Histological classification and cytology reporting format described in General Rules for the Description of Thyroid Cancer, the 8^th edition (2019) (the Japanese General Rules) were briefly introduced. Moreover, the differences between “the Japanese General Rules”, and WHO Histological Classification, the 4^th edition (2017) and The Bethesda System for Reporting Thyroid Cytopathology, the 2^nd edition (2018) were also explained. The Japanese General Rules did not accept the borderline lesions of thyroid tumor which were newly shown in WHO Histological Classification. We believe it is not necessary to introduce these borderline lesions in daily practice in Japan. Borderline lesions were proposed for avoiding over-surgery for thyroid cancer patients. In the United States, when the patient is diagnosed as malignant on cytology, total thyroidectomy is generally recommended. However, there is no over-surgery in Japan, because surgeons have several choices of treatment for thyroid cancer patients. This article is the first that the Japanese General Rules was shown by foreign language. Therefore, this will be advantageous to us when we present our opinion concerning histology and cytology of thyroid tumor to the world.

Metabolic associated fatty liver disease (MAFLD) is a new concept proposed in 2020. This study aimed to explore the relationship between serum 25-hydroxy vitamin D (25(OH)D) level and MAFLD based on a population survey dataset (the third National Health and Nutrition Examination Surveys of the United States). Multivariate logistic regression was used to estimate the odds ratio (OR) of serum 25(OH)D level for MAFLD. A total of 12,878 participants were included in this analysis. Among them, 4,027 (31.27%) cases were diagnosed with MAFLD and 8,851 (66.40%) were without MAFLD (non-MAFLD). Patients with vitamin D sufficiency and insufficiency totaled 6,983 (54.22%) and 5,895 (45.78%), respectively. The incidence of MAFLD and the grade of hepatic steatosis were both significantly higher in vitamin D insufficiency group. Multivariate analysis showed that vitamin D insufficiency was an independent risk factor for MAFLD after adjusted for other confounders (OR: 1.130, 95%CI: 1.035 to 1.234). In MAFLD population, the average serum 25(OH)D level decreased with the numbers of metabolic risks in MAFLD cases. Serum 25(OH)D level was not associated with the severity of fibrosis or steatosis in MAFLD group. In Conclusion, lower serum 25(OH)D level is associated with higher prevalence of MAFLD in general population. No relationship was found between serum 25(OH)D level and the severity of hepatic steatosis or fibrosis in MAFLD.

Lenvatinib is a standard therapy for radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, because of the high incidence of adverse events resulting from this treatment, it is not easy to maintain the dose intensity of lenvatinib, especially in Japanese patients. Although the prognostic impact of lenvatinib dose interruption has been reported, the target dose intensity of lenvatinib to optimize survival benefits remains unknown. We therefore propose a target dose intensity of lenvatinib during the first 8 weeks of treatment. We retrospectively analyzed 42 RR-DTC patients who were treated with lenvatinib for more than 8 weeks. We performed receiver operating characteristic curve analysis to determine the cut-off value of 8 weeks’ relative dose intensity (8w-RDI) to predict treatment response, and identified that the optimal cut-off value of 8w-RDI was 60% (sensitivity: 81.8%; specificity: 80.6%). Median progression-free survival (PFS) (not reached [NR] vs. 11.0 months; hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.11–0.72; p < 0.01) and overall survival (NR vs. 27.6 months; HR 0.44; 95% CI 0.11–0.91; p = 0.03) were longer in the higher 8w-RDI (≥60%) patients than in the lower 8w-RDI (<60%) patients. Multivariate analysis revealed that 8w-RDI at ≥60% was an independent prognostic factor for PFS (HR 0.29; 95% CI 0.09–0.96; p = 0.04). Targeting for ≥60% of the relative dose intensity during the first 8 weeks of lenvatinib treatment can be sufficient to achieve significant tumor shrinkage and prolong PFS in RR-DTC patients.

Graves’ disease (GD) may coexist with papillary thyroid microcarcinoma (PTMC). The main purpose of this study was to evaluate whether treatment with radioactive iodine (RAI) may cause acute exacerbation of PTMC concurrent with GD or not. From the medical records of 10,257 GD patients who underwent RAI therapy between 2000–2017, 12 subjects with concurrent PTMC were retrieved. Further, 49 patients with concurrent GD and PTMC who underwent no RAI administration throughout their clinical course were enrolled as controls. Size of the PTMC nodules was evaluated based on maximal diameter and tumor volume-doubling rate (TV-DR). Among the 12 subjects who underwent RAI therapy (median dose, 13 mCi), 2 showed tumors >10 mm in maximal diameter with slow growth for more than 10 years, while the other 10 showed tumors with maximal diameter ≤10 mm. No subject showed any clinical findings of nodal or distant metastasis during the follow-up periods (0.4–11.5 years) before surgery or during active surveillance. No significant differences were observed in the TV-DR values (median, 0.044/year; range, –0.81–1.40) between the study subjects and controls (median, 0.025/year; range, –0.70–1.29; p = 0.69). When comparing the TV-DR before and after RAI administration in 3 individuals in particular, in whom PTMC were cytologically confirmed before RAI administration and whose prospective follow-up data were available, tumor progression was observed to be stable or decreased after RAI administration. There were no acute exacerbations or unfavorable outcomes of concurrent PTMC and GD after low-dose RAI administration.

Gender differences in risks for macrovascular complications in type 2 diabetes mellitus (T2DM) have been well established. However, the impact of gender differences on diabetic retinopathy (DR) has not been fully elucidated. We therefore retrospectively explored gender-specific determinants for DR in patients with T2DM in a small sized Japanese cohort in Okinawa. There were 214 patients who were diagnosed as no DR (n = 142) and non-proliferative DR (n = 72) in 2009. During the follow-up of median 7 years, 41/142 of incidence, 26/72 of progression, and 67/214 of incidence and progression were observed, respectively. DR was assessed using the modified international clinical DR severity scales. The risks for incidence, progression as well as incidence and progression of DR were comparable between men and women, respectively. Cox proportional hazard models in multivariate analyses demonstrated that the only common determinant in both men and women for DR was the duration of T2DM. Regarding gender-specific determinants, lower level of serum albumin in men as well as higher HbA1c, lower level of estimated glomerular filtration rate, and lower level of serum uric acid in women were extracted, respectively. Although precise mechanisms for such gender-specific determinants of DR still remain unsolved, the present study would highlight a couple of factors associated with gender-specific determinants for DR in a limited numbers of Japanese cohort. Prospective observational studies on gender-specific determinants of DR in a large scale cohort are warranted to further clarify underlying mechanisms.

Cytotoxic chemotherapy, including cyclophosphamide, vincristine, and dacarbazine (CVD) therapy, is widely used to treat metastatic pheochromocytoma and paraganglioma. Because these diseases are rare, studies are needed to establish treatment strategies. This was a single-center and retrospective study to analyze the efficacy of chemotherapy for patients with metastatic pheochromocytoma and paraganglioma diagnosed in 1983–2020. Clinical characteristics, tumor volume response, biochemical response based on catecholamine level, overall survival, and progression-free survival were evaluated. Patients with a complete response or partial response in tumor volume or catecholamine level were classified as responders. Sixteen patients were administered chemotherapy for a median of 16.5 cycles (interquartile range, 10–42). The tumor volume response was classified as follows: partial response (N = 4), stable disease (N = 9), and progressive disease (N = 3) (disease control rate = 81%). The biochemical responses were as follows: complete response (N = 2), partial response (N = 5), no change (N = 3), and progressive disease (N = 1) (disease control rate = 91%). The 5-year survival rate was 50% (95% confidence interval [CI], 21–74%) and median overall survival was 4.4 years (95% CI, 2.4 years–not reached). Overall survival and progression-free survival between responders and nonresponders were not statistically different. One patient developed myelodysplastic syndrome during CVD therapy. In conclusion, chemotherapy achieved disease control among more than half of patients, although survival did not differ between responders and nonresponders. Further fundamental research and prospective trials are needed to analyze the efficacy of CVD therapy.

ACTH-cortisol dissociation is recognized in patients with critical illnesses. Cytokines, including tumor necrosis factor-α and interleukin-6 induce hypercortisolemia by enhancing the ACTH-independent synthesis and secretion of cortisol and by reducing cortisol breakdown. Subsequently, hypercortisolemia suppresses ACTH secretion by negative feedback inhibition. ACTH-cortisol dissociation in patients with systemic inflammatory diseases has not been reported. Here, we examined whether ACTH-cortisol dissociation is recognized in patients with Kawasaki disease (KD) associated with hypercytokinemia, as well as the possible cytokine involvement in ACTH-cortisol dissociation, retrospectively. The levels of serum cortisol, plasma ACTH, and cytokine-induced proteins, i.e., plasma C-reactive protein (CRP), serum ferritin, and urinary β2-microglobulin (U-β2MG), in 232 patients with KD were measured at diagnosis. Quartile groups based on cytokine-induced protein levels were formed (Q1, Q2, Q3, and Q4). We found a low median plasma ACTH [median (range): 8.9 (<2.0–332.0) pg/mL] but a high median serum cortisol level [median (range): 25.8 (1.4–99.8) μg/dL] in the entire study population. The median serum cortisol levels were significantly higher in the CRP-Q4, ferritin-Q4, and U-β2MG-Q4 groups than in the CRP-Q1, ferritin-Q2, and U-β2MG-Q1 groups, respectively (p < 0.01; p < 0.01; p < 0.001). The median plasma ACTH levels were significantly lower in the CRP-Q4 and ferritin-Q4 groups than in the CRP-Q1 and ferritin-Q1 groups, respectively (p < 0.001; p < 0.001). ACTH-cortisol dissociation was identified in patients with KD. Our findings suggest that inflammatory cytokines are involved in ACTH-independent hypercortisolemia in patients with KD. ACTH-cortisol dissociation in other systemic inflammatory diseases needs further investigation.

Iodine transportation is an important step in thyroid hormone biosynthesis. Uptake of iodine into the thyroid follicle is mediated mainly by the basolateral sodium–iodide symporter (NIS or solute carrier family 5 member 5: SLC5A5), and iodine efflux across the apical membrane into the follicular lumen is mediated by pendrin (SLC26A4). In addition to these transporters, SLC26A7, which has recently been identified as a causative gene for congenital hypothyroidism, was found to encode a novel apical iodine transporter in the thyroid. Although SLC5A5 and SLC26A4 have been well-characterized, little is known about SLC26A7, including its regulation by TSH, the central hormone regulator of thyroid function. Using rat thyroid FRTL-5 cells, we showed that the mRNA levels of Slc26a7 and Slc26a4, two apical iodine transporters responsible for iodine efflux, were suppressed by TSH, whereas the mRNA level of Slc5a5 was induced. Forskolin and dibutyryl cAMP (dbcAMP) had the same effect as that of TSH on the mRNA levels of these transporters. TSH, forskolin and dbcAMP also had suppressive effects on SLC26A7 promoter activity, as assessed by luciferase reporter gene assays, and protein levels, as determined by Western blot analysis. TSH, forskolin and dbcAMP also induced strong localization of Slc26a7 to the cell membrane according to immunofluorescence staining and confocal laser scanning microscopy. Together, these results suggest that TSH suppresses the expression level of Slc26a7 but induces its accumulation at the cell membrane, where it functions as an iodine transporter.

Only limited information is available on the inter-relationships between genetic and non-genetic factors such as diet and sunlight exposure with serum 25-hydroxyvitamin D [25(OH)D] concentration. This cross-sectional study aimed to examine the independent and interactive associations of season, dietary vitamin D intake, and SNPs of 11 vitamin D-related candidate genes with serum 25(OH)D concentration among 2,721 adults aged ≥40 years at baseline from the Yangpyeong cohort, a part of the Korean Genome Epidemiology Study (KoGES). The interactions between season or dietary vitamin D and 556 SNPs were evaluated using 2-degree of freedom joint tests. Season was strongly (p_difference = 1.00 × 10^–12) and dietary vitamin D intake was slightly but significantly associated with serum 25(OH)D concentration (p_difference = 0.0119). Among five SNPs (rs11723621-GC, rs7041-GC, rs10500804-CYP2R1, rs7129781-CYP2R1, and rs2852853-DHCR7) identified in the screening steps, only one, rs10500804-CYP2R1, significantly interacted with season (p_interaction = 8.01 × 10^–5). The inverse association between number of minor alleles of rs10500804-CYP2R1 and concentration of 25(OH)D was significant only in summer/fall. Conversely, dietary vitamin D intake was positively associated only in winter/spring. In conclusion, season, dietary vitamin D intake, and four SNPs in GC, CYP2R1, and DHCR7 are independently and rs10500804-CYP2R1 is interactively associated with serum 25(OH)D concentration. Serum 25(OH)D is influenced by genotype of rs10500804-CYP2R1 in summer/fall when sunlight exposure is high, while dietary vitamin D intake is an important determinant of serum 25(OH)D during the seasons with low cutaneous vitamin D synthesis.

The circular RNA PRKCI (circ-PRKCI; ID: hsa_circ_0122683) is highly expressed in human papillary thyroid cancer (PTC) tumors according to GSE93522 dataset. However, its role in PTC tumorigenesis remains to be documented. Here, quantitative real-time PCR showed that expression of circ-PRKCI was abnormally upregulated in human PTC patients’ tumors and cells, and higher circ-PRKCI might predict lymph node metastasis and recurrence. Functionally, cell behaviors were measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay, colony formation assay, fluorescence-activated cell sorting method, scratch wound assay, transwell assay, western blotting, and assay kits for glucose and lactate. As a result, circ-PRKCI knockdown could suppress cell cycle progression of PTC cells and restrain the abilities of cell proliferation, colony formation, wound closure, invasion, glucose consumption and lactate production, accompanied with decreased levels of matrix metalloproteinase-2 (MMP2), MMP9 and Snail. Moreover, above-mentioned inhibition could be imitated by overexpressing microRNA-335-5p (miR-335). Molecularly, circ-PRKCI functioned as a sponge for miR-335 and miR-335 could further targeted E2F transcription factor-3 (E2F3), according to dual-luciferase reporter assay and RNA immunoprecipitation. However, downregulating miR-335 diminished the effects of circ-PRKCI role on cell growth, metastasis and glycolysis in PTC cells; besides, there was a counteractive effect between miR-335 upregulation and E2F3 upregulation in PTC cells as well. Furthermore, xenograft experiment revealed that silencing circ-PRKCI could retard tumor growth of PTC cells in vivo. Collectively, circ-PRKCI exerted oncogenic role in PTC by antagonizing cell progression and glycolysis via regulating miR-335/E2F3 axis, suggesting circ-PRKCI was a potential biomarker and target for PTC.

This review evaluated the risk of rheumatoid arthritis in patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors (Dpp-4i). The MEDLINE (via PubMed), Embase, the Cochrane Library databases and web of science were used to search the effects of Dpp-4i on rheumatoid arthritis in patients with type 2 diabetes from inception to 7 September, 2020. We included studies that met the following criteria:(i) A randomized controlled trial (RCT), prospective or retrospective cohort study examining the relationship between Dpp-4i and rheumatoid arthritis. Exclusion criteria included the following: Reviews and researches related to other diseases or subjects; and studies without data on the prevalence of rheumatoid arthritis were excluded. Risk of Bias table contained in Review Manager 5.3 and Newcastle-Ottawa scale (NOS) were used for quality assessment of included RCT and observational studies separately. Meta-analysis was used to estimate the risk of disease. We conducted a subgroup analysis of duration of follow-up, adjusted (adjusted RR or unadjusted RR), sample size and study design. A total of 10 independent studies assessing 1,420,414 patients were included in this analysis. In this meta-analysis, we found that there was nonsignificant increase of rheumatoid arthritis with Dpp-4 inhibitor exposure (RR 0.96, 95%CI (0.69–1.32)). Our results revealed that Dpp-4 inhibitors do not seem to increase the risk of rheumatoid arthritis. Long-term follow-up monitoring is necessary.

The PIONEER and SUSTAIN serial trials are designed to assess the efficacy outcomes with semaglutide in patients with type 2 diabetes, but are not powered to assess various safety outcomes. We sought to assess the risk of semaglutide in leading to various serious adverse events (SAEs) in patients with type 2 diabetes. Studies eligible for inclusion were the PIONEER and SUSTAIN trials of semaglutide. We conducted meta-analysis to generate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Meta-analysis was performed using both random-effects and fixed-effects model to evaluate the robustness of pooled results. We implemented subgroup analysis according to drug dosages and routes of administration and type of comparators. Twenty-one trials were included. Semaglutide versus control significantly reduced total SAEs (RR 0.92, 95% CI 0.87–0.97; I² = 0) and atrial fibrillation (RR 0.69, 95% CI 0.50–0.95; I² = 0), but significantly increased deep vein thrombosis (RR 3.66, 95% CI 1.09–12.25; I² = 0) and diarrhoea (RR 2.66, 95% CI 1.19–5.95; I² = 0). Semaglutide had no significant effects on 248 other kinds of SAEs. No statistically significant subgroup effects were observed. Semaglutide has a good safety profile in general and reduces atrial fibrillation by 31%, but increases diarrhoea by 166% and deep vein thrombosis by 266%. These findings may guide that semaglutide should be preferred or avoided in T2D patients with specific susceptibility factors.