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Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus131 I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients. [ABSTRACT FROM AUTHOR]

The prognostic stratification of the current AJCC/UICC TNM classification for adrenocortical carcinoma (ACC) has been validated in only a few studies. In this study, it was hypothesized that redefining the T category cut-off would result in a significant improvement in estimated stage-related survival. In 935 patients with ACC from the SEER database, optimal cut-off values based on tumor size were first determined to redefine T1 and T2 categories. Cox proportional hazards regression analysis and receiver operating characteristics (ROC) were then used to determine the prognostic value of the revised version. A new cut-off value of 9.5 cm tumor size was established to differentiate between T1 and T2 tumors, leading to a revised TNM classification. As a result, a more homogeneous distribution of patients with ACC across all stages was observed. Notably, the predictive value of the newly proposed TNM classification in the ROC analysis exceeded that of the 7th and 8th editions of the AJCC/UICC classification system. Finally, the prognostic superiority of the revised TNM classification was confirmed in a multivariate Cox proportional hazards regression model. In conclusion, the present study demonstrates that updating the current staging system with revised T1 and T2 categories significantly improves the prediction of cancer-specific survival (CSS) in patients with ACC. [ABSTRACT FROM AUTHOR]

One feature of papillary thyroid cancer (PTC) is the frequently present somatic BRAFV600E mutation. PTCs are also characterized by a lymphocytic infiltration, which may correlate with an improved clinical outcome. The objective of the study was the characterization of BRAFV600E specific anti-immunity in PTC patients and correlation analyses with the clinical outcome. Fourteen HLA A2 positive PTC patients were included into the study of whom tumor tissue samples were also available. Of those, 8 PTC patients revealed a somatic BRAFV600E mutation. All PTC patients were also MHC class II typed. Tetramer analyses for detection of MHC class I and MHC class II-restricted, BRAFV600E epitope-specific T cells using unstimulated and peptide-stimulated T cells were performed; correlation analyses between MHC phenotypes, T cell immunity, and the clinical course were performed. In regard to unstimulated T cells, a significantly higher amount of BRAFV600E epitope specific T cells was detected compared to a control tetramer. Importantly, after overnight peptide stimulation a significantly higher number of BRAFV600E positive and BRAF WT epitope-specific T cells could be seen. In regard to the clinical course, however, no significant differences were seen, neither in the context of the initial tumor size, nor in the context of lymph node metastases or peripheral metastastic spread. In conclusion, we clearly demonstrated a BRAF-specific tumor immunity in PTC-patients which is, however, independent of a BRAFV600E status of the PTC patients. [ABSTRACT FROM AUTHOR]

The majority of incidentally discovered adrenal tumors are later characterized as non-producing adrenocortical adenomas (NPA). We asked whether laboratory abnormalities in parameters that reflect glucocorticoid action can be found in patients with NPA despite their nature of being clinically unapparent. Since glucocorticoids are potent immunosuppressants we studied blood counts and differential blood counts along with corticotropin and dehydroepiandrostenedione sulfate (DHEAS) blood concentrations, as well as cortisol values before and after an overnight 1 mg dexamethasone suppression test. We compared the results of normal individuals, of patients with adrenal adenomas and normal hormone profiles and with subclinical autonomous glucocorticoid hypersecretion, as well as overt cortisol excess. We found that almost all indices of the blood counts were significantly different between the patients groups. In particular, patients with adrenal non-producing adenomas already showed signs of glucocorticoid excess, including relative lymphocytopenia, lowered DHEAS, and ACTH concentrations than control individuals. We also found that the extent of lymphocytopenia correlated with the concentrations of DHEAS and ACTH, and DHEAS correlated well with ACTH. We conclude that the basal ACTH and DHEAS values along with the differential blood counts give good information on the extent of glucocorticoid excess and that silent adrenal adenomas seem to oversecrete glucocorticoids at concentrations that already alter these parameters. [ABSTRACT FROM AUTHOR]

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue. [ABSTRACT FROM AUTHOR]

A rapid and fully automated chemiluminescent immunoassay for the detection of thyrotropin receptor autoantibodies (TSHR-Ab) based on a bridge technology was compared with two bioassays that measure either stimulating (TSAb) or blocking (TBAb) antibodies for the detection and differentiation of TSHR-Ab. A total of 229 patients with various thyroid disorders [151 with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 32 with nodular goiter, and 11 with thyroid cancer] were included. The bridge immunoassay was performed according to the manufacturer's instructions (cut-off>0.55 IU/l). TSAb and TBAb were measured with reporter bioassays. Blocking activity was defined as percent inhibition of luciferase expression relative to induction with bovine TSH alone (cut-off>34% inhibition). TSAb was reported as percentage of specimen-to-reference ratio (> 140 SRR%). The 3 TSHR-Ab assays were negative in all patients with benign euthyroid nodular goiter and differentiated thyroid cancer. In contrast, in all patients with GD, irrespective of the disease duration, TSHR-Ab positivity was present in 127 of 151 (84%) and 140 (93%) for the bridge assay and TSAb bioassay, respectively (p<0.001). Fifteen of 151 (10%) GD samples were positive in the TSAb bioassay but negative in the bridge assay. The bridge assay and the TSAb bioassay correlated positively (r=0.39, p<0.0001) in patients with GD. Both assays detected TSHR-Ab in all ten untreated hyperthyroid patients with GD. In GD patients with a duration of less than six months, 27/29 (93%) and 28 (97%) were TSHR-Ab positive with the bridge and TSAb bioassay, respectively. In comparison, TSHR-Ab were present in two of 35 (6%) and five (14%) HT patients with the bridge and TSAb bio-assay, respectively. TSHR blocking antibodies were present in one (3%) patient with HT and in two (1%) patients with GD; these two GD patients were also bridge assay positive but TSAb bioassay negative. In conclusion, the bridge immunoassay and both bioassays are highly sensitive for the detection of TSHR-Ab. The bridge assay is, however, also positive in the presence of TSHR blocking antibodies detected in a TBAb bioassay. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcers are a severe complication in patients with diabetes mellitus. Vitamin D is associated with impaired β-cell function and insulin resistance, and is necessary for wound healing and bone metabolism. We measured the serum concentrations of 25-hydroxyvitamin D3 in 104 patients (63 inpatients, 41 outpatients) with diabetic foot ulcers and compared them to 99 healthy humans (control) and 103 patients with diabetes mellitus type 2 without diabetic foot ulcers. Calcium, creatinine, and parathyroid hormone were measured in patients with diabetic foot ulcers. The data were analysed together with glycosylated hemoglobin A1c and the severity of diabetic foot lesions according to the Armstrong classification. Levels of 25-hydroxyvitamin D3 were lower (11.8 ± 11.3 ng/ml, p < 0.001) in patients with diabetic foot ulcers (mean age 70 ± 12 years) than in the control group (27.2 ± 12.2 ng/ml). No difference was found between in- and outpatients. Fifty-eight (55.8%) of patients with diabetic foot ulcers had a severe 25-hydroxyvitamin D3 deficiency with levels below 10 ng/ml. Only 12% of the patients had 25-hydroxyvitamin D3 levels above 20 ng/ml. Secondary hyperparathyroidism was found in 27.9% of patients and 11.5% of the patients were hypocalcemic. There was a negative correlation (r = -0.241) (p < 00.1) between Armstrong classification and 25-hydroxyvitamin D3 status. In conclusion, patients with diabetic foot syndrome are at high risk of 25-hydroxyvitamin D3 deficiency. Thus, any patient with diabetic foot syndrome should undergo 25-hydroxyvitamin D3 measurement and supplementation, if values are found to be decreased. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) have been shown to be a valuable prognostic marker for different solid cancers. Within the present study we quantified CTCs in thyroid cancer (TC) patients. Special focus was given to disease-free PTC patients with undetectable serum thyroglobulin (Tg) levels. Altogether, 67 TC patients (33 papillary, 20 follicular, 14 medullary) were included in the study. CTC numbers, which were normalized to 3.3 × 105 peripheral blood mononuclear cells, were correlated with clinical outcome. TC patients had significantly higher CTC numbers compared to controls. The number of CTCs correlated to the initial tumor stage. Importantly, in comparison to controls, differentiated TC patients with serum Tg levels < 0.3 ng/ml (no evidence of tumor recurrence) revealed a significantly higher amount of CTCs, also associated to their former tumor stage. Regarding the tumor-free papillary TC (PTC) patients the number of CTCs additionally correlated to the time point of radioiodine (RI) therapy: PTC patients with RI therapies > 8 years before CTC measurement had significantly higher CTC numbers compared to those with RI therapy < 8 years ago. We found a clear correlation between the number of CTCs and the tumor stage. Importantly, PTC patients who are in remission may still have increased numbers of CTCs. Follow- up analyses in these patients will reveal whether these data will have a clinical impact. [ABSTRACT FROM AUTHOR]

Calcitonin (CT), a tumor marker for medullary thyroid cancer (MTC), can be stimulated with pentagastrin or calcium. Because of the unavailability of pentagastrin, basal CT measurement is frequently used for the preoperative diagnosis of MTC. The aim of the study was to define basal serum calcitonin (bCT) cut-off thresholds for diagnosing MTC. Within a retrospective analysis, 114 patients (51 males) were included fulfilling the criteria of an increased preoperative bCT level (> 10 pg/ml) and the criteria of an available postoperative histology analysis. Based on a ROC plot analysis, the cut-off values for the diagnosis of MTC vs. non-malignancy (C cell hyperplasia and goiter) were identified. The most precise bCT thresholds for the identification of MTC were = 46 pg/ml for males (sensitivity: 93.6 %, specificity: 95.0 %, PPV: 97 %, NPV: 90 %) and = 35 pg/ml for females (sensitivity: 87.3 %, specificity: 87.5 %, PPV: 98 %, NPV: 50 %). Using these cut-offs, only 6 % of male patients were not identified of having MTC, whereas 5 % were false positive (having instead C cell hyperplasia). In females, the discrepancy was higher since 13 % of female MTC patients were false negative by using the cut-off of = 35 pg/ml, and 13 % had false positive results (suffering from C cell hyperplasia). Gender-specific bCT cut-offs for the identification of MTC vs. C cell hyperplasia and non-malignancy were defined, which can be used in clinical routine. In female patients, however, the accuracy is much lower compared to males. [ABSTRACT FROM AUTHOR]

Dear Editor, Drs. Kiaei and Molinaro 1 put forth two criticisms of the manuscript published by us 2. They state that the experimental design of this study is flawed and that the authors falsely claim that negative Thyretain™ TSI Reporter BioAssay results for two Graves' diseases patients undergoing drug treatments means the absence of stimulating antibodies. To substantiate this claim Drs. Kiaei and Molinaro point out that the manufacturer of the Thyretain TSI Reporter BioAssay clearly states in the package insert that "[t]he effects of various drug therapies on the performance of this Kit have not been established" 1. Second, the package insert explicitly states that "[a] negative result does not exclude the possibility of the presence of TSI" and results of the test should be interpreted in conjunction with information available from other clinical information, such as physical symptoms and thyroid hormone testing, as recommended by the American Thyroid Association (ATA)". Furthermore they state that the "authors of the manuscript did not consider the manufacturer's warning regarding the intended patient population and the ATA guidelines regarding the interpretation of the test results in conjunction with other clinical information. Instead, the authors based their conclusions on the negative Thyretain TSI Reporter BioAssay results and ignored the patients' clinical history of Graves' disease." [ABSTRACT FROM AUTHOR]