The Dysregulated IL-23/TH17 Axis in Endometriosis Pathophysiology.

Endometriosis is a chronic inflammatory disease in which endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. IL-23 is a key contributor in the development and differentiation of TH17 cells, driving TH17 cells toward a pathogenic profile. In a variety of inflammatory and autoimmune disorders, TH17 cells secrete proinflammatory cytokines, including IL-17, contributing to disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. In this article, we address whether IL-23-driven TH17 cells contribute to cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. The results indicated dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared with controls. In vitro studies using primary human TH cells determined that rIL-23 mixture treatment increased pathogenic TH17 cell frequency. Similarly, rIL-23 treatment of cell lines (12Z cells, EECCs, HUVECs, and hESCs) representative of the endometriotic lesion microenvironment increased cytokines and growth factors, which play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, rIL-23 treatment altered numbers of myeloid and T cell subsets in peritoneal fluid and increased giant cells within the lesion. Lesions from rIL-23-treated mice did not reveal significant alterations in proliferation/vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on endometriosis pathophysiology.

Fetal-placental antigens and the maternal immune system: Reproductive immunology comes of age.

Reproductive physiology and immunology as scientific disciplines each have rich, largely independent histories. The physicians and philosophers of ancient Greece made remarkable observations and inferences to explain regeneration as well as illness and immunity. The scientific enlightenment of the renaissance and the technological advances of the past century have led to the explosion of knowledge that we are experiencing today. Breakthroughs in transplantation, immunology, and reproduction eventually culminated with Medawar's discovery of acquired immunological tolerance, which helped to explain the transplantation success and failure. Medawar's musings also keenly pointed out that the fetus apparently breaks these newly discovered rules, and with this, the field of reproductive immunology was launched. As a result of having stemmed from transplantation immunology, scientist still analogizes the fetus to a successful allograft. Although we now know of the fundamental differences between the two, this analogy remains a useful tool to understand how the fetus thrives despite its immunological disparity with the mother. Here, we review the history of reproductive immunology, and how major and minor histocompatibility antigens, blood group antigens, and tissue-specific "self" antigens from the fetus and transplanted organs parallel and differ.

Prognosis prediction and immunotherapy optimisation for cryptogenic new-onset refractory status epilepticus.

BACKGROUND: Cryptogenic new-onset refractory status epilepticus (cNORSE) currently lacks comprehensive knowledge regarding its clinical dynamics, prognostic factors and treatment guidance. Here we present the longitudinal clinical profiles, predictive factors for outcomes and the optimal duration of immunotherapy in patients with cNORSE. METHODS: This retrospective secondary endpoint analysis investigated patients with cNORSE identified from a prospective autoimmune encephalitis cohort at a national referral centre in Korea. The main outcomes included longitudinal functional scales, seizure frequency and the number of antiseizure medications. Measures encompassed NORSE-related clinical parameters such as the duration of unconsciousness, immunotherapy profiles, cytokine/chemokine analysis, and serial MRI scans. RESULTS: A total of 74 patients with cNORSE were finally analysed (mean age: 38.0±18.2; 36 (48.6%) male). All patients received first-line immunotherapy, and 91.9% (68/74) received second-line immunotherapy. A total of 83.8% (62/74) regained consciousness within a median duration of 30 days (14-56), and 50% (31/62) achieved good outcome (mRS ≤2) at 2 years. Poor 1-year outcomes (mRS ≥3) were predicted by the presence of mesial temporal lobe (mTL) and extra-mTL lesions at 3-month MRI, and prolonged unconsciousness (≥60 days). Those with mTL atrophy exhibited a higher seizure burden post-NORSE. The optimal duration of immunotherapy appeared to be between 18 weeks and 1-year post-NORSE onset. CONCLUSIONS: This study elucidates longitudinal clinical dynamics, functional outcomes, prognostic factors and immunotherapy response in patients with cNORSE. These findings might contribute to a more standardised understanding and clinical decision-making for cNORSE.

Preoperative assessment of microvascular invasion risk using gadoxetate-enhanced MRI for predicting outcomes after liver transplantation for single hepatocellular carcinoma within the Milan criteria.

OBJECTIVE: To compare therapeutic outcomes after liver transplantation (LT) between hepatocellular carcinomas (HCC) with low and high risk for microvascular invasion (MVI) within the Milan criteria evaluated preoperatively. METHODS: Eighty patients with a single HCC who underwent LT as the initial therapy between 2008 and 2017 were included from two tertiary referral medical centers in a HBV-predominant population. A preoperative MVI-risk model was used to identify low- and high-risk patients. Recurrence-free survival (RFS) after LT between the two risk groups was compared using Kaplan-Meier curves with the log-rank test. Prognostic factors for RFS were identified using a multivariable Cox hazard regression analysis. RESULTS: Eighty patients were included (mean age, 51.8 years +/- 7.5 [standard deviation], 65 men). Patients were divided into low-risk (n = 64) and high-risk (n = 16) groups for MVI. The RFS rates after LT were significantly lower in the MVI high-risk group compared to the low-risk group at 1 year (75.0% [95% CI: 56.5-99.5%] vs. 96.9% [92.7-100%], p = 0.048), 3 years (62.5% [42.8-91.4%] vs. 95.3% [90.3-100%], p = 0.008), and 5 years (62.5% [42.8-91.4%] vs. and 95.3% [90.3-100%], p = 0.008). In addition, multivariable analysis showed that MVI high risk was the only significant factor for poor RFS (p = 0.016). CONCLUSION: HCC patients with a high risk of MVI showed significantly lower RFS after LT than those without. This model could aid in selecting optimal candidates in addition to the Milan criteria when considering upfront LT for patients with HCC if alternative treatment options are available. CLINICAL RELEVANCE STATEMENT: High risk for microvascular invasion (MVI) in hepatocellular carcinoma patients lowered recurrence-free survival after liver transplantation, despite meeting the Milan criteria. Identifying MVI risk could aid candidate selection for upfront liver transplantation, particularly if alternative treatments are available. KEY POINTS: • A predictive model-derived microvascular invasion (MVI) high- and low-risk groups had a significant difference in the incidence of MVI on pathology. • Recurrence-free survival after liver transplantation (LT) for single hepatocellular carcinoma (HCC) within the Milan criteria was significantly different between the MVI high- and low-risk groups. • The peak incidence of tumor recurrence was 20 months after liver transplantation, probably indicating that HCC with high risk for MVI had a high risk of early (≤ 2 years) tumor recurrence.

Laparoscopic radiofrequency ablation of subcapsular hepatocellular carcinomas: risk factors related to a technical failure.

BACKGROUND: This study aimed to evaluate the risk factors related to a technical failure after laparoscopic radiofrequency ablation (RFA) for subcapsular hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: A total of 110 patients with 114 HCCs who underwent laparoscopic RFA for HCCs (new HCC [n = 85] and local tumor progression [LTP] [n = 29]) between January 2013 and December 2018 were included. We evaluated the incidence of technical failure on immediate post-RFA CT images. Risk factors for a technical failure after laparoscopic RFA were assessed using univariable logistic regression analyses. The cumulative LTP rate was estimated using the Kaplan-Meier method. RESULTS: Technical failure was noted in 3.5% (4/114) of the tumors. All four tumors that showed a technical failure were cases of LTP from previous treatment and were invisible on laparoscopy. On univariate analysis, LTP lesion, invisibility of the index tumor on laparoscopy, and peri-hepatic vein location of the tumor were identified as risk factors for a technical failure. The cumulative LTP rates at 1, 3, and 5 years were estimated to be 2.8%, 4.8%, and 4.8%, respectively. CONCLUSIONS: LTP lesion, invisibility of the index tumor on laparoscopy, and peri-hepatic vein location of the tumor were identified as the risk factors for a technical failure after laparoscopic RFA.

Endometrial Epithelial ARID1A Is Required for Uterine Immune Homeostasis during Early Pregnancy.

A growing body of work suggests epigenetic dysregulation contributes to endometriosis pathophysiology and female infertility. The chromatin remodeling complex subunit AT-rich interaction domain 1A (ARID1A) must be properly expressed to maintain normal uterine function. Endometrial epithelial ARID1A is indispensable for pregnancy establishment in mice through regulation of endometrial gland function; however, ARID1A expression is decreased in infertile women with endometriosis. We hypothesized that ARID1A performs critical operations in the endometrial epithelium necessary for fertility besides maintaining gland function. To identify alterations in uterine gene expression resulting from loss of epithelial ARID1A, we performed RNA-sequencing analysis on pre-implantation uteri from LtfiCre/+Arid1af/f and control mice. Differential expression analysis identified 4181 differentially expressed genes enriched for immune-related ingenuity canonical pathways including agranulocyte adhesion and diapedesis and natural killer cell signaling. RT-qPCR confirmed an increase in pro-inflammatory cytokine and macrophage-related gene expression but a decrease in natural killer cell signaling. Immunostaining confirmed a uterus-specific increase in macrophage infiltration. Flow cytometry delineated an increase in inflammatory macrophages and a decrease in uterine dendritic cells in LtfiCre/+Arid1af/f uteri. These findings demonstrate a role for endometrial epithelial ARID1A in suppressing inflammation and maintaining uterine immune homeostasis, which are required for successful pregnancy and gynecological health.

Rim-arterial enhancing primary hepatic tumors with other targetoid appearance show early recurrence after radiofrequency ablation.

OBJECTIVES: To evaluate early (≤ 2 years) local tumor progression (LTP), intrahepatic distant metastasis (IDR), and extrahepatic metastasis (EM) of primary hepatic malignant tumors with arterial rim enhancement (RE) after RFA in comparison with non-RE tumors. METHODS: Three hundred forty-nine patients who underwent RFA for primary hepatic malignant tumors between January 2009 and December 2016 were included. The patients' tumors were classified into non-RE, RE only (RO), and RE plus other targetoid appearances (REoT). Cumulative LTP, IDR, and EM rates at 1 and 2 years after RFA were calculated using the Kaplan-Meier method and compared using the log-rank test. Prognostic factors for the outcomes were assessed using a Cox proportional hazards model. RESULTS: There were 303 non-RE, 19 RO, and 27 REoT tumors. The REoT tumors had a significantly higher rate of IDR and EM than non-RE (p = 0.04 for IDR; and p < 0.01 for EM, respectively) at 1 year after RFA. At 2 years, LTP and EM rates were significantly higher for REoT than for non-RE (p = 0.001 for LTP; and p = 0.444 for EM, respectively). The RO tumors did not have different outcomes than non-RE at 1 and 2 years after RFA. Multivariable analysis verified that REoT was a significant factor for IDR (p = 0.04) and EM (p = 0.01) at 1 year and LTP (p = 0.02) at 2 years. CONCLUSIONS: Tumors with REoT had poor LTP, IDR, and EM within 2 years after RFA than non-RE tumors. However, tumors with RO showed similar results as non-RE tumors. KEY POINTS: • Tumors with Rim enhancement plus other targetoid appearances (REoT) had a significantly higher rate of recurrence than non-rim enhancing (RE) tumors at 1 and 2 years after RFA. • Tumors with rim enhancement only did not have different outcomes than non-RE at 1 and 2 years after RFA.

Comparison of ablation performance between dual internally cooled wet tip and conventional dual internally cooled tip radiofrequency electrodes: an experimental study in ex vivo bovine liver.

OBJECTIVE: To evaluate the performance of dual internally cooled wet tip (ICWT) radiofrequency electrodes in comparison to dual internally cooled tip (ICT) electrodes. METHODS: Twenty ablation zones were created for each type of electrodes. Planned procedure time was 6 min. Diameters of the ablation zone along the x-, y-, and z-axes (Dx, Dy, and Dz), ablation zone sphericity, quantitative sphericity measurement, and ablation volume were measured and compared between the two electrode types. Circularity of the ablation zone on the surface with x- and z- axes (zx plane) and amount of energy applied were also compared. RESULTS: Dx and Dz were significantly longer with ICWT than those with ICT (Dx: 3.0 vs. 2.8 cm, p = .018; and Dz: 2.7 vs. 2.3 cm, p < .001, respectively). Dy was not significantly different (3.0 vs. 2.9 cm, p = .220). Moreover, 85% (17/20) and 30% (6/20) of ablation zones from ICWT and ICT were spherical (p = .001), respectively. Quantitative measurement showed that ICWT was more spherical compared to ICT (0.962 vs. 0.881, p = .001). The ablation volume was also significantly higher with ICWT (11.55 vs. 9.45 cm3, p = .003). The ablation zone on the zx plane was more circular with ICWT (0.907 vs. 0.883, p = .028). The amount of energy applied was significantly bigger with ICWT (18508 vs. 16998 WS, p = .003). CONCLUSION: Dual ICWT electrodes were better able to create more spherical and larger ablation zones than dual ICT electrodes.

Extracellular contrast-enhanced MRI with diffusion-weighted imaging for HCC diagnosis: prospective comparison with gadoxetic acid using LI-RADS.

OBJECTIVES: The aim of this study was to evaluate the diagnostic performance of introducing diffusion-weighted imaging (DWI) as a major feature to extracellular agent (ECA)-MRI for diagnosing HCC in comparison with gadoxetic acid (hepatobiliary agent, HBA)-MRI using Liver Imaging Reporting and Data System (LI-RADS) v2018. METHODS: This was a prospective intra-individual comparison study using two different types of contrast agents for liver MRI conducted at a tertiary referral academic center. One hundred forty-seven observations in 122 patients at high risk for HCC scheduled for liver surgery were included. The sensitivity, specificity, and accuracy of LI-RADS category 5 (LR-5) for HCC diagnosis according to conventional and modified LI-RADS on ECA- and HBA-MRI were measured and compared. Modified LI-RADS incorporated hyperintensity on DWI as a major feature with ECA-MRI, and hypointensity on transitional phase (TP) and/or hepatobiliary phase (HBP) as washout appearance on HBA-MRI, respectively. RESULTS: Modified LI-RADS on ECA-MRI had higher sensitivity and accuracy than modified LI-RADS on HBA-MRI (90.3% vs. 74.9%, p < 0.001; and 91.9% vs. 76.9%, p < 0.001, respectively), as well as higher specificity, although the difference did not reach statistical significance (96.0% vs. 88.0%, p = 0.157). The specificity of modified LI-RADS ECA-MRI was slightly lower than both conventional criteria but without a significant difference (96.0% vs. 100%, p = 0.317). CONCLUSIONS: Using DWI findings as a major feature for modified LR-5 on ECA-MRI showed better sensitivity and accuracy than modified LR-5 on HBA-MRI, without significantly compromising specificity compared with conventional LR-5 on ECA- or HBA-MRI. KEY POINTS: • Prospective intra-individual comparison study using two different types of contrast agents, extracellular agent (ECA) and gadoxetic acid (hepatobiliary agent, HBA), for liver MRI was conducted. • Applying diffusion restriction of a hepatic observation on ECA-MRI as a major feature of LI-RADS v2018 resulted in higher sensitivity and accuracy of LR-5 observations for HCC diagnosis than conventional LI-RADS v2018, and even compared to modified LI-RADS using modified washout on HBA-MRI. • Despite increase in sensitivity and accuracy of LR-5 observations on modified LI-RADS on ECA-MRI, the specificity was not significantly different compared with conventional LI-RADS.

Apparent diffusion coefficient as a potential marker for tumour differentiation, staging and long-term clinical outcomes in gallbladder cancer.

OBJECTIVES: To evaluate the correlation between tumour differentiation or stage of gallbladder cancer (GBC) and the apparent diffusion coefficient (ADC), as well as to assess whether ADC value can predict long-term disease-free survival (DFS) after surgery. METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. Between March 2008 and June 2016, 79 patients who underwent magnetic resonance (MR) imaging with diffusion-weighted image and subsequent surgery for GBC were included in this study. Correlations between quantitative ADC values and tumour differentiation or stage based on the American Joint Committee on Cancer (AJCC) were assessed using Spearman's correlation analysis. Prognostic factors for DFS were identified with multivariate Cox regression analysis using imaging and clinical characteristics. RESULTS: All patients were classified as having well- (n = 18), moderately (n = 35) or poorly differentiated GBCs (n = 26). The ADC value of GBCs was significantly correlated with tumour differentiation and AJCC stage (p < 0.001 and p < 0.001, respectively). Sixty-nine patients were followed up for 2.0-92.4 months (median, 23.5 months). On multivariate analysis, the significant prognostic factor for DFS was not tumour differentiation or AJCC stage but a binary tumour ADC value (hazard ratio, 4.29; p = 0.009). DFS rates were significantly different according to the classification of tumour ADC value (cut-off value = 1.04 × 10-3 mm2/s; p = 0.004). CONCLUSION: The ADC value of GBCs was significantly correlated with tumour differentiation as well as AJCC stage. In addition, it predicted long-term outcomes after surgery in patients with GBC. KEY POINTS: • ADC values of GBC and tumour differentiation were negatively correlated. • Lower ADC values of GBC were significantly correlated with higher tumour stage. • Tumour ADC value could be useful for risk stratification of GBC patients.

IL-17A Contributes to the Pathogenesis of Endometriosis by Triggering Proinflammatory Cytokines and Angiogenic Growth Factors.

Endometriosis is a chronic, inflammatory disease characterized by the growth of endometrial tissue in aberrant locations outside the uterus. Neoangiogenesis or establishment of new blood supply is one of the fundamental requirements of endometriotic lesion survival in the peritoneal cavity. IL-17A is emerging as a potent angiogenic and proinflammatory cytokine involved in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. However, sparse information is available in the context of endometriosis. In this study, we demonstrate the potential importance of IL-17A in the pathogenesis and pathophysiology of endometriosis. The data show a differential expression of IL-17A in human ectopic endometriotic lesions and matched eutopic endometrium from women with endometriosis. Importantly, surgical removal of lesions resulted in significantly reduced plasma IL-17A concentrations. Immunohistochemistry revealed localization of IL-17A primarily in the stroma of matched ectopic and eutopic tissue samples. In vitro stimulation of endometrial epithelial carcinoma cells, Ishikawa cells, and HUVECs with IL-17A revealed significant increase in angiogenic (vascular endothelial growth factor and IL-8), proinflammatory (IL-6 and IL-1ß), and chemotactic cytokines (G-CSF, CXCL12, CXCL1, and CX3CL1). Furthermore, IL-17A promoted tubulogenesis of HUVECs plated on Matrigel in a dose-dependent manner. Thus, we provide the first evidence, to our knowledge, that endometriotic lesions produce IL-17A and that the removal of the lesion via laparoscopic surgery leads to the significant reduction in the systemic levels of IL-17A. Taken together, our data show a likely important role of IL-17A in promoting angiogenesis and proinflammatory environment in the peritoneal cavity for the establishment and maintenance of endometriosis lesions.

Chronic effects of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on female mouse reproductive outcomes.

BACKGROUND: Angiogenesis is an essential process in endometriosis disease progression. Earlier, we demonstrated that anti-angiogenic peptide, ABT-898 prevents neoangiogenesis of human endometriotic lesions in a xenograft mouse model. Since angiogenesis is essential for normal ovarian and uterine function, we evaluated effects of ABT-898 on normal female reproductive processes in mice. METHODS: Cycling female C57BL/6N mice were dosed with ABT-898 (100 mg/kg) or 5 % dextrose control for 21 consecutive days to cover multiple estrous cycles (average estrous cycle 4 to 5 days in mice). Pregnant female mice were dosed with ABT-898 (100 mg/kg) or control on alternate days over the course of gestation, beginning at gestation day 7.5 to 17.5 (gestation length 21 days). Histological analysis along with CD31 and Vimentin immunohistochemistry were performed on ovaries and uteri obtained from treated and control mice. To understand the influence of ABT-898 on systemic angiogenic factors, a Pro Mouse Cytokine 9-plex assay was performed on plasma samples obtained from mice prior to treatment, during the second week of ABAT-898 or control treatment and on the last day of treatment. RESULTS: ABT-898 did not affect the number of estrous cycles over the 21 day treatment compared to control. Histological analysis of ovaries found no difference in the number of primordial, primary, secondary, and antral follicles between ABT-898 treated and control groups. Similarly, no difference was observed in the microvessel density between ABT-898 treated and control uteri, ovarian follicles or corpus luteum when assessed using CD31 or vimentin immunohistochemistry. Electron microscopy revealed similar capillary structure and appearance in both ABT-898 treated and control uteri. Although peripheral blood angiogenic cytokine profiles (IL-15, IL-18, M-CSF, b-FGF, PDGF-bb, MIG, MIP-2, LIF and VEGF) changed over the course of the intervention, there was no significant difference between ABT-898 and control groups at any of the studied time points. Treatment with ABT-898 during pregnancy had no effect on litter size at birth, pup weight at birth or pup weight at weaning. CONCLUSION: Our findings suggest that ABT-898 may not alter angiogenesis dependent reproductive processes in female mice. However, an extensive reproductive toxicology screening is required to substantiate use of ABT-898 in future.

Senescing human bone-marrow-derived clonal mesenchymal stem cells have altered lysophospholipid composition and functionality.

Mesenchymal stem cells (MSCs) have been used in a wide range of research and clinical studies because MSCs do not have any ethical issues and have the advantage of low carcinogenicity due to their limited proliferation. However, because only a small number of MSCs can be obtained from the bone marrow, ex vivo amplification is inevitably required. For that reason, this study was conducted to acquire the metabolic information to examine and control the changes in the activities and differentiation potency of MSCs during the ex vivo culture process. Endogenous metabolites of human bone-marrow-derived clonal MSCs (hcMSCs) during cellular senescence were profiled by ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/QTOFMS). To select significant metabolites, we used the linear mixed effects model having fixed effects for batch and time (passage) and random effects for metabolites, determining the mean using a t test and the standard deviation using an F test. We used structural analysis with representative standards and spectrum patterns with different collision energies to distinctly identify eight metabolites with altered expression during senescence as types of lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), such as LPC 16:0 and LPE 22:4. The present study revealed changes in endogenous metabolites and mechanisms due to senescence.

Eosinophilic meningoencephalitis successfully treated with glucocorticoids and intravenous immunoglobulin: a case report.

Eosinophilic meningoencephalitis is a rare inflammatory condition of the central nervous system. As a limited number of cases has been reported, debate remains on the optimal treatment. We present a case of idiopathic eosinophilic meningoencephalitis successfully treated with glucocorticoids and intravenous immunoglobulin (IVIG). After extensive evaluation to rule out other possible causes, the patient was treated with intravenous (IV) dexamethasone and showed significant improvement within a few days. However, neurologic impairment persisted, and follow-up lumbar puncture results showed only a mild decrease in pleocytosis. Even after an additional 5 days of IV methylprednisolone, cerebrospinal fluid (CSF) pleocytosis persisted, and brain magnetic resonance imaging (MRI) showed an increase in enhanced lesions, implying persistent neuroinflammation. The patient was maintained on high-dose oral prednisolone for 2 months, and additional immune-modulatory effects were treated with IVIG. Follow-up MRI at 2 months showed a significant decrease in the extent of multiple enhanced lesions and a normalized CSF profile. The patient was maintained on regular maintenance doses of IVIG for an additional 6 months without any neurologic signs or symptoms. Inflammation is the key pathophysiology underlying neurological damage in eosinophilic meningoencephalitis. A literature review revealed that corticosteroid treatment is the only anti-inflammatory treatment used in cases of idiopathic meningoencephalitis, resulting in sufficient response in most patients but only partial response or death in a few cases. This is the first case report of IVIG use in idiopathic eosinophilic meningoencephalitis, suggesting the possibility of a new treatment modality for refractory cases.

Malignancy Risk of Follicular Neoplasm (Bethesda IV) With Variable Cutoffs of Tumor Size: A Systemic Review and Meta-Analysis.

CONTEXT: The decision on diagnostic lobectomy for follicular neoplasms (FN) is challenging. OBJECTIVE: This meta-analysis investigates whether an appropriate size cutoff exists for recommending surgery for thyroid nodules diagnosed as FN by fine needle aspiration. METHODS: The Ovid-Medline, EMBASE, Cochrane, and KoreaMed databases were searched for studies reporting the malignancy rate of FN/suspicious for FN (FN/SFN) according to tumor size, using search terms "fine needle aspiration," "follicular neoplasm," "lobectomy," "surgery," and "thyroidectomy." RESULTS: Fourteen observational studies comprising 2016 FN/SFN nodules with postsurgical pathologic reports were included, and 2 studies included malignancy rates with various tumor sizes. The pooled malignancy risk of FN/SFN nodules according to size was: odds ratio (OR) 2.29 (95% CI, 1.68-3.11) with cutoff of 4 cm (9 studies), OR 2.39 (95% CI, 1.45-3.95) with cutoff of 3 cm (3 studies), and OR 1.81 (95% CI, 0.94-3.50) with cutoff of 2 cm (5 studies). However, tumors ≥2 cm also showed a higher risk (OR 2.43; 95% CI, 1.54-3.82) based on the leave-one-out meta-analysis after removal of 1 influence study. When each cutoff size was evaluated by summary receiver operating characteristic (sROC) curves, the cutoff of 4 cm showed the highest summary area under the curve (sAUC, 0.645) compared to other cutoffs (sAUC, 0.58 with 2 cm, and 0.62 with 3 cm), although there was no significant difference. CONCLUSION: Although the risk of malignancy increases with increasing tumor size, the risk remains significant at all tumor sizes and no cutoff limit can be recommended as a decision-making parameter for diagnostic surgery in Bethesda IV thyroid nodules.

Clonal hematopoiesis in LGI1-antibody encephalitis.

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1)-antibody encephalitis (LGI1e), the major form of autoimmune encephalitis (AE) presented with memory loss and faciobrachial dystonic seizure, commonly develops in aged population. Hematologic aging is often accompanied by clonal hematopoiesis (CH), a phenomenon in which specific mutations accumulate, potentially leading to autoimmune disorders or malignancies. Our research aimed to investigate the connection between clonal hematopoiesis of indeterminate potential (CHIP) and LGI1e. METHODS: Peripheral blood samples from consecutive LGI1e patients were collected and analyzed for 24 clonal CHIP using targeted gene sequencing. The results were compared to a control dataset from an ethnically matched health care cohort. Patient characteristics were analyzed based on their CHIP status. RESULTS: A total of 52 LGI1e patients were enrolled for this study. Among them, three patients (5.8%) exhibited functional mutations in the ASXL1 gene, one of the CHIP-associated genes analyzed by targeted sequencing. This frequency was significantly higher compared to that of the control cohort (1%, p = 0.015). Nevertheless, the patients showed no difference in the clinical characteristics, laboratory results, and immunotherapy outcomes. INTERPRETATION: LGI1e showed high frequency of ASXL1 functional mutation in the CHIP analysis, which may contribute to the underlying pathogenesis. Further research is needed to determine its direct role in the development of autoimmunity and disease progression.

Combined Transarterial Chemoembolization and Radiofrequency Ablation for Hepatocellular Carcinoma Infeasible for Ultrasound-Guided Percutaneous Radiofrequency Ablation: A Comparative Study with General Ultrasound-Guided Radiofrequency Ablation Outcomes.

OBJECTIVES: This study aimed to evaluate the therapeutic outcomes of transarterial chemoembolization combined with radiofrequency ablation (TACE + RFA) for hepatocellular carcinomas (HCC) measuring ≤3 cm infeasible for ultrasound (US)-guided percutaneous RFA. METHODS: Twenty-four patients who underwent fluoroscopy-guided TACE + RFA for single HCC between January 2012 and December 2016 were screened. To evaluate the TACE + RFA outcomes compared with those of US-guided RFA, 371 patients who underwent US-guided RFA during the same period were screened. We compared local tumor progression (LTP) and intrahepatic distant recurrence (IDR) between the two groups before and after propensity score (PS) matching, and performed univariable and multivariable Cox proportional hazard regression analyses for all patients. RESULTS: PS matching yielded 21 and 42 patients in the TACE + RFA and US-guided RFA groups, respectively. Cumulative LTP rates after PS matching were not significantly different between the two groups at 1 (0.0% vs. 7.4%, p = 0.072), 2 (10.5% vs. 7.4%, p = 0.701), and 5 years (16.9% vs. 10.5%, p = 0.531). IDR rates did not differ significantly between the two groups at 1 (20.6% vs. 10%, p = 0.307), 2 (25.9% vs. 25.9%, p = 0.999), or 5 years (49.9% vs. 53%, p = 0.838). Multivariable analysis showed that treatment type was not a significant factor for LTP or IDR. CONCLUSION: The outcomes of TACE + RFA for HCC were similar to those of general US-guided RFA. Fluoroscopy-guided TACE + RFA may be an effective treatment when US-guided RFA is not feasible.

Treatment Outcomes of Percutaneous Radiofrequency Ablation for Hepatocellular Carcinomas: Effects of the Electrode Type and Placement Method.

OBJECTIVE: To investigate the association among the electrode placement method, electrode type, and local tumor progression (LTP) following percutaneous radiofrequency ablation (RFA) for small hepatocellular carcinomas (HCCs) and to assess the risk factors for LTP. MATERIALS AND METHODS: In this retrospective study, we enrolled 211 patients, including 150 males and 61 females, who had undergone ultrasound-guided RFA for a single HCC < 3 cm. Patients were divided into four combination groups of the electrode type and placement method: 1) tumor-puncturing with an internally cooled tip (ICT), 2) tumor-puncturing with an internally cooled wet tip (ICWT), 3) no-touch with ICT, and 4) no-touch with ICWT. Univariable and multivariable Cox proportional-hazards regression analyses were performed to evaluate the risk factors for LTP. The major RFA-related complications were assessed. RESULTS: Overall, 83, 34, 80, and 14 patients were included in the ICT, ICWT, no-touch with ICT, and no-touch with ICWT groups, respectively. The cumulative LTP rates differed significantly among the four groups. Compared to tumor puncturing with ICT, tumor puncturing with ICWT was associated with a lower LTP risk (adjusted hazard ratio [aHR] = 0.11, 95% confidence interval [CI] = 0-0.88, P = 0.034). However, the cumulative LTP rate did not differ significantly between tumor-puncturing with ICT and no-touch RFA with ICT (aHR = 0.34, 95% CI = 0.03-1.62, P = 0.188) or ICWT (aHR = 0.28, 95% CI = 0-2.28, P = 0.294). An insufficient ablative margin was a risk factor for LTP (aHR = 6.13, 95% CI = 1.41-22.49, P = 0.019). The major complication rates were 1.2%, 0%, 2.5%, and 21.4% in the ICT, ICWT, no-touch with ICT, and no-touch with ICWT groups, respectively. CONCLUSION: ICWT was associated with a lower LTP rate compared to ICT when performing tumor-puncturing RFA. An insufficient ablation margin was a risk factor for LTP.

Risk Group Stratification for Recurrence-Free Survival and Early Tumor Recurrence after Radiofrequency Ablation for Hepatocellular Carcinoma.

PURPOSE: Although the prognosis after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) may vary according to different risk levels, there is no standardized follow-up protocol according to each patient's risk. This study aimed to stratify patients according to their risk of recurrence-free survival (RFS) and early (≤2 years) tumor recurrence (ETR) after RFA for HCC based on predictive models and nomograms and to compare the survival times of the risk groups derived from the models. METHODS: Patients who underwent RFA for a single HCC (≤3 cm) between January 2012 and March 2014 (n = 152) were retrospectively reviewed. Patients were classified into low-, intermediate-, and high-risk groups based on the total nomogram points for RFS and ETR, respectively, and compared for each outcome. Restricted mean survival times (RMSTs) in the three risk groups were evaluated for both RFS and ETR to quantitatively evaluate the difference in survival times. RESULTS: Predictive models for RFS and ETR were constructed with c-indices of 0.704 and 0.730, respectively. The high- and intermediate-risk groups for RFS had an 8.5-fold and 2.9-fold higher risk of events than the low-risk group (both p < 0.001), respectively. The high- and intermediate-risk groups for ETR had a 17.7-fold and 7.0-fold higher risk than the low-risk group (both p < 0.001), respectively. The RMST in the high-risk group was significantly lower than that in the other two groups 9 months after RFA, and that in the intermediate-risk group became lower than that in the low-risk group after 21 months with RFS and 24 months with ETR. CONCLUSION: Our predictive models were able to stratify patients into three groups according to their risk of RFS and ETR after RFA for HCC. Differences in RMSTs may be used to establish different follow-up protocols for the three risk groups.