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Intrathyroidal thymic carcinoma (ITTC) is a rare malignancy of the thyroid. It is thought to originate from ectopic thymic tissue or embryonic thymic rest, in, or adjacent to, the thyroid. We analyzed the backgrounds, clinicopathological features, and prognosis of 20 patients with ITTC, treated at our hospital. Thirteen of the 15 patients (86%) who underwent ultrasonography were diagnosed as malignant, based on imaging findings. 16 of the 17 patients (93%) who underwent cytology, were diagnosed or suspected to be malignant. Locally curative surgery (thyroidectomy and lymph node dissection) was performed for 19 patients. Large tumor size (4 cm) was positively related to pathological node metastasis (p = 0.0389). Fourteen patients, including nine Ex-positive patients, underwent adjuvant external beam radiotherapy (EBRT) of the neck after surgery. Two patients showed recurrence of thyroid bed after and neither of them underwent adjuvant EBRT after surgery. Two patients who underwent EBRT showed recurrences of the lateral nodes (level V and level II), but they were easily dissected by re-operation. Ten- and 20-year local recurrence-free survival rates were 84.9% and 60.6%, respectively. To date, four patients showed distant recurrence, and 10- and 20-year distant recurrence-free survival rates were 75.0% and 75.0%, respectively. Our findings indicate that 1) the prognosis of ITTC is generally favorable, and 2) large tumor size is significantly related to lymph node metastasis. Two patients showing recurrence of the central region did not undergo EBRT; thus, further comparative studies are desirable to elucidate whether EBRT can prevent significant local recurrence.

The World Health Organization (WHO) classifies follicular thyroid carcinoma (FTC) into three categories: minimally invasive (mFTC), encapsulated angioinvasive (eaFTC), and widely invasive (wFTC). This study investigated whether this classification is appropriate. We enrolled 523 patients who underwent initial surgery at Kuma Hospital between 1998 and 2015 and were diagnosed with FTC. Capsular invasion (CI) was classified as none, minimal (microscopic), or wide (macroscopic) invasion. Vascular invasion (VI) was divided according to the number of invasive foci into three degrees: VI(-), VI(1+), and VI(2+). For 507 M0 patients, age ≥55 years (p = 0.004), non-oxyphilic histology (p = 0.043), and male sex (p0.001) predicted poor distant recurrence-free survival (DR-FS) on univariate analysis; however, tumor size4 cm and wide CI did not. The DR-FS rates significantly decreased from VI(-) to VI(2+) in a step-by-step fashion, including VI(-) vs. VI(1+) (p = 0.011) and VI(1+) vs. VI(2+) (p = 0.014). Multivariate analysis revealed that older age (p = 0.0004), non-oxyphilic histology (p = 0.041), male sex (p = 0.0052), VI(1+) (p = 0.017), and VI(2+) (p0.001) independently predicted distant recurrence. The DR-FS rates did not significantly differ among mFTC, wFTC/VI(-), and eaFTC/VI(1+). The DR-FS rate of eaFTC/VI(2+) was worse than that of eaFTC/VI(1+) (p = 0.042), but did not differ from that of wFTC/VI(1+/2+). Our findings suggest that subclassifying eaFTC according to the degree of VI and restricting wFTC to VI-positive cases would be better in the WHO classification. Revising the definition for wide CI is recommended.

Thyroid tumors arising from follicular cells can generally be divided into malignant and benign tumors. However, some cases are difficult to clearly diagnose whether they are benign or malignant. Therefore, in the most recent version of World Health Organization (WHO) classification, some borderline lesions such as follicular tumor of uncertain malignant potential (FT-UMP), well-differentiated tumor of uncertain malignant potential (WDT-UMP), and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were proposed. In this study, we investigated the clinical aspects, including the prognosis, of FT-UMP patients. We investigated the clinical features of 339 patients with FT-UMP. On ultrasound, 68% of the tumors were diagnosed as intermediate, and only 5% of those tumors were diagnosed as malignant. On cytology, 40% of the tumors were diagnosed as follicular neoplasm, and only 1% of these were suspected to be or diagnosed as malignancy. The diagnosis was based on questionable capsular invasion for 332 patients, questionable vascular invasion for 2 patients, and both for 5 patients. Eighty-six percent of the tumors showed low cell proliferation activity. To date, five patients (1%) have shown distant recurrence during postoperative follow-up and underwent various treatments such as radioactive iodine therapy, orthopedic surgery, and denosumab injection. None of these patients have died due to thyroid carcinoma. Our findings suggest that FT-UMP is generally an indolent disease, but some patients show distant recurrence. Physicians should carefully follow patients, although it remains unknown how long they should be observed after surgery.

Background: Active surveillance for low-risk papillary microcarcinoma (PMC) of the thyroid is an accepted and safe management strategy. However, some patients undergo conversion surgery after the initiation of active surveillance for various reasons. We investigated the reasons for conversion surgery and whether and how they changed over time. Methods: We enrolled 2288 patients with PMC who underwent active surveillance. Of these, 162 (7.1%) underwent conversion surgery >12 months after initiating active surveillance due to disease progression (57 patients), patient preference (43 patients), physician preference (31 patients), other associated thyroid or parathyroid diseases (24 patients), and other reasons (7 patients). We analyzed cumulative conversion rates not only in the whole cohort but also in the first three major subsets based on the reasons for surgery. We also divided our whole cohort into two groups based on the period of active surveillance commencement: the first-half group (February 2005-November 2011; 561 patients) and the second-half group (December 2011-June 2017; 1727 patients). Results: The criteria for PMC progression did not differ between the first- and second-half groups. The proportion of female patients in the physician preference group was significantly higher than that in the disease progression and the patient preference groups. Tumor size at surgery was larger, and tumor volume-doubling rate was higher in the disease progression group than in the other two groups. Patients in the second-half group were significantly less likely to undergo conversion surgery than those in the first-half group. Furthermore, conversion surgery rates in the second-half group were significantly lower than those in the first-half group in the patient preference, physician preference, and disease progression groups. Conclusions: Patients with PMC in the second-half group were significantly less likely to undergo conversion surgery than those in the first-half group regardless of the reason. This is probably because data accumulation of favorable outcomes with active surveillance significantly contributed to physicians' confidence and patients' trust and understanding of this disease.

Background/aim Radioactive iodine-refractory differentiated thyroid carcinoma (RR-DTC) has been treated with multi-kinase inhibitors (MKIs), e.g., sorafenib (SOR) and lenvatinib (LEN). We analyzed the outcomes of RR-DTC patients who underwent SOR or LEN treatment at Kuma Hospital. Patients and methods We enrolled 21 and 18 patients treated with SOR and LEN, respectively. Results The incidence of partial response in the LEN group was significantly higher than that in the SOR group. Serum thyroglobulin significantly decreased from the beginning of treatment to 1 month later in the LEN group (not in the SOR group). The neutrophil-lymphocyte ratio (NLR) was significantly decreased at 1 month later in both groups. An NLR ≥3 at the start of MKI treatment had a prognostic impact. Conclusion For RR-DTC, LEN could be more effective than SOR, at least in the short term. The first-line drug should be selected based on other factors (e.g., adverse events, patient background).

Background/aim To date, thyroglobulin-doubling rate (Tg-DR) and tumor volume-doubling rate (TV-DR) of metastatic lesions have been identified as dynamic prognostic factors for differentiated thyroid carcinoma (DTC). In this study, we investigated the prognostic impact for another dynamic factor, the neutrophil-to-lymphocyte ratio (NLR), for DTC with distant metastasis. Patients and methods We enrolled 321 patients in total, and NLR at the first detection of distant metastasis (initial NLR) was collected for 312. Results Patients with initial NLR >3 had a significantly poorer cause-specific survival than those with initial NLR ≤3. On multivariate analysis, initial NLR >3 was recognized as an independent prognostic factor together with Tg-DR >1/year, TV-DR >1/year, radioactive iodine-refractory distant metastasis, and distant metastasis to organs other than the lung. Conclusion Careful observation and active therapies, including multitarget kinase inhibitors, are recommended for patients with NLR >3 at the first detection of distant metastasis or during follow-up.

Hyalinizing trabecular tumor (HTT) of the thyroid is a mostly benign disease. Its cytological and pathological diagnosis is often difficult, because HTT cells and papillary thyroid carcinoma (PTC) cells share similar features (e.g., intranuclear cytoplasmic inclusions and nuclear grooves). At our institution, 38 patients were diagnosed as or highly suspected of having HTT without the possibility of PTC, based on cytology: 19 of these patients underwent immediate surgery (surgery group) and the remaining 19 underwent active surveillance without surgery (AS group). The surgery-group patients' tumor sizes were significantly larger (p < 0.0001) than those in the AS group. During AS (median 38 months), only one patient (5%) showed tumor enlargement by ≥3 mm; the AS was continued. Of the 34 patients pathologically diagnosed with HTT, 22 (65%) were cytologically diagnosed or highly suspected as having HTT without the possibility of PTC. Of the nine patients who were suspected to have HTT but PTC was possible and surgery was performed, two (22%) and seven (78%) were pathologically diagnosed as having PTC and HTT, respectively. Five patients were cytologically diagnosed with PTC, but pathologically diagnosed as having HTT. No patients showed HTT recurrence during postoperative follow-up (median 60 months). These findings suggest that (1) active surveillance can be a valid strategy for managing tumors that are cytologically diagnosed as HTT with no possibility of PTC; (2) surgery is recommended for tumors suspected of being HTT but may be PTC, and (3) the prognosis of HTT in both the AS and surgery groups was excellent.

Parathyroid Lipoadenoma (PLA) contains abundant mature adipose tissue and is a rare cause of hyperparathyroidism. This study aimed to investigate the clinical features of PLA in nine patients with primary hyperparathyroidism, including two men and seven women, with ages ranging from 45-84 years (median 60 years). PLA accounted for 0.5% of all parathyroid tumors during the study period. One patient presented with anorexia due to hypercalcemia; however, the other eight patients were asymptomatic. The median preoperative serum intact-parathyroid hormone (iPTH) and calcium levels were 143 pg/mL (range, 102-378) and 10.8 mg/dL (range, 10.3-11.3), respectively. PLA was difficult to identify using ultrasonography (US) as it appears as a moderately hyperechoic nodule and is difficult to distinguish from the surrounding adipose tissues. Only 33% of the lesions (three out of nine lesions) were accurately identified. However, they could be distinctly differentiated from the surrounding tissue using computed tomography (CT). All PLAs were also detected using the sesta-methoxyisobutylisonitrile single-photon emission-computed tomography (SPECT). All the patients were treated by a single gland extirpation. The median size and weight of the PLA were 14 mm (range, 10-22) and 567 mg (range, 200-1,533), respectively. In conclusion, the clinical manifestations of PLA are similar to those of ordinal parathyroid adenomas, except for their unique US and CT images. PLA should be considered as a potential etiologic factor in cases of hyperparathyroidism when the lesions are demonstrated as hyperechoic nodules or unidentified by US but detected by CT or SPECT imaging.

Older age is recognized as a predictor of poor prognosis in papillary thyroid carcinoma (PTC) patients. However, young age is associated with disease progression of PTC measuring 1 cm or smaller in patients on active surveillance. In this study, we investigated the relationship between patient age and prognosis of PTC belonging to very low-, low-, and intermediate-risk groups based on the guidelines published by the Japan Association of Endocrine Surgery in 2018. We enrolled 4,870 PTC patients with no high-risk features and assigned each to one of three categories: very low risk (N = 1,161), low risk (N = 1,746), and intermediate risk (N = 1,963). In very low-risk patients, the local recurrence-free survival (RFS) rate of young patients (55 years) was significantly worse (p = 0.0437) than that of older patients (≥55 years). In low-risk patients, although age did not affect local recurrence, older patients were more likely to show distant recurrence on univariate (p = 0.0005) and multivariate analyses (p = 0.0017). In the intermediate-risk series, the local RFS rate of older patients tended to be poor (p = 0.0538), and older age was significantly associated with distant RFS (univariate, p = 0.0356; multivariate, p = 0.0439) and carcinoma death (univariate, p0.0001; multivariate, not done because of no other suitable factors). The prognostic significance of patient age depends on risk classification: younger age significantly predicts local recurrence in very low-risk PTC, while older age predicts worse prognosis in low- and intermediate-risk patients. These findings indicate that young age is related to rapid growth in early-phase PTC.

A marine strain, designated KK4T, was isolated from the surface of a starfish, Patiria pectinifera, which was collected from seawater off the coast of Hokkaido, Japan. Strain KK4T is a Gram-stain-negative, non-spore-forming, rod-shaped, aerobic bacterium that forms yellow-pigmented colonies. A phylogenetic relationship analysis, based on 16S rRNA gene sequences, revealed that strain KK4T was closely related to Ulvibacter marinus IMCC12008T, Ulvibacter antarcticus IMCC3101T and Ulvibacter litoralis KMM 3912T, with similarities of 96.9, 95.8 and 95.6 %, respectively, but low sequence similarities ( Flavobacteriaceae . Genomic similarities between strain KK4T and the three Ulvibacter type strains based on average nucleotide identity and digital DNA–DNA hybridization values were lower than the species delineation thresholds. Moreover, phylogenetic tree based on genome sequences showed that strain KK4T was clustered with U. marinus IMCC12008T and formed a branch independent from the cluster including type species of the genera Ulvibacter , Marixanthomonas , Marinirhabdus , Aureitalea and Aequorivita . Amino acid identity values between strain KK4T/ U. marinus IMCC12008T and the neighbour type species/strains were 61.9–68.2% and 61.5–67.4 %, which were lower than the genus delineation threshold, implying the novel genus status of strain KK4T. Strain KK4T growth occurred at pH 6.0–9.0, 4–30 °C and in NaCl concentrations of 0.5–5.0 %, and optimally at pH 7.0, 25 °C and 3.0 %, respectively. Unlike Ulvibacter strains, strain KK4T could assimilate glucose, mannose, galactose and acetate. The major quinone and fatty acids were menaquinone-6 and iso-C15 : 0 (27.5 %), iso-C15 : 1 G (22.5 %) and iso-C17 : 0 3-OH (12.8 %), respectively. Based on genetic, phylogenetic and phenotypic properties, strain KK4T represents a novel species of the genus Patiriisocius, for which the name Patiriisocius marinistellae gen. nov., sp. nov. is proposed. The type strain is KK4T (=JCM 33344T=KCTC 72225T). In addition, based on the current data, Ulvibacter marinus should be reclassified as Patiriisocius marinus comb. nov.

Guidelines published by the Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) for patients with papillary thyroid carcinoma describe four risk classes (very low-, low-, intermediate- and high-risk) for deciding on therapeutic strategies. Here, we investigate cause-specific survival (CSS) of high- and intermediate-risk patients, taking their age into consideration. CSS of intermediate-risk patients ≥55 years was poorer than that of those55 years (p0.0001) (20-year CSS rates, 96.9% vs. 98.7%). CSS of intermediate-risk patients55 years was excellent but still poorer (p = 0.0152) than that of low- or very low-risk patients (20-year CSS rates, 100%). CSS of high-risk patients55 years (20-year CSS rates, 96.0%) was similar (p = 0.7412) to that of intermediate-risk patients ≥55 years, while high-risk patients ≥55 years (20-year CSS rates, 80.6%) showed much poorer prognosis (p0.0001) than the others. In high-risk patients55 years, distant metastasis (M1), extrathyroid extension (Ex), node metastasis ≥3 cm, and extranodal tumor extension, and in those ≥55 years, M1, Ex, and tumor size4 cm were regarded as prognostic factors on multivariate analysis. We therefore conclude that 1) prognosis of high-risk patients ≥55 years should be carefully treated because of significantly poor prognosis, 2) prognostic factors of high-risk patients vary according to patient age, and 3) overtreatment of intermediate-risk patients and young high-risk patients should be avoided; however, appropriate treatment strategies need to be established, considering that their prognoses are excellent, but still poorer than low- or very low-risk patients.

Active surveillance for papillary thyroid microcarcinomas (PTMCs) initiated in Japan is becoming adopted worldwide as a management option. However, it remains unclear how to manage newly appearing PTMCs in the remnant thyroid after hemithyroidectomy. We investigated the outcomes of similar observational management (OM) for PTMCs appearing in the remnant thyroid after hemithyroidectomy for papillary thyroid carcinoma (PTC) and benign thyroid nodules. Eighty-three patients were newly diagnosed with PTMC in the remnant thyroid between January 1998 and March 2017. Of these, 42 patients underwent OM with3 times ultrasound examinations. Their initial diagnoses were PTC (initially malignant group) in 37 patients and benign nodule (initially benign group) in 5 patients. We calculated the tumor volume doubling rate (TV-DR) during OM for each PTMC. The TV-DR (/year) was-0.1, -0.1-0.1, 0.1-0.5, and0.5 in 12, 19, 5, and 6 patients, respectively. The TV-DRs in both groups did not statistically differ, but six patients (16%) in the initially malignant group showed moderate growth (TV-DR0.5/year). They underwent conversion surgery and none of them had further recurrence. The remaining 36 patients retained OM without disease progression. The TV-DR in the initially malignant group was not significantly associated with patients' backgrounds or their initial clinicopathological features. None of the patients in this study showed distant metastases/recurrences or died of thyroid carcinoma. Although a portion of PTMCs appearing after hemithyroidectomy for thyroid malignancy are moderately progressive, OM may be acceptable as a management option for PTMCs appearing in the remnant thyroid after hemithyroidectomy.

Some thyroid tumors that are cytologically diagnosed as benign may be pathologically diagnosed as malignant. Here, we investigated the long-term outcomes of patients with thyroid tumors with benign cytology, and the factors for malignancy. We retrospectively reviewed the cases of 3,102 patients with thyroid tumors1 cm cytologically diagnosed as benign at our hospital during a 1-year period from January 2007. The median follow-up duration for all patients was 68.7 (range 0.0-168.7) months. Immediate surgery and delayed surgery were performed in 393 and 148 patients, respectively. Eventually, 541 (17.4%) of the 3,102 patients underwent a thyroidectomy, and 2,561 (82.6%) were observed without surgery. Among the surgically treated patients, the tumors of 525 (97.0%) and 16 (3.0%) were pathologically diagnosed as benign and malignant, respectively. There was no significant difference in age, gender, tumor size, serum thyroglobulin level at surgery, or the tumor volume-doubling rate (TV-DR) between the benign and malignant cases. Only the ultrasonographic findings based on our hospital's classification system were directly and significantly linked to pathological diagnosis (p0.01). Among the tumors of the 667 patients who were followed without surgery for10 years, 89.9% remained unchanged and 7.2% were reduced in size. Ultrasonographic evaluation provides important information for therapeutic decision-making regarding surgery versus observation for cytologically benign tumors.

One of the hallmarks of life as an animal is the need and ability to consume food, digest it and convert this biomass into essential nutrients, the digestive system is, in fact, one of the centrally important organs in any animal. It is also a complex environment and the body dedicates a huge amount of resources towards supporting it. Blood vessels, nerves, hormones and energy are abundant in and around the digestive system, and understanding this immensely important organ and how it functions can yield discoveries that impact our health. One way that digestive research is producing results is the discovery of specific peptides in the digestive system of animals that might have therapeutic value in humans. Professor Minoru Kihara, based at the Laboratory of Animal Nutrition and Digestive Physiology, School of Biological Sciences at Tokai University, Japan, is leading a research team that is discovering that the level of similarity in the peptides found in the digestive tract of animals can be high, even between disparate species like humans and fish. This means the fish stomach may offer important benefits to human health.

Background: The cribriform-morular variant (CMV) is a rare subtype of papillary thyroid carcinoma (PTC), and is often associated with familial adenomatous polyposis (FAP). This variant is generally...

The eighth edition of the tumor–node–metastasis classification system (TNM-8th) reflects the prognosis of papillary thyroid cancer (PTC) better than the seventh edition. This study investigated methods to further improve the prognostic accuracy of the TNM-8th. We enrolled 5683 patients who underwent surgery for PTC at the Kuma Hospital. We subdivided tumor extension (T4a) into T4a1 and T4a2 based on intraoperative gross findings and N1 according to size (

Previous reports by us and other investigators showed that among athyreotic patients on levothyroxine (LT4) following total thyroidectomy patients with normal serum thyroid-stimulating hormone (TSH) levels had mildly low serum free triiodothyronine (FT3) levels, whereas patients with mildly suppressed serum TSH levels had normal serum FT3 levels and patients with strongly suppressed serum TSH had elevated serum FT3 levels. The objective of this study was to clarify which of these three patient groups are closer to their preoperative euthyroid condition based on reported subjective symptoms. We prospectively studied 148 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy. Symptoms reflecting thyroid function documented preoperatively and following 12 months of LT4 after thyroidectomy were compared. In 65 patients with strongly suppressed TSH levels significant changes in symptoms with tendencies towards thyrotoxicosis were seen with regards to heat and cold tolerance (p < 0.01), bowel movements (p < 0.05), and hand tremors (p < 0.05). In 33 patients with normal TSH levels, significant changes in symptoms with tendencies towards hypothyroidism were seen with regards to heat and cold tolerance (p < 0.05) and activity (p < 0.05). Lastly, in 50 patients with mildly suppressed TSH levels and FT3 levels equivalent to preoperative levels, all symptom items remained equivalent to their preoperative levels. Symptoms reflecting thyroid function in patients on LT4 following total thyroidectomy suggested that patients with mildly suppressed TSH levels were closest to a euthyroid status. These data provide useful findings regarding the management of patients following total thyroidectomy.

We report on the growth of papillary microcarcinoma during active surveillance and before clinical presentation.We conducted a retrospective study of 169 patients with papillary microcarcinoma who were enrolled in active surveillance at our hospital between 2000 and 2004. Patients were followed for a median of 10.1 years using serial ultrasonography (median, 12 examinations), used to calculate the tumor doubling time. To contextualize tumor growth rates during active surveillance, we calculated the hypothetical tumor doubling time before clinical presentation. To resolve the limitations in tumor doubling time, tumor doubling rates were inversely transformed into doubling rates.The doubling rates (per year) during active surveillance (median: 0.0) were0.5, 0.1 to 0.5, -0.1 to 0.1, and-0.1 in 5, 38, 97, and 29 cases, respectively. The proportions of tumors with rather rapid growth, slow growth, stable, and a decrease in size were 3%, 22%, 57%, and 17%, respectively.Tumor growth of papillary microcarcinomas varies from rather rapid growth to a decrease in size during active surveillance.

The revised Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) guidelines for patients with papillary thyroid carcinoma (PTC) describe four risk classes: very-low-risk, low-risk, intermediate-risk, and high-risk. Here we conducted a retrospective analysis to evaluate the appropriateness of these guidelines' risk classification of PTCs. Lymph node recurrence-free, distant recurrence-free and cause-specific survivals at 15-year of high-risk group were significantly poorer than those at 15-year of intermediate-group and these survivals of intermediate-group were poorer than of low- or very-low-risk patients. In the subset analyses based on patient age (≥55 years and

Widely invasive follicular thyroid carcinoma (wi-FTC) is regarded as having an aggressive character and a dire prognosis, but it has not been known whether all wi-FTCs have a dire prognosis. Herein we retrospectively analyzed the cases of 133 patients with wi-FTCs to determine the prognostic significance of vascular invasion and cell-proliferation activity based on the Ki-67 labeling index (LI). Of the 119 patients without distant metastasis (M0), 11 (9.2%) showed recurrence during the postoperative follow-up. In a univariate analysis, the recurrence-free survival (RFS) rates of the M0 patients with vascular invasion and those with a Ki-67 LI ≥5% were significantly poorer (p = 0.0013 and p = 0.0268, respectively) than those of the patients without vascular invasion or with a Ki-67 LI5%. Other clinicopathological factors such as patient age, gender, tumor size, and oxyphilic tumor were not significantly related to the patients' RFS. In a multivariate analysis, positive vascular invasion independently affected the RFS (p = 0.0133), but Ki-675% did not (p = 0.1348). To date, only five patients have died of their thyroid carcinoma; four cases were M1. In conclusion, although M0 wi-FTC generally has a favorable prognosis, cases with positive vascular invasion or a high Ki-67 LI are likely to recur, and careful postoperative follow-up is necessary.

We had reported that orally administered ghrelin-containing salmon stomach extract prevents doxorubicin (DOX)-induced cardiotoxicity. In this study, we investigated the binding affinity of salmon ghrelin to rat ghrelin receptor and the cardioprotective effects of subcutaneous (sc) injected synthetic salmon ghrelin in rats with DOX-induced acute heart failure in order to clarify the potential efficacy of salmon ghrelin. Intracellular calcium mobilization assay was performed on rat GHS-R1a-expressing CHO cells to reveal ghrelin activity. Rats were divided into five groups; the normal control (I), and toxic control (II) groups were given saline (sc, twice daily), and the salmon acyl-ghrelin (sAG) (III), salmon unacylated-ghrelin (sUAG) (IV), and rat acyl-ghrelin (rAG) (V) groups were given corresponding synthetic ghrelins (sc, twice daily), respectively. After seven days of treatment, DOX (20 mg/kg BW) or saline was administered to the corresponding groups by intraperitoneal injection. The toxic control group was the negative control group for the DOX-induced cardiotoxicity groups. While sAG displayed similar affinity to rAG upon application to GHS-R1a-expressing cells, and also decreased DOX-induced apoptosis and increased food intake, sUAG did not. Both sAG and rAG improved DOX-induced deterioration, showing anti-oxidative activity. The anti-oxidative activity of sAG might contribute to the protective effects on cardiomyocytes. The results also suggest that, similar to rAG, sAG is a potent protectant against DOX-induced cardiotoxicity and a potential functional component in orally administered ghrelin-containing salmon stomach extract, which prevented DOX-induced cardiotoxicity in our previous study.

Background Our previous kinetic analyses of changes in the tumor volume (TV) of papillary thyroid microcarcinomas during active surveillance revealed that the tumors' growth varied over time from rather rapid growth to shrinkage and that the hypothetical TV-doubling rates (DRs) before the patients' presentation were much larger than their observed TV-DRs, indicating that rapid growth phases preceded their presentation. Whether this phenomenon also occurs in medullary thyroid carcinoma (MTC) was unknown. Methods We retrospectively analyzed the cases of 46 MTC patients (18 hereditary, 28 sporadic; 9–80 years old at surgery, median 53.5 years; 19 males and 27 females) with elevated postoperative calcitonin (Ct) suggesting persistent disease. We calculated each patient's Ct-DR and his/her hypothetical TV-DR, using the tumor size and age at surgery. Results Ct-DRs (/year) after surgery were >0.5, 0.1–0.5, −0.1–0.1, and ≤0.1 in 9, 21, 12, and 4 patients, respectively (median 0.17). The hypothetical TV-DRs (/year) before surgery were >1, 0.5–1.0, 0.1–0.5 and

Background Old age is a known prognostic factor for mortality in patients with papillary thyroid carcinoma (PTC). This study aimed to investigate the relationship between cause-specific survival (CSS) following PTC and the extent of old age. Methods We enrolled 4692 patients aged ≥ 55 years with PTC who underwent surgery between 1989 and 2009 at Kuma Hospital (median follow-up period 140 months). The presence of at least one of the following was used to classify the patients as high risk: (1) tumor sizes > 4 cm, (2) node metastasis ≥ 3 cm, (3) significant extrathyroid extension corresponding to T4a, (4) extranodal tumor extension, and (5) distant metastasis. T1N0M0 PTC was classified as low risk, and all other patients were classified as intermediate risk. We divided all patients into three categories based on age: 55–64, 65–74, and ≥ 75 years. Results One low-risk patient (0.04%), 18 intermediate-risk patients (1.5%), and 105 high-risk patients (9.4%) died of PTC, and CSS of high-risk patients was poorer than that of others (p p = 0.0017 for 55–64 years vs. 65–74 years, and p = 0.0109 for 65–74 years vs. ≥ 75 years). Conclusions Advanced age has a significant prognostic impact on CSS only for high-risk patients with PTC.

Introduction. Young patients with papillary thyroid carcinoma (PTC) generally have excellent prognoses despite their often-advanced disease status. The reasons for this excellent prognosis are poorly understood. Objective. To investigate the natural history of PTC in young patients, we compared the observed tumor volume-doubling rate (TV-DR) with the hypothetical tumor volume-doubling rate (hTV-DR) before presentation in young PTC patients. DR is an inverse of the doubling time and indicates the number of doublings that occur in a unit of time. A negative value indicates the number of times the volume is reduced by half per unit time. Methods. We enrolled 20 patients with the following characteristics: age ≤19 years, diagnosed with PTC according to the cytology results between 2013 and 2018 and followed-up with periodical ultrasound examinations for ≥3 months before surgery for various reasons. Seventeen patients later underwent surgery confirming the diagnosis. We calculated TV-DRs using serial measurements of tumor diameters after presentation and hTV-DRs using tumor diameters and patients’ age at presentation, assuming that a single cancer cell was present at the patient’s birth and that the tumor grew at a constant rate. These values indicate the lowest growth rates necessary for a single cancer cell to achieve the full tumor size at presentation. Results. Thirteen patients had positive TV-DRs (/year) ranging from 0.09 to 1.89, indicating tumor growth, and the remaining seven patients had negative values (−0.08 to −1.21), indicating regression. The median TV-DR was 0.29. The hTV-DRs (1.48–2.66, median 1.71) were significantly larger than the TV-DRs (p<0.001), indicating much faster growth before presentation. Conclusions. These data suggest that deceleration of tumor growth had already occurred at presentation in the majority of the cases. This might explain why disease-specific survival is excellent despite frequent findings of advanced disease in young patients with PTC.

Background Based on our long-term observation of medullary thyroid carcinoma (MTC) patients, we hypothesized that some MTCs have spontaneous deceleration or regression of tumor growth over a long term and that a minority may acquire growth acceleration. We thus compared the calcitonin doubling time (Ct-DT) in the earlier and later half-periods of MTC patients’ postoperative course. Methods We followed 26 MTC patients (14 hereditary and 12 sporadic MTCs) with postoperative hypercalcitoninemia with periodic measurements of serum calcitonin (Ct) for >10 years without major interventions. The median period of Ct measurements was 18.3 years (range 10.6–30.2 years). We divided the individual patients’ study periods into the earlier and later halves and calculated the Ct-DTs for both periods. Results In the hereditary group, the Ct-DT in the later half-period (Later-Ct-DT) was significantly longer than that in the earlier half-period (Earlier-Ct-DT) (median 20.0 years vs. 7.1 years, p = 0.013). These values in the sporadic group were 20.0 years versus 11.1 years, respectively (p =0.774). Twelve patients (seven hereditary and five sporadic) had Later-Ct-DTs significantly longer than their Earlier-Ct-DTs (median 27.4 years vs. 4.9 years) and good prognoses. Two patients (one hereditary, one sporadic) had Later-Ct-DTs significantly shorter than their Earlier-Ct-DTs, and both developed structural recurrence and died of the disease. Conclusion Many of the hereditary and some of the sporadic MTC patients had elongated Ct-DTs over a long period, suggesting spontaneous deceleration and regression of tumor growth. A minority of the MTC patients showed Ct-DT shortening, suggesting tumor growth acceleration.

Background Medullary thyroid carcinoma (MTC) originates from calcitonin-producing cells of the thyroid. In 2009, we published our first report on the biological characteristics and prognosis of 118 MTC patients. Herein, we enrolled a larger number of patients with longer follow-up periods to further study the biological characteristics and appropriate therapies for MTC. Methods In general, hemithyroidectomy and total thyroidectomy were performed for sporadic MTC confined to the thyroid lobe and for hereditary MTC with central node dissection, respectively. Moreover, prophylactic modified radical neck dissection was performed on the side of macroscopic tumors. Results In total, 233 patients (99 hereditary and 134 sporadic) were enrolled. The median follow-up time was 128 months (range 7–445 months). Biochemical cure was obtained in 36 (62%) of the 58 patients who underwent prophylactic MND and were pathologically positive for lateral node metastasis. None of the patients had recurrence in the preserved thyroid. Distant recurrence was detected in 19 patients, and 12 died of MTC. Preoperative calcitonin and carcinoembryonic antigen levels, tumor size (T) > 4 cm, the male sex, clinical and pathological node metastases (N1), distant metastasis (M1), extrathyroid extension (Ex), and a lack of biochemical cure had prognostic impacts on distant recurrence and/or carcinoma-related mortality on univariate analysis. On multivariate analysis, Ex was independently correlated with distant recurrence, and Ex, T > 4 cm, and M1 independently affected carcinoma-related mortality. Conclusion MTC patients had excellent prognosis in our institutions, indicating that our surgical strategies were appropriate.

Background: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PMC) was adopted as a management modality in both the Japanese guidelines in 2011 and the American Thyroid Association guidelines in 2015. AS was initiated at Kuma Hospital in 1993 but was not immediately accepted by all physicians. This study investigated the history of acceptance of AS at Kuma Hospital over time. The results should assist in the implementation of AS at other hospitals in Japan and other countries. Methods: This study included 4023 patients who were cytologically diagnosed with low-risk PMC at Kuma Hospital during the 24-year period between October 1993 and June 2016. The trend in the frequency of AS use over time was analyzed, dividing the 24-year study period into five parts based on the change in frequency of AS use: 1993–1997, 1998–2002, 2003–2006, 2007–2013, and 2014–2016. Results: The frequency of AS use in the present cohort was 65%. The frequency gradually increased from 30% in 1993–1997 to 88% in 2014–2016, with a slight decrease from 51% in 1998–2002 to 42% in 2003–2006. Until 2007, patients were mostly seen by surgeons, and the frequency of AS use varied remarkably among individual surgeons. Since 2007, the number of patients whose therapeutic strategies are determined by endocrinologists has increased, and the frequency of AS use for low-risk PMC by endocrinologists has been higher than that by surgeons. Conclusions: At Kuma Hospital, acceptance of AS for low-risk PMC gradually increased over the 24-year study period, but AS was not equally accepted by all physicians. Such variations in the acceptance of AS among individual physicians are also expected to exist in other hospitals. However, due to increasing evidence of the safety and superiority of AS over immediate surgery for this indolent disease, it is expected that AS will gain faster acceptance in other hospitals in Japan and around the world.

Introduction In Japan, prophylactic central node dissection (p-CND) for papillary thyroid carcinoma (PTC) has been routinely performed in many institutions, including ours (Kuma Hospital, Japan). We evaluated the recurrence to a central lymph node in patients with cN0M0 PTC who underwent routine p-CND. Materials and methods We enrolled 4301 patients with cN0M0 PTC who underwent an initial surgery between 1987 and 2005 (median age 51 years). The postoperative follow-up periods ranged from 4 to 362 months (median 164 months). Only 15 patients underwent radioactive iodine (RAI) ablation (≥30 mCi) after total or near total thyroidectomy. Results Of the 4301 patients with N0M0 PTC who underwent p-CND, 2548 (59%) were diagnosed as pN1a on postoperative pathological examination. To date, only 52 cases (1.2%) showed recurrence to a central lymph node. The 10-year and 20-year central node recurrence-free survival rates were excellent at 99.1 and 98.2%, respectively. On multivariate analysis, age ≥55 years, significant extrathyroid extension, tumor size >2 cm, and ≥5 pathologically confirmed central node metastases (but not the presence of central node metastasis) independently affected central node recurrence. Conclusions Under the situation of routine p-CND, the central node recurrence-free survival of cN0M0 PTC is excellent. However, future studies, including double-arm studies from Japan, should examine whether the omission of p-CND cN0M0 PTC is appropriate without RAI ablation in consideration of various factors, including the pros and cons of p-CND.

Introduction Papillary thyroid carcinoma (PTC) generally shows an excellent prognosis except in cases with aggressive backgrounds or clinicopathological features. Although the cause-specific survival (CSS) of PTC patients has been extensively investigated, the overall survival (OS) of these patients is unclear. We herein investigated both the OS and CSS of a large PTC patient series. Materials and methods We enrolled 5897 PTC patients who underwent initial surgery between 1987 and 2005 (658 males and 5339 females; median age 51 years). Their median postoperative follow-up period was 177 months. Univariate and multivariate analyses for OS and CSS assessed the effects of gender, older age (≥55 years), distant metastasis at diagnosis (M1), significant extrathyroid extension, tumor size (cutoffs 2 and 4 cm), large node metastasis (N ≥ 3 cm), and extranodal tumor extension. Results To date, 387 patients (7%) in this series have died from various causes, including 117 (2%) due to PTC. The 10-, 15-, and 20-year OS rates are 97, 95, and 90%, respectively. Older age and M1 were important prognostic factors for OS and CSS. Older age was a more significant factor than M1 for OS and vice versa for CSS. In the older patients, M1 was a prominent prognostic factor for both OS and CSS. In the young patients, M1 had less prognostic impact than in the older patients, and the prognostic values of M1 and N ≥ 3 cm for OS and CSS were identical and similar, respectively. Conclusions The most important prognostic value for OS was patient age, indicating that PTC is generally indolent. However, the control of distant metastasis in older patients remains a future challenge in order to further improve their OS and CSS. PTC of ≥3 cm in young patients should be carefully followed, even in the absence of metastases, and these patients should undergo aggressive therapies for recurrent lesions and metastases.

The tumor-node-metastasis (TNM) staging system is most commonly adopted to evaluate the prognosis of patients with thyroid carcinoma. The 8th edition of the TNM staging system, an extensively revised version of the 7th edition, was recently released. We aimed to investigate whether and how well the 8th edition reflects the cause-specific survival (CSS) of patients with papillary thyroid carcinoma by analyzing the cases in 5,892 patients who underwent initial surgery at Kuma Hospital between 1987 and 2005. The median postoperative follow-up duration was 178 months (range: 6-357 months). One patient with T4b disease was excluded from the analysis. Overall, 116 (2.0%) patients died of thyroid carcinoma. The proportion of variance explained (PVE) for CSS in the 7th and 8th editions was 10.69 and 10.97, respectively. Using the 7th edition, CSS of patients with stage IVA and stage III disease was similar (p = 0.32). In contrast, using the 8th edition, CSS was poorer in stage II than in stage I (p < 0.001), in stage III than in stage II (p < 0.001), and in stage IVB than in stage III (p < 0.001). Similar results were observed for disease-free survival. Although we could not establish any objective evidence that the 8th edition is superior to the 7th edition, the 8th edition is simpler and more convenient, as it includes fewer stages and addresses the issue of the 7th edition where stage IVA and III patients had similar prognoses.

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 7th to the 8th edition. The diagnostic criteria for poorly differentiated carcinoma (PDC) were also updated in the latest World Health Organization (WHO) classification. In this study, we investigated whether these changes are appropriate for accurately predicting prognosis. Three hundred and twenty-nine patients diagnosed with postoperative pathologically confirmed FTC, who underwent initial surgery at our hospital between 1984 and 2004, were enrolled. For this study, patients were re-evaluated and diagnosed with FTC (N = 285) or PDC (N = 44) without typical nuclear findings of papillary thyroid carcinoma. For FTC, the 8th TNM classification was a more accurate predictor of prognosis than the 7th TNM classification. In the 8th TNM classification, cause-specific survival became significantly poorer from Stage I to IVB. The cause-specific survival of PDC based on the latest WHO classification was worse than, but did not significantly differ from, that of PDC based only on the former WHO classification. For PDC, neither of the TNM classifications could accurately predict prognosis. Taken together, we conclude that (1) the 8th TNM classification more accurately reflects the prognosis of FTC than the 7th TNM classification; (2) PDC based on the former WHO classification should be retained, at least in Japan; and (3) the TNM classification may not be suitable for predicting the prognosis of PDC.

Background: Some investigators reported that among athyreotic patients on levothyroxine (LT4) monotherapy following total thyroidectomy, the patients with normal serum thyrotropin (TSH) levels had mildly low serum free triiodothyronine (fT3) levels, whereas the patients with mildly suppressed serum TSH levels had normal serum fT3 levels, and the patients with strongly suppressed serum TSH had elevated serum fT3 levels. The objective of the present study was to clarify which of these three patient groups is closer to their preoperative euthyroid condition. Methods: A total of 133 consecutive euthyroid patients with papillary thyroid carcinoma who underwent a total thyroidectomy were prospectively studied. The patients' serum levels of lipoproteins, sex hormone-binding globulin, and bone metabolic markers measured preoperatively were compared with the levels measured at postoperative LT4 therapy 12 months after the thyroidectomy. Results: The postoperative serum sex hormone-binding globulin (p

Aim The most frequent recurrence site of papillary thyroid carcinoma (PTC) is the cervical lymph nodes. The introduction of an electric linear probe for use with ultrasonography in 1996 improved preoperative lateral neck evaluations. Before 2006, however, our hospital routinely performed prophylactic modified neck dissection (p-MND) for N0 or N1a PTCs >1 cm to prevent node recurrence. In 2006, we changed our policy and the indications for p-MND to PTCs >3 cm and/or with significant extrathyroid extension. Here, we retrospectively compared lymph node recurrence-free survival between PTCs with/without p-MND. Methods We examined the cases of N0 or N1 and M0 PTC patients who underwent initial surgery in 1992–2012. To compare lymph node recurrence-free survival between patients who did/did not undergo p-MND, we divided these patients into three groups (excluding those whose surgery was in 2006): the 2045 patients whose surgery was performed in 1992–1996 (Group 1), the 2989 with surgery between 1997 (post-introduction of ultrasound electric linear probes) and 2005 (Group 2), and the 5332 operated on in 2007–2012 (Group 3). Results The p-MND performance rate of Group 3 (9%) was much lower than that of Group 1 (80%), but the lymph node recurrence-free survival of the former was significantly better, probably due to differences in clinical features and neck evaluations by ultrasound between the two groups. Our analysis of the patients aged

We report three cases of chromophobe renal cell carcinoma-like thyroid carcinoma as a novel clinicopathologic entity possibly associated with tuberous sclerosis complex. A 15-year-old female, a 19-year-old male, and a 21-year-old male presented with primary thyroid carcinoma. Two of the patients had associated tuberous sclerosis complex. Macroscopically, the carcinomas showed invasive growth. Histologically, the carcinoma cells showed a trabecular pattern with thin vascular stroma, and were characterized by abundant eosinophilic cytoplasm with perinuclear clearing, a prominent cell border, a wrinkled nuclear membrane, and binucleation, which are all features of chromophobe renal cell carcinoma. Immunohistochemically, the carcinoma cells were positive for thyroglobulin, TTF1, and PAX8, and negative for CD10, calcitonin, and carcinoembryonic antigen. Vascular invasion was visible in all cases, but distant metastasis was not detected during follow-up. The original pathological diagnoses of the three cases were widely invasive follicular thyroid carcinoma, poorly differentiated thyroid carcinoma, and oxyphilic variant of papillary thyroid carcinoma. Thus, the cases were similar to chromophobe renal cell carcinoma associated with tuberous sclerosis complex as they were characterized by histologic findings consistent with chromophobe renal cell carcinoma, occurrence in an adolescent or young adult, and favorable prognosis regardless of the presence of vascular invasion and an infiltrating growth pattern resembling poorly differentiated carcinoma. The etiopathogenesis also seemed to suggest the presence of the tuberous sclerosis complex genetic abnormality.