Systematic review and meta-analysis of observational studies on BD-IPMNS progression to malignancy.

BACKGROUND: The vast majority of presumed branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are referred to a surveillance program due to the relatively low risk of malignancy. We aim to evaluate all available data from observational studies focused on the risks of BD-IPMN progression and malignancy to provide vital insights into its management in clinical practice. METHODS: A comprehensive search was conducted at PubMed, Cochrane, Web of Science and Embase for observational studies published before January 1st, 2020. The progression of BD-IPMN was defined as the development of worrisome features (WFs) or high-risk stigmata (HRS) during surveillance. Overall malignancy was defined as all malignancies, such as malignant IPMN, concomitant pancreatic ductal adenocarcinoma (PDAC) and other malignancies, including BD-IPMN with high-grade sec. Baltimore consensus 2015 or BD-IPMN with high-grade dysplasia (carcinoma in situ) sec. WHO 2010. A meta-analysis was performed to investigate the presence of a mural nodule as a possible predictor of malignancy. RESULTS: Twenty-four studies were included, with a total of 8941 patients with a presumed BD-IPMN. The progression rate was 20.2%, and 11.8% underwent surgery, 29.5% of whom showed malignancy at the final pathology. Of those, 78% had malignant IPMNs, and 22% had concomitant pancreatic cancer. Overall, 0.5% had distant metastasis. The meta-analysis showed that the risk of malignancy in the presence of a mural nodule >5 mm had a RR of 5.457 (95% CI 1.404-21.353), while a nonenhancing mural nodule or an enhancing mural nodule < 5 mm had a RR of 5.286 (95% CI 1.805-15.481) of harboring malignancy. CONCLUSION: Most presumed BD-IPMNs entering surveillance do not become malignant. Of those submitted to surgery, concomitant PDAC adds to the overall risk of detecting malignancy.

Serum PSA levels are not affected by the menstrual cycle or the menopause, but are increased in subjects with polycystic ovary syndrome.

BACKGROUND/AIMS: Prostatic specific antigen (PSA) is the most specific prostatic tumor marker in man. Recently, PSA has been detected in a variety of tissues and fluids in women, and its determination suggested as a marker of hyperandrogenism. However, precise information about the physiology of PSA in females is not available. The goal of this study was to assess serum concentrations of PSA in healthy pre-menopausal women (healthy pre-menopausal group), menopausal women (menopause group) and patients with polycystic ovary syndrome (PCOS group). METHODS: PSA, androgens, LH, FSH, 17-beta-estradiol (E2), progesterone (Pg) were assessed in 40 post-menopausal women, 35 fertile controls and 35 women with PCOS. RESULTS: No significant difference in PSA concentrations could be demonstrated in different phases of the menstrual cycle in healthy pre-menopausal group and between pre- and post-menopausal groups. No correlations could be demonstrated between serum PSA levels and the following parameters: age, body mass index (BMI), LH, FSH, E2, testosterone (T), DHEAS, and SHBG, both in pre- and post-menopausal women. Significantly higher PSA levels (median=14 pg/ml) were found in the PCOS group compared to both pre-menopausal (median=5 pg/ml) and menopausal (median= 5 pg/ml) groups (p< 0.05). CONCLUSIONS: only minor fluctuations of serum PSA concentrations are observed in healthy pre- and post-menopausal women, while serum level is higher in PCOS, and therefore PSA can be considered a suitable marker of female hyperandrogenism.

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level.

OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

Thyroid vascularity and blood flow are not dependent on serum thyroid hormone levels: studies in vivo by color flow doppler sonography.

OBJECTIVE: Thyroid blood flow is greatly enhanced in untreated Graves' disease, but it is not known whether it is due to thyroid hormone excess or to thyroid hyperstimulation by TSH-receptor antibody. To address this issue in vivo patients with different thyroid disorders were submitted to color flow doppler sonography (CFDS). SUBJECTS AND METHODS: We investigated 24 normal subjects, and 78 patients with untreated hyperthyroidism (49 with Graves' hyperthyroidism, 24 with toxic adenoma, and 5 patients with TSH-secreting pituitary adenoma (TSHoma)), 19 patients with thyrotoxicosis (7 with thyrotoxicosis factitia, and 12 with subacute thyroiditis), 37 euthyroid patients with goitrous Hashimoto's thyroiditis, and 21 untreated hypothyroid patients with Hashimoto's thyroiditis. RESULTS: Normal subjects had CFDS pattern 0 (absent or minimal intraparenchimal spots) and mean intraparenchimal peak systolic velocity (PSV) of 4.8+/-1.2cm/s. Patients with spontaneous hyperthyroidism due to Graves' disease, TSHoma, and toxic adenoma had significantly increased PSV (P<0.0001, P=0.0004, P<0.0001 respectively vs controls) and CFDS pattern. Patients with Graves' disease had CFDS pattern II (mild increase of color flow doppler signal) in 10 (20%) and pattern III (marked increase) in 39 cases (80%). Mean PSV was 15+/-3cm/s. Patients with toxic adenoma had CFDS pattern I (presence of parenchymal blood flow with patchy uneven distribution) in 2 (8%), pattern II in 16 (70%) and pattern III in 5 (22%). Mean PSV was 11+/-2.4cm/s. Patients with TSHoma showed CFDS pattern I in one case (20%) and pattern II in 4 (80%). Mean PSV was 14.8+/-4.2cm/s. Patients with thyrotoxicosis had normal PSV (4.2+/-1. 1cm/s in subacute thyroiditis, 4+/-0.8cm/s in thyrotoxicosis factitia, P=not significant vs controls) and CFDS pattern 0. Untreated euthyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern 0, and mean PSV (4.3+/-0.9cm/s; P=not significant vs controls). Untreated hypothyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern I in 14 cases (67%), pattern II in 4 (19%) and pattern 0 in 3 (14%) and mean PSV (5.6+/-1. 4cm/s) was higher than that of controls (P=0.026). CONCLUSIONS: An increase in both intrathyroidal vascularity and blood velocity was observed in patients with spontaneous hyperthyroidism but not in thyrotoxicosis due to either ingestion of thyroid hormones or to a thyroidal destructive process. The slightly increased vascularity and blood velocity observed in patients with hypothyroid Hashimoto's thyroiditis suggests that thyroid stimulation by either TSH-receptor antibody or TSH is responsible for the increased thyroid blood flow.

Comparison of radioiodine with radioiodine plus lithium in the treatment of Graves' hyperthyroidism.

Effectiveness of radioiodine for Graves' hyperthyroidism depends also on its intrathyroidal persistence. The latter is enhanced by lithium by blocking iodine release from the thyroid. One hundred ten patients with Graves' hyperthyroidism were randomly assigned to treatment with radioiodine or radioiodine plus lithium, stratified according to goiter size (< or =40 or >40 mL) and evaluated for changes in thyroid function and goiter size, at monthly intervals, for 12 months. Cure of hyperthyroidism occurred in 33 of 46 patients (72%) treated with radioiodine and in 45 of 54 patients (83%) treated with radioiodine plus lithium. The probability of curing hyperthyroidism was higher and its control prompter (P = 0.02) in the radioiodine-plus-lithium group. Patients with < or =40-mL goiters had similar persistence of hyperthyroidism (13%), but lithium-treated patients had hyperthyroidism controlled earlier (P = 0.04). Among patients with >40-mL goiters, hyperthyroidism was cured in 6 of 15 patients (40%) treated with radioiodine alone and in 12 of 16 patients (75%) treated with radioiodine plus lithium (P = 0.07), and cure occurred earlier in the latter (P = 0.05). Goiters shrank in both groups (P < 0.0001), more effectively and promptly (P < 0.0005) in the radioiodine-plus-lithium group. Serum free T4 and T3 levels increased shortly after therapy only in the radioiodine group (P < 0.01). Lithium carbonate enhances the effectiveness of radioiodine therapy, in terms of prompter control of hyperthyroidism, in patients with small or large goiters. In the latter group, lithium also increases the rate of permanent control of hyperthyroidism.

L-thyroxine directly affects expression of thyroid hormone-sensitive genes: regulatory effect of RXRbeta.

L-thyroxine (T4) has been considered mainly a prohormone, the hormonal action of which is related to its conversion to 3,5,3'-triiodothyronine (T3) in peripheral tissues. In this study we investigated in transient transfection assays whether T4 might directly affect the expression of thyroid hormone (TH) sensitive genes. The reporter construct ME-TRE-TK-CAT or TSH-TRE-TK-CAT containing the nucleotide sequence of the TH response element (TRE) of either malic enzyme (ME) or TSHbeta genes, was transfected with either TH receptor (TR) alpha alone or in combination with retinoid X receptor (RXR) beta into NIH3T3 cells. Addition of 100 nM T4 to the culture medium in the presence of TRalpha increased the basal level of ME-TRE-TK-CAT expression by 4.5-fold. T4 action was due to a direct interaction with TRalpha and not to its conversion to T3, since T4 effect persisted in the presence of 5'-deiodinase inhibitors (propylthiouracil, iopanoic acid) effectively preventing T3 generation, as assessed by the absence of T3 by HPLC in the cellular extracts of transfected cells. In a dose-response study half-maximal stimulation by T4 was achieved at a concentration of 100 nM, whereas 50% of maximal induction was produced by 1 nM T3 and 6 nM triiodothyroacetic acid (TRIAC). Coexpression of RXRbeta greatly enhanced the transcriptional activity of the ME-TRE-TK-CAT gene when either T3, T4 or TRIAC was added to the culture medium of NIH3T3 cells, but established a hormonal hierarchy in the reporter activation different than that observed in the presence of TRalpha alone (TRIAC > T3 > or = T4, instead of T3 > TRIAC > T4). T4 at a concentration of 100 nM could activate the TH/TR-dependent down-regulation mediated by the negative TSH-TRE, although at a lower level than that obtained with similar concentrations of T3 (35 and 55% inhibition, respectively). Our results demonstrate that, in addition to the action mediated through its monodeiodination to T3, T4 exerts a direct effect on genes that are either positively or negatively regulated by TH. Moreover, RXRbeta, forming heterodimers with TRs, appeared to exert a central role in modulating the sensitivity of TH-responsive genes to different iodothyronines.

Color flow Doppler sonography rapidly differentiates type I and type II amiodarone-induced thyrotoxicosis.

Amiodarone-induced thyrotoxicosis (AIT) occurs both in abnormal thyroid glands (nodular goiter, latent Graves' disease) (type I AIT) or in apparently normal thyroid glands (type II AIT). Differentiation of the two forms is crucial, because type I AIT responds well to methimazole and potassium perchlorate combined treatment, whereas type II AIT is effectively managed by glucocorticoids. Differential diagnosis is often difficult, although thyroid radioactive iodine uptake is usually low-to-normal in type I and low-suppressed in type II, and serum interleukin-6 levels are normal/slightly elevated in type I, markedly elevated in type II. Color flow Doppler sonography (CFDS) is a technique that shows intrathyroidal blood flow and provides real-time information on thyroid morphology and hyperfunction. To investigate the usefulness of CFDS in differentiating the two types of AIT, 27 consecutive AIT patients, 11 type I and 16 type II, were evaluated by CFDS before starting antithyroid treatment. Gender, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar in the two groups. All type II AIT patients had a CFDS pattern 0 (ie, absent vascularity), in agreement with the pathogenesis of the disease, due to thyroid damage. Likewise, nine patients with subacute thyroiditis, another destructive process of the thyroid gland, also had a CFDS pattern 0. Eleven patients with type I AIT had a CFDS pattern ranging from pattern I (presence of parenchymal blood flow with patchy uneven distribution) (7 patients, 64%) to pattern II (ie, mild increase of color flow Doppler signal with patchy distribution) (1 patient, 9%) and pattern III (markedly increased color flow Doppler signal with diffuse homogeneous distribution)(3 patients, 27%), similar to that found in patients with untreated Graves' disease patients, thus indicating a hyper-functioning gland. Control subjects and euthyroid patients under long-term amiodarone treatment had absent thyroid hypervascularity and a CFDS pattern 0. These findings demonstrate that CFDS distinguishes type I and II AIT. Because of its rapidity and noninvasive features, CFDS represents a valuable tool for a quick differentiation between the two types of AIT. This can avoid any delay in initiating the appropriate treatment for a rapid control of thyrotoxicosis in patients whose tachyarrhythmias or other cardiac disorders make thyroid hormone excess extremely deleterious.

Treatment of amiodarone-induced thyrotoxicosis, a difficult challenge: results of a prospective study.

Amiodarone-induced thyrotoxicosis (AIT) occurs in both abnormal (type I) and apparently normal (type II) thyroid glands due to iodine-induced excessive thyroid hormone synthesis in patients with nodular goiter or latent Graves' disease (type I) or to a thyroid-destructive process caused by amiodarone or iodine (type II). Twenty-four consecutive AIT patients, 12 type I and 12 type II, were evaluated prospectively. Sex, age, severity of thyrotoxicosis, and cumulative amiodarone dose were similar. Type II patients had higher serum interleukin-6 (IL-6; median, 440 vs. 173 fmol/L; P < 0.001), but lower serum thyroglobulin levels. Several weeks of thionamide therapy in eight type II or prolonged glucocorticoid administration in two type I patients had previously failed to control hyperthyroidism. Type II patients were given prednisone (initial dose, 40 mg/day) for 3 months and achieved normal free T3 and IL-6 after an average of 8 and 6 days, respectively. Exacerbation of thyrotoxicosis with increased serum IL-6 values, observed in 4 patients while tapering steroid, was promptly corrected by increasing it. Type I patients, given methimazole (30 mg/day) and potassium perchlorate (1 g/day), achieved normal free T3 and IL-6 concentrations after an average of 4 weeks. Exacerbation of thyrotoxicosis with markedly increased IL-6 was controlled by prednisone in 3 of 4 cases. Distinction of different forms of AIT is essential for its successful management. Type II AIT should be treated with glucocorticoids; type I AIT should be treated with methimazole and potassium perchlorate. Exacerbation of thyrotoxicosis, which may occur in both forms and is probably related to destructive processes, should be controlled by the addition/increase in glucocorticoids.

Measurement of serum free thyroid hormone concentrations: an essential tool for the diagnosis of thyroid dysfunction.

Free thyroid hormones (free thyroxine, FT4, and free triiodothyronine, FT3) represent a more useful index of thyroid status than total thyroid hormones, because the latter are influenced by variations of thyroid hormone-binding proteins, especially T4-binding globulin (TBG). Thus, increased serum total T4 (TT4) and, in many instances, T3 (TT3) concentrations are encountered in euthyroid subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia and transthyretin-associated hyperthyroxinemia, while decreased serum TT4 and TT3 levels are associated with TBG deficiency: under these circumstances, measurement of serum FT4 and FT3 levels correctly establishes the diagnosis of euthyroidism. In cases of suspected hyperthyroidism, a diagnostic strategy can be suggested based on serum FT3 (and TSH) measurement, since FT4 may occasionally be elevated, also in euthyroid subjects, e.g., in patients under chronic amiodarone or L-T4 treatment. When hypothyroidism is suspected, the most reliable test appears to be FT4 (together with TSH), because FT3 may still be normal in patients with subclinical or mild thyroid failure. In any case, it is essential that reliable free thyroid hormone assays be used, which are devoid of methodological limitations responsible for artifactual results under particular circumstances, such as thyroid hormone-binding protein abnormalities, pregnancy and nonthyroidal illness.