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Cheung Moon-Wo. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1994. / Includes bibliographical references (leaves [131]-[151]). / Acknowledgement / Abstract / List of Abbreviation / Chapter Chapter 1 --- Introduction / Thyroid diseases - a background / Thyroid function tests and their significance / Cellular actions of thyroid hormones / Thyroid hormone action at the molecular hormones / Chapter Chapter 2 --- Aims of the project / Introduction / Subcellular localization of human neutrophil alkaline phosphatase / Prospect of a quantitative assay of leucocyte alkaline phosphatase / Chapter Chapter 3 --- Subjects and methods / Specimen preparation / Assay for total protein / Assay for leucocyte alkaline phosphatase activity / Other Assays / Chapter Chapter 4 --- Results / Relationship between LAP score and specific activity of Leucocytic Alkaline Phosphatase(SA-LALP) / Diagnosis of hypothyroidism in relation to TSH and FT4. / "Relation between SA-LALP, TSH and FT4" / Relation between FT3 and other results / Relationship between SA-LALP and TSH / "ROC plot, distribution of SA-LALP and LAP score values" / Chapter Chapter 5 --- Discussion / Chapter Chapter 6 --- Conclusion / Appendix / Chapter I --- Summary of patient particulars / Chapter II --- Summary of test results of patients / Chapter III --- Consent form for participate subjects / Chapter IV --- References

by Iris Frances Forster Benzie. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1989. / Bibliography: leaves 170-184.

The most common type of thyroid cancer, differentiated thyroid cancer (DTC), is diagnosed by radioactive iodine whole body scanning (WBS) and treated with radiotherapy using iodine-131 (131I). The success of this diagnosis/treatment approach relies on the relatively selective localisation of the sodium/iodide symporter (NIS) in cells of the thyroid gland. However, in some de-differentiated thyroid cancers, NIS expression is lost. This results in the inability of WBS to stage the disease and it also decreases the effectiveness of treatment with 131I. A number of reports have shown that de-differentiated thyroid carcinomas, however, continue to express thyroid stimulating hormone receptor (TSHR). TSHR is, therefore, a potential target for the diagnosis and treatment of radioiodine resistant de-differentiated thyroid carcinoma. In this study an anti-TSHR monoclonal antibody (mAb9) and human recombinant TSH (rhTSH) were radiolabelled and evaluated for their potential use in the diagnosis and treatment of radioiodine resistant thyroid cancer. A number of radiolabelling methods and quality control experiments were initially carried out to ensure high purity radiolabelled mAb9 and rhTSH were produced. In vitro studies were conducted to assess the binding affinity of 125I-mAb9, 111In-mAb9 and 125I-rhTSH to the TSHR in thyroid cancer cell lines, TPC-1, FTC-133, and FRTL5, and in a TSHR transfected cell line, GPI. SPECT/CT animal studies were performed in mice to investigate whether 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to TSHR in the thyroid of mice in vivo. 125I-mAb9, 111In-mAb9 and 125I-rhTSH bound to GPI cells but did not bind specifically to the TSHR in FTC-133, TPC-1 and FRTL5 cells as well as to the thyroid of normal mice in vivo. Radiolabelled mAb9 and radiolabelled rhTSH are therefore unlikely to be of use in the diagnosis and treatment of radioiodine resistant de-differentiated thyroid cancer.

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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 hippocampus, which is a critical brain region for episodic autobiographical memory (AM), is particularly vulnerable to damage following periods of early thyroid hormone (TH) deficiency. Although numerous studies have examined AM performance in adult patients with hippocampal damage, no study has yet examined AM in children exposed to early TH deficiency, such as children with congenital hypothyroidism (CH) and offspring of women who were hypothyroid during pregnancy (HYPO). Given that both animal and human studies have shown that early TH deficiency results in significant hippocampal abnormalities and memory impairments, the purpose of this dissertation was to investigate the effects of early TH deficiency on AM and hippocampal structure and function during childhood. Study I examined AM performance in a large sample of typically developing children and adolescents in order to validate the use of the newly-developed Children’s Autobiographical Interview (CAI). In Study II, the CAI was used to investigate AM performance in children with early TH deficiency (i.e., CH and HYPO groups). Similar to the findings observed in adults with hippocampal damage, CH and HYPO groups both exhibited weaknesses in episodic AM, but not semantic AM, relative to controls. In addition, structural MRI revealed mild bilateral hippocampal volume reductions in HYPO, but not CH, which is consistent with animal models suggesting that early prenatal TH deficiency (i.e., HYPO) may be associated with greater abnormalities in hippocampal structure than postnatal TH deficiency (i.e., CH). Study III investigated children’s AM accuracy performance using a staged event and indicated that children with early TH deficiency had proportionally less accurate recollections of the staged event than controls. Importantly, smaller hippocampal volumes in both CH and HYPO groups predicted lower AM accuracy scores. Finally, in Study IV, functional MRI revealed that children with early TH deficiency exhibited abnormal (i.e., greater bilateral) hippocampal activation during episodic AM retrieval, but not during semantic AM retrieval, relative to controls, which may reflect neural compensation or may be a by-product of the degree of hippocampal damage. Overall, this dissertation provides critical new insight into the long-term effects of early TH deficiency on children’s AM performance and the hippocampus.