Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial.

OBJECTIVES: Sonochemotherapy, which uses microbubble (MB)-assisted ultrasound (US) to deliver chemotherapeutic agents, has the potential to enhance tumour chemotherapy. The combination of US and MB has been demonstrated to prolong the survival of patients with pancreatic cancer. This phase 2 clinical trial aimed to determine the clinical efficacy and safety of sonochemotherapy for inoperable pancreatic ductal adenocarcinoma by using US and MB. METHODS: Eighty-two patients with stage III or IV pancreatic cancer were recruited from July 2018 to March 2021 and followed up until September 2022. US treatment was performed with a modified diagnostic US scanner for 30 min after chemotherapeutic infusion. The primary endpoint was overall survival (OS), and the secondary endpoints were Eastern Cooperative Oncology Group (ECOG) status < 2, progression-free survival (PFS), disease control rate (DCR), and adverse events. RESULTS: Seventy-eight patients were randomly allocated (40 to chemotherapy and 38 to sonochemotherapy). The median OS was longer with sonochemotherapy than with chemotherapy (9.10 vs. 6.10 months; p = 0.037). The median PFS with sonochemotherapy was 5.50 months, compared with 3.50 months (p = 0.080) for chemotherapy. The time of ECOG status < 2 was longer with sonochemotherapy (7.20 months) than with chemotherapy (5.00 months; p = 0.029). The DCR was 73.68% for sonochemotherapy compared with 42.50% for the control (p = 0.005). The incidence of overall adverse events was balanced between the two groups. CONCLUSIONS: The use of sonochemotherapy can extend the survival and well-being time of stage III or IV pancreatic cancer patients without any increase in serious adverse events. TRIAL REGISTRATION: ChineseClinicalTrials.gov ChiCTR2100044721 CLINICAL RELEVANCE STATEMENT: This multicentre, randomised, controlled trial has proven that sonochemotherapy, namely, the combination of diagnostic ultrasound, microbubbles, and chemotherapy, could extend the overall survival of patients with end-stage pancreatic ductal adenocarcinoma from 6.10 to 9.10 months without increasing any serious adverse events. KEY POINTS: • This is the first multicentre, randomised, controlled trial of sonochemotherapy for clinical pancreatic cancer treatment using ultrasound and a commercial ultrasound contrast agent. • Sonochemotherapy extended the median overall survival from 6.10 (chemotherapy alone) to 9.10 months. • The disease control rate increased from 42.50% with chemotherapy to 73.68% with sonochemotherapy.

Tumor cell-derived exosomes mediating hsa_circ_0001739/lncRNA AC159540.1 facilitate liver metastasis in colorectal cancer.

BACKGROUND: The current study probed into how tumor cell-derived exosomes (Exos) mediated hsa_circ_0001739/lncRNA AC159540.1 to manipulate microRNA (miR)-218-5p/FTO-N6-methyladenosine (m6A)/MYC signal axis in liver metastasis in colorectal cancer (CRC). METHODS: hsa_circ_0001739 and lncRNA AC159540.1 were identified as the upstream regulator of miR-218-5p using ENCORI and LncBase databases. Expression patterns of miR-218-5p, hsa_circ_0001739, lncRNA AC159540.1, FTO, and MYC were detected, accompanied by loss-and-gain-of function assays to examine their effects on CRC cell biological functions. SW480 cells-derived Exos were purified, followed by in vitro studies to uncover the effect of hsa_circ_0001739/lncRNA AC159540. RESULTS: miR-218-5p was downregulated while hsa_circ_0001739/lncRNA AC159540.1 was upregulated in CRC tissues and cells. Silencing of hsa_circ_0001739/lncRNA AC159540.1 restrained the malignant phenotypes of CRC cells. Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 competitively inhibited miR-218-5p to elevate FTO and MYC. The inducing role of Exos-mediated hsa_circ_0001739/lncRNA AC159540.1 in CRC was also validated in vivo. CONCLUSION: Conclusively, Exos-mediated circ_0001739/lncRNA AC159540.1 regulatory network is critical for CRC, offering a theoretical basis for CRC treatment.

sMicroRNA-28-5p acts as a metastasis suppressor in gastric cancer by targeting Nrf2.

The transcription factor nuclear factor (erythroid-2)-related factor 2 (Nrf2) can principally serve a mode of protection for both the normal cells and cancer cells from cellular stress, and elevates cancer cell survival. microRNA-28 (miR-28) has been involved in the regulation of Nrf2 expression in breast epithelial cells. However, no comprehensive analysis has been conducted regarding the function of miR-28-5p regulating Nrf2 in gastric cancer (GC). In this study, we aimed to evaluate their interaction and biological roles in the migration and invasion of GC cells. The expression of Nrf2 in the cancer tissues harvested from 42 patients with GC was examined by an array of molecular techniques comprising of Immunohistochemical staining, RT-qPCR and Western blot analysis. Kaplan-Meier method was adopted for analysis of the correlation of Nrf2 with the prognosis of GC patients. Interaction between miR-28-5p and Nrf2 was determined using the bioinformatics analysis and dual luciferase reporter gene assay. Gain- and loss-of-function studies of miR-28-5p and Nrf2 were conducted to elucidate their effects on GC cell migration, invasion and metastasis, as well as expression pattern of several epithelial-mesenchymal transition (EMT)-related proteins. Results indicated that the expression pattern of Nrf2 was significantly upregulated in GC tissues and indicative of poor prognosis of GC patients. miR-28-5p was verified to target Nrf2 and downregulate its expression. GC cells with overexpression of miR-28-5p or Nrf2 knockdown exhibited a marked reduction in the migrated and invasive abilities, along with the N-cadherin expression yet an increase of E-cadherin expression. Furthermore, miR-28-5p exerted an inhibitory function on the metastatic and tumorigenicity of GC cells. In conclusion, miR-28-5p is a comprehensive tumor suppressor that inhibits GC cell migration and invasion through repressing the Nrf2 expression. Therefore, miR-28-5p may serve as a potential biomarker for the prognosis of GC and a novel therapeutic target in advanced GC.

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.

The prevalence of Lynch syndrome (LS) varies significantly in different populations, suggesting that ethnic features might play an important role. We enrolled 3330 consecutive Chinese patients who had surgical resection for newly diagnosed colorectal cancer. Universal screening for LS was implemented, including immunohistochemistry for mismatch repair (MMR) proteins, BRAFV600E mutation test and germline sequencing. Among the 3250 eligible patients, MMR protein deficiency (dMMR) was detected in 330 (10.2%) patients. Ninety-three patients (2.9%) were diagnosed with LS. Nine (9.7%) patients with LS fulfilled Amsterdam criteria II and 76 (81.7%) met the revised Bethesda guidelines. Only 15 (9.7%) patients with absence of MLH1 on IHC had BRAFV600E mutation. One third (33/99) of the MMR gene mutations have not been reported previously. The age of onset indicates risk of LS in patients with dMMR tumors. For patients older than 65 years, only 2 patients (5.7%) fulfilling revised Bethesda guidelines were diagnosed with LS. Selective sequencing of all cases with dMMR diagnosed at or below age 65 years and only of those dMMR cases older than 65 years who fulfill revised Bethesda guidelines results in 8.2% fewer cases requiring germline testing without missing any LS diagnoses. While the prevalence of LS in Chinese patients is similar to that of Western populations, the spectrum of constitutional mutations and frequency of BRAFV600E mutation is different. Patients older than 65 years who do not meet the revised Bethesda guidelines have a low risk of LS, suggesting germline sequencing might not be necessary in this population.

The injury of recurrent laryngeal nerve and thyroid regeneration after irreversible electroporation ablation of most part of thyroid gland-an experimental study on swine model.

To study the thyroid regeneration and injury of recurrent laryngeal nerve after irreversible electroporation (IRE). 12 pigs were divided into three groups: six pigs underwent IRE, other pigs were used as controls. IRE was performed near tracheoesophageal groove, to ablate most part of thyroid gland. Parathyroid and thyroid function, recurrent laryngeal nerve injury and thyroid computed tomography (CT) imaging were regularly investigated. The histopathology results were analyzed to detect thyroid regeneration. Masson's trichrome method for collagen and immunohistochemistry were performed for Soluble protein-100 (S100) and neurofilaments on nerve section. In IRE group, there were no symptoms of recurrent laryngeal nerve-related injury. No abnormalities of recurrent laryngeal nerve were shown on hematoxylin-eosin (HE) staining, Masson's trichrome staining, Neurofilament (NF) staining and S100 staining. There were no significant changes for thyroid and parathyroid function in all pigs. Immediately after IRE, CT showed hypoattenuation in the ablated thyroid gland and it became swelling. 14 days after IRE, thyroid CT showed hetergenous attenuation in the electroporation zone, and the size and attenuation of thyroid gland were normal after two months. There was cell apoptosis in the thyroid gland after IRE. Seven and 14 days after IRE, there was fragmentation of nucleus within the follicle, and some follicles were empty. Two months later, complete regeneration of thyroid tissue was shown. IRE was shown to be both effective and safe with complete regeneration of thyroid tissue and preservation of the function and structure of the recurrent laryngeal nerve.

An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma.

To further identify novel susceptibility loci of nasopharyngeal carcinoma (NPC), we here extended our previous genome-wide association study (GWAS) by boosting statistical power with larger sample size and validating more SNPs in the ranking list based on the GWAS P-values. The discovery stage consisting of 463,250 SNPs in 1,583 cases and 2,979 controls of southern Chinese ancestry revealed 1,257 top SNPs to be associated with NPC, which were brought forward for validation in 1,925 cases and 1,947 controls of southern Chinese. Further, 11 SNPs were selected for another independent validation in 3,538 cases and 3,644 controls of southern Chinese. The joint analysis with 7,046 cases and 8,570 controls resulted in two associations surpassing genome-wide significance (P < 5 × 10-8), including TERT-CLPTM1L at chromosome 5p15 (rs401681; P = 2.65 × 10-14; odds ratio, OR = 0.82) and CIITA at chromosome 16p13 (rs6498114; P = 4.01 × 10-9; OR = 0.87). Conditional analysis revealed that rs401681 accounts for all the tested associations at TERT-CLPTM1L locus, which has been linked with multiple cancers' susceptibilities. Moreover, bioinformatics analyses showed that both SNPs are located in the regulatory regions and correlated with the expression of nearby genes (rs401681 for CLPTM1L and TERT, and rs6498114 for CIITA). CLPTM1L and TERT have been implicated in cancers, and CIITA is considered as the "master control factor" for the expression of NPC-associated MHC class II genes. These suggested that both SNPs might be functional. Altogether, our findings expand our understanding of the genetic contribution to NPC risk and provide novel biological insights into NPC pathogenesis.

Transvaginal Ultrasound-Guided Core Needle Biopsy of Pelvic Masses.

OBJECTIVES: This study assessed the efficacy and safety of transvaginal ultrasound (US)-guided core needle biopsy (CNB) for obtaining adequate pelvic mass samples for histologic analysis and evaluated factors that may affect biopsy success. METHODS: Two hundred cases underwent transvaginal US-guided CNBs for primary inoperable tumors, suspicion of metastases to the ovaries or peritoneum, recurrence, or other solid lesions in the pelvis. Biopsy samples were obtained from the pelvic cavity (67.0%), vaginal cuff or vaginal wall (17.5%), or peritoneal cake (15.5%). The potential influences of the biopsy site (pelvic cavity, vaginal cuff or vaginal wall, or peritoneal cake), vascularization, ascites, tumor size, and tumor type (inoperable, metastases, recurrence, or solid pelvic tumor) on the success of transvaginal US-guided CNB were evaluated by a univariate analysis. RESULTS: Adequate samples were obtained in 192 of 200 biopsies (96.0%), of which 190 yielded successful diagnoses (95.0%). The biopsy site had a significant effect on biopsy adequacy, as there was a significantly lower probability of obtaining satisfactory specimens for histologic verification from the peritoneal cake compared to pelvic tumors and the vaginal cuff or vaginal wall (P < .01). Adequacy was also affected by tumor size (P < .05) but not by vascularization, ascites, or tumor type. No complications occurred during the biopsy procedures. CONCLUSIONS: Transvaginal US-guided CNB is a safe and effective alternative to more invasive methods for evaluating pelvic lesions, such as laparoscopy and laparotomy.

Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.

BACKGROUND: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated. METHODS: In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC. RESULTS: We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients. CONCLUSION: Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.

BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. METHODS: We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. FINDINGS: Associations exceeding the genome-wide significance threshold (p<5 × 10(-8)) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10(-19), odds ratio [OR] 1·84 [95% CI 1·61-2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10(-14)). This association is distinct from MHC associations with Epstein-Barr virus infection. INTERPRETATION: To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. FUNDING: Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).

A single nucleotide polymorphism in the Epstein-Barr virus genome is strongly associated with a high risk of nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr virus (EBV) commonly infects the general population and has been associated with nasopharyngeal carcinoma (NPC), which has a high incidence in certain regions. This study aimed to address how EBV variations contribute to the risk of NPC. METHODS: Using logistic regression analysis and based on the sequence variations at EBV-encoded RPMS1, a multi-stage association study was conducted to identify EBV variations associated with NPC risk. A protein degradation assay was performed to characterize the functional relevance of the RPMS1 variations. RESULTS: Based on EBV-encoded RPMS1 variations, a single nucleotide polymorphism (SNP) in the EBV genome (locus 155391: G>A, named G155391A) was associated with NPC in 157 cases and 319 healthy controls from an NPC endemic region in South China [P < 0.001, odds ratio (OR) = 4.47, 95% confidence interval (CI) 2.71-7.37]. The results were further validated in three independent cohorts from the NPC endemic region (P < 0.001, OR = 5.20, 95% CI 3.18-8.50 in 168 cases vs. 241 controls, and P < 0.001, OR = 5.27, 95% CI 4.06-6.85 in 726 cases vs. 880 controls) and a non-endemic region (P < 0.001, OR = 7.52, 95% CI 3.69-15.32 in 58 cases vs. 612 controls). The combined analysis in 1109 cases and 2052 controls revealed that the SNP G155391A was strongly associated with NPC (P(combined) < 0.001, OR = 5.27, 95% CI 4.31-6.44). Moreover, the frequency of the SNP G155391A was associated with NPC incidence but was not associated with the incidences of other EBV-related malignancies. Furthermore, the protein degradation assay showed that this SNP decreased the degradation of the oncogenic RPMS1 protein. CONCLUSIONS: Our study identified an EBV variation specifically and significantly associated with a high risk of NPC. These findings provide insights into the pathogenesis of NPC and strategies for prevention.

Associations between impulsivity, aggression, and suicide in Chinese college students.

BACKGROUND: Although there are accumulating data regarding the epidemiology of suicide in China, there are meager data on suicidal ideation and attempts among college students. Interestingly, elevated impulsivity is thought to facilitate the transition from suicidal thoughts to suicidal behavior. Therefore, the objective of this research was to identify the associations between suicide and the personality factors of impulsivity and aggression. METHODS: This study's sampling method employed stratified random cluster sampling. A multi-stage stratified sampling procedure was used to select participants (n = 5,245). We conducted structured interviews regarding a range of socio-demographic characteristics and suicidal morbidity. The Patient Health Questionnaire depression module (PHQ-9) was used to acquire the information about thoughts of being better off dead or hurting themselves in some ways during the past two weeks. The impulsivity symptoms in this study were assessed with the BIS-11-CH (i.e., the Chinese version of the BIS-11), and the Aggressive symptoms were assessed with the BAQ. The statistical package for social science (SPSS) v.13.0 program (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Socio-demographic variables such as ethnic and gender were compared between groups, through the use of χ2 tests. The nonparametric test (k Independent Sample test, Kruskal-Wallis H) was performed to determine differences between the personality factors of impulsivity and aggression and suicide. RESULTS: In total, 9.1% (n = 479) of the 5,245 students reported they have ever thought about committing suicide; and 1% (n = 51) reported a history of attempted suicide (attempters). The analyses detected significant differences in scores on cognitive impulsivity (p < 0.01), when comparing individuals who only had suicidal ideation and individuals who had attempted suicide. Moreover, significant differences were found between ideators only and attempters on scores of self-oriented attack (p < .001). CONCLUSIONS: Suicidal ideation is prevalent among Chinese university students. Students with high aggression scores were more susceptible to committing suicide. Scores on self-oriented attack and cognitive impulsivity may be important factors for differentially predicting suicide ideation and suicide attempts.

Contrast-enhanced ultrasound liver imaging reporting and data system v2017: patient outcomes after treatment for early-stage hepatocellular carcinoma nodules with category 3-5 and category M.

OBJECTIVE: To evaluate correlation between contrast-enhanced ultrasonography Liver Imaging Reporting and Data System (CEUS LI-RADS; v. 2017) categories (LR 3-5 vs LR-M) and outcomes in patients with early-stage hepatocellular carcinoma (HCC) after initial therapy. METHODS: In this retrospective study, 272 patients with high risks for HCC and solitary clinically or pathologically confirmed HCC were identified between January 2010 and December 2015. Patients were initially treated by resection and radiofrequency ablation (RFA) according to the Barcelona Clinic Liver Cancer staging system and were followed up until December 31, 2018. Recurrence-free survival (RFS) and overall survival (OS) were compared between nodules assigned as LR 3-5 or LR M according to CEUS LI-RADS v. 2017 by using the Kaplan-Meier curve, log-rank test, and Cox proportional hazard model. RESULTS: Early washout is the key determinating whether a nodule is classed as LR-M. Treatment procedures and LI-RADS category showed an independent correlation with OS and RFS (p < 0.05). LR 3-5 category were more correlated with better OS (88.6 months and 74.2 months, respectively; p = 0.017) compared with LR-M. Surgical resection demonstrated longer OS and RFS than RFA in LR-M patients and longer OS in LR 3-5 patients (p < 0.05). Besides, there was no significantly difference in OS and RFS between two categories in resection (p > 0.05), while for patients treated with RFA, LR 3-5 patients showed significant longer OS and RFS than LR-M patients (p < 0.05). CONCLUSION: Patients with HCC assigned as LR-M showed worse RFS and OS and surgical resection tended to be a more effective treatment for these patients. ADVANCES IN KNOWLEDGE: Putting forward a theory that CEUS LI-RADS categories could independently predict the outcome for patients with solitary HCC at early-stage after initial treatment.

Direct sequencing and characterization of a clinical isolate of Epstein-Barr virus from nasopharyngeal carcinoma tissue by using next-generation sequencing technology.

Epstein-Barr virus (EBV)-encoded molecules have been detected in the tumor tissues of several cancers, including nasopharyngeal carcinoma (NPC), suggesting that EBV plays an important role in tumorigenesis. However, the nature of EBV with respect to genome width in vivo and whether EBV undergoes clonal expansion in the tumor tissues are still poorly understood. In this study, next-generation sequencing (NGS) was used to sequence DNA extracted directly from the tumor tissue of a patient with NPC. Apart from the human sequences, a clinically isolated EBV genome 164.7 kb in size was successfully assembled and named GD2 (GenBank accession number HQ020558). Sequence and phylogenetic analyses showed that GD2 was closely related to GD1, a previously assembled variant derived from a patient with NPC. GD2 contains the most prevalent EBV variants reported in Cantonese patients with NPC, suggesting that it might be the prevalent strain in this population. Furthermore, GD2 could be grouped into a single subtype according to common classification criteria and contains only 6 heterozygous point mutations, suggesting the monoclonal expansion of GD2 in NPC. This study represents the first genome-wide analysis of a clinical isolate of EBV directly extracted from NPC tissue. Our study reveals that NGS allows the characterization of genome-wide variations of EBV in clinical tumors and provides evidence of monoclonal expansion of EBV in vivo. The pipeline could also be applied to the study of other pathogen-related malignancies. With additional NGS studies of NPC, it might be possible to uncover the potential causative EBV variant involved in NPC.

Correlation of Skp2 overexpression to prognosis of patients with nasopharyngeal carcinoma from South China.

S-phase kinase-associated protein 2 (Skp2), which plays a role in cell cycle regulation, is commonly overexpressed in a variety of human cancers and associated with poor prognosis. However, its role in nasopharyngeal carcinoma (NPC) is not well understood. In this study, we examined the clinical significance of Skp2, with a particular emphasis on overall survival (OS) and disease-free survival (DFS), in NPC cases in South China, where NPC is an epidemic. Additionally, we explored the function of Skp2 in maintaining a cancer stem cell-like phenotype in NPC cell lines. Skp2 expression was assessed for 127 NPC patients using tissue microarrays and immunohistochemistry and analyzed together with clinicopathologic features, OS, and DFS. Skp2 expression was detectable, or positive, in 75.6% of patients. Although there was no correlation between Skp2 and any clinicopathologic factor, Skp2 expression significantly portended inferior OS (P = 0.013) and DFS (P = 0.012). In the multivariate model, Skp2 expression remained significantly predictive of poor OS [P = 0.009, risk ratio (RR) = 4.06] and DFS (P = 0.008, RR = 3.56), and this was also true for clinical stage (P = 0.012 and RR=3.201 for OS; P = 0.002 and RR=1.94 for DFS) and sex (P = 0.016 and RR=0.31 for OS; P = 0.006 and RR = 0.27 for DFS). After Skp2 knockdown, a colony formation assay was used to evaluate the self-renewal property of stem-like cells in the NPC cell lines CNE-1 and CNE-2. The colony formation efficiency in CNE-1 and CNE-2 cells was decreased. In Skp2-transfected CNE-1 and CNE-2 cells, side population (SP) proportion was increased as detected by flow cytometry. Skp2 is an independent prognostic marker for OS and DFS in NPC. Skp2 may play a role in maintaining the cancer stem cell-like phenotype of NPC cell lines.

Edaravone attenuates cadmium-induced toxicity by inhibiting oxidative stress and inflammation in ICR mice.

The neurotoxicity caused by cadmium (Cd) is well known in humans and experimental animals. However, there is no effective treatment for its toxicity. In this study, we established Cd toxicity models in cultured cells or mice to investigate the detoxification effect of edaravone (Eda). We found that Eda protected GL261 cells from Cd toxicity and prevented the loss of cell viability. In Cd-exposed mice, liver, kidney and testicular damage, as well as cognitive dysfunction were observed. Oxidative stress and inflammatory responses, such as decreased SOD and CAT, increased LDH and MDA, and abnormal changes in the inflammatory factors TNF-α, IL-1ß, IL-6 and IL-10 were detected in serum and brain tissue. Eda protected mice from Cd-induced toxicity and abrogated oxidative stress and inflammatory responses. Also, Eda prevented inflammatory activation of microglia and astrocytes and was accompanied by restoration of the neuronal marker protein MAP2, indicating restoration of neuronal function. In addition, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the response of Eda to the elimination of Cd toxicity. In conclusion, Eda does contribute to the clearance of Cd-induced toxicity.

Development and validation of a nomogram for preoperative prediction of level VII nodal spread in papillary thyroid cancer: Radiologic-pathologic correlation.

PURPOSE: To develop and validate a diagnostic nomogram for preoperative prediction of the level VII nodal spread in papillary thyroid cancer (PTC) by incorporating CT features. METHODS: A dataset of 7896 patients experiencing thyroidectomy for thyroid cancer was collected retrospectively from two hospitals, and 300 patients were finally included in this study. The CT features of metastatic LN were extracted with a one by one match of radiologic-pathologic correlation. Multivariable binary logistic regression analysis was used to develop predicting model, and then a nomogram was developed utilizing a primary cohort of 152 patients from hospital #1. The nomogram was validated in external cohort of 62 patients from hospital #2 and an independent cohort of 86 patients from hospital #1. The performance of the nomogram was evaluated with respect to its calibration, discrimination. RESULTS: 531 LNs from 300 patients were analyzed. 42.6% LNs were > 5 mm in short diameter. A total of 7 selected CT features were significantly associated with LN status (P < 0.05), including nodular enhancement, cystic change, calcification and so on. These features were contained in the prediction nomogram. The model showed good discrimination and good calibration, with a C-index of 0.938 (95% CI, 0.913 to 0.963) and 0. 795 (95% CI, 0. 726 to 0.864) for the primary cohort and the validation cohort, respectively. Decision curve analysis demonstrated that the nomogram was clinically applicable. CONCLUSIONS: This nomogram incorporating pathologically relevant CT features has demonstrated a high diagnostic value for predicting level VII nodal spread in PTC. Our work may help thyroid surgeon to decide whether upper mediastinal lymphadenectomy should be performed, which is associated with thoracotomy or other surgery.

Preoperative Evaluation of Central Lymph Nodes in Papillary Thyroid Carcinoma Using High-Resolution Ultrasound and Shear-Wave Elastography.

ABSTRACT: The aim of this study was to discuss the diagnostic value of high-resolution ultrasound and virtual touch tissue imaging quantification (VTIQ) for distinguishing metastatic and benign central lymph nodes (CLNs) in patients with papillary thyroid carcinoma. This retrospective study involved 86 pathologically proven benign lymph nodes (LNs) and 118 metastatic LNs in patients with papillary thyroid carcinoma. We analyzed the sonographic features of CLNs (size, shape, distribution, hilum, echogenicity, cystic change, calcification, vascularity, shear-wave velocity [SWV]). The prevalence of sonographic features and the SWV was compared between metastatic and benign CLNs. The size, shape, margin, distribution, presence of hilum, echogenicity, calcification, and vascularity were significantly different between benign and metastatic CLNs (P < 0.05 for all). The mean maximum SWV for malignant CLNs was 3.139 ± 0.408 m/s, whereas that of benign CLNs was 2.418 ± 0.369 m/s (P < 0.05). The cutoff point of the SWV for differentiating benign and malignant LNs was 2.675 m/s. Logistic regression analysis showed that round or irregular shape, aggregation or fusion, calcification, and VTIQ value greater than 2.675 m/s of CLNs were independent risk factors for malignancy, with an odds ratio of 5.77, 3.05, 3.23, and 62.85, respectively. High-resolution ultrasound and VTIQ can provide valuable information for distinguishing metastatic from benign CLNs.

Value of dual-phase, contrast-enhanced CT combined with ultrasound for the diagnosis of metastasis to central lymph nodes in patients with papillary thyroid cancer.

AIMS: To evaluate the diagnostic performance of computed tomography combined with ultrasound (CT/US) in metastatic central lymph nodes (CLNs) compared with US in patients with papillary thyroid cancer (PTC). MATERIAL AND METHODS: Six-hundred patients with surgically proven PTC who underwent both US and CT examination before CLN dissection were evaluated retrospectively. All cases were divided into four subgroups according to the tumor size and number. Diagnostic performances of US, CT and CT/US were evaluated. RESULTS: Among 600 patients with CLN dissection, CT/US showed higher sensitivity (89.10%) and accuracy (83.00%) than US alone (76.06%, 76.50%). In the subgroup of solitary non-microcarcinomas, the AUC of CT/US was significantly higher than that for US alone (0.827 vs. 0.722, P < 0.05). For the subgroup of solitary or multiple microcarcinomas, the performance efficiency of CT had no obvious advantage over that of US (0.698 vs. 0.740, 0.798 vs. 0.802, P > 0.05). For the subgroup of multiple non-microcarcinomas, CT, US and US/CT had high diagnostic efficacy (AUC > 0.8, Accuracy >80%. P > 0.05), and there was no significant difference between them. CONCLUSIONS: In the subgroup of solitary non-microcarcinoma, CT combined with US provided better diagnostic efficacy, and for those cases, complementary CT examination was recommended. In other subgroups, the diagnostic efficacy of US/CT was similar to that of US alone, and there was no significant benefit from additional CT examination.