). In this study, we investigated the immunophenotype and immune-modulatory activities of hFCPCs. With institutional review board approval, hFCPCs were isolated from fetuses at 11–13 weeks of gestation. hFCPCs showed strong expression of HLA class I molecules but low or no expression of HLA class II and co-stimulatory molecules, which was not changed significantly after 4 days of IFN-γ treatment. In a mixed lymphocyte reaction (MLR), hFCPCs showed no allogeneic immune response to peripheral blood lymphocytes (PBLs) and suppressed concanavalin A (Con A)-mediated proliferation of PBLs in a dose-dependent manner. In addition, hFCPCs inhibited Con A-induced secretion of pro-inflammatory cytokines TNF-α and IFN-γ from PBLs but showed no significant decrease of secretion of IL-10, anti-inflammatory cytokine. Co-culture of hFCPCs with stimulated PBLs for 4 days resulted in a significant increase in CD4+CD25+FoxP3+ T regulatory cells (Tregs). hFCPCs expressed LIF, TGF-β1, TSG-6, and sHLA-G5 but did not express IDO and HGF. Stimulation of hFCPCs with TNF-α for 12 h showed slight induction in the expression of LIF, TSG-6, IDO, and HGF, whereas stimulation with IFN-γ did not affect expression of any of these factors. These results suggest that hFCPCs have low allogeneic immunogenicity and immune-modulatory activity in vitro, comparable to those of MSCs. However, compared with MSCs, hFCPCs were less responsive to TNF-α and IFN-γ, and the mechanisms underlying responses to these two cell types appeared distinct.

BackgroundTear deficiency due to lacrimal gland (LG) dysfunction is one of the major causes of dry eye disease (DED). Therefore, LG stem cell-based therapies have been extensively reported to regenerate injured lacrimal tissue; however, the number of stem cells in the LG tissue is low, and 2D long-term cultivation reduces the differentiation capacity of stem cells. Nevertheless, 3D LG organoids could be an alternative for a DED therapy because it is capable of prolonged growth while maintaining the characteristics of the LG tissue. Here, we report the development of LG organoids and their application as cell therapeutics.MethodsDigested cells from human LG tissue were mixed with Matrigel and cultured in five different media modified from human prostate/salivary organoid culture media. After organoid formation, the growth, specific marker expression, and histological characteristics were analyzed to authenticate the formation of LG organoids. The secretory function of LG organoids was confirmed through calcium influx or proteomics analysis after pilocarpine treatment. To explore the curability of the developed organoids, mouse-derived LG organoids were fabricated and transplanted into the lacrimal tissue of a mouse model of DED.ResultsThe histological features and specific marker expression of LG organoids were similar to those of normal LG tissue. In the pilocarpine-treated LG organoid, levels of internal Ca2+ions and β-hexosaminidase, a lysosomal protein in tear fluid, were increased. In addition, the secreted proteins from pilocarpine-treated lacrimal organoids were identified through proteomics. More than 70% of the identified proteins were proven to exosome through gene ontology analysis. These results indicate that our developed organoid was pilocarpine reactive, demonstrating the function of LG. Additionally, we developed LG organoids from patients with Sjogren’s syndrome patients (SS) and confirmed that their histological features were similar to those of SS-derived LG tissue. Finally, we confirmed that the mouse LG organoids were well engrafted in the lacrimal tissue two weeks after transplantation.ConclusionThis study demonstrates that the established LG organoids resemble the characteristics of normal LG tissue and may be used as a therapy for patients with DED.

Radiation proctitis is the collateral damage that occurs to healthy cells during radiation treatment of pelvic malignancies. Conservative treatment of radiation proctitis can mitigate inflammatory symptoms, but, to date, no therapeutic options are available for direct recovery of the damaged colonic epithelium. The present study assessed the ability of colon organoid-based regeneration to treat radiation proctitis. Radiation proctitis was induced in mice by irradiating their recta, followed by enema-based transplantation of mouse colon organoids. The transplanted colon organoids were found to successfully engraft onto the damaged rectal mucosa of the irradiated mice, reconstituting epithelial structure and integrity. Lgr5+ stem cells were shown to be pivotal to colon organoid mediated regeneration. Endoscopic examination showed the efficacy of localized transplantation of colon organoids with fibrin glue to irradiated sites. These findings provide useful insights into the use of colon organoid-based regenerative therapy for the treatment of radiation proctitis.

SUMMARYPalatine tonsil (hereinafter referred to as “tonsil”) plays role in the immune system’s first line of defense against foreign pathogens. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic since the infection was first reported in China in December 2019. The aim of this study was to establish tonsil epithelial cell-derived organoids and to examine their feasibility as anex vivomodel for SARS-CoV-2 infection. Using an optimized protocol, we achieved 3D tonsil organoid culture from human tonsil tissue that reflects the distinctive characteristics of the tonsil epithelium, such as its cellular composition, histologic properties, and molecular biological features. Notably, we verified that SARS-CoV-2 can infect tonsil organoids with a robust replication efficiency. Furthermore, treatment with remdesivir, an antiviral agent, effectively protected them from viral infection. Therefore, tonsil organoids could be available for investigation of SARS-CoV-2 infection-mediated pathology and for preclinical screening of novel antiviral drug candidates.One-sentence SummaryThis study established tonsil epithelial cell-derived organoids and demonstrated their feasibility as anex vivomodel for SARS-CoV-2 infection.

Although differentiation between central chondroid tumors is important, their parallelism makes it a diagnostic conundrum for clinicians and radiologists. The objective of this study was to evaluate the efficiency of quantitative single photon emission computed tomography (SPECT)/computed tomography (CT) in differentiating grade I chondrosarcomas from enchondromas. We reviewed SPECT/CT images of patients with enchondromas and grade I chondrosarcomas arising in the long bones. Volume, mean standardized uptake value (SUVmean), and maximum standardized uptake value (SUVmax) of tumors were calculated from SPECT/CT images. In addition, clinical characteristics and radiological information were assessed. Of a total of 34 patients, 14 had chondrosarcomas. Chondrosarcoma group had significantly larger volume, and higher SUVmean and SUVmax of tumors than enchondroma group. There was no significant difference in age and tumor size between two groups. Areas under the receiver-operating characteristic curve (AUCs) for tumor volume, SUVmean, and SUVmax were 0.727, 0.757, and 0.875. In pairwise analyses, SUVmax had larger AUC than SUVmean (p = 0.0216). With a cut-off value of 15.6 for SUVmax, its sensitivity and specificity were 86% and 75% for differentiating between enchondroma and grade I chondrosarcoma. Quantitative SPECT/CT is a potential method to differentiate grade I chondroarcomas from enchondromas in patients with central chondroid tumors.

The palatine tonsils (hereinafter referred to as "tonsils") serve as a reservoir for viral infections and play roles in the immune system's first line of defense. The aims of this study were to establish tonsil epithelial cell-derived organoids and examine their feasibility as an ex vivo model for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The tonsil organoids successfully recapitulated the key characteristics of the tonsil epithelium, including cellular composition, histologic properties, and biomarker distribution. Notably, the basal layer cells of the organoids express molecules essential for SARS-CoV-2 entry, such as angiotensin-converting enzyme 2 (ACE2), transmembrane serine protease 2 (TMPRSS2) and furin, being susceptible to the viral infection. Changes in the gene expression profile in tonsil organoids revealed that 395 genes associated with oncostatin M signaling and lipid metabolism were highly upregulated within 72 h after SARS-CoV-2 infection. Notably, remdesivir suppressed the viral RNA copy number in organoid culture supernatants and intracellular viral protein levels in a dose-dependent manner. Here, we suggest that tonsil epithelial organoids could provide a preclinical and translational research platform for investigating SARS-CoV-2 infectivity and transmissibility or for evaluating antiviral candidates.

Objective Recently developed 18F-labelled amyloid beta (Aβ) positron emission tomography (PET) tracers have demonstrated potentials to enable more prevalent application of amyloid imaging in the clinical setting. The aim of this study is to demonstrate cerebral retention of Aβ in cognitively normal older adults, by implementing voxel-based analysis on images acquired from 18F-Florbetaben amyloid PET. Methods Fifty cognitive normal elderly subjects were recruited and included in the study. Demographic data and cognitive measurements were collected. Magnetic resonance imaging (MRI) and 18F-Florbetaben PET data were obtained followed by whole brain voxel-based analysis. Results Compared to the florbetaben (FBB) (-) counterpart, FBB (+) showed significantly higher Aβ deposition in the brain regions comprising anterior cingulate, middle cingulate, posterior cingulate and precuneus (family wise error corrected p

Ji Han Lee,1 Won Sang Jung,2 Woo Hee Choi,3 Hyun Kook Lim4 1Washington University in St Louis, St Louis, MO, USA; 2Department of Radiology, 3Department of Nuclear Medicine, 4Department of Psychiatry, Saint Vincent Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea Objective: Among patients with Alzheimer’s disease (AD), sleep disturbances are common and serious noncognitive symptoms. Previous studies of AD patients have identified deformations in the brain stem, which may play an important role in the regulation of sleep. The aim of thisstudy was to further investigate the relationship between sleep disturbances and alterations in brain stem morphology in AD.Materials and methods: In 44 patients with AD and 40 healthy elderly controls, sleep disturbances were measured using the Neuropsychiatry Inventory sleep subscale. We employed magnetic resonance imaging-based automated segmentation tools to examine the relationship between sleep disturbances and changes in brain stem morphology.Results: Analyses of the data from AD subjects revealed significant correlations between the Neuropsychiatry Inventory sleep-subscale scores and structural alterations in the left posterior lateral region of the brain stem, as well as normalized brain stem volumes. In addition, significant group differences in posterior brain stem morphology were observed between the AD group and the control group.Conclusion: This study is the first to analyze an association between sleep disturbances and brain stem morphology in AD. In line with previous findings, this study lends support to the possibility that brain stem structural abnormalities might be important neurobiological mechanisms underlying sleep disturbances associated with AD. Further longitudinal research is needed to confirm these findings. Keywords: Alzheimer’s disease, sleep, brain stem, MRI, shape analysis

Current strategies for cartilage cell therapy are mostly based on the use of autologous chondrocytes or mesenchymal stem cells (MSCs). However, these cells have limitations of a small number of cells available and of low chondrogenic ability, respectively. Many studies now suggest that fetal stem cells are more plastic than adult stem cells and can therefore more efficiently differentiate into target tissues. However, the characteristics and the potential of progenitor cells from fetal tissue remain poorly defined. In this study, we examined cells from human fetal cartilage at 12 weeks after gestation in comparison with bone marrow-derived MSCs or cartilage chondrocytes from young donors (8–25 years old). The fetal cartilage-derived progenitor cells (FCPCs) showed higher yields by approximately 24 times than that of chondrocytes from young cartilage. The morphology of the FCPCs was polygonal at passage 0, being similar to that of the young chondrocytes, but it changed later at passage 5, assuming a fibroblastic shape more akin to that of MSCs. As the passages advanced, the FCPCs showed a much greater proliferation ability than the young chondrocytes and MSCs, with the doubling times ranging from 2~4 days until passage 15. The surface marker profile of the FCPCs at passage 2 was quite similar to that of the MSCs, showing high expressions of CD29, CD90, CD105, and Stro-1. When compared to the young chondrocytes, the FCPCs showed much less staining of SA-β-gal, a senescence indicator, at passage 10 and no decrease in SOX9 expression until passage 5. They also showed a much greater chondrogenic potential than the young chondrocytes and the MSCs in a three-dimensional pellet culture in vitro and in polyglycolic acid (PGA) scaffolds in vivo. In addition, they could differentiate into adipogenic and osteogenic lineages as efficiently as MSCs in vitro. These results suggest that FCPCs have stem cell properties to some extent and that they are more active in terms of proliferation and chondrogenic differentiation than young chondrocytes or MSCs.

We developed a novel dentin-pulp-like organoid. It has both stem-cell and odontoblast characteristics using a mesenchymal cell lineage of human dental-pulp stem cells (hDPSCs). The mixture of hDPSCs and Matrigel was transferred into the maintenance medium (MM) and divided into four different groups according to how long they were maintained in the odontogenic differentiation medium (ODM). All organoids were harvested at 21 days and analyzed to find the optimal differentiation condition. To assess the re-fabrication of dentin-pulp-like organoid, after dissociation of the organoids, it was successfully regenerated. Additionally, its biological activity was confirmed by analyzing changes of relevant gene expression and performing a histology analysis after adding Biodentine&reg, into the ODM. The organoid was cultured for 11 days in the ODM (ODM 11) had the most features of both stem cells and differentiated cells (odontoblasts) as confirmed by relevant gene expression and histology analyses. Micro-computed tomography and an electron microscope also showed mineralization and odontoblastic differentiation. Finally, ODM 11 demonstrated a biologically active response to Biodentine&reg, treatment. In conclusion, for the first time, we report the fabrication of a dentin-pulp-like organoid using mesenchymal stem cells. This organoid has potential as a future therapeutic strategy for tooth regeneration.

Osteoarthritis (OA) is the most common and increasing joint disease worldwide. Current treatment for OA is limited to control of symptoms. The purpose of this study was to determine the effect of specificity protein 1 (SP1) inhibitor Mithramycin A (MitA) on chondrocyte catabolism and OA pathogenesis and to explore the underlying molecular mechanisms involving SP1 and other key factors that are critical for OA. Here, we show that MitA markedly inhibited expressions of matrix-degrading enzymes induced by pro-inflammatory cytokine interleukin-1β (IL-1β) in mouse primary chondrocytes. Intra-articular injection of MitA into mouse knee joint alleviated OA cartilage destruction induced by surgical destabilization of the medial meniscus (DMM). However, modulation of SP1 level in chondrocyte and mouse cartilage did not alter catabolic gene expression or cartilage integrity, respectively. Instead, MitA significantly impaired the expression of HIF-2α known to be critical for OA pathogenesis. Such reduction in expression of HIF-2α by MitA was caused by inhibition of NF-κB activation, at least in part. These results suggest that MitA can alleviate OA pathogenesis by suppressing NF-κB-HIF-2α pathway, thus providing insight into therapeutic strategy for OA.

We aimed to evaluate the prognostic value of early response assessment using a volumetric fluorine-18-fluorodeoxyglucose (F-FDG) PET analysis in chemotherapy-treated patients with non-small-cell lung cancer (NSCLC).We retrospectively reviewed 33 patients with NSCLC who received first-line chemotherapy and performed F-FDG PET/computed tomography before (baseline PET) and after two cycles of chemotherapy (interim PET). The maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV) of the total malignant lesion were measured in baseline (SUV1 and MTV1) and interim (SUV2 and MTV2) PET images, and percentage changes in SUVmax (ΔSUV) and MTV (ΔMTV) were calculated between the two images. We compared PET parameters and clinicopathologic variables in terms of the 2-year overall survival (OS).The median follow-up period was 14.3 months and the 2-year OS was 31%. In PET images, the mean SUV1, MTV1, SUV2, MTV2, ΔSUV, and ΔMTV were 13.1±4.5, 307.9±340.0 cm, 9.5±5.1, 180.4±29.6 cm, 27±28%, and 42±65%, respectively. In univariable analysis, M stage, TNM stage, and all six PET parameters associated significantly with OS. Both the MTV1 and the ΔMTV were tested against OS controlling for M stage, one at time, and the effect remained significant in multivariable analyses.A smaller baseline MTV and greater decrease in MTV between baseline and interim PET images are associated with a significantly prolonged OS. A volume-based F-FDG PET analysis would facilitate prediction of clinical outcome and identification of treatment-resistant patients early during chemotherapy and could thus be used in personalized treatment approaches for patients with NSCLC.

Current approaches for the engineering of osteochondral grafts are associated with poor tissue formation and compromised integration at the interface between the cartilage and bone layers. Many researchers have attempted to provide osteochondral grafts of combined cartilage and bone for osteochondral repair to help overcome the limitations of standard procedures. Solid freeform fabrication is recognized as a promising tool for creating tissue engineering scaffolds due to advantages such as superior interconnectivity and a highly porous structure. This study aimed to develop a three-dimensional plotting system to enable the manufacturing of a biphasic graft consisting cartilage and subchondral bone for application to osteochondral defects. The material advantages of both synthetic (poly L lactide-co-polyglycolide) and natural (alginate) polymers were combined for a supporting frame and cell printing. Specifically, in order to promote the maturity of the osteochondral graft in our study, cartilage-derived ECM (cECM) or hydroxyapatate (HA) substances blended with alginate was plotted together with human fetal cartilage-derived progenitor cells in the cartilage or subchondral bone layer under a multi-nozzle deposition system. Notably, a plotted biphasic graft shows good integration between cartilage and subchondral bone layers without structural separation. Furthermore, the non-toxicity of the cECM and HA substances were proved from a live/dead assay of plotted cell-laden alginate. A fabricated osteochondral graft with cECM and HA substances showed dominant cartilage and bone tissue formation in a differentiation assay. Future studies should be done to modify the alginate physical properties for long-lasting structural stability.

Cartilage tissue engineering typically involves the combination of a biodegradable polymeric support material with chondrocytes. The culture environment in which cell-material constructs are created and stored is an important factor. The aim of the present study was to investigate the effects of combined stimuli on cartilage zonal organization which is important to maintain cartilage functions such as lubrication and cushion. For that purpose, we developed a joint mimicking loading system which was composed of compression and shear stress. To mimic the joint loading condition, we manufactured a stimuli system that has a device similar to the shape of a femoral condyle in human knee. The fibrin/hyaluronic acid mixture with chondrocytes were dropped into support made of silicon, and placed under the device. The cartilage explants were stimulated with the joint mimicking loading system for 1 hour per day over the course of 4 weeks. The amounts of GAG and collagen in the stimulated tissue were more than that of the static cultured tissue. Cells and collagen were arranged horizontally paralleled to the surface by stimuli, while it did not happen in the control group. The results of this study suggests that mechanical load exerting in the joint play a crucial role in stimulation of extracellular matrix (ECM) production as well as its functional rearrangement.

Previous studies have shown aberrant functional connectivity in preclinical Alzheimer’s disease (AD). However, the effects of beta-amyloid (Aβ) retention on regional functional synchronization in cognitively normal older adults still remain unclear. The aim of this study was to explore the distinctive association pattern between Aβ retention and regional functional synchronization in cognitively normal older adults. Sixty-one older adults with normal cognition underwent functional magnetic resonance imaging and regional functional synchronizations were quantified using regional homogeneity (ReHo). Subjects were dichotomized using 18F-Florbetaben positron emission tomography imaging into subjects with (Aβ+; n = 30) and without (Aβ-; n = 31) Aβ burden. The Aβ+ group exhibited significantly higher ReHo in the fusiform gyrus and lower ReHo in the precuneus compared with the Aβ- group. We found significant negative correlations between global Aβ retention and ReHo in the precuneus and medial prefrontal cortex and positive correlations between global Aβ retention and ReHo in the bilateral lingual gyrus, left fusiform gyrus, and right middle temporal gyrus in the Aβ+ group. Our findings suggest that regional functional synchronization might have distinctive association patterns with Aβ retention in the cognitively normal older adults. These findings can enrich the functional characterization of early stages of disease progression in AD.

Background We evaluated the suitability of 18F-fluorodeoxythymidine (18F-FLT) positron emission tomography (PET)/computed tomography (CT) for assessment of the early response to induction therapy and its value for predicting clinical outcome in patients with acute myeloid leukemia (AML). Adult patients who had histologically confirmed AML and received induction therapy were enrolled. All patients underwent 18F-FLT PET/CT after completion of induction. PET/CT images were visually and quantitatively assessed. Cases with intensely increased bone marrow uptake in more than one third of the long bones and throughout the central skeleton were interpreted as PET-positive for resistant disease (RD). PET results were compared to the clinical response and outcome. Results In visual PET analysis of 10 eligible patients (7 male, 3 female; median age 58 years), 5 patients were interpreted as being PET-positive and 5 as PET-negative. Standardized uptake values were significantly different between PET-positive and PET-negative groups. Eight of 10 patients achieved clinical complete remission (CR)/CR with incomplete blood count recovery (CRi). Five CR/CRi patients had PET-negative findings, but 3 CR patients had PET-positive findings. Both of the RD patients had PET-positive findings. During follow-up, 2 CR patients with PET-positive findings relapsed, or were strongly suspected of relapse, 4 months after consolidation. Conclusion 18F-FLT PET/CT after induction therapy showed good sensitivity and negative-predictive value for evaluating RD in patients with AML. This preliminary study suggests that 18F-FLT PET/CT may be valuable as a noninvasive tool for early assessment of the response to treatment and may provide prognostic value for survival in patients with AML.

Background Limited disease small-cell lung cancer responds well to concurrent chemoradiation therapy (CCRT), but shows high relapse rate and short RFS. We aimed to evaluate tumor metabolic activities measured using FDG-PET as a prognostic factor and analyze its relationships with markers of tumor biologic behavior. Patients and Methods Forty-one LD-SCLC patients receiving 4 cycles of EP (etoposide 120 mg/m 2 , days 1-3; cisplatin 60 mg/m 2 , day 1), 2 cycles of EP (etoposide 130 mg/m 2 , days 1-3; cisplatin 30 mg/m 2 , day 1)-CCRT were enrolled. Maximum standardized uptake value (SUV; SUVmax) of primary tumor was revised with SUV of liver (SUVlivermax). Differences between pre-, posttreatment average SUV uptake of primary tumor, and intrathoracic lymph nodes were presented as ΔSUVliveravg. Thirty-one tumor biopsy specimens were immunostained for GLUT-1, Bcl-2, and HIF-1α. Results The median overall survival (OS), and RFS were 13.7 and 10.4 months, respectively. In multivariate analysis, pretreatment lactate dehydrogenase (LDH) and ΔSUVliveravg correlated with RFS (hazard ratio [HR], 2.8, P = .043; HR, 0.3, P = .004). Sex, LDH, objective tumor metabolic response, and SUVlivermax correlated with OS (HR, 12.1, P = .006; HR, 3.7, P = .037; HR, 10.1, P = .008; and HR, 0.2, P = .014, respectively). High GLUT-1 positivity (> 75%), and LDH level (> 400 U/L) correlated with better objective response rate ( P = .012) and HIF-1α immunoreactivity score ( P = .029). Conclusion ΔSUVliveravg and GLUT-1 expression might predict RFS and ORR in patients with LD-SCLC treated with definitive CCRT.

We evaluated whether the maximum standardized uptake values (SUVmax) of primary tumor from the initial staging by (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) of patients with breast cancer could identify patients at risk for early recurrence within 2 years, particularly in comparison to the American Joint Committee on Cancer (AJCC) stage.We reviewed the staging (18)F-FDG PET/CT images of patients with primary breast cancer and their medical records. The SUVmax of the primary tumor was measured. The presence or absence of FDG uptake in the axillary lymph node (ALN) was also assessed. The patient's pathologic primary tumor stage (pT), pathologic regional lymph node stage (pN), stage grouping, age, estrogen receptor (ER) and progesterone receptor (PR) status, and neoadjuvant chemotherapy history were evaluated with the FDG uptake parameters for recurrence within 2 years following the end of first-line therapy.Recurrence within 2 years was present in 9.1 % (n = 40) out of the 441 patients assessed. The FDG uptake in ALN, pT, pN, stage grouping and neoadjuvant chemotherapy history were prognostic for early recurrence, while primary tumor SUVmax, age, and ER or PR status were not significant on logistic regression. On multivariate analysis, only the stage grouping (odds ratio 2.79; 95 % CI 1.73, 4.48; p 0.0001) and neoadjuvant chemotherapy history (odds ratio 2.70; 95 % CI 1.22, 5.98; p = 0.0141) could identify patients at increased risk for recurrence within 2 years.Primary tumor FDG uptake measured by SUVmax, and visual assessment of FDG uptake in the ALN in the initial staging PET/CT of patients with breast cancer may not have additional prognostic value compared with the AJCC stage grouping for early recurrence.

The therapeutic effect of bone marrow stimulation techniques (BSTs) is mainly attributed to the role of mesenchymal stem cells (MSCs) from the bone marrow. However, no studies have directly shown the amount of MSCs drained by BSTs. This study hypothesized that differences in the opening of subchondral bone affect the number of MSCs drained from the bone marrow. We purposed that as the exposed area and hole size of BSTs vary, the number of MSCs drained out was measured. Three groups of different BSTs were designed that have variations in the sizes of total exposed area and individual holes. Three different BSTs using a curette, 1.5- and 0.8-mm awls were carried out on the full-thickness femoral cartilage defect of young rabbits. After BST, the number of MSCs in the blood clot was measured by CFU-Fs assay. As the size of the total exposed area increased, so did the number of MSCs obtained. The number of MSCs drained from bone marrow may vary depending on different BSTs and this could affect therapeutic efficacy of cartilage defect. As current microfracture (MF) method cannot drain the most MSCs clinically, more improved surgery technique is needed.

Objective Among patients with Alzheimer’s disease (AD), sleep disturbances are common and serious noncognitive symptoms. Previous studies of AD patients have identified deformations in the brain stem, which may play an important role in the regulation of sleep. The aim of this study was to further investigate the relationship between sleep disturbances and alterations in brain stem morphology in AD. Materials and methods In 44 patients with AD and 40 healthy elderly controls, sleep disturbances were measured using the Neuropsychiatry Inventory sleep subscale. We employed magnetic resonance imaging-based automated segmentation tools to examine the relationship between sleep disturbances and changes in brain stem morphology. Results Analyses of the data from AD subjects revealed significant correlations between the Neuropsychiatry Inventory sleep-subscale scores and structural alterations in the left posterior lateral region of the brain stem, as well as normalized brain stem volumes. In addition, significant group differences in posterior brain stem morphology were observed between the AD group and the control group. Conclusion This study is the first to analyze an association between sleep disturbances and brain stem morphology in AD. In line with previous findings, this study lends support to the possibility that brain stem structural abnormalities might be important neurobiological mechanisms underlying sleep disturbances associated with AD. Further longitudinal research is needed to confirm these findings.

With recent advancement in amyloid imaging, diagnostic application of this new modality has become a great interest among researchers. New ligands, such as 18F- florbetaben, florbetapir and flutemetamol, have been discovered to overcome limitations of preexisting ligand Pittsburgh compound B. We report here a case of a 37-year-old male patient whose initial complaints comprised of gradual cognitive decline, apraxia, disorientation and sleep disturbances. 18F-Florbetaben amyloid imaging of the patient showed diffuse amyloid retention with prominent striatal uptake. This finding supports the clinical utility of amyloid imaging in diagnostic process of early-onset AD. Moreover, striatal dominant uptake pattern demonstrated in this patient include some meaningful clinical implications that warrant special attention among clinicians.

This study assessed the effect of bevel direction on the success rate of ultrasound guided radial artery catheterization. A total of 204 patients requiring radial artery catheterization were randomly divided into bevel-up (n = 102) and bevel-down (n = 102) groups. Success rate, cannulation time, and number of attempts were compared groups. In the bevel-down group, an arterial line was placed on the first attempt in 86 of 102 (84.3 %; 95 % confidence interval [CI] = 76 % to 90 %) patients versus 73 of 102 (71.6 %; 95 % CI = 62.1 % to 79.4 %) in the bevel-up group (p = 0.028). In the bevel-down group, the mean time to a successful radial arterial cannulation was 33.3 ± 6.3 seconds (95 % CI = 32.1-34.6) versus 35.9 ± 7.6 seconds (95 % CI = 34.4-37.2) in the bevel-up group (p = 0.011). The median score was 33.2 and interquartile range [IQR] was 10.9 (30.3-41.2) for the mean cannulation time in the bevel-up group. In the bevel-down group, the mean score was 32.3 (IQR 3.90, 30–33.9) for mean cannulation time. In the bevel-down group, 11 of 102 (7 %; 95 % CI = 0 to 16 %) patients developed a posterior wall puncture versus 22 of 102 ((21.6 %; 95 % CI = 14.7 to 17.2 %) in the bevel-up group. The bevel-down approach during ultrasound-guided radial artery catheterization exhibited a higher success with fewer complications compared to the bevel-up approach. Clinical Research Information Service is Korean Clinical Trials Registry ( KCT0001836 ). It was registered retrospectively 30th Nov 2015.

Background Although there is substantial evidence of associations between frontal-striatal circuits and cerebral vascular burden in late-onset depression (LOD), relationships between vascular burden and hippocampal subfields are not clear. The purpose of this study was to investigate relationships between cerebral vascular burden and hippocampal subfield volume in LOD patients. Methods Fifty subjects with LOD and 50 group-matched healthy control subjects underwent magnetic resonance imaging scanning. Hippocampal subfields volumes were measured and compared between the groups. In addition, association patterns between white matter hyperintensity (WMH) volumes, clinical measures and hippocampal subfield volumes were investigated in the LOD group. Results Subjects with LOD exhibited significant hippocampal volume reductions in the total hippocampus, cornu ammonis (CA) 1 and 3 and dentate gyrus (DG) areas compared with healthy subjects. Total WMH volume was negatively correlated with left total hippocampal volume and CA1 in the LOD group. In addition, depression severity was negatively associated with left and right CA3 volumes in the LOD group. Limitation Our findings of distinctive relationships between WMH and hippocampal subfields demonstrate a simple correlation, but do not prove causation Conclusion This study is the first to elaborate distinctive association patterns between hippocampal subfield volumes and cerebral vascular burden in LOD. These structural changes in the hippocampal CA1, CA3 and DG areas might be at the core of the underlying neurobiological mechanisms of hippocampal dysfunction in LOD. However, longitudinal studies will be needed to identify the mechanisms of these structural changes.

The aim of this study was to examine and compare two automated quantitative software tools (PMOD and MIMneuro) for the quantification of amyloid positron emission tomography (PET). A total of 30 subjects—15 Alzheimer’s disease (AD) patients and 15 cognitively normal age- and sex-matched controls—were enrolled. All subjects underwent structural volumetric magnetic resonance imaging (MRI) and amyloid PET scans with F-18 florbetaben. Regional standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were obtained using PMOD and MIMneuro. The SUVRs using both PMOD and MIMneuro showed high discriminatory power between the AD patients and cognitively normal controls. While PMOD and MIMneuro yielded significantly different SUVRs in some brain regions, the two methods had good overall agreement. MIMneuro provides comparable performance to PMOD without the need to acquire brain MRI. Therefore, MIMneuro might be suitable for clinical use to determine amyloid positivity.

We aimed to evaluate the diagnostic and prognostic value of post-treatment fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in patients treated for ovarian malignancy. We retrospectively reviewed post-treatment PET/CT images of patients treated for histologically confirmed ovarian malignancy. The diagnostic accuracy of PET/CT for detection of disease recurrence or second primary malignancy was calculated, and the impact of PET/CT on patient management was evaluated. The association between PET/CT result and overall survival (OS) was assessed using Cox regression analysis. In total, 416 PET/CT cases of 268 ovarian malignancy patients (mean age, 50 ± 13 years) were included. Of 416 cases, 87 (21 %) were interpreted as PET/CT positive and 329 as negative. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value were 98.8, 98.2, 98.3, 93.1 and 99.7 %, respectively. Of 362 cases for surveillance, changes in management occurred based on PET/CT in 38 (11 %). Of 54 cases with clinical suspicion, PET/CT ruled out disease recurrence in 9 (17 %). The median follow-up period from PET/CT imaging was 26.7 months, and 24 patients (9 %) died during the follow-up period. In univariate analyses, age, FIGO stage, history of prior recurrence and PET/CT results were significantly associated with OS. PET/CT results remained significantly associated with OS in the multivariate analysis (p

OBJECTIVES The purpose of this study was to evaluate the clinical value of preoperative [(18)F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) by comparing it to neck sonography in papillary thyroid carcinoma. METHODS The diagnostic accuracies of PET/CT and sonography for detecting cervical node metastasis were compared. The association between FDG uptake in the primary tumor and the prognostic factors of differentiated thyroid cancer, such as tumor size, multiplicity, extrathyroid extension, and lymph node metastasis, was also assessed. RESULTS Positron emission tomography/computed tomography showed lower sensitivity and higher specificity than sonography for detection of cervical node metastasis; however, no statistically significant difference was noted (P > .99). Only the tumor size was associated with FDG uptake in the primary tumor. CONCLUSIONS [(18)F]Fluoro-2-deoxy-d-glucose PET/CT could not provide additional information compared to neck sonography.

We fabricated a large area silica nano-particle monolayer on glass substrates for the cell growth by the Langmuir-Blodgett technique. A thin film of 300 nm sized mono-dispersed silica particles was constructed on the air-water interface and transferred onto a glass substrate. Chondrocytes were cultured on nano-structured substrates and bare glass substrates for 8 days. The characterizations of chondrocytes on nano-structured substrate were conducted on 3rd and 6th day using confocal laser microscopy and with MTT assay for 8 days. The chondrocytes cultured on nano-structured substrate showed podia like spike and their size was larger than that formed on bare glass substrate. The metabolic activity of chondrocytes on nano-structured substrate was lower than that on bare glass substrate at early-stage, but it was recovered after 4 days.