Ekspresija gena za protein visoke pokretljivosti 2 skupine A (HMGA2) u diferenciranim karcinomima i benignim bolestima štitnjače [High-mobility group A protein 2 (HMGA2) gene expression in differentiated carcinoma and benign thyroid diseases]

The identification of molecular markers allowing to differentiate between benign and malignant thyroid tumors, or aggressive types of differentiated thyroid cancer (DTC) from those with indolent clinical course, remains a challenge. HMGA2 has oncogenic potential. Correlation between upregulation of HMGA2 gene or protein expression and disease aggressiveness has been proven in several malignant neoplasms, but not in DTC. Aim of this research was to determine HMGA2 gene expression levels by qRT-PCR in tissue samples from patients with different clinical stages of DTC, with thyroid follicular adenoma (FA), and in non-neoplastic thyroid disease, namely nodular goiter (NG). By retrospective analyses of 222 tissue samples (113 DTC, 55 FA, 54 NG), it was determined with high sensitivity and specificity that HMGA2 overexpression predicts DTC or FA. Statistically significantly higher HMGA2 gene expression was found in clinically more advanced stages of DTCs, and was highest in patients with distant metastases, and lowest in DTCs limited to thyroid. Higher levels of HMGA2 gene expression were linked to more aggressive types of DTC (with larger tumor size, higher T-stage, multicentricity, extracapsular extension, limfovascular invasion and invasion beyond thyroid, higher pN-stage, larger number of lymphonodal metastases, and lymph node capsule penetration), and to worse clinical responses and outcomes (higher ATA-risk-stratification group, worse ATA-clinical outcome of therapy, non-avidity for radioiodine, higher risk of locoregional recurrence, and higher risk of death from DTC). HMGA2 possibly has a role in DTC carcinogenesis

Medularni karcinom štitnjače - pregled značajki i novosti u sustavnom liječenju

Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from parafollicular (C cells) of the thyroid and accounts for 2-4% of all thyroid malignancies. MTC may be sporadic or inherited, the latter as part of the MEN 2 syndromes. Germline mutations in the RET proto-oncogene (REarranged during Transfection) are driver mutations in hereditary MTC, whereas somatic RET mutations and, less frequently, RAS mutations, have been described in tumor tissues of sporadic MTC. Genetic screening for germline mutations in RET proto-oncogene identifies gene carriers of germline mutations. That enables primary prevention (the avoidance of disease onset by total prophylactic thyroidectomy), or at least secondary prevention (early detection) of the disease. Radical surgery with complete tumor resection is still pivotal in attaining cure for MTC. Despite recent advances, the treatment of advanced, metastatic, and progressive MTC remains challenging. Metastatic MTC can have an indolent clinical course; therefore, it is necessary to assess which patient to cure and when to initiate the treatment. Multidisciplinary boards of various specialists involved in the diagnostics and therapy of the patients with MTC in highly specialized centers with a high volume of patients provide optimal patient management. Multikinase inhibitors (MKI) vandetanib and cabozantinib were approved for the treatment of progressive or symptomatic metastatic/unresectable MTC. Although these treatments have been shown to improve progression-free survival (PFS) with higher overall response rates (ORR) compared with placebo, no MKI has been shown to increase the overall survival (OS) yet, except in the subgroup of patients with RETM918T-mutations on cabozantinib therapy. As these drugs are nonselective, significant off-target toxicities may occur. Recently, next-generation small-molecule tyrosine kinase inhibitors (TKIs) have been developed. These highly selective RET-inhibitors are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. The selective RET-inhibitor selpercatinib has been very recently registered for the treatment of RET-mutated thyroid cancer.Medularni karcinomi štitnjače (MKŠ) rijetke su zloćudne bolesti podrijetla parafolikularnih (C-stanica) štitnjače i čine oko 2-4% svih zloćudnih tumora štitnjače. MKŠ može biti sporadičan ili nasljedan, potonji kao dio MEN 2 sindroma. N asljedne mutacije protoonkogena RET (od engl. REarranged during Transfection) pokretačke su mutacije kod nasljednih MKŠ, dok su somatske RET mutacije, ili, rjeđe, RAS mutacije, opisane u tumorskom tkivu kod sporadičnih MKŠ. Genetski probir na nasljedne mutacije protoonkogena RET identificira nosioce nasljednih genetskih mutacija. To omogućuje primarnu (sprječavanje razvoja bolesti provođenjem profilaktičke totalne tireoidektomije) ili barem sekundarnu prevenciju bolesti (rano otkrivanje MKŠ-a). Radikalna operacija s kompletnom resekcijom tumora još je uvijek ključna u postizanju izlječenja kod MKŠ. Naime, unatoč nedavnim dostignućima, liječenje uznapredovalog, metastatskog i progresivnog MKŠ-a i dalje predstavlja izazov. Metastatski MKŠ može biti indolentnog kliničkog tijeka, stoga je potrebno procijeniti kojeg bolesnika liječiti i kada liječenje započeti. Multidisciplinarni timovi različitih specijalista uključenih u dijagnostiku i liječenje bolesnika s MKŠ-om u visoko specijaliziranim centrima s velikim brojem bolesnika omogućuju njihovo optimalno zbrinjavanje. Multikinazni inhibitori (MKI) vandetanib i kabozantinib, odobreni su za liječenje progresivnog ili simptomatskog metastatskog/ neresektabilnog MKŠ. Premda je ovo liječenje pokazalo dobit u preživljenju bez progresije bolesti (PFS, od engl. Progression Free Survival) uz veću ukupnu stopu odgovora (ORR, od engl. Overall Response Rate) naspram placeba, MKI nisu polučili dobit u ukupnom preživljenju (OS, od engl. Overall Survival), osim kod podskupine bolesnika s RETM918T-mutacijama na terapiji kabozantinibom. Multikinazni inhibitori su neselektivni, stoga je moguća značajna toksičnost terapije. Nedavno su razvijene nove generacije tirozin-kinaznih inhibitora (TKI). Ovi visoko selektivni RET-inhibitori specifično su dizajnirani za visoko učinkovito i selektivno ciljanje onkogenih RET alteracija, što ih čini obećavajućim lijekovima u liječenju uznapredovalog MKŠ. Selektivni RET-inhibitor selperkatinib vrlo je nedavno registriran za liječenje RET-mutiranih karcinoma štitnjače

Novosti u imunoterapiji melanoma

Melanoma is considered to be the most immunogenic malignant tumour. This fact is recognized for many years, and certain forms of immunotherapy have been used in melanoma therapy for a considerable time. Treatment options for patients with metastatic melanoma have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents (immunotherapies and targeted therapies). During this period, melanoma immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic Tlymphocyteassociated antigen4 (CTLA4) and, recently, the programmed cell-death protein 1 (PD1) immune checkpoints. These changes in the treatment options have dramatically improved patient outcomes, with the median overall survival of patients with metastatic melanoma increasing from approximately 9 months before 2011 to at least 2 years, and probably longer. Various types of immunotherapy, like pembrolizumab, nivolumab, ipilimumab, combined therapy with nivolumab and ipilimumab, and T-VEC, have been established in recent years as the standard-of-care treatment for metastatic melanoma patients.Melanomi se smatraju najimunogenijim zloćudnim tumorima. Ova je činjenica prepoznata već niz godina, te se neki oblici imunoterapije već dugo primjenjuju u liječenju melanoma. Terapijske opcije za liječenje bolesnika s metastatskim melanomom dramatično su se promijenile u zadnjih pet godina, te je Američka agencija za lijekove (FDA) odobrila osam novih lijekova (imunoterapije i ciljane terapije). Tijekom ovog razdoblja, imunoterapija melanoma promijenila se iz terapije bazirane na citokinima u protutijelima posredovanu blokadu citotoksičnog T-limfocitnog antigena 4 (CTLA-4), a u zadnje vrijeme u protutijelima posredovanu inhibiciju imunoloških kontrolnih točaka, prvenstveno proteina programirane stanične smrti 1 (PD-1). Ove su promjene terapijskih opcija dramatično poboljšale ishod liječenja bolesnika, te se medijan ukupnog preživljenja kod bolesnika s metastatskim melanomom povisio s približno 9 mjeseci prije 2011. godine, na najmanje 2 godine, a vjerojatno i dulje. Različiti oblici imunoterapije, poput pembrolizumaba, nivolumaba, ipilimumaba, kombinirane terapije nivolumabom i ipilimumabom, te T-VEC, postali su zadnjih godina standardni oblici liječenja bolesnika s metastatskim melanomom

Novosti u imunoterapiji melanoma

Melanoma is considered to be the most immunogenic malignant tumour. This fact is recognized for many years, and certain forms of immunotherapy have been used in melanoma therapy for a considerable time. Treatment options for patients with metastatic melanoma have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents (immunotherapies and targeted therapies). During this period, melanoma immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic Tlymphocyteassociated antigen4 (CTLA4) and, recently, the programmed cell-death protein 1 (PD1) immune checkpoints. These changes in the treatment options have dramatically improved patient outcomes, with the median overall survival of patients with metastatic melanoma increasing from approximately 9 months before 2011 to at least 2 years, and probably longer. Various types of immunotherapy, like pembrolizumab, nivolumab, ipilimumab, combined therapy with nivolumab and ipilimumab, and T-VEC, have been established in recent years as the standard-of-care treatment for metastatic melanoma patients.Melanomi se smatraju najimunogenijim zloćudnim tumorima. Ova je činjenica prepoznata već niz godina, te se neki oblici imunoterapije već dugo primjenjuju u liječenju melanoma. Terapijske opcije za liječenje bolesnika s metastatskim melanomom dramatično su se promijenile u zadnjih pet godina, te je Američka agencija za lijekove (FDA) odobrila osam novih lijekova (imunoterapije i ciljane terapije). Tijekom ovog razdoblja, imunoterapija melanoma promijenila se iz terapije bazirane na citokinima u protutijelima posredovanu blokadu citotoksičnog T-limfocitnog antigena 4 (CTLA-4), a u zadnje vrijeme u protutijelima posredovanu inhibiciju imunoloških kontrolnih točaka, prvenstveno proteina programirane stanične smrti 1 (PD-1). Ove su promjene terapijskih opcija dramatično poboljšale ishod liječenja bolesnika, te se medijan ukupnog preživljenja kod bolesnika s metastatskim melanomom povisio s približno 9 mjeseci prije 2011. godine, na najmanje 2 godine, a vjerojatno i dulje. Različiti oblici imunoterapije, poput pembrolizumaba, nivolumaba, ipilimumaba, kombinirane terapije nivolumabom i ipilimumabom, te T-VEC, postali su zadnjih godina standardni oblici liječenja bolesnika s metastatskim melanomom

Dodatni unos joda u trudnoći

People of all ages can be affected by iodine deficiency; however, pregnant women and children are especially at a high risk. Because of changes that occur in maternal thyroid hormone economy during pregnancy and the potential unfavorable effects of iodine deficiency on the offspring, an adequate dietary iodine intake throughout the pregnancy is highly important. Therefore, the World Health Organization, United Nations Children\u27s Fund and International Council for the Control of Iodine Deficiency Disorders have proposed that dietary intake of iodine during pregnancy should be 200-300 µg/day to compensate for the augmented T4 requirements in pregnant women. It has been shown that in countries with a longstanding and well-established universal salt iodination program where iodine sufficiency has been reached, there is a fraction of pregnant women that still have low median urinary iodine concentration, which indicates insufficient dietary iodine. Studies performed in such countries emphasize that pregnant women should use multivitamin and/ or mineral tablets specifically prepared for the needs of pregnancy and containing iodine supplements. Only the United States of America and Canada have official recommendations concerning iodine supplementation. In other countries, no such firm decisions have yet been made by medical community and public health authorities. In Croatia, an iodine sufficient country, the situation is the same. There is a need to collect adequate data on iodine supplementation and urinary iodine during pregnancy, along with the universal salt iodination program, so that definitive conclusions can be made.Nedostatak joda može zahvatiti bilo koju dobnu skupinu, ali je ta opasnost osobito visoka kod trudnica i djece. Dostatan unos joda u prehrani kroz cijelo razdoblje trudnoće je veoma važan zbog promjena koje nastaju u kretanju majčinih hormona štitnjače tijekom trudnoće i mogućih negativnih učinaka nedostatka joda na dijete. Stoga su Svjetska zdravstvena organizacija, Fundacija za djecu Ujedinjenih naroda i Međunarodni savjet za kontrolu bolesti uzrokovanih nedostatkom joda predložili unos joda prehranom tijekom trudnoće od 200-300 µg/dan kako bi se nadoknadile povećane potrebe za T4 kod trudnica. Pokazalo se da u zemljama s dugotrajnim i dobro uspostavljenim sveopćim program om za jodiranje soli u kojima je postignut dostatan unos joda uvijek postoji skupina trudnica koje ipak imaju nizak medijan koncentracije joda u mokraći, što pak ukazuje na nedostatak joda u prehrani. U istraživanjima provedenim u takvim zemljama naglašava se kako bi trudnice trebale uzimati tablete multivitamina ili minerala koje sadrže dodatak joda i namijenjene su upravo za primjenu u trudnoći. Sjedinjene Američke Države i Kanada su jedine zemlje koje imaju službene preporuke za dodavanje joda, dok u drugim zemljama takve čvrste odluke medicinske struke i javnozdravstvenih vlasti još nisu donešene. Takva je situacija i u Hrvatskoj, zemlji s dostatnim unosom joda. Uz programe općeg jodiranja soli potrebno je prikupiti dovoljno podataka o dodavanju joda i koncentraciji joda u mokraći za vrijeme trudnoće kako bi se mogli donijeti valjani zaključci

Aspiracijska citologija štitnjače

Fine needle aspiration (FNA) of the thyroid has been utilized as a diagnostic method for 40 years. The main purpose of thyroid FNA is to differentiate nodules that require surgery from those that do not. The sensitivity of thyroid FNA ranges from 65% to 99%, and its specificity from 72% to 100%. Ultrasound-guided FNA of the thyroid is recommended, especially for sampling of a small, deep nodule. One to four aspirations suffice in single nodular lesions measuring less than 3 cm in diameter. Although the criteria used to establish specimen adequacy are somewhat controversial, most institutions require the presence of follicular cells. FNA diagnosis of thyroid disease is a clinicocytologic diagnosis, and correlation with clinical findings is mandatory for success. At our institution, diagnostic FNA lesions are subdivided into the following general diagnostic categories: benign, indeterminate, and malignant. Benign lesions include lesions with the diagnosis of benign thyroid nodule, nodular goiter, and thyroiditis. Indeterminate lesions include cellular follicular lesion, follicular neoplasm and Hürthle cell neoplasm. Malignant neoplasms include papillary carcinoma, high-grade follicular carcinoma, medullary carcinoma, anaplastic carcinoma, large cell lymphoma, and metastatic carcinoma. No clinical or laboratory test is sensitive and specific enough to distinguish reliably whether a follicular neoplasm identified on FNA is benign or malignant. This position may be changed with the development of molecular approaches to the diagnosis. CD44v6 and galectin-3 seem to be most promising tumor markers for thyroid malignancies of follicular epithelial cell origin.Aspiracijska citologija štitnjače tankom iglom rabi se kao dijagnostička metoda već 40 godina. Glavni cilj aspiracijske citologije štitnjače je razlučiti čvorove štitnjače koji zahtijevaju kirurško liječenje od onih čvorova kod kojih to nije potrebno.Osjetljivost aspiracijske citologije štitnjače varira između 65% i 99%, a specifičnost između 72% i 100%. Preporuča se provoditi ju uz nadzor ultrazvuka, poglavito kod malih, dublje smještenih čvorova. Kod čvorova promjera manjeg od 3 cm dovoljno je izvršiti jednu do četiri aspiracije. Premda se kriteriji za prikladnost uzorka razlikuju od ustanove do ustanove, većina ih zahtijeva prisutnost folikularnih stanica. Citološka dijagnoza bolesti štitnjače zapravo je kliničko-citološka dijagnoza, jer se temelji na korelaciji citomorfološke slike i dostupnih kliničkih podataka. U našoj ustanovi dijagnostičke citološke promjene štitnjače dijelimo u tri glavne kategorije: benigne, neodređenog značaja i maligne. Benigne promjene uključuju dijagnoze kao što su benigni čvor štitnjače, nodularna struma i tireoiditis. Promjene neodređenog značaja uključuju celularnu folikularnu promjenu, folikularni tumor i tumor Hürthleovih stanica. Maligne promjene uključuju papilarni karcinom, slabo diferencirani folikularni karcinom, medularni karcinom, anaplastični karcinom, limfom velikih stanica i metastatski karcinom. Niti jedan klinički ni laboratorijski test nije dovoljno osjetljiv ni specifičan da bi pouzdano razlučio maligne od benignih citološki dijagnosticiranih folikularnih tumora štitnjače. Ovakvo stanje moglo bi se izmijeniti primjenom molekularne dijagnostike tumora pri čem se CD44v6 i galektin-3 nameću kao obećavajući biljezi malignih stanica podrijetla folikularnih epitelnih stanica

Malignancy Risk Assessment in Adenomatoid Nodules and Suspicious Follicular Lesions of the Thyroid Obtained by Fine Needle Aspiration Cytology

Our aim was to assess malignancy risk in adenomatoid nodules and suspicious follicular lesions of the thyroid obtained by fine needle aspiration (FNA) cytology. Retrospective research was performed of 276 patients who underwent thyroid surgery after preoperative ultrasound-guided FNA diagnosis of either adenomatoid nodule, cellular follicular lesion, »suspicious for follicular neoplasm» or follicular neoplasm. Out of 276 patients, FNA reports showed 15 diagnoses (5%) of adenomatoid nodules, 73 (26%) cellular follicular lesions, 76 (28%) »suspicious for follicular neoplasm«, and 112 diagnoses (41%) of follicular neoplasm. FNA reports were compared with pathohistological findings. In FNA reports of adenomatoid nodule (N=15), there were seven (47%) pathohistological diagnoses (PHDs) of nodular goiter, and eight (53%) PHDs of follicular adenoma. In FNA reports of cellular follicular lesion (N=73), there were 2 (3%) PHDs of thyroiditis, 32 (44%) PHDs of nodular goiter, 38 (52%) PHDs of follicular adenoma, and one (1%) PHD of papillary carcinoma. In FNA reports of »suspicious for follicular neoplasm« (N=76), there was one (1%) PHD of thyroiditis, 24 (32%) PHDs of nodular goiter, 47 (62%) PHDs of follicular adenoma and four (5%) diagnoses of papillary carcinoma. In FNA reports of follicular neoplasm (N=112), there were 25 (22%) PHDs of nodular goiter, 72 (64%) PHDs of follicular adenoma, and 15 (14%) PHDs of thyroid carcinoma. We found significant difference (p<0.01) between investigated FNA report groups according to malignancy risk. Stratification of cytologic diagnoses of follicular thyroid lesions into different subcategories with various probabilities of malignancy allows more accurate estimation of malignancy risk and individualized patient treatment, when deciding between immediate operation and close follow-ups with repeat FNA