[The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia].

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.

[Analysis on Cellular Immune Function Recovery after HLA Mismatched Allogeneic Hematopoietic Stem Cell Micro-Transp- lantation in Elderly AML Patients].

OBJECTIVE: To investigate the recovery of cellular immunity in elderly patients with acute myeloid leukemia (AML) after micro-transplantation (MST) and the changes of cellular immunity during relapse, as well as their clinical significance. METHODS: A total of 41 elderly AML patients who received MST treatment in a single center and 25 healthy elderly people were included. Immune function among different age groups in normal population was compared. Furthermore, immune fuction was compared between elderly AML patients of different age groups who achieved continuous complete remission (CR) after MST treatment and normal controls, between high risk group and medium-low risk group, as well as among before diagnosis, after CR, and relapse. Peripheral blood of patients and normal controls was collected, and the percentage of lymphocyte subsets was detected by multi-color flow cytometry. RESULTS: Thirty-five patients achieved CR after MST treatment while six patients did not. After MST treatment, CD3+ T cells, CD8+T cells and activated T cells in all age groups were higher than normal. Significant recovery of CD3+ and CD8+T cells was observed in both high risk and medium-low risk groups, and the overall recovery of immune cells in medium-low risk group was better. It was also observed that B lymphocytes and NK cells could not return to normal levels within 1 year after MST treatment. The proportion of CD3+ T cells, CD4+ T cells, and CD4/CD8 ratio were significantly decreased during relapse compared with continuous CR after MST (P<0.05). CONCLUSION: MST treatment can promote the recovery of CD3+T cells, CD8+T cells and other killer cells, so as to improve the cellular immune function of elderly patients, which provides a new immune cell therapy for elderly AML.

[Evaluation of Extrathyroidal Extension of Papillary Thyroid Microcarcinoma With Three-Dimensional Tomographic Ultrasound Imaging].

Objective To evaluate extrathyroidal extension (ETE) in papillary thyroid microcarcinoma (PTMC) with three-dimensional tomographic ultrasound imaging (3D-TUI). Methods A total of 97 thyroid nodules of 79 patients with PTMC treated in PUMC Hospital from February 2016 to January 2018 were included in this study.Two ultrasound experts performed independent blinded assessment of the relationship between thyroid nodules and thyroid capsule by two-dimensional ultrasound (2D-US) and 3D-TUI.The results of 2D-US and 3D-TUI in evaluating ETE were compared with intraoperative findings and postoperative histological and pathological results. Results Among the 97 nodules,54 (55.7%) nodules had ETE.The diagnostic sensitivity (68.5% vs.37.0%;χ2=10.737,P=0.002),accuracy (74.5% vs.56.7%;χ2=6.686,P=0.015),and area under the receiver operating characteristic curve[0.761 (95%CI=0.677-0.845) vs.0.592 (95%CI=0.504-0.680);Z=3.500,P<0.001] of 3D-TUI were higher than those of 2D-US.However,3D-TUI and 2D-US showed no significant difference in the specificity (84.1% vs.81.4%;χ2=0.081,P=0.776),negative predictive value (67.9% vs.50.7%;χ2=3.645,P=0.066),or positive predictive value (84.1% vs.71.4%;χ2=1.663,P=0.240). Conclusion Compared with 2D-US,3D-TUI demonstrates increased diagnostic efficiency for ETE of PTMC.

DARMF-UNet: A dual-branch attention-guided refinement network with multi-scale features fusion U-Net for gland segmentation.

Accurate gland segmentation is critical in determining adenocarcinoma. Automatic gland segmentation methods currently suffer from challenges such as less accurate edge segmentation, easy mis-segmentation, and incomplete segmentation. To solve these problems, this paper proposes a novel gland segmentation network Dual-branch Attention-guided Refinement and Multi-scale Features Fusion U-Net (DARMF-UNet), which fuses multi-scale features using deep supervision. At the first three layers of feature concatenation, a Coordinate Parallel Attention (CPA) is proposed to guide the network to focus on the key regions. A Dense Atrous Convolution (DAC) block is used in the fourth layer of feature concatenation to perform multi-scale features extraction and obtain global information. A hybrid loss function is adopted to calculate the loss of each segmentation result of the network to achieve deep supervision and improve the accuracy of segmentation. Finally, the segmentation results at different scales in each part of the network are fused to obtain the final gland segmentation result. The experimental results on the gland datasets Warwick-QU and Crag show that the network improves in terms of the evaluation metrics of F1 Score, Object Dice, Object Hausdorff, and the segmentation effect is better than the state-of-the-art network models.

Sparse-to-dense coarse-to-fine depth estimation for colonoscopy.

Colonoscopy, as the golden standard for screening colon cancer and diseases, offers considerable benefits to patients. However, it also imposes challenges on diagnosis and potential surgery due to the narrow observation perspective and limited perception dimension. Dense depth estimation can overcome the above limitations and offer doctors straightforward 3D visual feedback. To this end, we propose a novel sparse-to-dense coarse-to-fine depth estimation solution for colonoscopic scenes based on the direct SLAM algorithm. The highlight of our solution is that we utilize the scattered 3D points obtained from SLAM to generate accurate and dense depth in full resolution. This is done by a deep learning (DL)-based depth completion network and a reconstruction system. The depth completion network effectively extracts texture, geometry, and structure features from sparse depth along with RGB data to recover the dense depth map. The reconstruction system further updates the dense depth map using a photometric error-based optimization and a mesh modeling approach to reconstruct a more accurate 3D model of colons with detailed surface texture. We show the effectiveness and accuracy of our depth estimation method on near photo-realistic challenging colon datasets. Experiments demonstrate that the strategy of sparse-to-dense coarse-to-fine can significantly improve the performance of depth estimation and smoothly fuse direct SLAM and DL-based depth estimation into a complete dense reconstruction system.

Sustained viral response and relapse after discontinuation of oral antiviral drugs in HBeAg-positive patients with chronic hepatitis B infection.

Objective: To investigate the sustained virological response and relapse in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive after stopping oral antiviral drugs, and to monitor the disease progression and the incidence of adverse events such as liver cirrhosis and hepatocellular carcinoma. Methods: This is a prospective observational study. Patients who continued nucleos(t)ide analogue (NA) treatment after achieving HBeAg seroconversion for more than 3 years were enrolled. After signing the informed consent form, patients stopped NA treatment and received follow-up. During the follow-up, the antiviral treatment information of the patients was collected, and the follow-up observation was carried out every 3 months since the enrollment. We monitored the virological indexes, liver and kidney function, serology and liver imaging during follow-up. The purpose of this study was to explore the sustained virological response rate, HBV DNA recurrence rate, clinical relapse rate and the related factors after drug withdrawal. Results: A total of 82 patients were enrolled, including 42 males (51.22%) and 40 females (48.78%), with a median age of 34.00 (31.00, 37.25) years. All enrolled patients were followed up for 1 year. At the end of the follow-up, 36.59% (30/82) of patients had sustained virological response, 63.41% (52/82) of patients had HBV DNA reactivation, 17.07% (14/82) of patients had clinical relapse, and 10.98% (9/82) of patients had HBeAg reversion. During the follow-up, there were no adverse events such as liver cirrhosis and hepatocellular carcinoma. The median level of hepatitis B surface antigen (HBsAg) in patients with sustained virological response was lower than that in patients with HBV DNA reactivation (2.92 vs.3.18 log10IU/ml, Z=-1.492/P=0.136), and the median level of baseline HBsAg in patients with HBV DNA reactivation was lower than that in patients with clinical relapse (3.01 vs.3.45 log10IU/mL, Z=-1.795/P=0.073), but the difference was not significant. There was no significant statistical difference between patients with sustained virological response and HBV DNA reactivation of the median total treatment time [69.50 (56.25, 86.00) vs.62.50 (44.00, 88.50) months, Z=-0.689/P=0.491], and the consolidation treatment time [41.50 (36.75, 54.75) vs.40.50 (36.00, 53.75) months, Z=-0.419/P=0.675]. Conclusion: The sustained virological response rate of HBeAg positive CHB patients after stopping oral antiviral treatment is lower, and it is more common in patients with lower HBsAg levels. Patients still need to be closely monitored after stopping NA therapy.

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B.

Objective: The aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. Methods: HBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-ß1, TGF-ß2, TGF-ß3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed. Results: A total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-ß1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001-1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046-0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972-0.999, p = 0.040). Conclusion: Cytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment.

Comparison of chemotherapy regimens plus rituximab in adult Burkitt lymphoma: A single-arm meta-analysis.

Background and aim: Given the paucity of evidence-based treatment recommendations, the most appropriate first-line regimen for adult Burkitt lymphoma is currently undefined. We aimed to identify the optimal treatment regimen containing rituximab for adult Burkitt lymphoma patients. Methods: The PubMed, Embase, Web of Science, and Cochrane databases were searched in December 2021 (10). We included all studies for the treatment of Burkitt lymphoma including rituximab. We excluded studies of patients aged ≤14 years old and those with sample numbers ≤10 patients. Random-effects models were used to compare different chemotherapy regimens regarding estimated 2-year overall survival (OS) rate, 2-year progression-free survival (PFS) rate, and overall response rate (ORR). Results: A total of 17 studies were included in this meta-analysis and divided into four groups: CODOX-M/IVAC, DA-EPOCH, GMALL-B-ALL/NHL2002, and Hyper-CVAD. DA-EPOCH was associated with a significantly higher 2-year OS rate [0.95, 95% confidence interval (CI) 0.86-1.00]. There was no significant difference in the 2-year PFS rates (0.81, 95% CI 0.76-0.85) and ORR (0.90, 95% CI 0.87-0.94) between these four treatment regimens. Conclusions: The meta-analysis indicates that DA-EPOCH could be more effective in providing curative treatment for adult Burkitt lymphoma patients, especially without CNS and BM involvement considering OS time. Due to the types of studies and the limited number of included studies, bias should be acknowledged and a randomized controlled trial (RCT) needs to be performed to further identify the optimal treatment regimen for such patients.

The reduction in CD8+PD-1+ T cells in liver histological tissue is related to Pegylated IFN-α therapy outcomes in chronic hepatitis B patients.

BACKGROUND: Antiviral therapy is recommended for patients with immune-active chronic hepatitis B (CHB) to decrease the risk of liver-related complications. However, the outcomes of the pegylated IFN-α (PEG-IFN-α) therapy vary among CHB patients. We aimed to identify factors that can influence the outcomes in CHB patients who received antiviral PEG-IFN-α monotherapy. METHODS: Thirty-two CHB patients who received PEG-IFN-α monotherapy were enrolled in this study. All of the patients underwent two liver biopsies at baseline and 6 months after the initiation of the therapy. CD8+ T cells, CD4+ T cells, CD68+ mononuclear cells, and PD-1 levels in the 64 liver biopsy specimens were examined via immunofluorescence. RESULTS: The overall median frequency of CD8+ T cells in the liver tissues of 32 CHB patients significantly decreased at 6 months after the therapy initiation (p < 0.01). In the FIER (fibrosis and inflammation response with HBeAg seroconversion) group, CD8+PD-1+ T cells significantly decreased at 6 months (p < 0.05), while CD8+PD-1- T cells had no significant difference. On the contrary, in the FIENR (no fibrosis and inflammation response and HBeAg seroconversion) group, CD8+PD-1- T cells significantly decreased after 6 months of PEG-IFN-α treatment (p < 0.05), while CD8+PD-1+ T cells had no significant difference. In addition, the levels of CD68+ mononuclear cells in the FIER group showed an overall increasing trend after treatment (p < 0.05). CONCLUSIONS: The changes in the levels of CD8+PD-1+ T cells and CD68+ mononuclear cells may be related to the response to PEG-IFN-α therapy.

Differentiation of Thyroid Nodules Difficult to Diagnose With Contrast-Enhanced Ultrasonography and Real-Time Elastography.

According to the 2015 American Thyroid Association (ATA), referred risk stratification and thyroid nodules with intermediate- and low-suspicion patterns are difficult to diagnose. The objective of this study is to evaluate the diagnostic performance of contrast-enhanced ultrasonography (CEUS) and elastosonography (ES) for the differentiation of these thyroid nodules. From November 2011 to June 2016, a total of 163 thyroid nodules with intermediate- and low-suspicion patterns in 150 consecutive patients at our hospital were studied before surgery. With surgical pathology as the standard, the diagnostic value of CEUS and ES was analyzed. There were 29 (17.8%) malignant lesions and 134 (82.2%) benign lesions. The enhancement patterns of CEUS, the echogenicity, and the elastography were significantly different between malignant and benign lesions (P < 0.05). Heterogenous enhancement was more common in malignant nodules, and the sensitivity, specificity, positive predictive value, negative predictive value, and odds ratio were 51.7, 88.1, 48.4, 89.4, and 10.1%, respectively. The diagnostic accuracy of CEUS was better than the conventional ultrasound [area under the curve (AUC), 0.729 vs. 0.616, P = 0.021]. The enhancement patterns of CEUS were helpful in the differential diagnosis of thyroid nodules with intermediate and low suspicion.

Changes in APRI and FIB-4 in HBeAg-negative treatment-naive chronic hepatitis B patients with significant liver histological lesions receiving 5-year entecavir therapy.

According to guidelines, antiviral therapy for adults with immune-active chronic hepatitis B (CHB) should be adopted to decrease the risk of liver-related complications. Fibrosis assessment during antiviral treatment is a key step in antiviral therapy evaluation. Liver biopsy is the gold standard for assessing the degree of liver necroinflammation and fibrosis. However, because of its cost and the risk of life-threatening complications, performing a liver biopsy more than once after long-term effective treatment is difficult. In this study, we aimed to evaluate changes in liver fibrosis during 5 years of entecavir (ETV) treatment using noninvasive fibrosis markers in hepatitis B e-antigen (HBeAg)-negative treatment-naive CHB patients who require antiviral therapy. A total of 303 HBeAg-negative treatment-naive patients were enrolled in this study. Liver biopsy was performed before initiation of antiviral therapy. The diagnosis of CHB was made according to Chinese guidelines for the management of CHB. Patients requiring antiviral therapy (liver fibrosis stage ≥ F2, METAVIR scoring system) were treated with ETV for at least 5 years. These patients were followed up at 6-month intervals. A clinical and virological evaluation was performed at baseline and again at 12, 24, 36, 48, and 60 months during ETV treatment. Aspartate Aminotransferase to Platelet Ratio Index (APRI) and Fibrosis-4 (FIB-4) index were used to assess dynamic changes in liver fibrosis in HBeAg-negative CHB patients after 1, 2, 3, 4, and 5 years of ETV treatment. All enrolled patients underwent liver biopsy at baseline. Using the METAVIR fibrosis stages, there were 107, 125, 54, and 17 patients in F1, F2, F3, and F4 stages, respectively. The APRI and FIB-4 indexes enabled the correct identification of patients with severe fibrosis (METAVIR F3-F4), with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI] 0.72-0.83) and 0.76 (95% CI 0.70-0.82), respectively. The APRI values decreased significantly in F2 and F3 patients after 1 year of ETV therapy (P < 0.01). However, for F4 patients, APRI values decreased significantly at year 3 (P < 0.05). The FIB-4 values of F2, F3, and F4 patients who received ETV treatment were significantly decreased after 1, 3, and 5 years of ETV therapy, respectively (P < 0.05). APRI and FIB-4 values decreased significantly during 5-year ETV treatment in HBeAg-negative CHB patients, indicating that these noninvasive fibrosis tests might be useful for monitoring improvement in liver fibrosis and assessing treatment efficacy during long-term ETV treatment.

Computer-aided system for diagnosing thyroid nodules on ultrasound: A comparison with radiologist-based clinical assessments.

BACKGROUND: The purpose of this study was to compare the diagnostic efficiency of a thyroid ultrasound computer-aided diagnosis (CAD) system with that of 1 radiologist. METHODS: This study retrospectively reviewed 342 surgically resected thyroid nodules from July 2013 to December 2013 at our center. The nodules were assessed on typical ultrasound images using the CAD system and reviewed by 1 experienced radiologist. The radiologist stratified the risk of malignancy using the Thyroid Imaging Reporting and Data Systems (TIRADS) and the American Thyroid Association (ATA) guidelines. RESULTS: The radiologist, using TI-RADS and ATA guidelines, performed better than the CAD system (P < .01). The sensitivity of the CAD system was similar to that of an experienced radiologist (P > .05; P < .01; and P > .05). However, we found that the CAD system had lower specificity (P < .01). CONCLUSION: The sensitivity of a thyroid ultrasound CAD system in differentiating nodules was similar to that of an experienced radiologist. However, the CAD system had lower specificity.

Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naïve Patients with Chronic Hepatitis B Virus Infection.

BACKGROUND: Estimating the grades of liver inflammation is critical in the determination of antiviral therapy in patients chronically infected with hepatitis B virus (HBV). The aim of this study was to investigate the correlation of serum levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) with the liver inflammation grades in treatment-naïve patients with chronic HBV infection. METHODS: We retrospectively enrolled 584 treatment-naïve HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used for statistical analysis of all relevant data. RESULTS: The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively (Χ2 = 26.00, P < 0.001). The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff, respectively; both antigens tended to decrease as the grade of inflammation increased (Χ2 = 99.68 and Χ2 = 99.23, respectively; both P < 0.001). The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 log S/CO, respectively, l to distinguish minimal grade and other grades of treatment-naïve HBeAg-positive patients with chronic HBV infection. CONCLUSIONS: Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values might help us to distinguish minimal grades and other grades and detect those who do not need antiviral therapy in treatment-naïve HBeAg-positive patients with chronic HBV infection.

Comparison of Ultrasound Features of Primary Metastatic Papillary Thyroid Carcinoma and Recurrent/Persistent Metastatic Cervical Lymph Nodes.

Objective To explore the ultrasound features and levels of cervical lymph node metastases in primary and recurrent/persistent papillary thyroid cancer (PTC).Methods We retrospectively analyzed the clinical data of 2181 patients who underwent cervical lymph nodes dissection for PTC from January 1st 2015 to January 1st 2016.Totally 418 PTC patients (with 622 lymph nodes) who met the inclusion criteria entered the final analysis.Patients who had not received any prior thyroid treatment (surgery with or without radioactive iodine) were categorized as the primary group (352 patients with 527 metastatic lymph nodes),and patients who had received prior treatment (thyroidectomy with or without radioactive iodine) for PTC were categorized as recurrent/persistent group (66 patients with 95 metastatic lymph nodes).Pathological results from lymph node dissections were used as the gold standards by means of level-to-level analysis.Results The mean of the minimum axis diameter of the lymph nodes in the primary group was (6.7±3.6)mm,and that of the recurrent/persistent group was (6.6±3.1)mm (U=0.180,P=0.857).The proportion of metastasis in the central area of primary group was 40.0%,which was significantly higher than that in the recurrent/persistent group (12.6%);the proportion of metastasis in the lateral area was 60.6% in the primary group,which was significantly lower than that in the recurrent/persistent group (87.4%)(χ2=26.288,P<0.001).In lateral metastatic lymph nodes,Ⅲ level was the most common place in both groups.Level Ⅴ metastatic lymph was rare in both primary group and recurrent/persistent group.Calcifications (63.1% vs. 48.2%;χ2=7.207,P=0.007) and peripheral vascularity (81.1% vs. 59.4%;χ2= 16.147, P<0.001) were more common in the recurrent/persistent group.The round shape,absence of an echogenic hilum,hyperechogenicity,and cystic aspects were not significantly different between these two groups (all P>0.05).Conclusions Primary metastatic lymph nodes often occur in the central area of lymph nodes,while lateral metastatic lymph nodes are more common in recurrent/persistent PTC.For metastatic lymph nodes,calcifications and peripheral vascularity are more common in recurrent/persistent PTC.

Cervical soft tissue recurrence of differentiated thyroid carcinoma after thyroidectomy indicates a poor prognosis.

BACKGROUND: We investigated cervical soft tissue recurrence of differentiated thyroid carcinoma (DTC) after thyroidectomy, and these lesions exhibited no evidence that they were lymph nodes (LNs). METHODS: Between January 2012 and April 2016, consecutive 6308 patients underwent thyroid surgery for DTC at our center. Among them, we encountered 21 patients with recurrent cervical soft tissue lesions, none of whom had previously undergone fine needle aspiration biopsy (FNAB). RESULTS: The 21 patients accounted for 0.33% of all 6308 patients, including twenty cases of papillary thyroid carcinoma and one case of follicular thyroid cancer. Approximately half (52.3%) of the recurrence were first detected by ultrasound (US). Eighteen lesions underwent complete preoperative US, but 6 lesions were misdiagnosed as metastatic LNs by US. Therefore, 54 age- and gender-matched recurrent or persistent LNs derived from DTC were randomly selected from the same database. The soft tissue lesions (mean size, 2.30 cm) were larger than the LNs. Fewer hyperechogenic hila and punctuations were found in the group of soft tissue recurrence (P < 0.05). During follow-up, distant metastasis was detected in 38.1% of patients in the soft tissue recurrence group. The distant metastasis rates showed that local soft tissue recurrence led to a poorer prognosis than cervical LN persistence or recurrence (P = 0.00). CONCLUSIONS: Although the incidence of DTC recurrence in cervical soft tissue was low, it may be a predictor for distant recurrence. To minimize the risk, a long-term postoperative evaluation, preferably with US, should be performed.

Role of Ultrasound in the Management of Thyroid Nodules and Thyroid Cancer.

The management of thyroid nodules can be classified into narrow-and broad-sense levels. The broad-sense procedures are used for special population and include screening,risk assessment of thyroid nodules,follow-up of benign thyroid nodules,surgical operation,post-operative follow-up,and assessment and treatment of recurrence and/or metastasis of thyroid cancer. The narrow-sense procedures are for individual patients and the whole process includes the assessment,supervision,treatment,and reassessment of thyroid lesion. Ultrasound plays different roles at different management stages. With the development of ultrasonic technology and improvement of diagnostic accuracy,ultrasound has gradually becoming an irreplaceable imaging tool in the diagnosis of thyroid nodules. In this article we review the history of thyroid ultrasound and the latest international guidelines on the management of thyroid nodules and differentiated thyroid cancer by focusing on the role of ultrasound throughout the management of thyroid nodules.

Ultrasound is helpful to differentiate Bethesda class III thyroid nodules: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Fine-needle aspiration (FNA) is the most dependable tool to triage thyroid nodules for medical or surgical management. However, Bethesda class III cytology, namely "follicular lesion of undetermined significance" (FLUS) or "atypia of undetermined significance" (AUS), is a major limitation of the US-FNA in assessing thyroid nodules. As the most important imaging method, ultrasound (US) has a high efficacy in diagnosing thyroid nodules. This meta-analysis aimed to assess the role of US in evaluating Bethesda class III thyroid nodules. METHODS: With keywords "Undetermined Significance," "Bethesda Category III," "Bethesda system," "Cytological Subcategory," "AUS/FLUS," "Atypia of Undetermined Significance," and "Ultrasound/US," papers in PubMed, Cochrane Library, Medline, Web of Science, Embase, and Google Scholar from inception to December 2016 were searched. A meta-analysis of these trials was then performed for evaluating the diagnostic value of thyroid ultrasound in Bethesda Category III thyroid nodules. RESULTS: Fourteen studies including 2405 nodules were analyzed. According to the criteria for US diagnosis of thyroid nodules in each article, with any one of suspicious features as indictors of malignancy, US had a pooled sensitivity of 0.75 (95% CI 0.72-0.78) and a pooled specificity of 0.48 (95% CI 0.45-0.50) in evaluating Bethesda Class III Nodules. The pooled diagnostic odds ratio was 10.92 (95% CI 6.04-19.74). The overall area under the curve was 0.84 and the Q* index was 0.77. With any 2 or 3 of US suspicious features as indictors of malignancy, the sensitivity and specificity were 0.77 (95% CI 0.71-0.83) and 0.54 (95% CI 0.51-0.58), 0.66 (95% CI 0.59-0.73) and 0.71 (95% CI 0.68-0.74), respectively. CONCLUSIONS: US was helpful for differentiating benign and malignant Bethesda class III thyroid nodules, with the more suspicious features, the more likely to be malignant.

"Onion Skin-liked Sign" in Thyroid Ultrasonography: A Characteristic Feature of Benign Thyroid Nodules.

BACKGROUND: Some ultrasonographic (US) signs overlap between benign and malignant nodules. The purpose of this study was to raise a special US sign of benign thyroid nodules, termed the "onion skin-liked sign." METHODS: Twenty-seven patients with 27 nodules who shrank naturally and the "onion skin-liked sign" appeared on the final US images were enrolled in the study. The ultrasound characters and risk stratifications at the start and end of observation were compared. Then, thirty goiters with fibrosis and thirty papillary thyroid carcinomas (PTC) were randomly selected from the database of our hospital, matched the sizes of 27 nodules at the end point of observation. The differences of "onion skin-liked sign" between the two groups were analyzed. RESULTS: The average duration of follow-up of 27 nodules was 24.0 ± 12.2 months (range, 12-65 months). At the end of the follow-up, the size of the nodules decreased on average by 1.26 ± 0.82 cm (range, 0.3-3.4 cm) and calcification was found in 21 nodules, compared with only 2 nodules with calcification at the start of the follow-up. In addition, only negligible or no blood flow signal could be detected at the periphery of all the nodules and 100% (27/27) were high suspicion at the end of observation. In matched groups, all PTC showed high suspicion of malignancy, 18/30 (60%) goiters with fibrosis were high suspicion and 11/30 (37%) were intermediate suspicion. Twenty-two patients in the group of nodular fibrosis presented "onion skin-liked sign," which was not shown in any patient of PTC group. The sensitivity, specificity, positive predictive value, and negative predictive value of "onion skin-liked sign" in predicting nodular goiter with fibrosis were 73.3%, 100%, 100%, and 78.9%, respectively. CONCLUSIONS: The "onion skin-liked sign" was a characteristic US feature of benign thyroid nodules detected in the follow-up of thyroid nodules. It is useful to differentiate PTCs and nodular goiters with fibrosis.

Antibodies Targeting Novel Neutralizing Epitopes of Hepatitis C Virus Glycoprotein Preclude Genotype 2 Virus Infection.

Currently, there is no effective vaccine to prevent hepatitis C virus (HCV) infection, partly due to our insufficient understanding of the virus glycoprotein immunology. Most neutralizing antibodies (nAbs) were identified using glycoprotein immunogens, such as recombinant E1E2, HCV pseudoparticles or cell culture derived HCV. However, the fact that in the HCV acute infection phase, only a small proportion of patients are self-resolved accompanied with the emergence of nAbs, indicates the limited immunogenicity of glycoprotein itself to induce effective antibodies against a highly evolved virus. Secondly, in previous reports, the immunogen sequence was mostly the genotype of the 1a H77 strain. Rarely, other genotypes/subtypes have been studied, although theoretically one genotype/subtype immunogen is able to induce cross-genotype neutralizing antibodies. To overcome these drawbacks and find potential novel neutralizing epitopes, 57 overlapping peptides encompassing the full-length glycoprotein E1E2 of subtype 1b were synthesized to immunize BALB/c mice, and the neutralizing reactive of the induced antisera against HCVpp genotypes 1-6 was determined. We defined a domain comprising amino acids (aa) 192-221, 232-251, 262-281 and 292-331 of E1, and 421-543, 564-583, 594-618 and 634-673 of E2, as the neutralizing regions of HCV glycoprotein. Peptides PUHI26 (aa 444-463) and PUHI45 (aa 604-618)-induced antisera displayed the most potent broad neutralizing reactive. Two monoclonal antibodies recognizing the PUHI26 and PUHI45 epitopes efficiently precluded genotype 2 viral (HCVcc JFH and J6 strains) infection, but they did not neutralize other genotypes. Our study mapped a neutralizing epitope region of HCV glycoprotein using a novel immunization strategy, and identified two monoclonal antibodies effective in preventing genotype 2 virus infection.

Determination of the human antibody response to the neutralization epitopes encompassing amino acids 313-327 and 432-443 of hepatitis C virus E1E2 glycoproteins.

It has been reported that monoclonal antibodies (MAbs) to the E1E2 glycoproteins may have the potential to prevent hepatitis C virus (HCV) infection. The protective epitopes targeted by these MAbs have been mapped to the regions encompassing amino acids 313-327 and 432-443. In this study, we synthesized these two peptides and tested the reactivity of serum samples from 336 patients, 210 of which were from Chronic Hepatitis C (CHC) patients infected with diverse HCV genotypes. The remaining 126 samples were isolated from patients who had spontaneously cleared HCV infection. In the chronic HCV-infected group (CHC group), the prevalence of human serum antibodies reactive to epitopes 313-327 and 432-443 was 24.29% (51 of 210) and 4.76% (10 of 210), respectively. In the spontaneous clearance group (SC group), the prevalence was 0.79% (1 of 126) and 12.70% (16 of 126), respectively. The positive serum samples that contained antibodies reactive to epitope 313-327 neutralized HCV pseudoparticles (HCVpp) bearing the envelope glycoproteins of genotypes 1a or 1b and/or 4, but genotypes 2a, 3a, 5 and 6 were not neutralized. The neutralizing activity of these serum samples could not be inhibited by peptide 313-327. Six samples (SC17, SC38, SC86, SC92, CHC75 and CHC198) containing antibodies reactive to epitope 432-443 had cross-genotype neutralizing activities. The neutralizing activity of SC38, SC86, SC92 and CHC75 was partially inhibited by peptide 432-443. However, the neutralizing activity of sample SC17 for genotype 4HCVpp and sample CHC198 for genotype 1b HCVpp were not inhibited by the peptide. This study identifies the neutralizing ability of endogenous anti-HCV antibodies and warrants the exploration of antibodies reactive to epitope 432-443 as sources for future antibody therapies.