Contrast-Enhanced Ultrasound and Strain Elastography for Differentiating Benign and Malignant Parotid Tumors.

OBJECTIVES: Preoperative differentiation between benign parotid tumors (BPT) and malignant parotid tumors (MPT) is crucial for treatment decisions. The purpose of this study was to investigate the benefits of combining contrast-enhanced ultrasound (CEUS) and strain elastography (SE) for preoperative differentiation between BPT and MPT. METHODS: A total of 115 patients with BPT (n=72) or MPT (n=43) who underwent ultrasound (US), SE, and CEUS were enrolled. US and CEUS features and the elasticity score were evaluated. Receiver operating characteristic curve (ROC) analysis was used to assess the diagnostic performance of SE, CEUS, and SE + CEUS with respect to identifying MPT from BPT. RESULTS: Solitary presentation, larger diameter, irregular shape, ill-defined margin, heterogeneous echogenicity, and calcification on US and higher elasticity score on SE had a significant association with malignancy. MPT also presented an unclear margin, larger size after enhancement, and "fast-in and fast-out" pattern on CEUS. The combination of SE and CEUS was effective for differentiating MPT from BPT (AUC: 0.88, 0.80-0.95), with a sensitivity of 86.0%, specificity of 88.9%, and accuracy of 87.8%, which were significantly higher than the values for SE (AUC: 0.75, 0.66-0.85) and CEUS (AUC: 0.82, 0.73-0.91) alone. CONCLUSION: The combination of CEUS and SE is valuable for distinguishing MPT from BPT.

N1-methyladenosine profiling of long non-coding RNA in colorectal cancer.

N1-methyladenosine (m1A), is a unique methyl group that confers post-transcriptional modification of gene expression, and plays important roles in various human diseases. However, the abundance of this modification and its effects on long non-coding RNAs (lncRNAs) in human colorectal cancer (CRC) remain unclear. In this study, methylated RNA immunoprecipitation sequencing was performed in three pairs of human CRC and nontumorous tissues to identify m1A peaks and its correlation with differential alterations of lncRNA expression in CRC. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment pathway analyses were applied to predict the potential roles of m1A on gene expression. We found that CRC and adjacent tissues had a noticeable difference in m1A distribution. Notably, HGGAGRA and WGGANGA were recognized as the most significantly enriched motifs, respectively. Co-analysis of methylation and RNA sequencing demonstrated downregulated lncRNAs along with m1A modification in CRC. GO and KEGG pathway analyses revealed that the unique distribution of m1A sites in lncRNAs had a significant correlation with CRC signaling pathways. In conclusion, our results delineated the distribution pattern of m1A methylation on lncRNAs, and provided potential roles of this modification in different pathways and tumor progression of CRC.

Determination of selpercatinib, a RET kinase inhibitor, in rat plasma and its application to a pharmacokinetic study.

Selpercatinib (LOXO-292) is a selective and potent RET inhibitor. A highly sensitive, rapid and specific high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method for quantification of selpercatinib in rat plasma is reported. The method was validated in terms of selectivity, linearity, accuracy and precision, extraction recovery and matrix effect, stability and carryover as per the US Food and Drug Administration guidelines for bioanalytical method validation. Selpercatinib was detected by an electrospray ionization interface under selective reaction monitoring conditions in the positive ion mode. The calibration curve was linear over the concentration range from 1 to 2000 ng/ml with r2 = 0.9951. The intra- and inter-batch accuracy values ranged from 97.45 to 100.97% and from 98.70 to 100.74% with coefficients of variation of 2.45-6.99% and 5.89-7.99%, respectively. The extraction recovery and IS-normalized matrix factor were acceptable for the bioanalysis of selpercatinib. Additionally, selpercatinib was found to be stable under the detected conditions. It showed linear pharmacokinetic characteristics following oral administration to rats at 2.0-18.0 mg/kg. The results showed that the novel method for detecting selpercatinib in rat plasma could be successfully applied for quantification of selpercatinib in biosamples from nonclinical studies.

Genomics and prognosis analysis of epithelial-mesenchymal transition in colorectal cancer patients.

BACKGROUND: The epithelial-mesenchymal transition (EMT) plays a pivotal role in various physiological processes, such as embryonic development, tissue morphogenesis, and wound healing. EMT also plays an important role in cancer invasion, metastasis, and chemoresistance. Additionally, EMT is partially responsible for chemoresistance in colorectal cancer (CRC). The aim of this research is to develop an EMT-based prognostic signature in CRC. METHODS: RNA-seq and microarray data, together with clinical information, were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. A total of 244 differentially expressed EMT-related genes (ERGs) were obtained by comparing the expression between normal and tumor tissues. An EMT-related signature of 11 genes was identified as crucially related to the overall survival (OS) of patients through univariate Cox proportional hazard analysis, least absolute shrinkage and selection operator (LASSO), and Cox regression analysis. Finally, we established a clinical nomogram to predict the survival possibility of CRC patients by integrating clinical characteristics and the EMT-related gene signature. RESULTS: Two hundred and forty-four differentially expressed ERGs and their enriched pathways were confirmed. Significant enrichment analysis revealed that EMT-related signaling pathway genes were highly related to CRC. Kaplan-Meier analysis revealed that the 11-EMT signature could significantly distinguish high- and low-risk patients in both TCGA and GEO CRC cohorts. In addition, the calibration curves verified fine concordance between the nomogram prediction model and actual observation. CONCLUSION: We developed a novel EMT-related gene signature for the prognosis prediction of CRC patients, which could improve the individualized outcome prediction in CRC.

MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2.

Angiotensin-converting enzyme 2 (ACE2) protects against hypoxic pulmonary hypertension (HPH) by inhibiting the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Under hypoxia, the hypoxia-inducible factor 1α (HIF-1α) inhibits ACE2 indirectly; however, the underlying mechanism is unclear. In the present study, we found that exposure to chronic hypoxia stimulated microRNA (miRNA) let-7b expression in rat lung via a HIF-1α-dependent pathway. Let-7b downregulated ACE2 expression by directly targeting the coding sequence of ACE2. Our in vitro and in vivo results revealed that let-7b contributed to the pathogenesis of HPH by inducing PASMCs proliferation and migration. Let-7b knockout mitigated right ventricle hypertrophy and pulmonary vessel remodeling in HPH by restoring ACE2 expression. Overall, we demonstrated that HIF-1α inhibited ACE2 expression via the HIF-1α-let-7b-ACE2 axis, which contributed to the pathogenesis of HPH by stimulating PASMCs proliferation and migration. Since let-7b knockout alleviated the development of HPH, let-7b may serve as a potential clinical target for the treatment of HPH.

Long non-coding RNA TTN-AS1 facilitates tumorigenesis of papillary thyroid cancer through modulating the miR-153-3p/ZNRF2 axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are crucial modulators in the tumorigenesis of numerous cancers, including papillary thyroid cancer (PTC). However, it is unclear whether lncRNA TTN antisense RNA 1 (TTN-AS1) can regulate PTC progression. The present study aimed to reveal the mechanism and function of TTN-AS1 in PTC. METHODS: TTN-AS1 expression in 92 pairs PTC tissues and four PTC cells was measured via a quantitative reverse transcriptase-polymerase chain reaction assay. The relationship of TTN-AS1 expression and clinical pathological features of PTC patients was analyzed using a chi-squared test. The biofunction of TTN-AS1 in PTC was identified by loss or gain-of-function assays. Based on bioinformatics analysis and mechanism experiments, the molecular mechanism of TTN-AS1 was analyzed and identified. RESULTS: A high level of TTN-AS1 was observed in PTC tissues and cells. The expression level of TTN-AS1 is possibly associated with lymphatic metastasis, TNM stage and the overall survival of PTC patients. Functionally, TTN-AS1 knockdown inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition in PTC, whereas overexpression of TTN-AS1 led to the opposite results. Mechanistically, TTN-AS1 acted as a competing endogenous RNA by sponging microRNA-153-3p (miR-153-3p) to elevate zinc and ring finger 2 (ZNRF2) expression. Additionally, a high level of TTN-AS1 in PTC was closely correlated with the activity of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. CONCLUSIONS: The findings obtained in the present study indicate that TTN-AS1 facilitated PTC progression by regulating the miR-153-3p/ZNRF2 axis and activating the PI3K/Akt/mTOR pathway.

HOTAIR induces the ubiquitination of Runx3 by interacting with Mex3b and enhances the invasion of gastric cancer cells.

BACKGROUND: Long non-coding RNAs (LncRNAs) exert their functions mainly by binding to their corresponding proteins. Runt-related transcription factor 3 (Runx3) is an important transcription factor that functions as a tumor suppressor in gastric cancer. Whether there is an interplay between LncRNAs and Runx3 remains unclear. METHODS: RPISeq was applied to screen the LncRNAs that potentially bind to Runx3. The interaction between LncRNA HOX antisense intergenic RNA (HOTAIR) and Runx3 was validated by RNA Immunoprecipitation and RNA pull-down assays. The role of Mex3b in the ubiquitination of Runx3 induced by HOTAIR was assessed by immunoprecipitation. Pearson's correlation between HOTAIR mRNA expression and Runx3 protein expression was analyzed. Cell migration and invasion were explored by transwell assays. RESULTS: We found that HOTAIR was bound to Runx3 protein and identified the fragment of HOTAIR spanning 1951-2100 bp as the specific binding site. In addition, mex-3 RNA binding family member B (Mex3b) was an E3 ligase involved in HOTAIR-induced ubiquitous degradation of Runx3. Silencing the expression of HOTAIR or Mex3b attenuated the degradation of Runx3. In human gastric cancer tissues, HOTAIR was negatively associated with the expression level of Runx3 protein (Pearson coefficient - 0.501, p = 0.025). Inhibition of HOTAIR significantly suppressed gastric cancer cell migration and invasion through upregulating claudin1, which could be reversed by co-deficiency of Runx3. CONCLUSIONS: These results uncovered the novel interaction between HOTAIR and Runx3, and provided potential therapeutic targets on the metastasis of gastric cancer.

Small-bowel capsule endoscopy in patients with unexplained chronic abdominal pain: a systematic review.

BACKGROUND: Patients frequently consult primary care physicians and gastroenterologists when experiencing chronic abdominal pain. Although its diagnostic efficacy in these settings is uncertain, small-bowel capsule endoscopy (SBCE) has been used to evaluate the unexplained reasons for abdominal pain. OBJECTIVE: To evaluate the diagnostic yield of SBCE in patients with unexplained chronic abdominal pain. DESIGN: We performed a retrospective review of publications reporting the diagnostic yield of SBCE in patients with unexplained chronic abdominal pain and calculated the overall diagnostic yield. SETTING: Two investigators independently searched studies from databases and analyzed the results. PATIENTS: A total of 1520 patients from 21 studies were included. INTERVENTIONS: Small-bowel capsule endoscopy. MAIN OUTCOME MEASUREMENTS: Per-patient diagnostic yield, with 95% confidence intervals (CI), was evaluated by a random-effect model. Clear categorical analysis also was performed. RESULTS: The pooled diagnostic yield of SBCE in patients with unexplained chronic abdominal pain was 20.9% (95% CI, 15.9%-25.9%), with high heterogeneity (I(2) = 80.0%; P ＜ .001). Inflammatory lesions were the most common (78.3%) positive findings, followed by tumors (9.0%). LIMITATIONS: Heterogeneity among studies, retrospective design, variable chronicity of abdominal pain, and different previous examinations before SBCE. CONCLUSION: SBCE provides a noninvasive diagnostic tool for patients with unexplained chronic abdominal pain, but the diagnostic yield is limited (20.9%). Among patients with positive findings, inflammatory lesions are the most common.

Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension.

We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1α (HIF-1α). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2α (HIF-2α) was employed in human PASMCs. Transgelin expression was diminished in HIF-2α-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2α did not transactivate the transgelin promoter directly. TGF-ß1 concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-ß1 under hypoxia was regulated by HIF-2α. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-ß1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2α upregulates transgelin indirectly and that accumulated TGF-ß1 is a mediator in the upregulation of transgelin by HIF-2α under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo.

FGFR1 governs iron homeostasis via regulating intracellular protein degradation pathways of IRP2 in prostate cancer cells.

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy.

Association between papillary thyroid carcinoma and lymphocytic thyroiditis: A retrospective study.

The aim of the present study was to evaluate the association between coexisting lymphocytic thyroiditis (LT) and the clinicopathological features of papillary thyroid carcinoma (PTC). The records of 458 patients with PTC who underwent a total thyroidectomy and lymph node dissection in Sir Run Run Shaw Hospital (Hangzhou, China) were analyzed. In accordance with the histopathology of thyroid parenchyma, the cases were divided into three groups, including Hashimoto's thyroiditis (HT), non-Hashimoto's type LT (NHLT) and no LT. Based on the histopathology, data on age, sex, maximum diameter of tumor, multifocality, extrathyroidal extension, metastatic lymph node size, extranodal extension and tumor grades in the different groups were analyzed and compared. The prevalence of coexisting LT was 29.0% (133/458), of which 7.6% (35/458) was HT and 21.4% (98/458) was NHLT. PTC concomitant with LT was significantly associated with female patients (95.5 vs. 70.2%; P<0.001), a lower rate of extrathyroidal extension and/or capsular invasion (25.6 vs. 39.7%; P=0.004), central lymph node metastasis (CLNM) ratio (10.71 vs. 17.37; P=0.014), higher number of dissected central lymph nodes (16.83 vs. 11.7; P<0.001), larger metastatic lymph nodes (0.66 vs. 0.46 cm; P<0.001), higher occurrence of multifocality (61.7 vs. 50.5%; P=0.029) and earlier pT stage (57.9 vs. 38.8%; P<0.001), regardless of the combined or separate consideration of HT and NHLT. Besides, LT was associated with multifocality [odds ratio (OR), 1.578; 95% confidence interval (CI), 1.046-2.382; P=0.030]. Furthermore, in patients with PTC, CLNM had a significant association with the male sex (OR, 2.000; 95% CI, 1.216-3.288; P=0.006), an age of <45 years (OR, 0.592; 95% CI, 0.398-0.879; P=0.009) and a tumor size of >1 cm (OR, 3.913; 95% CI, 2.431-5.734; P<0.001). In conclusion, patients with PTC and LT showed a greater female preponderance, multifocality, a lower extrathyroidal extension and a lower CLNM ratio. LT was associated with an increased risk of multifocality in PTC.

The safety and efficacy of delayed surgery by simulating clinical progression of observable papillary thyroid microcarcinoma: a retrospective analysis of 524 patients from a single medical center.

Objective: When active surveillance (AS) is developed in the patients with low-risk papillary thyroid microcarcinoma (PTMC), a medical center needs to ensure the delayed operation that is caused by PTMC clinical progression to have the same prognosis as that of immediate operation. The objective of this study was to investigate the efficacy of delayed surgery by simulating clinical progression (tumor size enlargement and appearance of lymph node metastasis) of PTMCs with AS in a single medical center. Methods: We retrospectively analyzed the response to therapy in 317 papillary thyroid carcinoma patients treated with total thyroidectomy and post-operative radioactive iodine ablation. They were classified into three groups according to tumor size (group A ≤0.5 cm; group B >0.5 cm and ≤1 cm; group C >1 cm and ≤1.5 cm) or two groups according to the presence (cN1) or absence (cN0) of the clinical lymph node (LN) metastasis. Groups C and cN1 were regarded as simulated clinical progression of observational PTMC and the operation for them was assumed to be "delayed surgery". However, Groups A, B and cN0 were regarded as no clinical progression and the operation for them was considered as immediate surgery. Results: There were no significantly differences in excellent response to therapy and recurrence-free survival not only among the group A, B and C, but also between the group cN0 and cN1. In other words, these insignificant differences were found between immediate and simulated "delayed" surgeries. Conclusion: For the PTMC patients suitable for AS, the oncological outcomes were also excellent even if surgery was delayed until after the presence of clinical progression, according to our clinical simulation. Furthermore, we consider that it was feasible for medical centers to assess the ability to implement AS for PTMC patients by retrospectively analyzing their own previous clinical data using the described simulation.

Predictive and Prognostic Assessment Models for Tumor Deposit in Colorectal Cancer Patients With No Distant Metastasis.

BACKGROUND: More and more evidence indicated that tumor deposit (TD) was significantly associated with local recurrence, distant metastasis (DM), and poor prognosis for patients with colorectal cancer (CRC). This study aims to explore the main clinical risk factors for the presence of TD in CRC patients with no DM (CRC-NDM) and the prognostic factors for TD-positive patients after surgery. METHODS: The data of patients with CRC-NDM between 2010 and 2017 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A logistic regression model was used to identify risk factors for TD presence. Fine and Gray's competing-risk model was performed to analyze prognostic factors for TD-positive CRC-NDM patients. A predictive nomogram was constructed using the multivariate logistic regression model. The concordance index (C-index), the area under the receiver operating characteristic (ROC) curve (AUC), and the calibration were used to evaluate the predictive nomogram. Also, a prognostic nomogram was built based on multivariate competing-risk regression. C-index, the calibration, and decision-curve analysis (DCA) were performed to validate the prognostic model. RESULTS: The predictive nomogram to predict the presence of TD had a C-index of 0.785 and AUC of 0.787 and 0.782 in the training and validation sets, respectively. From the competing-risk analysis, chemotherapy (subdistribution hazard ratio (SHR) = 0.542, p < 0.001) can significantly reduce CRC-specific death (CCSD). The prognostic nomogram for the outcome prediction in postoperative CRC-NDM patients with TD had a C-index of 0.727. The 5-year survival of CCSD was 17.16%, 36.20%, and 63.19% in low-, medium-, and high-risk subgroups, respectively (Gray's test, p < 0.001). CONCLUSIONS: We constructed an easily predictive nomogram in identifying the high-risk TD-positive CRC-NDM patients. Besides, a prognostic nomogram was built to help clinicians identify poor-outcome individuals in postoperative CRC-NDM patients with TD. For the high-risk or medium-risk subgroup, additional chemotherapy may be more advantageous for the TD-positive patients rather than radiotherapy.

The Different Effects of Skeletal Muscle and Fat Mass on Height Increment in Children and Adolescents Aged 6-11 Years: A Cohort Study From China.

Objective: This study aimed to investigate the contribution of body composition including skeletal muscle mass (SMM) and body fat mass (BFM) to longitudinal growth among children and adolescents aged 6-11 years old. Methods: This cohort study was conducted from the annual health examination between 2019 and 2020. Annual height gain and weight gain and changes in SMM and BFM were calculated and compared between sexes, different nutritional status, and growth curve shifting mode. Spearman analyses and multiple linear regression analysis were performed to identify the impact of SMM, BFM, or body mass index (BMI) on height gain. Results: Of the 584 subjects, the annual height gains of boys (4.76 cm in the 6-9-year group and 4.63 cm in the 10-11-year group) were significantly lower than those of girls (5.48 and 5.74 cm, respectively). Spearman analysis showed that SMM gain and height gain were positively and significantly correlated in each examination of all children (r = 0.535 for boys and 0.734 for girls, p < 0.001). Conversely, BFM and height gains were negatively (r = -0.5240 for boys and -0.232 for girls, p < 0.001) correlated. Multiple linear regression analysis identified SMM gain as an independent predictor (95% CI: 1.20,1.44) of height gain after adjusting for age, gender, BMI, BFM gain, and percentage of body fat (PBF). Conclusion: SMM gains, rather than BFM gains, were associated with height gains in children and adolescents aged 6-11 years. Monitoring SMM changes in routine healthcare might motivate children and adolescents to achieve dietary and exercise recommendations, thereby growing taller without gaining excessive weight.

Needle tract seeding of papillary thyroid carcinoma after fine-needle capillary biopsy: A case report.

BACKGROUND: Fine-needle biopsy is an accurate and cost-efficient tool for the assessment of thyroid nodules. It includes two primary methods: Fine-needle capillary biopsy (FNCB) and fine-needle aspiration biopsy. Needle tract seeding (NTS) is a rare complication of thyroid fine-needle biopsy mainly caused by fine-needle aspiration biopsy rather than FNCB. Here, we present an extremely rare case of a papillary thyroid carcinoma (PTC) patient with FNCB-derived NTS. CASE SUMMARY: We report a 32-year-old woman with PTC who showed subcutaneous NTS 1 year after FNCB and thyroidectomy. NTS was diagnosed based on clinical manifestations, biochemistry indices, and imaging (computed tomography and ultrasound). Pathological identification of PTC metastases consistent with the puncture path is the gold standard for diagnosis. Surgical resection was the main method used to treat the disease. After surgery, thyroid function tests and ultrasound scans were performed every 3-6 mo. To date, no evidence of tumor recurrence has been observed. CONCLUSION: FNCB is a safe procedure as NTS is rare, and can be easily removed surgically with no recurrence. Accordingly, NTS should not limit the usefulness of FNCB.

The effect of the area proportion of the metastatic lesion within the central metastatic lymph node on response to therapy in papillary thyroid carcinoma.

Lymph node (LN) metastasis has been strongly associated with locoregional recurrence and decreased survival time of patients with papillary thyroid carcinoma (PTC). Although the characteristics of the metastatic LNs (mLN) have been determined, including size, number, micro-metastasis and extra-nodal extension (ENE), further analysis is warranted. The present study introduced a new parameter known as the area proportion of the metastatic lesion within the central mLNs (APmCLN). The objective was to evaluate the impact of the APmCLN on response to therapy in patients with PTC. In total, 355 patients with PTC treated with total thyroidectomy and neck dissection, post-operative radioactive iodine and thyroid-stimulating hormone suppression were retrospectively studied. The patients were classified into two groups: Group A (APmCLN ≤75%) and group B (APmCLN >75%). The association of various clinicopathological characteristics between these two groups was investigated. Univariate and multivariate analyses were used to evaluate risk factors associated with a non-Excellent response to therapy and recurrence-free survival (RFS). The analysis showed that APmCLN >75% was significantly associated with extra-thyroidal extension, clinically apparent nodes (cN1), pathological N1b (pN1b), ENE, greater number and larger size of central mLN and larger size of the central LN metastatic lesion. Furthermore, it was reported that chronic lymphocytic thyroiditis, larger central mLN size and APmCLN >75% were independent risk factors for a non-excellent response to therapy. Finally, it was determined that the rate of excellent response to therapy was significantly higher in pathological N1 (pN1) patients with APmCLN ≤75% (108/144, 75.0%) compared with patients with APmCLN >75% (27/47, 57.4%) (P=0.022). However, there was no significant difference (P=0.247) between patients with APmCLN ≤75% and pN0 (132/164, 80.5%). RFS was 89.4% in patients with pN1-APmCLN >75%, whereas those with pN1-APmCLN ≤75% and pN0 did not experience a relapse. Patients with PTC with APmCLN >75% should be regarded as high-risk and may require more aggressive treatment and careful follow-up.

A clinical model to predict distant metastasis in patients with superficial gastric cancer with negative lymph node metastasis and a survival analysis for patients with metastasis.

BACKGROUND: Distant metastasis (DM) is relatively rare in superficial gastric cancer (SGC), especially in patients without lymph node metastasis. This study aimed to explore the main clinical risk factors for DM in patients with superficial gastric cancer-no lymph node metastasis (SGC-NLNM) and the prognostic factors for patients with DM. METHODS: Records of patients with SGC-NLNM between 2004 and 2015 were collected from the public Surveillance, Epidemiology, and End Results (SEER) database. Both univariate and multivariate logistic regressions were performed to analyze the clinical risk factors for DM. The Kaplan-Meier method and Cox regression model were used to identify prognostic factors for patients with DM. A nomogram was built based on multivariate logistic regression and evaluated by the C-index, the calibration, and the area under the receiver operating characteristic curve (AUC). RESULTS: We developed and validated a nomogram to predict DM in patients with SGC-NLNM, showing that race, age, primary site, depth, size, and grade were independent risk factors. The built nomogram had a good discriminatory performance, with a C-index of 0.836 (95% confidence interval [CI]: 0.813-0.859). Calibration plots showed that the predicted DM probability was identical to the actual observations in both the training and validation sets. AUC was 0.846 (95% CI: 0.820-0.871) and 0.801 (95% CI: 0.751-0.850) in the training and validation sets, respectively. The results of the survival analysis revealed that surgery (hazard ratio [HR] = 0.249; 95% CI, 0.125-0.495), chemotherapy (HR = 0.473; 95% CI, 0.353-0.633), and grade (HR = 1.374; 95% CI, 1.018-1.854) were independent prognostic factors associated with cancer-specific survival (CSS), but radiotherapy was not (log-rank test, p = 0.676). CONCLUSIONS: We constructed a sensitive and discriminative nomogram to identify high-risk patients with SGC-NLNM who may harbor dissemination at initial diagnosis. The tumor size and primary site were the largest contributors to DM prediction. Compared with radiotherapy, aggressive surgery, and chemotherapy may be better options for patients with DM.

Predicting non-small-volume central lymph node metastases (>5 or ≥2 mm) preoperatively in cN0 papillary thyroid microcarcinoma without extrathyroidal extension.

The ability to identify patients with aggressive papillary thyroid microcarcinoma (PTMC) from the low-risk patients is critical to planning proper management of PTMC. Lymph node metastases showed association with recurrence and low survival rate, especially in patients with >5 or ≥2 mm metastatic lymph nodes. Therefore, this study aimed to investigate the preoperatively predictive factors of non-small-volume (metastatic lymph nodes >5 or ≥2 mm in size) central lymph node metastases (NSVCLNM) in PTMC patients. A total of 420 patients with clinically node-negative (cN0) PTMC without extrathyroidal extension underwent thyroidectomy plus central neck dissection (CND) between January 2013 and December 2015, were retrospectively analyzed. Of the 420 patients, 33 (7.9%) had NSVCLNM. The 5-year recurrence-free survival was significantly less in cN0 PTMC patients with NSVCLNM, when compared with patients without NSVCLNM (80.8% vs 100%, P < .001). Multivariate logistic regression revealed age ≤36 years (P < .001), male sex (P = .002), ultrasonic tumor sizes of >0.65 cm (P < .001), and ultrasonic multifocality (P = .039) were independent predictive factors of NSVCLNM. A prediction equation (Y = 1.714 × age + 1.361 × sex + 1.639 × tumor size + 0.842 × multifocality -5.196) was developed, with a sensitivity (69.7%) and a specificity (84.0%), respectively, at an optimal cutoff point of -2.418. In conclusion, if the predictive value was >-2.418 according to the equation, immediate surgery including CND rather than active surveillance might be considered for cN0 PTMC patients.

Predictive factors for non-small-volume central lymph node metastases (more than 5 or ≥ 2 mm) in clinically node-negative papillary thyroid carcinoma.

The benefits of prophylactic central neck dissection (pCND) for treating patients with clinical node-negative (cN0) papillary thyroid carcinoma (PTC) remain controversial. Lymph node metastases have been strongly associated with local recurrence and low survival, especially in PTC patients with 5 or more or ≥2 mm metastatic lymph nodes. The following study investigates the incidence and risk factors of more than 5 or ≥2 mm metastatic lymph nodes in the central compartment.A total of 611 patients with cN0 PTC were retrospectively analyzed. Cervical lymph nodes were harvested, and the size of metastatic lymph nodes was consequently analyzed.Non-small-volume central lymph node metastases (NSVCLNM), defined as more than 5 or ≥2 mm metastatic lymph nodes) were detected in 67 (11.0%) patients. Male gender, age ≤36 years, multifocal lesions, extrathyroidal extension, and tumor size > 0.85 cm were independent risk factors for NSVCLNM in cN0 PTC. The sensitivity and specificity of having ≥3 risk factors for predicting NSVCLNM was 46.3% and 86.8%, respectively.These findings suggest that pCND is a suitable treatment strategy for cN0 PTC patients with 3 or more risk factors for NSVCLNM.

RhoA-Rho associated kinase signaling leads to renin-angiotensin system imbalance and angiotensin converting enzyme 2 has a protective role in acute pulmonary embolism.

INTRODUCTION: Acute pulmonary embolism (APE) is a cardiovascular disease with high morbidity and mortality. Although the anatomical obstruction of the pulmonary vascular bed initiates APE, recent studies have suggested that vasoconstrictors in the renin-angiotensin system (RAS) play a role in the severity of APE. MATERIALS AND METHODS: We performed a 5-year retrospective clinical study to analyze the key RAS components in APE patients, including angiotensin converting enzyme (ACE), ACE2, angiotensin II (Ang II) and angiotensin 1-7(Ang(1-7)). The role of RhoA-Rho associated kinase (ROCK) signaling in regulating RAS vasoconstrictors was detected in rat pulmonary artery endothelial cells and in an APE rat model. RESULTS: In clinical study, we found that the levels of RAS vasoconstrictors were correlated with the clinical classification of APE patients, ACE and Ang II were unregulated, whereas ACE2 and Ang(1-7) were downregulated in the high-risk group compared to the healthy volunteers. In animal study, we found that activated RhoA-ROCK signaling was responsible for the imbalance in RAS vasoconstrictors both in vitro and in vivo, and further evidence indicated that ROCK inhibitors (Y27632 or HA1077) and an ACE2 activator (Resorcinol naphthalein) restored the dysregulated RAS vasoconstrictors significantly and had a protective role in an APE rat model. CONCLUSIONS: Our study revealed that RhoA-ROCK signaling leads to RAS imbalance in APE patients, and ACE2 activation might be a novel therapeutic target in APE treatment.