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Biomedical subjects

R Michael Tuttle

Publications and source records attributed to R Michael Tuttle.

At least 19 recordsLinked to original sources
PubMed2006

Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients.

BACKGROUND: Poorly differentiated thyroid carcinomas (PDTC) occupy an intermediate position at the prognostic level on the spectrum of thyroid carcinoma progression. However, their histologic definition is controversial. The objective of the current study was to assess the prognostic significance of PDTC defined on the basis of mitosis and necrosis and search for prognostic markers within this group of tumors that are predictive of overall survival (OS) and progression-free survival (PFS). METHODS: PDTC was defined as thyroid carcinoma with follicular cell differentiation at the histologic and/or immunohistochemical levels and displaying tumor necrosis and/or > or = 5 mitoses per 10 high-power fields (x400). Retrospective chart review and microscopic examination identified 58 patients with primary tumors meeting the above criteria and seen at the Memorial Sloan-Kettering Cancer Center between 1992 and 2004. These 58 patients were analyzed for various histologic, clinical, and imaging parameters. Each parameter was correlated with OS and PFS. RESULTS: Of the 58 patients studied, 22 (38%) patients died of disease with a 5-year OS rate of 60%. Forty-three of the 58 patients (74%) developed disease recurrence or disease progression, with a 5-year PFS rate of 25%. The median follow-up for the entire patient population was 42.6 months (range, 4-205 mos). A tumor size > 4 cm was found to be correlated with a decreased PFS time (P < 0.001). Those tumors with a capsule demonstrated a significantly improved OS compared with unencapsulated tumors (P = 0.001). The extent of capsular invasion was found to be a significant adverse factor for PFS (P = 0.05). The presence of extrathyroid extension into perithyroid soft tissue was found to be correlated with a decreased OS (P = 0.001) and PFS (P = 0.004). Of 27 patients with distant metastasis, 19 (70%) had concentrated radioactive iodine (RAI) at their metastatic sites. On multivariate analysis, extrathyroid extension and tumor size emerged as the only significant variables in predicting PFS (P = 0.04 and P = 0.01, respectively) whereas extrathyroid extension was found to be the sole independent prognostic factor for OS (P = 0.01). Growth pattern and cell type did not appear to influence outcome. CONCLUSIONS: PDTC defined on the basis of mitosis and necrosis constitutes a group of tumors that is more aggressive and homogeneous than PDTC defined by growth pattern. Within this group of patients, microstaging (tumor size, the extent of capsular invasion, and, especially, extrathyroid extension), and not growth pattern or cell type, is able to stratify patients into different prognostic categories. RAI uptake occurs in a significant number of patients with PDTC.

Adenocarcinoma, Follicular↗
PubMed2005

Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning.

CONTEXT/OBJECTIVE: Approximately 15% of thyroid cancer patients develop subsequent metastases. The clinical course of patients with metastatic thyroid carcinoma is highly variable. We hypothesized that the metabolic activity of metastatic lesions, as defined by retention of 2-[(18)F]fluoro-2-deoxyglucose (FDG), would correlate with prognosis. DESIGN/PATIENTS: The initial FDG-positron emission tomography (PET) scans from 400 thyroid cancer patients were retrospectively reviewed and compared with overall survival (median follow-up, 7.9 yr). We examined the prognostic value of clinical information such as gender, age, serum thyroglobulin, American Joint Committee on Cancer (AJCC) stage, histology, radioiodine avidity, FDG-PET positivity, number of FDG-avid lesions, and the glycolytic rate of the most active lesion. RESULTS: Age, initial stage, histology, thyroglobulin, radioiodine uptake, and PET outcomes all correlated with survival by univariate analysis. However, only age and PET results continued to be strong predictors of survival under multivariate analysis. The initial American Joint Committee on Cancer stage was not a significant predictor of survival by multivariate analysis. There were significant inverse relationships between survival and both the glycolytic rate of the most active lesion and the number of FDG-avid lesions. CONCLUSIONS: FDG-PET scanning is a simple, expensive, but powerful means to restage thyroid cancer patients who develop subsequent metastases, assigning them to groups that are either at low (FDG negative) or high (FDG positive) risk of cancer-associated mortality. We propose that the aggressiveness of therapy for metastases should match the FDG-PET status.

Adult↗
PubMed2005

Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive and highly lethal human cancers. Median survival after diagnosis is 4-6 months despite available radiotherapy and chemotherapy. Additional treatments are needed for ATC. Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulus, which is expressed by ATC. Previously, anti-VEGF antibody was used to block VEGF-dependent angiogenesis in ATC xenografts. This treatment induced partial (56%) but not complete tumor regression. Aplidin (APLD) is a marine derived antitumor agent currently in phase II clinical studies. Multiple activities of this compound have been described which likely contribute to its antiproliferative effect. Notably, APLD has been shown to have antiangiogenic properties which include: inhibition of VEGF secretion, reduction in the synthesis of the VEGF receptor (FLT-1), and blockade of matrix metalloproteinase production by endothelial cells. We hypothesized that Aplidin, with its broad spectrum of action and antiangiogenic properties, would be a potentially effective drug against ATC. METHODS: Thirty BALB/c nu/nu mice were injected with ATC cells (ARO-81, 1 x 10(6)) and allowed to implant for 3 weeks. Animals were randomized to receive daily intraperitoneal injections of vehicle, low dose (0.5 mg/kg/day), or high dose (1.0 mg/kg/day) APLD. After 3 days, the animals were killed and the tumors were removed, weighed, and divided for RNA and protein analyses. RESULTS: APLD significantly reduced ATC xenograft growth (low dose, 20% reduction, P = 0.01; high dose, 40% reduction, P < 0.001). This was associated with increased levels of apoptosis related proteins polyadenosylribose polymerase 85 (PARP-85, 75% increase, P = 0.024) and caspase 8 (greater than fivefold increase, P = 0.03). APLD treatment was further associated with lost or reduced expression of several genes that support angiogenesis to include: VEGF, hypoxia inducible factor 1(HIF-1), transforming growth factor-beta (TGFbeta), TGFbeta receptor 2 (TGFbetaR2), melanoma growth stimulating factor 1 (GRO1), cadherin, and vasostatin. CONCLUSIONS: This data supports the hypothesis that APLD may be an effective adjunctive therapy against ATC. The demonstrated molecular impact against angiogenic related genes specifically supports future strategies combining APLD with VEGF interacting agents.

Angiogenesis Inhibitors↗
PubMed2005

Intensity-modulated radiation therapy for the treatment of nonanaplastic thyroid cancer.

PURPOSE: Intensity-modulated radiation therapy (IMRT) enables highly conformal treatment for thyroid cancer (TC). In this study, we review outcomes/toxicity in a series of TC patients treated with IMRT. METHODS AND MATERIALS: Between July 2001 and January 2004, 20 nonanaplastic TC patients underwent IMRT. Mean age was 55. There were 3 T2 and 17 T4 patients. Sixteen patients had N1 disease. Seven patients had metastases before RT. Fifteen underwent surgery before RT. Radioactive iodine (RAI) and chemotherapy were used in 70% and 40%, respectively. Median total RT dose was 63 Gy. RESULTS: With two local failures, 2-year local progression-free rate was 85%. There were six deaths, with a 2-year overall survival rate of 60%. For patients with M0 disease, the 2-year distant metastases-free rate was 46%. The worst acute mucositis and pharyngitis was Grade 3 (n = 7 and 3, respectively). Two patients had Grade 3 acute skin toxicity and 2 had Grade 3 acute laryngeal toxicity. No significant radiation-related late effects were reported. CONCLUSIONS: IMRT for TC is feasible and effective in appropriately selected cases. Acute toxicity is manageable with proactive clinical care. Ideal planning target volume doses have yet to be determined. Additional patients and long-term follow-up are needed to confirm these preliminary findings and to clarify late toxicities.

Adolescent↗
PubMed2005

Thyroid cancers express CD-40 and CD-40 ligand: cancers that express CD-40 ligand may have a greater risk of recurrence in young patients.

The immune response might suppress thyroid cancer recurrence. Although the factors that control this are unknown, CD-40 and CD-40 ligand might be important. To test this, we stained 36 papillary (PTC) and four follicular (FTC) thyroid carcinomas for CD-40 (n = 37) and CD-40 ligand (n = 36) and graded staining from absent (grade 0) to intense (grade 3). Follicular cells of the majority of thyroid tumors expressed CD-40 (30/37, 81%) and CD-40 ligand (15/24, 69%). Cancers from young patients (< or =21 years of age) that expressed CD-40 contained more numerous lymphocytes/high-power field (36 +/- 11) than cancers that failed to express CD-40 (4 +/- 3, p = 0.01), but there was no correlation with clinical outcome. Among young patients, CD-40 ligand expression was more intense in multifocal (1.1 +/- 0.2 vs. 0.45 +/- 0.2, p = 0.037), aggressive (1.14 +/- 0.14 vs. 0.65 +/- 0.2, p = 0.05) and recurrent tumors (1.2 +/- 0.2 vs. 0.65 +/- 0.2, p = 0.05) and associated with reduced disease-free survival (p = 0.03). We conclude that the majority of thyroid cancers express CD-40 and CD-40 ligand. In patients < or =21 years of age, tumors with intense expression of CD-40 ligand are more often multifocal, aggressive, and recurrent.

Adenocarcinoma, Follicular↗
PubMed2005

BRAF mutations are uncommon in papillary thyroid cancer of young patients.

Mortality is low for young patients (younger than 21 years) with papillary thyroid cancer (PTC), and different mutations might contribute to this. Previous studies detected ret/PTC rearrangements more frequently in PTC from children than adults, and recent reports describe a high incidence of BRAF T1796A transversion in adult PTC. However, BRAF mutations have not been adequately studied in PTC from young patients. We amplified and sequenced segments of the BRAF gene spanning the T1796A transversion site in 14 PTC from patients 10-21 years of age (mean, 17.5 +/- 3.5 years). The PTC (7 = class 1; 5 = class 2; 1 = class 3) ranged from 0.7-2.9 cm in diameter (mean, 1.4 +/- 0.75 cm). None of them (0/14) contained BRAF T1796A and none recurred (mean follow-up, 66 +/- 40 months). This incidence of BRAF T1796A is significantly less than that reported for adult PTC (270/699, 38.6%, p = 0.0015) in several series. None of our PTC (0/10) contained ras mutations, but 7/12 (58%) contained ret/PTC rearrangements. We conclude that BRAF mutations are less common in PTC from young patients, and ret/PTC rearrangements were the most common mutation found in these childhood PTC.

Adolescent↗
PubMed2004

Differentiated thyroid carcinomas from children and adolescents express IGF-I and the IGF-I receptor (IGF-I-R). Cancers with the most intense IGF-I-R expression may be more aggressive.

Adult thyroid cancers express IGF and IGF-I receptor (IGF-I-R), but the clinical impact is not clear. No previous study examined any childhood thyroid cancers that are well-differentiated and have a favorable prognosis. We used immunohistochemistry to determine IGF-I and IGF-I-R in 23 papillary thyroid cancers (PTC) and 6 follicular thyroid cancers (FTC) from children and adolescents. IGF-I was detected in 45% and IGF-I-R in 43% of cancers. IGF-I and IGF-I-R were found more often in PTC (IGF-I = 9/23, IGF-I-R = 8/19) than normal surrounding thyroid (IGF-I = 0/10, p = 0.032 and IGF-I-R = 0/10, p = 0.030). There were too few FTC to support independent statistical analysis, but IGF-I was found in 4 of 6 FTC (0/10 normal), and IGF-I-R was found in 2 of 4 FTC (0/10 normal). IGF-I-R staining was more intense in aggressive (invasive, metastatic, recurrent, or persistent) than indolent tumors (confined to the gland, p = 0.029). Over time, six tumors recurred, five of which expressed IGF-I-R. Overall recurrence risk was significantly greater for tumors that expressed IGF-I-R (p = 0.05) but only approached statistical significance (p = 0.08) when disease-free survival was determined. We conclude that differentiated thyroid cancers of children and adolescents express IGF-I and IGF-I-R. Tumors that express IGF-I-R are more likely to show aggressive clinical features (invasion beyond the capsule, metastasis, or recurrence) and persistence despite treatment.

Adenocarcinoma, Follicular↗
PubMed2004

Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity.

The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms.

Adult↗
PubMed2004

Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults.

PURPOSE: The fluoropyrimidine carbamate (capecitabine) is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (TP) inside target tissues. 5-FU interferes with DNA synthesis by blocking thymidylate synthase (TS) but is inactivated by dihydropyrimidine dehydrogenase (DPD). Favorable enzyme profiles (high TP and low DPD) generate high intratumor levels of 5-FU that are effective against many tumors, especially those with low TS. Capecitabine has not been tested against thyroid cancers, and it is not known to what extent thyroid cancers express TP, TS or DPD. METHODS: To test this, we determined TP, TS and DPD in 19 thyroid cancers from young patients (14 papillary, 4 follicular, 1 medullary) by immunohistochemistry. After approval by the Human Use Committee, the intensity of TP, TS, and DPD staining was determined by two independent examiners and graded (absent=0 to intense=3) with >90% concordance. RESULTS: TS was detected in 7/19 cancers (37%), TP in 14/19 cancers (74%) and DPD in 14/19 cancers (74%). In six tumors, TP was more intense that DPD, suggesting capecitabine sensitivity. Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance. Overall, 6/19 tumors (32% of the total) had a favorable expression profile, and all of them were papillary cancers. CONCLUSIONS: We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable). The results support the hypothesis that capecitabine is activated in the majority of differentiated thyroid cancers and that 32% have favorable expression of all three enzymes (TP, TS, and DPD).

Adolescent↗
PubMed2004

Cytoplasmic localization of the paired box gene, Pax-8, is found in pediatric thyroid cancer and may be associated with a greater risk of recurrence.

The paired box-8 protein (Pax-8) has been observed in the nucleus of normal adult thyroids, follicular adenomas, follicular thyroid cancers, and papillary thyroid cancers (PTC) but not undifferentiated thyroid cancers. To our knowledge, Pax-8 has not been studied in pediatric thyroid cancer. Because of the more favorable prognosis for PTC in children compared to young patients, we hypothesized that Pax-8 expression might be different in pediatric thyroid cancers. To test this, we stained 47 thyroid lesions from children and young patients for Pax-8. Pax-8 was located in the cytoplasm (cPAX) or nucleus (nPAX) in the majority of samples. There was no significant difference in nPAX between benign and malignant lesions. However, cPAX was more commonly seen in PTC than autoimmune diseases (p = 0.01) and the intensity of cPAX staining correlated with tumor size (p = 0.041), metastasis, age, completeness of resection, local invasion, and tumor size (MACIS) scores (p = 0.045), and the presence of invasion, metastasis, recurrence, or persistence (p = 0.012). Disease-free survival was significantly reduced for cancers with intense cPAX staining (p = 0.0003). These data show that cPAX is common in PTC, and although limited by small sample size, suggest an association with higher MACIS scores, an aggressive clinical course, and an increased risk of clinically evident recurrence for children and young patients.

Adolescent↗
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↗