Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression.

Rho in filopodia (Rif), a member of the Rho family of small GTPases, induces filopodia formation primarily on the dorsal surface of cells; however, its function remains largely unclear. Here, we show that Rif interacts with Ror1, a receptor for Wnt5a that can also induce dorsal filopodia. Our immunohistochemical analysis revealed a high frequency of coexpression of Ror1 and Rif in lung adenocarcinoma. Lung adenocarcinoma cells cultured on Matrigel established front-rear polarity with massive filopodia on their front surfaces, where Ror1 and Rif were accumulated. Suppression of Ror1 or Rif expression inhibited cell proliferation, survival, and invasion, accompanied by the loss of filopodia and cell polarity in vitro, and prevented tumor growth in vivo. Furthermore, we found that Rif was required to activate Wnt5a-Ror1 signaling at the cell surface leading to phosphorylation of the Wnt signaling pathway hub protein Dvl2, which was further promoted by culturing the cells on Matrigel. Our findings reveal a novel function of Rif in mediating Wnt5a-Ror1-Dvl2 signaling, which is associated with the formation of polarized filopodia on 3D matrices in lung adenocarcinoma cells.

maea affects head formation through ß-catenin degradation during early Xenopus laevis development.

Canonical Wnt signalling plays important roles in early embryogenesis, such as axis formation due to its activation and head formation due to its inhibition. ß-catenin protein stability is a key factor in canonical Wnt signalling. Several E3 ubiquitin ligases contribute to ß-catenin degradation through the ubiquitin/proteasome system. We characterised an E3 ubiquitin ligase gene, Xenopus laevis macrophage erythroblast attacher (maea), during early development. maea transcripts were ubiquitously detected in early embryos. The expression levels of the Wnt target genes nodal homolog 3, gene 1 (nodal3.1), and siamois homeodomain 1 (sia1), which were induced by injection with ß-catenin mRNA, were reduced by maea.S mRNA co-injection. maea.S overexpression at the anterior dorsal region enlarged head structures, whereas Maea knockdown interfered with head formation in Xenopus embryos. Maea.S decreased and ubiquitinated ß-catenin protein. ß-catenin-4KRs protein, which mutated the four lysine (K) residues known as ubiquitinated sites to arginine (R) residues, was also ubiquitinated and degraded by Maea.S. These findings suggest that Maea contributes to ß-catenin degradation by ubiquitination of unknown lysine residues in early Xenopus development.

ccl19 and ccl21 affect cell movements and differentiation in early Xenopus development.

We characterized Xenopus laevis C-C motif chemokine ligand 19.L (ccl19.L) and C-C motif chemokine ligand 21.L (ccl21.L) during early Xenopus embryogenesis. The temporal and spatial expression patterns of ccl19.L and ccl21.L tended to show an inverse correlation, except that the expression level was higher in the dorsal side at the gastrula stage. For example, even at the dorsal sector of the gastrulae, ccl19.L was expressed in the axial region and ccl21.L was expressed in the paraxial region. Dorsal overexpression of ccl19.L and ccl21.L and knockdown of Ccl19.L and Ccl21.L inhibited gastrulation, but their functions were different in cell behaviors during morphogenesis. Observation of Keller sandwich explants revealed that overexpression of both ccl19.L and ccl21.L and knockdown of Ccl21.L inhibited the convergent extension movements, while knockdown of Ccl19.L did not. ccl19.L-overexpressing explants attracted cells at a distance and ccl21.L-overexpressing explants attracted neighboring cells. Ventral overexpression of ccl19.L and ccl21.L induced secondary axis-like structures and chrd.1 expression at the ventral side. Upregulation of chrd.1 was induced by ligand mRNAs through ccr7.S. Knockdown of Ccl19.L and Ccl21.L inhibited gastrulation and downregulated chrd.1 expression at the dorsal side. The collective findings indicate that ccl19.L and ccl21.L might play important roles in morphogenesis and dorsal-ventral patterning during early embryogenesis in Xenopus.

ccr7 affects both morphogenesis and differentiation during early Xenopus embryogenesis.

Chemokines play important roles in early embryogenesis, including morphogenesis and cell differentiation, before the immune system is established. We characterized Xenopus laevis CC-type chemokine receptor 7 S (ccr7.S) to clarify its role during early development. ccr7 transcripts were detected ubiquitously in early embryos. Dorsal overexpression of ccr7.S inhibited gastrulation, and ccr7.S mRNA-injected embryos had short axes and widely opened neural folds. Because the Keller sandwich explants of the injected embryos elongated well, ccr7.S might affect cell migration, but not convergent extension movements. Ventral ccr7.S overexpression induced secondary axes and chrd.1 upregulation in gastrula-stage embryos. Animal cap assays showed increased expression of neural and cement gland marker genes at later stages. Ccr7.S knockdown reduced chrd.1 expression and inhibited gastrulation at the dorsal side. Our findings suggest that ccr7.S plays important roles in morphogenetic movement and cell differentiation.

TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine of key importance for controlling embryogenesis and tissue homeostasis. How TGF-beta signals are attenuated and terminated is not well understood. Here, we show that TMEPAI, a direct target gene of TGF-beta signaling, antagonizes TGF-beta signaling by interfering with TGF-beta type I receptor (TbetaRI)-induced R-Smad phosphorylation. TMEPAI can directly interact with R-Smads via a Smad interaction motif. TMEPAI competes with Smad anchor for receptor activation for R-Smad binding, thereby sequestering R-Smads from TbetaRI kinase activation. In mammalian cells, ectopic expression of TMEPAI inhibited TGF-beta-dependent regulation of plasminogen activator inhibitor-1, JunB, cyclin-dependent kinase inhibitors, and c-myc expression, whereas specific knockdown of TMEPAI expression prolonged duration of TGF-beta-induced Smad2 and Smad3 phosphorylation and concomitantly potentiated cellular responsiveness to TGF-beta. Consistently, TMEPAI inhibits activin-mediated mesoderm formation in Xenopus embryos. Therefore, TMEPAI participates in a negative feedback loop to control the duration and intensity of TGF-beta/Smad signaling.

Chaperone complex BAG2-HSC70 regulates localization of Caenorhabditis elegans leucine-rich repeat kinase LRK-1 to the Golgi.

Mutations in LRRK2 are linked to autosomal dominant forms of Parkinson's disease. We identified two human proteins that bind to LRRK2: BAG2 and HSC70, which are known to form a chaperone complex. We characterized the role of their Caenorhabditis elegans homologues, UNC-23 and HSP-1, in the regulation of LRK-1, the sole homologue of human LRRK2. In C. elegans, LRK-1 determines the polarized sorting of synaptic vesicle (SV) proteins to the axons by excluding SV proteins from the dendrite-specific transport machinery in the Golgi. In unc-23 mutants, SV proteins are localized to both presynaptic and dendritic endings in neurons, a phenotype also observed in lrk-1 deletion mutants. Furthermore, we isolated mutations in the hsp-1 gene that can suppress the unc-23, but not the lrk-1 defect. We show that UNC-23 determines LRK-1 localization to the Golgi apparatus in cooperation with HSP-1. These results describe a chaperone-dependent mechanism through which LRK-1 localization is regulated.

Prognosis After Brain Metastasis from Differentiated Thyroid Carcinoma.

BACKGROUND: In patients with differentiated thyroid carcinoma (DTC), lung and bone metastasis sometimes occur. However, brain metastasis (BM) is extremely rare. Because most previous reports about BM from DTC included a relatively small number of cases, the clinical characteristics and outcomes of BM are still unclear. PATIENTS AND METHODS: Between 1965 and 2013, among 961 patients who had died because of DTC, 24 patients were diagnosed with BM from DTC. One patient with BM from DTC is still alive. To identify the prognostic factors for longer survival after BM, the medical records of these 25 patients were retrospectively reviewed. RESULTS: The median age at BM diagnosis was 66 years. Typical symptoms associated with BM had appeared in 20 patients (80%). The Karnofsky Performance Status (KPS) was good (≥70) in 10 patients and poor (≤60) in 15 patients. Seven patients had a single intracranial lesion of BM, 6 patients had 2 or 3 lesions, and 9 patients had 4 or more. Eleven patients did not receive any treatment for BM, and 14 patients underwent surgical resection, radiation therapy, or both. One-year and 5-year disease-specific survival rates were 28 and 10.6%, respectively. Good KPS (≥70), small number of intracranial lesions (≤3), and treatment for BM were prognostic factors for long survival on univariate analysis (p < 0.05). On multivariate analysis, only treatment for BM was significant. CONCLUSION: Treatment of BM from DTC is indicated in patients who have a good KPS and fewer intracranial lesions, and some of them may achieve long survival.

Outcome and characteristics of patients with malignant pleural effusion from differentiated thyroid carcinoma.

Metastatic differentiated thyroid carcinoma (DTC) is an uncommon cause of malignant pleural effusion (MPE) and the characteristics and clinical course have been rarely described. Herein, we report a retrospective review of the clinical course of 18 patients (15 women and 3 men) with MPE from DTC who underwent treatment at our institution between January 2005 and December 2014. MPE from DTC was diagnosed based on cytology and/or level of thyroglobulin in the pleural fluid. Pathologically, papillary carcinoma was found in 16 patients and follicular carcinoma in 2 patients. Median ages at initial diagnosis of DTC and MPE were 64 years (range, 22-79) and 74 years (range, 39-86), respectively. All patients showed radiologically apparent lung metastases, with MPE developing after 0-212 months (median, 25). In 16 patients (88.9%), other coexistent distant metastases at the time of MPE diagnosis were found in the bone (n = 10), brain (n = 5), and skin (n = 2). All patients were treated conservatively with palliative thoracentesis or chest tube drainage with or without pleurodesis. Recurrent MPE after treatment was seen in 9 patients; discharge to home health care after treatment for MPE was possible for 14 patients. The overall survival after initial diagnosis varied considerably from 14 months to 37 years, but the median survival after appearance of MPE was 10 months (range, 1-28). Systemic therapy for iodine-resistant recurrent thyroid disease may need to be considered as a treatment option for patients with MPE.

DNA demethylation in hormone-induced transcriptional derepression.

Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.

Antimicrobial prophylaxis for the prevention of surgical site infection after thyroid and parathyroid surgery: a prospective randomized trial.

BACKGROUND AND OBJECTIVE: The effectiveness of antimicrobial prophylaxis (AMP) in the prevention of surgical site infection (SSI) following thyroid and parathyroid surgery remains uncertain. The objective of this prospective randomized controlled trial (Ito-RCT1) was to assess the effectiveness of AMP in clean neck surgery performed to treat thyroid and parathyroid disease. METHODS: Participants comprised patients scheduled for clean neck surgery for thyroid and parathyroid disease at Ito Hospital. Patients whose surgery included sternotomy or resection of the trachea, larynx, pharynx, or esophagus were excluded. AMP consisted of 2 g of piperacillin (PIPC) (group A, n = 541) or 1 g of cefazolin (CEZ) (group B, n = 541) administered intravenously immediately after endotracheal intubation. Patients in the control group (Group C, n = 1,082) did not receive AMP. RESULTS: Statistical analysis was performed to compare the AMP group (Group A + Group B) with the control group (Group C). Drug-induced acute reactions correlated to PIPC or CEZ did not occur in the AMP group. No significant differences in the postoperative incidence of liver or renal dysfunction were seen between the AMP and control groups. Postoperative incidence of urinary tract infection was significantly higher in the control group (p = 0.002). The incidence of SSI events was very low, with only 1 event (0.09 %) in the AMP group and 3 events (0.28 %) in the control group, and this difference between groups was not significant (p = 0.371). CONCLUSIONS: AMP is not necessary to prevent SSI after clean thyroid or parathyroid surgery.

Clinicopathologic features and outcomes in patients with diffuse sclerosing variant of papillary thyroid carcinoma.

BACKGROUND: Diffuse sclerosing variant (DSV) of papillary thyroid carcinoma (PTC) is a rare variant more common among younger patients. MATERIALS AND METHODS: Excluding patients with microcarcinoma, 5848 patients with PTC underwent initial surgery between 1995 and 2011. Twenty-two patients (0.4 %) were histologically diagnosed with DSV, of whom 20 (91 %) were <45 years old. We compared clinicopathologic characteristics and outcomes between patients with DSV and those with classical PTC <45 years old. Univariate analysis by the Kaplan-Meier method in relation to cause-specific survival (CSS) and disease-free survival (DFS) rates was performed with regard to the following variables: sex; anti-thyroglobulin antibody (TgAb) positivity; presence of distant metastasis; pathological lymph node metastasis; extra-thyroidal invasion; and pathological variant (classical vs. DSV). RESULTS: The 20 patients with DSV <45 years old comprised 18 females and 2 males. Frequencies of TgAb, pN1b, and local recurrence were higher in the DSV group than in the classical PTC group. Ten-year CSS and DFS rates for PTC patients <45 years old were 99.7 and 88.6 % in the classical PTC group and 100 and 60.5 % in the DSV group. CSS rate did not differ between groups, but DFS rate was significantly lower in the DSV group than in the classical PTC group (p < 0.0001, log-rank test). Multivariate analysis identified DSV group and pN1b as prognostic factors for recurrence in young PTC patients. CONCLUSIONS: Most DSV patients were young and had a background of chronic thyroiditis. Outcomes for DSV were very good, but recurrence was more common than in classical PTC.

Papillary Thyroid Carcinoma in Children and Adolescents: Long-Term Follow-Up and Clinical Characteristics.

BACKGROUND: The aim of this study was to analyze the clinical features and clinical outcomes of papillary thyroid carcinoma (PTC) in the pediatric and adolescent population treated in our institution. METHODS: The subjects were 227 PTC patients 20 years of age or under treated initially between 1979 and 2012. Their mean age at diagnosis was 18-year old (range 7-20 years). Patient characteristics and outcomes in the period before 1999 and the period after 2000 were compared. Cause-specific survival (CSS) rates and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method. RESULTS: Two patients died of their disease and 45 patients had recurrent disease (36 in lymph node, seven in a remnant thyroid, and 11 in the form of distant metastasis). The 10-, 20-, and 30-CSS rates were 99.3, 99.3, and 96.5%, respectively, and the 10-, 20-, and 30-DFS were 83.6, 70.7, and 64.0%, respectively. Gender and preoperative lymph node metastasis were identified as significant factors related to DFS in the multivariate analysis. After the year 2000, there were significantly more patients with a small primary tumor size, significantly more patients without distant metastasis at presentation and significantly more patients without extrathyroidal invasion. CONCLUSION: The number of patients with advanced cancer has been declining in recent years. Lobectomy with prophylactic unilateral central neck dissection is considered acceptable for patients without the risk factors for recurrence.

IQGAP1 protein regulates nuclear localization of ß-catenin via importin-ß5 protein in Wnt signaling.

In the canonical Wnt signaling pathway, the translocation of ß-catenin is important for the activation of target genes in the nucleus. However, the molecular mechanisms underlying its nuclear localization remain unclear. In the present study, we found IQGAP1 to be a regulator of ß-catenin function via importin-ß5. In Xenopus embryos, depletion of IQGAP1 reduced Wnt-induced nuclear accumulation of ß-catenin and expression of Wnt target genes during early embryogenesis. Depletion of endogenous importin-ß5 associated with IQGAP1 also reduced expression of Wnt target genes and the nuclear localization of IQGAP1 and ß-catenin. Moreover, a small GTPase, Ran1, contributes to the nuclear translocation of ß-catenin and the activation of Wnt target genes. These results suggest that IQGAP1 functions as a regulator of translocation of ß-catenin in the canonical Wnt signaling pathway.

CHIP-dependent termination of MEKK2 regulates temporal ERK activation required for proper hyperosmotic response.

The extracellular signal-regulated kinase (ERK) pathway is an important signalling pathway that regulates a large number of cellular processes, including proliferation, differentiation and gene expression. Hyperosmotic stress activates the ERK pathway, whereas little is known about the regulatory mechanisms and physiological functions of ERK activation in hyperosmotic response. Here, we show that MAPK/ERK kinase kinase 2 (MEKK2), a member of the MAPKKK family, mediated the specific and transient activation of ERK, which was required for the induction of aquaporin 1 (AQP1) and AQP5 gene expression in response to hyperosmotic stress. Moreover, we identified the E3 ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a binding partner of MEKK2. Depletion of CHIP by small-interference RNA or gene targeting attenuated the degradation of MEKK2 and prolonged the ERK activity. Interestingly, hyperosmolality-induced gene expression of AQP1 and AQP5 was suppressed by CHIP depletion and was reversed by inhibition of the prolonged phase of ERK activity. These findings show that transient activation of the ERK pathway, which depends not only on MEKK2 activation, but also on CHIP-dependent MEKK2 degradation, is crucial for proper gene expression in hyperosmotic stress response.

WNK4 is an essential effector of anterior formation in FGF signaling.

With no lysine (K) (WNK) kinase family is conserved among many species and regulates SPAK/OSR1 and ion cotransporters. WNK is also involved in developmental and cellular processes, but the molecular mechanisms underlying its regulation in these processes remain unknown. In this study, we found that WNK4 is involved in fibroblast growth factor (FGF) signaling during Xenopus development. In Xenopus embryos, depletion of WNK4 by antisense morpholino oligonucleotides (MOs) results in a severe defect in anterior development and impaired expression of endogenous anterior markers. Defects in head formation or expression of anterior marker genes caused by suppression of endogenous WNK4 expression could be rescued by expression of wild-type WNK4, but not mutant WNK4 lacking its kinase activity. It is notable that morphants of Xenopus WNK4 inhibited the expression of anterior marker genes and the target genes induced by FGF signaling. Moreover, knockdown of Wnk4 significantly reduced the phosphorylation level of Osr1 induced by FGF. These results provide the first evidence that FGF signaling regulates WNK4 function required for anterior formation in Xenopus development.

Does completion thyroidectomy improve the outcome of patients with minimally invasive follicular carcinoma of the thyroid?

BACKGROUND: The diagnosis of minimally invasive follicular thyroid carcinoma (MIFTC) is often made histologically after thyroid lobectomy. We attempted to determine whether completion thyroidectomy should be considered necessary for all patients diagnosed with MIFTC after thyroid lobectomy. METHODS: The subjects of this study were a total of 324 patients who underwent thyroid lobectomy as initial surgery at our institution between 1989 and 2010 and diagnosed histologically as MIFTC. Completion thyroidectomy was performed on 101 patients, and the other 223 patients were followed up without further treatments. Cumulative cause-specific survival (CSS) rates and distant-metastasis-free survival (DMFS) rates were calculated by the Kaplan-Meier method. Differences between groups were analyzed for statistical significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazards model. RESULTS: During the follow-up period, 39 patients were diagnosed with distant metastasis, and 7 patients died of their disease. Age at the initial surgery was found to be a significant factor related to DMFS in both the univariate and multivariate analysis and to also be related to CSS in the univariate analysis. Completion thyroidectomy did not have a significant effect on DMFS or CSS according to the results of the univariate analysis, but it had significant effect on DMFS according to the results of the multivariate analysis. CONCLUSIONS: Although we were unable to demonstrate sufficient statistical evidence that completion thyroidectomy improved the outcome of MIFTC patients, it is noteworthy none of the patient who underwent completion thyroidectomy died of the disease.

A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation.

Histone modifications induced by activated signalling cascades are crucial to cell-lineage decisions. Osteoblast and adipocyte differentiation from common mesenchymal stem cells is under transcriptional control by numerous factors. Although PPAR-gamma (peroxisome proliferator activated receptor-gamma) has been established as a prime inducer of adipogenesis, cellular signalling factors that determine cell lineage in bone marrow remain generally unknown. Here, we show that the non-canonical Wnt pathway through CaMKII-TAK1-TAB2-NLK transcriptionally represses PPAR-gamma transactivation and induces Runx2 expression, promoting osteoblastogenesis in preference to adipogenesis in bone marrow mesenchymal progenitors. Wnt-5a activates NLK (Nemo-like kinase), which in turn phosphorylates a histone methyltransferase, SETDB1 (SET domain bifurcated 1), leading to the formation of a co-repressor complex that inactivates PPAR-gamma function through histone H3-K9 methylation. These findings suggest that the non-canonical Wnt signalling pathway suppresses PPAR-gamma function through chromatin inactivation triggered by recruitment of a repressing histone methyltransferase, thus leading to an osteoblastic cell lineage from mesenchymal stem cells.

Optimal timing of surgery for differentiated thyroid cancer in pregnant women.

BACKGROUND: Differentiated thyroid cancer (DTC) is the second most common cancer diagnosed in pregnant women, but there is no consensus as to whether surgery should be performed during pregnancy or after delivery. METHODS: We retrospectively reviewed the records of 45 patients with DTC operated on during pregnancy or within 1 year after delivery, and we compared the clinicopathological features and outcomes of the patients operated during pregnancy (group A, n = 24) and the patients operated after delivery (group B, n = 21). RESULTS: All 45 patients were histologically diagnosed with well-differentiated papillary thyroid cancer. Nineteen (79 %) of the 24 patients in group A underwent thyroidectomy during the second trimester. No complications associated with surgery or general anesthesia were reported in either group. There were no significant differences between the two groups in terms of age, tumor size, incidence of lymph node metastasis, or incidence of extrathyroidal extension. No distant metastases were detected in any of the patients. Two small for date infants (8.3 %) and 2 heavy for date infants (8.3 %) were delivered in group A, but only 1 small for date infant (4.7 %) was delivered in group B. There were no miscarriages, and none of the infants in either group had birth defects. Because 3 patients in group A and 1 patient in group B experienced a local recurrence, salvage surgeries were performed. CONCLUSIONS: Although thyroid surgery was performed safely in the second trimester, surgery after delivery was also acceptable. Surgery after delivery is recommended for most patients with non-aggressive DTC.

Thyroid lobectomy for papillary thyroid cancer: long-term follow-up study of 1,088 cases.

BACKGROUND: Total thyroidectomy is well accepted as initial surgery for papillary thyroid cancer (PTC), but the extent of the thyroidectomy remains a matter of controversy. This study was designed to investigate the long-term clinical outcome of PTC patients who had undergone thyroid lobectomy and to elucidate the indications of lobectomy as initial surgery. METHODS: The cases of 1,088 PTC patients who underwent thyroid lobectomy with curative intent at Ito Hospital between 1986 and 1995 were analyzed retrospectively in this study. None of the patients had received postoperative radioactive iodine (RAI) ablation therapy. The median follow-up period was 17.6 years. All clinical outcomes, including recurrence and death as a result of PTC or other reasons, were evaluated. To establish the indications for lobectomy as initial surgery for PTC, the potential risk factors, such as age, sex, primary tumor size, extrathyroidal invasion, and clinical lymph node metastasis at the time of the initial surgery, were assessed statistically for associations with recurrence and disease-related death. RESULTS: The remnant-thyroid recurrence-free survival (RT-RFS) rate, the regional- lymph-node recurrence-free survival (L-RFS) rate, and the distant-recurrence-free survival (D-RFS) rate as of 25 years after surgery were 93.5, 90.6, and 93.6%, respectively. The cause-specific survival (CSS) rate at 25 years was 95.2%. Univariate and multivariate analyses showed that none of the factors assessed were significantly associated with the RT-RFS rate. Tumor size, clinical lymph node metastasis, and extrathyroidal invasion were significantly associated with the L-RFS rate. The D-RFS and CSS rates were both significantly lower in the group of patients who were aged 45 years old or older, the group whose tumors were larger than 40 mm, and the group with extrathyroidal invasion. Based on the above findings, we classified the patients into four groups according to age <45 or ≥ 45 years, tumor size ≤ 40 or >40 mm, whether clinical lymph node metastasis was present, and whether extrathyroidal invasion was present. None of the patients without any of these four risk factors died of PTC. On the other hand, 22 patients who died of PTC were positive for one or more of these four factors. CONCLUSIONS: The long-term clinical outcome of the PTC patients who had been treated by lobectomy without RAI ablation was excellent. Based on the above results, we concluded that lobectomy is a valid alternative to total thyroidectomy for the treatment of PTC patients who are younger than aged 45 years, whose tumor diameter is 40 mm or less, and who do not have clinical lymph node metastasis or extrathyroidal invasion.

Follicular thyroid carcinoma with distant metastasis: outcome and prognostic factor.

Follicular thyroid carcinoma (FTC) usually has a good prognosis unless there is distant metastasis (DM). In this retrospective study we evaluated the outcome of FTC patients with DM and attempted to identify prognostic factors. The subjects of this study were the 106 of FTC patients who underwent thyroidectomy at our hospital between 1989 and 2010 who had been diagnosed with DM at presentation or had developed DM after the initial surgery. Their cumulative cause-specific survival (CSS) rate from diagnosis of DM to date of last follow-up was calculated by the Kaplan-Meier method. Prognostic factors were identified by univariate analysis (the log-rank test) and multivariate analysis (Cox's proportional hazards model). The site of the DM was the lung in 36 patients, bone in 33 patients, both lung and bone in 28 patients and other sites in 9 patients. During the follow-up period, 22 patients died of their disease. The DMs were treated by radioactive iodine (RI) therapy in 80 patients, by surgical treatment in 36 patients and by external beam radiation therapy (EBRT) in 27 patients. The CSS rates at 5, 10, and 15 years after the first DM was diagnosed were 82.2%, 63.8%, and 23.9%, respectively. Univariate analyses and multivariate analysis identified age at diagnosis of DM and primary tumor size as significant factors related to CSS. In this study, we could not show RI therapy, EBRT or surgical treatment for DM had an impact on the outcome.