Interobserver Variability and Diagnostic Performance in Predicting Malignancy of Pancreatic Intraductal Papillary Mucinous Neoplasm with MRI.

Background The 2017 international consensus guidelines for intraductal papillary mucinous neoplasm (IPMN) of the pancreas are widely used. Purpose To evaluate the interobserver agreement and diagnostic performance of MRI assessment in predicting the malignant potential of IPMN according to radiologists' experience. Materials and Methods This multicenter retrospective study included 100 patients with pathologically proven pancreatic IPMN (77 patients with surgery, 23 patients with biopsy) who underwent contrast-enhanced MRI between 2016 and 2021. Eight post-fellowship radiologists (four more-experienced [8-20 years] and four less-experienced [1-4 years] reviewers) evaluated MRI for high-risk stigmata and worrisome features identified by the most recent 2017 guidelines. Interobserver agreement was determined using Fleiss κ statistics according to radiologist experience. The diagnostic performance for malignant IPMN was assessed using receiver operating characteristic curve analysis. Results Among 100 patients (mean age, 66 years ± 10 [SD]; 57 men), 52 (52%) had malignant IPMN. For high-risk stigmata, interobserver agreement was substantial for main pancreatic duct size of at least 10 mm (κ = 0.78; 95% CI: 0.75, 0.82), enhancing mural nodule of at least 5 mm (κ = 0.70: 95% CI: 0.66, 0.74), and at least one high-risk stigmata (κ = 0.73: 95% CI: 0.69, 0.76). The worrisome features showed fair to substantial interobserver agreement (κ range, 0.22-0.80). More-experienced reviewers demonstrated better agreement in the assessment of at least one high-risk stigmata than less-experienced reviewers (κ = 0.77 vs κ = 0.69, P < .001). The overall diagnostic performance of each reviewer was good for the prediction of malignant pancreatic IPMN (area under the receiver operating characteristic curve [AUC] range, 0.77-0.84; median AUC, 0.82), with substantial agreement (κ = 0.76). Conclusion The 2017 international consensus guidelines enabled good diagnostic performance and substantial interobserver agreement for high-risk stigmata but not worrisome features on the evaluation of the malignant pancreatic IPMN using MRI. Agreement tended to be better among more-experienced reviewers than among less-experienced reviewers. © RSNA, 2023 Supplemental material is available for this article.

Perfluorobutane-enhanced ultrasonography with a Kupffer phase: improved diagnostic sensitivity for hepatocellular carcinoma.

OBJECTIVES: To evaluate the diagnostic accuracy of perfluorobutane contrast-enhanced ultrasonography (CEUS) for hepatocellular carcinoma (HCC) and to explore how accuracy can be improved compared to conventional diagnostic criteria in at-risk patients. METHODS: A total of 123 hepatic nodules (≥ 1 cm) from 123 at-risk patients who underwent perfluorobutane CEUS between 2013 and 2020 at three institutions were retrospectively analyzed. Ninety-three percent of subjects had pathological results, except benign lesions stable in follow-up images. We evaluated presence of arterial phase hyperenhancement (APHE), washout time and degree, and Kupffer phase (KP) defects. KP defects are defined as hypoenhancing lesions relative to the liver in KP. HCC was diagnosed in two ways: (1) Liver Imaging Reporting and Data System (LI-RADS) criteria defined as APHE and late (≥ 60 s)/mild washout, and (2) APHE and Kupffer (AK) criteria defined as APHE and KP defect. We explored grayscale features that cause misdiagnosis of HCC and reflected in the adjustment. Diagnostic performance was compared using McNemar's test. RESULTS: There were 77 HCCs, 15 non-HCC malignancies, and 31 benign lesions. An ill-defined margin without hypoechoic halo on grayscale applied as a finding that did not suggest HCC. Regarding diagnosis of HCC, sensitivity of AK criteria (83.1%; 95% confidence interval [CI]: 72.9-90.7%) was higher than that of LI-RADS criteria (75.3%; 95% CI: 64.2-84.4%; p = 0.041). Specificity was 91.3% (95% CI: 79.2-97.6%) in both groups. CONCLUSION: On perfluorobutane CEUS, diagnostic criteria for HCC using KP defect with adjustment by grayscale findings had higher diagnostic performance than conventional criteria without losing specificity. KEY POINTS: • Applying Kupffer phase defect instead of late/mild washout and adjusting with grayscale findings can improve the diagnostic performance of perfluorobutane-enhanced US for HCC. • Adjustment with ill-defined margins without a hypoechoic halo for features unlikely to be HCC decreases false positives for HCC diagnosis using the perfluorobutane-enhanced US. • After adjustment with grayscale findings, the sensitivity and accuracy of the APHE and Kupffer criteria were higher than those of the LI-RADS criteria; specificity was 91.3% for both.

LI-RADS Version 2018 Targetoid Appearances on Gadoxetic Acid-Enhanced MRI: Interobserver Agreement and Diagnostic Performance for the Differentiation of HCC and Non-HCC Malignancy.

BACKGROUND. In LI-RADS version 2018, observations showing at least one of five targetoid appearances in different sequences or postcontrast phases are categorized LR-M, indicating likely non-hepatocellular carcinoma (HCC) malignancy. OBJECTIVE. The purpose of this study was to evaluate interobserver agreement for LI-RADS targetoid appearances among a large number of radiologists of varying experience and the diagnostic performance of targetoid appearances for differentiating HCC from non-HCC malignancy. METHODS. This retrospective study included 100 patients (76 men, 24 women; mean age, 58 ± 9 [SD] years) at high risk of HCC who underwent gadoxetic acid-enhanced MRI within 30 days before hepatic tumor resection (25 randomly included patients with non-HCC malignancy [13, intrahepatic cholangiocarcinoma; 12, combined HCC-cholangiocarcinoma]; 75 matched patients with HCC). Eight radiologists (four more experienced [8-15 years]; four less experienced [1-5 years]) from seven institutions independently assessed observations for the five targetoid appearances and LI-RADS categorization. Interobserver agreement and diagnostic performance for non-HCC malignancy were evaluated. RESULTS. Interobserver agreement was poor for peripheral washout (κ = 0.20); moderate for targetoid transitional phase or hepatobiliary phase appearance (κ = 0.33), delayed central enhancement (κ = 0.37), and targetoid restriction (κ = 0.43); and substantial for rim arterial phase hyperenhancement (κ = 0.61). Agreement was fair for at least one targetoid appearance (κ = 0.36) and moderate for at least two, three, or four targetoid appearances (κ = 0.43-0.51). Agreement for individual targetoid appearances was not significantly different between more experienced and less experienced readers other than for targetoid restriction (κ = 0.63 vs 0.43; p = .001). Agreement for at least one targetoid appearance was fair among more experienced (κ = 0.29) and less experienced (κ = 0.37) reviewers. Agreement for at least two, three, or four targetoid appearances was moderate to substantial among more experienced reviewers (κ = 0.45-0.63) and moderate among less experienced reviewers (κ = 0.42-0.56). Existing LR-M criteria of at least one targetoid appearance had median accuracy for non-HCC malignancy of 62%, sensitivity of 84%, and specificity of 54%. For all reviewers, accuracy was highest when at least three (median accuracy, 79%; sensitivity, 68%; specificity, 82%) or four (median accuracy, 80%; sensitivity, 54%; specificity, 88%) targetoid appearances were required. CONCLUSION. Targetoid appearances and LR-M categorization exhibited considerable interobserver variation among both more and less experienced reviewers. CLINICAL IMPACT. Requiring multiple targetoid appearances for LR-M categorization improved interobserver agreement and diagnostic accuracy for non-HCC malignancy.

Erythroid Differentiation Regulator 1 Strengthens TCR Signaling by Enhancing PLCγ1 Signal Transduction Pathway.

Erythroid differentiation regulator 1 (Erdr1) has previously been reported to control thymocyte selection via TCR signal regulation, but the effect of Erdr1 as a TCR signaling modulator was not studied in peripheral T cells. In this report, it was determined whether Erdr1 affected TCR signaling strength in CD4 T cells. Results revealed that Erdr1 significantly enhanced the anti-TCR antibody-mediated activation and proliferation of T cells while failing to activate T cells in the absence of TCR stimulation. In addition, Erdr1 amplified Ca2+ influx and the phosphorylation of PLCγ1 in CD4 T cells with the TCR stimuli. Furthermore, NFAT1 translocation into nuclei in CD4 T cells was also significantly promoted by Erdr1 in the presence of TCR stimulation. Taken together, our results indicate that Erdr1 positively modulates TCR signaling strength via enhancing the PLCγ1/Ca2+/NFAT1 signal transduction pathway.

Paracrine roles of hormone receptors in Riehl's melanosis: A quantitative analysis of oestrogen and progesterone receptor expression patterns.

The incidence of Riehl's melanosis (RM) is most common in the fifth or sixth decade of life with a female preponderance. As the skin is regarded a non-reproductive organ on which sex steroid hormones act, a possible relationship between the pathogenesis of RM and sex steroid hormone receptors can be inferred. This study intended to evaluate the expression profile of oestrogen receptor (ER)ß and progesterone receptor (PR) in RM. Twelve lesional and perilesional normal-appearing skin samples of RM patients and the skin of 12 healthy controls were retrieved for the analysis. Real-time PCR analysis and immunohistochemical studies were conducted for ERß and PR, respectively. The lesional and perilesional normal-appearing skin of 12 patients with RM and the skin of 12 healthy controls were retrieved for the analysis. Interestingly, the dermal ERß immunostaining intensity was increased more in lesional skin than in perilesional skin. When compared to healthy controls, increased expression of ERß and PR mRNAs was observed in the lesional skin of patients with RM. Of note, epidermal and dermal ERß and dermal PR expressions showed increased staining intensities in the lesional skin of RM patients compared with healthy controls. The altered expression of ERß and PR in RM supports the possible role of these hormone receptors in the pathogenesis of RM.

The antimicrobial protein REG3A regulates keratinocyte proliferation and differentiation after skin injury.

Epithelial keratinocyte proliferation is an essential element of wound repair, and abnormal epithelial proliferation is an intrinsic element in the skin disorder psoriasis. The factors that trigger epithelial proliferation in these inflammatory processes are incompletely understood. Here we have shown that regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in keratinocytes during psoriasis and wound repair and in imiquimod-induced psoriatic skin lesions. The expression of REG3A by keratinocytes is induced by interleukin-17 (IL-17) via activation of keratinocyte-encoded IL-17 receptor A (IL-17RA) and feeds back on keratinocytes to inhibit terminal differentiation and increase cell proliferation by binding to exostosin-like 3 (EXTL3) followed by activation of phosphatidylinositol 3 kinase (PI3K) and the kinase AKT. These findings reveal that REG3A, a secreted intestinal antimicrobial protein, can promote skin keratinocyte proliferation and can be induced by IL-17. This observation suggests that REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis.

CT-based nomogram for predicting survival after R0 resection in patients with gallbladder cancer: a retrospective multicenter analysis.

OBJECTIVES: To establish a prognostic nomogram for patients undergoing R0 resection for gallbladder cancer based on preoperative CT. METHODS: A total of 151 patients (64 males, 87 females; mean age, 73.26 years) with gallbladder cancer who underwent CT and surgery with margin-negative resection were retrospectively collected at two tertiary institutions. The demographic and radiologic parameters were analyzed using univariate and multivariate Cox regression analyses to identify independent prognostic factors. The final CT-based nomogram was constructed to predict prognosis after curative resection of gallbladder cancer. Calibration curves for the survival probabilities were obtained for internal validation. RESULTS: Mass-forming type (hazard ratio [HR], 28.80), bile duct invasion (HR, 4.76), duodenal invasion (HR, 6.32), colon invasion (HR, 4.37), gallstones (HR, 0.09), and cholecystitis (HR, 2.56) were significant independent predictors for recurrence-free survival (p < .05). Mass-forming type (HR, 8.16, p < .001), bile duct invasion (HR, 2.92, p = .013), duodenal invasion (HR, 3.72, p = .012), and regional lymph node metastasis (HR, 2.07, p = .043) were independent predictors of poor cancer-specific survival (CSS) and were used to construct the nomogram. The nomogram showed a good predictive ability for the probabilities of survival on the calibration curves, and the concordance index of the model in predicting CSS was .768. CONCLUSION: Preoperative CT findings could predict the prognosis of gallbladder cancer, and the CT-based nomogram accurately predicted CSS in patients with gallbladder cancer after attempted curative resection. KEY POINTS: • Among the preoperative imaging features, mass-forming type, bile duct invasion, duodenal invasion, and regional lymph node metastasis were independent predictors of poor cancer-specific survival. • The nomogram constructed using preoperative CT findings showed a good predictive ability for the survival on calibration curves, and the concordance index of the model in predicting cancer-specific survival was 0.768.

Transabdominal Ultrasound for Follow-Up of Incidentally Detected Low-Risk Pancreatic Cysts: A Prospective Multicenter Study.

OBJECTIVE. The purpose of this study is to investigate the detection rate of transabdominal ultrasound (TAUS) for pancreatic cysts incidentally detected on CT or MRI as well as the factors that influence detection rates. SUBJECTS AND METHODS. Fifty-seven patients with low-risk pancreatic cysts (n = 77; cyst size, 5 mm to 3 cm) that were incidentally detected on CT or MRI were prospectively enrolled at five institutions. At each institution, TAUS was independently performed by two radiologists who assessed detection of cysts, cyst location and size, and the diameter of the main pancreatic duct (MPD). Cyst detection rates based on cyst size, location, and multiplicity and the body mass index of the patient were compared using the Mann-Whitney test. Kappa statistics and the interclass correlation coefficient were used to evaluate interobserver agreement regarding cyst detection and consistency of cyst size and the diameter of the MPD on TAUS versus prior CT or MRI. RESULTS. The detection rate for known low-risk pancreatic cysts was 81.8% (63/77) and 83.1% (64/77) for TAUS conducted by each of the two radiologists. The detection rate for larger (≥ 10 mm) cysts was significantly higher than that for smaller cysts (89.0% vs 63.6% for TAUS performed and interpreted by radiologist 1 [TAUS 1] and 89.0% vs 68.2% for TAUS conducted and interpreted by radiologist 2 [TAUS 2]; p < .05). A higher detection rate was noted for cysts located outside the tail of the pancreas compared with those located in the tail (89.5% vs 65.0% for TAUS 2; p = .01), and the detection rate was also significantly higher for single cysts than for multiple cysts (90.9% vs 69.7% for TAUS 1; p = .02). However, no significant difference was observed for body mass index. Interobserver agreement was excellent regarding the size of the detected cysts (inter-class correlation coefficient: 0.964 [95% CI, 0.940-0.979] for CT, TAUS 1, and TAUS 2 and 0.965 [95% CI. 0.924-986] for MRI, TAUS 1, and TAUS 2) and the diameter of the MPD (interclass correlation coefficient, 0.934; 95% CI, 0.898-0.959). CONCLUSION. TAUS could be a useful alternative imaging tool for surveillance of known low-risk pancreatic cysts, especially single pancreatic cysts and those that are of larger size (≥ 1 cm) or are located outside the tail.

The Wound Healing Peptide, AES16-2M, Ameliorates Atopic Dermatitis In Vivo.

Peptide materials have recently been considered for use in various industrial fields. Because of their efficacy, safety, and low cost, therapeutic peptides are studied for various diseases, including atopic dermatitis (AD). AD is a common inflammatory skin disease impairing the patient's quality of life. Various therapies, such as treatments with corticosteroids, calcineurin inhibitors, and antibody drugs, have been applied, but numerous side effects have been reported, including skin atrophy, burning, and infection. In the case of antibody drugs, immunogenicity against the drugs can be a problem. To overcome these side effects, small peptides are considered therapeutic agents. We previously identified the small wound healing peptide AES16-2M with a sequence of REGRT, and examined its effects on AD in this study. Interestingly, the administration of AES16-2M downregulated the AD disease score, ear thickness, serum IgE, and thymic stromal lymphopoietin (TSLP) in AD mice. The thickness of the epidermal layer was also improved by AES16-2M treatment. In addition, quantities of IL-4-, IL-13-, and IL-17-producing CD4 T cells from peripheral lymph nodes and spleens were reduced by injection of AES16-2M. Furthermore, the expression of TSLP was significantly reduced in AES16-2M-treated human keratinocytes. Therefore, these results suggest that AES16-2M can be a novel candidate for AD treatment.

Interobserver Variability and Diagnostic Performance of Gadoxetic Acid-enhanced MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma.

Background Accurate identification of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) before treatment is critical for selecting a proper treatment strategy. Purpose To evaluate the interobserver agreement and the diagnostic performance of the MRI assessment of MVI in HCC according to the level of radiologist experience. Materials and Methods This retrospective study included 100 patients with surgically confirmed HCCs smaller than 5 cm who underwent gadoxetic acid-enhanced MRI between 2013 and 2016. Eight postfellowship radiologists (four with 7-13 years of experience [more experienced] and four with 3-6 years of experience [less experienced]) evaluated four imaging features (nonsmooth tumor margin, irregular rim-like enhancement in the arterial phase, peritumoral arterial phase hyperenhancement, peritumoral hepatobiliary phase hypointensity) and assigned the possibility of MVI. Interobserver agreement was determined by using Fleiss κ statistics according to reviewer experience and tumor size (≤3 cm vs >3 cm). With reference standards of histopathologic specimens, the diagnostic performance in the identification of MVI was assessed by using receiver operating characteristic curve analysis. Results In 100 patients (mean age, 58 years ± 10 [standard deviation]; 70 men) with 100 HCCs (mean size, 2.8 cm ± 0.9), 39 (39%) HCCs had MVI. The overall interobserver agreement was fair to moderate for the imaging features and their combinations (κ = 0.38-0.47) and MVI probability (κ = 0.41; 95% confidence interval: 0.33, 0.45). More experienced reviewers demonstrated higher agreement in MVI probability than less experienced reviewers (κ = 0.55 vs 0.36, respectively; P = .002). Diagnostic performance of each reviewer was modest for MVI prediction (area under the receiver operating characteristic curve [AUC] range, 0.60-0.74). The AUCs for the diagnosis of MVI were lower for HCCs larger than 3 cm (range, 0.55-0.69) than for those less than or equal to 3 cm (range, 0.59-0.75). Conclusion Considerable interobserver variability exists in the assessment of microvascular invasion in hepatocellular carcinoma using MRI, even for more experienced radiologists. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Tang in this issue.

Technical success rates and reliability of spin-echo echo-planar imaging (SE-EPI) MR elastography in patients with chronic liver disease or liver cirrhosis.

OBJECTIVES: To determine the technical success rates of MR elastography (MRE) according to established gradient-recalled echo (GRE) and spin-echo echo-planar imaging (SE-EPI) sequences and to compare liver stiffness (LS) values between the sequences during expiratory and inspiratory phases in patients with chronic liver disease or liver cirrhosis. METHODS: One hundred and eight patients who underwent MRE were included in this retrospective study. MRE was performed at 3 T based on both sequences during expiration as well as inspiration. Technical failure of MRE was determined if there was no pixel value with a confidence index higher than 95% and/or no apparent shear waves imaged. LS measurements were performed using free-drawing region of interest. To evaluate clinical factors related to the technical success rate of MRE, we assessed etiology of liver disease, ascites, body habitus, iron deposition, and liver morphology of patients. Statistical analysis was performed with the Wilcoxon test, Bland-Altman plot, independent t test, Mann-Whitney test, and McNemar test. RESULTS: The technical success rate of MRE in SE-EPI was significantly higher than that of GRE (98.1% vs. 80.7%, p < 0.0001). On the basis of univariate analysis, height, weight, and BMI were significantly associated with failure of MRE (p < 0.05). There was no significant difference in LS values between GRE and SE-EPI (2.82 kPa vs. 2.92 kPa (p > 0.05)). However, the LS values were significantly higher during inspiration than expiration with both GRE and SE-EPI (p < 0.0001). CONCLUSION: MRE in SE-EPI during expiratory breath-hold can be used as a reliable examination to evaluate liver fibrosis. KEY POINTS: • The technical success rate of MR elastography in spin-echo echo-planar imaging (SE-EPI) was significantly higher than that in gradient-recalled echo (GRE) during both the inspiratory and expiratory phases. • Liver stiffness values were significantly higher during inspiration than during expiration in both GRE and SE-EPI. • MR elastography in SE-EPI during expiratory breath-hold can be used as a reliable examination in patients with liver fibrosis.

Prevalence and Antimicrobial Characteristics of Shiga Toxin-Producing Escherichia coli Isolates from Pork in Korea.

Shiga toxin-producing Escherichia coli (STEC) strains are important food-borne pathogens that can be transmitted through the consumption of food products derived from pigs. Moreover, antimicrobial resistance in STEC has been a matter of increasing concern. The aim of this study was to investigate the prevalence and antimicrobial characteristics of STEC isolates from pork in Korea. We isolated 131 isolates of E. coli from 334 pork samples collected from slaughterhouses and retail markets from 2008 to 2009. Among the 131 isolates, 6 (4.58%) were confirmed to belong to 6 different serotypes of STEC. All six STEC isolates contained stx1 and eaeA virulence genes, and four of them additionally carried the hly gene. The minimum inhibitory concentration (MIC) of 15 antibiotics (amoxicillin/clavulanic acid, ampicillin, cephalothin, cefoxitin, ceftiofur, gentamicin, neomycin, streptomycin, nalidixic acid, ciprofloxacin, colistin, chloramphenicol, florfenicol, tetracycline and sulfamethoxazole/trimethoprim) toward the STEC isolates was determined. As a result, three strains were associated with high MICs for florfenicol and chloramphenicol (64 µg/mL). Furthermore, all three strains were found to contain the florfenicol-resistant gene (floR) but not the chloramphenicol-resistant gene (cat). Sequence alignment and BLAST analysis of the polymerase chain reaction products of the floR gene indicated that they contained sequences with homology to the floR gene of E. coli or Salmonella enterica serovar, Heidelberg. This is the first report on the detection of floR in STEC isolated from pork obtained from retail markets in Korea.

The Role of Erythroid Differentiation Regulator 1 (ERDR1) in the Control of Proliferation and Photodynamic Therapy (PDT) Response.

Erythroid differentiation regulator 1 (ERDR1) was newly identified as a secreted protein that plays an essential role in maintaining cell growth homeostasis. ERDR1 enhances apoptosis at high cell densities, leading to the inhibition of cell survival. Exogenous ERDR1 treatment decreases cancer cell proliferation and tumor growth as a result of increased apoptosis via the regulation of apoptosis-related gene expression. Moreover, ERDR1 plays a pivotal role in skin diseases; ERDR1 expression in actinic keratosis (AK) is negatively correlated with the increase in apoptosis. Because of its high specificity and efficiency, photodynamic therapy (PDT) is a common therapy for patients with various skin diseases, including cancer. Many studies indicate that apoptosis is mainly induced by PDT treatment. As an apoptosis inducer, the recovery of the ERDR1 expression after PDT is correlated with good therapeutic outcomes. Here, we review recent findings that highlight the function of ERDR1 in the control of apoptosis. Thus, ERDR1 may have a role in the apoptosis regulation of target cells in the lesions, as the recovery of its expression after PDT is correlated with good therapeutic outcomes.

Melanogenic Properties and Expression Profiles of Melanogenic Paracrine Molecules in Riehl's Melanosis.

Riehl's melanosis is a hyperpigmentary disorder that occurs predominantly on the face and neck. To date, the pathogenesis of Riehl's melanosis with regards to the melanogenic properties and paracrine melanogenic molecules has not well been studied. This study was aimed to provide a novel perspective on the pathogenesis of Riehl's melanosis by identifying the relevant paracrine melanogenic molecules in Riehl's melanosis. Skin biopsies were performed on lesional and normal-appearing perilesional skin of 12 patients with Riehl's melanosis and 12 age- and sex-matched healthy controls. Histopathological and immunohistochemical staining for paracrine melanogenic molecules was analyzed. The major histopathological findings of Riehl's melanosis were basal hyperpigmentation, melanocyte proliferation, interface change, dermal pigmentary incontinence, vascular proliferation, and dermal inflammation. Dermal expression intensities of stem cell factor (SCF) and c-kit were increased in the lesional skin of Riehl's melanosis. In addition, increased expression of epidermal and dermal ET-1 was also observed in the lesional skin of Riehl's melanosis. Increased tissue expressions of SCF, c-kit, and ET-1 in Riehl's melanosis support the role of these paracrine melanogenic molecules in the pathogenesis of Riehl's melanosis. The findings from this study might present useful information on the pathogenetic mechanism of Riehl's melanosis.

Erythroid Differentiation Regulator 1 Ameliorates Collagen-Induced Arthritis via Activation of Regulatory T Cells.

Erythroid differentiation regulator 1 (Erdr1) has been identified as an anti-inflammatory factor in several disease models, including collagen-induced arthritis (CIA), but its exact mechanisms are still not fully understood. Here, the involvement of regulatory T (Treg) cells in Erdr1-improved CIA was investigated. In the CIA model, Erdr1 was confirmed to reduce collagen-specific IgM in plasma and plasma cells in draining lymph nodes. Importantly, the downregulated Treg cell ratio in draining lymph nodes from CIA mice was recovered by Erdr1 treatment. In addition, administration of Erdr1 improved the CIA score and joint tissue damage, while it revealed no effect in Treg cell-depleted CIA mice, indicating that Treg cells mediate the therapeutic effects of Erdr1 in the CIA model. Results from in vitro experiments also demonstrated that Erdr1 significantly induced Treg cell differentiation and the expression of Treg activation markers, including CD25, CD69, and CTLA4 in CD4+Foxp3+ cells. Furthermore, Erdr1-activated Treg cells dramatically suppressed the proliferation of responder T cells, suggesting that they are functionally active. Taken together, these results show that Erdr1 induces activation of Treg cells and ameliorates rheumatoid arthritis via Treg cells.

The Novel Synthetic Peptide AESIS-1 Exerts a Preventive Effect on Collagen-Induced Arthritis Mouse Model via STAT3 Suppression.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is associated with systemic inflammation and results in the destruction of joints and cartilage. The pathogenesis of RA involves a complex inflammatory process resulting from the action of various proinflammatory cytokines and, therefore, many novel therapeutic agents to block cytokines or cytokine-mediated signaling have been developed. Here, we tested the preventive effects of a small peptide, AESIS-1, in a mouse model of collagen-induced arthritis (CIA) with the aim of identifying a novel safe and effective biological for treating RA. This novel peptide significantly suppressed the induction and development of CIA, resulting in the suppression of synovial inflammation and cartilage degradation in vivo. Moreover, AESIS-1 regulated JAK/STAT3-mediated gene expression in vitro. In particular, the gene with the most significant change in expression was suppressor of cytokine signaling 3 (Socs3), which was enhanced 8-fold. Expression of the STAT3-specific inhibitor, Socs3, was obviously enhanced dose-dependently by AESIS-1 at both the mRNA and protein levels, resulting in a significant reduction of STAT3 phosphorylation in splenocytes from severe CIA mice. This indicated that AESIS-1 regulated STAT3 activity by upregulation of SOCS3 expression. Furthermore, IL-17 expression and the frequency of Th17 cells were considerably decreased by AESIS-1 in vivo and in vitro. Collectively, our data suggest that the novel synthetic peptide AESIS-1 could be an effective therapeutic for treating RA via the downregulation of STAT3 signaling.

Erythroid differentiation regulator 1 strengthens TCR signaling in thymocytes by modulating calcium flux.

Erythroid differentiation regulator 1 (Erdr1) has been identified as a stromal survival factor released under stressful conditions. Previously, Erdr1 was reported to be expressed highly in thymus, but roles of Erdr1 in thymus were not known. Here, the effects of Erdr1 on T cell development were investigated. The expression of Erdr1 was higher in thymus than bone marrow and Erdr1 was detected in both the cortex and medulla of thymus. Erdr1 treatment significantly induced the expression of activation marker, CD69, from thymocytes in the presence of TCR stimuli in vitro and the induction was dependent on increased Ca2+ influx. In addition, in vivo administration of Erdr1 resulted in significant increase of total and positive selected thymocyte numbers, particularly in the number of CD3TCRhiCD69+ DP thymocytes. Taken together, our results show that Erdr1 enhances the strength of TCR signaling and cellularity of thymocytes by amplifying Ca2+ influx in thymocytes receiving TCR signals.

Preoperative CT findings for prediction of resectability in patients with gallbladder cancer.

OBJECTIVES: To predict residual tumor (R) classification in patients with a surgery for gallbladder (GB) cancer, using preoperative CT. METHODS: One hundred seventy-three patients with GB cancer who underwent CT and subsequent surgery were included. Two radiologists assessed CT findings, including tumor morphology, location, T stage, adjacent organ invasion, hepatic artery (HA) invasion, portal vein invasion, lymph node metastasis, metastasis, resectability, gallstone, and combined cholecystitis. The R classification was categorized as no residual tumor (R0) and residual tumor (R1 or R2). We analyzed the correlation between CT findings and R classification. We also followed up the patients as long as five years and analyzed the relationship between the R classification and the overall survival (OS). RESULTS: There were 134 patients with R0 and 39 patients with R1/R2. On multivariable analysis, liver invasion (Exp(B) = 3.19, p = 0.010), bile duct invasion (Exp(B) = 3.69, p = 0.031), and HA invasion (Exp(B) = 3.74, p = 0.039) were independent, significant predictors for residual tumor. When two of these three criteria were combined, the accuracy for predicting a positive resection margin was 83.38% with a specificity of 93.28%. The OS and the median patient survival time differed significantly according to the resection margin, i.e., 56.0% and 134.4 months in the R0 resection and 5.1% and 10.8 months in the R1/R2 resection group (p < 0.001). CONCLUSIONS: Preoperative CT findings could aid in planning surgery and determining the resectability using the high-risk findings of residual tumor, including liver invasion, bile duct invasion, and HA invasion. KEY POINTS: • Liver invasion, bile duct invasion, and HA invasion were significant preoperative CT predictors for residual tumor in GB cancer. • HA invasion showed the highest OR on multivariate analysis and the highest predictor point on a nomogram for predicting a positive resection margin. • Association of two factors can predict positive resection margin with an accuracy of 83.38% and a specificity of 93.28%.

Early Prediction of the Severity of Acute Pancreatitis Using Radiologic and Clinical Scoring Systems With Classification Tree Analysis.

OBJECTIVE: The objective of our study was to develop a decision tree model for the early prediction of the severity of acute pancreatitis (AP) using clinical and radiologic scoring systems. MATERIALS AND METHODS: For this retrospective study, 192 patients with AP who underwent CT 72 hours or less after symptom onset were divided into two cohorts: a training cohort (n = 115) and a validation cohort (n = 77). Univariate analysis was performed to identify significant parameters for the prediction of severe AP in the training cohort. For early prediction of disease severity, a classification tree analysis (CTA) model was constructed using significant scoring systems shown by univariate analysis. To assess the diagnostic performance of the model, we compared the area under the ROC curve (AUC) with each selected single parameter. We also evaluated the diagnostic performance in the validation cohort. RESULTS: The Acute Physiology and Chronic Health Evaluation (APACHE)-II score, bedside index for severity in acute pancreatitis (BISAP) score, extrapancreatic inflammation on CT (EPIC) score, and Balthazar grade were included in the CTA model. In the training cohort, our CTA model showed a trend of a higher AUC (0.853) than the AUC of each single parameter (APACHE-II score, 0.835; BISAP score, 0.842; EPIC score, 0.739; Balthazar grade, 0.700) (all, p > 0.0125) while achieving specificity (100%) higher than and accuracy (94.8%) comparable to each single parameter (both, p < 0.0125). In the validation cohort, the CTA model achieved diagnostic performance similar to the training cohort with an AUC of 0.833. CONCLUSION: Our CTA model consisted of clinical (i.e., APACHE-II and BISAP scores) and radiologic (i.e., Balthazar grade and EPIC score) scoring systems and may be useful for the early prediction of the severity of AP and identification of high-risk patients who require close surveillance.

Prevalence and clinicopathologic characteristics of multiple myeloma with cutaneous involvement: A case series from Korea.

BACKGROUND: Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the presence of a clonal proliferation of tumor cells. Cutaneous involvement of MM is very rare and remains poorly understood. OBJECTIVE: The aim of this study was to examine the clinical and histopathologic characteristics of cutaneous involvement in MM and identify factors associated with overall survival of MM with cutaneous involvement. METHODS: The medical records of 1228 patients with MM were retrieved and analyzed. Of those patients, 14 with cutaneous involvement of MM (1.14%) were further evaluated for their clinical and histopathologic findings. RESULTS: Patients with cutaneous involvement showed significantly reduced overall survival compared with those without cutaneous involvement (median, 28 vs. 57 months; hazard ratio, 1.929; 95% confidence interval, 1.030-3.613). In subgroup analyses of patients with MM with cutaneous involvement, erythematous nodules (P = .004), multiple cutaneous lesions (P = .002), and absence of a grenz zone (P = .004) were clinicopathologic features associated with reduced overall survival after Bonferroni correction. LIMITATIONS: The retrospective design and the small sample size are the limitations. CONCLUSION: Cutaneous involvement accounted for about 1.14% of patients with MM and was associated with reduced overall survival.