Clinical and molecular characterisation of metastatic papillary thyroid cancer according to radioiodine therapy outcomes.

PURPOSE: Radioiodine (RAI) therapy remains the gold-standard approach for distant metastatic differentiated thyroid cancer (TC). The main objective of our work was to identify the clinical and molecular markers that may help to predict RAI avidity and RAI therapy response of metastatic lesions in a cohort of papillary thyroid cancer (PTC) patients. METHODS: We performed a retrospective analysis of 122 PTC patients submitted to RAI therapy due to distant metastatic disease. We also analysed, through next-generation sequencing, a custom panel of 78 genes and rearrangements, in a smaller cohort of 31 metastatic PTC, with complete follow-up, available RAI therapy data, and existing tumour sample at our centre. RESULTS: The most frequent outcome after RAI therapy was progression of disease in 59.0% of cases (n = 71), with median estimate progression-free survival of 30 months. RAI avidity was associated with PTC subtype, age and stimulated thyroglobulin at first RAI therapy for metastatic disease. The most frequently altered genes in the cohort of 31 PTC patients' primary tumours were RAS isoforms (54.8%) and TERT promoter (TERTp) (51.6%). The presence of BRAF p.V600E or RET/PTC alterations was associated with lower avidity (p = 0.012). TERTp mutations were not associated with avidity (p = 1.000) but portended a tendency for a higher rate of progression (p = 0.063); similar results were obtained when RAS and TERTp mutations coexisted (p = 1.000 and p = 0.073, respectively). CONCLUSIONS: Early identification of molecular markers in primary tumours may help to predict RAI therapy avidity, the response of metastatic lesions and to select the patients that may benefit the most from other systemic therapies.

Impact of POR*28 Variant on Tacrolimus Pharmacokinetics in Kidney Transplant Patients with Different CYP3A5 Genotypes.

BACKGROUND: The introduction of tacrolimus (TAC) to clinical practice was essential to the establishment of transplantation as a therapy for patients with chronic renal disease. However, the higher interindividual variation of TAC metabolism has been an important limiting factor for its clinical use. Although the relationship between CYP3A5 polymorphisms and TAC pharmacokinetics (PK) is well established, the effects of other genetic variants on TAC metabolism, such as POR*28, still remain uncertain. OBJECTIVE: The study aimed to evaluate the impact of POR variants on TAC PK in renal transplant patients with different CYP3A5 genotypes (expressers and non-expressers). METHODS: A total of 115 patients were included in this study. Genomic DNA was isolated from peripheral blood, and the real-time PCR technique was used to analyze the polymorphism POR rs1057868; C>T. RESULTS: During the initial post-transplant period, variant allele carriers (*1/*28 and *28/*28) showed a lower TAC dose requirement than POR wild homozygotes (*1/*1). Regarding the influence of the different polymorphisms of POR within the CYP3A5 expresser and non-expresser groups, no differences were observed in any of the PK parameters analyzed during 12 months after transplantation. CONCLUSION: In the studied population, the variant allelic POR*28 was significantly associated with lower TAC dose requirements and higher Co/D ratio in the first-month post-transplant. However, the effects of this polymorphism on the CYP3A5 enzyme activity were not observed.

Isolated adrenal metastases of papillary thyroid carcinoma.

Not required for Clinical Vignette.

Outcomes of Thyrotropin Alfa Versus Levothyroxine Withdrawal-Aided Radioiodine Therapy for Distant Metastasis of Papillary Thyroid Cancer.

Background: Thyrotropin alfa (rhTSH) is not currently approved by the Food and Drug Administration or European Medicines Agency for the preparation of radioactive iodine therapy (RAIT) in patients with distant metastatic papillary thyroid cancer (PTC). There are only a few studies comparing rhTSH with levothyroxine withdrawal (LTW) in this context. Our main aim was to compare the two methods of RAIT preparation in terms of avidity and structural/biochemical response in distant metastatic PTC. We also intended to evaluate whether the two methods of RAIT preparation represented independent prognostic factors for progression-free survival (PFS) and disease-specific survival (DSS) in this subset of patients. Methods: We performed a retrospective analysis of all patients with PTC treated with RAIT for distant metastatic disease between 2006 and 2018. We included 95 PTC patients-27 (28.4%) had LTW and 68 (71.6%) had rhTSH for RAIT. Results: The two groups presented similar clinicopathological characteristics, except for median age at PTC diagnosis, which was higher in the rhTSH group (p = 0.001), but the median age at first RAIT for distant metastatic disease was not different between the two methods of preparation, 63 years old (interquartile range [IQR] 23) in the LTW group versus 70 (IQR 26.75), p = 0.06. Avidity was similar between the two groups (p = 0.973). Median estimate PFS (p = 0.076) and DSS (p = 0.084) were also similar between LTW and rhTSH. Regarding RAIT-related side effects, only 1 (3.7%) patient and 5 (7.4%) patients in the LTW and rhTSH groups, respectively, reported sialadenitis (p = 0.670). Conclusions: There were no differences between the two methods of RAIT preparation regarding avidity and clinical response. rhTSH may be used as an alternative method of preparation for RAIT in patients with known distant lesions, as it presents similar clinical outcomes to LTW and a good safety profile.

Avidity and Outcomes of Radioiodine Therapy for Distant Metastasis of Distinct Types of Differentiated Thyroid Cancer.

CONTEXT: The recommendations for radioactive-iodine treatment (RAIT) in metastatic differentiated thyroid cancer (DTC) are mostly based in the experience with papillary histotype and do not consider the differences within the distinct types of DTC, in terms of RAIT uptake and response. OBJECTIVE: This work aims to investigate the association between histology and RAIT avidity and response, and to evaluate whether histotype was an independent prognostic factor in progression-free survival (PFS) and disease-specific survival (DSS) after RAIT for distant metastatic disease. METHODS: A retrospective analysis was conducted of all DTC patients who underwent RAIT for distant metastatic disease, from 2001 to 2018, at a thyroid cancer referral center. We included 126 patients: 42 (33.3%) classical variant papillary thyroid cancer (cvPTC), 45 (35.7%) follicular variant PTC (fvPTC), 17 (13.5%) follicular thyroid cancer (FTC) and 22 (17.5%) Hürthle cell carcinoma. Main outcome measures included RAIT avidity and response. RESULTS: RAIT avidity was independently associated with histology (P < .001) and stimulated thyroglobulin (Tg) at first RAIT for distant lesions (P = .007). Avidity was lowest in HCC (13.6%), intermediate in cvPTC (21.4%), and highest in fvPTC (75.6%) and FTC (76.5%). Regarding RAIT response, HCC and FTC were not different; both showed significantly more often progression after RAIT than fvPTC and cvPTC. Histology influenced PFS (P = .014), but tumor type was not a significant prognostic factor in DSS. Instead, age at diagnosis, resection status, and stimulated Tg at the first RAIT were significantly associated with DSS. CONCLUSION: DTC histotype influenced RAIT avidity and PFS. It is crucial to better detect the metastatic patients that may benefit the most from RAIT.

CYP3A5 and PPARA genetic variants are associated with low trough concentration to dose ratio of tacrolimus in kidney transplant recipients.

PURPOSE: Genetic polymorphisms have been associated with variation in the metabolism of tacrolimus (TAC) in kidney transplant patients. This study is aimed at assessing the impact of allelic variants of CYP3A5 and PPARA genes on the pharmacokinetics (PK) of TAC in Brazilian kidney transplant recipients in the first-year post-transplant. METHODS: A total of 127 patients were included for genetic evaluation. Genomic DNA was isolated from peripheral blood and real-time PCR was used to analyze the main polymorphisms described for the genes CYP3A5 (rs776746; C > G) and PPARA (rs4823613; A > G and rs4253728; G > A). RESULTS: CYP3A5 expressors showed a lower Co/dose ratio than non-expressors, with the median values of this parameter <1.01 ng/mL/mg in the first group at all evaluated times. Additionally, PPARA variant homozygotes had a lower Co/D ratio than wild allele carriers in the 12-month post-transplant period, with a median value of 0.65 ng/mL/mg. In the CYP3A5 expressers, the presence of the variant homozygous genotype PPARA was associated with a lower value of Co/D compared with the other genotypic groups at month 12. CONCLUSION: In the population under study, polymorphisms on CYP3A5 and PPARA were identified as determining and independent factors associated with the reduction of Co/D of TAC. Thus, the genotyping of these genetic variants may be a useful tool for the individualized prescription of TAC in kidney transplant patients.

Effects of Combined Resistance Plus Aerobic Training on Body Composition, Muscle Strength, Aerobic Capacity, and Renal Function in Kidney Transplantation Subjects.

ABSTRACT: Lima, PS, de Campos, AS, de Faria Neto, O, Ferreira, TCA, Amorim, CEN, Stone, WJ, Prestes, J, Garcia, AMC, and Urtado, CB. Effects of combined resistance plus aerobic training on body composition, muscle strength, aerobic capacity, and renal function in kidney transplantation subjects. J Strength Cond Res 35(11): 3243-3250, 2021-Immunosuppression and a sedentary lifestyle may exacerbate complications such as early graft dysfunction and muscle loss, and reduce patient survival after kidney transplantation (KT). Therefore, the purpose of this study was to evaluate changes in body composition (BC), muscular strength, aerobic, and renal function in KT subjects submitted to combined resistance plus aerobic training. Twelve KT subjects were randomly assigned into groups: (G1) 12 weeks of combined training (3 males and 4 females, 54 ± 3 years); or (G2) nonexercise control (5 females, 43 ± 18 years). The subjects were evaluated for BC (dual-energy X-ray absorptiometry), estimated V̇o2peak, right-hand maximal grip strength (RHMGS) and left-hand maximal grip strength (LHMGS), and renal function. Post-training revealed that G1 reduced body fat percentage (p = 0.046), uric acid (Δ = -0.87; p = 0.023), urea (Δ = -9.43; p = 0.032), and creatinine (Δ = -0.15; p = 0.045), increased fat-free mass, estimated V̇o2peak, RHMGS, LHMGS (p < 0.05), and estimated glomerular filtration rate (eGFR) (Δ = 11.64; p = 0.017). G2 increased urea (Δ = 8.20; p = 0.017), creatinine (Δ = 0.37; p = 0.028), and decreased eGFR (Δ = -16.10; p = 0.038). After 12 weeks, urea (Δ = 24.94; p = 0.013), uric acid (Δ = 1.64; p = 0.044), and creatinine (Δ = 0.9; p = 0.011) were lower, whereas eGFR (Δ = 36.51; p = 0.009) was higher in G1. These data indicate that combined training instigates positive changes in BC, muscular strength, aerobic capacity, and renal function after KT.

Thyroid Cancer: The Quest for Genetic Susceptibility Involving DNA Repair Genes.

The incidence of thyroid cancer (TC), particularly well-differentiated forms (DTC), has been rising and remains the highest among endocrine malignancies. Although ionizing radiation (IR) is well established on DTC aetiology, other environmental and genetic factors may also be involved. DNA repair single nucleotide polymorphisms (SNPs) could be among the former, helping in explaining the high incidence. To further clarify the role of DNA repair SNPs in DTC susceptibility, we analyzed 36 SNPs in 27 DNA repair genes in a population of 106 DTCs and corresponding controls with the aim of interpreting joint data from previously studied isolated SNPs in DNA repair genes. Significant associations with DTC susceptibility were observed for XRCC3 rs861539, XPC rs2228001, CCNH rs2230641, MSH6 rs1042821 and ERCC5 rs2227869 and for a haplotype block on chromosome 5q. From 595 SNP-SNP combinations tested and 114 showing relevance, 15 significant SNP combinations (p < 0.01) were detected on paired SNP analysis, most of which involving CCNH rs2230641 and mismatch repair variants. Overall, a gene-dosage effect between the number of risk genotypes and DTC predisposition was observed. In spite of the volume of data presented, new studies are sought to provide an interpretability of the role of SNPs in DNA repair genes and their combinations in DTC susceptibility.

Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility.

Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan® assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective.

Second Primary Cancer in Patients with Differentiated Thyroid Cancer: Does Radioiodine Play a Role?

BACKGROUND: Well-differentiated thyroid cancer (WDTC) is the most common endocrine neoplasia, and its incidence is rising. Studies have reported an increased risk of second primary cancer (SPC) in WDTC survivors, but its relationship with radioiodine treatment (RAIT) and other risk factors remains controversial. This study evaluated whether RAIT is an independent risk factor for SPC in WDTC patients. METHODS: This was a retrospective single-center study. A total of 2031 patients with WDTC diagnosed between 1998 and 2009, treated and followed at the authors' tertiary cancer center, were included. RESULTS: The median age of patients was 48 years (range 5-90 years); 83% were women and 77% underwent RAIT. The median follow-up was 8.8 years (range 5.0-17.0 years). A total of 130 SPC were diagnosed: 108/1570 (6.9%) received RAIT (RAIT+) and 22/461 (4.8%) did not (RAIT-). The most common SPC was breast cancer (31%), followed by genitourinary and gastrointestinal cancer (18% each). The 10-year cumulative incidence of SPC was 8.2% in RAIT+ and 4.5% in RAIT-. The absolute risk increase in the RAIT+ group versus the RAIT- group at 10 years of follow-up was 0.039 [confidence interval (CI) 0.011-0.067] per patient-year. The number needed to harm (NNH) was 25.6 [CI 15.0-87.2], indicating that on average during a 10-year follow-up period, there is one additional case of SPC for every 26 patients receiving RAIT. When controlling for age, sex, and familial and personal histories of cancer, there was an 84% increase in the risk of SPC in the RAIT+ group compared to the RAIT- group (p = 0.026; relative risk = 1.84 [CI 1.02-3.31]). There was an association between SPC incidence and total cumulative activity administered, which was statistically significant >200 mCi. The incidence of SPC was higher in both the WDCT and the RAIT+ cohorts compared to the general population (standardized incidence ratios = 1.32 and 1.40, respectively). CONCLUSION: These results indicate that in spite of the low incidence of SPC in WDTC patients, the risk is increased after RAIT, particularly for activities >200 mCi. Thus, considering the excellent survival of patients with WDTC, clinicians need to weigh the risks and benefits of RAIT, especially in patients with low-risk thyroid cancer.

Bone scan usefulness in patients with painful hip or knee prosthesis: 10 situations that can cause pain, other than loosening and infection.

In recent years, with the higher median life expectancy, the number of hip and knee replacements has increased. Clinical examination and morphological studies are essential to evaluate patients with a painful arthroplasty. Nuclear medicine examinations also play an important role, their main usefulness being the exclusion of prosthesis complications. Nevertheless, conventional examinations, namely bone scan and white blood cell scintigraphy, can also identify complications, such as loosening and infection. This study describes the normal and pathologic patterns of a bone scan and exemplifies ten common situations that can cause pain in patients with hip or knee arthroplasty, other than loosening and infection, which can be disclosed on a bone scintigraphy. The ten situations that should be considered and looked for when analysing a bone scan are: referred pain, patellofemoral pain syndrome, fractures, fissures, abscess/haematoma, bone insert behaviour, heterotopic ossification, greater trochanter pseudarthrosis, osteoarthritis extension in a knee with an unicompartmental prosthesis, and systemic disease with bone involvement.

Ability of the rhTSH stimulation test to predict relapse in patients with differentiated thyroid carcinoma, after long-term follow-up.

The analysis of serum thyroglobulin (Tg) following thyroid-stimulating hormone (TSH) stimulation (sTg) has been recommended in the follow-up of differentiated thyroid carcinoma (DTC) patients, however, its routine use remains controversial. The aim of the current study was to evaluate the accuracy of sTg testing following recombinant human (rh) TSH stimulation in DTC patients, with a follow-up of 12.4 years. Retrospective studies were conducted of 125 DTC patients, who underwent rhTSH stimulation testing between 1999 and 2002. The exclusion criteria were: Patients with anti-Tg antibodies, Tg levels >1 ng/ml under TSH suppression and the absence of radioactive iodine (RAI) ablation therapy following surgery. In total, 49 patients were included in the study and all had been previously treated with total or near total thyroidectomy (with or without central neck dissection) and RAI, postoperatively. The Tg functional sensitivity was 1.0 ng/ml. The follow-up for patients was performed annually. During the median follow-up of 12.4 years after the rhTSH stimulation test, nine patients exhibited recurrence (18.4%). Of the nine patients, six exhibited sTg levels >2 ng/ml (positive result) and three exhibited levels <2 ng/ml (negative result). Relapse occurred at a mean of 5.9 years following the rhTSH stimulation test. The positive predictive value and negative predictive value (NPV) of positive sTg were 50 and 91.9%, respectively, with a sensitivity of 66.6% and a specificity of 85.0%. The rhTSH-stimulated Tg levels have a high NPV, allowing the identification of the patients who are free of the tumour. These results are consistent with the previously published data; however, to the best of our knowledge, this is the study with the longest follow-up duration after rhTSH stimulation.

The role of CCNH Val270Ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer.

Well-differentiated thyroid cancer (DTC) is the most common form of thyroid cancer (TC); however, with the exception of radiation exposure, its etiology remains largely unknown. Several single nucleotide polymorphisms (SNPs) have previously been implicated in DTC risk. Nucleotide excision repair (NER) polymorphisms, despite having been associated with cancer risk at other locations, have received little attention in the context of thyroid carcinogenesis. In order to evaluate the role of NER pathway SNPs in DTC susceptibility, we performed a case-control study in 106 Caucasian Portuguese DTC patients and 212 matched controls. rs2230641 (CCNH), rs2972388 (CDK7), rs1805329 (RAD23B), rs3212986 (ERCC1), rs1800067 (ERCC4), rs17655, rs2227869 (ERCC5), rs4253211 and rs2228529 (ERCC6) were genotyped using TaqMan® methodology, while conventional PCR-RFLP was employed for rs2228000 and rs2228001 (XPC). When considering all DTC cases, only rs2230641 (CCNH) was associated with DTC risk; a consistent increase in overall DTC risk was observed for both the heterozygous genotype (OR=1.89, 95% CI=1.14-3.14) and the variant allele carriers (OR=1.79, 95% CI=1.09-2.93). Histological stratification analysis confirmed an identical effect on follicular TC (OR=2.72, 95% CI=1.19-6.22, for heterozygous; OR=2.44, 95% CI=1.07­5.55, for variant allele carriers). Considering papillary TC, the rs2228001 (XPC) variant genotype was associated with increased risk (OR=2.33, 95% CI=1.05-5.16), while a protective effect was observed for rs2227869 (ERCC5) (OR=0.26, 95% CI=0.08­0.90, for heterozygous; OR=0.25, 95% CI=0.07-0.86, for variant allele carriers). No further significant results were observed. Our results suggest that NER polymorphisms such as rs2230641 (CCNH) and, possibly, rs2227869 (ERCC5) and rs2228001 (XPC), may influence DTC susceptibility. However, larger studies are required to confirm these results.

Polymorphisms in base excision repair genes and thyroid cancer risk.

Thyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2% of all human cancers, and the best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age (± 2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCC1 Arg194Trp and Arg399Gln, OGG1 Ser326Cys, APEX1 Asp148Glu, MUTYH Gln335His and PARP1 Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in agreement with the limited available evidence. By histological stratification analysis, we observed that the association between the presence of heterozygosity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility.

Evaluation of whole-body retention of iodine-131 ((131)I) after postoperative remnant ablation for differentiated thyroid carcinoma - thyroxine withdrawal versus rhTSH administration: A retrospective comparison.

Previous studies demonstrated that preparation with recombinant human thyroid-stimulating hormone (rhTSH) for thyroid remnant ablation results in lower extrathyroidal radiation compared to hypothyroidism. The results of 50 radioiodine therapies (RITs) under rhTSH, regarding iodine half-life, were evaluated and compared with 50 RITs performed on patients with hypothyroidism following thyroxine withdrawal. The patients were treated with 3700 MBq (100 mCi) of (131)I. Forty-eight hours after RIT, patients were measured with a radiation detector at a 1-meter (m) distance for evaluation of the effective dose (µSv/h). TSH and thyroglobulin (Tg) maximal values were also compared. rhTSH-stimulated patients had a significantly lower whole-body retention of (131)I (8.5±7.3 µSv/h), extrapolated from the measurements of the effective dose at a 1-m distance, compared to endogenously stimulated patients (13.6±8.1 µSv/h; p=0.001). Furthermore, TSH mean and Tg median levels were significantly higher in the rhTSH-stimulated patients (89.9±15.3 mU/l and 7.7 ng/ml, respectively) compared to the hypothyroid group (59.2±25.1 mU/l and 3.3 ng/ml; p<0.001 and p=0.003, respectively). Compared to thyroid hormone withdrawal, the use of rhTSH prior to RIT was associated with significantly lower whole-body retention of (131)I and with greater efficacy in reaching TSH levels greater than 30 mU/l, confirming data previously described.

Metastatic follicular carcinoma associated with hyperthyroidism.

PURPOSE: A 68-year-old man with metastatic follicular thyroid carcinoma had T3 hyperthyroidism. MATERIAL AND METHODS: A bone scan showed intense uptake in the thyroid and multiple areas of increased uptake in the skeleton. Hyperthyroidism persisted after total thyroidectomy. Treatment with I-131 induced a transient state of euthyroidism lasting approximately 9 months. Further tumor growth and relapse of hyperthyroidism eventually occurred and the patient died 25 months after surgery. Molecular and cytogenetic analyses were performed. RESULTS: No mutations were detected of either of the thyrotropin receptor or of the alpha subunit of the stimulatory guanine-nucleotide-binding proteins. Hyperthyroidism was unlikely the result of thyroid-stimulating receptor antibodies. Comparative genomic hybridization analysis showed that the tumor was characterized by multiple chromosomal imbalances. CONCLUSIONS: This is an unusual case of follicular thyroid carcinoma with initial high I-131 uptake by the thyroid and bone metastases and concurrent hyperthyroidism. Despite the increased I-131 uptake in the tumor, I-131 treatment only transiently controlled the hyperthyroidism and had no effect on tumor size. The cause of hyperthyroidism remained unknown. T3 predominance was unlikely the result of type 2 deiodinase overexpression because loss of genetic material was demonstrated at chromosome 14 long arm, where type 2 deiodinase is mapped.