Dosimetry in the therapy of metastatic differentiated thyroid cancer administering high 131I activity: the experience of Busto Arsizio Hospital (Italy).

AIM: The purpose of the present work was to evaluate the impact of 131I high activity therapy treatments of metastatic differentiated thyroid cancer (MDTC) in terms of feasibility, tolerance, efficacy, and the impact of dosimetry in order to optimize the process. METHODS: Seventeen MDTC patients underwent 27 treatments with 131I, with activity ranging from 6.2 GBq to 24.1 GBq. Red marrow (RM) peritherapy dosimetry was based on the Standard Operating Procedure of European Association of Nuclear Medicine (EANM SOP), while metastases dosimetry on the guidelines of Italian Association of Physicists in Medicine and Italian Association of Nuclear Medicine. In 12 cases prospective dosimetry was performed too, with the purpose of evaluating the possibility of maximizing the therapeutic activity, complying the 2 Gy red marrow (RM) dose constraint. The absorbed dose to 45 lesions was evaluated. The severity of myelotoxic effects was monitored during the follow-up. RESULTS: Treatments were generally well tolerated, also at the highest RM absorbed doses. RM absorbed doses ranged from 0.49 to 6.67 Gy, lesion doses from 1.1 Gy to 778 Gy. In case of repeated treatments on the same site, in 13 cases on a total of 15, an absorbed dose reduction was observed. RM prospective and peritherapeutic dosimetry differed somewhat: absorbed doses measured during therapy ranged from -7% to +40% with respect to provisional absorbed doses. CONCLUSION: In our experience high activity treatments were well-tolerated. Prospective dosimetry needs further investigation to become sufficiently reliable in order to comply the 2 Gy constraint. Lesions became progressively less iodine-avid in case of repeated treatments, so the "first big-shoot" treatment with the highest safe activity seems to be desirable to obtain the maximum efficacy.

Anaplastic thyroid carcinoma. Practical aspects of multimodal therapy and data emerging from a 40-year experience at a single Italian institution.

Anaplastic thyroid carcinoma is a rare malignant neoplasia with high biological aggressiveness and rapid and lethal clinical course. In selected patients, an aggressive multimodal therapy could decrease illness progression both in the neck e in other sites. However, it is not clear if these combined treatments improve survival. In our institution, the Department of Nuclear Medicine has a 40-year experience in monitor and treatment of a group of 48 patient with ATC confirmation that clinical presentation could overlap pre-existent nodular goitre or rapid enlarging mass of recent onset. At onset, age do not change final poor prognosis and the survival seems most favorable in patients with a primary tumor size <6 cm. A better mean survival was noticed in those patients who respond to the multimodal therapy (8 months vs 4.6 months). Radioiodine (131 I) therapy is unnecessary due to the loss of NIS expression of the ATC cells. Therefore, after quick clinical and instrumental work up, our experience and the literature data suggest that the first line therapy is represented from external radiotherapy combined also with cisplatin or doxorubicin, followed by "curative" surgical procedure of the primary lesion in the neck and subsequent chemotherapy. For those patients who show distant metastasis at onset chemotherapy is the first line therapy followed by external radiotherapy and when possible subsequent surgical procedure.

Prevalence, clinical significance and prognostic value of anti-thyroglobulin antibodies in the follow-up of patients with differentiated thyroid carcinoma: a retrospective study.

AIM: Elevated persistent value of antithyroglobulin antibodies (Ab-Tg) in differentiated thyroid carcinoma (DTC) patients may interfere with Tg determination. The aim of the study was to evaluate the use of Ab-Tg as tumor marker as a replacement for thyroglobulin (Tg). METHODS: From 1990 al 2004 767 patients have been treated and followed, mean follow-up years 6.9+/-2.4. Thirty-two patients Ab-Tg positive after radioiodine ablation, who had showed during the follow-up stable indosable value di Tg, have undergone analysis. RESULTS: The recurrences were statistically more significant when Ab-Tg were increased, than when Ab-Tg were stable or diminished during the time (P<0.0001). Lymphocytic thyroditis was found in thirteen patients (40.6%) at histological specimen after thyroidectomy. The persistence of lymphocytic thyroditis has not modified the value of Ab-Tg as tumor marker (P<0.001). The 10/32 (31.2%) patients Tg negative have been compared to the 61/712 patients Ab-Tg positive (8.6%) who relapse. The recurrence rate was significantly higher for the first group of patients than that for the second (P<0.0001). Multivariate analisys showed N1 (P<0.001; OR 2.51) and Ab-Tg positive (P<0.001; OR: 6.15) associated with recurrences. CONCLUSIONS: Ab-Tg must be determined, in concomitance with Tg, during the follow-up of DTC, to establish the accuracy of Tg, in order to use it as tumour marker. It must be kept in mind that the strongest indication for relapse due to Ab-Tg is an increasing of level in the same patient measured in the long time. Persistent elevated Ab-Tg levels are prognostic of future recurrences.

Fine needle aspiration cytology of the thyroid: a comparison of 5469 cytological and final histological diagnoses.

OBJECTIVE: We evaluated the efficacy of fine needle aspiration cytology (FNAC) of the thyroid in a series of 5469 lesions with histological control and studied the causes of, and the possibility of reducing the limitations of the method. METHODS: FNAC was always performed by a pathologist under the guidance of a clinician, using a 22-gauge needle. Generally two aspirations were carried out, and usually four slides were obtained for each nodule; they were then stained with May-Grünwald-Giemsa and with Papanicolaou. The cytological diagnoses were classified in four groups: inadequate, benign, suspicious and malignant. RESULTS: We obtained a complete sensitivity of 93.4%, a positive predictive value of malignancy of 98.6%, and a specificity of 74.9%. At histological control, the cytological diagnosis of Hurthle cell neoplasm corresponded to a significantly higher incidence of malignant neoplasms than the diagnosis of non-Hurthle cell follicular neoplasm (32.1% versus 15.5%). There were 66 false-negative findings, the main cause of diagnostic error (24 cases) being failure to recognize the follicular variant of papillary carcinoma. The number of inadequate FNACs was low (4.2%). CONCLUSION: Our study confirmed the great efficacy of thyroid FNAC. A cytological diagnosis of Hurthle cell neoplasm should be considered an indicator of high risk. Awareness that failure to recognize the follicular variant of papillary carcinoma was the main problem in the interpretation of thyroid FNAC should lead to a decrease of false-negative diagnoses. The inadequate rate was very low, as it was the pathologist personally who performed the needle aspiration.

Management of occult adrenocorticotropin-secreting bronchial carcinoids: limits of endocrine testing and imaging techniques.

The differential diagnosis and the identification of the source of ACTH in occult ectopic Cushing's syndrome due to a bronchial carcinoid still represents a challenge for the endocrinologist. We report our experience in six patients with occult bronchial carcinoid in whom extensive hormonal, imaging, and scintigraphic evaluation was performed. All patients presented with hypercortisolism associated with high plasma ACTH values. The CRH test and high dose dexamethasone suppression test suggested an ectopic source of ACTH in three of six patients. During bilateral inferior petrosal sinus sampling, none of the patients showed a central to peripheral ACTH gradient. At the time of diagnosis, none of the patients had radiological evidence of the ectopic source of ACTH, whereas pentetreotide scintigraphy identified the lesion in two of four patients. Finally, a chest computed tomography scan revealed the presence of a bronchial lesion in all patients, and pentetreotide scintigraphy identified four of six lesions. In all patients a bronchial carcinoid was found and removed. In one patient with scintigraphic evidence of residual disease after two operations, radioguided surgery, using a hand-held gamma probe after iv administration of radiolabeled pentetreotide, was performed; this allowed detection and removal of residual multiple mediastinal lymph node metastases. In conclusion, our data show that there is not a single endocrine test or imaging procedure accurate enough to diagnose and localize occult ectopic ACTH-secreting bronchial carcinoids. Radioguided surgery appears to be promising in the presence of multiple tumor foci and previous incomplete removal of the tumor.

Fine needle aspiration cytology of primary lymphoma of the thyroid: a report of 17 cases.

Between 1980 and 1998, 4272 thyroid surgical specimens with a preoperative fine needle aspirate were sent to our Anatomical Pathology Department. Among these cases there were 17 primary thyroid lymphomas, which constituted 0.3% of all the thyroid lesions and 2.3% of the thyroid malignancies. Seven cases were diffuse large B-cell (DLBC) lymphomas and 10 were MALT lymphomas. Of the DLBC lymphomas six were correctly diagnosed by fine needle aspiration cytology (FNAC) and one was diagnosed as positive for malignancy, and among MALT lymphomas four were diagnosed as lymphoma, four as suspicious for lymphoma, and three as Hashimoto's thyroiditis (HT). Our data indicate that the diagnosis of primary thyroid lymphoma of high grade is easy, and immunocytochemistry (ICC) can confirm suspicious cases. The diagnosis of MALT lymphoma is more difficult; ICC can confirm suspicious cases, and false-negative results seem to be caused by sampling error, because HT usually coexists with MALT lymphoma.

Differentiated thyroid carcinoma in children and adolescents: a 37-year experience in 85 patients.

UNLABELLED: This study reports on 85 differentiated thyroid carcinoma (DTC) (72 papillary, 13 follicular) patients, younger than 18 yr of age at the time of diagnosis, consecutively treated during the period 1958-1995. METHODS: Follow-up (median: 111 mo, range 1-324 mo) consisted of clinical examination, serum thyroglobulin (Tg), 131I whole-body scintigraphy (whole-body scan) and other imaging procedures. RESULTS: Forty-six patients had undergone total thyroidectomy, 38 partial thyroidectomy and 1 thyroid biopsy. In 47 patients, lymph-adenectomy was also performed. Five patients were treated after surgery by external radiotherapy, 59 by 131I therapy and 16 by both modalities. Iodine-131 therapy was successful in ablating thyroid remnants in 35/48 cases, lymph node metastases in 8/11 cases and lung metastases in 12/16 cases. Among the patients with scintigraphic-confirmed disappearance of lung metastases, serum Tg was still detectable in 10 cases, but continued to decrease spontaneously even without further therapeutic doses of 131I. All patients were still alive after a median period of 137 mo (range 5-444 mo). Six patients experienced a recurrence of the disease in the neck. Sixty-seven patients were free of disease, 3 had lymph node metastases, 4 lung metastases and 11 had detectable levels of Tg without demonstrable metastases. No impairment of female fertility or untoward genetic effects were noticed. One male patient, treated with 3.33 GBq of 131I, was infertile due to oligospermia. One case of gastric cancer and one of breast cancer occurred 8 and 19 yr, respectively, after 131I therapy. CONCLUSION: Iodine-131 therapy is highly effective in reducing lung metastases, but undetectable levels of Tg are seldom achieved. Total thyroidectomy and 131I therapy is an effective and safe treatment for the majority of patients with DTC diagnosed in childhood or adolescence.

Assessment of female fertility and carcinogenesis after iodine-131 therapy for differentiated thyroid carcinoma.

UNLABELLED: The aim of this study was to evaluate female fertility, carcinogenic, and genetic effects after treatment with 131I of differentiated thyroid carcinoma. METHODS: A total of 814 females of child-bearing age were studied. The fertility of 627 females who received 131I therapy was compared to 187 untreated females. Birth histories of the children born from these women were registered. The carcinogenic effect was evaluated by comparing the incidence of tumors in 730 patients treated with 131I with an internal control group, as well as with local population incidence. RESULTS: There was no significant difference in the fertility rate, birth weight and prematurity between the two groups. Only one case of a ventricular septal defect was observed in a child born to a women treated with 131I. The overall standardized incidence ratio (SIR) of second tumors was 1.19 (95% CI: 0.76-1.77) in patients treated with 131I. An elevated SIR was registered for salivary gland tumors and melanoma. No case of leukemia was registered. CONCLUSION: The risk of long-term effects of 131I treatment of differentiated thyroid carcinoma is quite low. Iodine-131 may be safely used in treating cases with a high risk of recurrence.

Preliminary results of [131]metaiodobenzylguanidine treatment in metastatic malignant pheochromocytoma.

The poor results of traditional therapy (for purposes of recovery or palliation) in malignant pheochromocytoma and the well proven uptake of [131I]metaiodobenzylguanidine (131I-MIBG) shown by these tumors, induced us to evaluate the clinical usefulness of radiometabolic therapy with 131I-MIBG. Four patients with malignant pheochromocytoma were subjected to 131I-MIBG therapy, between 1987 and 1991, in our department. They all were in an advanced stage of the disease and showed severe symptoms and poor reaction to traditional therapy. The cumulative activity given was 7.4-22.2 GBq. All patients demonstrated transient subjective improvement; in addition, both biochemical and haemodynamic parameters ameliorated. Two patients showed a reduction in the size and number of metastases seen on scintigraphy. One patient died due to progression of the disease. Three patients are still alive and in good condition. No remarkable early or late side-effects were reported. We suggest that 131I-MIBG radiometabolic therapy in advanced-stage malignant pheochromocytoma could be useful in reducing symptoms. Further investigation might show whether a greater reduction in the size of the tumor could be achieved using different therapeutic schedules or by treating the disease in its earlier stages.

Preliminary results of [131I]metaiodobenzylguanidine treatment in metastatic carcinoid tumors.

The successful use of [131I]metaiodobenzylguanidine (131I-MIBG) in the scintigraphic localisation and treatment of several tumors deriving from neuroectoderm has led us to its application in metastatic carcinoid tumors. We selected five patients (two men and three women; age range 53-79 years) who showed progression of the disease with severe related symptoms, poor response to traditional therapy and a good uptake of 131I-MIBG in neoplastic tissue. A cumulative radioactivity of 3.7-22.2 GBq was given. All patients had a clear subjective improvement with a better quality of life for a period of 2-36 months, sometimes accompanied by decreased 5-hydroxyindoleacetic acid urinary excretion. Results concerning objective remission of the disease were unsatisfactory. No remarkable early or late side-effect was noted. We believe 131I-MIBG is useful for symptomatic treatment of metastatic carcinoid in seriously ill patients too. Different treatment schedule and recruitment of patients with less advanced disease could make pathological remission a possible goal.

Therapeutic possibilities of 131I-MIBG in metastatic carcinoid tumors--preliminary report.

The poor results of traditional therapy in advanced carcinoid tumors and the well-proven uptake of 131I-MIBG shown by some of these tumors induced us to attempt a radiometabolic approach. We selected for the treatment 5 patients (3 men and 2 women) who showed progression of disease, a fairly good uptake of 131I-MIBG with severe related symptoms, and a poor response to traditional therapy. A cumulative radioactivity of 5.5-29.6 GBq was given. Acute side effects after 131I-MIBG administration or late radiation-induced damages were not observed. Symptoms increased during the first 2-4 weeks in 2 patients: in one of these relief was achieved with drugs. Results concerning objective remission of the disease were unsatisfactory. In contrast, definite improvement of symptoms was shown in 2 of 5 patients, resulting in a better quality of life.

Effects of aspartame and carbohydrate administration on human and rat plasma large neutral amino acid levels and rat brain amino acid and monoamine levels.

Thirty fasted human volunteers were given 0.83 and 8.3 mg aspartame/kg body weight alone, as part of a basal low carbohydrate meal (648 kcal, 10% carbohydrate) or as part of a high energy carbohydrate-rich meal (1290 kcal, 34% carbohydrate). Amino acid concentrations in plasma were determined before and 30, 60 and 180 min after the consumption of aspartame. Under these conditions, which mimic realistic aspartame consumption, aspartame had no significant effect on plasma concentration of any amino acid. In addition, the effect of aspartame alone or with carbohydrates on plasma and brain amino acid levels was studied in rats after acute or subacute (14 d) oral treatment. In subacute dosing experiments aspartame was included in the diet. Brain monoamine concentrations were also measured in the same animals. Plasma concentrations of large neutral amino acids were modified under acute conditions. In contrast, after subacute treatment no significant differences in plasma or brain amino acid concentrations or in brain monoamine concentrations were observed.

Upper gastrointestinal involvement in diabetes mellitus: study of esophagogastric function.

The aim of our study was to evaluate in 18 diabetic patients (11 with and 7 without evidence of autonomic neuropathy as revealed by common cardiovascular tests) alterations indicative of autonomic nervous involvement of the gastrointestinal tract, independently of the presence of suggestive symptoms. All patients, without evidence of obstructive or mucosal pathology of the upper gastrointestinal tract, underwent the following: 1) study of gastric emptying time of nonabsorbable radiopaque markers (90, 120, 150 and 210 min); 2) study of gastric acid secretion: basal (BAO) and peak (PAO) acid output after sham-feeding (PAOSF) and peak acid output after pentagastrin (PAOPENT).PAOSF/PAOPENT ratio is an index of vagal integrity; 3) esophageal manometry. Our data confirm that a delayed gastric emptying of undigestible solids is a frequent finding in diabetic subjects. This was highly significant (p less than 0.01) at 150 min after a standard meal, in patients with signs of autonomic neuropathy and was often associated with asymptomatic esophageal motor abnormalities. No correlation was found with index of vagal integrity, hormonal pattern and degree of glycemic control. Autonomic neuropathy cannot be considered the only explanation for gastric and esophageal abnormalities in decompensated diabetes.

Differential response to immobilization stress of striatal dopaminergic and hippocampal noradrenergic systems in aged rats.

The effect of restraint stress on synthesis of central norepinephrine (NE) and dopamine (DA) was studied in adult and old rats. The rate of in vivo synthesis of the two catecholamines was determined in hippocampus (a prevalently noradrenergic area) and in striatum (a prevalently dopaminergic area) by measuring the accumulation of DOPA for 60 min after decarboxylase inhibition. NE synthesis was stimulated by stress in the first 30 min, after which the accumulation of DOPA declined. The stimulation was much greater in old rats. In striatum, endogenous DOPA concentration was significantly lower in old rats. Stress significantly enhanced DOPA accumulation in the first 30 min in both age groups but after this interval accumulation continued linearly only in young rats. These results indicate that in aged rats the response to stress of some noradrenergic and dopaminergic systems may be altered in opposite directions.

Changes in monoamines and their metabolite levels in some brain regions of aged rats.

The concentrations of dopamine (DA) norepinephrine (NE), serotonin (5HT) and their metabolites, HVA, DOPAC, MHPG-SO4 and 5HIAA were measured in several brain areas of rats aged 4, 18 and 29 months. Dopamine and its metabolites showed a decline, statistically correlated with age, in all the dopaminergic areas considered, indicating that this system is profoundly affected in the senescent rat. The changes in the noradrenergic system were more complex. This neurotransmitter was reduced in spinal cord and in limbic area, but was not modified in hippocampus, cerebellum, striatum and s. nigra. In cortex, MHPG-SO4, the main NE metabolite, showed a significantly age-related increase. Tyrosine hydroxylase (TH) activity was low in striatum, and brainstem but not in hypothalamus of aged rats. Neither 5HT nor its metabolites was affected by age. The results indicate that central catecholaminergic systems are markedly affected in senescent rats.

Changes with age in rat central monoaminergic system responses to cold stress.

Changes with age in responses to stress of certain central monoaminergic systems were investigated. Three groups of rats, 4, 18 and 29 months old, were exposed to cold and the effect of this stress on hypothalamic tyrosine hydroxylase, and on the metabolism of DA and 5HT in different brain regions was evaluated. Senescent rats were unable for several hours to compensate the loss of body heat. Corticosterone secretion however was equally stimulated. Hypothalamic tyrosine hydroxylase activity was enhanced in the young rats but not in the old ones. However, the two groups of senescent rats did not show the increase in HVA levels noted in striata of young rats 2 hours after cold exposure. In contrast, the 18 and 29-month-old rats presented enhanced serotonergic tonus, indicated by the greater increase in 5HIAA determined by stress.

Methadone exposure in utero: effects on brain biogenic amines and behavior.

Gravid rats were treated with methadone, 10 mg/kg/day, or vehicle, from day 5 of gestation to term. The offspring were nursed by foster mothers receiving either methadone or vehicle to form 4 groups: (A) methadone during gestation and lactation, (B) methadone during gestation, (C) methadone during lactation, and (D) no drug treatment. Brain monoamines and metabolites were examined at 21 days of age and found to be decreased in groups A and B. Animals treated comparably to group B and sacrificed at 90 days of age showed no abnormalities in brain monoamines excepting a decrease in dopamine metabolites in limbic areas. Another group treated in utero with methadone was tested at 90 days fo age for shuttle-box avoidance acquisition using massed trials. Methadone-exposed subjects exhibited more avoidances, escapes and intertrial shuttles than controls by the third day of training. These results suggest that subtle but lasting changes in limbic dopamine functions as a consequence of fetal exposure to methadone may make rats hyper-responsive in a massed-trial avoidance procedure in the shuttle-box.