ATYPICAL CARCINOID OF THE LARYNX AND MULTIFOCAL METASTASES.

Neuroendocrine carcinoma (NEC) of the larynx is the most frequent neuroendocrine neoplasm of the head and neck and the most common nonsquamous carcinoma of the larynx. It usually occurs in the supraglottic area, in smoking men. We report a case of a 58-year-old woman with no history of smoking who presented with an atypical carcinoid, arising in the right piriform sinus of the larynx. During the 5-year follow-up, the patient developed metastases in the lymph nodes, palatine tonsils, parotid glands, breasts and skin. For this reason the patient underwent several surgical procedures, radiotherapy and eventually was qualified for chemotherapy. Our case shows that NEC of the larynx can have an atypical presentation. The diagnosis requires careful pathological evaluation with immunohistochemistry and a wide spectrum of imaging. The serum concentration of chromogranin A seems to be not useful in the diagnosis and follow-up of laryngeal NEC.

131I thyroid activity and committed dose assessment among family members of patients treated with radioactive iodine.

The main goal of the present study was estimation of an internal contamination of 131I among family members of patients treated with radioactive iodine. Thyroid activity measurements of 131I in examined volunteers were performed using a whole-body spectrometer at the institute of nuclear physics, Polish academy of sciences. During this research, 20 relatives of patients treated with 131I were examined: eight women and 12 men with an age in the range from 3 to 72 years. In the case of nine individuals, the activity of 131I in the thyroid was below the detection limit, but among the remaining 11 individuals, the activity varied from (9 ± 3) Bq up to (1140 ± 295) Bq. Subsequently, based on the measurements of thyroid 131I activities, the corresponding doses were assessed. The highest estimated effective dose reached 218 µSv, while the thyroid equivalent dose was 2.4 mSv. In addition, the experimental data obtained were statistically analysed together with the results of surveys of the individuals participating in the study by means of correspondence analysis and nonparametric tests: Mann-Whitney, gamma, χ2 and Yule Phi coefficient. These analyses revealed relationships between 131I activities in the thyroids of the examined individuals and their housing conditions as well as consumption of meals prepared by the patients.

Transcriptomic population markers for human population discrimination.

BACKGROUND: Numerous studies have demonstrated significant differences in the expression level across continental human populations. Most of published results were performed on B-cell lines materials examined under specific laboratory conditions, without further validation in a primary biological material. The goal of our study was to identify mRNA markers characterized by a significant and stable difference in the gene expression profile in Caucasian and Chinese populations, both in the commercially available B-lymphocyte cell lines and in the primary samples of the peripheral blood. RESULTS: The preliminary selection of population-differentiating transcripts was based on Illumina expression microarray analysis of the representative group of ethnically-specified B-lymphocyte cell lines. Twenty genes with the inter-population difference in the mean expression characterized by the at least 1.5-fold change and FDR <  0.05 were identified. Subsequently, a two-step validation procedure was carried out. In the first step, a subset of selected population- differentiating transcripts was tested in the independent set of B-lymphocyte cell lines, using TLDA cards. Based on TLDA analysis, three transcripts representing Fch > 2 were chosen for validation. The differentiating status was confirmed for all of them: UTS2, UGT2B17 and SLC7A7. The mean expression of UTS2 was higher in CHB (25.8-fold change compared to CEU), while the expression of UGT2B17 and SLC7A7 was higher in CEU (3.2- and 2.2-fold change, respectively). In the next validation step, two transcripts were verified in the primary biological material. As an ultimate result of our study, two mRNA markers (UTS2 and UGT2B17) exhibiting population differences in the expression level in both B-cell line and in the blood were identified. Further statistical analysis confirmed the discriminatory potential of these two markers. CONCLUSIONS: An inter-population differences on the level of gene expression were identified in both B-cell lines and peripheral blood samples. These findings may have a practical application in the field of forensic science. In particular, these transcripts, targeted by specific probes, may be used as population-specific targets in the efforts aiming to separate mixture of blood from individuals of different populations. Notwithstanding, these results have to be confirmed on extended population group.

131I INTERNAL CONTAMINATION AND COMMITTED DOSE ASSESSMENT AMONG NUCLEAR MEDICINE MEDICAL PERSONNEL.

This study presents 131I thyroid activity measurements of 56 employees of the Department of Nuclear Medicine and Endocrine Oncology, Centre for Oncology in Gliwice. The research instrument was a whole-body spectrometer. In 44 out of 56 examined staff members, the determined 131I activity was found to be above the detection limit. The measured activities ranged from 6 ± 2 to 457 ± 118 Bq. The maximum estimated committed effective dose reached was 1.5 mSv/y. The results were compared with previous measurements conducted in another Polish nuclear medical unit. From this comparison, we can see that radiological safety among nuclear medicine personnel can be improved by appropriate work organisation. Reducing exposure of workers can be achieved by properly organised turnovers concerning the most vulnerable worksites. In addition, to lower the radiation risk, it is essential to comply strictly with the isolation regime for the patients.

Papillary thyroid carcinoma in a boy with familial tuberous sclerosis complex attributable to a TSC2 deletion-a case report.

Tuberous sclerosis complex (tsc), a phacomatosis, is a rare genetic disease (autosomal dominant; incidence: 1 in 6,800-17,300) associated with mutations in the TSC1 and TSC2 genes, 70% of which are sporadic. The disease causes benign tumours in the brain, kidneys, heart, lungs, skin, and eyes; thyroid lesions are extremely rare. A 13-year-old euthyroid boy with a hereditary form of tsc (del 4730G in TSC2, also seen in 2 sisters and the father) was admitted to hospital with a thyroid nodule. Physical examination revealed a nodular left lobe with increased consistency. Thyroid ultrasonography revealed a heterogeneous left lobe, predominantly hypoechoic with multiple microcalcifications and the presence of suspicious cervical lymph nodes on the left side. A macrocalcification was observed on the right lobe. Fine-needle biopsy results showed a few groups of cells with discrete atypical characteristics, including abundant cytoplasm, nuclei with conspicuous nucleoli, intra-nuclear inclusions, and nuclear grooves. The patient underwent total thyroidectomy with lymphadenectomy. Histopathology examination confirmed papillary thyroid carcinoma. The coincidence of endocrine neoplasia including thyroid cancer and tsc is rare, and tsc with papillary thyroid carcinoma has never been described in a child. Studies of mutations in the tumour suppressor genes TSC1, TSC2, and STK11, activating the mtor (mammalian target of rapamycin) pathway, might support their role in the pathogenesis of thyroid cancer.

The role of FDG-PET in localization of recurrent lesions of differentiated thyroid cancer (DTC) in patients with asymptomatic hyperthyroglobulinemia in a real clinical practice.

INTRODUCTION: Available methods, including serum thyroglobulin (Tg) measurement and whole-body scan (WBS) performed after radioiodine administration, allow for a precise diagnostics in differentiated thyroid cancer (DTC). However, some asymptomatic patients demonstrate negative WBS despite a high Tg serum concentration. In these subjects, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered. The primary aim of our study was to evaluate a diagnostic value of FDG-PET in asymptomatic hyperthyroglobulinemia. The secondary one was to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level. MATERIAL: One hundred and ten FDG-PET/CT scans were retrospectively analyzed, 85 scans were done under TSH stimulation and 25 on LT4 suppressive therapy. Follow-up ranged between 4 and 9 years. RESULTS: The first FDG-PET/CT detected cancer foci in 49 subjects with a global sensitivity of 45%. When the sensitivity was evaluated with reference to TSH stimulation and suppression, its values were 50 and 28% respectively. In 42 patients, FDG-PET failed to diagnose the reason for elevated Tg level. During further follow-up, in 17 of them, DTC recurrence was detected by other methods (CT, MRI, US). Fourteen subjects with asymptomatic hyperthyroglobulinemia were free of DTC progression for at least 4 years. CONCLUSIONS: FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during the 5-year follow-up.

EurEAs_Gplex--A new SNaPshot assay for continental population discrimination and gender identification.

Assays that allow analysis of the biogeographic origin of biological samples in a standard forensic laboratory have to target a small number of highly differentiating markers. Such markers should be easy to multiplex and the assay must perform well in the degraded and scarce biological material. SNPs localized in the genome regions, which in the past were subjected to differential selective pressure in various populations, are the most widely used markers in the studies of biogeographic affiliation. SNPs reflecting biogeographic differences not related to any phenotypic traits are not sufficiently explored. The goal of our study was to identify a small set of SNPs not related to any known pigmentation/phenotype-specific genes, which would allow efficient discrimination between populations of Europe and East Asia. The selection of SNPs was based on the comparative analysis of representative European and Chinese/Japanese samples (B-lymphocyte cell lines), genotyped using the Infinium HumanOmniExpressExome microarray (Illumina). The classifier, consisting of 24 unlinked SNPs (24-SNP classifier), was selected. The performance of a 14-SNP subset of this classifier (14-SNP subclassifier) was tested using genotype data from several populations. The 14-SNP subclassifier differentiated East Asians, Europeans and Africans with ∼100% accuracy; Palestinians, representative of the Middle East, clustered with Europeans, while Amerindians and Pakistani were placed between East Asian and European populations. Based on these results, we have developed a SNaPshot assay (EurEAs_Gplex) for genotyping SNPs from the 14-SNP subclassifier, combined with an additional marker for gender identification. Forensic utility of the EurEAs_Gplex was verified using degraded and low quantity DNA samples. The performance of the EurEAs_Gplex was satisfactory when using degraded DNA; tests using low quantity DNA samples revealed a previously not described source of genotyping errors, potentially important for any SNaPshot-based assays.

miRNAs with the potential to distinguish follicular thyroid carcinomas from benign follicular thyroid tumors: results of a meta-analysis.

The detection of somatic mutations in indeterminate or follicular proliferation fine-needle aspiration cytologies (FNACs) is able to clarify only a subgroup of those FNACs. Therefore, further markers to differentiate this problematic FNAC category by the identification of mutation negative thyroid cancers and benign nodules are urgently needed. Our objective was to evaluate previously published miRNA markers and discover novel ones from all publicly available miRNA expression profiling data sets. By literature review and data repository search we gathered 3 data sets describing human miRNA expression profiles of follicular thyroid cancer (FTC) and follicular adenoma (FA) samples. Literature review summarized 27 previously published miRNAs, which were validated in the 3 available data sets. By means of uniform statistical analysis 6 further miRNAs were identified and tested in an independent, previously published microarray data set. Meta-analysis confirmed 7 out of 27 previously published, and 4 out of 6 de novo identified miRNAs. The low confirmation rate of previously published miRNA markers was induced by low numbers of samples in the analyzed studies and high false discovery rates that were higher than 0.2. Finally, miR-637, miR-181c-3p, miR-206, and miR-7-5p were discovered as de novo potential FTC markers and validated in at least one independent, previously published data set. Two out of these new identified miRNAs (miR-7-5p and miR-206) were validated by qPCR in an independent sample set of 32 FTC and 46 FA samples. Especially miR-7-5p was able to differentiate benign and malignant thyroid tumors in several datasets.

Circulating microRNAs (miR-423-5p, miR-208a and miR-1) in acute myocardial infarction and stable coronary heart disease.

AIM: The microRNAs (miRs) are small non-coding RNAs which regulate expression of multiple genes involved in atherogenesis. MicroRNA are also present in circulation. The aims of this study were: 1) assessment of expression level of miR-1, miR-208a and miR-423-5p in plasma in patients with STEMI, stable CAD and healthy individuals; 2) evaluation of correlation between plasma miRs and left ventricle ejection fraction, end- systolic and end-diastolic diameters and troponin release in patients with STEMI. METHODS: Study group consisted of 26 patients: 1) acute MI group (N.=17); 2) stable CAD group (N.=4); and 3) subjects with no history of CAD (control group, N.=5). Expression of miR-423-5p, miR-208 and miR-1 was measured in plasma before PCI, 6, 12 and 24 hours later. Expression level ofmiRs was measured using TaqMan® MicroRNA Assays. Expression was assessed by Pfaffl method, and miR-39 was used for normalization of the results. RESULTS: In stable CAD in comparison to control group the expression level of miR-1, miR-208a and miR-423-5p did not show significant differences. Also there was no significant increase of number of miR copies at 6, 12 and 24 hours after PCI. There was a significantly higher number of miR-423-5p copies in patients with acute MI before the pPCI. After 6, 12 and 24 hours post-procedure the expression level was similar to the control group and significantly lower than the baseline level. Conversely, the expression level of miR-1 and miR-208a were not significantly different than in the control group. In patients with acute MI there were no significant correlations between the expression level of miRs and any of the echocardiographic parameters of LV as well as level of troponin I at any time-point of the follow-up. CONCLUSION: Early in acute myocardial infarction the expression of miR-423-5p in plasma is significantly increased with subsequent normalization within 6 hours. Potentially it is an early marker of myocardial necrosis.

A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas.

BACKGROUND: Papillary thyroid cancer (PTC) incidence increased dramatically in children after the Chernobyl accident, providing a unique opportunity to investigate the molecular features of radiation-induced thyroid cancer. In contrast to the previous studies that included age-related confounding factors, we investigated mRNA expression in PTC and in the normal contralateral tissues of patients exposed and non-exposed to the Chernobyl fallout, using age- and ethnicity-matched non-irradiated cohorts. METHODS: Forty-five patients were analysed by full-genome mRNA microarrays. Twenty-two patients have been exposed to the Chernobyl fallout; 23 others were age-matched and resident in the same regions of Ukraine, but were born after 1 March 1987, that is, were not exposed to ¹³¹I. RESULTS: A gene expression signature of 793 probes corresponding to 403 genes that permitted differentiation between normal tissues from patients exposed and from those who were not exposed to radiation was identified. The differences were confirmed by quantitative RT-PCR. Many deregulated pathways in the exposed normal tissues are related to cell proliferation. CONCLUSION: Our results suggest that a higher proliferation rate in normal thyroid could be related to radiation-induced cancer either as a predisposition or as a consequence of radiation. The signature allows the identification of radiation-induced thyroid cancers.

2012 European thyroid association guidelines for metastatic medullary thyroid cancer.

Distant metastases are the main cause of death in patients with medullary thyroid cancer (MTC). These 21 recommendations focus on MTC patients with distant metastases and a detailed follow-up protocol of patients with biochemical or imaging evidence of disease, selection criteria for treatment, and treatment modalities, including local and systemic treatments based on the results of recent trials. Asymptomatic patients with low tumor burden and stable disease may benefit from local treatment modalities and can be followed up at regular intervals of time. Imaging is usually performed every 6-12 months, or at longer intervals of time depending on the doubling times of serum calcitonin and carcinoembryonic antigen levels. Patients with symptoms, large tumor burden and progression on imaging should receive systemic treatment. Indeed, major progress has recently been achieved with novel targeted therapies using kinase inhibitors directed against RET and VEGFR, but further research is needed to improve the outcome of these patients.

Gene expression profiles for radiation-induced thyroid cancer.

The question whether radiation-induced thyroid cancer differs by its molecular biology from sporadic disease still remains. Studies on tissue from patients who developed thyroid cancer after the Chernobyl accident have provided a unique opportunity to look for biological consequences of low-dose irradiation by comparing the gene expression profile of sporadic papillary thyroid cancer (PTC), whose aetiology is unknown, and PTC induced by internal radiation. So far, four transcriptomic studies comparing radiation-induced and sporadic thyroid cancer have been reported. However, no final conclusion has been drawn regarding the presence of a radiation signature, as either no difference was noted or the reported differences were not sufficiently convincing due to the low number of cases analysed or to the presence of confounding factors. The list of putative biological and clinical factors that may influence the PTC gene expression profile is long, but there are sufficient data reported in the literature to link expression profiles with differing pathological variants of PTC. The comparison of expression profiles in the tumour samples allows the search for a radiation signature, whereas the comparison of expression profiles of the normal contralateral tissues offers a substantial opportunity for assessing the existence of a susceptibility to radiation that could be responsible for tumour development. We have undertaken this analysis as part of a European Union-funded project, GENRISK-T. Gene expression profiles were investigated in tumours that have arisen in the population exposed to fallout from Chernobyl (i.e. born before 26 April 1986) and were compared with profiles of tumours of similar pathology arising in an age-matched population, residing in the same geographical area (same ethnicity) and born after 1 January 1987. RNA samples from these tumours and their contralateral normal tissues were obtained from the Chernobyl Tissue Bank. Several lines of evidence suggest that the predisposition to developing cancer after radiation exposure is variable in the general population and may be measurable from gene expression.

Gene expression profile analysis in laryngeal cancer by high-density oligonucleotide microarrays.

The assessment of gene expression profile in laryngeal cancer shall allow to implement molecular biology methods in diagnostics, as well as in prognosis of the course of disease. Thus, it may influence the choice of the most optimal decisions in regards to the method of treatment, extent of surgical procedure, or the necessity of adding post-operative radiotherapy. The aim of the project was to analyse the gene expression profile of laryngeal cancer using oligonucleotide microarrays, aiming to derive novel molecular markers for that carcinoma. The study comprised a group of 14 patients (12 males and 2 females) with squamous cell laryngeal carcinoma, diagnosed and surgically treated between 2005 - 2007 in the ENT Department of the Silesian Medical University in Katowice, Poland. RNA was isolated from frozen tissue fragments. To assess gene expression profile, high density oligonucleotide microarrays (Affymetrix U 133 Plus 2.0) were applied, with over 54 thousand probesets for over 47 thousand transcripts. Four genes, previously not assesed in diagnostic context in laryngeal carcinoma, seemed to be valuable markers of that neoplasm. These are: metalloproteinase ADAM12, cycline-dependent kinase 2 - CDK2, kinesine 14 - KIF14, suppressor 1 of checkpoint - CHES1.

Optimization of the method of RNA isolation from paraffin blocks to assess gene expression in breast cancer.

UNLABELLED: Molecular oncology increasingly needs the assessment of tumor gene expression profile (transcriptome), most commonly by determination of RNA-based molecular markers employing the technique of quantitative real-time polymerase chain reaction (Q-PCR). However, as all are methods based on RNA, to date, the experience in Q-PCR is mostly limited to freshly collected material frozen at -80 degrees C, i.e. showing no signs of RNA degradation. The aim of the present study was to implement into practice a method of RNA isolation from formalin-fixed and paraffin-embedded (FFPE) breast carcinoma samples collected during routine surgical and histopathological procedure, to further employ it in expression analysis by Q-PCR. The RNA isolation kit RNeasy FFPE (QIAGEN) was used. It was demonstrated that in samples subjected to DNAse digestion, the mean concentration of the obtained RNA was low (46 ng/microl), while during the isolation performed using solely gDNA Eliminator columns, the authors obtained RNA with an almost fourfold higher concentration value. A comparison was made between isolation effectiveness using varying amounts of input material. It was noted that isolation efficacy was lower when three sections were employed (the concentration value of 178 ng/microl) as compared to 5-8 sections (279 and 302 ng/microl, respectively). RNA quality assessment was also performed employing the method of capillary electrophoresis by the "lab-on-a-chip" technology of Agilent Bioanalyzer 2100. Freshly prepared material yielded in single cases samples containing RNA18S and RNA28S populations, while in samples isolated from archival paraffin blocks, the obtained RNA showed more considerable degradation, thus, was of lesser quality. In the analysis of 20 samples from the second collected series, the majority of samples were characterized by the RNA Integrity Number (RIN) values in the range of 2-2.5, still indicative of a substantial degree of RNA degradation. The mean isolation effectiveness in the second series was 885 ng/microl. In 10 of 20 blocks isolated, we succeeded in obtaining sufficient RNA concentration, above 500 ng/microl. It was also noted that the storage time did not affect the amount of RNA obtained from a block: while isolating RNA from freshly prepared blocks, we achieved similar concentrations as when analyzing the archival material. CONCLUSIONS: the key in preserving RNA quality in paraffin blocks is the timing of material collection and fixing. Routine paraffin blocks allow for obtaining RNA for molecular studies, yet with features of considerable degradation.

Prevalence of RAS point mutations in papillary thyroid carcinoma; a novel mutation at codon 31 of K-RAS.

The aim of this study was to assess the incidence of point mutations in RAS oncogenes of papillary thyroid carcinoma (PTC). Tumour specimens were obtained from 29 PTCs. The fragments of exons 1 and 2 of RAS oncogenes family (H- RAS, K- RAS, N- RAS) were amplified and then, point mutations were detected by SSCP and/or by RFLP analysis. Several DNA samples were directly sequenced to confirm the results. Two mutations were found in this study (GAA/CAA at codon 31 of K- RAS and CAA/CAC at codon 61 of N- RAS oncogene). These data confirm the results of previous studies, showing that RAS mutations are more rarely found in PTC than in follicular neoplasms. The influence of a novel mutation at codon 31 of K- RAS oncogene on the development of PTC needs further studies.

Association of NFKB1 -94ins/del ATTG promoter polymorphism with susceptibility to and phenotype of Graves' disease.

Recently, a functional polymorphism in the NFKB1 gene promoter (-94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and Japanese-Kurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the -94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P=0.00005; OR=1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P=0.009; OR=1.49 (1.10-2.01)), and the age of disease onset (P=0.009; OR=1.45 (1.09-1.91)). Our results suggest that NFKB1 -94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.

Is there a need to redefine the upper normal limit of TSH?

Mild forms of hypothyroidism--subclinical hypothyroidism--have recently been discussed as being a risk factor for the development of overt thyroid dysfunction and for a number of clinical disorders. The diagnosis critically depends on the definition of the upper normal limit of serum TSH as, by definition, free thyroxine serum concentrations are normal. Cut-off levels of 4-5 mU TSH/l have been conventionally used to diagnose an elevated TSH serum concentration. Recent data from large population studies have suggested a much lower TSH cut-off with an upper limit of 2-2.5 mU/l but application of strict criteria for inclusion of subjects from the general population studies aiming at assessing TSH reference intervals (no personal or family history of thyroid disease, no thyroid antibodies and a normal thyroid on ultrasonography) did not result in an unequivocal upper limit of normal TSH at 2.0-2.5 mU/l. When summarizing the available evidence for lowered upper TSH cut-off values and their potential therapeutic implications there is presently insufficient justification to lower the upper normal limit of TSH and, for practical purposes, it is still recommended to maintain the TSH reference interval of 0.4-4.0 mU/l. Classifying subjects with a TSH value between 2 and 4 mU/l as abnormal, as well as intervening with thyroxine treatment in such subjects, is probably doing more harm than good.

Risk of malignant tumors in first-degree relatives of patients with differentiated thyroid cancer -- a hospital based study.

In presented study the risk of incidence of familial differentiated thyroid cancer as well as the risk of other malignant tumors in families of DTC patients was evaluated. 999 patients with differentiated thyroid cancer and 825 persons without any history of malignant disease were evaluated on the occurrence of malignant neoplasm within their families. Information about 6614 first degree relatives of DTC index patients and 4939 first degree relatives of control persons were recorded. The incidence of cancers at various sites was compared between first-degree relatives of index patients and control persons and odds ratio with 95% confidence intervals (CI) were calculated for thyroid cancer and other cancer sites. Within 999 families of thyroid cancer index patients 23 families with more than one case of DTC were found. The risk of the development of thyroid cancer in the first degree was 6 (95% CI 1.8-19) times greater in the index group than in the control group. No increased risk for development of other malignancies was observed. Results of our study confirm previous reports of increased risk of thyroid cancer in first-degree relatives of differentiated thyroid cancer patients. However, the relatively small number of first-degree relatives affected with thyroid cancer (24/6614) does not justify at present any screening in the first-degree relatives of patients affected with differentiated thyroid cancer. Simultaneously, no increased risk of other malignant neoplasm was observed in the differentiated cancer families.

Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review.

Well under 15% of differentiated thyroid carcinoma (DTC) is diagnosed at < or =18 years of age. The population is heterogenous and the differences between prepubertal children and pubertals and adolescents are to be considered. Although very little has been reported on children with sporadic DTC under the age of 10 years, juvenile DTC has at least some undeniable differences with adult DTC: (1) larger primary tumor at diagnosis; (2) metastatic pattern and features, namely: (a) greater prevalence of neck lymph node and distant metastases at diagnosis, (b) lungs almost the sole distant metastatic site, (c) pulmonary metastases nearly always functional; (3) closer-to-normal and more frequent sodium-iodide symporter (NIS) expression; and (4) higher recurrence rate but longer overall survival. These differences are especially distinct in prepubertal children. The goals of primary treatment of juvenile DTC are to eradicate disease and extend not only overall, but recurrence-free survival (RFS). Extending RFS is itself a desirable goal in children because it improves quality-of-life, alleviates anxiety during psychologically formative years, reduces medical resource consumption, and may increase overall survival. Primary treatment of DTC generally comprises a combination of surgery, radioiodine ((131)I) ablation, and thyroid hormone therapy applied at varying levels of intensity. Therapeutic decision-making must rely on retrospective adult and/or pediatric outcome studies and on treatment guidelines formulated mostly for adults. Differences between juvenile and adult DTC and physiology dictate distinct treatment strategies for children. We, and many others, advocate a routine intensive approach because of the more advanced disease at diagnosis, propensity for recurrence, and greater radioiodine responsiveness in children, as well as published evidence of significant survival benefits, especially regarding RFS. This intensive approach consists of total thyroidectomy and central lymphadenectomy in all cases, completed by modified lateral lymphadenectomy when necessary and followed by radioiodine administration. However, absence of prospective studies and of universal proof of overall cause-specific survival benefits of this approach have led some to propose more conservative strategies. Most European centers give radioiodine ablation to the vast majority of juvenile DTC patients. Ablation seeks to destroy any residual cancer, including microfoci, as well as healthy thyroid remnant. Large studies have documented the procedure to decrease cause-specific death rates and, in children, to significantly lessen locoregional recurrence rates (by factors of 2-11) independent of the extent of surgery. There is universal agreement on treating inoperable functional metastases with large radioiodine activities. Treatment is especially effective in small tumor foci up to 1 cm in diameter, and should be administered every 6-12 months until complete response, loss of functionality, or attainment of cumulative activities between 18.5-37 GBq (500-1000 mCi). Radioiodine therapy is generally safe. Short-term side effects include nausea and vomiting (more frequent in children than in adults), transient neck pain and edema, sialadenitis (<5% incidence), mild myelosuppression (approximately 25%), transient impairment of gonadal function both in females and males (sperm quality in boys), or nasolacrimal obstruction (approximately 3%), with most cases generally being asymptomatic-moderate, self-limiting, or easily prevented or treated. If pregnancy is ruled out before each (131)I administration, and conception avoided in the year afterward, radioiodine therapy appears not to impair fertility. However, therapeutic (131)I carries a small but definite increase in cancer risk, particularly in the salivary glands, colon, rectum, soft tissue and bone. To better guide primary treatment, different therapeutic combinations should be prospectively compared using RFS as the primary endpoint. Efforts also should be made to identify molecular signatures predicting recurrence, metastasis and mortality.

RET polymorphisms in codons 769 and 836 are not associated with predisposition to medullary thyroid carcinoma.

The study was undertaken to verify whether the RET gene polymorphisms are associated with MTC in patients negative for germline mutations. Two hundred five patients with apparent sporadic MTC were subjected to genetic analysis of RET exons 10, 11, 13, 14, 16 and 22 RET germline mutation carriers were identified with 10.7% frequency. The frequency among 26 patients not older than 30 was 27%. In patients excluded for known mutations we analyzed two polymorphic sites: RET codon 769 and 836. As control group, 90 healthy subjects were investigated. In young patients the observed allelic frequencies were 32% for variant L769/CTG and 5% for variant S836/AGT. Although these values were higher than in older MTC patients (22 and 3%, respectively), as well as in the control group (27 and 2%) the difference was insignificant. We conclude that in Polish patients polymorphisms at RET codons 769 and 836 are not associated with medullary thyroid carcinoma.