In patients with well-differentiated neuroendocrine tumours, there is no apparent benefit of somatostatin analogues after disease control by peptide receptor radionuclide therapy.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) and somatostatin analogues (SSAs) are commonly combined as primary treatment for neuroendocrine neoplasms (NEN), and SSAs given as maintenance. We sought to evaluate whether sequential therapy with PRRT followed by SSAs has progression or survival benefits in patients with NEN after disease control by PRRT. METHODS: This prospective, randomised, single-centre study had as principal eligibility criteria: unresectable, locally advanced, or metastatic, histologically confirmed well-differentiated NEN; no symptoms/biochemical diagnosis of carcinoid syndrome; no SSAs or ≤ 3 months of SSAs before PRRT; and stable disease or partial or complete response after PRRT. Altogether, 115 patients were randomised 2:1 to an SSA group (n = 74) given octreotide acetate LAR every 4 weeks, or a control group (n = 41) receiving only best supportive care. Octreotide treatment was to stop upon intolerable toxicity or patient refusal, or, at physician/patient discretion, upon NEN progression. The primary endpoint was progression-free survival (PFS), the secondary endpoint, and overall survival (OS). RESULTS: Median (25th-75th percentile) follow-up from the first PRRT activity to death or latest observation was 6.6 (3.18-10.22) years. During that time, 71/115 patients (62%) progressed, 52/74 (70%) in the SSA group, and 19/41 (46%) in the control group (p = 0.01). Eighty-eight/115 patients (76%) died, 58/74 (78%) in the SSA group, and 30/41 (73%) in the control group (p = 0.52). Median (95% CI) PFS was 4.7 (2.8-7.7) years in the SSA group, and 6.4 (4.1-not reached) years in controls. Overall, median OS was 6.6 years. Neither PFS nor OS differed between groups (p = 0.129, p = 0.985, respectively). CONCLUSIONS: In patients with disease control after PRRT, subsequent SSA treatment appeared not to be associated with better PFS or OS. Whether to continue SSA administration upon progression after PRRT requires evaluation in a prospective, randomised, controlled multicentre study with a relatively homogeneous sample.

Paediatric-onset and adult-onset Graves' disease share multiple genetic risk factors.

BACKGROUND: Graves' disease (GD) is an autoimmune thyroid disease (AITD) with a peak incidence between 30 and 50 years of age. Although children and adolescents may also develop the disease, the genetic background of paediatric-onset GD (POGD) remains largely unknown. Here, we looked for similarities and differences in the genetic risk factors for POGD and adult-onset GD (AOGD) as well as for variants associated with age of GD onset. MATERIALS AND METHODS: A total of 1267 GD patients and 1054 healthy controls were included in the study. Allele frequencies of 40 established and suggested GD/AITD genetic risk variants (39 SNPs and HLA-DRB1*03) were compared between POGD (N = 179), AOGD (N = 1088) and healthy controls. Subsequently, multiple linear regression was used to explore the relationship between age of GD onset and genotype for each locus. RESULTS: We identified six POGD risk loci, all of them were also strongly associated with AOGD. Although for some of the analysed variants, including HCP5 (rs3094228), PRICKLE1 (rs4768412) and SCGB3A2 (rs1368408), allele frequencies differed nominally between POGD and AOGD patients, these differences were not significant after applying multiple testing correction (Pcor  = 0.05/40 = 1.25 × 10-3 ). Regression analysis showed that patients with higher number of HCP5 risk alleles tend to have a significantly earlier onset of GD (P = 6.9 × 10-5 ). CONCLUSIONS: The results of our study revealed that POGD and AOGD share multiple common genetic risk variants. Moreover, we demonstrated for the first time that HCP5 polymorphism is associated with an earlier age of GD onset in a dose-dependent manner.

Coexistence of TERT Promoter Mutations and the BRAF V600E Alteration and Its Impact on Histopathological Features of Papillary Thyroid Carcinoma in a Selected Series of Polish Patients.

TERT promoter (TERTp) mutations are important factors in papillary thyroid carcinomas (PTCs). They are associated with tumor aggressiveness, recurrence, and disease-specific mortality and their use in risk stratification of PTC patients has been proposed. In this study we investigated the prevalence of TERTp mutations in a cohort of Polish patients with PTCs and the association of these mutations with histopathological factors, particularly in coexistence with the BRAF V600E mutation. A total of 189 consecutive PTC specimens with known BRAF mutational status were evaluated. TERTp mutations were detected in 8.5% of cases (16/189) with the C228T mutation being the most frequent. In six of the PTC specimens (3.2%), four additional TERTp alterations were found, which included one known polymorphism (rs2735943) and three previously unreported alterations. The association analysis revealed that the TERTp hotspot mutations were highly correlated with the presence of the BRAF V600E mutation and their coexistence was significantly associated with gender, advanced patient age, advanced disease stage, presence of lymph node metastases, larger tumor size, and tumor-capsule infiltration. While correlations were identified, the possibility of TERTp mutations being key molecular modulators responsible for PTC aggressiveness requires further studies.

Gender-dependent and age-of-onset-specific association of the rs11675434 single-nucleotide polymorphism near TPO with susceptibility to Graves' ophthalmopathy.

The role of TPO gene polymorphism in the susceptibility to Graves' disease (GD) remains unclear. However, single-nucleotide polymorphisms (SNPs) near TPO have been recently associated with serum levels of thyroid peroxidase (TPO) antibody in two independent genome-wide association studies. Moreover, we have observed a strong association between the rs11675434 SNP located near TPO and the presence of clinically evident Graves' ophthalmopathy (GO). The aim of the current study was to reevaluate and dissect this association in an extended group of 1231 well-characterized patients with GD (1043 adults and 188 children) and 1130 healthy controls from the Polish Caucasian population, considering possible gender-dependent and age-of-onset-specific effects of the studied SNP. We found that the T allele of rs11675434 was significantly more frequent in GD patients with than without GO (odds ratio (OR)=1.26, 95% confidence interval (CI)=1.05-1.51, P=0.012), which was consistent with our previous findings. Further analyses performed in subgroups of patients showed that the association with GO was significant in adult patients with age of GD onset ⩾45 years (OR=1.34, 95% CI=1.03-1.75, P=0.031), but not in children and adolescents or adult patients with earlier onset of the disease (OR=1.72, 95% CI=0.77-3.84, P=0.18 and OR=1.05, 95% CI=0.79-1.40, P=0.75, respectively). Moreover, a strong association with GO was present in males (OR=2.06, 95% CI=1.40-3.02, P=0.0002), whereas it was absent in females (OR=1.10, 95% CI=0.90-1.35, P=0.35). The results of our study further suggest that rs11675434 SNP located near TPO is associated with the development of GO, especially in males and patients with later age of GD onset.

Heterogeneity of the Clinical Presentation of the MEN1 LRG_509 c.781C>T (p.Leu261Phe) Variant Within a Three-Generation Family.

Multiple neuroendocrine neoplasia type 1 (MEN1) is a rare genetic disorder with an autosomal dominant inheritance, predisposing carriers to benign and malignant tumors. The phenotype of MEN1 syndrome varies between patients in terms of tumor localization, age of onset, and clinical aggressiveness, even between affected members within the same family. We describe a heterogenic phenotype of the MEN1 variant c.781C>T (LRG_509t1), which was previously reported only once in a family with isolated hyperparathyroidism. A heterozygous missense variant in exon 4 of the gene was identified in the sequence of the MEN1 gene, i.e., c.781C>T, leading to the amino acid change p.Leu261Phe in a three-generation family. In the screened family, 5/6 affected members had already developed hyperparathyroidism. In the index patient and two other family members, an aggressive course of pancreatic neuroendocrine tumor (insulinoma and non-functioning neuroendocrine tumors) with dissemination was diagnosed. In the index patient, late diagnosis and slow progression of the disseminated neuroendocrine tumor have been observed (24 years of follow-up). The very rare variant of MEN1, LRG_509t1 c.781C>T /p.Leu261Phe (LRG_509p1), diagnosed within a three-generation family has a heterogenic clinical presentation. Further follow-up of the family members should be carried out to confirm the spectrum and exact time of clinical presentation.

A Direct Comparison of Patients With Hereditary and Sporadic Pancreatic Neuroendocrine Tumors: Evaluation of Clinical Course, Prognostic Factors and Genotype-Phenotype Correlations.

Introduction: Pancreatic neuroendocrine tumors (PNETs) in hereditary syndromes pose a significant challenge to clinicians. The rarity of these syndromes and PNETs itself make it difficult to directly compare them with sporadic PNETs. Despite research suggesting differences between these two entities, the same approach is used in hereditary and sporadic PNETs. Methods: We included 63 patients with hereditary PNET (GpNET) and 145 with sporadic PNET (SpNET) in a retrospective observational study. Clinical and genetic data were collected in two Polish endocrine departments from January 2004 to February 2020. Only patients with confirmed germline mutations were included in the GpNET cohort. We attempted to establish prognostic factors of metastases and overall survival in both groups and genotype-phenotype correlations in the GpNET group. Results: Patients with GpNET were younger and diagnosed earlier, whereas their tumors were smaller and more frequently multifocal compared with patients with SpNET. Metastases occurred more frequently in the SpNET group, and their appearance was associated with tumor size in both groups. GpNET patients had longer overall survival (OS). OS was affected by age, age at diagnosis, sex, grade, stage, tumor diameter, occurrence and localization of metastases, type of treatment, and comorbidities. In the MEN1 group, carriers of frameshift with STOP codon, splice site, and missense mutations tended to have less advanced disease, while patients with mutations in exon 2 tended to have metastases more frequently. Conclusions: Direct comparisons of GpNET and SpNET demonstrate significant differences in the clinical courses of both entities, which should force different approaches. A larger group of patients with GpNET should be assessed to confirm genotype-phenotype correlations.

Genetic predisposition to papillary thyroid cancer.

Approximately 5% of differentiated thyroid cancers are hereditary. Hereditary non-medullary thyroid cancer may occur as a minor component of familial cancer syndromes (e.g. familial adenomatous polyposis) or as a primary feature (familial non-medullary thyroid cancer [FNMTC]). Among FNMTC, PTC is the most common. Although a hereditary predisposition to non-medullary thyroid cancer is well established, the susceptibility genes are poorly known. Up to now, by linkage analysis using microsatellite markers, several putative loci have been described - 1q21, 6q22, 8p23.1-p22, and 8q24; however, validation studies have been unsuccessful. In the present review we discuss the results of linkage analysis and the most recent results of genome wide association studies (GWAS) with high resolution SNP (single nucleotide polymorphism) arrays.

Germinal mutations of RET, SDHB, SDHD, and VHL genes in patients with apparently sporadic pheochromocytomas and paragangliomas.

INTRODUCTION: Pheochromocytomas and paragangliomas are derived from neural crest cells and are localized mainly in adrenal medulla and sympathetic or parasympathetic ganglia. They can be inherited (25%) and be part of multi-endocrine syndromes such as MEN2 syndrome, von Hippel-Lindau syndrome, pheochromocytoma/paraganglioma syndrome, neurofibromatosis type 1, and Sturge-Weber syndrome. Clinical presentation can sometimes be atypical and does not always allow proper diagnosis. In such situations, DNA analysis can be helpful, especially when the pheochromocytoma is the first and only symptom. MATERIAL AND METHODS: We analyzed DNA from 60 patients diagnosed and treated in the Centre of Oncology with a diagnosis of pheochromocytoma or paraganglioma. DNA analysis was carried out for RET (exons 10, 11, 13, and 16), SDHB, SDHD, and VHL genes. Techniques used for the analysis were direct sequence analysis, MSSCP, and RFLP. RESULTS: Germinal mutations were found in 16 patients (26,7%). Most frequent were mutations in RET proto-oncogene, followed by VHL gene, one mutation in SDHB, and one in SDHD genes. A comparison of some of the clinical features of both groups (with and without mutation) showed statistically significant differences. CONCLUSIONS: The results of our study show that genetic predisposition is frequent in chromaffin tissue tumours, which indicates that DNA analysis is necessary in every case, also because of possible atypical clinical presentation. (Pol J Endocrinol 2010; 61 (1): 43-48).

An Intronic HCP5 Variant Is Associated With Age of Onset and Susceptibility to Graves Disease in UK and Polish Cohorts.

CONTEXT: The genetic background of young-onset Graves disease (GD) remains largely unknown. An intronic variant in human leukocyte antigen (HLA) complex P5 (HCP5) has previously been associated with GD susceptibility and age of onset in a cohort of Polish patients. OBJECTIVE: We aimed to investigate the association of the HCP5 variant rs3094228 with GD susceptibility and age of onset in a UK cohort and conduct a meta-analysis of UK and Polish data. DESIGN AND PARTICIPANTS: rs3094228 was genotyped in 469 UK patients with GD using Taqman chemistry. Genotype frequencies were compared with genotypic data available from the Wellcome Trust case-control consortium using logistic regression analysis. To determine whether rs3094228 is independently associated with age of GD onset, the HLA DRB1*0301 tagging variant, rs535777, was also genotyped. RESULTS: The C allele of rs3094228 was overrepresented in the UK GD cohort compared with controls (P allele=5.08 × 10-9, odds ratio 1.76; [95% confidence interval, 1.46-2.13]). This association was more marked in young-onset GD (<30 years) (P allele=1.70 × 10-10 vs P allele=0.0008). The meta-analysis of UK and Polish data supported the association of the C allele with GD susceptibility (P allele=1.79 × 10-5) and age of onset (P allele=5.63 × 10-8). Haplotype analysis demonstrated that rs3094228 is associated with age of GD onset (P = 2.39 × 10-6) independent of linkage disequilibrium with HLA DRB1*0301. CONCLUSION: The rs3094228 HCP5 polymorphism is independently associated with GD susceptibility and age of onset in a UK GD cohort. Our findings indicate a potential role of long noncoding ribonucleic acids, including HCP5, in GD pathogenesis, particularly in the younger population.

Multiple endocrine neoplasia type 1 in Poland: a two-centre experience.

INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1) has been causing problems for clinicians since it was first described in 1954 by Wermer. Not only its rarity, but also its variable clinical manifestations and lack of genotype-phenotype correlation make it hard to establish evidence-based guidelines for the management of this syndrome. Nationwide registers and population-based research are the best means to improve knowledge about this rare disease. As yet, there is no example of such research in the Polish population of MEN1 patients. MATERIAL AND METHODS: We performed a retrospective analysis of clinical and genetic data of patients diagnosed with MEN1 syndrome and followed-up in two polish referral centres in the years 1994-2018. RESULTS: We analysed 79 patients, of whom the majority were women. The mean age of the patient population was 43 years, mean age at MEN1 diagnosis was 37.95 years, and mean interval from initial symptoms to MEN1 diagnosis was 6.93 years. Primary hyperparathyroidism (PHP), gastroenteropancreatic neuroendocrine tumour (GEP-NET), and pituitary adenoma (PA) developed in 90%, 52%, and 47% of patients, respectively. The dominance of insulinoma with low prevalence of gastrinoma is the most vivid difference, when compared to previously described populations. Moreover, we found 3.5-fold higher risk of developing a pituitary tumour in patients with a frameshift mutation with the STOP codon of the MEN1 gene. CONCLUSIONS: The Polish population of patients with MEN1 is different than previously described European and Asian populations, primarily in prevalence of functional NETs. A frameshift mutation with the STOP codon of the MEN1 gene significantly increases the risk of PA. Further studies with a larger cohort of patients are needed to fully describe the Polish population and improve diagnosis and management of the syndrome.

[131I-MIBG therapy in the treatment of pheochromocytoma in children--own experiences]. / Terapia 131I-MIBG w leczeniu guzów chromochlonnych u dzieci--doswiadczenia wlasne.

Three cases of pheochromocytoma in children/adolescents or young adults treated by 131I-MIBG are presented in this study. In one patient 131I-MIBG was administrated after ineffective surgical treatment and chemotherapy of a benign retroperitoneal tumor, whereas in two other patients 131I-MIBG therapy was carried out because of malignant pheochromocytoma dissemination. In a child with retroperitoneal paraganglioma decrease of tumor size and its fibrosis after 131I-MIBG therapy allowed radical surgery and complete recovery. In two other cases partial remission was achieved. All patients showed a good subjective response with improvement of the general condition and better blood pressure control. In two children adverse reactions such as leucopenia, hypothyroidism or hypogonadism were observed. The presented data confirm effectiveness and acceptable tolerance of 131I-MIBG treatment in pheochromocytoma, what is very important in pediatric patients.

131-I MIBG therapy of malignant pheochromocytoma and paraganglioma tumours - a single-centre study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare tumors deriving from chromaffin cells of adrenal medulla or paraganglia. They are usually benign but 10-35% of them present malignant behavior. The aim of the study was to evaluate the efficacy and safety of 131-I MIBG therapy in malignant pheochromocytoma /paraganglioma patients (MPPGL). MATERIAL AND METHODS: 18 patients (7 women and 11 men) were included in this study. Between 2002 and 2016 they underwent 131-I MIBG therapy because of MPPGL and their medical data were analyzed retrospectively. Clinical indications for the treatment included progressive disease or massive tissue involvement independently from disease progression. Tumor response for the first time was assessed 3 months after the last treatment according to Response Evaluation Criteria in Solid Tumors criteria and by 131-I MIBG scans. RESULTS: The mean single dose used was 7.25 GBq (196 mCi) and mean cumulative dose 33.08 GBq ( 894 mCi). In 2 (11%) patients complete tumor response was achieved. In 1 (6%) patient partial response was obtained. In 13 (72%) patients stable disease was observed. In 2 (11%) patients progression was diagnosed three months after treatment discontinuation. In the whole studied group the progression free survival time was 85 months and overall 5-year survival was 87%. CONCLUSIONS: Radionuclide treatment with use of 131-I MIBG may be effective form of palliative treatment for patients with inoperative neoplasm spread, progressive disease or patients requiring alleviation of symptoms. < p > < /p >.

Guidelines of Polish National Societies Diagnostics and Treatment of Thyroid Carcinoma. 2018 Update.

Significant advances have been made in thyroid can-cer research in recent years, therefore relevant clinical guidelines need to be updated. The current Polish guidelines "Diagnostics and Treatment of Thyroid Carcinoma" have been formulated at the "Thyroid Cancer and Other Malignancies of Endocrine Glands" conference held in Wisla in November 2015 [1].

Octreotide suppression test in diagnosing and predicting the outcome of therapy in patients with neuroendocrine tumors. Preliminary report.

INTRODUCTION: Chromogranin A (CgA) is a non-specific marker of neuroendocrine tumors (NET) and is important in monitoring the disease course and NET treatment. AIM OF THE STUDY: Usefulness of suppression test of CgA secretion with octreotide in diagnosis and predicting the therapy outcome in NET patients. MATERIAL AND METHODS: The study included 32 patients with NET of gastrointestinal tract, lung and of unknown origin. CgA level in blood plasma on fasting, before and 30, 60, 90 and 120 minutes after subcutaneous administration of 100 mug octreotide, was determined in all patients. The subjects were divided into two subgroups with relation to CgA level and to the results of somatostatin receptor scintigraphy (SRS). RESULTS: Statistically significant CgA decrease after octreotide administration in all study time points and positive results of SRS were found in the patients with the elevated CgA level. No statistically significant decrease of CgA level after octreotide was found in the group with normal CgA levels. In this group, 13 patients had a negative result of SRS, and somatostatin receptors expression was found in one patient. Tolerance of somatostatin analogs (SSA) therapy was very good. CONCLUSIONS: Octreotide suppression test with CgA level assessment in NET patients is a simple, straightforward examination, providing information on the predicted response to the applied SSA and the data on initial clinical tolerance of those agents. This examination can also be a screening test useful in planning the treatment with SSA in patients with NET.

Interaction of HLA-DRB1 alleles with CTLA-4 in the predisposition to Graves' disease: the impact of DRB1*07.

OBJECTIVE: To study interactions between the two most widely confirmed Graves' disease (GD) loci: HLA-DRB1 and CTLA-4. HLA-DRB1*03 (risk allele) and DRB1*07 (protective allele) were analyzed in this aspect, the linked TNF G(-308)A polymorphism was also considered. DESIGN: A case-control study of 429 patients with GD compared to 308 healthy subjects. The impact of genes and their interactions were analyzed by stepwise logistic regression. RESULTS: The independent effects of DRB1*03 and DRB1*07 were confirmed in our study both by stratification studies and logistic regression. CTLA-4 did not appear to be associated with GD when the interactions with other genes were considered. By logistic regression we observed a significant interaction between DRB1*07 and CTLA-4 and revealed that CTLA-4 49G attenuated the DRB1*07-related protection, the effect noticed also in three-way stratification studies. We confirmed that the TNF G(-308)A polymorphism is only a marker of the DRB1 status. CONCLUSION: Our results stress the importance of complex gene interactions in the multigene predisposition to GD. The interactions between two predisposing loci, DRB1 and CTLA-4, are exerted rather by DRB1*07 than DRB1*03 allele: CTLA-4 acts via switching off the protective DRB1*07 influence, whereas the effect of DRB1*03 is independent.

[Hypoparathyroidism after surgery on thyroid cancer: is there a delayed chance for recovery after a prolonged period of substitutive therapy?]. / Niedoczynnosc przytarczyc po operacji raka tarczycy: czy istnieje szansa na opóznione samoistne wyrównanie funkcji gruczolów?

INTRODUCTION: Transient and persistent hypoparathyroidism (HPT) belong to the well known complications of total thyroidectomy performed because of thyroid carcinoma. The true frequency of persistent hypoparathyroidism is often higher than estimated in the reports published by the specialized centers with low rate of complications. THE AIM OF THE STUDY: Investigation whether the repeated check-up, performed over 2 years post thyroidectomy, reveals some cases of recovery in patients diagnosed with persistent HPT post thyroid cancer surgery. MATERIAL AND METHODS: In total, 115 patients were included into the study, all of them treated with vitamin D derivatives and calcium supplementation. In 17 of them a diagnosis of transient hypoparathyroidism was made on the basis of evaluation performed 6 months after surgery, the remaining 98 were diagnosed with persistent HPT. Parathyroid (PTH) function was reevaluated after withdrawal of active vitamin D derivatives for 10 days and of calcium carbonate for two days during the hospital stay in patients admitted for radioiodine scan, thus after thyroxine withdrawal. The control group consisted of 123 DTC (differentiated thyroid carcinoma) patients without parathyroid dysfunction. On the basis of intact PTH serum level and calcium and phosphorus estimations HPT was unequivocally confirmed in 49 patients (50%). The remaining 49 patients exhibited normal PTH level and in 43 (86%) of them Ca(2+) level was also within normal range, thus delayed, recovery from HPT was stated. RESULTS: Our results indicate that reevaluation of hypoparathyroidism post total thyreoidectomy is necessary, as delayed recover of parathyroid dysfunction is a frequent phenomenon. We also propose criteria of reevaluation of HTP in patients on chronic substitutive therapy.

[Evaluation of the therapeutic benefits in relation to the extent of surgery in patients with differentiated thyroid carcinoma]. / Ocena korzysci terapeutycznych z zastosowania okreslonego zakresu operacji u chorych na zrósnicowane raki tarczycy.

INTRODUCTION: Evaluation of the therapeutic benefits in relation to the stage of thyroid cancer and to the extent of surgery and the risk of postoperative complications. MATERIAL AND METHODS: Retrospective analysis of differentiated thyroid carcinoma (DTC) patients staged T1M0 versus T2-T4M0 was performed. All of them were treated or diagnosed in Institute of Oncology in Gliwice between 1986-1998. Previously they were operated in various surgical centers all-over Poland. The risk of death, local relapse and postoperative complications were analyzed using the decisiontree model to evaluate the therapeutic benefits. RESULTS: The recurrent laryngeal nerve injury (transient or permanent) was observed in retrospective analysis in 21% of patients, while postoperative hyperparathyroidism in 15.8%. The analysis of the therapeutic benefit index showed no advantage of total thyroidectomy in the T1M0 group (0.96 vs. 0.98 in patients treated by less than total thyroidectomy). The advantage of radical surgery was confirmed in T2-T4M0 group. The therapeutic benefit index was 0.92 in patients treated by total thyroidectomy and 0.69 in those who received less extensive operation. CONCLUSIONS: The analysis of therapeutic benefits confirmed the limit of 1 cm tumor diameter between less extensive surgery and total thyroidectomy. It showed that total thyroidectomy brings a significant therapeutic benefits in patients in > T1M0 stage. The improvement of overall survival and decrease of local relapse far outweigh the disadvantages related to postoperative complications.

[Recombinant human TSH stimulation in radioiodine treatment of disseminated differentiated thyroid cancer--update of current and our own experiences]. / Stymulacja rhTSH w leczeniu jodem promieniotwórczym funkcjonalnych przerzutów zaawansowanego zrósnicowanego raka tarczycy--omowienie aktualnego stanu wiedy i przeglad doswiadczen wlasbych.

Traditionally, for diagnostic and therapeutic application of radioiodine in patients with differentiated thyroid cancer (DTC), a 4 to 6 week withdrawal of thyroid hormone was applied. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and associated morbidity. The results of rhTSH administration and endogenous TSH stimulation are equivalent in detecting recurrent DTC. At the present time rhTSH is approved as an adjunct for diagnostic procedures and thyroid ablation in patients with DTC. In addition, rhTSH has potential for use in facilitating the treatment of metastases in patients with DTC. In this review we have summarized our own experiences with rhTSH aided radioiodine therapy in patients with disseminated thyroid cancer. Generally, rhTSH was very well tolerated and treatment results were comparable to those achieved with thyroid hormone withdrawal.

Occurrence of phaeochromocytoma tumours in RET mutation carriers - a single-centre study.

INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant genetic syndrome caused by germline mutation in RET proto-oncogene. The most common mutations are in a cysteine rich domain. Phaeochromocytoma will develop in approximately 50% of RET proto-oncogene carriers. MATERIAL AND METHODS: The studied population consisted of 228 RET proto-oncogene mutation carriers. Monitoring for the diagnosis of phaeochromocytoma was carried out in all patients with established genetic status. Mean time of follow up was 138 months. Surveillance consisted of periodically performed clinical evaluation, 24-hour urinary determinations of total metanephrines complementary with imaging (CT, MR, MIBG scintigraphy). RESULTS: Phaeochromocytoma developed in 41 patients (18% of all RET proto-oncogene mutations carriers). The mean age of diagnosis for the whole cohort was 43 years. In eight cases phaeochromocytoma was the first manifestation of the MEN 2 syndrome. Only eight (20%) patients were symptomatic at diagnosis of phaeochromocytoma. The mean size of the tumour was 4.3 cm. There was no extra-adrenal localisation. We observed one case of malignant phaeochromocytoma. CONCLUSIONS: In patients with MEN 2 syndrome phaeochromocytomas are usually benign adrenal tumours with high risk of bilateral development. Taking to account the latter risk and non-specific clinical manifestation of the neoplasm it is mandatory to screen all RET proto-oncogene mutations carriers for phaeochromocytoma.

Differences in Gene-Gene Interactions in Graves' Disease Patients Stratified by Age of Onset.

BACKGROUND: Graves' disease (GD) is a complex disease in which genetic predisposition is modified by environmental factors. Each gene exerts limited effects on the development of autoimmune disease (OR = 1.2-1.5). An epidemiological study revealed that nearly 70% of the risk of developing inherited autoimmunological thyroid diseases (AITD) is the result of gene interactions. In the present study, we analyzed the effects of the interactions of multiple loci on the genetic predisposition to GD. The aim of our analyses was to identify pairs of genes that exhibit a multiplicative interaction effect. MATERIAL AND METHODS: A total of 709 patients with GD were included in the study. The patients were stratified into more homogeneous groups depending on the age at time of GD onset: younger patients less than 30 years of age and older patients greater than 30 years of age. Association analyses were performed for genes that influence the development of GD: HLADRB1, PTPN22, CTLA4 and TSHR. The interactions among polymorphisms were analyzed using the multiple logistic regression and multifactor dimensionality reduction (MDR) methods. RESULTS: GD patients stratified by the age of onset differed in the allele frequencies of the HLADRB1*03 and 1858T polymorphisms of the PTPN22 gene (OR = 1.7, p = 0.003; OR = 1.49, p = 0.01, respectively). We evaluated the genetic interactions of four SNPs in a pairwise fashion with regard to disease risk. The coexistence of HLADRB1 with CTLA4 or HLADRB1 with PTPN22 exhibited interactions on more than additive levels (OR = 3.64, p = 0.002; OR = 4.20, p < 0.001, respectively). These results suggest that interactions between these pairs of genes contribute to the development of GD. MDR analysis confirmed these interactions. CONCLUSION: In contrast to a single gene effect, we observed that interactions between the HLADRB1/PTPN22 and HLADRB1/CTLA4 genes more closely predicted the risk of GD onset in young patients.