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Ziel: Abschätzung der Risiken des Rezidivs des differenzierten Schilddrüsenkarzinoms, der Karzinom-bedingten Mortalität und der Karzinom-bedingten Reduktion der Lebenserwartung in Abhängigkeit von der Anzahl der zum Erreichen eines krankheitsfreien Zustands benötigten I-131-Therapien (Radioiodtherapien) und der für die Krankheitsfreiheit benötigten kumulativen Aktivität. Methoden: Analyse anhand von in der Würzburger Schilddrüsenkarzinom-Datenbank erfassten Verlaufsdaten unter Berücksichtigung eigener zusätzlicher Erhebungen zum follow-up.von 896 Patienten, die nach einer oder mehreren Radioiodtherapien im Therapieverlauf Erkrankungsfreiheit erreichten (negative TSH-stimulierte Thyreoglobulin-Messung in Kombination mit einer negativen I-131-Ganzkörperszintigraphie). Ergebnisse: Die erfassbare Nachsorgedauer betrug in Median 9.0 Jahre (Spannbreite 0.1-31.8 Jahre). Rezidiv-Raten nach 5 und 10 Jahren und am Ende der Nachsorge betrugen 1,0±0,3%, 4,0±0,7% und 6,2±1,1%. Die Schilddrüsenkarzinom-bedingte Sterberate betrug jeweils 0,1±0,1%, 0,5±0,3% und 3,4±1,1%. Mit einer zunehmenden Anzahl von benötigten Radioiodtherapien nahm die Rezidivrate zu (p=0.001). Die Schilddrüsenkarzinom-bedingte Sterblichkeitsrate ist ab 4 benötigten Radioiodtherapien erhöht. Bei Patienten, die nach einer Radioiodtherapie krankheitsfrei waren, finden sich zwischen Niedrig- und Hochrisikopatienten keine Unterschiede bezüglich Rezidiv- und Sterblichkeitsrate. Bei Patienten, die zwei Radioiodtherapien benötigten, waren Rezidiv- und Sterblichkeitsrate der Hochrisikopatienten erhöht. Bezüglich der kumulativ benötigten Aktivität zeigten sich nur bei Patienten, die eine kumulative Aktivität von über 22,2 GBq benötigten, erhöhte Rezidiv- und Sterberaten. Im vorliegenden Studienkollektiv mit einer inhärent guten Prognose zeigte sich eine uneingeschränkte Lebenserwartung unabhängig von der benötigen Anzahl der Radioiodtherapien oder der benötigten kumulativen Aktivität. Fazit: Falls mehr als eine Radioiodtherapie oder eine hohe kumulative I-131 Aktivität benötigt wird, um einen krankheitsfreien Zustand zu erreichen, muss mit einer Rezidiv- und Schilddrüsenkarzinom-bedingten Sterblichkeits-Rate gerechnet werden, vor allem bei Hochrisikopatienten. / Purpose: To assess the risk of differentiated thyroid cancer (DTC) recurrence, DTC-related mortality and life expectancy in relation to the number of courses of 131-I therapy (RIT) and cumulative 131-I activities required to achieve complete remission (CR). Methods: The study was a database review of 1,229 patients with DTC, 333 without and 896 with CR (negative TSHstimulated thyroglobulin and negative 131-I diagnostic wholebody scintigraphy) after one or more courses of RIT. Results: The median follow-up was 9.0 years (range 0.1–31.8 years) after CR. Recurrence rates at 5 years, 10 years and the end of follow-up were 1.0±0.3 %, 4.0±0.7 % and 6.2 ±1.1 %, and DTC-related mortality was 0.1±0.1 %, 0.5± 0.3 % and 3.4±1.1 %, respectively. Recurrence rates also increased with an increasing number of RIT courses required (p=0.001). DTC-related mortality increased from four RIT courses. In patients with CR after one RIT course, there were no differences in recurrence or DTC-related mortality rates between low-risk and high-risk patients. In patients requiring two RIT courses these rates remain elevated in high-risk patients. Recurrence and DTC-related mortality rates were only significantly elevated in those requiring a cumulative activity over 22.2 GBq (600 mCi) from multiple RIT courses for CR. Regardless of the number of RIT courses or activity needed, life expectancy was not significantly lowered. Conclusion: If more than one RIT course is needed to achieve CR, higher recurrence and DTC-related mortality rates are observed, especially in high-risk patients. Patients requiring >22.2 GBq 131-I for CR should be followed in the same way as patients in whom CR is never reached as long-term mortality rates are similar.

The RET proto-oncogene encodes a receptor tyrosine kinase (RTK) that is widely expressed in neuroendocrine tissues and is essential for embryonic development of the kidney and enteric nervous system. Mutations leading to constitutive activation of the RET protein underlie various tumours of endocrine tissues. Conversely, loss-of-function mutations of RET lead to Hirschsprung disease, a congenital disorder characterized by a loss of enteric neurons throughout the colon and small intestine. Intracellular trafficking of RTKs through multiple cellular compartments has been shown to impact on downstream signalling. To date, the intracellular trafficking of RET has not been investigated. Here, we show that RET is rapidly internalized after activation and that trafficking to cytoplasmic endosomes plays an important role in downstream signalling. RET is alternatively spliced into multiple isoforms that are co-expressed in cells; therefore, we further investigated RET internalization in an isoform-specific context. This study revealed a number of differences between RET isoforms including differences in sub-cellular localization pre-activation, rate of internalization, and ability to recycle to the plasma membrane. Differential trafficking of RET isoforms alter their downstream signalling properties, providing an additional mechanism to explain the distinct contributions of RET isoforms to cellular processes. Finally, we investigated the impact of altered sub-cellular localization in the context of thyroid carcinoma. Activation of RET has been implicated in a number of thyroid tumours that differ in their inherent oncogenicity. We observed that altered subcellular localization of oncogenic forms of RET, RET/PTCs, enhance their oncogenicity. Interestingly, RET/PTC tumours are indolent and rarely metastasize compared to other RET-mediated forms of cancer. Further investigation revealed that RET/PTC oncogenes are expressed off relatively weak promoters, resulting in quantitatively less RET/PTC oncoprotein expression in these tumours compared to mutant RET expression in more aggressive cancers. Together, our results represent the first in-depth study of the trafficking properties of RET and indicate the importance of proper sub-cellular localization and trafficking in the maintenance of normal cell metabolism. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2009-11-19 22:51:47.38

Dominant-activating mutations in the RET (rear-ranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.

Resumo: O carcinoma medular de tireóide familiar (CMTF) é uma doença autossômica dominante relacionada a mutações do proto-oncogene RET, que ocorre principalmente nas regiões cisteínas da proteína RET dependentes dos códons 10 e 11. Responde por 5 a 15% dos casos de CMT hereditários. Para caracterizar o CMT de natureza familiar, este deve estar presente em pelo menos 4 indivíduos de uma mesma família. O presente trabalho objetivou o estudo clínico-genético de uma família portadora de carcinoma medular de tireóide. Esta família consiste de 25 indivíduos (13 homens e 2 mulheres) distribuídos em três gerações. Destes, seis apresentam a doença ativa: um homem da 1ª geração e dois homens e três mulheres da 2ª geração. Nenhum membro da 3ª geração desenvolveu a doença até agora. Foram coletadas amostras de sangue periférico de 19 desses indivíduos. Nestas amostras foram realizadas amplificações dos segmentos gênicos de interesse pela técnica da reação em cadeia da polimerase (PCR) e os respectivos seqüenciamentos. Até o momento, detectou-se em dois indivíduos, mutação no códon 10 (cys611tyr). Esta mutação tem uma incidência baixa (1-3%) nos casos de CMTF, mas, no entanto, implica em alto risco de agressividade do tumor. Além disso, detectou-se a presença de 3 polimorfismos (G691S, L769L, S904S), nos éxons 11, 13 e 15. Enquanto que a mutação cys611tyr está relacionada ao desenvolvimento do CMTF, sua relação com os polimorfismos encontrados e o papel desta relação com esses tumores não está esclarecida. A realização do rastreamento genético das mutações no RET deve ser considerada pela sua praticidade, custo-benefício e sensibilidade e especificidade do método. Além disso, a determinação de mutações nos familiares com CMT implicará em indicação cirúrgica preventiva e aconselhamento genético familiar. / Abstract: Familial medullary thyroid carcinoma (FMTC) is an autosomic dominant disorder related to mutations in the RET proto-oncogene. These mutation occur mostly in the extracellular rich cistein domains of the RET protein, related to the codons 10 and 11. The FMTC represents 5-15% of hereditary medullary thyroid carcinoma (MTC). To characterize MTC of familial origin, at least four members of a family must be affected. The present study focused upon clinical-genetics characteristics of a 25-member family (13 men and 12 women) distributed through three generations. Six of them had MTC: one first generation man, two men and three women from the second generation. Up until now, no member from the third generation has developed the disease. We studied 19 of these individuals for mutations in the RET protooncogene. A cys611tyr mutation was found in two of the kindreds. This mutation has a low incidence (1-3%) in FMTC, but implies in high aggressiveness risk. Moreover, we found the polymorphisms G691S, L769L, S904S in the exons 11, 13 and 15, respectively. While cys611tyr mutation is responsible for cases of FMTC, its relationship to these polymorphisms and the consequences of this interrelation to tumor development is still unknown. The screening for RET proto-oncogene mutations in relatives of MTC patients must be considered for its practicability, low cost, high specificity and sensibility. Besides, the determination of mutations in FMTC patients' kindred will conduct them to prophylactic surgery and familial counseling. / Orientador: Célia Regina Nogueira / Coorientador: Denise Perone / Banca: Glaúcia Mozeto / Banca: Laura Ward / Doutor

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Made available in DSpace on 2014-06-11T19:31:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-27Bitstream added on 2014-06-13T20:41:56Z : No. of bitstreams: 1 colenci_bpc_dr_botfm.pdf: 920335 bytes, checksum: 5efcb4f17d304fb708911364da3ccb52 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O carcinoma medular de tireóide familiar (CMTF) é uma doença autossômica dominante relacionada a mutações do proto-oncogene RET, que ocorre principalmente nas regiões cisteínas da proteína RET dependentes dos códons 10 e 11. Responde por 5 a 15% dos casos de CMT hereditários. Para caracterizar o CMT de natureza familiar, este deve estar presente em pelo menos 4 indivíduos de uma mesma família. O presente trabalho objetivou o estudo clínico-genético de uma família portadora de carcinoma medular de tireóide. Esta família consiste de 25 indivíduos (13 homens e 2 mulheres) distribuídos em três gerações. Destes, seis apresentam a doença ativa: um homem da 1ª geração e dois homens e três mulheres da 2ª geração. Nenhum membro da 3ª geração desenvolveu a doença até agora. Foram coletadas amostras de sangue periférico de 19 desses indivíduos. Nestas amostras foram realizadas amplificações dos segmentos gênicos de interesse pela técnica da reação em cadeia da polimerase (PCR) e os respectivos seqüenciamentos. Até o momento, detectou-se em dois indivíduos, mutação no códon 10 (cys611tyr). Esta mutação tem uma incidência baixa (1-3%) nos casos de CMTF, mas, no entanto, implica em alto risco de agressividade do tumor. Além disso, detectou-se a presença de 3 polimorfismos (G691S, L769L, S904S), nos éxons 11, 13 e 15. Enquanto que a mutação cys611tyr está relacionada ao desenvolvimento do CMTF, sua relação com os polimorfismos encontrados e o papel desta relação com esses tumores não está esclarecida. A realização do rastreamento genético das mutações no RET deve ser considerada pela sua praticidade, custo-benefício e sensibilidade e especificidade do método. Além disso, a determinação de mutações nos familiares com CMT implicará em indicação cirúrgica preventiva e aconselhamento genético familiar. / Familial medullary thyroid carcinoma (FMTC) is an autosomic dominant disorder related to mutations in the RET proto-oncogene. These mutation occur mostly in the extracellular rich cistein domains of the RET protein, related to the codons 10 and 11. The FMTC represents 5-15% of hereditary medullary thyroid carcinoma (MTC). To characterize MTC of familial origin, at least four members of a family must be affected. The present study focused upon clinical-genetics characteristics of a 25-member family (13 men and 12 women) distributed through three generations. Six of them had MTC: one first generation man, two men and three women from the second generation. Up until now, no member from the third generation has developed the disease. We studied 19 of these individuals for mutations in the RET protooncogene. A cys611tyr mutation was found in two of the kindreds. This mutation has a low incidence (1-3%) in FMTC, but implies in high aggressiveness risk. Moreover, we found the polymorphisms G691S, L769L, S904S in the exons 11, 13 and 15, respectively. While cys611tyr mutation is responsible for cases of FMTC, its relationship to these polymorphisms and the consequences of this interrelation to tumor development is still unknown. The screening for RET proto-oncogene mutations in relatives of MTC patients must be considered for its practicability, low cost, high specificity and sensibility. Besides, the determination of mutations in FMTC patients’ kindred will conduct them to prophylactic surgery and familial counseling.

Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.

Background: Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated carcinoma that may arise on top of normal or abnormal thyroid. Making the diagnosis by fine needle aspiration (FNA) of the thyroid with a long-standing history of multinodular goiter (MNG) is not uncommon. We report a case discussing the cytopathologic findings and the relationship with long-standing goiter and thyroid exposure to radioactive iodine treatment. Case: A 90-year-old male patient presented with a > 45-year history of MNG that was associated with thyrotoxicosis and multiple courses of radioiodine (I-131) treatment. He developed recent symptoms of dyspnea, dysphagia, neck swelling and unintentional weight loss. Computed tomography of the neck was done revealing a large MNG with retrosternal extension and calcifications. FNA was performed revealing highly anaplastic cells with a colloid background and presence of neutrophils. The diagnosis of ATC was made. The patient refused any kind of management and was discharged upon his request. He died 2 days after the procedure, and no autopsy was performed. Conclusion: ATC is an aggressive, undifferentiated thyroid carcinoma that can be diagnosed by FNA and save the patient a surgical intervention. A background of MNG and history of radioactive iodine therapy is not uncommon.