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.

Enhanced O-GlcNAc modification induced by the RAS/MAPK/CDK1 pathway is required for SOX2 protein expression and generation of cancer stem cells.

Cancer stem cells (CSCs) have tumour initiation, self-renewal, and long-term tumour repopulation properties, and it is postulated that differentiated somatic cells can be reprogrammed to CSCs by oncogenic signals. We previously showed that oncogenic HRASV12 conferred tumour initiation capacity in tumour suppressor p53-deficient (p53-/-) primary mouse embryonic fibroblasts (MEFs) through transcription factor NF-κB-mediated enhancement of glucose uptake; however, the underlying mechanisms of RAS oncogene-induced CSC reprogramming have not been elucidated. Here, we found that the expression of the reprogramming factor SOX2 was induced by HRASV12 in p53-/- MEFs. Moreover, gene knockout studies revealed that SOX2 is an essential factor for the generation of CSCs by HRASV12 in mouse and human fibroblasts. We demonstrated that HRASV12-induced cyclin-dependent kinase 1 (CDK1) activity and subsequent enhancement of protein O-GlcNAcylation were required for SOX2 induction and CSC generation in these fibroblasts and cancer cell lines containing RAS mutations. Moreover, the CDK inhibitor dinaciclib and O-GlcNAcylation inhibitor OSMI1 reduced the number of CSCs derived from these cells. Taken together, our results reveal a signalling pathway and mechanism for CSC generation by oncogenic RAS and suggest the possibility that this signalling pathway is a therapeutic target for CSCs.

WNK regulates Wnt signalling and ß-Catenin levels by interfering with the interaction between ß-Catenin and GID.

ß-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the ß-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of ß-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between ß-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting ß-Catenin, and that WNK regulates the ß-Catenin level. Furthermore, we show that WNK inhibitors induced ß-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of ß-Catenin and a therapeutic target of cancer.

Glycogen synthase kinase 3ß functions as a positive effector in the WNK signaling pathway.

The with no lysine (WNK) protein kinase family is conserved among many species. Some mutations in human WNK gene are associated with pseudohypoaldosteronism type II, a form of hypertension, and hereditary sensory and autonomic neuropathy type 2A. In kidney, WNK regulates the activity of STE20/SPS1-related, proline alanine-rich kinase and/or oxidative-stress responsive 1, which in turn regulate ion co-transporters. The misregulation of this pathway is involved in the pathogenesis of pseudohypoaldosteronism type II. In the neural system, WNK is involved in the specification of the cholinergic neuron, but the pathogenesis of hereditary sensory and autonomic neuropathy type 2A is still unknown. To better understand the WNK pathway, we isolated WNK-associated genes using Drosophila. We identified Glycogen synthase kinase 3ß (GSK3ß)/Shaggy (Sgg) as a candidate gene that was shown to interact with the WNK signaling pathway in both Drosophila and mammalian cells. Furthermore, GSK3ß was involved in neural specification downstream of WNK. These results suggest that GSK3ß/Sgg functions as a positive effector in the WNK signaling pathway.

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.

Chemosensitivity of anaplastic thyroid cancer based on a histoculture drug response assay.

The chemosensitivity of anaplastic thyroid cancer (ATC) to some cytotoxic agents was investigated by the histoculture drug response assay (HDRA). Thirty specimens from 22 patients with ATC were obtained from surgically resected subjects. The drugs tested were paclitaxel (PTX), docetaxel (DOC), adriamycin (ADM), nedaplatin (254-S), cisplatin (CDDP), carboplatin (CBDCA), etoposide (VP-16), 5-fluorouracil (5-FU), mitomycin C (MMC), and cyclophosphamide (CPA). PTX was the most effective agent, and 25 of 29 cases (86.2%) had high inhibition rates (IRs; over 70%), while DOC, another taxane, had lower IRs (median, 32.6%). 254-S had the second highest IR (median 68.1%), higher than other platins, CDDP (median 47.3%) and CBDCA (median 27.4%). The IR of 50% dose PTX (20 µg/mL, median 30.6%) was markedly decreased, while that of 50% dose 254-S (10 µg/mL, median 63.3%) still retained its inhibition effect compared to 100% dose. Most recurrent samples had higher IRs than primary lesions, but the IRs of different drugs differed between primary and recurrent lesions, even with samples from the same patients. PTX has a higher IR to ATC tissues in the HDRA, which suggests that it may be a key drug for the treatment of patients with ATC.

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.

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.

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.

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.

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.

Management of thyroid carcinoma showing thymus-like differentiation (CASTLE) invading the trachea.

PURPOSE: To define the clinicopathological features and discuss the optimal management of carcinoma showing thymus-like differentiation (CASTLE). METHODS: We retrospectively analyzed six patients with CASTLE. RESULTS: The subjects comprised two men and four women (average age at initial diagnosis, 61 years, range 47-75 years). Preoperative biopsy yielded a correct diagnosis in two patients. Five patients underwent surgery and one was treated with radiation therapy alone. Four had extrathyroidal invasion and three had lymph node metastasis. During the clinical course, tracheal invasion was detected in five patients, the upper extent of the tumor being the lower half of the first tracheal ring. Two of these patients underwent tracheal sleeve resection. Two patients received postoperative radiotherapy for nodal metastasis, and one, after palliative surgery. The median follow-up period was 67 months (range 38-129). Recurrence was found 10 years post-therapy in the patient treated with radiation therapy only, resulting in death soon after. Although local recurrence was not found in the remaining five patients, new pulmonary metastases were diagnosed in the patient who underwent non-curative surgery. CONCLUSIONS: CASTLE can be diagnosed preoperatively by core needle biopsy and CD5 staining. Curative resection with neck dissection followed by radiotherapy can yield a good outcome. Larynx-sparing complete resection may be more feasible for CASTLE, even though it has a higher incidence of tracheal invasion than differentiated thyroid carcinoma.

Does Hürthle cell carcinoma of the thyroid have a poorer prognosis than ordinary follicular thyroid carcinoma?

BACKGROUND: Hürthle cell carcinoma (HCC) is a rare form of thyroid carcinoma and is considered an oxyphilic variant of follicular thyroid carcinoma. However, little is known about its biological characteristics or clinical behavior. We conducted a retrospective study to determine whether the prognosis of HCC differs from that of ordinary follicular thyroid carcinoma (OFC). METHODS: The subjects were the 558 patients with follicular thyroid carcinoma who underwent initial surgery at our institution between 1989 and 2010 and consisted of 73 patients with HCC and 485 patients with OFC. There were 410 females and 148 males, and their median age was 51 years. A univariate analysis was conducted in relation to cumulative cause-specific survival (CSS) according to the Kaplan-Meier method for the following variables: age at the time of initial surgery, gender, tumor size, invasiveness, distant metastasis at presentation, and histological type (HCC vs OFC). Differences between groups were analyzed for significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional hazard model. RESULTS: A total of 4 patients (5.5%) in the HCC group had distant metastasis compared with 106 patients (21.9%) in the OFC group. Significant factors in relation to CSS in the univariate analyses were age, tumor size, and invasiveness, but there were no significant differences between the HCC group and the OFC group. Multivariate analysis showed that age, tumor size, and distant metastasis at presentation were significant factors. CONCLUSIONS: HCC does not have a poorer prognosis than OFC.

Diagnostic accuracy of fine needle aspiration biopsy cytology and ultrasonography in patients with thyroid nodules diagnosed as benign or indeterminate before thyroidectomy.

Fine-needle aspiration biopsy cytology (FNABC) and ultrasonography (US) play an important role in differentiating benign thyroid nodules from malignant nodules. We retrospectively investigated the prevalence of follicular thyroid carcinoma (FTC) in patients with thyroid nodules whose FNABC and US readings were not malignant before thyroidectomy. Between 2007 and 2008, 3333 patients underwent thyroidectomy at our institution, and the 737 of them who had thyroid nodule that had been diagnosed as hyperplastic nodule or follicular tumor by FNABC and US preoperatively were the subjects in this study. Postoperative histopathology showed hyperplastic nodule in 416 patients, follicular adenoma in 200 patients, FTC in 99 patients, and other disease in 22 patients. By FNABC, 34 (6.7%) of the 505 patients with diagnosis as benign and 65 (28%) of the 232 patients with diagnosis as indeterminate, were diagnosed as having FTC. The diagnosis was FTC in 56 (9.6%) of the 582 patients with a preoperative diagnosis of hyperplastic nodule by US and 43 (27.7%) of the 155 patients with a diagnosis of follicular tumor by US. The diagnosis of FTC was made in 21 (4.8%) of 438 patients who were concurrently diagnosed as benign by FNABC and as hyperplastic nodule by US, and in 30 (34.1%) of 88 patients who were diagnosed as indeterminate by FNABC and follicular tumor by US. FNABC has been the mainstay for the preoperative evaluation of thyroid nodule. The results of this study showed that US can also be a useful tool for diagnosing FTC.

Changes in the thyroid function of Graves' disease patients treated by subtotal thyroidectomy.

The extent of thyroidectomy in Graves' disease is still a matter of controversy. Subtotal thyroidectomy has been used as the standard surgical procedure for Graves' disease in Japan, but high hyperthyroidism relapse rates have been reported. We retrospectively studied serial changes in the thyroid function Graves' disease patients after they had been treated by subtotal thyroidectomy and assessed whether subtotal thyroidectomy should be recommended as the standard surgical procedure for the treatment of Graves' disease. The subjects were 478 Graves' disease patients who underwent subtotal thyroidectomy at our institution between 1994 and 1997 and were followed up on a regular basis, and their thyroid function 2-3 years after surgery (the early period) and 8-10 years after surgery (the late period) was evaluated and compared. The evaluations in the late period showed that 57% of the euthyroid patients in the early period remained euthyroid, 30% had developed a relapse of hyperthyroidism, and 13 % had become hypothyroid. Approximately 80% of the patients who were overtly hyperthyroid or overtly hypothyroid in the early period remained so in the late period. During the entire periods 47 patients had subclinical hyperthyroidism and were followed up without any postoperative medication. Twenty (42.6%) of them developed overt hyperthyroidism, 11 (23.4%) experienced a spontaneous remission, and 16 (34%) continued to be subclinically hyperthyroid. Because thyroid function after subtotal thyroidectomy is unstable and reduces quality of life, subtotal thyroidectomy is concluded not to be suitable as a standard surgical procedure for the treatment of Graves' disease.

Outcomes and prognostic factors of 251 patients with minimally invasive follicular thyroid carcinoma.

BACKGROUND: Radioiodine ablation after total thyroidectomy is the generally accepted treatment for patients with widely invasive follicular thyroid carcinoma (FTC). The therapeutic strategy for minimally invasive FTC, on the other hand, is still a matter of controversy. The histological diagnosis of minimally invasive FTC is often made after lobectomy. The aim of this study was to determine the factors associated with the development of distant metastases in patients with minimally invasive FTC. METHODS: Between 1989 and 2006, 251 patients with minimally invasive FTC underwent initial surgery at our hospital. Their median follow-up period was 7.2 years. There were 194 women and 57 men. Their mean age at the time of surgery was 46 years. Distant metastases were diagnosed in 54 patients (21.5%). In 22 of them distant metastases were diagnosed at the time of the initial surgery (M1), and in the other 32 they were diagnosed during the follow-up period. Age at initial surgery, sex, primary tumor size, histological findings (differentiation, and extent of vascular and capsular invasion), completion total thyroidectomy, and distant metastases at initial surgery were assessed as prognostic factors for distant-metastases-free survival (DMFS) and cause-specific survival (CSS). The Kaplan-Meier method and log-rank test were used to analyze time-dependent variables. The Cox proportional hazard model was used to perform the multivariate analysis. RESULTS: Univariate analysis showed that age (45 years or older) and primary tumor size (4 cm or more) were significant prognostic factors related to postoperative distant metastases in the group of 229 patients without distant metastases at time of the initial surgery. The cumulative survival rate was significantly poorer in M1 patients, patients aged 45 years or older, and patients whose primary tumor size was 4 cm or more. Multivariate analysis showed that age was a significant prognostic factor both for DMFS and CSS. CONCLUSIONS: Age was the most powerful prognostic factor for patients with minimally invasive follicular thyroid cancer. The prognoses of patients younger than 45 years old were excellent and distant metastases rarely occurred. Routine completion total thyroidectomy and radioiodine ablation is thought unnecessary for these patients.

Clinical features, treatment, and long-term outcome of papillary thyroid cancer in children and adolescents without radiation exposure.

BACKGROUND: Cancer of the thyroid gland is rare in children and adolescents. A history of neck irradiation is a well-established risk factor for tumor development, and most previous reports focused on cases that were induced by radiation exposure. We present here a retrospective review of the clinical features, treatment, and long-term outcome of children and adolescents with papillary thyroid cancer (PTC) without a history of radiation exposure who were treated at our institution over a period of ~50 years. METHODS: We retrospectively investigated 142 PTC patients without an irradiation history who were younger than 20 years of age when treated from 1961 to 2005 (17 males and 125 females; mean age = 16.3 ± 2.7 years; follow-up = 21.8 ± 12.0 years). The clinicopathological results were evaluated using the medical records. Disease-free survival (DFS) and cause-specific survival (CSS) were assessed with the Kaplan-Meier method and compared with the log-rank test. Parametric analyses were performed using Student's t test and nonparametric analyses were performed using the Mann-Whitney U test. RESULTS: At diagnosis, three patients had distant lung metastasis and 33 had gross neck lymph node (LN) metastasis. All patients were treated with surgery (hemi/partial thyroidectomy in 45 patients, subtotal thyroidectomy in 85, total thyroidectomy in 12, no LN dissection in 50, central compartment dissection in 20, and modified radical neck dissection in 72), and postoperative external beam radiation therapy was administered to 59. Postoperative ablative therapy using I(131) was not performed in this series. Recurrence was found for regional LN (n = 25), lung (n = 9), remnant thyroid (n = 5), and others (n = 4). DFS and CSS at 40 years were 74.1 and 97.5%, respectively. DFS was significantly worse in patients aged <16 years with a family history of thyroid cancer, preoperative neck gross LN metastasis, maximum tumor diameter, and extrathyroidal invasion. Preoperative gross neck LN metastasis and distant metastasis at diagnosis were significant factors for CSS. No other factors contributed to DFS and CSS. When the clinical features of children and adolescents were compared, the incidence of preoperative gross neck LN metastasis and distant metastasis at diagnosis and tumors with a maximum diameter >10 mm were significantly higher in the children group than in the adolescent group. DFS was significantly shorter in the children group than in the adolescent group, but no significant difference was found in CSS between these two groups. CONCLUSIONS: The prognosis of PTC in children and adolescents is excellent, regardless of the extent of thyroidectomy and LN dissection. We recommend that only children or adolescents with preoperative gross neck LN metastasis and distant metastasis at diagnosis should be subjected to postoperative ablative therapy.