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Medullary thyroid cancer (MTC) is a rare thyroid malignancy, which arises from parafollicular C-cells. It occurs in the hereditary or sporadic form. Hereditary type is a consequence of activation of the RET proto-oncogene by germline mutations, whereas about 80% of sporadic MTC tumors harbor somatic, mainly RET or rarely RAS mutations. According to the current ATA guidelines, a postoperative MTC risk stratification and long-term follow-up are mainly based on histopathological data, including tumor stage, the presence of lymph node and/or distant metastases (TNM classification), and serum concentration of two biomarkers: calcitonin (Ctn) and carcinoembryonic antigen (CEA). The type of RET germline mutation also correlates with MTC clinical characteristics. The most common and the best known RET mutation in sporadic MTC, localized at codon 918, is related to a more aggressive MTC course and poorer survival. However, even if histopathological or clinical features allow to predict a long-term prognosis, they are not sufficient to select the patients showing aggressive MTC courses requiring immediate treatment or those, who are refractory to different therapeutic methods. Besides the RET gene mutations, there are currently no other reliable molecular prognostic markers. This review summarizes the present data of genomic investigation on molecular prognostic factors in medullary thyroid cancer.

Introduction: Pheochromocytomas in hereditary syndromes tend to grow multifocal with adrenal involvement on both sides. Surgical treatment with bilateral adrenalectomy inevitably leads to life-long hormonal dependence, which significantly affects quality of life. The development of minimally invasive adrenal surgery has created a chance to preserve adrenal cortex function in these patients. The aim of the present study was to evaluate the safety of laparoscopic cortical-sparing adrenal surgeries and their efficacy in the prevention of postoperative adrenal insufficiency in patients with hereditary pheochromocytomas. Material and methods: We retrospectively analysed the medical histories of 10 patients, who underwent 10 laparoscopic cortical sparing adrenal surgeries from January 2015 to January 2019 in our centre. The decision to perform sparing surgery was based on preoperative diagnosis of hereditary syndrome in line with the result of DNA analysis or its diagnosis based on the clinical appearance. All surgeries were performed laparoscopically from transperitoneal access in the lateral decubitus position, with preserving 1/3–1/4 adrenal tissue. The sufficiency of remnant adrenal tissue was assessed in all patients. The median time of follow-up was three years (ranged 0.5–4 years). Results: No intraoperative complications were observed. One case of acute heart failure was the only early postoperative adverse event. There were no late postoperative complications and no local recurrences observed. In one out of three patients undergoing sparing surgery as a second procedure after former total adrenalectomy, adrenal cortex failure occurred. In all patients after unilateral surgery or after bilateral surgery performed simultaneously (total adrenalectomy at one side and sparing surgery contralaterally), function of remnant adrenal tissue was preserved. Conclusions: In hereditary pheochromocytomas, with minimal risk of malignant process, laparoscopic cortical sparing adrenal surgeries are the safe approach and provide the chance to preserve adrenal cortex function.

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].

Immunotherapy using monoclonal antibodies - checkpoint inhibitors - is a dynamically evolving discipline of clinical oncology and a new hope for patients with advanced and disseminated cancer. However, the activation of T-lymphocytes can at the same time lead to autoimmune response and destruction of healthy organs, which is a serious adverse effect that can also affect the endocrine system. Here we present possible endocrine complications of immunotherapy with contemporary inhibitors of immune checkpoints (CTLA-4, PD-1, PD-L1/L2), their frequency, symptoms, and proposed grade-dependent treatment.Failure to diagnose endocrine pathology can in adverse circumstances lead to treatment failure and condemn the patient's fate. Due to tremendous progress in cancer immunotherapy during the last few years and an increase in the number of treated patients, endocrinologists should become acquainted with the specificity of this mode of oncological treatment.

ObjectiveThe risk of autoimmune diseases (AD) in patients with Turner Syndrome (TS) is twice higher than in the general female population and four times higher than in the male population. The causes of the increased incidence of AD in TS are still under discussion. We hypothesized the presence of a specific humoral, cellular, and regulatory T cell (Treg) immunity profile which predisposes to AD, disorders of immunity, and disorders of immune regulation.MethodsThe study encompassed 37 girls with TS and with no signs of infection. The control group included 11 healthy girls with no hormonal disorders. A medical history focused on AD and immunity disorders was taken from all participants. The levels of: immunoglobulins IgG, IgA, IgM, total lymphocytes, lymphocytes subpopulations CD3+, CD4+, CD8+, CD19+, natural killer cells, Treg cells (CD4+ CD25+ CD127− FOXP3+), anti-inflammatory cytokines (interleukin-10, transforming growth factor-β), anti-nuclear antibodies, glutamic acid decarboxylase (GAD65 Abs), anti-thyroid peroxidase (anti-TPO Ab), and anti-thyroglobulin (anti-TG Ab) autoantibodies were determined in each participant.ResultsThe mean age and BMI in the TS group and in controls were comparable (11.9 ± 4.1 vs. 12.5 ± 4.0 years; 19.2 ± 3.4 vs. 19.7 ± 4.6, p > 0.05). Mean hSDS was significantly higher in controls (−2.2 ± 0.9 vs. −0.4 ± 1.5, p

Objective Estrogen replacement therapy (ERT) for Turner syndrome (TS) is a widely discussed topic; however, the optimal model of ERT for patients with delayed diagnosis and/or initiation of therapy is still unclear, mainly due to insufficient data. We present the results of a prospective observational single-center study in which the efficacy of late-onset puberty induction by one-regimen transdermal ERT in TS girls was evaluated. Methods The analysis encompassed 49 TS girls (63.3% with 45,X) with hypergonadotropic hypogonadism in whom unified transdermal ERT protocol was used for puberty induction (first two months 12.5 μg/24 h, thereafter 25.0 μg/24 h until breakthrough bleeding). Clinical visits for examination and therapy modification took place every 3–6 months. Transabdominal pelvic ultrasound examinations were performed at least twice: at the beginning and at the end of follow-up. Results The mean (SD) age at ERT induction was 15.1 (1.3) years. The duration of follow-up was 2.4 (1.1) years. Half of all the patients had at least B2 after 0.57 years, B3 after 1.1 years, B4 after 1.97 years, and menarche after 1.82 years from ERT initiation. With earlier initiation of ERT (≤14 years), B2 (p = 0.059) was achieved faster and B4 (p = 0.018) significantly slower than with the later start of ERT. Thirty-four (94.4%) patients had at least stage B3 at menarche. The karyotype, initial weight, and body mass index had no impact on puberty tempo during ERT. The uterine volume increased significantly during ERT in all the study group (p 14 years). Conclusion The presented easy-to-use fixed-dose regimen for late-onset puberty induction allowed for a satisfactory rate of achieving subsequent puberty stages and did not influence the growth potential.

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 Wisła in November 2015 [1].

Introduction: Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations. Material and methods: Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing. Results: RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations. Conclusions: RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients. However, their role in MTC tumorigenesis remains unclear. (Endokrynol Pol 2015; 66 (2): 121–125)

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).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.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%.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.

Multi kinase inhibitors (MKIs) are new drugs, which show activity against receptors of different growth factors leading to the inhibition of tumor cells growth and proliferation. This review summarizes a 10-year experience with the use of MKIs in thyroid cancer (TC). It focuses not only on sorafenib, lenvatinib, vandetanib and cabozantinib, already approved in TC, but also presents an overview of the results of different trials with distinct MKIs so far carried out in TC. Areas covered: Published results of phase I, II and III studies and other reports evaluated the efficacy of different targeted drugs in TC. Expert opinion: Despite numerous clinical trials with distinct MKIs, only four of them unequivocally demonstrated a beneficial effect on progression free survival in radioiodine refractory differentiated or medullary TC. In contrast to other solid tumors, we are still lacking in convincing evidences of their impact on overall survival. We still do not have any strong proof fulfilling evidence-based medicine criteria, when to start MKIs and which drug to use. The questions whether we really have to wait for disease progression in patients with a large tumor burden and/or aggressive types TC or when to stop MKIs treatment remain open.

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.

Medullary thyroid cancer (MTC) can be caused by germline mutations of the RET proto-oncogene or occurs as a sporadic form. It is well known that RET mutations affecting the cysteine-rich region of the protein (MEN2A-like mutations) are correlated with different phenotypes than those in the kinase domain (MEN2B-like mutations). Our aim was to analyse the whole-gene expression profile of MTC with regard to the type of RET gene mutation and the cancer genetic background (hereditary vs sporadic). We studied 86 MTC samples. We demonstrated that there were no distinct differences in the gene expression profiles of hereditary and sporadic MTCs. This suggests a homogeneous nature of MTC. We also noticed that the site of the RET gene mutation slightly influenced the gene expression profile of MTC. We found a significant association between the localization of RET mutations and the expression of three genes: NNAT (suggested to be a tumour suppressor gene), CDC14B (involved in cell cycle control) and NTRK3 (tyrosine receptor kinase that undergoes rearrangement in papillary thyroid cancer). This study suggests that these genes are significantly deregulated in tumours with MEN2A-like and MEN2B-like mutations; however, further investigations are necessary to demonstrate any clinical impact of these findings.

Background: The risk of immunoglobulin resistance is still likely to occur in Kawasaki disease (KD) despite adequate treatment. The Kobayashi score (KS) is used to predict unresponsiveness to treatment although the usefulness of the score in populations other than Asian seems to be debatable. Aim: The analysis of clinical and laboratory parameters predisposing to immunoglobulin resistance and coronary complica­tions in children hospitalised due to KD. Methods: The data of children hospitalised due to KD between 2003 and 2016 underwent analysis. Clinical and laboratory parameters were analysed, including all parameters present in KS in relation to the risk of intravenous immunoglobulin (IVIG) resistance and the occurrence of coronary complications in the form of aneurysms and dilatations. Results: Seventy-three children (51 boys; aged 1.5–135 months) with KD were hospitalised. In eight (11%) patients IVIG re­sistance was observed. We reported aneurysms or coronary dilatations in 13 (17.8%) children. The criterion for increased risk of IVIG resistance based on KS (≥ 4 points) was fulfilled by 21 (29%) children. Resistance to IVIG and coronary complications were observed in four (19.1%) and two (9.5%) children with the score ≥ 4 points, respectively, and four (7.7%) and 11 (21.6%) from the group < 4 points in KS, respectively. The prevalence of IVIG resistance and coronary artery complications was not different between the group with ≥ 4 and the group with < 4 points (p = 0.22, p = 0.32, respectively). A higher risk of IVIG resistance was confirmed in children with a longer duration of fever (13.0 days with IVIG resistance vs. 9.2 days with a good response to IVIG, p = 0.04). For the prediction of the occurrence of coronary artery aneurysms the following were of great importance: the day of diagnosis (which was usually the day of the beginning of treatment), the number of symptoms, and the maximal platelet count (p = 0.001; p = 0.019 and p = 0.026, respectively). Conclusions: In our study population we did not demonstrate the usefulness of KS to predict IVIG resistance or the risk of the occurrence of coronary artery aneurysms. However, prolonged fever, late diagnosis, poorly symptomatic course of the disease, and a high platelet count at the time of the follow-up remain independent risk factors.

The main purpose of our retrospective study was to evaluate the medical care of the patients with subclinical hypothyroidism (sHT) and to investigate the rationale for administering L-thyroxine (LT-4) to young sHT patients.Patients and Methods. Based on a retrospective review of the charts of 261 patients referred to the Endocrinology Outpatient Clinic between 2009 and 2014 with suspicion of sHT, 55 patients were enrolled for further analysis. Data collected was baseline age, anthropometric measurements, serum TSH, fT4, fT3, anti-thyroid autoantibodies, positive family history, absence/presence of clinical symptoms, length of follow-up, and data concerning LT-4 therapy (therapy: T1; no therapy: T0).Results. T1 encompassed 33 (60.0%) patients. There were no differences between T1 and T0 (p>0.05) with regard to age, TSH concentrations, BMIZ-score, and hSDS values, though follow-up was longer in T1 (p<0.01). Four (11.8%) children in T1 and none in T0 had a positive family history of thyroid disorders. Fifteen (68.2%) patients in group T0 became euthyroid. One (1.8%) girl (T1) developed overt hypothyroidism.Conclusions. A small percentage of patients can proceed to overt hypothyroidism. Only positive family history seemed to influence the decision to initiate LT-4 therapy. Further prospective studies are warranted in order to establish treatment indications, if any, and the mean recommended dosage of LT-4.

Background More than 10% of healthy population has one or more accessory spleens. The most common location is the hilum of the spleen or area near the tail of the pancreas. The radiological appearance of accessory spleens in oncologic patients who underwent splenectomy can be misinterpreted as a recurrence, especially in the case of compensatory growth of an accessory spleen in successive radiological examinations. CASER REPORTS: We present the cases of three patients who underwent splenectomy for gastric carcinoid, gastric adenocarcinoma and cancer of the left adrenal gland, respectively. CT examination and/or PET-CT scan revealed suspicious findings in the left upper abdomen. In one patient, the dimensional increase of this finding in successive examinations was initially considered suggestive for cancer recurrence. Scintigraphy with (99m)Tc-nanocolloid was able to confirm the presence of an accessory spleen in all these patients. Conclusions Splenic scintigraphy is an economical, accessible and accurate tool in differential diagnosis of accessory spleens in patients after splenectomy.

For Turner syndrome (TS) patients, smooth transition from pediatric to adult health care is a critical point. The study objective was to evaluate the medical follow-up of young women with TS in one clinical center 3 years after the latest guidelines had been introduced by the TS Study Group. A questionnaire study was performed in 59 TS adults selected from a database of 117 patients. Twenty-two of them, aged 23.0 ± 2.8 years, consented to participate. Nineteen responders (86.4%) were followed up by general practitioners who were not aware of the TS diagnosis in 14 (63.6%) cases. Eight (36.4%) were seen regularly by the relevant specialists. Adequate medical assessment varied from 5% (celiac serology) to 74% (gynecology assessment) and 82% (ear-nose-throat) of participants. None of the patients had undergone all of the recommended investigations according to recommendation. Height deficiency, body mass index, age at TS diagnosis and level of education did not correlate with the number of assessments performed (p = 0.687, p = 0.810, p = 0.641, and p = 0.568, respectively). Three years after the introduction of the current guidelines, medical follow-up in the transition phase is still inadequate. Improvement in transitional health care is warranted through better patient education, referring to physicians caring for adults with TS and better cooperation with general practitioners with wider popularization of the TS recommendations among them.

AimAlthough recombinant human thyrotropin (rhTSH) is widely used in treating differentiated thyroid cancer (DTC), almost all clinical investigation has been in adults. The aim of our retrospective study was to evaluate outcomes of adjuvant, rhTSH-aided radioiodine treatment in children/adolescents with DTC and to compare them to131I therapy duringl-thyroxin withdrawal (THW).MethodsPatients with the diagnosis of DTC who were ≤18 years of age and had no signs of persistent disease at the time of131I treatment were included; 48 patients were treated after rhTSH (rhTSH group) and 82 after THW group. The median time of follow-up after therapy was 67 months and was longer in the THW group (99 vs 43 months,PResultsOn the day of131I administration, all but one patient had TSH levels above 25 μIU/ml. Peak TSH concentration was significantly higher in the rhTSH group (152 μIU/ml vs 91 μIU/ml). Similarly, the thyroglobulin concentration was higher in the rhTSH group (9.7 ng/ml vs 1.8 ng/ml). No side effects requiring medical intervention were recorded after rhTSH administration. The evaluation of disease outcomes during TSH stimulation (6–18 months after131I treatment) revealed equal rates of thyroid ablation (71%) in both groups. During subsequent follow-up, five patients showed recurrence (P>0.05).ConclusionsIn children/adolescents, rhTSH-aided adjuvant radioiodine treatment is associated with rates of remnant ablation and short-term recurrence similar to THW. As this preparation has several advantages over THW, rhTSH may become the preferred method of TSH stimulation once studies of long-term outcomes show non-inferiority to THW in this age group.

Somatic RET mutations are detectable in two-thirds of sporadic cases of medullary thyroid cancer (MTC). Recent studies reported a high proportion of RAS somatic mutations in RET negative tumours, which may indicate RAS mutation as a possible alternative genetic event in sporadic MTC tumorigenesis. Thus, the aim of the study was to evaluate the frequency of somatic RAS mutations in sporadic medullary thyroid cancer in the Polish population and to relate the obtained data to the presence of somatic RET mutations.Somatic mutations (RET, RAS genes) were evaluated in 78 snap-frozen MTC samples (57 sporadic and 21 hereditary) by direct sequencing. Next, three randomly selected RET-negative MTC samples were analysed by the next generation sequencing.RAS mutation was detected in 26.5% of 49 sporadic MTC tumours. None of all the analysed samples showed N-RAS mutation. When only RET-negative samples were considered, the prevalence of RAS mutation was 68.7%, compared to 6% observed in RET-positive samples. Most of these mutations were located in H-RAS codon 61 (72%). None of 21 hereditary MTC samples showed any RAS mutations.RAS mutations constitute a frequent molecular event in RET-negative sporadic medullary thyroid carcinoma in Polish patients. However, their role in MTC tumorigenesis remains unclear.

Summary Background: More than 10% of healthy population has one or more accessory spleens. The most common location is the hilum of the spleen or area near the tail of the pancreas. The radiological appearance of accessory spleens in oncologic patients who underwent splenectomy can be misinterpreted as a recurrence, especially in the case of compensatory growth of an accessory spleen in successive radiological examinations. Caser Reports: We present the cases of three patients who underwent splenectomy for gastric carcinoid, gastric adenocarcinoma and cancer of the left adrenal gland, respectively. CT examination and/or PET-CT scan revealed suspicious findings in the left upper abdomen. In one patient, the dimensional increase of this finding in successive examinations was initially considered suggestive for cancer recurrence. Scintigraphy with 99mTc-nanocolloid was able to confirm the presence of an accessory spleen in all these patients. Conclusions: Splenic scintigraphy is an economical, accessible and accurate tool in differential diagnosis of accessory spleens in patients after splenectomy.

Objective: Clinical studies suggest that the thyroid autoantibodies and/or hypothyroidism are not present in Turner’s syndrome (TS) patients before the age of 8 years and are more frequent in patients with the X isochromosome. The aim of the study was to analyze the dynamics of thyroid dysfunction in girls with TS. Design: 86 TS patients with a median age of 10.6 years were followed for 4.6 ± 3.0 years. Outcomes: The prevalence of thyroid abnormalities increased from 25.5 to 50% during the follow-up. Finally, 31 (36%) patients had positive thyroid autoantibodies and 27 (31.4%) had subclinical hypothyroidism. Hashimoto’s thyroiditis was diagnosed in 15 patients. Median age of developing thyroid antibodies and subclinical hypothyroidism was 14.1 and 14.8 years, respectively. The youngest hypothyroid patient was 1.8 years old and the youngest girl with positive anti-thyroid antibodies was 5.5 years old. Autoantibodies appeared mainly after the age of 13. The risk of developing subclinical hypothyroidism was greatest between 12 and 14 years of age. The prevalence of thyroid abnormalities was not related to the karyotype. Conclusions: Thyroid autoimmunity and dysfunctions in TS may start early, their prevalence increases with age, independently of karyotype and without any clinical symptoms and signs.

The efficacy of growth promoting hormonal therapy is assessed on the basis of growth rate as well as bone age progression until the patients reach their final height. The aim of our study was to investigate which hormonal therapy influences in most appropriate way height velocity and bone age progression in patients with Turner syndrome (TS) and to establish the optimal age to initiate treatment. Patients were divided into five groups according to the type of hormonal therapy: 1) 11 patients treated with growth hormone (GH); 2) 18 patients treated with GH and oxandrolone (Ox); 3) 7 patients treated with GH, Ox and estrogens (E); 4) 6 patients treated with OX and E; and the control group (Group 0) of 62 untreated patients. The patients height was expressed in hSDS calculated on the basis of growth chart for patients with TS (hSDST). Bone age (BA) was assessed according to Greulich-Pyle method.The mean values of deltahSDST in the first and second year of therapy in individual groups were significantly different. The difference resulted from significantly higher value of deltahSDST in group treated with GH+Ox. Analysis of regression between deltaCA and deltaBA revealed regression coefficients alpha of equation deltaBA= alpha x deltaCA: in group 0: 0.817; group GH: 1.233; group GH+Ox: 0.861; group GH+Ox+E: 0.997; group Ox+E: 1.141. There was significant difference between regression coefficients in studied groups. It resulted from significantly higher value of alpha in group treated with GH than in a group 0 and treated with GH+Ox. Only group treated with GH+Ox showed a significant negative correlation between baseline CA and deltaBA during the therapy. We can conclude that all regimens of hormonal therapy improved height in our patients but the highest increase of height during the therapy and the smallest progression of the bone age in the same time were observed in patients treated with GH+Ox.

TKI constitute a new group of drugs evaluated in TC patients. The efficacy of some of them in prolongation of progression free survival has been recently documented. However, possible side effects may affect the quality of life as well as limit their clinical use. Only drugs which were known to inhibit VEGFR were considered. In the study adverse effects were evaluated in patients treated in our centre within the prospective clinical trials phase II and III. The aim of the study was to analyze the frequency and severity of side effects related to TKI in TC patients. Thus, we retrospectively re-evaluated side effects on the basis of Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The comparison of the drugs was not aimed. 37 therapies with TKI due to advanced TC were assessed. 19 subjects were given vandetanib, 15 - lenvatinib, 3 - axitinib. Median treatment duration was 26.7 months (range: 4.0 - 62.2). The drug was discontinued due to TC progression in 9 subjects, adverse events in 5 and for other reasons in 4. Adverse events leading to treatment withdrawal were: weight loss (1), lymphopenia (1), QTC prolongation (1), tracheo-esophageal fistula (1) and purulent meningitis (1). The results are given in table ​table11. Table 1 Frequency and severity of the most common treatment-related side effects.

Introduction Calcitonin (Ct) and carcinoembrional antigen (CEA) are widely used as tumor markers for the post-operative follow-up of patients with medullary thyroid carcinoma (MTC). In patients with elevated serum Ct and CEA their dynamics can be described by calculating the doubling time (DT) - the time, they need to double the serum concentration. Previous reports concluded that the Ct and CEA DT have prognostic value in MTC patients. Patients and methods We retrospectively analyzed data of 70 MTC patients with elevated serum Ct or CEA. In total, doubling times were calculated and the DT of the less favorable marker was used to stratify the patients into the low- and high-risk group with the cut-off value of 2 years. The survival analysis was performed using Cox proportional hazard method. Results The doubling time < = 2 years of the less-favorable marker had significant prognostic impact for recurrence-free survival, HR = 2.61 (1.43-4.71) and overall survival, HR = 8.99 (3.51-23.04). Conclusions The calcitonin and carcinembrional antigen doubling times of less than two years are negative prognostic factors for MTC recurrence-free and total survival in patients with persistent or recurrent disease. They may be used as predictive factors for more intensive search of disease localization in asymptomatic hypercalcitoninemia and for therapy choice in symptomatic disease.