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Objective: Knowledge of referral patterns for specialty cancer care is sparse. Information on both the need and reasons for referral of high-risk, well-differentiated thyroid cancer patients should provide a foundation for eliminating obstacles to appropriate patient referrals and improving patient care., Methods: We surveyed 370 endocrinologists involved in thyroid cancer management. From information in a clinical vignette, respondents were asked to identify the reasons they would need to refer a high-risk patient to a more specialized facility for care. We performed multivariable analysis controlling for hospital and physician characteristics., Results: Thirty-two percent of respondents reported never referring thyroid cancer patients to another facility. Of those that would refer a high-risk patient to another facility, the opportunity for a patient to enter a clinical trial was the most common reason reported (44%), followed by high-dose radioactive iodine (RAI) with or without dosimetry (33%), lateral neck dissection (24%), and external beam radiation (15%). In multivariable analysis, endocrinologists with a higher percentage of their practice devoted to thyroid cancer care were significantly less likely to refer patients to another facility (P = .003)., Conclusion: The majority of endocrinologists treating thyroid cancer patients report referring a high-risk patient to another facility for some or all of their care. Knowledge of the patterns of physician referrals and the likelihood of need for referral are key to understanding discrepancies in referral rates and obstacles in the referral process.

Context: Little is known about practice patterns in thyroid cancer, a cancer that is increasing in incidence., Objective: We sought to identify aspects of thyroid cancer management that have the greatest variation., Design/setting/participants: We surveyed 944 physicians involved in thyroid cancer care from 251 hospitals affiliated with the US National Cancer Database. Physicians were asked questions in the following four domains: thyroid surgery, radioactive iodine use, thyroid hormone replacement postsurgery, and long-term thyroid cancer management. We calculated the ratio of observed variation to hypothetical maximum variation under the assumed distribution of the response. Ratios closer to 1 indicate greater variation., Results: We had a 66% response rate. We found variation in multiple aspects of thyroid cancer management, including the role of central lymph node dissections (variation, 0.99; 95% confidence interval [CI], 0.98-1.00), the role of pretreatment scans before radioactive iodine treatment (variation, 1.00; 95% CI, 0.98-1.00), and all aspects of long-term thyroid cancer management, including applications of ultrasound (variation, 0.97; 95% CI, 0.93-0.99) and radioactive iodine scans (variation, 0.99; 95% CI, 0.97-1.00). For the management of small thyroid cancers, variation exists in all domains, including optimal extent of surgery (variation, 0.91; 95% CI, 0.88-0.94) and the role of both radioactive iodine treatment (variation, 0.91; 95% CI, 0.89-0.93) and suppressive doses of thyroid hormone replacement (variation, 1.00; 95% CI, 0.99-1.00)., Conclusion: We identified areas of variation in thyroid cancer management. To reduce the variation and improve the management of thyroid cancer, there is a need for more research and more research dissemination.

Background: There is variation in the use of radioactive iodine (RAI) as treatment for well-differentiated thyroid cancer. The factors involved in physician decision-making for RAI remain unknown., Methods: We surveyed physicians involved in postsurgical management of patients with thyroid cancer from 251 hospitals. Respondents were asked to rate the factors important in influencing whether a thyroid cancer patient receives RAI. Multivariable analyses controlling for physician age, gender, specialty, case volume, and whether they personally administer RAI, were performed to determine correlates of importance placed on patients' and physicians' worry about death from cancer and differences between low- versus higher-case-volume physicians., Results: The survey response rate was 63% (534/853). Extent of disease, adequacy of surgical resection, patients' willingness to receive RAI, and patients' age were the factors physicians were most likely to report as quite or very important in influencing recommendations for RAI to patients with thyroid cancer. Interestingly, both physicians' and patients' worry about death from thyroid cancer were also important in determining RAI use. Physicians with less thyroid cancer cases per year were more likely than higher-volume physicians to report patients' (p<0.001) and physicians' worry about death (p=0.016) as quite or very important in decision-making. Other factors more likely to be of greater importance in determining RAI use for physicians with lower thyroid cancer patient volume versus higher include the accepted standard at the affiliated hospital (p=0.020), beliefs about RAI expressed by colleagues comanaging patients (p=0.003), and patient distance from the nearest facility administering RAI (p=0.012)., Conclusion: In addition to the extent of disease and adequacy of surgical resection, physicians place importance on physician and patient worry about death from thyroid cancer when deciding whether to treat a patient with RAI. The factors important to physician decision-making differ based on physician thyroid-cancer case-volume, with worry about death being more influential for low-case-volume physicians. As the mortality from thyroid cancer is low, the importance placed on death in decision making may be unwarranted.

Since 1981, meta-iodobenzylguanidine (MIBG), labeled with (131)I and later (123)I, has become a valuable agent in the diagnosis and therapy of a number of endocrine tumors. Initially, the agent located pheochromocytomas and paragangliomas (PGLs), both sporadic and familial, in multiple anatomic sites; surgeons were thereby guided to excisional therapies, which were previously difficult and sometimes impossible. The specificity in diagnosis has remained above 95%, but sensitivity has varied with the nature of the tumor: close to 90% for intra-adrenal pheochromocytomas but 70% or less for PGLs. For patients with neuroblastoma, carcinoid tumors, and medullary thyroid carcinoma, imaging with radiolabeled MIBG portrays important diagnostic evidence, but for these neoplasms, use has been primarily as an adjunct to therapy. Although diagnosis by radiolabeled MIBG has been supplemented and sometimes surpassed by newer scintigraphic agents, searches by this radiopharmaceutical remain indispensable for optimal care of some patients. The radiation imparted by concentrations of (131)I-MIBG in malignant pheochromocytomas, PGLs, carcinoid tumors, and medullary thyroid carcinoma has reduced tumor volumes and lessened excretions of symptom-inflicting hormones, but its value as a therapeutic agent is being fulfilled primarily in attacks on neuroblastomas, which are scourges of children. Much promise has been found in tumor disappearance and prolonged survival of treated patients. The experiences with therapeutic (131)I-MIBG have led to development of new tactics and strategies and to well-founded hopes for elimination of cancers. Radiolabeled MIBG is an exemplar of theranostics and remains a worthy agent for both diagnosis and therapy of endocrine tumors., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Three endocrine neoplasms-bilateral pheochromocytomas, somatotrophic pituitary adenoma inducing acromegaly, and papillary carcinoma of the thyroid-occurred concurrently in a patient. A genetic mutation was hypothesized. Possible previously described genetic mutations were explored., Methods: Clinical assessments, laboratory data, images of tumors, histopathology, and immunohistochemistry of excised tissues documented the three neoplasms. Clinical assessment of the patient, family history, and a review of the literature sought a familial basis for the disorders., Results: The methods confirmed the presence of three endocrine neoplasms. Each neoplasm was surgically excised and histologically verified. Surgical and (131)I treatments reduced the papillary carcinoma, but eventually this tumor progressed to a lethal degree. History, including that of nine siblings, uncovered no familial neoplasms. No similar case was found in the literature, but possible associations with germline mutations were considered., Conclusions: The concurrent development of pheochromocytomas, pituitary somatotrophic adenoma, and papillary thyroid carcinoma appears to be unique. Nevertheless, such tumors, particularly bilateral pheochromocytomas, strongly suggest a de novo germline mutation in a gene not previously associated with multiple endocrine neoplasia syndromes.

Background: Radiation safety is an essential component in the treatment of patients with thyroid diseases by ¹³¹I. The American Thyroid Association created a task force to develop recommendations that would inform medical professionals about attainment of radiation safety for patients, family members, and the public. The task force was constituted so as to obtain advice, experience, and methods from relevant medical specialties and disciplines., Methods: Reviews of Nuclear Regulatory Commission regulations and International Commission on Radiological Protection [corrected] recommendations formed the basic structure of the recommendations. Members of the task force contributed both ideas and methods that are used at their respective institutions to aid groups responsible for treatments and that instruct patients and caregivers in the attainment of radiation safety. There are insufficient data on long-term outcomes to create evidence-based guidelines., Results: The information was used to compile delineations of radiation safety. Factors and situations that govern implementation of safety practices are cited and discussed. Examples of the development of tables to ascertain the number of hours or days (24-hour cycles) of radiation precaution appropriate for individual patients treated with ¹³¹I for hyperthyroidism and thyroid cancer have been provided. Reminders in the form of a checklist are presented to assist in assessing patients while taking into account individual circumstances that would bear on radiation safety. Information is presented to supplement the treating physician's advice to patients and caregivers on precautions to be adopted within and outside the home., Conclusion: Recommendations, complying with Nuclear Regulatory Commission regulations and consistent with guidelines promulgated by the National Council on Radiation Protection and Measurement (NCRP-155), can help physicians and patients maintain radiation safety after treatment with ¹³¹I of patients with thyroid diseases. Both treating physicians and patients must be informed if radiation safety, an integral part of therapy with ¹³¹I, is to be attained. Based on current regulations and understanding of radiation exposures, recommendations have been made to guide physicians and patients in safe practices after treatment with radioactive iodine.

The molecular mechanisms driving the conserved metazoan developmental shift referred to as the mid-blastula transition (MBT) remain mysterious. Typically, cleavage divisions give way to longer asynchronous cell cycles with the acquisition of a gap phase. In Drosophila, rapid synchronous nuclear divisions must pause at the MBT to allow the formation of a cellular blastoderm through a special form of cytokinesis termed cellularization. Drosophila Fragile X mental retardation protein (dFMRP; FMR1), a transcript-specific translational regulator, is required for cellularization. The role of FMRP has been most extensively studied in the nervous system because the loss of FMRP activity in neurons causes the misexpression of specific mRNAs required for synaptic plasticity, resulting in mental retardation and autism in humans. Here, we show that in the early embryo dFMRP associates specifically with Caprin, another transcript-specific translational regulator implicated in synaptic plasticity, and with eIF4G, a key regulator of translational initiation. dFMRP and Caprin collaborate to control the cell cycle at the MBT by directly mediating the normal repression of maternal Cyclin B mRNA and the activation of zygotic frühstart mRNA. These findings identify two new targets of dFMRP regulation and implicate conserved translational regulatory mechanisms in processes as diverse as learning, memory and early embryonic development.

Objective: The purpose of this study was to evaluate the feasibility of staging differentiated thyroid carcinoma (DTC) before initial radioiodine therapy using diagnostic radioiodine-131 ((131)I) scintigraphy with SPECT/CT and to determine the additional value of SPECT/CT., Materials and Methods: Forty-eight patients (12 men and 36 women; age range, 17-82 years) with DTC underwent diagnostic (131)I planar imaging and SPECT/CT scintigraphy reinterpreted by two readers, one of whom was not blinded to patients' clinical details. Staging and scoring of carcinomas was done by use of TNM with three levels of sequential information: histopathologic analysis and chest radiograph data, planar images, and SPECT/CT data. Restaging based on the imaging findings was designated as "iTNM.", Results: Diagnostic (131)I scintigraphy allowed TNM staging of DTC before initial radioiodine therapy. Planar images detected previously unsuspected distant disease in four (50%) of eight patients with a score of M1. SPECT/CT changed the planar scan interpretation for 19 (40%) of 48 patients, detecting regional nodal metastases in four patients and clarifying equivocal focal neck uptake in 15 patients. Compared with histopathologic analysis and chest radiograph data, planar images and SPECT/CT changed the postsurgical DTC stage for 10 (21%) of 48 patients. SPECT/CT information changed the proposed (131)I therapeutic dose for 28 (58%) of 48 patients, on the basis of our department protocol., Conclusion: Diagnostic (131)I scintigraphy, planar images, and SPECT/CT complete the postsurgical staging of DTC. SPECT/CT reduces the number of equivocal diagnoses on planar imaging and improves the interpretation of (131)I scintigraphy. The consequent changes in TNM scores and staging should influence the (131)I dose prescribed at initial therapy.

Fragile X mental retardation protein (FMRP) is an RNA-binding protein that is required for the translational regulation of specific target mRNAs. Loss of FMRP causes Fragile X syndrome (FXS), the most common form of inherited mental retardation in humans. Understanding the basis for FXS has been limited because few in vivo targets of FMRP have been identified and mechanisms for how FMRP regulates physiological targets are unclear. We have previously demonstrated that Drosophila FMRP (dFMRP) is required in early embryos for cleavage furrow formation. In an effort to identify new targets of dFMRP-dependent regulation and new effectors of cleavage furrow formation, we used two-dimensional difference gel electrophoresis and mass spectrometry to identify proteins that are misexpressed in dfmr1 mutant embryos. Of the 28 proteins identified, we have identified three subunits of the Chaperonin containing TCP-1 (CCT) complex as new direct targets of dFMRP-dependent regulation. Furthermore, we found that the septin Peanut, a known effector of cleavage, is a likely conserved substrate of fly CCT and is mislocalized in both cct and in dfmr1 mutant embryos. Based on these results we propose that dFMRP-dependent regulation of CCT subunits is required for cleavage furrow formation and that at least one of its substrates is affected in dfmr1- embryos suggesting that dFMRP-dependent regulation of CCT contributes to the cleavage furrow formation phenotype., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: The hereditary paraganglioma syndromes (PGLs) are autosomal dominant conditions with an increased risk for tumors of the sympathetic and parasympathetic neuroendocrine systems. The recognition of patients with hereditary PGL and identification of the responsible gene are important for the management of index patients and family members., Methods: We present the clinical, radiological, biochemical, and family history findings of a 15-year-old boy patient with a glomus vagale versus glomus jugulare tumor., Results: Evaluation of the family history and the patient's history led to the identification of a familial succinate dehydrogenase subunit D (SDHD) gene mutation (F933>X67), consistent with a diagnosis of hereditary PGL1. Although this family had all head and neck tumors, this SDHD mutation has previously been described in a family with primarily functional pheochromocytomas., Conclusions: This case report highlights the variable expressivity of a single mutation in SDHD, (F933>X67). Careful and comprehensive screening is warranted for individuals at risk.

Background: Infringement by differentiated thyroid carcinoma on the brain is rare but, when suspected, the patient deserves special attention. A patient with an enlarging metastasis of thyroid carcinoma to the skull that was impinging on the brain illustrates diagnostic and therapeutic strategies applicable to the treatment of metastatic carcinoma., Methods: A case study was performed. Computed tomography (CT) and magnetic resonance imaging (MRI) were done, serum thyroglobulin was measured, and tumor responses to thyroxine and (131)I treatments were monitored. Tumor dosimetry, enabled by scintigraphy with (131)I employing single photon emission tomography fused with CT (SPECT-CT), was performed., Results: The metastasis was from a follicular variant of papillary thyroid carcinoma. During thyrotropin stimulation the tumor enlarged. The tumor decreased in volume after each of two (131)I therapies. Dosimetry indicated delivery of 1970 and 2870 cGy to the tumor and 35 and 42 cGy to the brain, respectively, in the two treatments. The patient has survived for more than 11 years since diagnosis., Conclusions: A metastasis from a follicular variant of papillary carcinoma increased in volume during hypothyroidism producing more infringement on the brain. Beyond the effects of thyroxine therapy, (131)I treatments induced recession of tumor volume. In patients with metastases that concentrate (131)I, dosimetry with SPECT-CT can predict absorbed doses of radiation to the tumor and to the adjacent organs and thus lay a basis for data-based decisions on (131)I therapies. Therapy may induce prolonged survival in patients with metastases infringing on the brain.

Hyperparathyroidism and/or parathyroid hyperplasia, medullary thyroid carcinoma (MTC), and pheochromocytomas compose the hallmarks of the multiple endocrine neoplasia type 2A (MEN 2A) syndrome. Revisiting a report in 1939 of a patient with hyperparathyroidism and parathyroid hyperplasia led to a search for evidence of MEN 2A. From medical records and discussion with family members, longitudinal follow-up of the patient and her descendants was obtained. Molecular diagnostics were integrated in the care of subsequent generations. The literature on hyperparathyroidism and MEN 2A was reviewed. Children of the proband exhibited all components of MEN 2A and the RET mutation of 634 TGC>CGC. The pedigree was typical for this mutation. Papers on anthropologic studies demonstrate skeletal evidence of hyperparathyroidism in humans centuries ago. The initial report of the proband preceded the publications defining both MTC and MEN 2A. The values of in-depth family histories and genetic analyses are exemplified.

Unlabelled: Appearances of and increases in Graves' ophthalmopathy (GO) have been reported after treatment of patients with hyperthyroidism with radioiodine. We sought to determine the rates of appearance or increase in manifestations of GO in American patients treated with radioiodine for hyperthyroidism., Methods: The study population, which consisted of 76 patients (range, 10.6-72 y), included 61 women and individuals of diverse ethnicity. The patients were followed for 1 y after radioiodine treatment. The clinical activity score (CAS) included 10 items of ophthalmic change that were evaluated at 2 and 6 mo and at 1 y; appearance of a new item scored 1 point. We evaluated interactions of 6 covariates-prolonged hyperthyroidism, prolonged hypothyroidism, smoking, treatment with an antithyroid drug (ATD), and serum levels of thyroid-stimulating immunoglobulin (TSI) and of high free T3 (FT3)--with the numbers of patients with 2 or more CAS points and with exophthalmometer readings increased by at least 2 mm. In addition, patients completed a scored quality-of-life (QOL) questionnaire at baseline and at 1 y to assess eye symptoms., Results: The mean CAS points for all patients at 2 mo was 0.63 and was not significantly different at 1 y. In 9 of 10 CAS items, there were few patients affected at 1 y and for the most part there were fewer patients affected than at baseline. However, exophthalmometer readings increased in 39% of patients by a mean of 2.6 mm. Individual patients frequently exhibited increases and decreases in item manifestations. Exophthalmometer readings decreased by 2 mm or less in 13%. Of the covariates, only hyperthyroidism prolonged by at least 2.5 mo was significantly associated with 2 or more CAS points at 1 y; no covariate was significantly associated with the development of increased exophthalmometer readings. Eye symptoms recorded in the QOL were insignificantly improved over the year; symptoms did not correlate with CAS points or with exophthalmometer readings., Conclusion: After radioiodine treatment, no substantial change was seen in manifestations of CAS items except for a modest increase in exophthalmometer readings in 39% of patients. Manifestations of CAS items frequently appeared and disappeared. Prolonged hyperthyroidism is best avoided. Ocular symptoms were insignificantly fewer at 1 y after radioiodine therapy. The observed changes do not warrant prophylactic treatment of patients with steroids.

A method for assembling Drosophila embryos in a microfluidic device was developed for studies of thermal perturbation of early embryonic development. Environmental perturbation is a complimentary method to injection of membrane-impermeable macromolecules for assaying genetic function and investigating robustness in complex biochemical networks. The development of a high throughput method for perturbing embryos would facilitate the isolation and mapping of signaling pathways. We immobilize Drosophila embryos inside a microfluidic device on minimal potential-energy wells created through surface modification, and thermally perturb these embryos using binary laminar flows of warm and cold solutions. We self-assemble embryos onto oil adhesive pads with an alcohol surfactant carrier fluid (detachment: 0.1 mL/min), and when the surfactant is removed, the embryo-oil adhesion increases to approximately 25 mL/min flow rates, which allows for high velocities required for sharp gradients of thermal binary flows. The microfluidic thermal profile was numerically characterized by simulation and experimentally characterized by fluorescence thermometry. The effects of thermal perturbation were observed to induce abnormal morphogenetic movements in live embryos by using time-lapse differential interference contrast (DIC) microscopy.

INTRODUCTIONThe Drosophila embryo is a superb source of proteins for studies aimed at characterizing a variety of cellular functions, including replication, transcription, translation, signal transduction, and the functions of the extracellular matrix and the cytoskeleton. The success of these studies is dependent upon the maintenance of an efficient laboratory fly facility. This article outlines the basic requirements for maintaining Drosophila in large or small laboratories.

INTRODUCTIONThe Drosophila embryo is a superb source of proteins for studies aimed at characterizing a variety of cellular functions, including replication, transcription, translation, signal transduction, and the functions of the extracellular matrix and the cytoskeleton. The success of these studies requires the efficient production of gram quantities of embryos by large populations of adult flies. This protocol outlines a simple and efficient method for maintaining a population of Drosophila.

During the cleavage stage of animal embryogenesis, cell numbers increase dramatically without growth, and a shift from maternal to zygotic genetic control occurs called the midblastula transition. Although these processes are fundamental to animal development, the molecular mechanisms controlling them are poorly understood. Here, we demonstrate that Drosophila fragile X mental retardation protein (dFMRP) is required for cleavage furrow formation and functions within dynamic cytoplasmic ribonucleoprotein (RNP) bodies during the midblastula transition. dFMRP is observed to colocalize with the cytoplasmic RNP body components Maternal expression at 31B (ME31B) and Trailer Hitch (TRAL) in a punctate pattern throughout the cytoplasm of cleavage-stage embryos. Complementary biochemistry demonstrates that dFMRP does not associate with polyribosomes, consistent with their reported exclusion from many cytoplasmic RNP bodies. By using a conditional mutation in small bristles (sbr), which encodes an mRNA nuclear export factor, to disrupt the normal cytoplasmic accumulation of zygotic transcripts at the midblastula transition, we observe the formation of giant dFMRP/TRAL-associated structures, suggesting that dFMRP and TRAL dynamically regulate RNA metabolism at the midblastula transition. Furthermore, we show that dFMRP associates with endogenous tral mRNA and is required for normal TRAL protein expression and localization, revealing it as a previously undescribed target of dFMRP control. We also show genetically that tral itself is required for cleavage furrow formation. Together, these data suggest that in cleavage-stage Drosophila embryos, dFMRP affects protein expression by controlling the availability and/or competency of specific transcripts to be translated.

Unlabelled: When thyroid tissues exhibited concentrations of therapeutic (131)I that appeared to be less than that predicted by data from the preceding diagnostic (131)I, the phenomenon was called stunning. We hypothesized that stunning arose from the early effects of the therapeutic dose of (131)I and that the initial uptake of (131)I, observed within the first day, was not impaired by the diagnostic dose., Methods: The hypothesis was tested by 2 types of studies. In each type, the fractional concentrations of (131)I in residual neck thyroid tissues of patients with papillary thyroid carcinoma were quantified. In the first study, fractional concentrations of diagnostic and therapeutic (131)I were measured at 2 d, a time when stunning has been observed, and expressed as ratios of radioactivity: therapeutic/diagnostic (Rx/Dx). Three different doses of diagnostic (131)I were prescribed to assess a dose response. In the second study, patients were prospectively recruited and tested to record disappearances of radioactivity from thyroid tissues. Diagnostic doses were 1.0 mCi (37 MBq) in all; therapeutic doses were 150 and 30 mCi (5,550 and 1,110 MBq), each to half of the patients. The disappearance curves were extrapolated to the period between 0 and 1 d, an interval when maximum uptake of ingested (131)I would be expected. The fractional concentrations of (131)I at 2 d and at 0-1 d were compared in terms of Rx/Dx ratios to assess changes at each time point., Results: In the first study, after diagnostic doses of 2, 1, and 0.5 mCi (74, 37, and 18.5 MBq), mean 2-d Rx/Dx values in 24, 29, and 17 patients were 0.35, 0.50, and 0.46 (P = 0.087). Of all patients, 74% exhibited Rx/Dx <0.6. In the second study, 6 of 10 patients exhibited disappearance curves of (131)I in which Rx/Dx was <0.6 at 2 d; 5 of the 6 had Rx/Dx values >0.97 at the 0- to 1-d point. In 1 patient the Rx/Dx was 0.54 at 2 d and 0.66 at the earlier time point. The other 4 patients had disappearance curves in which Rx/Dx values were >1.0 throughout or were above 0.6 and did not greatly change., Conclusion: Two days after the administration of (131)I, the mean fractional concentration of radioactivity in thyroid tissues after a therapeutic dose is <60% of the diagnostic dose in most patients, but no correlation of Rx/Dx with the mCi in the diagnostic dose was seen. In 5 of 6 patients in whom the Rx/Dx at 2 d was <0.6, the maximum fractional concentrations of therapeutic and diagnostic (131)I (i.e., the tissue uptakes during the first day) were similar; this pattern was most apparent after therapies with 150 mCi. These results support the hypothesis that "stunning" of thyroid tissues, often observable by 2 d, is primarily the consequence of early destructive effects from therapeutic (131)I.

Most pheochromocytomas/paragangliomas should be evaluated with anatomical imaging (computed tomography or magnetic resonance imaging) followed by functional imaging (nuclear medicine modalities). Functional imaging assures that the tumor is indeed a pheochromocytoma/paraganglioma and enables more thorough localization, especially detecting as many lesions as possible (in particular for metastatic disease). Functional imaging for pheochromocytomas/paragangliomas, can use radiolabeled ligands specific for pathways of synthesis, metabolism, and inactivation of catecholamines or nonspecific ligands. In an overview of the available nuclear medicine modalities, we summarize the accumulated experience and recommend when functional imaging should be applied to patients with pheochromocytoma/paraganglioma.

Survival of patients with metastatic pheochromocytoma that have exceeded 30 years without therapy to reduce tumors have been reported. We reviewed the records of 38 patients with malignant pheochromocytoma who had received 131I-metaiodiobenzylguanidine (131I-MIBG) treatments between 1981 and 1996 to evaluate longevity. Survival from diagnosis to last follow-up exceeded 5 years in 21 of 38 (55%) and >or=10 years in 50%. In 17 of 21, the interval from diagnosis to 131I-MIBG therapy was greater than 5 years. Survival following 131I-MIBG was >or=5 years in 12 of 17 and >or=10 years in 7 of 17 patients despite continued evidence of excessive circulating catecholamines. Objective responses to 131I-MIBG therapy were seen in about 30% and were usually of a few years, duration, but one individual exhibited marked reductions in volume and function of tumors that have persisted for 21 years. No feature, including a remission of >5 years following surgical excision, was found to predict prolonged survival. In summary, many patients with malignant pheochromocytoma will follow a course extending over many years. The role of 131I-MIBG therapy in longevity is uncertain, but this radiopharmaceutical reduces evidence of tumors in some patients. Criteria for selecting patients who will benefit from treatment remain to be determined.

Purpose: This article describes a patient with dual radiation-induced malignancies after treatment of neuroblastoma., Materials and Methods: A 12-year-old boy with a history of neuroblastoma was treated with chemotherapy, I-131 MIBG, and radiotherapy at age 4. He was disease-free for 8 years, but then developed left shoulder pain resulting from osteosarcoma. A thyroid malignancy was discovered during the evaluation., Results: The patient was treated with thyroidectomy and then chemotherapy according to a Children's Cancer Group Study protocol., Conclusion: Radiation-induced sarcoma should be suspected whenever a patient who has received radiation several years previously presents with pain or swelling in the irradiated area.

We describe the maternal-effect and zygotic phenotypes of null mutations in the Drosophila gene for the epsilon-subunit of mitochondrial ATP synthase, stunted (sun). Loss of zygotic sun expression leads to a dramatic delay in the growth rate of first instar larvae and ultimately death. Embryos lacking maternally supplied sun (sun embryos) have a sixfold reduction in ATP synthase activity. Cellular analysis of sun embryos shows defects only after the nuclei have migrated to the cortex. During the cortical divisions the actin-based metaphase and cellularization furrows do not form properly, and the nuclei show abnormal spacing and division failures. The most striking abnormality is that nuclei and spindles form lines and clusters, instead of adopting a regular spacing. This is reflected in a failure to properly position neighboring nonsister centrosomes during the telophase-to-interphase transition of the cortical divisions. Our study is consistent with a role for Sun in mitochondrial ATP synthesis and suggests that reduced ATP levels selectively affect molecular motors. As Sun has been identified as the ligand for the Methuselah receptor that regulates aging, Sun may function both within and outside mitochondria.

Drosophila melanogaster cellularization is a dramatic form of cytokinesis in which a membrane furrow simultaneously encapsulates thousands of cortical nuclei of the syncytial embryo to generate a polarized cell layer. Formation of this cleavage furrow depends on Golgi-based secretion and microtubules. During cellularization, specific Golgi move along microtubules, first to sites of furrow formation and later to accumulate within the apical cytoplasm of the newly forming cells. Here we show that Golgi movements and furrow formation depend on cytoplasmic dynein. Furthermore, we demonstrate that Lava lamp (Lva), a golgin protein that is required for cellularization, specifically associates with dynein, dynactin, cytoplasmic linker protein-190 (CLIP-190) and Golgi spectrin, and is required for the dynein-dependent targeting of the secretory machinery. The Lva domains that bind these microtubule-dependent motility factors inhibit Golgi movement and cellularization in a live embryo injection assay. Our results provide new evidence that golgins promote dynein-based motility of Golgi membranes.

Fragile X syndrome, the most common form of inherited mental retardation, is caused by loss of function for the Fragile X Mental Retardation 1 gene (FMR1). FMR1 protein (FMRP) has specific mRNA targets and is thought to be involved in their transport to subsynaptic sites as well as translation regulation. We report a saturating genetic screen of the Drosophila autosomal genome to identify functional partners of dFmr1. We recovered 19 mutations in the tumor suppressor lethal (2) giant larvae (dlgl) gene and 90 mutations at other loci. dlgl encodes a cytoskeletal protein involved in cellular polarity and cytoplasmic transport and is regulated by the PAR complex through phosphorylation. We provide direct evidence for a Fmrp/Lgl/mRNA complex, which functions in neural development in flies and is developmentally regulated in mice. Our data suggest that Lgl may regulate Fmrp/mRNA sorting, transport, and anchoring via the PAR complex.

A patient with widely metastatic papillary thyroid cancer who had been previously treated with (131)I and external beam radiation presented with purple nodular lesions on his face and scalp. On biopsy, the nodules were papillary carcinoma with cells that stained for thyroglobulin. Subsequently he developed decreased left eye visual acuity, and fundoscopy revealed lesions typical of choroidal metastases. Dermal and choroidal metastases of papillary thyroid carcinoma are both rare. However, the significance of these clinical manifestations may be overlooked and ignored unless the diagnosis is considered. New skin nodules or visual acuity decline in a patient with papillary thyroid cancer may represent manifestations of distant metastatic disease and should prompt thorough evaluation with dermatological examination and fundoscopy. Choroidal and skin metastases have almost always occurred in patients with advanced disease, but initial presentation with these lesions is possible, and in such instances a thorough search for additional sites of metastatic disease is recommended. Occasionally such metastases may respond to (131)I therapy or external beam radiation.

We report a case of cryptococcal thyroiditis presenting with hyperthyroidism that evolved through a transient euthyroid phase to hypothyroidism and finally recovered to normal function. This four-phase clinical presentation is similar to that of subacute thyroiditis, and it is unusual in the setting of infectious nonviral thyroiditis. Cryptococcal thyroiditis is rare; only three cases have been reported. Our patient is the first who survived the disseminated cryptococcal infection with thyroid involvement, thus enabling longitudinal clinical and endocrinologic follow-up.

The early Drosophila embryo undergoes two distinct membrane invagination events believed to be mechanistically related to cytokinesis: metaphase furrow formation and cellularization. Both involve actin cytoskeleton rearrangements, and both have myosin II at or near the forming furrow. Actin and myosin are thought to provide the force driving membrane invagination; however, membrane addition is also important. We have examined the role of myosin during these events in living embryos, with a fully functional myosin regulatory light-chain-GFP chimera. We find that furrow invagination during metaphase and cellularization occurs even when myosin activity has been experimentally perturbed. In contrast, the basal closure of the cellularization furrows and the first cytokinesis after cellularization are highly dependent on myosin. Strikingly, when ingression of the cellularization furrow is experimentally inhibited by colchicine treatment, basal closure still occurs at the appropriate time, suggesting that it is regulated independently of earlier cellularization events. We have also identified a previously unrecognized reservoir of particulate myosin that is recruited basally into the invaginating furrow in a microfilament-independent and microtubule-dependent manner. We suggest that cellularization can be divided into two distinct processes: furrow ingression, driven by microtubule mediated vesicle delivery, and basal closure, which is mediated by actin/myosin based constriction.

Background: Iodine 123 meta-iodobenzylguanidine (MIBG) scintigraphy has been used in patients with clinical suspicion of pheochromocytoma to confirm the nature of an adrenal or extraadrenal mass or to identify occult disease. Additionally, it may be used to identify unsuspected bilaterality or metastases in the setting of a known unilateral adrenal mass before operation. We sought to determine the role of (123)I MIBG scintigraphy in this apparently routine preoperative setting. Our hypothesis was that (123)I MIBG would provide additional preoperative information that could modify operative intervention., Methods: All patients undergoing (123)I MIBG scintigraphy at our institution between 1992 and 2002 were identified. MIBG results, operative procedures and findings, and pathologic findings were retrospectively reviewed and compared., Results: The (123)I MIBG scintigraphy was performed in a total of 315 patients. Of these, 48 were patients with an initial biochemical diagnosis of pheochromocytoma and a unilateral adrenal mass. 47 of the 48 (98%) primary scans were positive for a single focus of activity concordant with anatomic imaging data from computed tomography or magnetic resonance imaging and operative findings. The (123)I MIBG did not reveal unsuspected metastatic or bilateral disease in any patient., Conclusion: In this large series of patients undergoing (123)I MIBG scintigraphy, the test served only to confirm diagnostic impressions and corroborate anatomic imaging. The (123)I MIBG did not alter the operative management of any patient with a solitary adrenal lesion in the clinical context of biochemically-proven catecholamine excess.

Hypothesis: Critical postoperative review of technetium Tc 99m sestamibi scintigraphy can identify an undescended parathyroid adenoma on scans initially interpreted as nondiagnostic or negative., Design: Case series., Setting: A single, tertiary care academic medical center., Patients: Three patients with persistent hyperparathyroidism., Intervention: Technetium Tc 99m sestamibi scanning., Outcome Measure: Medical records, operative reports, selective venous sampling results, and sestamibi scans were reviewed to identify scintigraphic findings diagnostic of an undescended parathyroid adenoma., Results: All patients were cured of their persistent or recurrent hyperparathyroidism during reoperation by resection of an undescended inferior parathyroid adenoma. Subsequent review of the preoperative sestamibi scans demonstrated scintigraphic evidence of the undescended adenoma. In each case there was asymmetry in the physiologic activity attributed to the ipsilateral submandibular gland that, in fact, corresponded to an ectopic parathyroid adenoma at the level of the carotid bifurcation., Conclusions: Careful attention to the contour of radioactivity in the region of the submandibular salivary gland may alert surgeons to the presence of an undescended inferior adenoma. After corroboration, this finding may facilitate a targeted operation.

Unlabelled: There is no consensus on the amount of (131)I for treatment of patients with well-differentiated thyroid carcinoma; usual amounts vary widely. Body retention of (131)I has been shown to be a valuable index of radiation toxicity. If a broad range of body retentions occurs among patients, then high and low retentions will be a basis for modifying the usual prescriptions for (131)I to ensure safety and increase efficacy., Methods: After withdrawal of thyroid hormone in 87 patients, the fractional retention of diagnostic (131)I in each body was measured at 2 d by a scintillation probe. In 43 patients, the retention was measured 2 d after therapeutic (131)I., Results: Diagnostic retention varied from 0.01 to 0.51, with a median of 0.15. These retentions did not correlate with any index of health, thyroid hormone, or carcinoma status. Seventeen patients, previously treated with (131)I, exhibited a significantly lower mean retention. In 43 patients, retention of diagnostic (131)I was highly correlated with retention of therapeutic (131)I: diagnostic predicted therapeutic retention with a mean error of 0.04. In 10 patients receiving thyroxine, the mean retention of diagnostic (131)I after recombinant human TSH (rhTSH) was strikingly lower, 0.06, with a range of 0.016-0.16., Conclusion: Body retentions of (131)I are easily measured and vary considerably among patients. Because increased therapeutic (131)I will impart greater irradiation of tumor, and body retention has been accepted as an index of toxicity from (131)I, the use of body retention could enable prescriptions of therapeutic (131)I that enable increased efficacy while ensuring safety. If tumor retention is not proportionally decreased with the body retention of (131)I after rhTSH, then rhTSH may enable increased therapeutic efficacy.

Malignant pheochromocytomas, a group of tumors that include metastatic paragangliomas, often produce hypertension and episodic symptoms from secretion of norepinephrine and sometimes epinephrine. In addition, the tumors usually manifest progressive metastases. Blockade of alpha and beta adrenergic receptors will control blood pressure and symptoms, but reduction of the malignancy has been difficult to achieve. Meta-iodobenzylguanidine (MIBG) follows the pathways of norepinephrine and, when labeled with 131-I, will concentrate sufficiently in the pheochromocytoma to impart therapeutic radiation. More than 100 patients have received treatment with 131-I-labeled MIBG at multiple medical centers. Individual doses were 3.7 to 18.5 GBq (100 to >500 mCi), and many patients received several doses separated by a few months. Partial remissions, recorded as decreased tumor presence and tumor function, have been observed in one-third or more of the treated patients. However, complete remissions are rare, and recurrence/progression within two years is the rule. Toxicity was generally modest and temporary. Subsequent chemotherapy increased the benefits attained by 131-I MIBG, but, in a small series of patients, this combination did not further change the outcome. Nevertheless, selective radiation from 131-I MIBG or a similar radiopharmaceutical could play a valuable role in treatments that combine several types of attacks on this recalcitrant malignancy.

Purpose: The survival for children with relapsed or metastatic neuroblastoma remains poor. More effective regimens with acceptable toxicity are required to improve prognosis. Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) selectively targets radiation to catecholamine-producing cells, including neuroblastoma cells. A pilot study was performed to examine the feasibility of a novel regimen combining (131)I-MIBG and myeloablative chemotherapy with autologous stem-cell rescue., Patients and Methods: Twelve patients with neuroblastoma were treated after relapse (five patients) or after induction therapy (seven patients). Eight patients had metastatic and four had localized disease at the time of therapy. All patients received (131)I-MIBG 12 mCi/kg on day -21, followed by carboplatin (1,500 mg/m(2)), etoposide (800 mg/m(2)), and melphalan (210 mg/m(2)) administered from day -7 to day -4. Autologous peripheral-blood stem cells or bone marrow were infused on day 0. Engraftment, toxicity, and response rates were evaluated., Results: The (131)I-MIBG infusion and myeloablative chemotherapy were both well tolerated. Grade 2 to 3 oral mucositis was the predominant nonhematopoietic toxicity, occurring in all patients. The median times to neutrophil (> or = 0.5 x 10(3)/microL) and platelet (> or = 20 x 10(3)/microL) engraftment were 10 and 28 days, respectively. For the eight patients treated with metastatic disease, three achieved complete response and two had partial responses by day 100 after transplantation., Conclusion: Treatment with (131)I-MIBG in combination with myeloablative chemotherapy and hematopoietic stem-cell rescue is feasible with acceptable toxicity. Future study is warranted to examine the efficacy of this novel therapy.

Radioiodine treatments of patients with well-differentiated thyroid carcinoma have generally been safe and beneficial. Safety can be ensured while efficacy is increased through practical methods of dosimetry that measure body retention of 131I. Prescriptions for therapeutic 131I can be decreased when the retention level is high and increased when the level is low. Assays of serum free T4 will alert the physician to possible increased radiation to blood and bone marrow, and appreciable concentrations of free T4 are indications to reduce the therapeutic 131I. Carcinomas > or = 1 cm in diameter that are not visible on diagnostic scintigraphy are unlikely to respond to the commonly prescribed mCi of 131I. Biologic responses to commonly prescribed levels of therapeutic 131I, as seen in toxic changes of normal tissues and in indices of tumor size, will be the final dosimeters. With lower levels of prescribed diagnostic 131I, stunning should not impair dosimetry. Thus, readily obtained measurements make dosimetry a practical method for improving carcinoma therapy with 131I.

Unlabelled: In some patients with well-differentiated thyroid carcinoma, dosimetry is necessary to avoid toxicity from therapy and to guide prescription of the administered activity of radioiodine., Methods: The presentations and courses of 2 patients exemplify the points. In the second patient, the clues to the need for dosimetry were the large size of the tumor and high circulating levels of thyroxine in the absence of exogenous hormone. The other patient manifested hyperthyroidism from stimulation of the tumors by thyroid-stimulating immunoglobulin. Dosimetry was performed by published methods., Results: Dosimetry of radioactivity in the body and blood warned of increased irradiation per gigabecquerel of administered (131)I. In each patient, the tumors sequestered a substantial amount of administered (131)I and secreted (131)I-labeled hormones that circulated for days. In 1 patient, the blood time--activity curve was complex, making a broad range of predictions for irradiation to blood and bone marrow. Still, dosimetry gave information that helped to avoid severe toxicity. At, respectively, 1.85 and 2.2 GBq (131)I, initial treatments were relatively low. There was a modest escalation in subsequent administered activities. Leukopenia with neutropenia developed in each patient, and one had moderate thrombocytopenia and anemia, but toxicity appeared to be transient. Each patient had a marked increase in well-being and evidence of reduced tumor function and volume., Conclusion: Two patients with advanced, well-differentiated thyroid carcinoma illustrate the need for dosimetry to help prevent toxicity to normal tissues from therapeutic radioiodine. Conversion of radioiodide to circulating radiothyroxine by functioning carcinomas increases the absorbed radiation in normal tissues. Yet, dosimetric data acquired for 4 d or more may be insufficient for accurate calculations of absorbed radiation in blood. Guidelines suggested for avoiding toxicity are based on the circulating thyroxine concentrations, the presence of thyroid stimulators, the amount of radioactivity retained in the body at 48 h, and the general status of the patient.

Drosophila cellularization and animal cell cytokinesis rely on the coordinated functions of the microfilament and microtubule cytoskeletal systems. To identify new proteins involved in cellularization and cytokinesis, we have conducted a biochemical screen for microfilament/microtubule-associated proteins (MMAPs). 17 MMAPs were identified; seven have been previously implicated in cellularization and/or cytokinesis, including KLP3A, Anillin, Septins, and Dynamin. We now show that a novel MMAP, Lava Lamp (Lva), is also required for cellularization. Lva is a coiled-coil protein and, unlike other proteins previously implicated in cellularization or cytokinesis, it is Golgi associated. Our functional analysis shows that cellularization is dramatically inhibited upon injecting anti-Lva antibodies (IgG and Fab) into embryos. In addition, we show that brefeldin A, a potent inhibitor of membrane trafficking, also inhibits cellularization. Biochemical analysis demonstrates that Lva physically interacts with the MMAPs Spectrin and CLIP190. We suggest that Lva and Spectrin may form a Golgi-based scaffold that mediates the interaction of Golgi bodies with microtubules and facilitates Golgi-derived membrane secretion required for the formation of furrows during cellularization. Our results are consistent with the idea that animal cell cytokinesis depends on both actomyosin-based contraction and Golgi-derived membrane secretion.

The historical background at the University of Michigan laid a foundation for the innovative development of radionuclides in diagnosis and treatment of endocrine diseases. From that background, Dr. William Beierwaltes, the chief of Nuclear Medicine, inspired two talented young chemists to synthesize unique radiopharmaceuticals that transformed diagnostic approaches to certain endocrine disorders. Dr. Raymond Counsell's 131-I-radiocholesterol, enabled imaging that defined function in the adrenal cortex, and thereby distinguished the different forms of Cushing's syndrome and of primary aldosteronism; in addition, this new technique differentiated benign adrenal cortical adenomas from other adrenal cortical tumors. Dr. Donald Wieland created metaiodobenzlylguanidine (MIBG), a compound that can be tagged with either 131-I or 123-I, and led to the scintigraphic depiction of adrenergic tumors, particularly pheochromocytomas and neuroblastoma, anywhere in the body of a patient. Treatments with large doses of MIBG have reduced the malignant forms of pheochromocytomas and brought remissions to children with neuroblastomas. MIBG also concentrated in the autonomic neurons and so the nerves of the heart were also portrayed. Subsequent novel syntheses included positron-emitting nuclides that, through positron emission tomography, have revealed the physiology and altered physiology of the human heart. These men and their discoveries exemplify the creative endeavors that compel us to seek further the wonders of nuclear science.

We hypothesized that elevated levels of serum thyroglobulin (Tg) are frequently found as the only index of residual neoplasm in patients with low-risk papillary thyroid carcinoma. The records of patients operated on for papillary thyroid carcinoma over a 2-year period were reviewed, and the patients were allocated to risk groups by a validated staging method that does not include Tg levels. Of the 35 patients who manifested a low-risk carcinoma, 9 (26%) exhibited elevated Tg concentrations (11-53 ng/mL) during thyroxine withdrawal after therapies, while clinical, scintigraphic, and radiographic studies at least 1 year later showed no evidence of tumor. Prior scintigraphic imaging of therapeutic doses of 131I in 8 of 9 patients demonstrated no distant metastases, further confirming the low-risk status of this group. The staging method predicts that only 0.9% of patients with low-risk papillary carcinoma will have a cause specific death in 20 years. Elevated Tg concentrations have not been shown to forecast independently the survival of patients with low-risk papillary carcinoma. Thus, although frequently encountered, elevated Tg concentrations are unlikely to predict shortened survival in patients with papillary carcinoma for whom low risk has been determined from other data.

Both pheochromocytomas and neuroblastomas can now be identified and located with a high level of accuracy. Scintigraphy with MIBG has become an indispensable diagnostic method for defining the extent and location of many if not most pheochromocytomas. To define the stage, to document the course and to evaluate the response to therapies in patients with neuroblastoma, imaging with MIBG is now essential.

Malignant pheochromocytomas have exhibited partial responses to treatments with 131-I metaiodobenzylguanidine (MIBG) and with chemotherapy. The authors combined these two therapeutic methods to determine if beneficial effects from each would be additive. Patients with documented malignant pheochromocytomas were recruited with the intent of administering 131-I MIBG in three substantial amounts of radioactivity at 3-month intervals followed by a year of chemotherapy in which cyclophosphamide, dacarbazine, and vincristine were to be given in 21-day cycles. Six patients entered the protocol. After the 131-I MIBG treatments, three patients manifested declines in the presence of tumor (smaller tumor volume or abnormalities on bone and 131-I MIBG scans) and the function of tumor (decreased rate of normetanephrine excretion as the major index). Two patients completed at least 9 months of chemotherapy and showed further reductions in the presence and function of tumors and were classified as having partial responses. Progressive disease afflicted three of the other four subjects. Even though toxicity was minimal from 131-I MIBG, it was sufficient to force reduction in the dosages or duration of chemotherapy. A combination of 131-I MIBG treatments and chemotherapy produced additive effects in reducing malignant pheochromocytomas. Toxicity moderately curtailed the proposed chemotherapy protocol.

Purpose: To assess the sensitivity of positron emission tomography (PET) with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) in pheochromocytomas and, secondarily, to compare images obtained with FDG PET to those obtained with metaiodobenzylguanidine (MIBG) scintigraphy., Materials and Methods: Twenty-nine patients with one or more known or subsequently proved pheochromocytomas underwent FDG PET (35 scans) and MIBG scintigraphy (35 scans). Tumor uptake of FDG was quantified on positive PET scans., Results: Tumor uptake of FDG was detected in 22 of 29 patients. Most benign (seven of 12 patients) and most malignant (15 of 17 patients) pheochromocytomas and their metastases avidly concentrated FDG. In four patients whose pheochromocytomas failed to accumulate MIBG, uptake of FDG in the tumors was intense. For the majority of the 16 patients whose tumors concentrated both agents, however, ratings for MIBG images compared to FDG PET images for delineation of the tumor in comparison to background and normal organ accumulation were superior for nine patients (56%) and as good or better for 14 (88%)., Conclusion: Most pheochromocytomas accumulate FDG. Uptake is found in a greater percentage of malignant than benign pheochromocytomas. FDG PET is especially useful in defining the distribution of those pheochromocytomas that fail to concentrate MIBG.

The positioning of centrosomes, or microtubule-organizing centres, within cells plays a critical part in animal development. Here we show that, in Drosophila embryos undergoing mitosis, the positioning of centrosomes within bipolar spindles and between daughter nuclei is determined by a balance of opposing forces generated by a bipolar kinesin motor, KLP61F, that is directed to microtubule plus ends, and a carboxy-terminal kinesin motor, Ncd, that is directed towards microtubule minus ends. This activity maintains the spacing between separated centrosomes during prometaphase and metaphase, and repositions centrosomes and daughter nuclei during late anaphase and telophase. Surprisingly, we do not observe a function for KLP61F in the initial separation of centrosomes during prophase. Our data indicate that KLP61F and Ncd may function by crosslinking and sliding antiparallel spindle microtubules in relation to one another, allowing KLP61F to push centrosomes apart and Ncd to pull them together.

Radioactive iodine treatment of thyrotoxicosis in considered one of, if not the most, successful therapy in Nuclear Medicine. A sixty year experience in virtually hundreds of thousands of patients supports the safety, efficacy and cost effectiveness of radioiodine. However, despite all of the data amassed since its introduction almost all aspects of its use from the indications, selection of patients, goals of therapy and selection of doses in the treatment of hyperthyroidism remain controversial and continue to be a subject of lively debate.