Thyroid carcinoma with high levels of function: treatment with (131)I.

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.

Lava lamp, a novel peripheral golgi protein, is required for Drosophila melanogaster cellularization.

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.

Radiopharmaceuticals for nuclear endocrinology at the University of Michigan.

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.

Serum thyroglobulin levels after thyroxine withdrawal in patients with low risk papillary thyroid carcinoma.

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.

Nuclear medicine imaging of pheochromocytoma and neuroblastoma.

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.

Antagonistic microtubule-sliding motors position mitotic centrosomes in Drosophila early embryos.

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.

Radioiodine therapy of thyrotoxicosis.

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.

Treatment of malignant pheochromocytomas with 131-I metaiodobenzylguanidine and chemotherapy.

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.

Pheochromocytomas: imaging with 2-[fluorine-18]fluoro-2-deoxy-D-glucose PET.

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.

Adrenocortical SPECT using iodine-131 NP-59.

Adrenal scintigraphy with 131I-labeled 6-beta-iodomethyl-19-norcholesterol (NP-59) is a technically demanding and complex procedure. However, it can provide crucial and unique information about the functional status of the adrenal glands and guide the appropriate therapeutic management of patients with biochemically proven disease. Since the introduction of this new investigational drug, scintigraphic imaging has been performed using conventional planar techniques. We present an interesting case of primary aldosteronism in which planar scintigraphy and SPECT were combined in an attempt to increase the sensitivity of the study. SPECT revealed scintigraphic evidence of bilateral adrenocortical hyperplasia. Interestingly, the CT scan of this patient showed only an equivocal abnormality in the left adrenal gland, suggestive of an adenoma.

Training students in education of the hypertensive patient: enhanced performance after a simulated patient instructor (SPI)-based exercise.

The process whereby a physician explains to the ill patient what has gone wrong and what can be done about it can be taught and evaluated by simulated patients (SPIs). This study was designed to determine whether a training experience in educating a diabetic SPI improves subsequent performance with a hypertensive SPI. Competence in educating a hypertensive SPI by students who had no prior training experience (n = 26) was compared to that of an experimental group (n = 20) that had a prior training session. Performance was assessed with a counseling skills scale and a case-specific content checklist (1 = poor to 5 = excellent). Students in the experimental group performed better than controls in both counseling skills (4.46 v 3.86, P < .01) and completeness of coverage of content (3.28 v 2.65, P < .01). Students in both groups focused more on clinical features and treatment than on laboratory testing and follow-up. The ability to counsel "patients" with hypertension can be enhanced by a prior learning experience with a diabetic SPI. Clinical application of knowledge about hypertension can be assessed by SPIs.

Treatment of micronodular lung metastases of papillary thyroid cancer: are the tumors too small for effective irradiation from radioiodine?

Our purpose was to determine if micronodular lung metastases from papillary thyroid cancer had diameters that were less than 1 mm and therefore of a size for which irradiation by radioiodine (131I) is inefficient. In five patients, lung metastases seen on computed tomography (CT) were enumerated and sized in the entire right lung and right upper lung giving volumes of measurable, ie, more than 1 mm diameter, tumors. Concentrations of diagnostic 131I were quantified scintigraphically in the same regions. Fractions of administered 131I per milliliter of tumor and the absorbed radiation from the subsequent treatments were calculated to see if the 131I levels in lungs were greater than expected for the visible tumor volumes. Two other patients manifesting similar findings had lung biopsies that were reviewed for size of metastases. The calculated fractions of administered activity per milliliter of tumor and the absorbed radiations from the treatments with 131I were exceptionally high. Biopsies revealed numerous tumors below the resolution of CT. We conclude that the fractions of administered activity and absorbed radiations of 131I in tumors were high because the measured tumor volumes underestimated the total tumor volumes. Many lung metastases were less than 1 mm in diameter.

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.

Costal2, a novel kinesin-related protein in the Hedgehog signaling pathway.

The Hedgehog (HH) signaling proteins control cell fates and patterning during animal development. In Drosophila, HH protein induces the transcription of target genes encoding secondary signals such as DPP and WG proteins by opposing a repressor system. The repressors include Costal2, protein kinase A, and the HH receptor Patched. Like HH, the kinase Fused and the transcription factor Cubitus interruptus (CI) act positively upon targets. Here we show that costal2 encodes a kinesin-related protein that accumulates preferentially in cells capable of responding to HH. COS2 is cytoplasmic and binds microtubules. We find that CI associates with COS2 in a large protein complex, suggesting that COS2 directly controls the activity of CI.

Hedgehog elicits signal transduction by means of a large complex containing the kinesin-related protein costal2.

The hedgehog gene of Drosophila melanogaster encodes a secreted protein (HH) that plays a vital role in cell fate and patterning. Here we describe a protein complex that mediates signal transduction from HH. The complex includes the products of at least three genes: fused (a protein-serine/threonine kinase), cubitus interruptus (a transcription factor), and costal2 (a kinesin-like protein). The complex binds with great affinity to microtubules in the absence of HH, but binding is reversed by HH. Mutations in the extracatalytic domain of FU abolish both the biological function of the protein and its association with COS2. We conclude that the complex may facilitate signaling from HH by governing access of the cubitus interruptus protein to the nucleus.

Selection of the optimal scanning agent for thyroid cancer.

Physical and biologic principles, availability, and experience in use determine which radiopharmaceuticals will be the optimal agents to portray scintigraphically thyroid cancers. However, clinical reasoning must dictate which scanning procedure to use and when. To identify functioning thyroid nodules, and thereby exclude malignancy and also disclose the source of excess thyroid hormone, technetium Tc 99m pertechnetate is the agent of choice. To evaluate patients with metastatic differentiated thyroid cancer (DTC) for possible radiopharmaceutical therapy, low doses (no more than and probably less than 74 MBq or 2 mCi) of 131I iodide are preferred. 131I is especially necessary if dosimetry is undertaken to help prescribe the optimal therapeutic dose of 131I. For less well differentiated tumors that do not concentrate 131I, most experience has been with thallium 201, which enables depiction of most metastases, but, in time, newer agents may be found to produce superior scans. The goal of imaging of the less well differentiated cancers must be to direct additional therapy such as external beam radiation of surgical excision. It is unlikely that any scanning procedure that depends on the physiologic and biochemical activities of DTC will have as much sensitivity for locating tumors in the euthyroid as in the hypothyroid patient. A majority of medullary carcinomas of the thyroid (MCT) have been portrayed by indium 111 octreotide and by 99mTc pentavalent dimercaptosuccinic acid; other agents have concentrated to lesser levels in the tumors or have not been investigated as extensively. As of now, metastatic MCT defies therapy, and, therefore, scanning to detect the tumors has little clinical utility.

131-I treatment of micronodular pulmonary metastases from papillary thyroid carcinoma.

BACKGROUND: Pulmonary metastases from papillary thyroid carcinoma shorten the survival of the hosts. Treatments with 131-I have been reported to induce disappearance of these tumors in a large proportion of afflicted patients. In this study, consecutive patients with diffuse micronodular lung metastases from papillary thyroid carcinoma were examined to determine if disappearance of tumor occurred, and how much disappeared, after substantial amounts of 131-I were administered. METHODS: Of 232 patients treated with 131-I for thyroid carcinoma between 1985 and 1994, 12 patients between the ages of 5 and 45 years exhibited evidence of micronodular metastases to the lungs that concentrated 131-I. Each patient had undergone total or nearly total thyroidectomy and cervical lymph node dissection. All neoplasms were well differentiated papillary carcinoma, but one also had focal, poorly differentiated insular components. Follicle formation by tumors varied from less than 10% to 100% of the histologic sections. Effects of treatment were measured by three indices: chest X-ray and/or CT images, scintigraphic images, and serum thyroglobulin levels. Individual activities of 131-I ranged from 2.2 gigabequerel (GBq) (initial activity in the 5-year-old patient) to 13 GBq, and were greater than 7.4 GBq in 6 patients. Only one treatment was given to three patients, two were given to seven, and more than two were given to two. The duration of follow-up was at least one year. RESULTS: In two patients, the only evidence of lung metastases was on scintigraphic images made a few days after treatment. Another patient had a normal X-ray but showed diffuse uptake of 131-I in the lungs on a diagnostic scintiscan. Of the nine patients with abnormal X-ray and CT images, seven showed improvement, but tumors disappeared in only two. In the ten patients with abnormalities on the diagnostic scintiscans, five eventually manifested no abnormality. At the outset, thyroglobulin levels exceeded 10 ng/mL in each patient; 3 individuals exhibited a decline in level by 25% or more, and a value of less than 6 ng/mL, uncomplicated by thyroglobulin antibodies, was seen in two patients. Only two patients attained normality in all three indices. Hematologic toxicity was modest and reversible. CONCLUSIONS: Despite a number of previous reports that pulmonary metastases from thyroid carcinoma disappear in approximately half of patients treated with 131-I, evidence of tumor reduction was found in most, but a complete remission occurred in only 2 of 12 patients. Nevertheless, 131-I therapy may be useful to decrease the tumor burden in many such patients.