Solid variant of papillary thyroid carcinoma (SVPTC) is a rare morphological variant of papillary thyroid carcinoma (PTC). SVPTC is histologically characterized by predominant solid, trabecular and insular nests of tumor cells while cytological features of PTC such as nuclear grooves and nuclear inclusions are preserved. In fine needle aspiration cytology smears, tumor cells of SVPTC may be presented in cohesive, syncytial or trabecular clusters accompanied by some discohesiveness in the absence of necrosis. Although SVPTC and poorly differentiated thyroid carcinoma (PDTC) share similar histological findings of solid nests, SVPTC can be differentiated from PDTC in the lack of tumor necrosis, severe nuclear atypia, and a higher mitotic index. Immunohistochemical expression of CK19 and HBME-1, common markers of PTC, is decreased in solid nests of SVPTC. In pediatric patients exposed to radiation after the Chernobyl nuclear accident, there was a higher prevalence of SVPTC with RET/PTC3 type rearrangement. BRAF mutations are also reported in a small number of adult patients with SVPTC without any prior radiation exposure. Patients with SVPTC may have a slightly higher incidence of metastasis and recurrence of the tumor compared to conventional PTC, although overall survival rate is comparable. In this article, the current knowledge of SVPTC will be reviewed and discussed with an emphasis on the histopathological feature.
Polycystic ovary syndrome (PCOS) diagnosis combines various clinical phenotypes. The definition of PCOS is still controversial because insulin resistance (IR) and dysmetabolism do not constitute PCOS diagnostic criteria. We analyzed whether a circulating biomarker zinc-α2-glycoprotein (ZAG) related to IR and metabolic dysfunction can predict PCOS phenotypes. We then recruited 100 PCOS patients and 99 healthy women as the control group to assess the relationship between ZAG and metabolic characteristics. The euglycemic-hyperinsulinemic clamp helped assess insulin sensitivity, and the enzyme immunometric assay was deployed for ZAG levels. Our PCOS cohort presented sixty-nine patients with hyperandrogenism, eighty-six patients with chronic oligoanovulation, and eighty-one patients with polycystic ovaries by ultrasonographic evaluation. Additionally, the circulating ZAG levels were considerably reduced in all PCOS patients compared with healthy women (p < 0.05 or p < 0.01). Additionally, sixty-nine PCOS patients had IR, and circulating ZAG levels were also different among the phenotypes. Furthermore, the normoandrogenic type specifically exhibited the highest circulating ZAG levels among all PCOS phenotypes (p < 0.05 or p < 0.01). Additionally, normoandrogenic phenotype patients had reduced HOMA-IR scores and greater M-values than those in the classic phenotypes (p < 0.05). The circulating ZAG levels, however, were not associated with oligoanovulation but were correlated with hyperandrogenism and PCO morphology. In summary, circulating ZAG levels serve as suitable PCOS phenotype biomarkers, aiding physicians to identify women who merit screening.
Little is known about the association between equol and bioavailable testosterone (BT) in adults. In this study, we examined the associations of urinary equol concentrations with serum concentrations of total, bioavailable and free testosterone (FT), dehydroepiandrosterone sulfide (DHEAS), free androgen index (FAI) and sex hormone-binding globulin (SHBG). This cross-sectional study included 1,904 women with a mean age of 59.7 years. Urinary equol concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). The serum androgenic indices and SHBG were also determined. Overall, urinary equol tended to be inversely associated with bioactive forms of androgenic indices (BT, FT or FAI) but not with total testosterone (TT) or DHEAS. Urinary equol was also positively associated with SHBG. In multi-covariate-adjusted analyses stratified by menopausal status, graded and inverse associations between urinary equol and bioactive forms of androgenic indices (BT, FT and FAI) were observed in postmenopausal women (all p-trends < 0.05), but not in premenopausal women. A significant positive association between urinary equol and SHBG was observed only in postmenopausal women. No significant associations were observed between urinary equol and TT or DHEAS in either group. A path analysis indicated that these associations of equol with androgens in postmenopausal women might be mediated by SHBG. In conclusion, urinary equol exhibited graded and inverse associations with BT or FT, but not TT in women. However, further longitudinal studies of human patients are needed to confirm these results and overcome the limitations of cross-sectional studies.
Central diabetes insipidus (CDI) is characterized by polyuria and polydipsia caused by impairment of arginine vasopressin (AVP) secretion. In this study, we evaluated plasma AVP concentrations during a hypertonic saline infusion test using a new AVP radioimmunoassay (RIA) which is now available in Japan. Thirteen control subjects, mostly with hypothalamo-pituitary disease but without CDI, and 13 patients with CDI were enrolled in the study. Whether or not subjects had CDI was determined based on the totality of clinical data, which included urine volumes and osmolality. Regression analysis of plasma AVP and serum Na concentrations revealed that the gradient was significantly lower in the CDI group than in the control group. The area under the receiver-operating-characteristic (ROC) curve was 0.99, and the <0.1 gradient cut-off values for the simple regression line to distinguish CDI from control had a 100% sensitivity and a 77% specificity. The ROC analysis with estimated plasma AVP concentrations at a serum Na concentration of 149 mEq/L showed that the area under the ROC curve was 1.0 and the <1.0 pg/mL cut-off values of plasma AVP had a 99% sensitivity and a 95% specificity. We conclude that measurement of AVP by RIA during a hypertonic saline infusion test can differentiate patients with CDI from those without CDI with a high degree of accuracy. Further investigation is required to confirm whether the cut-off values shown in this study are also applicable to a diagnosis of partial CDI or a differential diagnosis between CDI and primary polydipsia.
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 those <55 years (p < 0.0001) (20-year CSS rates, 96.9% vs. 98.7%). CSS of intermediate-risk patients <55 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 patients <55 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 (p < 0.0001) than the others. In high-risk patients <55 years, distant metastasis (M1), extrathyroid extension (Ex), node metastasis ≥3 cm, and extranodal tumor extension, and in those ≥55 years, M1, Ex, and tumor size >4 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.
The chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) plays essential roles in organogenesis of embryos. Recently COUP-TFII is also implicated in several diseases in adults. Here we focus on the role of COUP-TFII in cisplatin-induced acute kidney injury (AKI). COUP-TFII was the most abundantly expressed in the kidney among organs. Male tamoxifen-inducible COUP-TFII-knockout mice or control mice were intraperitoneally treated with 30 mg/kg body weight of cisplatin at 12 weeks old to induce AKI. The kidney samples were subject to morphological studies, terminal deoxynucleotidyl transferase-mediated deoxyuridine nick-end labeling (TUNEL) assay, immunohistochemistry and RT-qPCR. Serum levels of creatinine, blood urea nitrogen (BUN) and tumor necrosis factor alpha (TNF-α) were measured. Administration of cisplatin induced a more severe AKI in adult COUP-TFII-knockout mice. An increase in dead cells in both the proximal tubules and thick ascending limb of Henle’s loop (TAL) was observed in the knockout mouse kidney. The expression levels of COUP-TFII decreased in the TAL by cisplatin administration. There was no difference in the expression levels of transporter mRNAs responsible for cellular cisplatin uptake between control and knockout mouse kidney. COUP-TFII-knockout mice and COUP-TFII-depleted cells exhibited an elevation in TNF-α levels, suggesting the involvement of the TNF-α pathway. Chromatin immunoprecipitation showed that COUP-TFII was enriched in the potential binding site, suggesting that COUP-TFII might directly suppress the TNF-α gene at transcriptional level. These results indicate the involvement of COUP-TFII in the pathophysiology of AKI and COUP-TFII may be a potential therapeutic target for AKI.
The aim of this prospective study was to analyze accuracy of sentinel lymph node biopsy with methylene blue dye for intraoperative detection of lateral metastases in clinically N0M0 medullary microcarcinomas with calcitonin <1,000 pg/mL and selection of true-positive patients for one-time therapeutic lateral dissection. In addition to total thyroidectomy and central neck dissection, all patients had bilateral sentinel biopsy of jugulo-carotid regions after methylene blue injection to decide upon necessity for lateral dissection. If sentinels were benign on frozen section, additional non-sentinels were extirpated, with no further lateral dissection. If sentinels were malignant, one-time lateral dissection was performed. 20 patients were included in this study. Hereditary disease form was observed in 3/20 (15%) of patients with RET proto-oncogene mutation C634F; remaining 17/20 (85%) were negative for germline mutations. There were no allergic reactions to methylene blue and identification rate of sentinels was 100%. In total, 2/20 (10%) cN0 patients had lymphonodal metastases, thus were reclassified as pN1b. Remaining 18/20 (90%) were classified pN0 based on standard pathohistology. Frozen section findings on sentinels were 100% match with standard pathohistology, and there were no skip metastases in lateral compartments. Sensitivity, specificity and accuracy of sentinel biopsy method with methylene dye and frozen section were 100%. Dzodic’s sentinel lymph node biopsy method can be used for intraoperative assessment of lateral compartments and optimization of initial surgery of medullary microcarcinomas with calcitonin <1,000 pg/mL. This way, cN0 patients with sentinel metastases can receive one-time lateral dissection, and those without benefit from less extensive surgery.
The appropriate localization of gastrinoma is still difficult. We aimed to evaluate the diagnostic accuracy of selective arterial calcium injection (SACI) for localization of gastrinomas including multiple lesions. This retrospective study included ten patients with surgically proven gastrinomas (gastrinoma group) and six patients without any findings suggesting Zollinger-Ellison syndrome (non-gastrinoma group). For SACI, calcium gluconate was injected into the arteries supplying pancreas, duodenum, and liver. Blood samples from the hepatic vein were obtained before and 30, 60, and 120 seconds after each injection. The results were considered positive when the increase in serum immunoreactive gastrin (IRG) levels within 60 seconds of calcium gluconate injection were more than 80 pg/mL and more than 20% from baseline. We evaluated the efficacy of SACI by comparing the SACI responses with definitive locations diagnosed by clinical and histopathological findings. In the gastrinoma group, false-positive responses were confirmed in seven of the ten patients. False-negative response was observed in one of the feeding arteries of one patient with gastrinomas in multiple locations. Conversely, the greatest increase in serum gastrin levels from baseline at 30 seconds indicated the true-positive responses in all patients with gastrinomas. In the non-gastrinoma group, calcium gluconate injection into gastroduodenal artery evoked positive responses in five of the six patients. In conclusion, our data suggest the strongest gastrin response evoked by SACI indicates the definitive location in patients with gastrinomas. In contrast, SACI could not accurately locate multiple gastrin-secreting lesions due to poor specificity.
Autoimmune thyroid disease (AITD) is characterized by a loss of self-tolerance to thyroid antigen. Tregs, whose proportions are controversial among CD4+ T cell from AITD patients (AITDs), are crucial in immune tolerance. Considering that drugs might affect Treg levels, we assumed that the differences originated from different treatment statuses. Thus, we performed a meta-analysis to explore proportions of Tregs in untreated and treated AITDs. PubMed, Embase and ISI Web of Knowledge were searched for relevant studies. Review Manager 5.3 and Stata 14.0 were used to conduct the meta-analysis. Subgroup analysis based on different diseases and cell surface markers was performed. Egger linear regression analysis was used to assess publication bias. Approximately 1,100 AITDs and healthy controls (HCs) from fourteen studies were included. Proportions of Tregs among CD4+ T cells of untreated AITDs were significantly lower than those in HCs (p = 0.002), but were not in treated patients (p = 0.40). Subgroup analysis revealed lower proportions of Tregs in untreated Graves’ disease patients (GDs) (p = 0.001) but did not show obvious differences in untreated Hashimoto’s thyroiditis patients (HTs) (p = 0.62). Furthermore, proportions of circulating FoxP3+ Tregs were reduced in untreated GDs (p < 0.00001) and HTs (p = 0.04). No publication bias was found. In this first meta-analysis exploring proportions of circulating Tregs among CD4+ T cells of AITDs with different treatment statuses, we found that Tregs potentially contribute to the pathogenesis of AITD but function differently in GD and HT. Remarkably, FoxP3+ Tregs, which were decreased in both diseases, might be promising targets for novel therapies.
In adrenal venous sampling (AVS) for patients with primary aldosteronism (PA), adrenocorticotropic hormone (ACTH) stimulation generally increased the success rate. The effect of ACTH stimulation on the left-right differences of laterality diagnosis in AVS remains unclear. A total of 167 patients with PA underwent successful AVS were examined. Patients with autonomous cortisol secretion were excluded. The proportion of dominant side in AVS was compared before and after ACTH stimulation. Unilateral disease on AVS was defined as a lateralization index of more than 4, both before and after ACTH stimulation. Before ACTH stimulation, unilateral disease was more frequently observed on the right side than the left side (right 33.5% vs. left 13.8%, p < 0.01). After ACTH stimulation, unilateral disease was more frequently observed on the left side than the right side, without statistical significance (left 15.6% vs. right 10.8%, p = 0.20). Among the 56 patients who had right unilateral disease before ACTH stimulation, 17 patients (30.0%) also had right unilateral disease after ACTH stimulation. The affected side of AVS was changed from right unilateral to bilateral after ACTH stimulation in 34 (60.7%) out of 56 patients. These patients had milder PA and CT scans showed no nodular lesions on the right side. In AVS, ACTH stimulation not only decreased unilateral results but also shifted to the dominant side. Overestimation should be carefully considered when the surgical indication for the right adrenal gland was decided based on AVS results without ACTH stimulation.
Carbohydrate response element binding protein (ChREBP), a glucose responsive transcription factor, mainly regulates expression of genes involved in glucose metabolism and lipogenesis. Recently, ChREBP is speculated to be involved in the onset and progression of diabetic nephropathy (DN). However, there exists no report regarding the localization and function of ChREBP in the kidney. Therefore, we analyzed the localization of Chrebp mRNA expression in the wild type (WT) mice kidney using laser microdissection method, and observed its dominant expression in the proximal tubules. In diabetic mice, mRNA expression of Chrebp target genes in the proximal tubules, including Chrebpβ and thioredoxin-interacting protein (Txnip), significantly increased comparing with that of WT mice. Co-overexpression of ChREBP and its partner Mlx, in the absence of glucose, also increased TXNIP mRNA expression as well as high glucose in human proximal tubular epithelial cell line HK-2. Since TXNIP is well known to be involved in the production of reactive oxygen species (ROS), we next examined the effect of ChREBP/Mlx co-overexpression, in the absence of glucose, on ROS production in HK-2 cells. Interestingly, ChREBP/Mlx co-overexpression also induced ROS production significantly as well as high glucose. Moreover, both high glucose-induced increase of TXNIP mRNA expression and ROS production were abrogated by ChREBP small interfering RNA transfection. Taken together, high glucose-activated ChREBP in the renal proximal tubules induce the expression of TXNIP mRNA, resulting in the production of ROS which may cause renal tubular damage. It is therefore speculated that ChREBP is involved in the onset and progression of DN.
Graves’ ophthalmopathy (GO) is characterized by an autoimmune reaction against thyrotropin (TSH) receptors and is diagnosed by TSH receptor antibody (TRAb). A novel assay for thyroid-stimulating antibody (TSAb) was recently introduced using a frozen Chinese hamster ovary cell line expressing TSH receptors, cyclic adenosine monophosphate (cAMP)-gated calcium channel, and aequorin (aequorin TSAb). The aim of this study was to evaluate the role of aequorin TSAb in GO. We studied 136 Japanese patients with GO (22 euthyroid and 8 hypothyroid GO patients) at our hospital. TRAbs were estimated by first generation TRAb (TRAb 1st), second generation TRAb (hTRAb 2nd), conventional porcine TSAb, and the new aequorin TSAb assays. Aequorin TSAb, porcine TSAb, TRAb 1st, and hTRAb 2nd were positive in 125/136 (92%), 110/136 (81%), 81/130 (62%), and 93/114 (82%) patients, respectively. In patients with hyperthyroid GO, they were positive in 98/106 (98%), 96/106 (91%), 78/101 (77%), and 84/93 (90%) patients, respectively. In patients with euthyroid GO, they were positive in 19/22 (86%), 9/22 (41%), 1/21 (5%), and 6/17 (35%) patients, respectively. Aequorin TSAb levels were significantly related to TRAb 1st (r = 0.4172, p < 0.0001), hTRAb 2nd (r = 0.2592, p < 0.0001), and porcine TSAb (r = 0.4665, p < 0.0001). Clinical activity score (CAS) was significantly greater in patients with high titers of aequorin TSAb than in those with low titers. Aequorin TSAb levels were significantly related to the signal intensity ratio of the enlarged eye muscle and proptosis evaluated by MRI before steroid pulse therapy. Aequorin TSAb assay was more sensitive than the conventional assays, especially in euthyroid GO.
McCune–Albright syndrome (MAS) is a rare disorder. MAS is classically defined by the occurrence of fibrous dysplasia, café-au-lait skin macules, and precocious puberty. In addition to precocious puberty, other hyperfunctioning endocrinopathies may occur. We evaluated hypothalamic–pituitary–adrenal function in two cases of typical MAS associated with fibrous dysplasia and growth hormone excess. Pituitary adenoma or hyperplasia was not detected by magnetic resonance imaging. Hormonal data showed normal or low cortisol levels, despite high ACTH levels in the blood. A high ratio of circulating ACTH to cortisol was found in the two cases. Insulin tolerance and CRH tests showed hyper-responses of ACTH and an insufficient increase in cortisol levels. No involvement of 11β-HSD1 by GH excess was suggested because basal levels of ACTH and cortisol showed no changes, even after therapy for acromegaly by somatostatin analogues. Patients with Cushing’s disease cases of pituitary macroadenoma can have high circulating ACTH precursor levels, and elevated ACTH precursors have been observed in ectopic ACTH syndrome. Autonomous cortisol excess was excluded by the level of midnight cortisol and the level of cortisol after a low-dose dexamethasone suppression test in the two cases. Finally, the gel filtration profiles of immunoreactive ACTH contents showed the presence of aberrant ACTH precursors. To the best of our knowledge, there have been no reports of MAS associated with aberrant ACTH precursors. Our findings in these cases emphasize that attention should be to secretion of inactive ACTH precursors in MAS.
The accuracy of factory-calibrated continuous glucose monitoring (fCGM) within hypoglycemic ranges, especially under the status of chronic hyperinsulinemic hypoglycemia like insulinomas, remains an issue. Even so, fCGM is known to be useful for detecting hypoglycemia unawareness in insulinoma cases. A 25-year-old woman presenting with sudden unconsciousness was diagnosed with insulinoma; fCGM facilitated diagnosis by continuous monitoring for hypoglycemia. Before surgery, she was treated with continuous and frequent bolus infusions of 50% glucose via central venous catheter. To evaluate the accuracy of fCGM values in this case, a comparison between fCGM and capillary blood glucose (CBG) values was also performed. According to the simultaneously measured values, those of fCGM were largely in accordance with those of CBG. Moreover, compared with the previously reported case not having glucose infusions via central venous catheter, both the mean absolute relative differences (MARDs) and the absolute differences (Δ glucose) between fCGM and CBG values were larger in the present case, although no significant differences of MARDs and Δ glucose between the two cases were observed in several different conditions including fasting, post-meal, hypoglycemia, and others. Therefore, we should note possible increased differences between fCGM and CBG values in cases using frequent intravenous glucose infusions as well as case-dependent differing levels of consistency between them.
Continuous subcutaneous insulin infusion (CSII) therapy using insulin pumps has become widely used in the treatment of type 1 diabetes mellitus (T1DM). This retrospective study aimed to assess the efficacy and safety of long-term insulin pump treatment in patients with T1DM aged ≥50 years. The study included patients aged ≥50 years, who had a diagnosis of T1DM based on clinical criteria and/or presence of autoantibodies characteristic of autoimmune diabetes, and had received ≥5 years of recent and uninterrupted treatment with a personal insulin pump. We analyzed records on HbA1c levels across the entire observation period. The cohort comprised 17 patients, of whom 6 (35%) were men and 11 (65%) were women. The mean duration of observation was 6.6 years, during which patients had a mean of 8.4 HbA1c measurements. Mean HbA1c level over the entire observation period was 6.7% (range, 5.3–7.4%). Overall, 11 patients (65%) had mean HbA1c levels at the ADA-recommended target of <7% and 5 patients (29%) had mean HbA1c <6.5%. Mean HbA1c level was significantly lower at the end of the observation period than at the start (6.52% versus 6.91%; difference, –0.39%; p < 0.01), indicating an improvement in glycaemic control over time. On average, patients experienced one level 1 hypoglycaemia episode every 2.4 days. This retrospective analysis of at least 5 years of follow-up of selected patients with T1DM aged ≥50 years at the start of observation, showed that CSII is a safe and effective treatment option in this age group.