Search

The incidence of thyroid cancer is increasing rapidly in many countries, resulting in rising societal costs of the care of thyroid cancer. We reported that the active surveillance of low-risk papillary microcarcinoma had less unfavorable events than immediate surgery, while the oncological outcomes of these managements were similarly excellent. Here we calculated the medical costs of these two managements. We created a model of the flow of these managements, based on our previous study. The flow and costs include the step of diagnosis, surgery, prescription of medicine, recurrence, salvage surgery for recurrence, and care for 10 years after the diagnosis. The costs were calculated according to the typical clinical practices at Kuma Hospital performed under the Japanese Health Care Insurance System. If conversion surgeries were not considered, the 'simple cost' of active surveillance for 10 years was 167,780 yen/patient. If there were no recurrences, the 'simple cost' of immediate surgery was calculated as 794,770 yen/patient to 1,086,070 yen/patient, depending on the type of surgery and postoperative medication. The 'simple cost' of surgery was 4.7 to 6.5 times the 'simple cost' of surveillance. When conversion surgeries and recurrence were considered, the 'total cost' of active surveillance for 10 years became 225,695 yen/patient. When recurrence were considered, the 'total cost' of immediate surgery was 928,094 yen/patient, which was 4.1 times the 'total cost' of the active surveillance. At Kuma Hospital in Japan, the 10-year total cost of immediate surgery was 4.1 times expensive than active surveillance.

Background: Although papillary thyroid microcarcinoma (PMC) is generally stable on active surveillance, conversion surgery is recommended for enlarging tumors. However, it remains unclear which enlargement threshold should be considered sufficient to trigger surgery. This study analyzed changes in the growth activity of PMC, before and after enlargement. Methods: We enrolled 824 patients with PMC, in whom active surveillance was initiated between 2005 and 2011 (median duration of follow-up: 6.04 years). Changes in the maximal tumor size and tumor volume were evaluated. Point of enlargement (PE) was defined as the time at which maximal tumor size or tumor volume had increased by ≥3 mm (PE-M) or by ≥50% (PE-V), respectively. In patients with PMC who underwent at least three ultrasound examinations during the study period, we compared the tumor doubling rates (TDRs, designated as the inverse of doubling time) between pre- and post-PEs. Results: Ten-year enlargement-free survival rates based on maximal tumor size and tumor volume were 86.9% and 54.9%, respectively. The median post-PE TDRs was significantly lower than that of pre-PEs (−0.091/year vs. 0.509/year [p 0.5/year) in only 6 (7.7%) and 11 (3.8%) patients and moderately enlarge (TDR 0.1–0.5/year) in 10 (12.8%) and 35 (12.1%) patients, respectively. Conversely, tumors shrank (TDR < −0.1/year) in 37 (47.4%) and 105 (36.1%) patients, respectively, and remained stable (TDR ranged between 0.1/year and −0.1/year) in 25 (32.1%) and 140 (48.1%) patients, respectively. Conclusion: Since most PMCs demonstrate a significant decrease in growth activity after enlargement, performing surgery immediately after the PE may be premature.

Background Recently, we have created a revised version of the eighth edition of the tumor–node–metastasis classification for papillary thyroid carcinomas (PTCs) by subdividing the T4a (T4a1 [moderate] and T4a2 [significant]) and N (N1 [N ≤ 3 cm] and N2 [N > 3 cm]) classifications. This re-staging better stratified patient outcomes. In this study, we investigated the prognostic significance of extranodal tumor extension (LNEx) in PTC. Methods Five thousand six hundred and eighty-three patients with PTC surgically treated in Kuma Hospital were enrolled. We evaluated LNEx based on intraoperative findings. Results One hundred and twenty-seven patients (2%) displayed LNEx. In contrast to what we observed for extrathyroid extension, the prognostic value of LNEx did not change based on the organ that had been invaded, and we therefore analyzed LNEx patients as a single group. In patients aged 55 or older, LNEx independently affected patients’ prognoses, as did T4a2 and N2. The cancer-specific survival (CSS) of patients in Stage I but having LNEx demonstrated the similar prognosis to patients in Stage II. Further, in the subset analysis for Stage II patients aged 55 or older, LNEx had a significant prognostic value for CSS in both the univariate and multivariate analyses, as did N2. The CSS of Stage II patients aged 55 or older with LNEx did not differ from that of Stage III patients. Conclusions It is appropriate that, similar to T4a2 or N2 patients, LNEx-positive patients younger than 55 years in Stage I and those aged 55 or older in Stage II are re-staged to II and III, respectively.

Agarivorans sp. strain Toyoura001 is a bacterium isolated from the gut of a wild abalone, Haliotis discus hannai. Here, we report the draft genome sequence of strain Toyoura001, which consists of 60 contigs comprising 4.67 Mb and 4,257 protein-coding genes.

Artificial diets affect the growth and gut morphology of carnivorous fishes. In this study, we compared a laboratory raised rockfish, Sebastes schlegelii (a carnivore), fed an artificial diet (Lab fish), and the wild-captured rockfish (Wild fish) to confirm the effect of an artificial diet on pyloric caecal morphology and motility. We also established an in vitro method to quantify pyloric caecal sac motility and compared it between Lab and Wild fish. The pyloric caecal length per unit body length, the pyloric caecal weight per unit body weight, and the pyloric caecal weight per length were significantly greater in the Wild fish than in the Lab fish. Additionally, both of the circular and longitudinal muscularis layers were significantly thicker in the Wild fish than in the Lab fish. The pyloric caecal motor frequency of the Wild fish was higher than that in the Lab fish, but the contractile pressure of the pyloric caeca did not change under conventional conditions. These results suggest that the thickness of the tunica muscularis of the pyloric caeca may be involved in its motility, and the pyloric caeca of the Lab fish may not be able to provide functionality in this respect. In conclusion, under artificial rearing conditions, the artificial diet reduced the thickness of the tunica muscularis and reduced the motor frequency of the pyloric caeca in rockfish.

Background: It is generally considered impossible to differentiate follicular carcinomas from follicular adenomas by means of ultrasonography or cytology before surgery. Therefore, follicular carcinoma is histopathologically diagnosed by verifying capsular and/or vascular invasion after surgery. However, ultrasonography may play an important role in diagnosing follicular carcinoma preoperatively in a small number of cases. Case Description: Four cases of follicular carcinoma or follicular neoplasm that transformed from a benign thyroid tumor and demonstrated a “nodule in nodule” appearance on ultrasonography are presented in this report. Characteristic ultrasound features of such patients are: (1) a “nodule in nodule” appearance, (2) a well-defined boundary line between the nodules, and (3) separate distribution of blood signals within each nodule. Conclusion: A small number of patients with follicular carcinomas or follicular neoplasms may present with a “nodule in nodule” appearance on ultrasonography. It was suggested a long time ago that follicular carcinomas may develop from benign thyroid tumors. The fact that follicular carcinomas appear within benign tumors may be evidence of thyroid tumorigenesis.

Ghrelin exhibits a cardioprotective effect. We examined whether orally administered ghrelin-containing salmon stomach extract (sSE) instead of chemically synthesized ghrelin protects against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were divided into four groups: (i) the control, (ii) DOX groups were fed a control diet (AIN-93G), (iii) the sSE, and (iv) DOX + sSE groups were fed a 10% sSE diet (AIN-93G + 10% sSE). After a 4-week pretreatment of sSE, DOX or saline was administered to the corresponding groups by intraperitoneal injection. The groups fed the 10% sSE diet consumed significantly more food than the groups fed the control diet before the DOX injection. No mortality was observed in the DOX + sSE group, whereas 40% (2 of 5) mortality was observed in the DOX group. Compared with the DOX group, levels of ascites and plasma cardiac troponin I improved in the DOX + sSE group. Significantly lesser DOX-induced collagen accumulation was observed in the left heart ventricle of the DOX group than in that of the DOX + sSE group. These results suggest that the dietary ghrelin contained in sSE mimics synthetic ghrelin in cardioprotective effect. Ghrelin in sSE (45 pmol/g) and the food intake-stimulating effect of sSE may explain, at least in part, the protective effect of orally administered teleost ghrelin.

Objective Genetic testing for RET germline mutation can be useful to distinguish whether a patient with medullary thyroid carcinoma (MTC) is genuinely sporadic or hereditary. Conducting a routine preoperative germline RET genetic screening for all patients with MTC has the clinical benefit, i.e., avoidance of unnecessary total thyroidectomy in the selected patients. We sought to clarify the incidence of germline RET mutation carriers in Japanese patients with apparently sporadic MTC and to address the differences in clinicopathological characteristics between true sporadic MTC and hereditary MTC in these patients, all of whom were treated at Kuma Hospital. Methods A total of 134 patients with apparently sporadic MTC who underwent surgery between 1996 and 2014 were enrolled. All patients underwent a germline RET gene mutation analysis preoperatively. Results Germline mutations in RET proto-oncogene were identified in 20 of the 134 (14.9%) apparently sporadic MTC patients. No significant difference in clinicopathological characteristics was observed between the patients with sporadic MTC ( n = 114) and those with hereditary MTC ( n = 20) except for the RET gene carriers’ younger age at diagnosis and presence of multifocal and bilateral lesions. Conclusion Germline RET mutations were identified in 14.9% of Japanese patients with apparently sporadic MTC. No clearly decisive clinicopathological characteristics was observed to distinguish whether an apparently sporadic MTC case was genuinely sporadic or unconsciously hereditary. For the treatment strategy decision, it is advantageous to conduct a routine preoperative germline RET genetic screening for all patients with MTC, even if their MTC is apparently sporadic.

The incidence of papillary microcarcinoma (PMC) of the thyroid is rapidly increasing globally, making the management of PMC an important clinical issue. Excellent oncological outcomes of active surveillance for low-risk PMC have been reported previously. Here, unfavorable events following active surveillance and surgical treatment for PMC were studied.From February 2005 to August 2013, 2153 patients were diagnosed with low-risk PMC. Of these, 1179 patients chose active surveillance and 974 patients chose immediate surgery. The oncological outcomes and the incidences of unfavorable events of these groups were analyzed.In the active surveillance group, 94 patients underwent surgery for various reasons; tumor enlargement and the appearance of novel lymph node metastases were the reasons in 27 (2.3%) and six patients (0.5%), respectively. One of the patients with conversion to surgery had nodal recurrence, and five patients in the immediate surgery group had a recurrence in a cervical node or unresected thyroid lobe. All of these recurrences were successfully treated. None of the patients had distant metastases, and none died of the disease. The immediate surgery group had significantly higher incidences of transient vocal cord paralysis (VCP), transient hypoparathyroidism, and permanent hypoparathyroidism than the active-surveillance group did (4.1% vs. 0.6%, p 0.0001; 16.7% vs. 2.8%, p 0.0001; and 1.6% vs. 0.08%, p 0.0001, respectively). Permanent VCP occurred only in two patients (0.2%) in the immediate surgery group. The proportion of patients on L-thyroxine for supplemental or thyrotropin (TSH)-suppressive purposes was significantly larger in the immediate surgery group than in the active surveillance group (66.1% vs. 20.7%, p 0.0001). The immediate surgery group had significantly higher incidences of postsurgical hematoma and surgical scar in the neck compared with the active surveillance group (0.5% vs. 0%, p 0.05; and 8.0% vs. 100%, p 0.0001, respectively).The oncological outcomes of the immediate surgery and active surveillance groups were similarly excellent, but the incidences of unfavorable events were definitely higher in the immediate surgery group. Thus, active surveillance is now recommended as the best choice for patients with low-risk PMC.

Background: An active-surveillance clinical trial of low-risk papillary microcarcinoma (PMC) patients has been performed at the authors' institution, Kuma Hospital, since 1993. Favorable oncological results have been reported. During the trial, a few patients were encountered with PMC that showed enlargement during pregnancy, and these cases have been reported. During pregnancy, a large amount of human chorionic gonadotropin (hCG) having weak thyrotropin (TSH) activity is produced, possibly affecting the progression of PMC. This study investigated how pregnancy and delivery influenced the progression of PMC in the entire active surveillance PMC patient series. Methods: From 1993 to 2013, 1841 patients with low-risk PMC chose the active surveillance program. Fifty of the 1549 female PMC patients experienced 51 pregnancies/deliveries. To minimize observer variation, a single specialist sonographer re-evaluated the changes in the size of these 50 patients' PMCs before and after the pregnancies/deliveries. Results: Four patients (8%) showed enlargement of PMC by ≥3 mm; one patient (2%) showed a decrease by ≥3 mm, and the remaining 44 patients (45 events, 90%) showed stable disease. None of the patients had a novel appearance of lymph node metastases during pregnancy. Of the four patients with enlargement, two underwent surgery after delivery, and the other two continued the active surveillance, since their tumors did not grow after the delivery. After delivery, the PMC of one of these four patients remained stable, and another showed a decrease in PMC size. To date, six more PMC patients underwent surgery after delivery for reasons other than disease progression due to pregnancy and delivery: two opted out of active surveillance, two were identified with a nodal metastasis during active surveillance after delivery, one had Graves' disease, and one showed enlargement of nodules of the contralateral lobe. Conclusions: Pregnancy and delivery was associated with an increase in size of PMCs in only 8% of the 51 pregnancies/delivery cases. None of the patients developed nodal metastasis during pregnancy. Thus, a possible future pregnancy does not prevent such patients from undergoing active surveillance, although watchful observation during pregnancy is recommended.

Oxyphilic cell carcinoma is a relatively rare type of differentiated thyroid carcinoma. We investigated the diagnosis of oxyphilic cell carcinoma based on surgical specimens and cytology to elucidate the indications for surgery for oxyphilic tumors. Among 330 patients pathologically diagnosed as having an oxyphilic cell carcinoma or adenoma, the incidence of carcinoma was 21%. The pathological diagnosis of oxyphilic cell carcinoma was related to tumor size (>4 cm). On cytology, 79% of the tumors were classified as category IV or greater by the Bethesda System for Reporting Thyroid Cytopathology (BSRTC), but no significant difference was established between category IV or greater and categories I-III regarding the incidence of carcinoma. Of 998 patients cytologically diagnosed as having oxyphilic cell tumors (BSRTC category IV), 426 underwent surgery and 66 (15%) were diagnosed as malignancies. In a univariate analysis, serum thyroglobulin (Tg) levels (>500 ng/dL) for anti-Tg antibody-negative patients, tumor size (>4 cm) and US class (≥3) significantly predicted malignant histology. A multivariate logistic analysis revealed that US finding was an independent predictor of malignant histology, and tumor size (>4 cm) also predicted malignancy when the Tg level was excluded from the variables. These findings suggest that, for thyroid tumors diagnosed as oxyphilic follicular neoplasms on cytology, surgical indications are tumors with US class ≥3, tumor size >4 cm, and Tg >500 ng/dL (with negative Tg-antibody). It is not appropriate to perform surgery for all cases for a precise histological classification, unlike the BSRTC recommendation.

Purpose For the differential diagnosis of medullary thyroid carcinoma (MTC) on thyroid nodules, ultrasound-guided fine-needle aspiration cytology is a useful and safe procedure, but its diagnostic accuracy is not high enough. As an ancillary method to accurately diagnose MTC, the calcitonin in fine-needle aspirate washout fluid (FNA-Ct) is used. However, no data are available about cut-off values of FNA-Ct using the currently available electrochemiluminescence immunoassay (ECLIA). Methods We investigated 180 thyroid nodules in 141 patients. After smearing, the syringe and needle used for the FNA were rinsed with normal saline (0.5 mL). The calcitonin in the washout was measured by ECLIA. Results The FNA-Ct in the non-MTC nodules of MTC patients, non-MTC nodules of non-MTC patients, and MTC nodules were 10.6–2100 pg/mL (median 24.6 pg/mL)

Follicular thyroid carcinoma (FTC), a form of differentiated thyroid carcinoma, is the second most common malignancy arising from thyroid follicular cells. Recently, the tumor-node-metastasis (TNM) classification for differentiated thyroid carcinoma was revised from the 7

The purpose of the study is to clarify the prevalence of calcifications within thyroid tumors on ultrasonography as well as the relationship between the calcification and histopathological types. Calcifications were classified into 6 (or 8) types according to their shape, size, and region. The prevalence of calcifications and types were investigated in new outpatients and patients who underwent thyroid surgery.Among 2,902 nodules in 2,678 new outpatients, 747 nodules (26%) had calcifications. The types showed a wide distribution. Among 941 patients with papillary carcinoma (PC), 725 patients (77%) had calcifications, and the types showed a wide distribution. 18 patients with the diffuse sclerosing variant of PC only showed punctate microcalcifications in the parenchyma (100%), 32 patients with the cyst-forming type of PC mostly fragmentary and massive types (100%), and 161 metastatic lymph nodes from PC mostly punctate microcalcifications and fragmentary types (48%). Among 337 patients with follicular carcinoma, 79 patients (23%) had calcifications, and the types were mostly fragmentary, massive, and egg-shell types. Among 41 patients with undifferentiated carcinoma, 33 patients (80%) presented with calcifications, which were mostly the massive and egg-shell types. Among 137 patients with medullary carcinoma, 99 patients (72%) had calcification, and the types showed a wide distribution. None of 173 patients with primary thyroid lymphoma had calcifications (0%).Calcifications on ultrasonography can be one of the characteristic findings and a full understanding of the prevalence of calcifications and types will markedly contribute to the ultrasonic diagnosis of thyroid tumors.

Background. Children and adolescents with papillary thyroid carcinomas (PTCs) have generally excellent prognoses despite their frequent extended disease. The tumor growth of young patients’ PTCs might show spontaneous slowing postoperatively. We compared young PTC patients’ postoperative thyroglobulin-doubling time (Tg-DT) with their preoperative hypothetical tumor volume-doubling time (hTV-DT).Methods. Fourteen PTC patients aged ≤18 years who underwent total thyroidectomy at Kuma Hospital in 1998–2016 had biochemically persistent disease postoperatively. We calculated their Tg-DTs and estimated their preoperative TV-DTs with the tumor size and the patient’s age at surgery, presuming that a single cancer cell was present at the patient’s birth.Results. Twelve patients had positive Tg-DTs ranging from 2.0 to 147 years, and the remaining two had negative Tg-DTs, indicating slow growth or even regression. The hTV-DTs were 0.3–0.6 years (median 0.5 years), which were significantly shorter than the Tg-DTs (p<0.001), indicating much faster growth preoperatively. The analyses of the nine patients without radioactive iodine administration (RAI) gave similar results (p<0.01).Conclusions. Irrespective of RAI, the patients’ postoperative Tg-DTs were significantly longer than their preoperative hTV-DTs and were negative values in two patients, indicating that the growth of these young patients’ PTCs had spontaneously slowed or even regressed postoperatively.

ObjectiveWe and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (l-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established.MethodsWe retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplementall-T4(+l-T4) group (n=103); the HT+l-T4group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4(FT4) and free T3(FT3) and the FT3/FT4ratio in individual patients with those of controls matched by serum TSH levels.ResultsThe TT+l-T4group had significantly higher FT4(P3(P3/FT4(Pl-T4group had FT4, FT3and FT3/FT4levels equivalent to those of the controls. The HT-alone group had significantly lower FT4(P3(P=0.083), and significantly higher FT3/FT4(PConclusionsThe presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3levels.

Low-risk thyroid papillary microcarcinomas (PMCs) without evidence of metastasis grow slowly if at all. However, we recommended surgery for tumors touching the trachea (TR) or located in the course of the recurrent laryngeal nerve (RN). Here we compared the cases of low-risk PMC patients who underwent immediate surgery to cases of TR- and RN-involved PMCs. We enrolled 1143 low-risk PMC patients who underwent immediate surgery in the years 2006–2014. The PMCs of 437 patients touched the TR on imaging studies: 270, 104, and 63 were graded as low, intermediate, and high risk, respectively, for TR invasion based on the angles between the tumor and the TR surface. The tumor was in the course of the RN in 144 patients, with 35 graded low risk and 109 high risk for RN invasion based on the normal rim of the thyroid in the direction of the RN. Invasion of the TR cartilage was observed only in high-risk patients. Peritracheal connective tissue was resected in 21, 15, and 6 of the high-, intermediate- and low-risk patients, respectively. Significant invasion of the RN requiring complete resection was observed in only nine patients at high risk for RN invasion. The incidence of TR invasion in high- and intermediate patients and the incidence of RN invasion in the high-risk patients were significantly higher than those of the low-risk patients. Tumors

Isolated whole stomachs of farmed Pacific bluefin tuna Thunnus orientalis were externally batch-cultured in cell culture medium at 24 °C for 8 h. This was done in order to confirm that gastric function was maintained during incubation (Exp. 1) so that the effectiveness of the ex vivo technique outlined in the present study in serving as an artificial method of gastric digestion could be determined (Exp. 2). During experiment 1, fresh or cold-stored stomachs (48 h on ice) were intra-gastrically infused with a saline solution (control group) or a skipjack tuna broth stimulant (infusion group). Pepsin-like protease activities within the gastric effluent of each study group were compared. In both control and infusion groups, fresh stomachs demonstrated higher pepsin-like protease activity. Within fresh stomachs, protease activity subsequent to stimulant infusion was significantly greater than it was in the control group. In cold-stored stomachs, however, no difference was observed in the protease activities of control and infusion groups. According to the results, fresh stomachs respond to luminal stimuli. Furthermore, fresh stomachs exhibited motility during incubation while cold-stored stomachs did not. Mucosal layers within fresh stomachs indicated histological normality subsequent to incubation. In experiment 2, both fresh and cold-stored stomachs were filled with a diet consisting of boiled fish paste. After a period of 8 h, dry matter loss of diet was significantly greater within fresh stomachs than it was in cold-stored stomachs. The level of pepsin-like protease activity within fresh stomachs was also higher than levels observed within cold-stored stomachs during the incubation period. These results suggest that fresh stomachs obtained from bluefin tuna maintained functionality ex vivo and that the technique outlined in the present study could be used effectively in the evaluation of bluefin tuna gastric digestion.

Calcitonin is the most sensitive tumor marker of medullary thyroid carcinoma (MTC) and a calcium stimulation test is used to improve this sensitivity. In Japan, the electrochemiluminescence immunoassay (ECLIA) is currently the only test performed to measure serum calcitonin. There is a gender difference in the reference value of serum calcitonin; however, a reference upper limit for use with ECLIA has been reported only for women, but not for men. We conducted the calcium stimulation test using ECLIA in 21 men with non-medullary thyroid carcinoma (non-MTC), before and after total thyroidectomy. Preoperatively, the basal calcitonin values were within normal limits in all patients. They increased to a mean value of 37.6 pg/mL after calcium stimulation, and we calculated that the reference upper limit was 83.7 pg/mL. The stimulation test results after total thyroidectomy showed undetectable basal and stimulated calcitonin values in every patient (

Background We reported that a minority of patients with low-risk papillary microcarcinoma of the thyroid showed disease progression during active surveillance and that older patients had significantly lower disease progression rates than younger patients. Here, we estimated lifetime (≤85 years old) probabilities of disease progression during active surveillance according to the age at presentation based on age decade-specific disease progression rates. Methods From 1993–2013, 1,211 low-risk papillary microcarcinoma patients aged 20–79 years underwent active surveillance at Kuma Hospital. We calculated the disease progression rate at the 10-year point of active surveillance for each age-decade group (20s to 70s) with the Kaplan-Meier method. The lifetime disease progression probability for each age group was calculated as (1 − cumulative probability of progression-free survival calculated with age decade-specific disease progression rates) until the patients reached their 80s (i.e., 85 years on average). Results The age decade-specific disease progression rates at 10 years of active surveillance were 36.9% (20s), 13.5% (30s), 14.5% (40s), 5.6% (50s), 6.6% (60s), and 3.5% (70s); the respective lifetime disease progression probabilities were 60.3%, 37.1%, 27.3%, 14.9%, 9.9% and 3.5% according to the age at presentation. Conclusion The estimated lifetime disease progression probabilities of papillary microcarcinoma during active surveillance vary greatly according to the age at presentation.

Background The external branch of the superior laryngeal nerve (SLN) is susceptible to injuries during thyroidectomy, causing voice impairment. Intraoperative nerve monitoring may facilitate identification of the nerve, reducing voice impairment. Methods A total of 252 patients undergoing thyroidectomy were randomly assigned to group N (the NIM-Response 3.0 system was used) or group C (the conventional technique using the Vari-Stim 3 was used) to identify the external branch of the SLNs. The primary endpoint was the identification rate of the external branch of the SLN. The secondary endpoint was the incidence of postoperative voice impairment. Results The visual and the electrostimulatory identification rates of the external branch of the SLN in group N and group C were 48.8% versus 17.8% (p

In papillary thyroid carcinoma (PTC), macroscopic extrathyroid extension (Ex) and clinical node metastasis (N) are prominent prognostic factors. Ex is divided into two grades in the UICC TNM classification: minimal and massive Ex. Massive Ex significantly affects patients' prognoses, whereas minimal Ex has little prognostic value. N is also divided into two grades in the TNM classification: N1a and N1b, depending on the location of metastasis, with N1b graded higher than N1a. However, massive Ex and/or N-positive PTC includes patients with a wide range of biological characteristics and prognoses, depending on their degrees of Ex and N. Other clinicopathological features such as age, gender, and tumor size also influence the prognosis. In evaluations of the biological characteristics of PTC patients with Ex and/or N, we should consider the degrees and relationships of Ex and N with other clinicopathological features.

We demonstrated previously that dynamic prognostic markers such as the thyroglobulin (Tg)-doubling time in thyroglobulin antibody (TgAb)-negative papillary thyroid carcinoma (PTC) and changes in pre- and postoperative TgAb levels in TgAb-positive PTC patients more keenly reflect patients' prognosis than conventional static prognostic factors. Here we investigated periodic changes in TgAb levels in 513 TgAb-positive PTC patients who underwent total thyroidectomy. The TgAb levels at 1 year after surgery decreased to50% of the preoperative values in 407 (79%) patients, and the remaining 106 (21%) patients showed no decrease in TgAb. In 426 patients, TgAb was also measured more than 1 year after surgery. Compared with their TgAb levels 1 year after surgery, 59 patients (14%) showed an increase in TgAb levels of20% during the follow-up. The postoperative Tg levels at 1 year after surgery remained positive in 44 (9%) patients despite their TgAb positivity. To date (median follow-up period 35 months), 12 of the 426 patients (3%) showed PTC recurrence, and 11 of these patients showed either or both a TgAb elevation later than 1 year after surgery and postoperative Tg positivity. Although further studies with longer follow-ups are necessary, we can conclude that changes in postoperative TgAb levels may be usable as a surrogate tumor marker for TgAb-positive PTC patients after total thyroidectomy.

A family with germline tandem V804M/Y806C mutations in the RET proto-oncogene was reported. The in vitro study results showing that these mutations were on the same allele and that RET with these mutations had a moderate transforming activity were confirmed by the clinical features of the offspring as a natural experiment. Thus, the tandem double RET mutations are pathogenetic for MEN 2B.

The two types of prognostic factors of papillary thyroid carcinoma (PTC) are static and dynamic. The following static prognostic factors have been conventionally adopted: age, tumor size, extrathyroid extension, lymph node metastasis, and distant metastasis based on pre-, intra- and post-operative findings. These factors are useful to decide therapeutic strategies for PTC patients, including the extent of surgery and radioactive iodine (RAI) ablation. However, even the combination of these factors evaluated pathologically postoperatively is not good enough at predicting recurrence in clinical settings. The dynamic prognostic factors of changes in serum thyroglobulin (Tg) and thyroglobulin antibody (TgAb) values in patients who have undergone a total thyroidectomy are important to evaluate the progression of carcinoma recurrence and to predict patients' cause-specific survival, regardless of their backgrounds and the clinicopathological features of their PTC. Dynamic prognostic factors are superior to static prognostic factors in terms of expressing the condition of recurrence on a real-time basis.

Differentiated thyroid carcinomas (DTCs) are generally indolent, but few therapeutic strategies are available after a metastatic recurrence that is refractory to radioactive iodine (RAI) therapy. Molecular-target therapy has shown promising results for DTCs with RAI-refractory recurrence. However, not all RAI-refractory recurrences are progressive, and even those that are progressive may not be immediately life-threatening. Here we investigated the prognosis and prognostic factors of 74 DTC patients (52 females, 22 males) in whom RAI-refractory metastases appeared. The five-year and 10-year cause-specific survival (CSS) rates of the 74 patients (8-82 yrs of age; median age at the detection of metastases, 61 yrs) were 95% and 70%, respectively, and the older patients (≥ 60 yrs, n=38) and male patients were significantly more likely to die of carcinoma. Also in multivariate analysis, older age (≥ 60 years) and male gender were independent predictors of carcinoma-related death. Taken together, our data indicate that RAI-refractory metastases of older patients and male patients are more progressive than those of other patients. Further studies are necessary to clarify the appropriate indications for molecular-target therapy for RAI-refractory and progressive metastases.

Papillary thyroid carcinoma (PTC) frequently metastasizes to the regional lymph nodes and, thus, guidelines edited by Japan Association of Endocrine Surgeons/Japanese Society of Thyroid Surgery routinely recommend central node dissection even for patients with no clinically detectable node metastasis (N0). However, in the central compartment, metastasis to the right paraesophageal node has not been intensively investigated. We investigated the incidence and predictors of right paraesophageal node metastasis based on pre- and intraoperative findings in 922 patients with N0 PTC in the right lobe. Fourteen percent of patients were microscopically positive for right paraesophageal node metastasis, and the incidence was smaller than that for pre- and right paratracheal node metastasis (46%). On multivariate analysis, a tumor size ≥ 2 cm and significant extrathyroid extension were independent predictors of metastasis. Microscopically pre- and right paratracheal node-positive PTC more often (p < 0.0001) metastasized to the right paraesophageal node. Taken together, in N0 PTC in the right lobe, right paraesophageal node dissection should be considered in tumors 2 cm or larger and/or with significant extrathyroid extension, or when pre- and right paratracheal node metastasis is suspected based on the intraoperative findings.

We previously reported that the Ki-67 labeling index (LI) in primary tumors and the thyroglobulin (Tg)-doubling time (DT) were potent prognostic indicators in patients with papillary thyroid carcinoma (PTC).To elucidate the relationship between these two factors.A total of 390 patients with PTC who underwent total thyroidectomy between 1998 and 2004 and in whom the Tg-DT was calculated were enrolled. We determined the Ki-67 LI in primary tumors and compared these values with the patients' clinicopathological factors, postoperative Tg status, Tg-DT, and prognosis. Tg status was categorized by postoperative serum Tg values: biochemically persistent disease (BPD), equivocal state, and biochemical remission.The Ki-67 LI was ≤5% in 312 patients (80%), 5%-10% in 48 patients (12%), and10% in 30 patients (8%). Ki-67 LI was significantly associated with BPD (p0.0001). The proportion of BPD patients increased with the higher Ki-67 LI category: 24, 67, and 87%, respectively. The Ki-67 LI had a significant inverse correlation with the Tg-DT (Spearman's ρ = -0.5267, p0.0001). Of the 378 patients without distant metastasis at surgery, 68 patients had recurrence, and 6 of the 390 patients died of PTC during the follow-up (mean 88 months). On multivariate analyses, the Ki-67 LI remained an independent predictor of disease-free survival and disease-specific survival when Tg-DT and Tg status were excluded from the analyses.Evaluation of the Ki-67 LI in primary tumors may allow the prediction of the postoperative Tg status, Tg-DT and prognosis of patients with PTC. Published by S. Karger AG, Basel.

In contrast to minimally invasive follicular thyroid carcinoma (FTC), widely invasive FTC is aggressive and is associated with a dire prognosis. However, prognostic factors of widely invasive FTC have not been intensively investigated. In this study, we investigated this issue in a series of 79 widely invasive FTC patients. In the subset of 70 patients who did not show distant metastasis at diagnosis (M0), only a tumor size larger than 4 cm had a prognostic impact on disease-free survival (DFS) both on uni- and multivariate analyses. Regarding the cause-specific survival (CSS) of 79 patients, only distant metastasis at diagnosis (M1) had a significant prognostic value on uni- and multivariate analyses. None of the 70 M0 patients with a tumor measuring 4 cm or less died of FTC. Other clinicopathological features such as age, gender, and oxyphilic carcinoma were of no prognostic value. These findings suggest that 1) M1 is the strongest prognostic factor for CSS of widely invasive FTC patients, and 2) a tumor size larger than 4 cm significantly affects the DFS and CSS of M0 patients. Aggressive therapies with careful follow-up are recommended, especially for these patients.

Although postoperative serum thyroglobulin (Tg) is a prognostic indicator for papillary thyroid carcinoma (PTC), it is unreliable when Tg antibody (TgAb) is positive. We evaluated the prognostic significance of changes in serum TgAb levels of pre- and post-total thyroidectomy in TgAb-positive PTC patients. We reviewed our medical charts of 225 TgAb-positive PTC patients in whom TgAb levels were measured before and 1-2 years after total thyroidectomy, performed between April 2002 and March 2007. We divided them into 3 groups based on changes in TgAb levels. Postoperative serum TgAb levels decreased by ≥ 50% in 181 patients (80.4%) (Group 1), by

In patients with papillary thyroid carcinoma (PTC), detectable serum thyroglobulin (Tg) after total thyroidectomy implies biochemically persistent disease (BPD). We reported that the thyroglobulin-doubling time (Tg-DT) was a potent prognostic indicator in patients with BPD. To identify factors that are related to BPD and Tg-DT, we performed new analyses on the data gathered in our previous study. Using the data of 426 patients with PTC in whom the Tg-DT was computed after total thyroidectomy, multivariate logistic analyses for BPD and Tg-DT were performed. Postoperatively, 142 (33%) patients had BPD. The percentages of BPD patients were significantly higher among the young (

Follicular thyroid carcinoma (FTC) is divided into two categories: minimally and widely invasive FTC. Generally, the prognosis of minimally invasive FTC is excellent, but patients showing certain characteristics have a dire prognosis. In this study, we investigated the prognostic factors of minimally invasive FTC using a series of 292 patients. On multivariate analysis, extensive (4 or more) vascular invasion, age ≥ 45 years, and tumor size > 4 cm were independent prognostic factors of patient disease-free survival (DFS). Distant metastasis at diagnosis (M1) was the strongest prognostic factor of cause-specific survival (CSS). Extensive vascular invasion and tumor size > 4 cm also independently affected patient carcinoma death. Capsular invasion was not related to patient prognosis. The ten-year DFS rate of patients with extensive vascular invasion was 80%, which was poorer than that of those having tumor size > 4 cm (91%) and aged 45 years or older (90%). These findings suggest that 1) M1 most strongly affects the CSS of patients, and 2) M0 patients with extensive vascular invasion may be candidates for completion total thyroidectomy and radioactive iodine ablation.

Tall cell variant (TCV) of papillary thyroid carcinoma (PTC) shows a poorer prognosis than conventional PTC. The World Health Organization (WHO) classification defines TCV as the tall cell component (TCC) in ≥50% of PTC lesions. We investigated whether and how the proportion of TCC affects the prognosis of patients with PTC with TCC. Seventy patients with TCC in ≥30% of their PTC lesions and 210 age- and gender-matched controls with no TCC who underwent locally curative surgery at Kuma Hospital (2006–2014) were enrolled. The 70 PTC patients were divided into two categories: TCC ≥50% (TCC-major, n = 19) and TCC 30–49% (TCC-minor, n = 51). We performed univariate and multivariate analyses of the relationships between disease-free survival (DFS) and variables including the TCC proportion in 276 patients who had no distant metastases at surgery (median follow-up 64 months). In the univariate analysis, TCC-major, TCC-minor, old age (≥65 years), clinical node metastasis, significant extrathyroid extension (Ex), and high Ki-67 labeling index (≥5%) significantly affected the DFS. In the multivariate analysis, TCC-major and Ex independently affected the DFS, but TCC-minor did not. In an analysis excluding TCC-major patients, TCC-minor was not an independent prognostic factor for DFS. Studies or larger patient series with longer follow-ups are necessary, but we speculate that in PTC with TCC, TCC-major significantly and independently affects the DFS, whereas TCC-minor does not. Our findings indicate that the WHO definition of TCV is appropriate and that the prognostic impact of TCC-minor is limited.

We investigated the prognostic impact of the Ki-67 labeling index (LI) in minimally invasive follicular thyroid carcinoma (FTC). We enrolled 192 patients (including four with distant metastasis at diagnosis) who were pathologically diagnosed as having minimally invasive FTC between 1998 and 2007 at Kuma Hospital. When the Ki-67 LI was higher than 5% in the hot area, we regarded it as a high Ki-67 LI. In a univariate analysis, patient age (≥45 years), high-frequent vascular invasion (≥4 in H&E specimens), and high Ki-67 LI significantly predicted the disease-free survival (DFS) of the patients. Since none of the patients

Ghrelin exhibits a cardioprotective effect. We examined whether orally administered ghrelin-containing salmon stomach extract (sSE) instead of chemically synthesized ghrelin protects against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were divided into four groups: (i) the control, (ii) DOX groups were fed a control diet (AIN-93G), (iii) the sSE, and (iv) DOX + sSE groups were fed a 10% sSE diet (AIN-93G + 10% sSE). After a 4-week pretreatment of sSE, DOX or saline was administered to the corresponding groups by intraperitoneal injection. The groups fed the 10% sSE diet consumed significantly more food than the groups fed the control diet before the DOX injection. No mortality was observed in the DOX + sSE group, whereas 40% (2 of 5) mortality was observed in the DOX group. Compared with the DOX group, levels of ascites and plasma cardiac troponin I improved in the DOX + sSE group. Significantly lesser DOX-induced collagen accumulation was observed in the left heart ventricle of the DOX group than in that of the DOX + sSE group. These results suggest that the dietary ghrelin contained in sSE mimics synthetic ghrelin in cardioprotective effect. Ghrelin in sSE (45 pmol/g) and the food intake-stimulating effect of sSE may explain, at least in part, the protective effect of orally administered teleost ghrelin.

Calcitonin is a very sensitive tumor marker of medullary thyroid carcinoma (MTC). MTC patients usually have very high values of serum calcitonin that can be used to diagnose the disease. To improve the diagnostic sensitivity in family members with small MTCs and to evaluate the postoperative biochemical cure status, a calcium stimulation test is widely used. Serum calcitonin has been measured using several methods, but in Japan, only an electrochemiluminescence immunoassay (ECLIA) is currently performed to determine serum calcitonin. Reference values for the calcium stimulation test using an ECLIA have not been reported. Here we conducted a calcium stimulation tests in 26 patients without MTC before and after total thyroidectomy. Preoperatively, the basal calcitonin values of all patients were within normal limits and increased to a mean of 14.4 pg/mL after calcium stimulation. We transformed the peak values before total thyroidectomy to a logarithmic distribution and calculated the normalized mean ± 1.96× standard deviation; the reference upper limit was thus expressed. In the female patients with non-MTC, the reference upper limit was 67.6 pg/mL. In all patients, the calcium stimulation test results after total thyroidectomy showed undetectable basal and stimulated calcitonin values (

Therapy using tyrosine-kinase inhibitors (TKIs) is now available for recurring or advanced medullary thyroid carcinoma (MTC). Here we investigated the calcitonin doubling time (Ct-DT) of MTC patients with distant recurrence postoperatively and for those with distant metastasis at the initial surgery. Of the 13 patients, six died due to the MTC at 5-93 months after the detection of distant metastasis. Their Ct-DTs were ≤ 1.58 years. The remaining seven patients have been alive for 73-123 months after the detection of metastasis, and their Ct-DTs were low at -4, -2.25 years and 9.17-33.92 years. Similar results were obtained by analyzing the value of 1/Ct-DT to avoid discontinuity in the DT values among the patients with increasing serum Ct values over time and those with decreasing Ct values over time. These findings suggest that it is appropriate to use TKIs only for patients with a short Ct-DT and a large 1/Ct-DT with a cutoff at around 1.5 years and 0.67/year, respectively, even if they have distant metastases.

Aim: It is difficult to differentiate follicular carcinomas (FC) from follicular adenomas (FA) because ultrasonography and cytology provide very similar findings. FC is histopathologically diagnosed to have capsular and/or vascular invasion. In a few patients, tumor protrusions are observed by preoperative ultrasonography as large forms of capsular invasion of follicular carcinomas. The aim of the study was to clarify the predictive value of tumor protrusions on preoperative ultrasonography for follicular carcinomas. Material and methods: A total of 531 patients (FC: 184 patients, FA: 347 patients) undergoing thyroid surgery were included in this study. A tumor protrusion on ultrasonography was defined as follows: 1) a solid tumor extending beyond a marginal line of capsular zone of the main tumor on B-mode ultrasonography; 2) intensive blood signals observed within the protrusion area on Doppler ultrasonography. The large form of capsular invasion was defined if the protrusion lesion was histopathologically diagnosed to be a capsular invasion of follicular carcinoma. Results: The sensitivity of tumor protrusion was 0.071, specificity 0.994, positive predictive value 0.867, and negative predictive value 0.669 for FC diagnosis. For the large form of capsular invasion in FC the sensitivity of tumor protrusion was 0.813, specificity 0.982, positive predictive value 0.684, and negative predictive value 0.982. Conclusions: A tumor protrusion with intensive blood signals extending from the main tumor on ultrasonography strongly suggests a large form of capsular invasion of follicular carcinoma.

The right recurrent laryngeal nerve (RLN) is more difficult to identify than the left RLN. The superior, lateral and inferior approaches are currently used to identify the RLN. This report presents a new technique, called the ima approach (the most inferior approach) for the quick identification of the right RLN.The ima approach involves dissection along the right common carotid artery and division of the most lateral branch of the inferior thyroid veins. The right RLN is identified at the bottom of the RLN triangle. This technique and the conventional inferior approach were applied to 81 and 19 patients with thyroid cancer, respectively.The ima approach required a significantly shorter time in identifying the nerve than the inferior approach (9.6 ± 16.6 and 31.2 ± 24.4 s, respectively, p0.0001).The ima approach is an easy, quick and safe technique for identifying the right RLN.

Age is an important prognostic factor of papillary thyroid carcinoma (PTC). In this study, we investigated the prognosis and prognostic factors of PTC in patients younger than 20 years. We enrolled 110 patients who underwent initial surgery at Kuma Hospital between 1987 and 2008. Tumor size > 4 cm, metastatic node ≥ 3 cm, and significant extrathyroid extension were more frequently detected in 8 patients with distant metastasis at diagnosis than in 102 patients without distant metastasis. Ten- and 20-year lymph node recurrence-free survival (LN-RFS) and distant recurrence-free survival (DRFS) rates were 84 and 80%, and 95 and 89%, respectively. Metastatic node ≥ 3 cm, age ≤ 16 years, tumor size > 4 cm, and male gender affected LN-RFS, and the former two had an independent prognostic value in multivariate analysis. Metastastic node ≥ 3 cm, significant extrathyroid extension, age ≤ 16 years, tumor size > 4 cm, and a male gender predicted a poor DRFS, and the former two were independent prognostic factors. To date, only 2 patients have died of PTC. These findings suggest that, in the subset of PTC patients younger than 20 years, metastatic node ≥ 3 cm, significant extension, and age ≤ 16 were important signs of aggressiveness of carcinoma, and careful treatment is necessary for patients with these characteristics, although the cause-specific survival was excellent.