Surgery is a Viable Treatment Option for Stage IE Primary Thyroid Lymphoma.

BACKGROUND: Stage IE primary thyroid lymphoma (PTL) has been diagnosed in approximately half of patients with PTL; however, the optimal treatment for stage IE PTL has not yet been established. METHODS: Stage IE PTL patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 1998 and 2019. Thereafter, the disease-specific survival (DSS) and treatment modalities (surgery alone, surgery + radiotherapy (RT) and/or chemotherapy (CT), and RT and/or CT) of these patients were compared by Kaplan-Meier curves and log-rank test after propensity score matching (PSM). Additionally, patients with PTL from the Affiliated Sixth People's Hospital of the Shanghai Jiao Tong University and School of Medicine (Shanghai, China) between 2007 and 2022 were retrospectively analyzed as an external cohort. RESULTS: Among the 1596 patients with PTL from the SEER database, 842 were identified as patients with stage IE PTL, with an average follow-up period of 7.8 years. Pairwise analysis after PSM revealed no significant difference between the DSS of the three treatment groups. A total of 38 patients with PTL were identified in the external cohort, with an average follow-up period of 3.4 years. Compared with the RT and/or CT group, the surgery-alone group showed no significant difference in the incidence of hypothyroidism (p = 0.161) but had significantly fewer treatment-related complications (p = 0.021), shorter treatment duration (p < 0.001), and lower treatment costs (p = 0.025). CONCLUSIONS: The results of our study demonstrate that surgery is a viable treatment option for patients with stage IE PTL.

The Predictive Factors of Combined Implant Application for Breast Cancer Patients Receiving Immediate Breast Reconstruction with a Pedicled Omental Flap.

BACKGROUND: Whether a laparoscopically harvested omental flap is adequate for total breast reconstruction could not be determined preoperativaly due to lack of reliable assessment methods. This study aimed to establish a statistical model to predict the probability of omental flap insufficiency. METHODS: In this study, 200 female patients with breast cancer receiving immediate breast reconstruction with pure pedicled omental flaps or pedicled omental flaps combined with implants after nipple-areolar complex-sparing mastectomy were divided into two groups depending on whether implants were needed or not. The clinical characteristics of these two groups were compared. Correlation of body mass index (BMI) and omental volume was analyzed. Binary logistic regression was performed to predict the probability of implant requirement based on clinical parameters, showing significant differences between the two groups. RESULTS: The patients who needed implants in adjunct treatment were younger. In addition, they had larger breast specimens and smaller omental volumes than the others whose omental flaps were sufficient for total breast reconstruction. Body mass index and omental volume showed a moderately positive correlation. Age, specimen volume, and BMI all were entered into the logistic regression equation. For the patients with a BMI lower than 24.0 kg/m2, the probability of requiring implants was 5.467 times that of comparable patients with a BMI of 24.0 kg/m2 or higher. At the cutoff of 0.61, the regression equation yielded a sensitivity of 84.2% and a specificity of 72.1% in recognizing subjects with the necessity of implant application. CONCLUSION: The combination of BMI, age, and volume of breast specimen could predict with high accuracy whether implants are required for breast cancer patients receiving pedicled omental flap-based breast reconstruction.

Clinical characteristics and long-term outcomes for parapharyngeal metastases of well-differentiated thyroid cancer during 131 I therapy and follow-up.

OBJECTIVE: Parapharyngeal metastases (PPM) are rarely observed in patients with well-differentiated thyroid cancer (WDTC). Radioiodine (131 I) therapy has been the main treatment for metastatic and recurrent DTC after thyroidectomy. This study was performed to evaluate the clinicopathological features and long-term outcomes associated with survival of patients with PPM at the end of follow-up. DESIGN: In total, 14,984 consecutive patients with DTC who underwent 131 I therapy after total or near-total thyroidectomy from 2004 to 2021 were retrospectively reviewed. Therapeutic efficacy was evaluated using the Response Evaluation Criteria in Solid Tumours v1.1 and logistic regression analysis. The disease status was determined using dynamic risk stratification. Disease-specific survival (DSS) was assessed using the Kaplan-Meier method and a Cox proportional hazards model. PATIENTS: Seventy-five patients with PPM from WDTC were enroled in this study. Their median age at the initial diagnosis of PPM was 40.2 ± 14.1 years, and the patients comprised 32 men and 43 women (male:female ratio, 1.00:1.34). Of the 75 patients, 43 (57.33%) presented with combined distant metastases. Fifty-seven (76.00%) patients had 131 I avidity and 18 had non-131 I avidity. At the end of follow-up, 22 (29.33%) patients showed progressive disease. Sixteen of the 75 patients died; of the remaining 59 patients, 6 (8.00%) had an excellent response, 6 (8.00%) had an indeterminate response, 10 (13.33%) had an biochemical incomplete response, and 37 (49.33%) had a structural incomplete response. Multivariate analysis confirmed that age at initial PPM diagnosis, the maximal size of PPM, and 131 I avidity had significant effects on progressive disease of PPM lesions (p = .03, p= .02, and p < .01, respectively). The 5- and 10-year DSS rates were 98.49% and 62.10%, respectively. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with a poor prognosis (p = .03 and p = .04, respectively). CONCLUSION: The therapeutic effect for PPM was closely associated with 131 I avidity, age at initial PPM diagnosis, and maximal size of PPM at the end of follow-up. Age of ≥55 years at initial diagnosis of PPM and the presence of concomitant distant metastasis were independently associated with poor survival.

Tumor microenvironment remodeling modulates macrophage phenotype in breast cancer lymphangiogenesis.

Hyaluronan (HA) is dynamically remodeled in tumor microenvironment (TME) and is reported to be closely related to tumor lymphatic metastasis by inducing lymphangiogenesis. Macrophages are known to be involved in neo-lymphatic vessels formation. However, few studies have investigated the role of HA-mediated TME remodeling on macrophages-dependent lymphangiogenesis. We previously showed that HA could drive macrophages to acquire the M2 phenotype. In this study, we attempt to study the crosstalk between HA in TME and macrophages dependent lymphangiogenesis. First, we found that the abundant assembly of HA in breast cancer tissue was accompanied by increased infiltration of macrophages featured by expressing lymphatic endothelial markers. Then, to further identify the remodeling of HA in regulating macrophage phenotype, we used HA fragments which are usually enriched in TME for this purpose. Our results showed that the reconstructed HA could induce bone marrow-derived macrophages (BMDMs) to express markers of lymphatic endothelium and form tube-like structures, suggesting a novel function of HA from TME on macrophages-dependent lymphangiogenesis. Finally, we found that inhibition of the HA-TLR4 pathway could reduce the ability of BMDMs to exhibit lymphatic endothelial phenotype. Our results provide new insight into tumor microenvironment remodeling and macrophages in breast cancer lymphangiogenesis.

Bilateral multifocality, a marker for aggressive disease, is not an independent prognostic factor for papillary thyroid microcarcinoma: A propensity score matching analysis.

CONTEXT: Multifocality and bilaterality are common in patients with papillary thyroid microcarcinoma (PTMC). However, their clinical behaviours and prognostic implications remain controversial. OBJECTIVE: To investigate the relationship between multifocality and classically aggressive characteristics and outcomes in patients with PTMC. METHODS: Clinical data of 3005 patients with PTMC were retrospectively reviewed at a tertiary medical centre. The role of unilateral and bilateral multifocality in aggressive characteristics and clinical outcomes of PTMC was evaluated using propensity score matching (PSM). RESULTS: A total of 573 patients had bilateral multifocal disease (B-MFD), 272 had unilateral multifocal disease (U-MFD), and 2160 had unifocal disease (UFD). Univariate analysis showed that patients in the multifocal disease (MFD) groups showed significantly different characteristics compared to patients in the UFD group in terms of age, chronic lymphocytic thyroiditis (CLT), follicular variant PTMC, tumour diameter, aggressive growth, including extrathyroidal extension (ETE), central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM), and TNM stage, and underwent radioactive iodine (RAI) therapy. Further stratified analysis revealed that patients in the B-MFD group reflected the differences between the MFD and UFD groups. However, those in the U-MFD group showed slight differences only in sex, CLT and cell subtypes, compared to the UFD group. In addition, PSM indicated differences in ETE, CLNM and LLNM between the B-MFD and UFD groups (p < .001), while only ETE differed between the U-MFD and UFD groups (p < .001). After a median follow-up period of 60 months, no difference was observed in recurrence-free survival between the UFD and B-MFD (p = .294) or U-MFD (p = .603) groups using PSM. CONCLUSION: This propensity score matching analysis provides strong evidence that bilateral multifocality, rather than unilateral multifocality, should be considered as an aggressive marker at presentation, and neither is an independent prognostic factor for clinical outcome in PTMC.

Risk factors of skip lateral lymph node metastasis in papillary thyroid carcinoma.

PURPOSE: Cervical lymph node metastasis is a prognostic factor of papillary thyroid carcinoma (PTC). This study aimed to investigate clinicopathological features and risk factors of skip lateral lymph node metastasis in PTC patients. METHODS: We retrospectively reviewed medical records of patients who underwent simultaneous total thyroidectomy with therapeutic central compartment lymph node dissection (LND) and lateral LND for primary PTC from 2014 to 2019. Univariate and multivariate logistic regression analyses were performed to identify clinicopathologic risk factors for skip metastasis. Receiver-operating characteristic (ROC) curves were constructed using the results of the multiple logistic regression analysis to identify data points with the highest sensitivity and lowest false-negative rate. RESULTS: The frequency of skip metastasis was approximately 12.8% (50/390). Multivariate logistic regression analysis showed that age (odds ratio [OR], 1.033; 95% confidence interval [CI], 1.008-1.059; P = 0.010), tumor size (OR 0.251; 95% CI 0.129-0.490; P < 0.001) and tumor located in the upper portion (OR 0.378; 95% CI 0.200-0.715; P = 0.003) were independent risk factors of skip metastasis (all P < 0.05). The ROC curves showed that the cut-off value of age for predicting skip metastasis was 44.5 years old (sensitivity = 0.620, specificity = 0.618, area under the curve [AUC] = 0.627, P = 0.004); the cut-off value of the tumor diameter for predicting skip metastasis was 1.05 cm (sensitivity = 0.503, specificity = 0.760, AUC = 0.682, P < 0.001). CONCLUSIONS: Skip metastasis was common in PTC. The PTC patients with age > 44.5 years, tumor diameter < 1.05 cm and tumor located in the upper portion should be carefully evaluated for skip metastasis.

Transoral endoscopic selective lateral neck dissection for papillary thyroid carcinoma: a pilot study.

BACKGROUND: Transoral endoscopic thyroid surgery via the vestibular approach (TOETVA) has been gradually accepted worldwide due to its scar-free effect on the neck. Even central cervical lymphadenectomy has been performed in some cases of papillary thyroid carcinoma (PTC). However, there are few reports involving lateral neck dissection with TOETVA. In this study, we attempted to perform selective lateral neck dissection (SLND) for PTC via a transoral vestibular approach. METHODS: This prospective study was conducted from January 2016 to December 2018 in twenty PTC patients with unilateral T1 tumors without capsular invasion and patients with abnormal level III and IV lymph nodes who underwent SLND via a transoral vestibular approach. RESULTS: Endoscopic surgery was successfully accomplished in all 20 PTC patients. The mean age was 29.2 ± 5.5 (20-41) years. The mean operation time was 146.0 ± 18.7 (114-193) min. The average postoperative hospital stay was 6.8 ± 1.3 (5-10) days. The mean number of removed nodes was 7.4 ± 2.5 (4-12) in the central neck and 10.9 ± 2.8 (6-16) in the lateral neck, and the positive yield amounts were 2.0 ± 1.2 (0-4) and 2.7 ± 1.9 (0-6), respectively. No major complications occurred except for 1 case of transient unilateral recurrent laryngeal nerve palsy and two cases of effusion in the operative area. No evidence of persistent or recurrent disease was observed in these patients during a mean follow-up of 24.3 ± 9.1 (6-36) months. The cosmetic results and protection of personal privacy of this procedure were excellent. CONCLUSION: Endoscopic SLND via the transoral vestibular approach is feasible, safe, and effective for selected PTCs. A multicenter large comparative study is necessary.

Comparison of Lobectomy and Total Thyroidectomy in Unilateral Papillary Thyroid Microcarcinoma Patients with Ipsilateral Lateral Lymph Node Metastasis Without Gross Extrathyroidal Extension.

BACKGROUND: Lateral lymph node metastasis (LLNM) occurs in a few of papillary thyroid microcarcinoma (PTMC) cases by the time of diagnosis. Total thyroidectomy (TT) is recommended in the 2015 American Thyroid Association guidelines as the initial surgical procedure for thyroid carcinoma patients with clinically apparent cervical lymph node metastasis. However, none of the controlled studies have focused on the proper extent of surgery for patients who have PTMC with concomitant LLNM without gross extrathyroidal extension (ETE). METHODS: A total of 2373 consecutive patients with PTMC were retrospectively reviewed. Finally, 129 unilateral PTMC patients with ipsilateral LLNM without gross ETE were enrolled in this study and classified into two groups: those who underwent unilateral lobectomy (LT) plus lymph node dissection (LND) (Group I) and those who underwent TT plus LND (Group II). Surgical outcomes and recurrence-free survival (RFS) during the follow-up period were compared between the two groups. RESULTS: There were 62 patients in Group I and 67 patients in Group II. Cases in Group II had a longer median operation time (150 min vs. 120 min, p < 0.001) and a higher incidence of postoperative hypoparathyroidism (p < 0.001), especially permanent hypoparathyroidism, than cases in Group I. But the RFS showed no statistically significant difference (p = 0.6005) between the two groups during a median follow-up period of 60 months. CONCLUSION: Thyroid LT alone plus ipsilateral LND may be an optimum initial procedure for unilateral PTMC patients with ipsilateral LLNM without gross ETE. A long-term follow-up, prospective, randomized controlled trial is warranted.

m6A RNA methylation regulators have prognostic value in papillary thyroid carcinoma.

BACKGROUND: N6-Methyladenosine (m6A) is a ubiquitous RNA modification with vital roles in various cancers, but little is known about its role in papillary thyroid carcinoma (PTC), a common endocrine malignancy. METHODS: In this study, an m6A RNA methylation regulator-based biomarker signature was developed for the effective prediction of prognosis in patients with PTC. The gene expression profiles of m6A RNA methylation regulators and the corresponding clinical information was downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed m6A RNA methylation regulators between tumor and normal control samples, and correlation expression levels, clinical parameters, and outcomes were evaluated. And a prognostic signature was built using a PTC cohort from TCGA. RESULTS: The expression level of HNRNPC was remarkably upregulated in tumor samples, while WTAP, RBM15, YTHDC2, YTHDC1, FTO, METTL14, METTL3, ALKBH5, KIAA1429, YTHDF1, and ZC3H13 were significantly downregulated in the cancer specimens compared with those in control samples. A three-gene prognostic signature comprising RBM15, KIAA1429, and FTO could predict overall survival in patients with PTC. In addition, the prognostic signature-based risk score was identified as an independent prognostic indicator for PTC. CONCLUSIONS: We established a robust m6A RNA methylation regulator-based molecular signature for predicting prognosis in patients with PTC with high accuracy; this signature might provide important guidance for therapeutic strategies.

Network meta-analysis of surgical treatment for secondary hyperparathyroidism.

BACKGROUND: Main surgical treatments for secondary hyperparathyroidism (SHPT) include subtotal parathyroidectomy (sPTX), total parathyroidectomy with autotransplantation (tPTX+AT), and total parathyroidectomy (tPTX); however, determining the best treatment is debatable. We conducted a network meta-analysis (NMA) comparing three treatments in terms of postoperative hypocalcemia (or hypoparathyroidism), postoperative recurrence, and reoperation. METHODS: We searched PubMed, Medline, the Cochrane Library, and Embase for relevant research from inception to July 30, 2019. We performed our Bayesian NMA using R 3.51 software to assess odds ratios (OR) and 95% confidence intervals (CI). Network and forest plots displayed study outputs. Potential publication bias was assessed with funnel plots using software Stata/MP 13.0. RESULTS: Twenty-six articles comprising 5063 patients were included in our NMA, which showed that postoperative hypocalcemia (or hypoparathyroidism) occurred more frequently in tPTX than in sPTX (OR = 3.50, 95% CI 1.10-11.0) or tPTX+AT patients (OR = 1.80, 95% CI 0.66-5.20). Regarding postoperative hypocalcemia (or hypoparathyroidism), there was no significant difference between sPTX and tPTX+AT (OR = 0.53, 95% CI 0.24-1.10). As for recurrence rates, statistically significant differences were observed between sPTX and tPTX (OR = 25.0, 95% CI 5.1-260), tPTX+AT and tPTX (OR = 20.0, 95% CI 4.2-200), and sPTX and tPTX+AT (OR = 1.30, 95% CI 0.65-2.50). Regarding reoperation rates, sPTX experienced higher incidence compared with tPTX+AT (OR = 1.20, 95% CI 0.53-2.70) or tPTX patients (OR = 2.70, 95% CI 1.20-14.00). CONCLUSIONS: TPTX+AT is recommended as the most efficient and safe surgical SHPT treatment with minimal adverse effects. Large-scale randomized controlled trials are recommended to confirm the NMA results.

Risk factors of metastasis to the lymph nodes posterior to the right recurrent laryngeal nerve in papillary thyroid carcinoma.

PURPOSE: To investigate the risk factors of lymph node posterior to the right recurrent laryngeal nerve (LN-prRLN) metastasis in papillary thyroid carcinoma. METHODS: Clinicopathologic feature data of 427 patients with right or double lobes who underwent surgery between January 2014 to August 2019 in the Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, were retrospectively analyzed. The risk factors of LN-prRLN metastasis were analyzed by the Chi-squared test and multivariate logistic regression. RESULTS: LN-prRLN metastasis was detected in 96 patients. Univariate analysis showed that age, right-side tumor diameter, capsular invasion, comorbid adenoma, and VIa compartment LN metastasis were significantly associated with LN-prRLN metastasis (all P < 0.05). Multivariate logistic regression analysis showed that right-side tumor diameter, capsular invasion, and VIa compartment LN metastasis were independent risk factors of LN-prRLN metastasis (all P ≤ 0.001). The receiver operating characteristic curve showed that the cutoff value of the right tumor diameter for predicting LN-prRLN metastasis was 1.25 cm (sensitivity = 0.5, specificity = 0.819, area under the curve = 0.720, P < 0.001). CONCLUSION: The incidence of LN-prRLN metastasis cannot be ignored, and our findings indicate that prophylactic LN-prRLN dissection should be performed in patients with right-side tumor diameter ≥ 1.25 cm, capsular invasion, and VIa compartment LN metastasis.

Tiam1 promotes thyroid carcinoma metastasis by modulating EMT via Wnt/ß-catenin signaling.

Aberrant expression of the guanine nucleotide exchange factor Tiam1 is implicated in the invasive phenotype of many cancers. However, its involvement in thyroid carcinoma and downstream molecular events remains largely undefined. Here, we examined the effects of Tiam1 on the invasiveness and metastasis of thyroid carcinoma in vitro and in vivo and explored the underlying mechanisms by investigating the regulation of Tiam1 expression and the downstream pathways affected. Our results showed that Tiam1 knockdown inhibited the migratory and invasive capacity of thyroid cancer cells, suppressed epithelial-mesenchymal transition (EMT), and inhibited Wnt/ß-catenin signaling in vitro. Moreover, Tiam1 knockdown suppressed liver metastasis development in vivo. The effects of Tiam1 on metastasis and EMT mediated by the Wnt/ß-catenin pathway were reversed by Rac1 silencing, suggesting that the prometastatic effect of Tiam1 is mediated by the activation of Rac1. These results indicate that Tiam1 may be a prognostic factor and potential therapeutic target for the treatment of thyroid cancers.

A Perioperative Small Dose of Dexamethasone Enhances Postoperative Recovery by Reducing Volume and Inflammatory Contents in Wound Drainage After Thyroid Surgery: A Double-Blinded, Randomized, Prospective Study.

BACKGROUND: The aims of this study were to assess the effect of perioperative dexamethasone on postoperative thyroid surgery recovery using measures of wound drainage volume and C-reactive protein (CRP) levels and leukocyte counts. MATERIALS AND METHODS: From January to September 2014, healthy patients, aged between 18 and 65 years, had elective thyroid surgery in the tertiary hospital. Eligible patients were randomized into either group D (dexamethasone 0.1 mg/kg IV) or group S (saline IV) after anesthesia induction. At the end of surgery, a drainage tube was placed at the thyroid bed with a negative pressure ball connected outside the wound. Drainage fluids were collected after thyroid surgery. The fluid volume and the levels of C-reactive protein and leukocyte counts inside were analyzed. All patients were followed up for 1 month. RESULTS: The median total drainage in group D (n = 103) was 43 ml (IQR: 21-83 ml), and 68 ml (IQR: 35-104 ml) in group S (n = 111), P = 0.002. More patients in group D were discharged on postoperative day 2 (74.8% vs. 54.1%, P = 0.002). The CRP levels and leukocyte counts were much less in group D than in group S (P = 0.002 and P < 0.001, respectively). Two patients (one in each group) had wound infections 1 week after surgery that healed one additional week later. CONCLUSIONS: One perioperative small dose of dexamethasone reduced wound drainage volume and inflammatory content after thyroid surgery, thereby possibly contributing to early recovery. The effects of dexamethasone have never been evaluated before under these conditions. REGISTRATION NUMBER: NCT02304250 ( http://www.clinicaltrials.gov ).

Cell adhesion-related gene somatic mutations are enriched in aggressive papillary thyroid microcarcinomas.

BACKGROUND: Approximately half of the documented increases in differentiated thyroid carcinoma is due to identification of papillary thyroid microcarcinomas (PTMCs). Knowing whether PTMC is aggressive is required for proper treatment, but until now, there has been no method for assessing these traits and understanding the underlying mechanisms for aggressiveness. METHODS: We performed whole-exome sequencing of 16 PTMCs and matched normal thyroid tissues and GO/KEGG analysis to study genetic alterations and biological consequences associated with aggressive PTMCs, and then sequenced these genes using a next-generation gene-panel approach in an additional 70 PTMC samples including aggressive (n = 50) and non-aggressive (n = 20) groups. RESULTS: We identified 254 somatic mutations of 234 genes, for which 178 mutations in 168 genes were found in the aggressive group, and 76 mutations in 74 genes were found in the non-aggressive group. Several recurrent mutations in BRAF, VCAN, ALDH1L1, and MUC5B were identified, and many novel but infrequent mutations in other genes were also found. The aggressive cohort had more mutational burdens than the non-aggressive group (P = 0.004). Nonsynonymous mutations of 13 genes (MUC5B, TNN, SSPO, PPFIA1, PCDHGA2, ITGA8, ITGA4, DCHS1, CRNN, ROCK1, RELN, LAMC2, and AEBP1) were involved in cell adhesion, and these were only present in the aggressive group. Targeted sequencing of these genes revealed significant enrichment in the aggressive group (P = 0.000004). CONCLUSION: PTC may have evolved from PTMC due to sharing similar gene mutations, and the accumulation of such mutations promoted the aggressiveness of PTMC. Gene mutants associated with cell adhesion may be used to predict PTMC aggressiveness and allow more selective treatment.

PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.

Protein phosphatase, Mg(2+)/Mn(2+) dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/ß-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC.

ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells.

Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/ß-catenin pathway, ZNRF3 overexpression negatively regulated ß-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and ß-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC.

Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-ß-induced tumor formation.

Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor ß (TGF-ß)/Smad signaling and is implicated in a wide range of cellular responses. However, the exact mechanism whereby Smurf2 controls TGF-ß-induced signaling pathways remains unknown. Here, we identified the relationship between the alternate TGF-ß signaling pathways: TGF-ß/PI3K/Akt/ß-catenin and TGF-ß/Smad2/3/FoxO1/PUMA and Smurf2. The results showed that TGF-ß promoted proliferation, invasion, and migration of human pancreatic carcinoma (PANC-1) cells through the PI3K/Akt/ß-catenin pathway. Inhibiting the PI3K/Akt signal transformed the TGF-ß-induced cell response from promoting proliferation to Smad2/3/FoxO1/PUMA-mediated apoptosis. The activation of Akt inhibited the phosphorylation/activation of Smad3 and promoted the phosphorylation/inactivation of FoxO1, inhibiting the nuclear translocation of both Smad3 and FoxO1 and inhibiting the expression of PUMA, a key apoptotic mediator. However, downregulation of Smurf2 in PANC-1 cells removed Akt-mediated suppression of Smad3 and FoxO1, allowing TGF-ß-induced phosphorylation/activation of Smad2/3, dephosphorylation/activation of FoxO1, nuclear translocation of both factors, and activation of PUMA-mediated apoptosis. Downregulation of Smurf2 also decreased invasion and migration in TGF-ß-induced PANC-1 cells. The in vivo experiments also revealed that downregulation of Smurf2 delayed the growth of xenograft tumors originating from PANC-1 cells especially when treated with TGF-ß. Taken together, these results indicate that expression of Smurf2 plays a central role in the determination and activation/inhibition of particular cellular pathways and the ultimate fate of cells induced by TGF-ß. An increased understanding of the intricacies of the TGF-ß signaling pathway may provide a new anti-cancer therapeutic target.

MiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3.

BACKGROUND/AIMS: Micro-RNA (miR)-146b-5p is overexpressed in papillary thyroid carcinoma (PTC) and associated with extrathyroidal invasion and advanced tumor stage. In the present study, we showed that miR-146b-5p is upregulated in PTC with lymph node metastasis. METHODS: A computational search and luciferase assay identified zinc RING finger 3 (ZNRF3), a negative regulator of Wnt/ß-catenin signaling, as a direct target of miR-146b-5p in PTC. RESULTS: MiR-146b-5p promoted migration and invasiveness and induced epithelial-mesenchymal transition (EMT) of PTC cells, whereas ZNRF3 overexpression reversed this effect. MiR-146b-5p increased the cell surface levels of the Wnt receptors Frizzled-6 and LRP6 and enhanced Wnt/ß-catenin signaling by downregulating ZNRF3, whereas an inhibitor of Wnt/ß-catenin suppressed the effect of miR-146b-5p on migration, invasiveness and EMT of PTC cells. CONCLUSION: These results indicate that miR-146b-5p induces EMT and may promote PTC metastasis through the regulation of Wnt/ß-catenin signaling, and suggest novel potential therapeutic targets for the treatment of PTC.

Relationships of FOXE1 and ATM genetic polymorphisms with papillary thyroid carcinoma risk: a meta-analysis.

We conducted the meta-analysis of all relevant case-control studies aiming to evaluate the relationships of common polymorphisms in forkhead box E1 (FOXE1) and ataxia telangiectasia mutated (ATM) genes to the risk of papillary thyroid carcinoma (PTC). A range of electronic databases were searched without language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). This meta-analysis was conducted using the STATA 12.0 software. Crude odds ratio (OR) with their 95 % confidence interval (CI) were calculated. Eight case-control studies with 2,085 PTC patients and 10,341 healthy controls were included. Fourteen common polymorphisms were evaluated, including rs3758249 A > G, rs907577 G > A, rs1867277 G > A, rs3021526 C > T, rs1443434 G > T, rs907580 G > A, rs965513 A > G, rs944289 C > T, and rs189037 G > A polymorphisms in the FOXE1 gene and rs373759 G > A, rs4988099 A > G, rs1801516 G > A, rs664677 T > C, and rs609429 G > C polymorphisms in the ATM gene. Our results demonstrated that the FOXE genetic polymorphisms might be closely related to an increased risk of developing PTC under five genetic models (all P < 0.005), especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. Nevertheless, no positive associations were found between the ATM genetic polymorphisms and the development of PTC (all P > 0.05). The current meta-analysis provided evidence that FOXE1 genetic polymorphisms may contribute to increased PTC risk, especially for rs3758249, rs907577, rs1867277, rs3021526, rs1443434, rs907580, rs704839, rs894673, and rs10119760 polymorphisms. However, the ATM genetic polymorphisms may not be important dominants of susceptibility to PTC.

Factors associated with mortality risk for malignant colonic obstruction in elderly patients.

BACKGROUND: Acute colonic obstruction is the most common complication of colorectal cancer (CRC) in elderly patients. Medical treatment has been associated with higher perioperative morbidity and mortality rates. There is a need for identification of elderly CRC patients who will do poorly so that results can be improved. The purpose of this study is to assess the 30-day outcome of elderly patients undergoing malignant colonic obstruction procedures and identify the associated factors of mortality. METHODS: A review of 233 elderly patients who received medical procedures for malignant colonic obstruction between April 2000 and April 2012 was conducted. Data regarding clinical variables, surgical procedures and outcomes, complications, and mortality were studied. Univariate and logistic regression analyses were performed on mortality risk factors. RESULTS: Patients had a mean age of 78.2 years (range 70-95). A total of 126 (54.1%) patients were classified ASA III and above. Eighty (34.3%) patients had right-sided colonic obstruction. In the 153 (65.7%) patients with left-sided colonic obstruction, 40 patients received self-expandable metallic stent (SEMS) treatment and 193 patients received surgery. A total of 62.2% (n = 145) patients had post operation complications. The overall 30-day mortality was 24.5% (n = 57). ASA grading, peritonitis and Dukes staging were independent risk factors for mortality. CONCLUSIONS: Medical procedures in elderly patients with malignant colonic obstruction are associated with significant complications and mortality. Identifying these high-risk patients and treating promptly may improve outcomes. SEMS treatment provides a useful alternative to surgical intervention.