Sex-dependent impact of obesity on aggressiveness of papillary thyroid cancer.

PURPOSE: To investigate the impact of body mass index (BMI) on the aggressiveness of papillary thyroid cancer (PTC). METHODS: A total of 1720 PTC patients with total thyroidectomy or lobectomy, from January 2017 to April 2020, were retrospectively evaluated. Based on BMI, they were divided into two groups, as follows: control (CON, < 24 kg/m2) and overweight and obesity (OB, ≥ 24 kg/m2), each sex being analyzed separately. RESULTS: In the whole cohort, the OB group had significantly higher rates of extrathyroidal extension (21.5 vs. 16.8%, p = 0.013), multifocality (43.2 vs. 37.7%, p = 0.018), and BRAF-V600E mutation (82.9 vs. 79.3%, p = 0.015) than the CON group. In males, the OB group had increased rates of tumor size over 1cm (54.4 vs. 42.7%, p = 0.008), extrathyroidal extension (24.9 vs. 12.4%, p = 0.001), and multifocality (42.7 vs. 33.5%, p = 0.038). The OB group had significantly higher adjusted odds ratios (ORs) of 1.63 (1.14-2.33, p = 0.008), 2.12 (1.26-3.57, p = 0.005), and 1.56 (1.07-2.29, p = 0.022) for tumor size over 1cm, extrathyroidal extension, and multifocality compared with CON. Additionally, overweight and obesity were analyzed alone and the rates of extrathyroidal extension (30/100, 30.0%, p = 0.001) and tumor size over 1cm (65/100, 65.0%, p = 0.001) were significantly higher in the obesity group than in the overweight and CON groups. The obesity group had robust higher adjusted ORs of 2.51(1.50-4.20, p < 0.001), 2.93 (1.50-5.73, p = 0.002) and 1.89 (1.11-3.22, p = 0.020) for tumor size over 1cm, extrathyroidal extension, and multifocality compared with CON. CONCLUSIONS: Overweight and obesity were predominant independent risk factors for PTC aggressiveness in males. These data indicated that the therapeutic treatment should be based on risk stratification by BMI in males.

HHEX suppresses advanced thyroid cancer by interacting with TLE3.

Haematopoietically Expressed Homeobox (HHEX) gene is highly expressed in the thyroid gland and plays critical roles in the development and differentiation of the thyroid gland. While it has been indicated to be downregulated in thyroid cancer, its function and the underlying mechanism remain unclear. Herein, we observed low expression and aberrant cytoplasmic localization of HHEX in thyroid cancer cell lines. Knockdown of HHEX significantly enhanced cell proliferation, migration and invasion, while overexpression of HHEX showed the opposite effects in vitro and in vivo. These data provide evidence that HHEX is a tumor suppressor in thyroid cancer. Additionally, our results showed that HHEX overexpression upregulated the expression of sodium iodine symporter (NIS) mRNA and also enhanced NIS promoter activity, suggesting a favorable effect of HHEX in promoting thyroid cancer differentiation. Mechanistically, HHEX exerted a regulatory effect on the expression of transducin-like enhancer of split 3 (TLE3) protein, which inhibited the Wnt/ß-catenin signaling pathway. Nuclear localized HHEX bound to and upregulated TLE3 expression by preventing TLE3 protein from being distributed to the cytoplasm and being ubiquitinated. In conclusion, our study suggested that restoring HHEX expression has the potential to be a new strategy in the treatment of advanced thyroid cancer.

Corrigendum: The Risk Stratification of Papillary Thyroid Cancer With Bethesda Category III (Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance) by Thyroid Fine-Needle Aspiration Could Be Assisted by Tumor Size for Precision Treatment.

[This corrects the article DOI: 10.3389/fendo.2022.822423.].

Microfluidic Production of Zwitterion Coating Microcapsules with Low Foreign Body Reactions for Improved Islet Transplantation.

Islet transplantation is a promising strategy for type 1 diabetes mellitus (T1DM) treatment, whereas implanted-associated foreign body reaction (FBR) usually induces the necrosis of transplanted islets and leads to the failure of glycemic control. Benefiting from the excellent anti-biofouling property of zwitterionic materials and their successful application in macroscopic implanted devices, microcapsules with zwitterionic coatings may be promising candidates for islet encapsulation. Herein, a series of zwitterion-coated core-shell microcapsules is fabricated (including carboxybetaine methacrylate [CBMA]-coated gelatin methacrylate [GelMA] [CBMA-GelMA], sulfobetaine methacrylate [SBMA]-coated GelMA [SBMA-GelMA], and phosphorylcholine methacrylate [MPC]-coated GelMA [MPC-GelMA]) by one-step photopolymerization of inner GelMA and outer zwitterionic monomers via a handmade two-fluid microfluidic device and it is demonstrated that they can effectively prevent protein adsorption, cell adhesion, and inflammation in vitro. Interestingly, the zwitterionic microcapsules successfully resist FBR in C57BL/6 mice after intraperitoneal implantation for up to 4 months. After successfully encapsulating xenogeneic rat islets in the SBMA-GelMA microcapsules, sustained normoglycemia is further validated in streptozotocin (STZ)-induced mice for up to 3 months. The zwitterion-modified microcapsule using a microfluidic device may represent a platform for cell encapsulation treatment for T1DM and other hormone-deficient diseases.

Development of a New Index Based on Preoperative Serum Lipocalin 2 to Predict Post-LSG Weight Reduction.

BACKGROUND: Bariatric surgery is the most effective therapy for obesity, but targeted weight reduction is not always achieved. Serum lipocalin-2 (LCN2) is closely associated with obesity, but its impact on weight loss after surgery is unknown. We aimed to access the reliability of LCN2 levels and other parameters as effective predictors of excellent weight loss (≥ 75% excess weight loss (EWL)) 1 year after bariatric surgery. METHODS: This retrospective study evaluated 450 patients (aged 18-65 years) with obesity at 3 months and 1 year after laparoscopic sleeve gastrectomy (LSG) surgery. Seventy-four patients who underwent LSG surgery and met the inclusion and exclusion criteria were included in this study. Serum LCN2, thyroid function, and metabolic and anthropometric parameters were assessed. Weight reduction was expressed as %EWL and percent total weight loss (%TWL) at 3 months and 1 year post surgery. Multivariable logistic regression analysis and receiver operating characteristic (ROC) curve analysis were used to evaluate predictors of ≥ 75%EWL. RESULTS: In our cohort, %EWL and %TWL were both strongly associated with preoperative serum LCN2 levels. The binary logistic regression analysis showed that preoperative LCN2, waist circumference, and glycated hemoglobin were independent predictors of excellent weight loss. CONCLUSIONS: Based on these results, we determined a new P index with better predictive value for excellent weight reduction (≥ 75%EWL) 1 year after LSG surgery.

The Risk Stratification of Papillary Thyroid Cancer With Bethesda Category III (Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance) by Thyroid Fine-Needle Aspiration Could Be Assisted by Tumor Size for Precision Treatment.

Purpose: To investigate the clinical characteristics of papillary thyroid cancer (PTC) classified as Bethesda category III [atypia of undetermined significance (AUS)/follicular lesion of undetermined significance (FLUS)] by fine-needle aspiration (FNA) for precision treatment. Methods: A total of 1,739 patients diagnosed with Bethesda category III (AUS/FLUS) by FNA were investigated, and 290 patients diagnosed with PTC were analyzed. Results: The rate of papillary thyroid microcarcinoma (PTMC) was 82.1% (238/290). The rates of lymph node metastases were 44.9% (22/49) and 25.2% (56/222) for PTC and PTMC, respectively (p = 0.006). The rates of extra-thyroid extension were 46.2% (24/52) and 19.8% (47/237) (p < 0.001). Compared with PTMC, PTC had significantly higher odds ratios (ORs) of 3.41 (1.81-6.44, p < 0.001), 2.19 (1.16-4.13, p = 0.016), and 2.51 (1.29-4.88, p = 0.007) for extra-thyroid extension, multifocality, and lymph node metastases, respectively, after adjustment for age and gender. The larger size and BRAF V600E mutation had a robust synergistic effect for invasive features. The rates of lymph node metastases, multifocality, and extra-thyroid extension were significantly increased with larger sizes harboring BRAF V600E mutation. Compared with PTMC harboring wild type (WT)-BRAF, PTC harboring BRAF V600E mutation had adjusted higher ORs of 3.01 (1.26-8.68, p = 0.015), 3.20 (1.22-8.42, p = 0.018), and 5.62 (2.25-14.01, p < 0.001) for lymph node metastases, multifocality, and extra-thyroid extension, respectively. Conclusions: In this study, risk stratification was recommended for patients with Bethesda category III (AUS/FLUS) nodules with a size under 1 cm harboring WT-BRAF being regarded as low risk and should be recommended for active surveillance. Nodules with a size over 1 cm harboring WT-BRAF or those under 1 cm harboring BRAF V600E mutation could be regarded as moderate risk, and molecular testing should be recommended. However, those with a size over 1 cm harboring BRAF V600E mutation should be regarded as high risk, and a diagnostic surgery should be recommended.

Age increased the cancer-specific mortality risk of thyroid cancer with lung metastasis.

OBJECTIVE: To investigate the relationship between age and cancer-specific mortality in thyroid cancer (TC) with lung-metastasis. PATIENTS AND METHODS: A total of 1418 patients with initial distant metastases from Surveillance, Epidemiology, and End Results databases were investigated. Patients with a median follow-up time of 8 months (interquartile range [IQR]: 2-27] and a median age of 66 years (IQR: 55-76) were divided into five groups by age and the association between age and TC-specific mortality was analysed. RESULTS: The TC-specific mortality rates were 32.78% (118/360), 46.71% (156/334), 53.93% (199/369), 58.96% (158/268) and 82.76% (72/87) in patients aged ≤55 years, >55 but ≤65 years, >65 but ≤75 years, >75 but ≤85 years and >85 years. Kaplan-Meier curves showed that TC-specific mortality rate was associated with increased age (p < .001). Compared with patients ≤55 years, patients aged >55 but ≤65 years, >65 but ≤75 years, >75 but ≤85 years and >85 years had significantly higher hazard ratios (HRs) of 1.69 (1.26-2.26), 1.97 (1.47-2.64), 2.18 (1.59-2.99) and 3.24 (2.08-5.06) after adjustments for sex, tumour size and radiation therapy (all p < .001). In TC with initial lung-metastasis, compared with patients ≤55 years, patients aged >55 but ≤65 years, >65 but ≤75 years, >75 but ≤85 years and >85 years had significantly higher adjusted HRs of 1.68 (1.20-2.36; p = .003), 2.18 (1.57-3.02), 2.16 (1.51-3.08) and 2.91 (1.79-4.75; p < .001). Similar results were obtained in papillary TC. CONCLUSIONS: The TC-specific mortality was increased with age in TC patients with initial lung-metastasis, indicating that further risk stratification based on age was necessary for TC over 55 years with lung-metastasis. Individual treatment strategies maybe recommended for such patients.

The relationship between Lipocalin-2 level and hepatic steatosis in obese patients with NAFLD after bariatric surgery.

BACKGROUND: Lipocalin-2 (LCN2) has a critical effect on obesity as well as its associated comorbidities. The present study focused on analyzing serum LCN2 levels of obese patients with nonalcoholic fatty liver disease (NAFLD) and on determining relationship of hepatic steatosis improvement with LCN2 levels after laparoscopic sleeve gastrectomy (LSG). METHODS: This work enrolled ninety patients with obesity and NAFLD. Twenty-three of them underwent LSG. Anthropometric and biochemical parameters and serum LCN2 levels were determined at baseline and those at 6-month post-LSG. Controlled attenuation parameter (CAP) measured by FibroScan was adopted for evaluating hepatic steatosis. RESULTS: Among severe obesity patients, serum LCN2 levels were significantly increased (111.59 ± 51.16 ng/mL vs. 92.68 ± 32.68 ng/mL, P = 0.035). The CAP value was higher indicating higher liver fat content (360.51 ± 45.14 dB/m vs. 340.78 ± 45.02 dB/m, P = 0.044). With regard to surgical patients, liver function, glucose, and lipid levels were significantly improved after surgery. Serum LCN2 levels significantly decreased (119.74 ± 36.15 ng/mL vs. 87.38 ± 51.65 ng/mL, P = 0.001). Decreased CAP indicated a significant decrease in liver fat content (358.48 ± 46.13 dB/m vs. 260.83 ± 69.64 dB/m, P < 0.001). The decrease in LCN2 levels was significantly related to the reduced hepatic fat content and improvement in steatosis grade after adjusting for gender, age, and BMI decrease. CONCLUSIONS: Serum LCN2 levels are related to obesity and NAFLD. The decreased serum LCN2 levels could be an indicator of hepatic steatosis improvement.

Lower Baseline Serum Triglyceride Levels Are Associated With Higher Decrease in Body Mass Index After Laparoscopy Sleeve Gastrectomy Among Obese Patients.

Aims: To investigate the predictive value of baseline serum triglyceride (TG) levels for improvements of metabolism after laparoscopic sleeve gastrectomy (LSG). Methods: 112 obese patients [body mass index (BMI) ≥ 35 kg/m2] underwent LSG and with complete information of anthropometric and metabolic parameters were divided into normal TG group (group A) and high TG group (group B), while group A had TG levels ≤ 1.7 mmol/L, and group B had TG levels > 1.7 mmol/L. The post-operative changes (Δ) in metabolic parameters between the two groups were compared. Results: In the whole cohort, the metabolic parameters were significantly improved at 6 months after LSG. BMI and waist circumference (WC) decreased significantly in the two groups. The ΔBMI among group A and group B were 11.42±3.23 vs 9.13±2.77 kg/m2 (p<0.001), respectively. ΔBMI was positively correlated with ΔWC (r=0.696, p<0.001), Δfasting insulin level (r=0.440, p=0.002), Δfasting serum C peptide level (r=0.453, p=0.002), and Δhomeostasis model assessment insulin resistance index (r=0.418, p=0.004) in group A. Compared with group B, group A had a significantly higher odds ratio (OR) of 2.83 (95% confidence interval [CI]1.25-6.38, p=0.012)and 2.73 (95% CI 1.11-6.72, p=0.029) for ΔBMI and ΔWC after adjustment for age and gender, respectively. Conclusions: Obese patients with baseline TG levels under 1.7 mmol/L had greater loss of weight at six months follow-up later LSG. This finding suggests that baseline TG level may have a predictive value for weight loss, at least in the short-term follow-up.

The Increased Risk of Thyroid Cancer-Specific Mortality With Tumor Size in Stage IVB Patients.

Purpose: To investigate the risk-stratifying utility of tumor size and a threshold for further stratification on cancer-specific mortality of thyroid cancer (TC) patients in stage IVB. Methods: One thousand three hundred and forty-five patients (620 males and 725 females) with initial distant metastasis over 55 years between 2004 and 2016 from Surveillance, Epidemiology, and End Results databases were investigated, with a median follow-up time of 23 months [interquartile range (IQR), 5-56 months] and a median age of 70 years (IQR, 63-77 years). TC-specific mortality rates were calculated under different classifications. Cox regressions were used to calculate hazard ratios (HRs) and Kaplan-Meier Analyses were conducted to investigate TC-specific survivals. Results: In the whole cohort, patients with tumors >4 cm had the highest TC-specific mortality (67.9%, 330/486), followed by tumor size >1 cm but ≤ 4 cm (43.08%, 190/441), and tumor size ≤ 1 cm (32.69%, 34/104). Kaplan-Meier curves showed the increased tumor size was associated with a statistically significant decrease in TC-specific survival (P < 0.001). Papillary thyroid cancer (PTC) patients with tumors >4 cm had significantly higher hazard ratios (HRs) of 2.84 (1.72-4.70) and 3.11 (1.84-5.26) after adjusting age, gender, race, and radiation treatment, compared with patients with tumors ≤ 1 cm (P < 0.001). The TC-specific mortalities and survivals were further investigated among more detailed subgroups divided by different tumor size, and a threshold of 3 cm could be observed (P < 0.005) for risk stratification. Conclusions: Mortality risk increased with tumor size in PTC patients in stage IVB. Our findings demonstrated the possibility of further stratification in IVB stage in current TNM staging system. Patients with tumor size over 3 cm had an excessively high risk of PTC-specific mortality, which may justify the necessity of more aggressive treatment for them.

miR-383 ameliorates high glucose-induced ß-cells apoptosis and hyperglycemia in high-fat induced diabetic mice.

Islet beta-cell dysfunction is an important condition leading to the development of diabetes. Numerous studies have found that miRNA regulates islet ß-cell function. In our previous research, the aberrant expression of miR-383 was revealed in type 2 diabetes mellitus (T2DM) serum. Herein, we aimed to assess the function and underlying mechanism of miR-383 in ß-cells through in vitro and in vivo experiments. Using high glucose media, the ß-cell injury was induced and transfected miR-383 overexpression vector to detect cell function in MIN6. Moreover, miR-383 overexpression lentivirus was administrated into high-fat induced diabetes mice to assess the in vivo effect. Results showed that overexpressing miR-383 reversed the cell apoptosis and oxidative stress, induced by high glucose which targets Toll-like receptors (TLR4) and Apolipoprotein C3 (ApoC3) genes. Furthermore, mechanistic studies demonstrated that miR-383 targeted the TLR4 and ApoC3 3' UTR consequently inhibiting TLR4 and ApoC3 expression in MIN6 cells. Besides, overexpression of miR-383 ameliorated hyperglycemia and pancreatic apoptosis in high-fat induced diabetic mice. Conclusively, miR-383 potentially alleviate pancreatic ß-cell injury induced by high glucose and ameliorates high-fat induced diabetes by suppressing TLR4 and ApoC3 expression.

Is a simplified TNM staging system more clinically relevant than the American Joint Committee on Cancer system for the follicular variant of papillary thyroid cancer?

BACKGROUND: Despite the recent release of the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual, risk stratification for the follicular variant of papillary thyroid cancer (FVPTC), which is the second common variant of papillary thyroid carcinoma (PTC) after classical PTC, remains controversial. This study aimed to develop a more accurate and relevant staging system specifically for FVPTC. METHODS: Patients with FVPTC who were included in the Surveillance, Epidemiology, and End Results (SEER) open database between 2010 and 2015 were divided into 47 groups according to their TNM classifications and age. Subsequently, these 47 groups were categorized into appropriate stages based on Kaplan-Meier survival curves, mortality analyses, a Cox proportional hazards model, and clinical considerations. RESULTS: Our retrospective analysis of 17,628 cases yielded the following new staging classification: stage I, defined as age <55 years and any T/N/M or age ≥55 years and T1-3/any N/M0 (n=17,427, 98.85%); stage II, age ≥55 and T4/any N/M0 or age ≥55 and any T/N0/M1 (n=173, 0.99%); and stage III, age ≥55 and any T/N1/M1 (n=28, 0.16%). The overall mortality rates per 1,000-person-years were 4.135 [95% confidence interval (CI): 3.653-4.681], 71.193 (95% CI: 51.354-98.697), and 199.744 (95% CI: 115.983-343.997) for our new stages I, II, and III, respectively. The hazard ratios for the new stages II and III (reference: stage I) were 5.081 (95% CI: 3.110-8.301) and 21.690 (95% CI: 11.402-41.258), respectively. CONCLUSIONS: Compared to the 8th edition of the AJCC staging system, our newly proposed system provided more accurate risk stratification for patients with FVPTC, as demonstrated by actual survival and mortality outcomes. This new model may thus help guide more personalized treatment for these patients.

Changes of serum retinol-binding protein 4 associated with improved insulin resistance after laparoscopic sleeve gastrectomy in Chinese obese patients.

BACKGROUND: Serum retinol-binding protein 4 (RBP4) plays a critical role in insulin resistance. The mechanism behind the impact of laparoscopic sleeve gastrectomy (LSG) on glucose metabolism is unclear. Hence, we aimed to investigate the triangle relationship between the RBP4, glucose metabolism, and LSG in patients of Chinese ethnicity. METHODS: The study enrolled eighty-two obese patients. Glucose-lipid metabolic index, uric acid (UA), superoxide dismutase (SOD), free triiodothyronine (FT3), free thyroxin (FT4) and thyrotropin (TSH) were measured. RBP4 levels were detected by enzyme-link immunosorbent assay. 30 obese patients underwent LSG were studied. All these markers were measured again at a time interval of 3 and 6 months after surgery. RESULTS: (1) Circulating RBP4 levels were positively associated with body mass index(BMI), blood glucose in 0 min (BG0), BG30, BG120, BG180, fasting inulin(FINS), fasting C peptide(FCP), homeostasis model of assessment for insulin resistance index (HOMA-IR), SOD, TSH and negatively associated with Matsuda index in obesity with a significant difference (P < 0.05). RBP4 levels in the patients with impaired fasting glucose (IFG), insulin resistance or hyperinsulinemia were significantly higher than the patients without IFG, insulin resistance or hyperinsulinemia (P = 0.035, P = 0.001, and P = 0.007). (2) LSG resulted in significantly decreased FBG, FINS, FCP and HOMA-IR at 3, 6 months after surgery (all P < 0.05). The RBP4 levels were significantly decreased after surgery (all P < 0.05) with no gender difference. (3) The change in RBP4 levels was significantly associated with the change in FINS, FCP, HOMA-IR, and HOMA-ß at 6 months and the change in TSH at 3 months after surgery in males (all P < 0.05). The change in RBP4 levels were significantly associated with the change in FINS, FCP, HOMA-IR, HOMA-ß, and TCH at 3 months after surgery in females (all P < 0.05). CONCLUSIONS: Overall, our results interpret the significant correlations between RBP4, glucose-lipid metabolism, oxidative stress and thyroid function in obese patients. Further, the LSG brings a decline in RBP4 levels and that may contribute partly to the improved insulin resistance in obese Chinese patients.

Rethinking the 8th AJCC System: Is It Suitable for Patients Aged <55 Years With Stage T4N1M0 Follicular Variant of Papillary Thyroid Carcinoma to Be Placed in Stage I?

PURPOSE: The newest (8th) edition of the TNM staging system published in 2017. In this edition, some significant changes happened from the previous edition. As a result, down-staging appeared in nearly one third of DTC patients. However, we don't know whether the new system predicts the survival of FVPTC patients accurately. Therefore, it is necessary to thoroughly evaluate the correlation between the new system and survival prediction in terms of FVPTC. METHODS: We enrolled 17,662 FVPTC patients from the Surveillance, Epidemiology, and End Results database. Factors associated with survival were identified by Cox regression analyses. The mortality rates per 1,000 person-years were calculated and compared. Cox proportional hazards regression quantified the risk of survival, and survival curves were produced by Kaplan-Meier analyses using log-rank tests. RESULTS: Age at diagnosis, race, T-stage at diagnosis, distant metastasis, radiation therapy, and surgery were independent factors associated with cancer-specific survival. Patients aged <55 years with stage T4N1M0 FVPTC had higher mortality rates per 1,000 person-years than patients in the same stage according to the 8th AJCC System. Cox proportional hazards regression reflected that patients aged <55 years with stage T1-3, any N, M0 or T4N0M0 disease (p=0.001) and patients aged ≥55 years with T1-2N0M0 disease (p=0.004) had significantly lower risks of cancer-specific survival (CSS) than those aged <55 years with stage T4N1M0 disease. The CSS curve of patients aged <55 years with stage T4N1M0 disease showed a decline on comparison with others belonging to stage I (p<0.001); and the curve was even not different from patients in stage II and stage III (p>0.05). CONCLUSION: Patients aged <55 years with stage T4N1M0 FVPTC had worse survival than patients in stage I; no difference was seen on comparison with stage II patients. We recommend this group of patients be upstaged in the 8th AJCC system.

The prognostic value of multiorgan metastases in patients with non-small cell lung cancer and its variants: a SEER-based study.

PURPOSE: This study aimed to investigate the prognostic value of different organs metastases in patients with non-small cell lung cancer (NSCLC) and its most common subtypes. METHODS: We identified 45,423 NSCLC cases (25,129 men and 20,294 women) between 2010 and 2013 with distant metastases, with complete clinical information obtained from the surveillance, epidemiology, and end results (SEER) database. RESULTS: Bone and liver were the most and the least common metastatic sites with rates of 37.1 and 16.8%, respectively. The mortality rates associated with bone, brain, liver, lung metastases, and multiorgan metastases (MOM) were 73.2, 72.7, 78.3, 65.4, and 77.5%, respectively. Kaplan-Meier analyses demonstrated that patients with MOM and liver metastasis had the worst survival. Compared with NSCLC cases with other organ metastasis, but without the four organs metastasis, hazard ratios (HRs) for lung, bone, brain, and liver metastases, and MOM were 0.906 (95% CI 0.866-0.947), 1.276 (95% CI 1.225-1.330), 1.318 (95% CI 1.260-1.379), 1.481 (95% CI 1.388-1.580), and 1.647 (95% CI 1.587-1.709), respectively. Similar results were obtained for adenocarcinoma (AD) cases. CONCLUSIONS: The mortality risk is highest with MOM and liver metastasis followed by bone, brain, other organ, and lung metastases in NSCLC and AD which is the most common variant for NSCLC. These results will be helpful for pre-treatment evaluation regarding the prognosis of NSCLC patients.

BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer.

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished. Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC. Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation. Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database. Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.

Interleukin-6 -572C/G polymorphism is associated with serum interleukin-6 levels and risk of idiopathic pulmonary arterial hypertension.

Interleukin 6 (IL-6) is a multifunctional proinflammatory cytokine that is elevated in patients with pulmonary arterial hypertension (PAH). Single nucleotide polymorphisms in the promoter region of IL-6 have been reported to transcriptional regulate the expression of IL-6. The aim of the present study is to investigate the roles of two common polymorphisms (-572C/G [rs1800796] and -6331T/C [rs10499563]) of IL-6 in idiopathic PAH (IPAH). A total of 338 IPAH patients and 352 age- and gender-matched healthy controls were enrolled. Genotyping of the two polymorphisms was performed by polymerase chain reaction and direct sequencing. Serum IL-6 levels were determined by ELISA assay. The frequencies of -572C/G genotypes CC, CG, and GG were found to be 63.6%, 32.3%, and 4.1% in IPAH patients group and 51.7%, 39.5%, and 8.8% in the controls, respectively. Compared with the individuals carrying the common genotype CC, the individuals carrying the GG genotype had a decreased risk of IPAH (adjusted odds ratio, 0.40; 95% confidence interval, 0.20-0.77; P = .006). The CG genotype and G allele carriers (CG/GG genotypes) were also observed to be associated with decreased risks of IPAH. Moreover, we found that individuals harboring -572GG or GC genotype showed significantly lower IL-6 levels than those harboring the -572CC genotype. No association between -6331T/C polymorphism and risk of IPAH or IL-6 levels was found. These results suggest that IL-6 promoter polymorphism -572C/G, but not -6331T/C, is associated with serum IL-6 levels and risk of IPAH.

The Clinical Characteristics of Obese Patients with Acanthosis Nigricans and Its Independent Risk Factors.

Objective: This study aimed to investigate the clinical characteristics and risk factors for acanthosis nigricans (AN) in obese patients. Methods: 80 obese patients without AN (OB group) and 128 obese patients with AN (AN group) were included in this study. Clinical data for each patients were collected. Serum levels of leptin were measured by ELISA. Results: Body mass index (BMI), uric acid (UA) levels, fasting insulin, and HOMA-IR were higher in AN than OB (P<0.05). The levels of leptin were significantly higher in AN than OB (P<0.001) after adjustment for BMI and gender. In male patients, AN showed lower serum levels of testosterone than OB (P<0.001). Multiple Logistic-regression analysis demonstrated that UA (OR 4.627, 95%CI 2.443-8.762, P<0.001) and Leptin (OR 4.098, 95%CI 1.237-13.581, P=0.021) were independent risk factors for AN. In addition, low testosterone level was an independent risk factor for AN in male obese patients (OR 39.062, 95%CI 5.523-283.808, P<0.001). Conclusions: AN is associated with more severe hyperinsulinemia and hyperuricemia in obese patients, as well as lower serum testosterone levels in male patients. UA and Leptin were independent risk factors for AN in obese patients. Low testosterone may be a valuable predictor of AN in male obese patients.