Davide Nacamulli

Nonparallel patterns of calcitonin and carcinoembryonic antigen levels in the follow-up of medullary thyroid carcinoma.

Serum levels of calcitonin (CT) and carcinoembryonic antigen (CEA) were evaluated in a group of 41 patients with histologically proven medullary thyroid carcinoma (MCT) before and sequentially after treatment for a period up to 7 years. Before thyroidectomy, CT levels were high in all patients, and significantly more elevated when metastases were present. On the other hand, CEA levels were high in most but not all the patients, and they also were found more frequently to be elevated in patients with metastases. After treatment, most of the patients without metastases showed persistently normal basal and pentagastrin stimulated CT and CEA levels. In some patients either without or with local metastases, postoperative CT levels, although considerably reduced, remained persistently above normal limits, whereas CEA levels became completely normal. This pattern may be due to the persistence of minute occult foci of the tumor, not sufficient to produce measurable amounts of CEA, which is not synthesized by all tumor cells. Most of the patients with metastases at diagnosis, showed still elevated CT and CEA levels after treatment. In the nonprogressive cases both markers decreased after adjunctive treatment or remained unchanged. In patients with progressive disease, an increase of CEA levels in the absence of a parallel increase of CT levels, which even decreased, was often observed. In one patient with progressive disease high CEA levels were seen for the first time when liver metastases had occurred. These data seem to suggest that, even though CEA production is not recognizable in all patients with MCT, in the CEA positive cases CEA levels may follow a nonparallel pattern and may have a distinct diagnostic meaning with respect to CT levels. In some cases, particularly in advanced disease, CEA may be a more useful marker of poor prognosis.

Molecular characteristics in papillary thyroid cancers (PTCs) with no 131I uptake

Objective  Papillary thyroid cancers (PTCs) with no iodine uptake have an aggressive behaviour and a poor prognosis. The aim of our study was to characterize, at molecular level, a subset of PTC with no 131 iodine (131I) uptake.

Influence of physiological dietary selenium supplementation on the natural course of autoimmune thyroiditis

Objective  Our study aimed to investigate whether physiological doses of selenium (Se) influence the natural course of autoimmune thyroiditis (AIT).

Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification

OBJECTIVE Medullary thyroid carcinoma (MTC) derives from the parafollicular C cells, being sporadic in 75% of cases and familial in 25%, due to RET proto-oncogene germinal mutations. In sporadic forms, stage at diagnosis is the most important negative prognostic factor. The aim of this study was to evaluate the prognostic impact of molecular and immunohistochemical markers in sporadic MTC. DESIGN AND METHODS We studied 60 patients with sporadic MTC. For each case, we sought RET somatic mutations in the primary cancer and in lymph node metastases. The primary cancer also underwent immunohistochemical examination for Ki-67. RESULTS A somatic RET mutation was found in 38% of patients, being M918T in 52% of them. We observed a statistically significant association between RET mutations and male gender (P<0.01), tumor size (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P<0.05), increased risk of persistent disease (P=0.01), and low overall survival (P<0.01). High Ki-67 levels were similarly associated with extra-thyroid spread (P<0.05), lymph nodes (P<0.05) and distant metastases (P<0.001), advanced stage (P=0.01), and low overall survival (P=0.01). Combining somatic RET analysis with Ki-67 assessment seems to be useful for increasing the specificity of Ki-67 assessment alone and identifying patients with a more aggressive cancer: in our series, only the patients who died during the follow-up had both a somatic RET mutation and a Ki-67 expression level >50 cells/mm(2). CONCLUSIONS The combined evaluation of RET and Ki-67 could act as an adjuvant prognostic marker useful for ameliorating the initial risk stratification of patients with sporadic MTC.

A multimodality therapeutic approach in anaplastic thyroid carcinoma: Study on 39 patients

The aim of this study was to investigate the role of multimodality treatment in patients with anaplastic thyroid carcinoma. From 1992 to 1999, 39 consecutive patients with a histologically or cytologically proven anaplastic thyroid carcinoma were referred to the Thyroid Center of Padua General Hospital. There were 28 females and 11 males with a median age of 69 years (range 39–88 years). About one-third of patients had a history of preceeding nodular goiter. Two patients had areas of differentiated thyroid carcinoma at histological examination. Local disease was present in 26 patients while distant metastases, mainly to the lung, were present in 22 at diagnosis or quickly developed during the observation period in all the others except one. Thirty-two patients were previously untreated: 9 of them were in good general condition, 1 had limited lung metastases, and the tumor mass was considered resectable by the surgeon. These 9 patients were treated with cisplatin once a week and radiotherapy (RT) 36Gy in 18 fractions over three weeks, followed by total thyroidectomy (TT) and by further chemotherapy (CHT) with adriamycin and bleomycin in 4 patients. Seven patients, 3 with lung metastases at diagnosis, had undergone TT, followed by RT in 5, in another hospital and were subsequently referred to our center due to the presence of distant metastases. Therefore, a total of 16 patients (Group 1) was treated with TT, RT and CHT in various order. Nine patients with distant metastases at diagnosis (Group 2) received CHT; one of them had a disappearance of lung metastases and was then treated by TT and further CHT. Group 3 consisted of 14 elderly patients in poor general conditions; 4 of these received local RT, while the remaining did not receive any treatment. Four complete responses were seen in patients from Group 1, and 1 from Group 2. One patient without distant metastases at diagnosis is alive and free of disease 6 months after TT and adjuvant CHT, and 12 months after diagnosis. Three had long-term survival (14, 24, 27 months) with a disease-free interval of 6-8-10 months. The patient from Group 2 who was treated in a second time by TT is alive without disease after 60 months. Median survival rate was 11 months for Group 1, 5.7 months for Group 2 and 4 months for Group 3. In some patients multimodality treatment (TT, RT and CHT) is associated with increased survival. Nine out of 16 patients, who underwent surgery and complementary treatment, had no local progression. In all but one distant metastases developed, mainly in the lung, during or after post-surgical CHT. The best results were obtained in younger patients with less advanced disease. Early diagnosis is mandatory. Only a few patients responded to CHT, confirming that anaplastic thyroid carcinoma is often resistant to anticancer drugs. Our experience with combination modalities suggests that aggressive and appropriate combinations of RT, TT and CHT may provide some benefit in patients with anaplastic thyroid carcinoma. Preoperative CHT and RT may enhance surgical resectability of the primary tumor.

BRAF in primary and recurrent papillary thyroid cancers: the relationship with 131I and 2-[18F]fluoro-2-deoxy-d-glucose uptake ability

OBJECTIVE BRAF V600E is a potential marker of poor prognosis in papillary thyroid cancers (PTC). In a previous report, we showed that recurrent PTC with no radioiodine ((131)I) uptake are frequently associated with BRAF mutations, a low expression of thyroid-related genes and a high expression of glucose type-1 transporter gene. AIM The aim of the present study was to assess BRAF status in a large series of recurrent PTC patients, considering paired primary and recurrent cancers. The BRAF genotype was correlated with the ability to concentrate (131)I and/or 2-[(18)F]fluoro-2-deoxi-d-glucose ((18)F-FDG) in the recurrent cancers, serum markers of recurrence, and patient outcome. DESIGN AND METHODS We studied 50 PTC patients with recurrent cervical disease submitted to a re-intervention, followed up in median for 9 years. BRAF analysis was conducted by direct sequencing and mutant allele-specific PCR amplification. In 18 cases, molecular analysis was also assessed in the primary cancer. Out of 50 patients, 30 underwent (18)F-FDG-positron emission tomography-computed tomography. RESULTS BRAF V600E-positive recurrent patients were found (131)I-negative in 94% of cases (P<0.001); 73% of the cancers carrying BRAF V600E were both (131)I-negative and (18)F-FDG positive. In paired primary and recurrent PTC, BRAF V600E was observed in 79% of the primary cancers and 84% of their recurrences. Three patients with (131)I-negative and BRAF V600E-positive recurrent cancers deceased during follow-up. CONCLUSIONS BRAF mutations are more common in thyroid recurrences with no (131)I uptake than in (131)I-positive cases. They are correlated with the ability to concentrate (18)F-FDG, and they can appear, albeit rarely, as a de novo event in the course of PTC recurrences.

BRAF analysis by fine needle aspiration biopsy of thyroid nodules improves preoperative identification of papillary thyroid carcinoma and represents a prognostic factor. A mono-institutional experience.

Abstract Background: The current preoperative diagnosis of a thyroid mass relies on microscopic evaluation of thyroid cells obtained by fine needle aspiration biopsy (FNAB). More recently, FNAB has been combined with molecular analysis to increase the accuracy of the cytological evaluation. In this mono-institutional prospective study, we evaluated whether the routine introduction of BRAF testing in thyroid FNAB could help ameliorate the preoperative recognition of papillary thyroid carcinoma (PTC) in “suspended” or malignant cytological categories. Moreover, we investigated the prognostic role of the BRAFV600E mutation in PTC. Methods: BRAFV600E analysis was performed in thyroid FNAB from 270 patients classified into one of five cytological categories THY1, THY2, THY3, THY4, THY5. All subsequently underwent thyroidectomy±node dissection, from October 2008 to September 2009 in our Department. For each cytological category, we considered the definitive histological diagnosis of PTC and the presence of the BRAFV600E mutation. In 141 patients with a final tissue diagnosis of PTC, we correlated the presence of BRAFV600E with gender, age, histotype, TNM, size of the lesion, extracapsular extension, node metastases and multifocality. Results: The prevalence of the BRAFV600E mutation, among PTCs at final tissue diagnosis, was 69%. It improved the FNAB diagnostic accuracy from 88% to 91%. The BRAFV600E mutation was correlated with older age, classical variant of PTC, advanced stages in patients >45 years. Conclusions: BRAFV600E testing could play a role in improving the diagnostic accuracy of FNAB for PTC, representing a useful adjuvant tool in presurgical characterization of thyroid nodes in particular cases. There is an association between the BRAFV600E mutation and some clinico-pathological characteristics of PTC.

Milk represents an important source of iodine in schoolchildren of the Veneto region, Italy

The aim of the present study is to evaluate the relationships between urinary iodine concentration (UIC) and the intake of milk and other foods, in a group of school children of the Veneto region, in North East Italy. A questionnaire, concerning the daily intake of milk, yoghurt, cheese and other animal foodstuffs, was distributed to 233 schoolchildren aged between 11 and 15 yr. The use of iodized salt was also investigated. UIC was measured in a casual urine sample of all children investigated. The iodine content of 28 samples of milk and of 13 samples of yoghurt, bought during the summer in shops of the same area, was measured. UIC values ranged between 25 and 436 μg/l, median value was 140 μg/l, mean value 149±78 μg/l. The median iodine content of milk and yoghurt were 278 μg/l and 216 μg/l, respectively. With regard to dietary habits, about 70% of the children took 200 ml of milk or more per day, which corresponds to a daily intake of iodine ranging between 50 and 100 μg a day. About 30% of schoolchildren used iodized salt. A highly significant correlation between UIC and milk intake was observed (p=0.0005), while the relationship was poor or absent in the case of both intake of other foodstuffs and use of iodized salt (p=0.38). In conclusion, the results of the study document the very important role of cows’ milk as a source of iodine in childhood in the Veneto region, Italy.

Restricted intraindividual urinary iodine concentration variability in nonfasting subjects.

Objective:Individual urinary iodine concentration (UIC) reflects iodine intake over a short time prior to sampling. Since eating habits are relatively constant in single subjects, UIC should be relatively constant in a given individual. The aim of our study was to verify this hypothesis by assessing UIC in repeated single urine samples from a group of healthy subjects.Design and Setting:A prospective sequential investigation was performed in 131 volunteer health workers or students recruited in our University hospital.Interventions:Single urine samples were taken in a nonfasting state, between 0900 and 1100 hours. Group 1 was composed by 131 subjects who collected one urine sample. Group 2 was composed by 11 subjects of the group 1, who collected multiple repeated urine samples (as a whole 158 urine samples, mean 14 samples each). UIC mean±s.d., median and coefficient of variation (CV%) was measured in both groups.Results:Interindividual UIC variation was wide, UIC ranging from 21 to 382 μg/l, mean 136±84 μg/l, median 124 μg/l, CV 62%. Also in the 11 subjects repeatedly sampling there were considerable differences among individual UIC average levels (ranging from 37±15 to 221±91 μg/l). However, in this second group, the intraindividual variation was considerably restricted (CV% 36).Conclusions:The present study shows that in a nonfasting state in mid-morning UIC is more stable from day to day in a single subject, depending on his eating habits, than in various subjects. Thus, a single urine sample even in nonfasting state may give some rough information about the individuals iodine status.

PROGNOSTIC VALUE OF EARLY POSTOPERATIVE CALCITONIN LEVEL IN MEDULLARY THYROID CARCINOMA

Aims Serum calcitonin (CT) assay is commonly used in the diagnosis and follow-up of medullary thyroid carcinoma (MTC). The aim of this study was to ascertain whether serum CT levels, measured in the first few days after surgery, could be used to evaluate the efficacy of treatment. Methods A group of 33 patients was studied. In all patients the follow-up was more than 20 months. Results Preoperatively basal CT serum levels were high in all patients. Twenty-four hours after surgery CT serum levels dropped to within the normal range in 8 patients and 72 hours after operation in 7 others. In this group 1 patient was at stage I, 11 at stage II and 3 at stage III. Basal and pentagastrin stimulated CT levels continued to be in the normal range in these 15 patients 6 and 12 months after surgery and at the subsequent year by follow-up visits. No clinical or radiological evidence of disease was found during the follow-up in this group. In the other 18 patients CT was reduced but still high 72 hours after surgery; 6 months later basal serum CT levels continued to be elevated or responsive to pentagastrin stimulation. In this group restaging showed tumor relapse in the thyroid bed in 2 patients, cervical lymphadenopathy in 11, and distant metastases (bone, liver) in 3. Conclusions Immediate postoperative CT serum levels seem to be the most useful index to evaluate the efficacy of surgical treatment and the presence of residual neoplastic tissue.