Can DNA Methylation Profiling Classify Histologic Subtypes and Grades in Soft Tissue Sarcoma?

BACKGROUND: A clear classification of the subtype and grade of soft tissue sarcoma is important for predicting prognosis and establishing treatment strategies. However, the rarity and heterogeneity of these tumors often make diagnosis difficult. In addition, it remains challenging to predict the response to chemotherapy and prognosis. Thus, we need a new method to help diagnose soft tissue sarcomas and determine treatment strategies in conjunction with traditional methods. Genetic alterations can be found in some subtypes of soft tissue sarcoma, but many other types show dysregulated gene expression attributed to epigenetic changes, such as DNA methylation status. However, research on DNA methylation profiles in soft tissue sarcoma is still insufficient to provide information to assist in diagnosis and therapeutic decisions. QUESTIONS/PURPOSES: (1) Do DNA methylation profiles differ between normal tissue and soft tissue sarcoma? (2) Do DNA methylation profiles vary between different histologic subtypes of soft tissue sarcoma? (3) Do DNA methylation profiles differ based on tumor grade? METHODS: Between January 2019 and December 2022, we treated 85 patients for soft tissue sarcomas. We considered patients whose specimens were approved for pilot research by the Human Biobank of St. Vincent's Hospital, The Catholic University of Korea, as potentially eligible. Based on this, 41% (35 patients) were eligible; 1% (one patient) was excluded because of gender mismatch between clinical and genetic data after controlling for data quality. Finally, 39 specimens (34 soft tissue sarcomas and five normal samples) were included from 34 patients who had clinical data. All tissue samples were collected intraoperatively. The five normal tissue samples were from muscle tissues. There were 20 female patients and 14 male patients, with a median age of 58 years (range 19 to 82 years). Genomic DNA was extracted from frozen tissue, and DNA methylation profiles were obtained. Genomic annotation of DNA methylation sites and hierarchical cluster analysis were performed to interpret results from DNA methylation profiling. A t-test was used to analyze different methylation probes. Benjamini-Hochberg-adjusted p value calculations were used to account for bias resulting from evaluating thousands of methylation sites. RESULTS: The most common histologic subtypes were liposarcoma (n = 10) and leiomyosarcoma (n = 9). The tumor grade was Fédération Nationale des Centres de Lutte Contre Le Cancer Grades 1, 2, and 3 in 3, 15, and 16 patients, respectively. DNA methylation profiling demonstrated differences between soft tissue sarcoma and normal tissue as 21,188 cytosine-phosphate-guanine sites. Despite the small number of samples, 72 of these sites showed an adjusted p value of < 0.000001, suggesting a low probability of statistical errors. Among the 72 sites, 70 exhibited a hypermethylation pattern in soft tissue sarcoma, with only two sites showing a hypomethylation pattern. Thirty of 34 soft tissue sarcomas were distinguished from normal samples using hierarchical cluster analysis. There was a different methylation pattern between leiomyosarcoma and liposarcoma at 7445 sites. Using the data, hierarchical clustering analysis showed that liposarcoma was distinguished from leiomyosarcoma. When we used the same approach and included other subtypes with three or more samples, only leiomyosarcoma and myxofibrosarcoma were separated from the other subtypes, while liposarcoma and alveolar soft-part sarcoma were mixed with the others. When comparing DNA methylation profiles between low-grade (Grade 1) and high-grade (Grades 2 and 3) soft tissue sarcomas, a difference in methylation pattern was observed at 144 cytosine-phosphate-guanine sites. Among these, 132 cytosine-phosphate-guanine sites exhibited hypermethylation in the high-grade group compared with the low-grade group. Hierarchical clustering analysis showed a division into two groups, with most high-grade sarcomas (28 of 31) separated from the low-grade group and few (3 out of 31) clustered together with the low-grade group. However, three high-grade soft tissue sarcomas were grouped with the Grade 1 cluster, and all of these sarcomas were Grade 2. When comparing Grades 1 and 2 to Grade 3, Grade 3 tumors were separated from Grades 1 and 2. CONCLUSION: We observed a different DNA methylation pattern between soft tissue sarcomas and normal tissues. Liposarcoma was distinguished from leiomyosarcoma using methylation profiling. High-grade soft tissue sarcoma samples showed a hypermethylation pattern compared with low-grade ones. Our findings indicate the need for research using methylation profiling to better understand the diverse biological characteristics of soft tissue sarcoma. Such research should include studies with sufficient samples and a variety of subtypes, as well as analyses of the expression and function of related genes. Additionally, efforts to link this research with clinical data related to treatment and prognosis are necessary. LEVEL OF EVIDENCE: Level III, diagnostic study.

CT and MRI findings beyond the subchondral bone in osteonecrosis of the femoral head to distinguish between ARCO stages 2 and 3A.

OBJECTIVES: To determine the diagnostic values of deep changes beyond the subchondral bone in osteonecrosis of the femoral head (ONFH) to distinguish between Association Research Circulation Osseous (ARCO) stages 2 and 3A. METHODS: This retrospective study included 124 hips with ONFH of stages 2 (n = 49; 23 females; mean age, 50.7 years) and 3A (n = 75; 20 females; mean age, 53.2 years) from May 2017 to August 2022, who underwent CT (n = 124) and MRI (n = 85). Deep changes beyond subchondral bone were analyzed on CT (bone resorption area and cystic change) and on MRI (bone marrow edema [BME] and joint effusion). Diagnostic performance and multivariate analysis were evaluated for detecting stage 3A. RESULTS: Stage 3A showed more frequent bone resorption area (72.0% vs. 4.1%), cystic change (52.0% vs. 0.0%), BME (93.5% vs. 43.6%), and joint effusion (76.0% vs. 24.5%) than stage 2 (p < 0.001, all). Bone resorption area and cystic change showed low sensitivities (52.0~72.0%) but high specificities (96.0~100.0%), while BME and joint effusion showed high sensitivities (76.0~93.0%) but low specificities (56.0~76.0%) for stage 3A. Predictors were in the order of bone resorption area, cystic change, and joint effusion (odds ratio: 32.952, 26.281, 9.603, respectively), and combined bone resorption area and cystic change had the best predictive value (AUC, 0.900) for stage 3A. CONCLUSIONS: Among deep changes, bone resorption area and cystic changes were highly specific and BME and joint effusion were highly sensitive for stage 3A. Combined bone resorption area and cystic change had the best predictive value for predicting ARCO stage 3A. KEY POINTS: • The exact classification between ARCO stage 2 and 3A is essential but it is sometimes difficult to distinguish between ARCO stage 2 and 3A only by subchondral fracture, especially early post-collapse stage with preservation of femoral head contour. • The predictors of stage 3A were in the order of bone resorption area, cystic change, and joint effusion and combined bone resorption area and cystic change had the best predictive value for predicting stage 3A. • Analysis of deep changes beyond the subchondral bone may make it easier to distinguish between ARCO stage 2 and 3A.

What Is New in Stage 3 of the 2019 Revised Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head: A Relationship to Bone Resorption.

PURPOSE: The aim of the study is to evaluate the stage 3 findings of the 2019 revision of the Association Research Circulation Osseous (ARCO) staging system for osteonecrosis of the femoral head between 3A and 3B and the relationship with bone resorption area. MATERIALS AND METHODS: We retrospectively enrolled 87 patients with ARCO stage 3 osteonecrosis of the femoral head, divided into stage 3A (n = 73) and 3B (n = 14). The revised stage 3 findings included subchondral fracture, fracture in necrotic portion, and flattening of the femoral head and were compared between stage 3A and 3B. The association between these findings and the causative features of bone resorption area was also evaluated. RESULTS: All stage 3 cases had subchondral fractures. In stage 3A, these fractures were generated by crescent sign (41.1%) and by fibrovascular reparative zone in 58.9%; however, in stage 3B, fibrovascular reparative zone generated 92.9% of these fractures and crescent sign only 7.1% with statistical significance ( P = 0.034). Necrotic portion fracture was noted in 36.7% and femoral head flattening was observed in 14.9% of all stage 3. Necrotic portion fracture (92.9% vs 26.0%) and femoral head flattening (71.4% vs 4.1%) were observed more frequently in stage 3B than 3A ( P < 0.001). Almost all subchondral fractures by fibrovascular reparative zone (96.4%) and necrotic portion fracture (96.9%), and all femoral head flattening was presented with bone resorption area with expanding areas. CONCLUSIONS: The ARCO stage 3 descriptions reflect severity in this order: subchondral fracture, necrotic portion fracture, and femoral head flattening. More severe findings are usually associated with expanding bone resorption areas.

Tenosynovial giant cell tumors of digits: MRI differentiation between localized types and diffuse types with pathology correlation.

OBJECTIVE: To compare the MRI findings between the localized- and diffuse-type tenosynovial giant cell tumors (TSGCTs) of digits with pathology correlation. METHODS: Twenty-eight patients with newly diagnosed TSGCTs of digits (22 localized and 6 diffuse types) who underwent preoperative MRI and surgical excision were included from Jan. 2015 to September 2021. MRI findings regarding nodularity, margins, morphology of hypointensity with pathology correlation, and disease extent (bone erosion, articular involvement, muscle involvement, tendon destruction, and neurovascular encasement) were assessed. RESULTS: Diffuse type was significantly larger (P = 0.006), more multinodular on both MRI and pathology (P = 0.038, both) with significant agreement, and infiltrative on both MRI and pathology (P < 0.001, both) with substantial agreement, and showed central granular on MRI and strong hemosiderin deposition on pathology (P = 0.022 and P = 0.021) with moderate agreement than localized type. Localized type showed significantly more frequent peripheral capsules on both MRI and pathology (P < 0.001, both) with moderate agreement than diffuse type. However, the septum on both MRI and pathology showed no statistically significant difference between the two groups (P = 0.529 and P = 0.372) without significant agreement. The disease extent was more severe in the diffuse type than the localized type regarding articular involvement (P < 0.001), muscle involvement (P < 0.001), and tendon destruction (P = 0.010). No statistically significant differences were found between the two groups regarding bone erosion (P = 0.196) or neurovascular bundle encasement (P = 0.165). CONCLUSIONS: Diffuse-type TSGCTs of digits presented as locally aggressive lesions with larger, multinodular, infiltrative masses exhibiting stronger hemosiderin deposition and more severe disease extents of articular, muscle, and tendon involvement than the localized type.

Acute left iliofemoral vein thrombosis: Comparison between simple and bony May-Thurner syndrome in CT venography.

OBJECTIVES: To explore the etiology of May-Thurner syndrome (MTS) with acute iliofemoral deep vein thrombosis (DVT) regarding imaging findings and clinical features. METHODS: We retrospectively analyzed 57 patients with acute left iliofemoral DVT from 2015 to 2020. The diameter of left common iliac vein (LCIV) at the maximal compression site and its percent compression regarding the average diameter of the uncompressed iliac vein were recorded in central and distal portions of the LCIV according to the location in the quadrant of lumbar vertebral body. Compression was categorized into simple and bony MTS; Simple MTS as LCIV compressed by the right common iliac artery (RCIA) versus Bony MTS as LCIV by lower lumbar degenerative changes regardless of RCIA compression. Initial computed tomographic venography (CTV) regarding chronic change of LCIV such as fibrotic atrophy or cordlike obliteration, extent of thrombus, and lumbar degenerative changes were evaluated. Therapeutic effect after initial therapy was assessed in follow-up CTVs after 3-6 months. RESULTS: All patients showed LCIV compression with 19 simple MTS (mean age, 42.8 ± 14.1 years [23-67 years]; 12 females; symptom for 4.4 ± 5.5 days) and 38 bony MTS (mean age, 73.0 ± 10.2 years [49-85 years]; 26 females; symptom for 5.5 ± 4.8 days). There was significant difference in age (p < .001) and no significant difference in sex or symptom duration between two groups (p = .691 and 0.415, respectively). All simple MTS showed compression only in the central LCIV and half of bony MTS showed compression in both central and distal LCIV (p < .001). Among the lumbar degenerative changes, symmetric anterolateral osteophyte (p < .001) and asymmetric osteophyte (p < .001) were significantly associated with bony MTS, but not scoliosis (p = .799), compared to simple MTS. Although there was no significant difference in chronic change of LCIV, thrombosis extent, and therapeutic effect between two groups (p > .05), chronic change of LCIV showed significant difference between single and dual compression (23.7% vs. 57.9%, p = .024) and residual thrombus after initial therapy was occurred in 21.1% of single compression and 47.4% in dual compression with non-significant trend (p = .082). CONCLUSION: Bony MTS related to lumbar degenerative changes with acute iliofemoral DVT occurs in older patients, presenting more than one stenosis at LCIV, inducing more chronic change with possibly weaker therapeutic effect than simple MTS.

Exosome from IFN-γ-Primed Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Improved Skin Inflammation and Barrier Function.

The pathogenesis of atopic dermatitis (AD) is multifactorial, including immune dysregulation and epidermal barrier defects, and a novel therapeutic modality that can simultaneously target multiple pathways is needed. We investigated the therapeutic effects of exosomes (IFN-γ-iExo) secreted from IFN-γ-primed induced pluripotent stem cell-derived mesenchymal stem cells (iMSC) in mice with Aspergillus fumigatus-induced AD. IFN-γ-iExo was epicutaneously administered to mice with AD-like skin lesions. The effects of IFN-γ-iExo treatment were investigated through clinical scores, transepidermal water loss (TEWL) measurements, and histopathology. To elucidate the therapeutic mechanism, we used an in vitro model of human keratinocyte HaCaT cells stimulated with IL-4 and IL-13 and performed extensive bioinformatics analysis of skin mRNA from mice. The expression of indoleamine 2,3-dioxygenase was higher in IFN-γ primed iMSCs than in iMSCs. In human keratinocyte HaCaT cells, treatment with IFN-γ-iExo led to decreases in the mRNA expression of thymic stromal lymphopoietin, IL-25, and IL-33 and increases in keratin 1, keratin 10, desmoglein 1, and ceramide synthase 3. IFN-γ-iExo treatment significantly improved clinical and histological outcomes in AD mice, including clinical scores, TEWL, inflammatory cell infiltration, and epidermal thickness. Bioinformatics analysis of skin mRNA from AD mice showed that IFN-γ-iExo treatment is predominantly involved in skin barrier function and T cell immune response. Treatment with IFN-γ-iExo improved the clinical and histological outcomes of AD mice, which were likely mediated by restoring proper skin barrier function and suppressing T cell-mediated immune response.

Iliac vein compression syndrome by lumbar degenerative changes is associated with deep vein thrombosis after total knee arthroplasty.

INTRODUCTION: This study aimed to identify whether iliac vein compression syndrome(IVCS) is associated with deep vein thrombosis(DVT) after total knee arthroplasty(TKA) and whether lower lumbar degenerative changes were risk factors for IVCS. MATERIALS AND METHODS: A total of 259 consecutive patients who underwent TKA from January 2019 to March 2022 was retrospectively reviewed. Preoperative plain radiographs of lumbar spines and CT venography (CTV) for DVT diagnosis at postoperative 7 days were performed in all patients. Imaging findings of lower lumbar degenerative changes were analyzed on plain radiograph including lateral osteophytes, scoliosis, lateralolisthesis, retrolisthesis, anterolisthesis, and lower lumbar lordosis angle (LLLA). Percent compression at the left common iliac vein (LCIV) and right common iliac vein (RCIV) as well as DVT were evaluated on CTV. Moreover, IVCS was defined as greater than 50% of compression of the iliac vein on CTV. RESULTS: DVT occurred in 79 patients (30.5%) after TKA. The overall occurrence of DVT was significantly higher in patients with IVCS of LCIV (52.8%) than those without (18.8%, P < 0.001). When DVT was further subdivided, compared to non-IVCS, IVCS of LCIV was significantly associated with bilateral DVT (P < 0.001, both), especially distal DVT (P < 0.001, both), and IVCS of RCIV was significantly associated with right-side DVT (P = 0.031), especially popliteal (P = 0.008) and distal DVT(P = 0.011). Female patients (OR: 3.945, P = 0.039), presence of left osteophyte (OR: 2.348, P = 0.006), and higher LLLA (OR: 1.082, P < 0.001) were significantly associated with IVCS of LCIV, and presence of right osteophyte (OR: 3.494, P = 0.017) was significantly associated with IVCS of RCIV. CONCLUSION: IVCS was significantly associated with DVT after TKA and lumbar degenerative changes with lateral osteophytes and hyperlordosis were significant risk factors for IVCS.

Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, pruritus, and abnormal epidermal barrier function. Compared with conventional mesenchymal stem cell (MSC), induced pluripotent stem cell (iPSC)-derived mesenchymal stem cell (iMSC) is recognized as a unique source for producing extracellular vesicles (EVs) because it can be obtained in a scalable manner with an enhanced homogeneity. Stimulation of iMSCs with inflammatory cytokines can improve the immune-regulatory, anti-inflammatory, and tissue-repairing potential of iMSC-derived EVs. RESULTS: Proteome analysis showed that IFN-γ-iMSC-EVs are enriched with protein sets that are involved in regulating interferon responses and inflammatory pathways. In AD mice, expression of interleukin receptors for Th2 cytokines (IL-4Rα/13Rα1/31Rα) and activation of their corresponding intracellular signaling molecules was reduced. IFN-γ-iMSC-EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and thymic stromal lymphopoietin and NF-kB activation; and recovered impaired skin barrier, as evidenced by upregulation of key genes of epidermal differentiation and lipid synthesis. CONCLUSIONS: IFN-γ-iMSC-EVs inhibit Th2-induced immune responses, suppress inflammation, and facilitate skin barrier restoration, contributing to AD improvement.

Dual conformational recognition by Z-DNA binding protein is important for the B-Z transition process.

Left-handed Z-DNA is radically different from the most common right-handed B-DNA and can be stabilized by interactions with the Zα domain, which is found in a group of proteins, such as human ADAR1 and viral E3L proteins. It is well-known that most Zα domains bind to Z-DNA in a conformation-specific manner and induce rapid B-Z transition in physiological conditions. Although many structural and biochemical studies have identified the detailed interactions between the Zα domain and Z-DNA, little is known about the molecular basis of the B-Z transition process. In this study, we successfully converted the B-Z transition-defective Zα domain, vvZαE3L, into a B-Z converter by improving B-DNA binding ability, suggesting that B-DNA binding is involved in the B-Z transition. In addition, we engineered the canonical B-DNA binding protein GH5 into a Zα-like protein having both Z-DNA binding and B-Z transition activities by introducing Z-DNA interacting residues. Crystal structures of these mutants of vvZαE3L and GH5 complexed with Z-DNA confirmed the significance of conserved Z-DNA binding interactions. Altogether, our results provide molecular insight into how Zα domains obtain unusual conformational specificity and induce the B-Z transition.

Endoplasmic reticulum stress increases LECT2 expression via ATF4.

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity, insulin resistance, and endoplasmic reticulum (ER) stress. Elevated circulating levels of the hepatokine leukocyte cell-derived chemotaxin-2 (LECT2) have also been noted in NAFLD; however, the mechanism underlying this association is unclear. To investigate a possible link between ER stress/unfolded protein response (UPR) signaling and LECT2 secretion, HepG2 cells were incubated with ER stress inducers with or without an ER stress-reducing chemical chaperone. Additionally, UPR pathway genes were knocked down and overexpressed, and a ChIP assay was performed. In diet-induced obese mice, hepatic expression of LECT2 and activating transcription factor 4 (ATF4) was measured. In HepG2 cells, LECT2 expression was increased by ER stressors, an effect blocked by the chemical chaperone. Among UPR pathway proteins, only knockdown of ATF4 suppressed ER stress-induced LECT2 expression, while overexpression of ATF4 enhanced LECT2 expression. The ChIP assay revealed that ATF4 binds to three putative binding sites on the LECT2 promoter and binding is promoted by an ER stress inducer. In steatotic livers of obese mice, LECT2 and ATF4 expression was concomitantly elevated. Our data indicate that activation of ER stress/UPR signaling induces LECT2 expression in steatotic liver; specifically, ATF4 appears to mediate upregulation of LECT2 transcription.

Neurotrophic isoindolinones from the fruiting bodies of Hericium erinaceus.

Four compounds, hericerin (1), isohericerinol A (2), N-de-phenylethyl isohericerin (3) and corallocin A (4) were isolated from the fruiting bodies of Hericium erinaceus, a lion's mane mushroom (Hericiaceae). Among them, isohericerinol A (2) was newly reported in nature. Further investigation of the neurotrophic effect of isolated compounds demonstrated that isohericerinol A (2) strongly increased the nerve growth factor (NGF) production in C6 glioma cells followed by corallocin A (4) and hericerin (1). Increased NGF production by these compounds promoted the neurite outgrowth in N2a neuronal cells. Western blot analysis also showed the increased protein expression of NGF, brain-derived neurotrophic factor (BDNF) and synaptophysin (SYP) in C6-N2a cells. Taken together, our present study characterized the neurotrophic constituents of H. erinaceus, which may support the potential use of memory improvement.

Cargo proteins in extracellular vesicles: potential for novel therapeutics in non-alcoholic steatohepatitis.

BACKGROUND: Extracellular vesicles (EVs) are recognized as novel cell-free therapeutics. Non-alcoholic steatohepatitis (NASH) remains a critical health problem. Herein, we show that EVs from pan peroxisome proliferator-activated receptor agonist-primed induced mesenchymal stem cell (pan PPAR-iMSC-EVs) has unique cargo protein signatures, and demonstrate its therapeutic function in NASH. RESULTS: A unique protein signatures were identified in pan PPAR-iMSC-EVs against those from non-stimulated iMSC-EVs. NASH mice receiving pan PPAR-iMSC-EVs showed reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation. Moreover, pan PPAR-iMSC-EVs promoted liver regeneration via inhibiting apoptosis and enhancing proliferation. CONCLUSIONS: We conclude that our strategy for enriching unique cargo proteins in EVs may facilitate the development of novel therapeutic option for NASH.

Degree of Anterolateral Ligament Injury Impacts Outcomes After Double-Bundle Anterior Cruciate Ligament Reconstruction.

PURPOSE: To evaluate the effect of anterolateral ligament (ALL) injury identified on preoperative magnetic resonance imaging (MRI) on postoperative outcomes after double-bundle (DB) anterior cruciate ligament reconstruction (ACLR). METHODS: For this retrospective study, the inclusion criteria were patients who were at least 3 years out of DB ACLR. Exclusion criteria included a delay in MRI over 4 weeks, delay in surgery over 6 months, single-bundle ACLR, and revision surgery. Enrolled patients were divided into 2 groups according to the ALL injury grade in preoperative MRI by a musculoskeletal radiologist who was blinded to the perioperative findings (the high-grade group with complete or nearly complete tear: n = 53 and the low-grade group with intact ALL or partial tear: n = 33). Knee laxity, clinical outcomes using the International Knee Documentation Committee (IKDC) examination form, and revision rates were compared at the last follow-up (8.1 ± 2.2 years). An independent t test was applied to compare continuous variables, and χ2 or Fisher exact test was used to compare the nominal variables. RESULTS: The anterior translation was 3.2 ± 1.9 mm in the high-grade group and 1.6 ± 1.0 mm in the low-grade group (P < .001). The high-grade group showed 18 cases with a pivot-shift grade of 2 or 3 (40.0%); however, the low-grade group showed only 1 case with a pivot-shift grade 2 or 3 (3.0%) (P = .002). The high-grade group also showed inferior outcomes in the IKDC objective grade (grade A: 49.0%; grade B: 17.0%; grade C: 30.2%; grade D: 3.8% vs grade A: 90.9%; grade B: 6.1%; grade C: 3.0%; grade D: 0%, P = .001) and IKDC subjective score (87.5 ± 9.9 vs 93.9 ± 5.3, P < .001). In addition, the high-grade group showed a greater revision rate (11.3% vs 0%, P = .045). CONCLUSIONS: DB ACLR for patients with high-grade ALL injury resulted in increased knee laxity, worse clinical outcomes, and higher revision rate compared to patients with low-grade ALL injury. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Degenerative lumbar scoliosis: added value of coronal images to routine lumbar MRI for nerve root compromise.

OBJECTIVES: Radiating pain in degenerative scoliosis is primary indication for surgery. However, axial and sagittal MR images are limited for identifying nerve root compromise. Therefore, we aimed to assess the value of coronal images for evaluating nerve root compromise in degenerative scoliosis. METHODS: Forty-six patients (mean 70 years; range 41-91 years; 8 men) with degenerative scoliosis were enrolled. Coronal images were added to routine MRI. Two radiologists independently reviewed 350 nerve roots in two MRI sets: sagittal images alone (set 1) and coronal and sagittal images combined (set 2). The following features were evaluated: interpedicular height, lateral osteophyte, asymmetric bulging disc, lateral listhesis, anterolisthesis, axial rotation angle, facet arthrosis, ligamentum flavum thickening, and pseudoarticulation. Symptomatic levels were determined by transforaminal selective nerve root block. RESULTS: There were 80 symptomatic and 270 asymptomatic nerve roots. The sensitivity (86%) and accuracy (93%) of set 2 were significantly higher than set 1 (53% and 87%) for radiculopathy, while specificity was similar between two sets (set 1, 97%; set 2, 95%). The AUC was significantly different between two sets (set 1, 0.853; set 2, 0.942). The negative interpedicular height difference, longer lateral osteophyte, asymmetric bulging disc, lateral listhesis, negative axial rotation angle difference, and pseudoarticulation were associated with change of grades between set 1 and set 2. CONCLUSION: Coronal images are helpful for diagnosing nerve root compromise in patients with degenerative scoliosis. KEY POINTS: • Sagittal and axial images have low sensitivity for detection of extraforaminal nerve root compromise in degenerative scoliosis. • Addition of coronal images may improve the sensitivity in nerve root compromise. • The structural changes that may contribute to nerve root compromise can also be easily assessed with coronal images.

Superolateral Hoffa Fat Pad Edema and Patellofemoral Maltracking: Systematic Review and Meta-Analysis.

OBJECTIVE. The purpose of this study is to clarify which imaging parameters of patellofemoral maltracking are associated with superolateral Hoffa fat pad (SHFP) edema. MATERIALS AND METHODS. A systematic search of the MEDLINE, Embase, and Cochrane Library databases was performed to identify studies evaluating the relationship between SHFP edema and patellofemoral maltracking. Parameters for assessing patellofemoral maltracking on MRI were reviewed for each study. Two reviewers performed study selection, methodologic quality assessment, and data extraction. RESULTS. Nine studies were eligible for inclusion in the present study. From the included studies, nine parameters assessing patellofemoral maltracking were analyzed: lateral patellofemoral angle, patellar tilt, patellar lateralization, trochlear depth, sulcus depth, sulcus angle, lateral trochlear inclination, distance between the tibial tuberosity and trochlear groove, and the Insall-Salvati ratio. Patients with SHFP edema had greater patellar tilt (standardized mean difference, 0.89°; 95% CI, 0.38-1.40°; p = 0.0006), greater patellar lateralization (standardized mean difference, 0.78 mm; 95% CI, 0.21-1.36 mm; p = 0.008), greater distance between the tibial tuberosity and trochlear groove (standardized mean difference, 0.96 mm; 95% CI, 0.48-1.44 mm; p < 0.0001), and higher Insall-Salvati ratio (standardized mean difference, 1.94; 95% CI, 1.29-2.60; p < 0.00001) than patients without SHFP edema. CONCLUSION. Patellofemoral maltracking imaging parameters, such as a more laterally displaced patella, greater TTTG distance, and patella alta, are correlated with SHFP edema.

Intramuscular peripheral nerve sheath tumors: schwannoma, ancient schwannoma, and neurofibroma.

PURPOSE: To analyze the prevalence of classic magnetic resonance imaging (MRI) findings of intramuscular peripheral nerve sheath tumors (PNSTs), including schwannoma, ancient schwannoma, and neurofibroma. METHOD: Thirty pathologically confirmed benign intramuscular PNSTs (24 schwannomas, 3 ancient schwannomas, and 3 neurofibromas) were retrospectively reviewed. Classic MRI findings of PNSTs including split fat sign, fascicular sign, target sign, entering and exiting nerve, and thin hyperintense rim were assessed for each intramuscular PNST. Denervation change of the affected muscle was also assessed. In ancient schwannoma and neurofibroma, the signal intensity (SI) and enhancement pattern were analyzed. RESULTS: All intramuscular schwannomas revealed two more classic MRI findings. Eight of the 24 intramuscular schwannomas revealed affected muscle denervation change. All intramuscular ancient schwannomas showed only split fat sign. All intramuscular ancient schwannomas showed denervation change of the associated muscle. All intramuscular neurofibroma showed split fat sign and one case with target sign was detected. Ancient schwannomas were isointense SI on T1-weighted image (T1WI) and one case had hyperintense foci. They showed heterogeneously hyperintense SI on T2-weighted image (T2WI) with heterogeneous enhancement. Neurofibromas were isointense SI (2/3) and slight hyperintense SI (1/3) on T1WI and heterogeneously hyperintense SI on T2WI with heterogeneous enhancement. One ancient schwannoma showed conglomerated calcifications. CONCLUSIONS: Intramuscular schwannomas were easily diagnosed based on MRI. In the case of intramuscular ancient schwannoma and neurofibroma with only split fat sign among the classic MRI findings, they might be distinguished from other intramuscular soft tissue tumors based on muscle denervation change or typical crescent split fat sign.

Fat quantification of multifidus muscle using T2-weighted Dixon: which measurement methods are best suited for revealing the relationship between fat infiltration and herniated nucleus pulposus.

OBJECTIVE: To reveal the best-suited method for fat quantification of lumbar multifidus to demonstrate its relationship to herniated nucleus pulposus (HNP) using T2-weighted Dixon. MATERIALS AND METHODS: One hundred eight patients who underwent MRI for low back pain were enrolled. Two readers independently analyzed the fat fraction (Ff) using axial two-dimensional (D), coronal 2-D, and coronal 3-D measurement. Pearson's correlation coefficient was calculated between age, body mass index (BMI), and the Ff, and age, sex, BMI, and Ff were compared between 'HNP group' and 'no HNP group'. Multivariate logistic regression analysis was performed to identify factors associated with HNP. RESULTS: Coronal 2-D Ff showed the highest correlation with age (r = 0.536, P < 0.001). Coronal 2-D Ff, and coronal 3-D Ff were significantly higher in those with HNP (coronal 2-D: 18.9 ± 2.9, coronal 3-D: 19.7 ± 2.6, respectively) than those without HNP (coronal 2-D: 17.2 ± 3.2, coronal 3-D: 17.4 ± 3.2, respectively). Ff of all three measurements were significantly higher in those with HNP ≥ 3 levels (axial 2-D: 20.7 ± 3.0, coronal 2-D: 21.1 ± 2.7, coronal 3-D: 21.6 ± 2.5, respectively) than those with HNP <3 levels (axial 2-D: 17.5 ± 4.3, coronal 2-D: 18.5 ± 2.7, coronal 3-D: 19.3 ± 2.5). The BMI was an independent predisposing factor to HNP (P = 0.011). Age and coronal 2-D Ff were significant predictors for multilevel HNP (P = 0.028 and 0.040, respectively). CONCLUSIONS: The Ff of the multifidus muscle on T2-weighted Dixon was associated with age, sex, and HNP. The coronal 2-D measurement was the best suited for fat quantification in multifidus muscle among three measurement methods.

Combining non-contrast and dual-energy CT improves diagnosis of early gout.

OBJECTIVES: To determine the incremental value of non-contrast CT (NCCT) on dual-energy CT (DECT) in symptomatic first metatarsophalangeal (MTP) joints in early gout. METHODS: One hundred and fifteen painful joints were consecutively enrolled and gout was diagnosed based on the 2015 EULAR/ACR criteria and/or arthrocentesis. Two readers independently evaluated DECT alone and combined NCCT and DECT (NCCT+DECT) based on four semiquantitative scales. Sensitivities and specificities were compared using McNemar's test. AUC was compared. RESULTS: Of the 115 joints, 72 were defined as an early gout group and 43 as a gout-negative group after exclusion. The sensitivity and specificity for the early gout group on DECT alone were as followed: reader 1 - 52.8% and 100.0% and reader 2 - 51.4% and 100.0%. NCCT+DECT results were as follows: reader 1 - 79.2% and 93.0% and reader 2 - 79.2% and 95.3%. AUC was significantly higher in NCCT+DECT compared to that in DECT alone for the early gout group (0.888 vs. 0.774 for reader 1, p = 0.0004; 0.896 vs. 0.816 for reader 2, p = 0.0142). The false-negative cases on DECT occurred more frequently with the first-onset gout, and tended to be affected by a longer duration of symptoms in the post-hoc analysis. CONCLUSION: The combined analysis of NCCT and DECT improves diagnostic capabilities in symptomatic early gout involving the first MTP joint. KEY POINTS: • MSU crystal depositions in early gout may be seen on non-contrast CT, while still being undetectable by DECT. • Combining non-contrast CT and DECT improves detection of early gout. • False negatives of DECT are more common than previously reported in cases of first-onset gout.

Effects of laser-assisted thinning versus opening on clinical outcomes according to maternal age in patients with repeated implantation failure.

Laser-assisted thinning (LAT) and laser-assisted opening (LAO) are performed as part of human in vitro fertilization (IVF) to increase the implantation rate in patients with a poor prognosis and in cases of repeated implantation failure. However, an insufficient number of studies have directly compared LAT and LAO using the same methods. Therefore, we compared the effects of LAT and LAO on clinical outcomes according to maternal age in patients with repeated implantation failure. This retrospective study was performed in 509 IVF cycles (458 patients). The cycles were divided based on maternal age and the method used (< 38 years LAT, n = 119 vs. LAO, n = 179 and ≥ 38 years LAT, n = 72 vs. LAO, n = 139). Cleavage-stage embryos before transfer were either thinned or opened using a 1.46-µm noncontact diode laser. We compared the implantation rates and pregnancy outcomes of cycles between LAT and LAO according to maternal age. The characteristics of patients did not differ significantly among the groups (p > 0.05), with the exception of mixed factor infertility, which was more common in the LAT group than in the LAO group among patients < 38 years of age (10.1% vs. 2.8%, p = 0.008). The LAT and LAO groups showed similar rates of biochemical pregnancy, clinical pregnancy, ongoing pregnancy, abortion, implantation, singleton pregnancy, and twin pregnancy (p > 0.05). In conclusion, LAT and LAO had similar clinical outcomes. Therefore, we did not find any evidence that LAT is superior to LAO. In fact, the patients ≥ 38 years of age who underwent LAO tended to have a lower abortion rate. Further study is necessary to confirm these results in a larger population.

Pioglitazone-Primed Mesenchymal Stem Cells Stimulate Cell Proliferation, Collagen Synthesis and Matrix Gene Expression in Tenocytes.

Various therapeutic effects of mesenchymal stem cells (MSCs) have been reported. However, the rapid clearance of these cells in vivo, difficulties in identifying their therapeutic mechanism of action, and insufficient production levels remain to be resolved. We investigated whether a pioglitazone pre-treatment of MSCs (Pio-MSCs) would stimulate the proliferation of co-cultured tenocytes. Pioglitazone increased the proliferation of MSCs and enhanced the secretion of VEGF (vascular endothelial growth factor) and collagen in these cells. We then examined the effects of Pio-MSCs on tenocytes using an indirect transwell culture system. A significant increase in tenocyte proliferation and cell cycle progression was observed in these co-cultures. Significant increases were observed in wound scratch closure by tenocytes from a Pio-MSC co-culture. Pio-MSCs also enhanced the secretion of collagen from tenocytes. A higher mRNA level of collagen type 1 (Col 1) and type 3 (Col 3), scleraxis (Scx), and tenascin C (TnC) was found in the tenocytes in Pio-MSC co-cultures compared with monocultured cells or tenocytes cultured with non-treated MSCs. Our results indicate that pioglitazone enhances the therapeutic effects of MSCs on tendon repair.