Effects of radioiodine treatment for differentiated thyroid cancer on testis function.

OBJECTIVE: To evaluate the effects of radioactive iodine (RAI) treatment for differentiated thyroid cancer (DTC) on testis function. DESIGN: A prospective longitudinal single-centre study was performed. A comprehensive andrological evaluation including hormonal assessment, semen analysis and scrotal ultrasound was undertaken in male patients undergoing RAI treatment for DTC. METHODS: Hormonal assessment of FSH, LH, testosterone (T), sperm concentration and motility and testis volume were determined in 20 patients in basal conditions, 6 and 12 months after RAI. Results were analysed in the whole group of patients and then separately in those who received one single ablative treatment ('Single' group, n = 10) and those who received multiple treatments ('Multiple' group, n = 10). RESULTS: In basal conditions, 3 of 20 (15%) patients had a reduced sperm count and belonged to the 'Multiple' group. After RAI, an increase of FSH (8·8 ± 1·2 UI/l vs 5·2 ± 1·2, P < 0·005) and a decrease in sperm concentration (28·8 ± 7·7 millions/ml vs 54·5 ± 7·1, P < 0·005) and testis volume (15·2 ± 3·1 vs 13·7 ± 0·8 ml, P < 0·005) occurred at 6 months in the whole group. One year after RAI, seven patients had oligozoospermia (five from the 'Multiple' group and two from the 'Single' group). Permanent impairment of one or more testis function parameters was observed in patients who underwent multiple RAI treatments: 50% for sperm count, 40% for FSH levels and testis volume and, respectively, in 20 and 10% of those who received one single RAI treatment. CONCLUSIONS: The single ablative RAI treatment in cancer patients is better tolerated respect multiple RAI treatments regard testis function. Multiple treatments for recurrent or metastatic disease may cause a permanent impairment of one or more parameters related to the reproductive potential of male patients.

Differential expression of junctional adhesion molecules in different stages of systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is characterized by early perivascular inflammation, microvascular endothelial cell (MVEC) activation/damage, and defective angiogenesis. Junctional adhesion molecules (JAMs) regulate leukocyte recruitment to sites of inflammation and ischemia-reperfusion injury, vascular permeability, and angiogenesis. This study was undertaken to investigate the possible role of JAMs in SSc pathogenesis. METHODS: JAM-A and JAM-C expression levels in skin biopsy samples from 25 SSc patients and 15 healthy subjects were investigated by immunohistochemistry and Western blotting. Subcellular localization of JAMs in cultured healthy dermal MVECs and SSc MVECs was assessed by confocal microscopy. Serum levels of soluble JAM-A (sJAM-A) and sJAM-C in 64 SSc patients and 32 healthy subjects were examined by enzyme-linked immunosorbent assay. RESULTS: In control skin, constitutive JAM-A expression was observed in MVECs and fibroblasts. In early-stage SSc skin, JAM-A expression was strongly increased in MVECs, fibroblasts, and perivascular inflammatory cells. In late-stage SSc, JAM-A expression was decreased compared with controls. JAM-C was weakly expressed in control and late-stage SSc skin, while it was strongly expressed in MVECs, fibroblasts, and inflammatory cells in early-stage SSc. Surface expression of JAM-A was higher in early-stage SSc MVECs and increased in healthy MVECs stimulated with early-stage SSc sera. JAM-C was cytoplasmic in resting healthy MVECs, while it was recruited to the cell surface upon challenge with early-stage SSc sera. Early-stage SSc MVECs exhibited constitutive surface JAM-C expression. In SSc, increased levels of sJAM-A and sJAM-C correlated with early disease and measures of vascular damage. CONCLUSION: Our findings indicate that JAMs may participate in MVEC activation, inflammatory processes, and impaired angiogenesis in different stages of SSc.

Overexpression of VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, leads to insufficient angiogenesis in patients with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc) is characterized by widespread microangiopathy, fibrosis, and autoimmunity. Despite the lack of angiogenesis, the expression of vascular endothelial growth factor A (VEGF) was shown to be upregulated in SSc skin and circulation; however, previous studies did not distinguish between proangiogenic VEGF(165) and antiangiogenic VEGF(165)b isoforms, which are generated by alternative splicing in the terminal exon of VEGF pre-RNA. OBJECTIVE: We investigated whether VEGF isoform expression could be altered in skin and circulation of patients with SSc. METHODS AND RESULTS: Here, we show that the endogenous antiangiogenic VEGF(165)b splice variant is selectively overexpressed at both the mRNA and protein levels in SSc skin. Elevated VEGF(165)b expression correlated with increased expression of profibrotic transforming growth factor-ß1 and serine/arginine protein 55 splicing factor in keratinocytes, fibroblasts, endothelial cells, and perivascular inflammatory cells. Circulating levels of VEGF(165)b were significantly higher in patients with SSc than in control subjects. Microvascular endothelial cells (MVECs) isolated from SSc skin expressed and released higher levels of VEGF(165)b than healthy MVECs. Transforming growth factor-ß1 upregulated the expression of VEGF(165)b and serine/arginine protein 55 in both SSc and healthy MVECs. In SSc MVECs, VEGF receptor-2 was overexpressed, but its phosphorylation was impaired. Recombinant VEGF(165)b and SSc-MVEC-conditioned medium inhibited VEGF(165)-mediated VEGF receptor-2 phosphorylation and capillary morphogenesis in healthy MVECs. The addition of anti-VEGF(165)b blocking antibodies abrogated the antiangiogenic effect of SSc-MVEC-conditioned medium. Capillary morphogenesis was severely impaired in SSc MVECs and could be ameliorated by treatment with recombinant VEGF(165) and anti-VEGF(165)b blocking antibodies. CONCLUSIONS: In SSc, a switch from proangiogenic to antiangiogenic VEGF isoforms may have a crucial role in the insufficient angiogenic response to chronic ischemia.

Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro.

OBJECTIVE: To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. METHODS: MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor ß (TGFß) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFß(1) and receptors TßRI and TßRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFß(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. RESULTS: In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFß and SDF-1 stimulation upregulated TGFß(1), TßRI and TßRII in SSc-MSCs. TßRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. CONCLUSION: SSc-MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis.

The genetics of systemic sclerosis: an update.

Systemic sclerosis (SSc) is a complex systemic disease characterised by fibrosis of the skin and internal organs, vasculopathy, and activation of the immune system. The complex pathophysiology of SSc implies the potential involvement of 'culprit' genes, either individually or, more likely, together, in driving the disease process. Most of the studies that have provided evidence for the contribution of various genes/loci in SSc pathogenesis are based on a candidate gene approach, on the basis of a shared autoimmune genetic background with other autoimmune diseases, such as systemic lupus erythematosus. In fact, autoimmune genes seem to play a pivotal role in SSc pathogenesis, while less is known about the genetic involvement in vasculopathy and fibrosis. Recently, the availability of genome-wide association studies, which make it possible to screen single-nucleotide polymorphisms across the entire genome without previous knowledge of candidate regions or genes, has yielded a wealth of new genetic susceptibility loci leading to the identification of new pathogenetic mechanisms of complex genetic disorders. In this article, we aim to provide a comprehensive review of recent studies on the genetics of SSc, including genes associated with autoimmunity, fibrosis, and vascular disease. We also discuss the most relevant data obtained in genetic association studies of large populations that included a replication strategy, or studies for which independent replication was available.

Microparticles and Kawasaki disease: a marker of vascular damage?

BACKGROUND: Microparticles (MPs) are increased in diseases characterised by endothelial injury. Kawasaki disease (KD) damages the endothelium provoking life-threatening involvement of coronary arteries. OBJECTIVES: To compare KD MPs vs. controls. METHODS. Thirty KD and 20 controls were enrolled. MPs were stained with monoclonal antibodies against platelets, endothelial cells (EC), monocytes, T and B cells, neutrophils, and quantified by FACS. RESULTS: The total number of MPs was significantly increased in KD versus controls (193x105±0.6x105 vs. 94x105±0.9x105 million/ml plasma p=0.01) and vs. KD after IVIG therapy (132x105±0.4x105million/ml plasma p=0.01). EC and T cells were the major source of MPs in KD (72x105±1x105 vs. 3x105±0.9x105million/ml plasma for T cells p=0.005; 76x105±0.7x105 vs. 45x105±0.4x105 million/ml plasma for EC p<0.02) followed by MPs derived from platelets (13x105±0.3x105 vs. 3x105±0.9x105 million/ml plasma p=0.028). Cell-derived MPs B were 17x105±0.4x105 vs. 20x105±0.8x105million/ml plasma in controls (p=0.7). No significant differences were observed in KD MPs derived from monocytes and neutrophils. After IVIG administration, a significant decrease of MPs derived from platelets (3x105±0.2x105 million/ml plasma p=0.03), EC (9x105±0.4x105 million/ml plasma p=0.01), T cells (72x105±1x105 million/ml plasma p=0.02) and B cells (7x105±0.3x105 million/ml plasma p=0.02) was observed. CONCLUSIONS: The number of KD MPs is significantly increased and EC and T cells are the major source. MPs may develop from endothelial damage and cell activation. Their role as markers of disease activity or as contributors to endothelial derangement in KD has to be further investigated.

Acute effects of two different initial heart rates on testing the repeated sprint ability in elite women soccer players.

BACKGROUND: Repeated sprint ability (RSA) in women's soccer is crucial to ensure high level of performance during the game. The aim of this study is to investigate the acute effects of two different initial heart rates intensities on fatigue when testing the RSA. METHODS: Since there are many kinds of pre-match warming-ups, the heart rate reached at the end of two different warm-up protocols (~90 vs. ≈60% HRmax) as an indicator of internal load has been selected and the respective RSA performances were compared. RSA tests were performed by 19 elite women soccer players (age: 22.5±3.3 years, height 163.9±7.3 cm, body mass 54.3±6.4 kg, BMI 20.6±1.5 kg/m2) with two sets of ten shuttle-sprints (15+15 m) with a 1:3 exercise to rest ratio, in different days (randomized order) with different initial HR% (60% and 90% HRmax). In order to compare the different sprint performances a Fatigue Index (FI%) was computed; the blood lactate concentrations (BLa-) were measured before and after testing, to compare metabolic energy. RESULTS: Significant differences among trials within each set (P<0.01) were found, as evidence of fatigue. Differences between sets were not found, (Factorial ANOVA 2x10; P>0.05). Although the BLa- after warm-up was higher between 90% vs. 60% HRmax (P<0.05), at the completion of RSA tests (after 3 minutes) the differences were considerably low and not significant (P>0.05). CONCLUSIONS: This study shows that, contrary to male soccer, the initial heart rates, induced by different modes of warming-up, do not affect the overall performance while testing RSA in women's soccer players.

Health outcomes of children fathered by patients treated with radioiodine for thyroid cancer.

CONTEXT AND OBJECTIVES: Radiation is known to be mutagenic. The present study analyses birth outcomes and the health of offspring from men previously exposed to (131) I treatment for thyroid carcinoma. METHODS: Data on 493 pregnancies (356 from 173 untreated fathers, 23 from 17 patients who have undergone surgery alone and 114 from 63 fathers who received (131) I) were obtained by interviewing male patients treated for thyroid carcinoma who had not received significant external radiation to the testes. Among these pregnancies, 73 were conceived from fathers who had received more than 370 MBq. RESULTS: The mean activity for the 114 pregnancies fathered by 63 patients was 3993 MBq leading to an estimated radiation dose of 9.2 cGy to the testes (MIRD committee coefficient). No significant differences between untreated and treated fathers were found for any adverse outcome. CONCLUSION: There was no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring, whatever the event considered. As our study is underpowered, the question of whether testicular irradiation, fractionated or not, is linked to impaired fertility or consequences on offspring remains to be established.

Therapeutic administration of 131I for differentiated thyroid cancer: radiation dose to ovaries and outcome of pregnancies.

UNLABELLED: Radiation is known to be mutagenic. The present study updates a 10-y-old study regarding pregnancy outcome and the health of offspring of women previously exposed to radioiodine ((131)I) during thyroid carcinoma treatment, by doubling the number of pregnancies that occurred after exposure. METHODS: Data on 2,673 pregnancies were obtained by interviewing female patients who were treated for thyroid carcinoma but had not received significant external radiation to the ovaries. RESULTS: The incidence of miscarriages was 10% before any treatment for thyroid cancer; this percentage increased after surgery for thyroid cancer, both before (20%) and after (19%) (131)I treatment, with no variation according to the cumulative dose. In contrast to previously reported data, miscarriages were not significantly more frequent in women treated with radioiodine during the year before conception, not even in women who had received more than 370 MBq during that year. The incidences of stillbirths, preterm births, low birth weight, congenital malformations, and death during the first year of life were not significantly different before and after (131)I therapy. The incidences of thyroid and nonthyroid cancers were similar in children born either before or after the mother's exposure to radioiodine. CONCLUSION: There is no evidence that exposure to radioiodine affects the outcomes of subsequent pregnancies and offspring. The question as to whether the incidences of malformations and thyroid and nonthyroid cancers are related to gonadal irradiation remains to be established. The doubling dose is still being heatedly debated, and the value of 1 Gy as the doubling dose in humans should be reevaluated.

Radioactive iodine (131I) effects on male fertility.

PURPOSE OF REVIEW: Radiometabolic therapy with radioactive iodine (I) is the standard treatment for differentiated thyroid cancer and is also currently the treatment of choice for Graves' disease in the United States. and in most countries. Men younger than 40 years of age represent about 10% of all radiometabolic treatments. Thus, the question arises whether I therapy is able to induce a damage to the fertility potential. RECENT FINDINGS: The different effects caused by I therapy employed in cancer and hyperthyroid patients are reviewed. Most articles about the first category of patients show a damage to the germinal epithelium directly related to the cumulative dose delivered. Although the small amounts used in hyperthyroidism are usually well tolerated in terms of sterility risk, the impairment caused by hyperthyroidism per se is probably higher than that caused by I treatment. SUMMARY: Young cancer patients, particularly those with node or lung metastases, who will probably undergo repeated treatments should be aware of the potential risks to their fertility. An evaluation of testicular function is thus advisable. When an impairment of fertility potential is already present, the option of freezing semen should be considered. The available studies concerning I therapy in hyperthyroidism suggest that this treatment does not cause a worsening of semen analysis but an amelioration in affected patients.

Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rhTSH or hormone withdrawal.

UNLABELLED: Technical aspects and results of the dosimetric assessments of postoperative radioiodine ablation in the framework of an international, prospective, controlled, randomized, comparative study of the effectiveness of ablation therapy with 3.7 GBq (131)I in differentiated thyroid cancer after stimulation with recombinant human TSH (rhTSH) or by thyroid hormone withdrawal (THW) are presented. METHODS: Sixty-three patients were randomized after thyroidectomy to either the THW or the rhTSH group. Scintigraphic neck images were acquired starting 48 h after radioiodine administration to assess biokinetics in the thyroid remnant. The activity in blood samples was quantified and data from whole-body probe measurements and scintigraphic whole-body scans were combined to deduce retention curves in blood and whole body, respectively. The absorbed dose to the blood was calculated using a modified approach based on the formalism of the MIRD Committee of the Society of Nuclear Medicine. RESULTS: The effective half-time in the remnant thyroid tissue was significantly longer after rhTSH than THW (67.6 +/- 48.8 vs. 48.0 +/- 52.6 h, respectively; P = 0.01), whereas the observed differences of the mean 48-h (131)I uptakes (0.5% +/- 0.7% vs. 0.9% +/- 1.0% after THW; P = 0.1) and residence times (0.9 +/- 1.3 vs. 1.4 +/- 1.5 h after THW; P = 0.1) between the rhTSH and THW groups were not statistically significant. The specific absorbed dose to the blood was significantly (P <0.0001) lower after administration of rhTSH (mean, 0.109 +/- 0.028 mGy/MBq; maximum, 0.18 mGy/MBq) than after THW (mean, 0.167 +/- 0.061 mGy/MBq; maximum, 0.35 mGy/MBq), indicating that higher activities of radioiodine might be safely administered after exogenous stimulation with rhTSH. CONCLUSION: Indication of an influence of the residence time of radioiodine in the blood on the fractional uptake into thyroid remnant was found. A novel regimen is proposed in which therapeutic activities to be administered are determined from the individual specific blood dose.

RET/PTC3 rearrangement and thyroid differentiation gene analysis in a struma ovarii fortuitously revealed by elevated serum thyroglobulin concentration.

Struma ovarii (SO) is usually asymptomatic and only in a few cases it is associated with thyrotoxicosis. The presurgical diagnosis is very uncommon. In the majority of cases a pelvic mass is discovered at physical examination or by abdominal ultrasound. Only the hystopathologic examination is able to reveal the characteristic features of SO, with thyroid cells organized in follicles as the main tumoral tissue constituent. The histologic recognition of malignancy is not easy and usually requires an exhaustive sampling of the lesion to evaluate the extracapsular invasion. We report the case of a 59-year-old woman who came to our observation for the fortuitous finding of elevated serum thyroglobulin (Tg) levels (600-800 ng/mL). Because the thyroid function was normal and the ultrasound showed only a subcentrimetric nodule, the clinical suspicious of a SO was considered. Ultrasound examination of the abdomen showed a solid mass of 2 cm in the left ovary. A (131)I uptake was observed at scintiscan in the site of the solid mass. Three months after the resection of the left ovary serum Tg levels were markedly reduced (106 ng/mL), and its values continued to decrease down to 34 ng/mL at last control. The histology showed that the ovarian mass was mainly constituted of thyroid tissue (98%), with no malignant features. The molecular analysis of several thyroid differentiation gene mRNAs in the SO tissue showed an abundant expression of all genes but pendrin (PDS). A reduced PDS mRNA expression might explain the defective thyroxine (T(4)) production. Despite the absence of malignant features, the expression of RET/PTC3 rearrangement was found, raising the possibility of a potential malignant nature of the tumor. A cancer-free period of 3-4 years, as in our patient, is not long enough to definitively exclude a late onset metastatic disease but, unfortunately, the patient died of nonmedical reasons. In conclusion, we report a case of SO that, to our knowledge, is the first in which the clinical suspicion arose from the inappropriately elevated presurgical serum levels of Tg. A quite exhaustive molecular analysis of thyroid specific genes and oncogenes provided two interesting findings: the low PDS mRNA expression, which may explain the low hormonal production and the absence of thyrotoxicosis and the presence of a RET/PTC3 rearrangement, which prompts the possibility of a late malignant evolution.

Ablation of thyroid residues with 30 mCi (131)I: a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal.

The aim of the study was to assess whether stimulation by recombinant human TSH (rhTSH) may be used in patients with differentiated thyroid carcinoma for postsurgical ablation of thyroid remnants using a 30-mCi standard dose of (131)I during thyroid hormone therapy. The rate of ablation was prospectively compared in three groups of patients consecutively assigned to one of three treatment arms: in the first arm, patients (n = 50) were treated while hypothyroid (HYPO); in the second arm, patients (n = 42) were treated while HYPO and stimulated in addition with rhTSH (HYPO + rhTSH); in the third arm, patients (n = 70) were treated while euthyroid (EU) on thyroid hormone therapy and stimulated with rhTSH (EU + rhTSH). The outcome of thyroid ablation was assessed by conventional HYPO (131)I scan performed in HYPO state 6-10 months after ablation. Basal serum TSH was elevated in the HYPO and HYPO + rhTSH groups. In the EU + rhTSH group, basal serum TSH was 1.3 +/- 2.5 micro U/ml (range, <0.005-11.9 micro U/ml). After rhTSH, serum TSH significantly increased in the HYPO + rhTSH group and the EU + rhTSH group. Basal 24-h radioiodine thyroid bed uptake was 5.8 +/- 5.7% (range, 0.2-21%) and 5.4 +/- 5.7% (range, 0.2-26%) in the HYPO and HYPO + rhTSH groups, respectively. In the HYPO + rhTSH group, mean 24-h thyroid bed uptake rose to 9.4 +/- 9.5% (range, 0.2-46%) after rhTSH (P < 0.0001). The 24-h uptake after rhTSH in the EU + rhTSH group was 2.5 +/- 4.3% (range, 0.1-32%), significantly lower (P < 0.0001) than that found in the HYPO and HYPO + rhTSH groups. The rate of successful ablation was similar in the HYPO and HYPO + rhTSH groups (84% and 78.5%, respectively). A significantly lower rate of ablation (54%) was achieved in the EU + rhTSH group. Mean initial dose rate (the radiation dose delivered during the first hour after treatment) was significantly lower in the EU + rhTSH group (10.7 +/- 12.6 Gy/h) compared with the HYPO + rhTSH group (48.5 +/- 43 Gy/h) and the HYPO group (27.1 +/- 42.5 Gy/h). In conclusion, our study indicates that by using stimulation with rhTSH, a 30-mCi standard dose of radioiodine is not sufficient for a satisfactory thyroid ablation rate. Possible reasons for this failure may be the low 24-h radioiodine uptake, the low initial dose rate delivered to the residues, and the accelerated iodine clearance observed in EU patients. Possible alternatives for obtaining a satisfactory rate of thyroid ablation with rhTSH may consist of increasing the dose of radioiodine or using different protocols of rhTSH administration producing more prolonged thyroid cells stimulation.

Patients with differentiated thyroid cancer who underwent radioiodine thyroid remnant ablation with low-activity ¹³¹I after either recombinant human TSH or thyroid hormone therapy withdrawal showed the same outcome after a 10-year follow-up.

BACKGROUND: No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (¹³¹I). AIM: The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq ¹³¹I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. PATIENTS: A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of ¹³¹I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. RESULTS: During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end of the 10-year follow-up, 140 of 159 (88.1%) patients were disease-free, whereas 19 of 159 (11.9%) remained affected. No correlation was found with the type of TSH stimulation, and no other clinical and pathological features showed any correlation with the final status. However, low levels of stimulated serum thyroglobulin (<5.4 ng/mL) at first control after remnant ablation identified a subgroup of not ablated patients who became spontaneously cured. CONCLUSIONS: Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) ¹³¹I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role.

RANK-RANKL-OPG in hemophilic arthropathy: from clinical and imaging diagnosis to histopathology.

OBJECTIVE: Hemarthrosis triggers hemophilic arthropathy, involving the target joints. The histopathogenesis of blood-induced joint damage remains unclear. The triad of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG; RANK-RANKL-OPG) controls bone turnover. Our aim was to evaluate RANK-RANKL-OPG expression in the synovium of hemophilic patients with severe arthropathy. METHODS: Synovial biopsies were obtained from 18 patients with hemophilic arthropathy and 16 with osteoarthritis (OA) who were undergoing total knee replacement and synovectomy. The severity of hemophilic arthropathy was evaluated according to ultrasonography score, the World Federation of Hemophilia (WFH) orthopedic joint scale, and the radiographic Pettersson score. RANK-RANKL-OPG expression was examined by immunohistochemistry and Western blotting. Serum levels of soluble RANKL (sRANKL) and OPG from an extended group of 67 patients with hemophilic arthropathy and 30 healthy controls were measured by ELISA. RESULTS: The mean ultrasonography, WFH orthopedic joint scale, and Pettersson scores in patients with hemophilic arthropathy indicated severe arthropathy. A decreased expression of OPG was found in hemophilic arthropathy synovium compared with patients with OA. RANK and RANKL immunopositivity was strong in the lining and sublining layers in hemophilic arthropathy synovial tissue. Western blotting confirmed the immunohistological findings. Serum levels of sRANKL and OPG in patients with hemophilia were lower than in healthy controls. CONCLUSION: In hemophilic arthropathy, the synovium highly expressed RANK and RANKL, whereas OPG immunopositivity decreased, suggesting an osteoclastic activation. Low tissue expression of OPG paralleled the serum levels of this protein and the severity of hemophilic arthropathy assessed by ultrasonography, Pettersson, and WFH orthopedic joint scale scores.

Radioiodine 131I treatment for large nodular goiter: recombinant human thyrotropin allows the reduction of radioiodine 131I activity to be administered in patients with low uptake.

BACKGROUND: (131)I therapy is effective in reducing the volume of large nodular goiters (thyroid volume [TV]), mainly after stimulation with recombinant human thyrotropin (rhTSH). The amount of (131)I to be administered inversely depends on thyroid radioactive iodine uptake (RAIU). In patients with low RAIU, we evaluated the efficacy of (131)I treatment at lower doses with respect to those calculated on the basal RAIU, after rhTSH stimulation. METHODS: Eighteen consecutive patients (17 women and 1 man, 49-83 years) with large nodular goiter were included in the study. At enrollment, 24th h RAIU, TSH, free thyroxine, free triiodothyronine, thyroglobulin antibodies, thyroid peroxidase antibodies, TSH receptors antibodies, urinary iodine, and TV were measured. RAIU was <40% in 11 patients (lower uptake group [LUG]) and >40% in 7 (higher uptake group [HUG]). RAIU difference in the two groups was significant (p < 0.0001). LUG patients were treated with rhTSH (0.03 mg i.m.) and RAIU was measured again after 24 hours. The administered amount of (131)I was aimed to give the thyroid a dose of 100 Gy, by the formula: (131)I activity = 370 MBq × TV (mL)/RAIU(%), taking into account RAIU value after rhTSH for LUG patients. Patients were re-evaluated 3 and 12 months after therapy. RESULTS: At enrollment, LUG and HUG patients did not differ for TV, free thyroxine, free triiodothyronine, TSH, and urinary iodine. LUG patients were older than HUG patients (p = 0.027). In LUG, the uptake increased after rhTSH (42.8% [36%-47.5%] vs. 30% [23.4%-31.6%], p = 0.0044). The (131)I activity was 1073 MBq (740-1103 MBq) in LUG and 851 MBq (677-918 MBq) in HUG (p = 0.22, NS), vs. 1300 MBq (1077-2150 MBq) in LUG, based on RAIU before rhTSH. At 3 and 12 months after radioiodine, TV was reduced to 74% [59%-84%] and 53% [42%-72%] in LUG and 75% [70%-77%] and 65% [54%-74%] in HUG, respectively. The reduction was significant with respect to the basal, both at 3 and 12 months, but not different between the two groups. CONCLUSIONS: One single dose of 0.03 mg of rhTSH increased the thyroid RAIU by 40% in patients with nodular goiter and low basal uptake. This allowed a mean reduction of 36% (26%-42%) in the administered (131)I activity without loss of effectiveness. In patients with low RAIU, rhTSH pre-treatment may optimize (131)I therapy.

Identification and functional analysis of novel dual oxidase 2 (DUOX2) mutations in children with congenital or subclinical hypothyroidism.

CONTEXT: Congenital hypothyroidism (CH) associated with goiter or a gland of normal size has been linked to dual oxidase 2 (DUOX2) mutations in the presence of iodide organification defect. OBJECTIVE: Thirty unrelated children with CH or subclinical hypothyroidism (SH) identified during infancy with a eutopic thyroid gland, coming from our Screening Centre for CH or referred from other regions of Italy, were studied with the perchlorate discharge test to identify organification defects. Eleven children with iodide organification defect were considered for the genetic analysis of TPO, DUOX2, and dual oxidase maturation factor 2 (DUOXA2) genes. PATIENTS: Eight children with CH and three with SH and eutopic thyroid gland were included in the study. After discontinuation of therapy, a partial or complete organification defect was shown after ¹²³I scintigraphy and perchlorate test. METHODS: TPO, DUOX2, and DUOXA2 genes were analyzed, and functional activity of DUOX2 variants was studied in HeLa cells. RESULTS: Sequencing of the DUOX2 gene revealed a deletion S965fsX994 in three children; two were euthyroid after 1 month of L-T4 discontinuation but developed SH after 5 and 18 months, respectively, whereas the other child had SH. One child with SH showed H678R, R701Q, and P982A substitutions, and another child with SH showed only the P982A. One child with SH showed the Y1150C mutation, and another euthyroid child showed the A728T mutation. Functional studies confirmed that S965fsX994, Y1150C, and A728T mutations were responsible for the defect in H2O2 production, whereas H678R, R701Q, and P982A did not alter H2O2 production in vitro. CONCLUSIONS: Genetic analysis of the DUOX2 gene was performed in 11 children with organification defect. Two new mutations (Y1150C and A728T) and the deletion S965FsX994 were responsible for the deficit in the organification process and the phenotypes. Three polymorphisms (H678R, P982A, and R701Q) were identified.

Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.

CONTEXT: Radioactive iodine (RAI) is a common therapy for hyperthyroidism due to Graves' disease. A small but significant proportion of patients have recurrence of hyperthyroidism after RAI therapy. Lithium might increase RAI effectiveness by increasing RAI retention in the thyroid. However, whether lithium favorably affects the long-term outcome of RAI therapy is still a matter of argument. OBJECTIVE: The objective of the study was to compare the efficacy of RAI given with or without concomitant lithium treatment. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a tertiary university center. PATIENTS: Six hundred fifty-one patients with newly diagnosed Graves' disease participated in the study. INTERVENTION: Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d) and 353 with RAI alone. MAIN OUTCOME MEASURES: Proportion of cured patients and time to achieve cure of hyperthyroidism during 1 yr of follow-up was measured. RESULTS: PATIENTS treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium prevented the serum free T(4) increase after methimazole withdrawal and RAI therapy. Side effects after RAI therapy occurred in a subset of patients and were mild, transient, and without differences in the two groups. CONCLUSIONS: RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves' disease.