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R Michael Tuttle

Publications and source records attributed to R Michael Tuttle.

36 records · Page 2Linked to original sources
PubMed2004

Ret/PTC activation in benign and malignant thyroid tumors arising in a population exposed to low-dose external-beam irradiation in childhood.

Ionizing radiation is the strongest risk factor known for the development of thyroid neoplasia. Although ret/PTC rearrangements have been identified in both spontaneous and radiation-induced papillary thyroid cancer, they seem more frequent among radiation-associated tumors. We studied the frequency of ret/PTC activation in a group of sporadic and radiation-induced thyroid carcinomas (n = 49) and adenomas (n = 13) among 44 individuals treated for Tinea Capitis with low-dose external irradiation as well as in 18 nonirradiated subjects. Total RNA recovered from paraffin-embedded thyroid cancer surgical specimens was analyzed for ret/PTC 1, 2, and 3 mutations using RT-PCR with Southern blotting to maximize detection sensitivity. Ret/PTC rearrangements were identified in 42.9% of thyroid carcinoma and 46.2% of adenoma subjects. Among the positive carcinoma specimens, three were follicular carcinomas. Ret/PTC 1, the predominant rearrangement, was more prevalent in nonirradiated compared with irradiated carcinomas (66.7 vs. 27.0%; P = 0.04). Ret/PTC activation was associated with male gender. The strengths of this study included analysis of age-, gender-, and ethnicity-matched groups; molecular analysis using two techniques; and a complete blinding of laboratory analysis from clinical features. The differences seen between these and other published results may be related to differences in radiation doses to the thyroid, latency period between time of radiation exposure and development of clinically apparent thyroid cancer, and ethnic background of the study populations.

Adenoma↗
PubMed2004

Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma.

The serum thyroglobulin (Tg) level is the most sensitive marker for detecting residual thyroid carcinoma. We hypothesized that the basal and TSH-stimulated Tg levels in patients with metastatic thyroid carcinoma would reflect tumor volume, histological subtype, and location of metastatic lesions. A retrospective review of 417 thyroid cancer survivors undergoing evaluation for residual disease with the assistance of recombinant human TSH (rhTSH) was performed. In 169 patients with metastatic disease, we found that the basal Tg level directly correlated with the number of lesions, and that it was highest in patients with follicular and lowest in those with papillary thyroid carcinoma. The basal Tg level was highest in patients with bone metastases and lowest in those with cervical metastases. The fold increase in the serum Tg after rhTSH treatment was highest in papillary thyroid carcinoma and lowest in Hurthle cell carcinoma. The fold increase in Tg was not influenced by tumor volume or by the site of metastatic lesions. Multivariate analysis showed multiple interactions between factors, but did not identify one factor that significantly influenced basal Tg or fold increase. We conclude that the location and volume of metastases influence basal Tg, but not its responsiveness to rhTSH, whereas the histological type of carcinoma influences both basal Tg and responsiveness to rhTSH.

Adenocarcinoma, Follicular↗
PubMed2004

The MACIS score predicts the clinical course of papillary thyroid carcinoma in children and adolescents.

MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) scores are employed to predict mortality for papillary thyroid carcinoma (PTC) in adults. However, this system has not been validated in children and adolescents. We hypothesized that MACIS scores would correlate with recurrent and persistent disease in children. Patients with PTC (n = 48) were divided into those with aggressive (invasive, metastasic, recurrent or persistent disease) or indolent (lacking these features) disease. Those with aggressive PTC (n = 11) had average MACIS score = 5.2 +/- 1.3, compared to 3.7 +/- 0.4 in patients with indolent disease (n = 37, p < 0.0005). A cutoff score of 4.0 provides a PPV of 29% and NPV of 94% in predicting recurrence, and a PPV of 43% and NPV of 91% in predicting persistent disease. MACIS scores may be useful in predicting outcome in the pediatric population.

Adolescent↗
PubMed2003

Postoperative management of differentiated thyroid cancer.

The large numbers of studies on the postoperative management of differentiated thyroid carcinoma allows us to use adjuvant treatment and follow-up studies more selectively based on patient risk for recurrence and mortality. Recurrent differentiated thyroid carcinoma is more easily and more effectively treated with early diagnosis. With this in mind, patients who are at high risk for life-threatening recurrent disease should be treated aggressively and followed up expectantly. In these patients, adjuvant treatment with 131I ablation and thyroid hormone suppression is appropriate. External irradiation may be considered, especially for patients with postoperative residual disease. Close follow-up with stimulated thyroglobulin and 131I whole body scans should be performed to facilitate early detection of recurrent disease. Low-risk patients may be effectively treated with more conservative management. 131I ablation has not resulted in improved survival in these patients. Follow-up with serum thyroglobulin after initial negative 131I whole body scan may be appropriate in these patients. Management of patients at intermediate risk remains controversial. Recombinant human thyrotropin allows us to obtain stimulated serum thyroglobulin and promises the ability to perform 131I ablation and whole body scan without the need for thyroid hormone withdrawal. Functional radionuclide imaging, such as FDG PET, now allows us to localize recurrent disease in patients with elevated serum thyroglobulin but negative 131I scan.

Adenocarcinoma, Follicular↗
PubMed2003

Autoimmune thyroid disease associated with environmental thyroidal irradiation.

Reports of increased rates of thyroid disease in populations exposed to radiation as a result of the Chernobyl accident have increased awareness and concern about the risk of autoimmune-related thyroid disease possibly associated with environmental radiation exposure. While the association between thyroidal irradiation and an increased risk of thyroid neoplasia is well established, much less attention has been devoted to the potential effects of environmental irradiation on the function of the thyroid. However, since the Chernobyl accident new studies have been published that appear to link radiation exposure to an increased risk of autoimmune thyroiditis. In order to assess the plausibility of this association, we reviewed published studies that evaluate the possible association between environmental thyroidal radiation and the presence of antithyroid antibodies as well as autoimmune thyroid disease (hypothyroidism and hyperthyroidism). These data have not been summarized elsewhere. Although some epidemiologic evidence of an association exists, long-term, well-designed studies are needed to accurately evaluate the complex association between low-dose environmental radiation exposure and clinically significant non-neoplastic thyroid disease. The results of these studies will be important in determining the appropriate clinical follow-up of persons exposed to environmental thyroidal irradiation.

Autoimmune Diseases↗
PubMed2003

Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes.

The immune response appears to be important in preventing metastasis and recurrence of thyroid cancer. We previously showed that papillary thyroid carcinoma (PTC) from children and adolescents that contain the most numerous proliferating lymphocytes have the best prognosis. However, the types of lymphocytes involved are not yet known. To further define this, we examined 21 PTCs from patients 21 yr of age or younger (52% were 18-21 yr of age) for the presence of CD4+ (helper), CD8+ (killer), CD19+ (B cells), and CD56+ (natural killer) cells as well as proliferating lymphocytes (Ki-67+). Nearly half the PTCs contained CD4+ (9 of 21, 43%), CD8+ (8 of 21, 38%), or CD19+ (10 of 21, 48%) lymphocytes. Only one PTC (1 of 21, 5%) contained CD56+ lymphocytes, and none contained all four cell types. By dual staining, none of these lymphocytes were proliferating (Ki-67+). However, PTCs containing either CD8+ cells (n = 8) or a combination of CD4+, CD8+, and CD19+ cells (n = 5) contained more numerous proliferating lymphocytes than did PTCs containing any other combination (14.2-fold increase, P = 0.03 and 13.1-fold increase, P = 0.003, respectively). During follow-up, none of the PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes recurred. However, the cohort is too small and the follow-up inadequate to provide accurate information on the clinical impact of these immunological findings. We conclude that the immune response against PTC is important and also complex, involving more than one type of lymphocyte.

Adolescent↗
PubMed2003

Tumor size and extent of disease at diagnosis predict the response to initial therapy for papillary thyroid carcinoma in children and adolescents.

Treatment of papillary thyroid carcinoma (PTC) in children and adolescents is controversial. We previously showed that large tumor size, multifocal disease, and extensive disease at diagnosis predict recurrence. We examined 47 patients with PTC to determine whether these features predict response to treatment. Overall, 70% of the patients (33/47) remitted with initial treatment. 79% (15/19), of Class I, 86% (12/14) of Class II, and 100% (6/6) of Class III, but none of Class IV patients (n = 8) (p < 0.001) achieved remission. Tumor size for patients who entered remission (2.0 +/- 0.2 cm) was less than for patients with persistent disease (4.2 +/- 0.4) (p < 0.0005). Extent of disease at diagnosis correlated with the number of radioactive iodine (RAI) treatments (p = 0.022) and dose (p = 0.002) required to achieve first remission. We conclude that extensive disease at diagnosis and larger tumor size predict failure to remit after initial treatment of PTC in children and adolescents.

Adolescent↗
PubMed2003

Treatment of recurrent papillary thyroid carcinoma in children and adolescents.

Mortality for children with papillary thyroid carcinoma (PTC) is low (< or = 10%), but recurrence is frequent (20%). In adults, recurrent PTC has a poor prognosis (50% remission) and a high mortality (16-63%). We hypothesized that treatment of recurrent PTC would be more effective in children than in adults. We reviewed the clinical course of 42 children with PTC in remission. Seven (7/42, 17%) recurred and records were available for six. All six received RAI (median = 130 mCi), and one had a cervical node removed. Five of the six (83%) achieved remission (median duration 67 mo, range 10-99 mo), one had a second recurrence and a third remission, and one patient (17%) had persistent disease. There were no deaths. In conclusion, although we had only one child less than 10 years of age in our study, these and previous data suggest that treatment of recurrent PTC in children is generally effective.

Adolescent↗
PubMed2003

Systemic administration of vascular endothelial growth factor monoclonal antibody reduces the growth of papillary thyroid carcinoma in a nude mouse model.

Papillary thyroid carcinomas (PTC) are the most common thyroid cancers in children. Most are successfully treated with surgery and radioactive iodine, but some persist. PTC express high levels of vascular endothelial growth factor (VEGF) and VEGF receptor (Flt-1). PTC with the most intense expression of VEGF have the greatest recurrence risk. We hypothesized that blockade of VEGF would inhibit PTC growth. To test this, we used systemic VEGF monoclonal antibody (VEGF-MAb) to treat PTC xenografts in nude mice. Treated animals (n = 9) received 200 microg VEGF-MAb by daily i.p. injection for 10 wk, while control animals (n = 9) received vehicle alone. Tumor size was significantly reduced in the treatment group (0.28 +/- 0.06 vs 1.05 +/- 0.25 g, p = 0.008). VEGF immunostaining was more intense (2.57 +/- 0.30 vs 1.75 +/- 0.25, p = 0.06) and the number of p53 positive cells was increased (1.66 +/- 0.24 vs 0.83 +/- 0.31, p = 0.048) in treated tumors. Animal weight was similar in both groups (29.1 +/- 1.1 vs 27.4 +/- 1.1 g, p = 0.30). In conclusion, systemic VEGF-MAb significantly reduced the growth of PTC, suggesting that VEGF-MAb might be useful for treatment of resistant PTC.

Angiogenesis Inhibitors↗
PubMed2003

Erythropoietin and the erythropoietin receptor are expressed by papillary thyroid carcinoma from children and adolescents. Expression of erythropoietin receptor might be a favorable prognostic indicator.

Erythropoietin (EPO) and the EPO receptor (EPO-R) have been implicated in solid tumors of the brain, breast, kidney and female genital tract. Based on their expression by a variety of tumors, we hypothesized that EPO and/or EPO-R might be expressed by thyroid cancers. To test this, we determined EPO and EPO-R expression by immunohistochemistry in 17 papillary thyroid carcinomas (PTC) from children and adolescents. Only a minority of PTC (4/17, 24%) expressed EPO, and there were no significant differences between the PTC that did or did not express EPO. In contrast, EPO-R was detected in the majority of PTC (11/17, 65%). The average tumor size (1.5 +/- 0.8 cm), MACIS score (3.6 +/- 0.2) and risk of recurrence (0/11) for the EPO-R(+) PTC were significantly less than those for PTC that failed to express EPO-R (average tumor size = 3.6 +/- 2.4 cm, p = 0.021; average MACIS score = 4.3 +/- 0.7, p = 0.004; recurrence = 3/6, p = 0.029). We conclude that the majority of PTC from children and adolescents express EPO-R, a finding associated with favorable prognostic indicators and a lower risk of recurrence.

Adolescent↗
PubMed2002

Genome-wide appraisal of thyroid cancer progression.

Several lines of evidence suggest that follicular cell-derived thyroid cancers represent a continuum of disease that progresses from the highly curable well-differentiated thyroid cancers to the universally fatal anaplastic cancers. However, the genetic mechanisms underlying thyroid cancer progression remain ill defined. We compared the molecular-cytogenetic profiles derived from comparative genomic hybridization (CGH) analysis of major histological variants of thyroid cancer to define genetic variables associated with progression. Overall, a sequential increase in chromosomal complexity was observed from well-differentiated papillary thyroid cancer to poorly differentiated and anaplastic carcinomas, both in terms of the presence of CGH detectable abnormalities (P = 0.003) and the median number of abnormalities per case (P < 0.001). The presence of multiple abnormalities common to all thyroid cancer variants, including gains of 5p15, 5q11-13, 19p, and 19q and loss of 8p, suggests that these tumors are derived from a common genetic pathway. Gains of 1p34-36, 6p21, 9q34, 17q25, and 20q and losses of 1p11-p31, 2q32-33, 4q11-13, 6q21, and 13q21-31 may represent secondary events in progression, as they were only detected in poorly differentiated and anaplastic carcinomas. Finally, recurrent gains at 3p13-14 and 11q13, and loss of 5q11-31 were unique to anaplastic carcinomas, suggesting they may be markers for anaplastic transformation. Our data suggests that the development of chromosomal instability underlies the progression to more aggressive phenotypes of thyroid cancer and sheds light on the possible genomic aberrations that may be selected for during this process.

Adult↗
PubMed2002

Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis.

To clarify the mechanism of tumorigenesis in papillary thyroid carcinoma (PTC) and ascertain whether genomic changes correlate with histologic features, we conducted a comprehensive molecular evaluation of PTC using comparative genomic hybridization (CGH) and microsatellite instability (MSI) analysis in a set of 17 histologically well-characterized PTC specimens. To our knowledge, this is the first study that evaluates chromosomal and nucleotide instability in the same PTC tumor specimens. Four of 15 samples (27%) had aberrations detected by CGH. All four had a partial or complete gain of chromosome 20, and 3 of 4 had a partial or complete loss of chromosome 13. No MSI was detected in any of the PTC samples (n=16), and all samples examined by immunohistochemistry (n=9) expressed the DNA repair enzymes hmlh1 and hmsh2. All PTC samples with abnormal CGH had vascular invasion or invasion of the thyroid capsule, and there was a significant correlation between the presence of chromosomal aberrations and capsular/vascular invasion (P=0.026). We conclude that although chromosomal and microsatellite instability are uncommon in PTC, tumors with chromosomal aberrations are more likely to be associated with invasion.

Adenocarcinoma, Papillary↗
PubMed2002

Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice.

BACKGROUND: Anaplastic thyroid cancer (ATC) does not respond well to any treatment and is one of the most aggressive of all human cancers. Based on the importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic blockade might reduce the growth of ATC. METHODS: We tested the in vivo effect of vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned, and stained for routine histology and immunohistochemistry. RESULTS: At 6 weeks, VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040 +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12-0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95% CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]). CONCLUSION: We conclude that systemic VEGF-mAb significantly reduces growth of ATC xenografts and is associated with increased VEGF and p53 expression. Thalidomide has no effect on tumor growth, but is also associated with increased VEGF and p53 expression. These observations provide the first evidence that VEGF-mAb-induced angiogenesis blockade may be of use for the treatment of ATC.

Angiogenesis Inhibitors↗
PubMed2002

Differentiated thyroid carcinoma that express sodium-iodide symporter have a lower risk of recurrence for children and adolescents.

The sodium-iodide symporter (NIS) is expressed by papillary (PTC) and follicular (FTC) thyroid carcinoma, and is essential for iodine uptake. We hypothesized that PTC and FTC with detectable NIS immunostaining would be more amenable to radioactive iodine ((131)I) treatment and follow a more benevolent course. To test this, we determined NIS expression by immunohistochemistry in 23 PTC, 9 FTC, and 12 benign thyroid lesions from children and adolescents. NIS expression was determined by two blinded examiners and graded as absent = 0, minimal = 1, moderate = 2, intense = 3, and very intense = 4. NIS was detected in 35% (eight of 23) of PTC, 44% (four of 9) of FTC, 25% (two of eight) of benign tumors, and 100% (four of four) of autoimmune lesions. The intensity of NIS expression was similar in PTC (0.61 +/- 0.24), FTC (0.56 +/- 0.24), and benign tumors (0.50 +/- 0.33) but was more intense in autoimmune lesions (3.0 +/- 0.7, p < 0.005). Distant metastases were found only among PTC with undetectable NIS (two of 15, 13%), and recurrence developed exclusively from PTC and FTC with undetectable NIS (four of 20, 20% versus zero of 12, p = 0.043). The dose of iodine 131 required to achieve remission in the five patients with PTC who had undetectable NIS (213.3 +/- 53 mCi) was greater than that required by patients with similar age and extent of disease for whom NIS expression is unknown (109 +/- 22 mCi, p = 0.06). We conclude that NIS expression is associated with a lower risk of recurrence for PTC and FTC of children and adolescents.

Adenocarcinoma, Follicular↗
PubMed2002

Intense expression of the b7-2 antigen presentation coactivator is an unfavorable prognostic indicator for differentiated thyroid carcinoma of children and adolescents.

Previous observations suggest that an immune response against thyroid carcinoma could be important for long-term survival. We recently found that infiltration of thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival, but the factors that control lymphocytic infiltration and proliferation are largely unknown. We hypothesized that the antigen presentation coactivators (B7-1 and B7-2), which are important in other immune-mediated thyroid diseases, might be important in lymphocytic infiltration of thyroid carcinoma. To test this, we determined B7-1 and B7-2 expression by immunohistochemistry [absent (grade 0) to intense (grade 3)] in 27 papillary (PTC) and 8 follicular (FTC) thyroid carcinomas and 9 benign thyroid lesions. B7-1 and B7-2 were expressed by the majority of PTC and FTC (78% of PTC and 100% of FTC expressed B7-1; 88% of PTC and 88% of FTC expressed B7-2). B7-1 expression was more intense in PTC (1.4 +/- 0.2; P = 0.01) and FTC (2.6 +/- 0.2; P < 0.001) than in benign tumors (0.57 +/- 0.30) or presumably normal adjacent thyroid (0.07 +/- 0.07) and was more intense in carcinoma that contained lymphocytes (1.95 +/- 0.21) than in carcinoma that did not (1.08 +/- 0.26; P = 0.016). B7-2 expression was of similar intensity in benign and malignant tumors (PTC, 1.6 +/- 0.2; FTC, 2.1 +/- 0.4; benign, 1.86 +/- 0.4), but was more intense than in presumably normal adjacent thyroid (0.64 +/- 0.25; P </= 0.013). B7-2 expression also correlated with the number of tumor-associated lymphocytes per high power field (r = 0.38; P = 0.02). Recurrence developed exclusively from tumors that expressed B7-2, and intense B7-2 expression was associated with a reduced probability of remission (P = 0.04). In conclusion, these data support the hypothesis that the antigen presentation coactivators B7-1 and B7-2 may be important for lymphocytic infiltration and the immune response against thyroid carcinoma.

Adolescent↗
PubMed2002

Is the serum thyroglobulin response to recombinant human thyrotropin sufficient, by itself, to monitor for residual thyroid carcinoma?

The serum thyroglobulin (Tg) response to elevated TSH is one of the most sensitive indexes of residual thyroid carcinoma. We have explored the possibility that this test alone would be sufficient to detect residual thyroid carcinoma in thyroid cancer patients after total thyroidectomy and radioiodine remnant ablation. We used recombinant human TSH (rhTSH) to elevate serum TSH, rather than withdraw the patients from thyroid hormone. Routine evaluations, including diagnostic radioiodine whole body scans (DxWBS) and serum Tg, were performed on 366 patients after preparation by rhTSH, over a 2-yr interval. A retrospective analysis of the data from these patients revealed that 76% of those whose stimulated Tg rose to more than 2 microg/liter had evidence for residual thyroid carcinoma, whereas the same was true for only 13% of those whose stimulated Tg was 2 microg/liter or less. Using risk group stratification, we analyzed outcomes in a low risk subset (which excluded patients with elevated Tg levels on suppression, known metastatic disease, and clinical or histological evidence of aggressive disease). In this low risk group, we found that a stimulated Tg of 2 microg/liter or less had a 91.7% negative predictive value. No low risk patient who had had a prior negative DxWBS and a stimulated Tg of 2 microg/liter or less had any evidence of residual thyroid carcinoma. We conclude that the stimulated Tg alone is not sufficient by itself to screen unselected patients, but that it may be sufficient in low risk patients, especially those who have had a prior negative DxWBS.

Carcinoma↗
PubMed2002

A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation.

UNLABELLED: Radioiodine remnant ablation (RRA) is frequently used after a thyroidectomy for differentiated thyroid carcinoma because it has been reported to reduce the number of local recurrences and to increase overall survival. Although the traditional method of preparation for RRA is thyroid hormone withdrawal, several physicians at our medical center have offered the option of having RRA after preparation by recombinant human thyroid-stimulating hormone (thyrotropin; TSH) over the past 2 y. During this same time period, other patients at our center were prepared for RRA by hormone withdrawal. METHODS: We took this opportunity to retrospectively review the rate of complete remnant ablation in patients having RRA after hormone withdrawal compared with those having RRA after recombinant human TSH. Only patients who had RRA after January 1, 1999, and follow-up diagnostic studies at our medical center, were included in the analysis. A successful ablation was defined as no visible radioiodine uptake on the follow-up diagnostic scans, performed with 185 MBq (5 mCi) (131)I. The 2 groups had comparable patient and tumor characteristics and received similar ablative activities of (131)I. RESULTS: We found that 84% of those prepared by recombinant human TSH, and 81% of those prepared by hormone withdrawal, had complete resolution of visible thyroid bed uptake after RRA (P = not significant). CONCLUSION: Given the biases that exist in retrospective studies, we cannot yet recommend RRA preparation by recombinant human TSH for routine use. However, these preliminary findings are favorable enough to support the design of a prospective randomized trial comparing RRA success rates after preparation by either thyroid hormone withdrawal or recombinant human TSH.

Adult↗