The evaluation of red blood cell folate and methotrexate levels during protocol M in childhood acute lymphoblastic leukemia.

BACKGROUND: After High-Dose Methotrexate (HD-MTX), folinic acid rescue therapy (Leucovorin) is administered to reduce side effects in pediatric acute lymphoblastic leukemia (ALL) patients. Leucovorin and MTX are structural analogues, possibly competing for cellular transport and intracellular metabolism. We hypothesize that Leucovorin accumulates during consecutive courses, which might result in a lower MTX uptake. METHODS: We prospectively measured red blood cell (RBC) folate and MTX levels during four HD-MTX and Leucovorin courses in 43 patients treated according the DCOG ALL-11 protocol with 2-weekly HD-MTX (5 g/m2/dose) and Leucovorin (15 mg/m2/dose) using LC-MS/MS. We estimated a linear mixed model to assess the relationship between these variables over time. RESULTS: Both RBC MTX-PG and folate levels increased significantly during protocol M. MTX-PG2-5 levels increased most substantially after the first two HD-MTX courses (until median 113.0 nmol/L, IQR 76.8-165.2) after which levels plateaued during the 3d and 4th course (until median 141.3 nmol/L, IQR 100.2-190.2). In parallel, folate levels increased most substantially after the first two HD-MTX courses (until median 401.6 nmol/L, IQR 163.3-594.2) after which levels plateaued during the 3d and 4th course (until median 411.5 nmol/L, IQR 240.3-665.6). The ratio folate/MTX-PG decreased significantly over time, which was mostly due to the relatively higher increase (delta) of MTX-PG. CONCLUSION: These results suggest that the increase in RBC folate levels does not seem to have a large effect on RBC MTX levels. Future studies, assessing competition of Leucovorin and MTX on other cellular mechanisms which might negatively affect treatment efficacy, are necessary.

No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon-like peptide-1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon-like peptide-1 receptor agonists. This report presents the case of a woman with pre-existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-5 clinical study (NCT00734474). CASE REPORT: Elevated serum calcitonin was noted in a 56-year-old woman with Type 2 diabetes mellitus at the 6-month discontinuation visit in a study of long-term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post-study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto-oncogene mutation. CONCLUSION: The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.

Optimal management of Graves orbitopathy: a multidisciplinary approach.

Graves' thyroid disease is a relatively common disorder in endocrinology and general internal medicine practice. Graves' hyperthyroidism is mediated by circulating stimulating autoantibodies. Up to 60% of patients with Graves' hyperthyroidism develop some form of Graves' orbitopathy. Immune reactivity to the thyroid-stimulating hormone receptor is also thought to play a role in the immunopathogenesis of Graves' orbitopathy. Graves' orbitopathy is characterised by a wide open eye appearance, caused by upper eyelid retraction and soft-tissue swelling that causes exophthalmus. Symptoms include photophobia, sandy feeling in the eye, painful eye movements and diplopia. Visual acuity may be reduced. In some cases emergency treatment is necessary to prevent irreversible vision loss. Smoking should be stopped. Mild to moderate Graves' orbitopathy may be an indication for corticosteroid treatment or radiotherapy. Once inflammatory signs and symptoms have waned, surgery can be performed to correct residual diplopia, exophthalmus or lid retraction. The presence of Graves' orbitopathy has consequences for the management of Graves' hyperthyroidism. Adequately controlled Graves' thyroid dysfunction is likely to improve Graves' orbitopathy, while radioactive iodine treatment can worsen the condition. Due to the wide variety in clinical presentation and the possible interference between treatment of thyroid disease and eye disease, the management of more complicated patients with Graves' orbitopathy can best be performed in combined thyroid-eye clinics, in which the patient is seen simultaneously by the ophthalmologist and the endocrinologist.

Follow-up of low-risk differentiated thyroid cancer patients who underwent radioiodine ablation of postsurgical thyroid remnants after either recombinant human thyrotropin or thyroid hormone withdrawal.

BACKGROUND: We previously demonstrated comparable thyroid remnant ablation rates in postoperative low-risk thyroid cancer patients prepared for administration of 3.7GBq (131)I (100 mCi) after recombinant human (rh) TSH during T(4) (L-T4) therapy vs. withholding L-T4 (euthyroid vs. hypothyroid groups). We now compared the outcomes of these patients 3.7 yr later. PATIENTS AND METHODS: Fifty-one of the 63 original patients (28 euthyroid, 23 hypothyroid) participated. Forty-eight received rhTSH and serum thyroglobulin (Tg) sampling. A (131)I whole-body scan was performed in 43 patients, and successful ablation was defined by criteria from the previous study. Based on the criterion of uptake less than 0.1% in thyroid bed, 100% (43 of 43) remained ablated. When no visible uptake instead was used, five patients (four euthyroid, one hypothyroid) had minimal visible activity. When the TSH-stimulated Tg criterion was used, only two of 45 (one euthyroid, one hypothyroid) had a stimulated Tg level greater than 2 ng/ml. RESULTS: No patient in either group died, and no patient declared disease free had sustained tumor recurrence. Nine (four euthyroid, five hypothyroid) had received additional (131)I between the original and current studies due to detectable Tg or imaging evidence of disease; with follow-up, all now had a negative rhTSH-stimulated whole-body scan and seven (three euthyroid, four hypothyroid) had a stimulated serum Tg less than 2 ng/ml. CONCLUSIONS: In conclusion, after a median 3.7 yr, low-risk thyroid cancer patients prepared for postoperative remnant ablation either with rhTSH or after L-T4 withdrawal were confirmed to have had their thyroid remnants ablated and to have comparable rates of tumor recurrence and persistence.

Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study.

CONTEXT: After surgery for differentiated thyroid carcinoma, many patients are treated with radioiodine to ablate remnant thyroid tissue. This procedure has been performed with the patient in the hypothyroid state to promote endogenous TSH stimulation and is often associated with hypothyroid symptoms and impaired quality of life. OBJECTIVE AND INTERVENTION: This international, randomized, controlled, multicenter trial aimed to compare the efficacy and safety of recombinant human TSH (rhTSH) to prepare euthyroid patients on L-thyroxine therapy (euthyroid group) to ablate remnant thyroid tissue with 3.7 GBq (100 mCi) 131I, compared with that with conventional remnant ablation performed in the hypothyroid state (hypothyroid group). Quality of life was determined at the time of randomization and ablation. After the administration of the 131-I dose, the rate of radiation clearance from blood, thyroid remnant, and whole body was measured. RESULTS: The predefined primary criterion for successful ablation was "no visible uptake in the thyroid bed, or if visible, fractional uptake less than 0.1%" on neck scans performed 8 months after therapy and was satisfied in 100% of patients in both groups. A secondary criterion for ablation, an rhTSH-stimulated serum thyroglobulin concentration less than 2 ng/ml, was fulfilled by 23 of 24 (96%) euthyroid patients and 18 of 21 (86%) hypothyroid patients (P = 0.2341). Quality of life was well preserved in the euthyroid group, compared with the hypothyroid group, as demonstrated by their lower pretreatment scores on the Billewicz scale for hypothyroid signs and symptoms, 27 +/- 7 vs. 18 +/- 4 (P < 0.0001) and their significantly higher Short Form-36 Health Assessment Scale scores in five of eight categories. Euthyroid patients had a statistically significant one third lower radiation dose to the blood, compared with patients in the hypothyroid group. CONCLUSIONS: This study demonstrates comparable remnant ablation rates in patients prepared for 131I remnant ablation with 3.7 GBq by either administering rhTSH or withholding thyroid hormone. rhTSH-prepared patients maintained a higher quality of life and received less radiation exposure to the blood.

Hashimoto's thyroiditis with papillary thyroid carcinoma (PTC)-like nuclear alterations express molecular markers of PTC.

AIMS: Focal papillary thyroid carcinoma (PTC)-like nuclear alterations have been documented in Hashimoto's thyroiditis; however, the molecular association between PTC and Hashimoto's thyroiditis is poorly understood. The aim of this study was to determine whether molecular expression patterns of PTC are present in association with PTC-like nuclear alterations in Hashimoto's thyroiditis. METHODS AND RESULTS: The expression of four genes known to be up-regulated in PTC [LGALS3 (galectin3), CITED1, KRT19 (cytokeratin 19) and FN1 (fibronectin-1)] and the human mesothelial cell protein identified by monoclonal antibody HBME1 was evaluated. Immunohistochemistry was performed on 23 cases of Hashimoto's thyroiditis with focal or diffuse Hürthle cell change and PTC-like nuclear alterations, 37 PTC and 18 normal thyroids. Focal expression of galectin3 (GAL3), CITED1, cytokeratin 19 (CK19), HBME1 and fibronectin-1 (FN1) was seen in 87%, 65%, 43%, 26% and 17% of Hashimoto's thyroiditis, respectively, only in thyrocytes showing PTC-like nuclear alterations. In contrast, diffuse expression of GAL3, CITED1, CK19, HBME1 and FN1 was seen in 100%, 95%, 70%, 87% and 89% of PTC, respectively. Normal thyroid tissues did not express any of these proteins. Following immunohistochemistry, four Hashimoto's thyroiditis cases were found to contain foci of PTC. These foci were highlighted by the diffuse and strong expression of PTC-associated proteins, which prompted additional retrospective scrutiny of the haematoxylin and eosin-stained sections leading to appreciation of complete PTC-type nuclear atypia. CONCLUSIONS: Focal PTC-like immunophenotypic changes in Hashimoto's thyroiditis suggest the possibility of early, focal premalignant transformation in some cases of Hashimoto's thyroiditis.

Nasolacrimal obstruction secondary to I(131) therapy.

PURPOSE: To report the finding of nasolacrimal drainage system obstruction associated with I(131) therapy for thyroid carcinoma from an updated and expanded cohort. METHODS: Patients with a history of epithelial derived thyroid carcinoma who had tearing were offered referral for evaluation by an oculoplastic surgeon. Patients underwent nasolacrimal probing and irrigation procedures with localization of their nasolacrimal obstruction. Therapy for the site of obstruction was instituted. RESULTS: Clinically significant tearing was identified in 26 patients, all of whom had previously undergone I(131) therapy (n = 563). Nineteen patients were evaluated and confirmed to have nasolacrimal drainage system obstruction; 7 have yet to be formally evaluated. Areas of obstruction included nasolacrimal duct, common canaliculus, and, rarely, distal upper and lower canaliculi. Patients were treated with a variety of modalities including silicone intubation, balloon dacryoplasty, dacryocystorhinostomy, and conjunctival dacryocystorhinostomy. CONCLUSIONS: The use of I(131) for thyroid carcinoma is associated with a 3.4% incidence of documented nasolacrimal drainage obstruction and an overall 4.6% incidence of documented or suspected obstruction. The true incidence may be higher, since - I(131) treated individuals were neither systematically evaluated nor questioned about tearing. It has yet to be established if the obstructions result from local toxicity caused by the passive flow of radioactive iodine containing tears through these tissues or the active uptake and concentration of I(131) in lacrimal drainage system tissues through the sodium/iodide supporter.

Effects of dose, intervention time, and radionuclide on sodium iodide symporter (NIS)-targeted radionuclide therapy.

The sodium iodide symporter (NIS) mediates iodide uptake into thyrocytes and is the molecular basis of thyroid radioiodine therapy. We previously have shown that NIS gene transfer into the F98 rat gliomas facilitated tumor imaging and increased survival by radioiodine. In this study, we show that: (1) the therapeutic effectiveness of (131)I in prolonging the survival time of rats bearing F98/hNIS gliomas is dose- and treatment-time-dependent; (2) the number of remaining NIS-expressing tumor cells decreased greatly in RG2/hNIS gliomas post (131)I treatment and was inversely related to survival time; (3) 8 mCi each of (125)I/(131)I is as effective as 16 mCi (131)I alone, despite a smaller tumor absorbed dose; (4) (188)ReO(4), a potent beta(-) emitter, is more efficient than (131)I to enhance the survival of rats bearing F98/hNIS gliomas. These studies demonstrate the importance of radiopharmaceutical selection, dose, and timing of treatment to optimize the therapeutic effectiveness of NIS-targeted radionuclide therapy following gene transfer into gliomas.

In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas.

Radioactive iodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by the sodium iodide symporter (NIS), is the first rate-limiting step in iodide accumulation which provides a mechanism for effective radioiodide treatment for patients with thyroid cancer. We hypothesize that NIS gene transfer to non-thyroid tumor cells will enhance intracellular radioiodide accumulation and result in better tumor control. Here, we performed non-invasive tumor imaging and (131)I therapy studies using rats bearing intracerebral F98 gliomas that have been retrovirally transduced with human NIS. Our results show that: (1) NIS is expressed in the intracerebral F98/NIS gliomas; (2) F98/NIS gliomas can be imaged by (99m)TcO(4) (whose uptake is also mediated by NIS) and (123)I scintigraphy; (3) significant amounts of radioiodide were retained in the tumors at 24 h after (123)I injection; (4) RAIU and NIS expression in the thyroid gland can be reduced by feeding a thyroxine-supplemented diet; and (5) survival time was increased in rats bearing F98/hNIS tumors by (131)I treatment. These studies warrant further investigating tumor imaging and therapeutic strategies based on NIS gene transfer followed by radioiodide administration in a variety of human cancers.

Gene expression in papillary thyroid carcinoma reveals highly consistent profiles.

Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase-PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase-PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.

Sodium iodide symporter in health and disease.

Radioiodine-concentrating activity in thyroid tissues has allowed the use of radioiodine as a diagnostic and therapeutic agent for patients with thyroid disorders such as well-differentiated thyroid cancer. However, some extrathyroidal tissues also take up radioiodine, contributing to unwanted side effects of radioiodine therapy. Now that the molecule that mediates radioiodine uptake, the sodium iodide symporter (NIS), has been cloned and characterized, it may be possible to develop novel strategies to differentially modulate NIS expression and/or activity, enhancing it in target tissues and impeding it in others. In addition to restoring NIS expression/activity to ensure sufficient radioiodine uptake for the diagnosis and treatment of advanced thyroid cancers, we envision that it may be possible to selectively increase or confer NIS expression/activity in tumors of nonthyroidal tissues to facilitate the use of radioiodine in their diagnosis and treatment. We also consider the molecular basis of thyroid and nonthyroid disorders that may be complicated by NIS deregulation. Finally, we explore the use of NIS as an imaging reporter gene to monitor the expression profile of the transgene in transgenic mouse animal models and in patients undergoing gene therapy clinical trials.

Using recombinant human TSH in the management of well-differentiated thyroid cancer: current strategies and future directions.

Mortality rates from thyroid cancer have fallen significantly in recent decades, almost certainly as the result of earlier diagnosis and improved treatment of differentiated (papillary and follicular) thyroid cancer. Enhanced survival is likely a result of early diagnosis and therapy applied at a disease stage when treatment is most effective. In the United States and Europe, most patients at high risk for relapse and death from thyroid cancer are treated with total or near-total thyroidectomy and receive radioiodine ablation of residual normal or malignant thyroid tissue, followed by treatment with thyroid hormone, a strategy that cures more than 80% of patients. Still, some die of the disease and nearly 15% have local recurrences, while another 5% to 10% develop distant metastases. Over 50% of recurrences appear in the first five years, but distant metastases may surface years, and sometimes decades, after initial therapy. Much has been learned about risk stratification to predict recurrence and death from thyroid cancer but individual patients continue to have adverse outcomes not always foreseen by a low tumor stage. Follow-up must accordingly be meticulous and prolonged. The National Cancer Center Network (NCCN) has recently established consensus practice guidelines that give explicit advice about the diagnosis and management of benign and malignant thyroid tumors, including paradigms for long-term follow-up and the treatment of recurrent disease. The guidelines confirm that diagnostic scanning with 131I and measurement of serum thyroglobulin (Tg) levels are the mainstay of follow-up, offering the opportunity to detect recurrent or persistent cancer at very early stages. These guidelines advocate TSH-stimulated serum Tg measurements, done either during thyroid hormone withdrawal or stimulation with recombinant human TSH (rhTSH, Thyrogen), that often identify the presence of cancer well before diagnostic whole-body scanning or other imaging studies can spot the tumor, which offers the opportunity to treat recurrent disease at an early stage. The use of rhTSH adds a new dimension to long-term follow-up that avoids putting patients through the symptoms of hypothyroidism, and offers the opportunity to follow some patients with rhTSH-stimulated serum Tg levels without performing 131I whole-body scans. A multicenter international study has shown that serum Tg measurements alone are not as sensitive in the identification of patients with persistent or recurrent tumor as are rhTSH-stimulated serum Tg determinations. Although not yet approved for preparation of patients for 131I therapy, rhTSH has been used successfully in a compassionate use program for this purpose in a relatively large number of patients. Formal clinical investigations now planned to provide guidelines for the use of rhTSH for therapeutic 131I portend a new set of effective therapeutic paradigms for the management of differentiated thyroid cancer.

Diagnostic evaluation of the adrenal incidentaloma: decision and cost-effectiveness analyses.

UNLABELLED: The goal of this study was to examine the clinical and economic outcomes of alternative diagnostic strategies for differentiating benign from malignant adrenal masses. METHODS: We used cost-effectiveness assessment derived from decision analysis and the economic perspective of the payer of health care services. One-time evaluation with fine-needle aspiration (FNA) and combinations of chemical-shift MRI, noncontrast CT, 131I-6beta-iodomethylnorcholesterol (NP-59) scintigraphy, with or without FNA, in a hypothetical cohort of 1000 patients with incidentally discovered unilateral, nonhypersecretory adrenal masses. We calculated and compared the diagnostic effectiveness, costs and cost-effectiveness of the alternative strategies based on estimates from published literature and institutional charge data. RESULTS: At an assumed baseline malignancy rate of 0.25, diagnostic utility varied from 0.31 (CT0) to 0.965 (NP-59) and diagnostic accuracy from 0.655 [noncontrast CT using a cut-off attenuation value of > or = 0 (CT0)] to 0.983 (NP-59). The average cost per patient per strategy ranged from $746 (NP-59) to $1745 (MRI +/- FNA). The best and worst potential cost-to-diagnostic utility ratios were 773 (NP-59) and 2839 (CT0) and 759 (NP-59) and 1982 (MRI +/- FNA) for cost and diagnostic accuracy, respectively. The NP-59 strategy was the optimal choice regardless of the expected outcome examined: cost, diagnostic utility, diagnostic accuracy or cost-effectiveness. Varying the prevalence of malignancy did not alter the cost-effectiveness advantage of NP-59 over the other diagnostic modalities. CONCLUSION: Based on available estimates of reimbursement costs and diagnostic test performance and using reasonable clinical assumptions, our results indicate that the NP-59 strategy is the most cost-effective diagnostic tool for evaluating adrenal incidentalomas over a wide range of malignancy rates and that additional clinical studies are warranted to confirm this cost-effectiveness advantage.

Specificity of radioiodinated MIBG for neural crest tumors in childhood.

UNLABELLED: The high sensitivity of metaiodobenzylguanidine (MIBG) scintigraphy for sympathomedullary tumors such as neuroblastoma and pheochromocytoma is well documented. The specificity of MIBG scintigraphy for these tumors is also high but has been incompletely characterized for other neural crest tumors and non-neural crest tumors of childhood. METHODS: The medical records and MIBG scans of all children who had undergone MIBG scintigraphy for known or suspected neuroblastoma or pheochromocytoma were retrospectively reviewed at five major referral centers. Those patients found to have pathologies other than neuroblastoma or pheochromocytoma form the basis of this study. RESULTS: One hundred children with a total of 110 lesions met the inclusion criteria. All had negative MIBG scans except 1 of 2 children with infantile myofibromatosis, 1 of 2 with neuroendocrine carcinomas, 1 of 2 with pancreaticoblastomas and 1 of 10 with primitive neuroectodermal tumors. CONCLUSION: MIBG scintigraphy is highly specific for neuroblastoma and pheochromocytoma. Only 4% (4/100) of nonsympathomedullary tumors (non-pheochromocytoma and non-neuroblastoma) in childhood showed MIBG uptake, of which only 2% (2/100) were of non-neural crest origin.

Diagnostic dilemma of small incidentally discovered adrenal masses: role for 131I-6beta-iodomethyl-norcholesterol scintigraphy.

Incidentally discovered adrenal masses are detected in 0.35% to 5. 00% of patients imaged with computed tomography (CT) for reasons other than suspected adrenal pathology. Most small adrenal masses are benign, although malignant tumors 2 cm. Although some lesions 1 to 2 to 1 to 2 to

Bone scans in neurofibromatosis: neurofibroma, plexiform neuroma and neurofibrosarcoma.

UNLABELLED: Neurofibromatosis type 1 or von Recklinghausen's disease is one of the most common autosomal dominant genetic disorders. Between 29% and 77% of patients may suffer from a wide range of skeletal abnormalities and, thus, patients with neurofibromatosis frequently undergo skeletal scintigraphy, at which time the common peripheral nerve soft-tissue tumors that occur in this syndrome (neurofibromas, plexiform neuromas and neurofibrosarcomas) may be demonstrated. METHODS: Single or multiphase 99mTc methylenediphosphonate (MDP) bone scans were performed in five patients with neurofibromatosis as part of their clinical evaluation. RESULTS: We imaged neurofibrosarcomas in three patients, cutaneous neurofibromas in one patient and a plexiform neuroma in one patient. CONCLUSION: Single- or multiphasic bone scans may localize common soft-tissue tumors in neurofibromatosis.

The incidental adrenal mass.

This article discusses the accuracy and complications of percutaneous biopsy of adrenal masses and the rapidly evolving new methods for noninvasive differential diagnosis using CT scan, MR imaging, and radio-nuclide scintigraphy. We offer our current recommendations for the evaluation of benign versus malignant adrenal masses and speculate on the optimal approach for the near future.