Recombinant human TSH changes the multidisciplinary approach to patients with differentiated thyroid carcinoma. Two-year experience.

BACKGROUND: Recombinant human TSH (rhTSH) is available for monitoring differentiated thyroid carcinoma. rhTSH testing modifies the guidelines for this disease. METHODS: A 2-year experience with rhTSH on 27 consecutive patients with papillary cancer is reported. The aim of the study was to evaluate the sensitivity and specificity of thyroglobulin (Tg) after rhTSH in detecting residual thyroid cancer after primary therapies. Sensitivity and specificity of rhTSH testing were also compared with neck ultrasound (US) and whole-body scan (WBS). Favourable results were regarded as: Tg levels <1 microg/L after rhTSH, no US image indicative of thyroid tissue or suspect neck nodes, and negative WBS after (131)I and (99m)Tc-MIBI. RESULTS: Side effects were mild. Unfavourable baseline Tg levels were noted in 15% of patients with local or metastatic disease. After rhTSH testing, unfavourable Tg levels were noted in a further 17% of patients. After 12-24 months, Tg levels on rhTSH re-testing were favourable in 14 out of 17 patients evaluated and indicative of no disease progression in 1; in 2, they were still indicative of an unsatisfactory effect of further radioiodine therapy. No significant increase in a subunit (alphaSU) was noted after rhTSH administration. Sera from patients with hypothyroidism or collected on the day of TSH peak after rhTSH, showed isoform profiles of TSH (and alphaSU) similar to those found after focusing rhTSH. Agreement between rhTSH testing and neck US was found in 85% of patients. Agreement among rhTSH, neck US and (131)I and (99m)Tc-MIBI WBS was found in 46% of subjects. The specificity of rhTSH testing, neck US, (131)I and (99m)Tc-MIBI WBS was 95%, 84%, 89% and 53%, while sensitivity was 100%, 87%, 40% and 71%, respectively. CONCLUSIONS: Our data show that full bioactivity of TSH after rhTSH is indirectly suggested by the negligible increase in alphaSU after rhTSH and the similar pattern of TSH isoforms after rhTSH and hypothyroidism. Neck US is the most sensitive imaging technique in detecting local or neck node recurrence of the disease, while (99m)Tc-MIBI WBS is the least specific. After primary treatments for papillary thyroid carcinoma, rhTSH testing under L-T4 therapy and neck US may be regarded as first-line evaluations. Under L-T4 regimen, Tg levels lower than 1 microg/L after rhTSH testing seem to be the best index of normality on follow-up in patients with a history of thyroid papillary carcinoma. In these patients, diagnostic (131)I WBS seems to be unnecessary.

131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients.

Incomplete response to therapy may compromise the outcome of children with advanced neuroblastoma. In an attempt to improve tumour response we incorporated 131I-metaiodobenzylguanidine (131I-MIBG) in the treatment regimens of selected stage 3 and stage 4 patients. Between 1986 and 1997, 43 neuroblastoma patients older than 1 year at diagnosis, 13 with stage 3 (group A) and 30 with stage 4 disease (group B) who had completed the first-line protocol without achieving complete response entered in this study. 131I-MIBG dose/course ranged from 2.5 to 5.5 Gbq (median, 3.7). The number of courses ranged from 1 to 5 (median 3) depending on the tumour response and toxicity. The most common acute side-effect was thrombocytopenia. Later side-effects included severe interstitial pneumonia in one patient, acute myeloid leukaemia in two, reduced thyroid reserve in 21. Complete response was documented in one stage 4 patient, partial response in 12 (two stage 3, 10 stage 4), mixed or no response in 25 (ten stage 3, 15 stage 4) and disease progression in five (one stage 3, four stage 4) Twenty-four patients (12/13 stage 3, 12/30 stage 4) are alive at 22-153 months (median, 59) from diagnosis. 131I-MIBG therapy may increase the cure rate of stage 3 and improve the response of stage 4 neuroblastoma patients with residual disease after first-line therapy. A larger number of patients should be treated to confirm these results but logistic problems hamper prospective and coordinated studies. Long-term toxicity can be severe.

Radioiodinated meta-iodobenzylguanidine in the diagnosis of childhood neuroblastoma.

In a group of 97 patients aged from 6 months to 12 years, all with suspected or proven neural crest tumours, metaiodobenzylguanidine (MIBG) scintigraphy was performed at the time of diagnosis and, in some instances, after induction chemotherapy. All the patients underwent a tumour biopsy with cytological and histological analysis, in addition to imaging examinations such as X-rays, ultrasound, computed tomography and magnetic resonance, within a short period before or after scintigraphy. In 82 of 97 cases MIBG was effective in detecting the primary tumour, hence the technique's sensitivity was 84%. A significant different of sensitivity between [131I]MIBG and [123I]MIBG was not demonstrated. As regards metastatic locations, MIBG scans revealed one or more bone metastases in 12 cases, bone marrow involvement (assumed to be present when diffuse and symmetric uptake in the spine, pelvis and possibly other skeletal sites were visualized) in 9 cases, and focal liver metastases or hepatomegaly in 4 cases. Probably owing to the restrictive diagnostic criterion adopted or to the early phase of the bone marrow involvement, the last was found by biopsy but missed by MIBG in 25 cases. The overall sensitivity in detecting metastases was low (48%), but it was much higher if only bone metastases were considered (81%). Twenty-nine patients who had positive scans at diagnosis were checked following 1-2 courses of induction chemotherapy (IC). MIBG scans remained positive in 22 primary tumours, while 7 primary masses were no longer detected. Out of 12 cases showing metastases at diagnosis, two cases with liver lesions became normal and in one case some, but not all, of the bone lesions were not detectable; 4 cases remained abnormal, while in 5 cases bone marrow involvement was not confirmed. Three cases were confirmed to be true negatives; in 4 other cases bone marrow involved not showing at diagnosis was revealed and confirmed by biopsy; 3 cases in which bone marrow involvement was not revealed by MIBG at diagnosis, had normal MIBG and biopsy results after IC; finally, 2 false negative bone marrow cases and 5 true negative cases at diagnosis remained unchanged, but were not checked by biopsy. Performing total body MIBG scintigraphy in childhood neuroblastoma at diagnosis is useful: 1) to predict the nature of the masses detected by other imaging techniques, when biopsy has not yet been performed; 2) for more accurate tumour staging, in addition to standard imaging investigations, MDP scintigraphy and bone marrow aspiration biopsy, thanks to its ability to detect metastatic lesions; 3) to anticipate the decrease in sensitivity of the technique in detecting both the primary mass and the metastases following induction chemotherapy.

Place of meta-[131I]iodobenzylguanidine in the treatment of neuroblastoma: the Genoa experience.

The aim of this paper is to focus on our previous experience with the treatment of Group 3 and 4 neuroblastoma patients and on the therapeutic use of [131I]MIBG, to better define the role of this radioactive drug in the treatment of neuroblastoma (NB). Analysis of the studies on Group 3 patients treated with chemotherapy and surgery showed that the progression-free survival (PFS) increased from 45% for patients treated before 1985 to 63% for patients treated in the period of 1985-1989 and to 78% for patients treated after 1989. [131I]MIBG administered in 17 Group 3 patients who did not achieve a radical excision of the primary resulted in 7 partial response (PR) and 5 minor response (MR), with 10 cases of long term survival. Results in Group 4 patients confirmed the good prognosis in the subset of children aged 6-12 months at diagnosis (PFS 86% at 5 years). In patients aged > 12 months at diagnosis intensive induction chemotherapy induced a higher response rate of 69% and PFS was 26% at 5 years. [131I]MIBG administered in advanced stage 4 patients induced a response in 50% of the cases (2 complete response [CR], 13 PR and 2 MR out of 34 children) and 8 children treated for residual primary (4 cases) or residual bone metastases (4 cases) are long term survivors. We conclude that [131I]MIBG is the treatment of choice in Group 3 patient with a residual primary tumor and could contribute to consolidate the response obtained in Group 4 patients.

Increased 17 alpha-hydroxyprogesterone response to ACTH in silent adrenal adenoma: cause or effect?

OBJECTIVE: Recent studies suggest a possible connection between silent adrenal nodules and mild forms of 21-hydroxylase deficiency. It remains unclear whether the enzymatic deficiency is generalized or intrinsic to the adrenal mass. To help to clarify this, we have studied 17 alpha-OH-progesterone (17OH-P) response to ACTH stimulation in a group of patients with adrenal 'incidentaloma' in comparison with normal subjects. In patients who underwent surgical treatment, the test was repeated to evaluate possible modifications in 17OH-P behaviour after resection of the adrenal mass. SUBJECTS AND METHODS: Fifteen subjects with incidentally discovered asymptomatic adrenal masses were studied. Basal hormone evaluations were normal, with normal cortisol suppression after low-dose dexamethasone. Iodocholesterol scanning, performed in 12 patients, showed normal bilateral adrenal uptake in 2 subjects and an increased uptake on the side of the lesion in 10 subjects. In every patient, ACTH stimulation was performed to evaluate the secretory response of cortisol, 17OH-P, progesterone and dehydroepiandrosterone sulphate. An identical test was performed in 10 control subjects with normal adrenal glands, matched for age and sex. In six patients with an adrenal lesion > 3.5 cm, the ACTH stimulation test was repeated one month after surgery. RESULTS: The 17OH-P response to ACTH stimulation was significantly higher in subjects with adrenal 'incidentaloma' than in controls (P < 0.01). In particular, 10 subjects out of 15 (66%) evidenced a 17OH-P peak > 18 nmol/l at 60 minutes. No differences were seen in baseline 17OH-P or cortisol levels or in cortisol response to ACTH between the two groups. Dehydroepiandrosterone sulphate concentrations were significantly lower in patients with adrenal 'incidentaloma' than in normals. In six patients who had an increased 17OH-P response to ACTH on initial evaluation, the ACTH test was repeated one month after surgery. In five of these patients, 17OH-P response to ACTH was clearly reduced, suggesting that in these cases the enzymatic defect was restricted to the adenoma. In the other patient, however, stimulated 17OH-P levels remained unchanged. In this case, therefore, all of the adrenal tissue seems to be involved, suggesting a late-onset 21-hydroxylase deficiency. No significant modifications in cortisol response to ACTH were observed. CONCLUSION: It seems therefore that in some cases of incidentaloma the steroidogenic enzymatic defect may be secondary to the adenomatous proliferation, while in others such defects may induce the development of silent adrenal nodules.

Semiquantitative evaluation of regional cerebral flow by means of SPECT with 99mTc-hexamethyl-propylene amine oxime in hypertensive patients under treatment.

Cerebral SPECT with 99mTc-HM-PAO allows a semiquantitative evaluation of regional cerebral blood flow (rCBF). Using this method we studied 25 patients affected by slight-to-moderate degree hypertension, in effective pharmacological treatment, and a control group of normotensives. On the cross-sections symmetrical ROIs were traced at the level of the cerebral lobes and the cerebellum. From the counts obtained on the ROIs the rCBF values were calculated in percentage units with Lassen's algorithm. We found no significant differences between the rCBF values of the two groups. In 5 hypertensive patients, however, focal areas of hypoperfusion were evidenced. These patients did not differ from the other hypertensives by pressure levels or other risk factors. Neurological, tomographic and flowmeter examinations of the supraaortic arteries proved to be normal. It is possible that SPECT with 99mTc-HM-PAO identifies a subgroup of hypertensives at risk of future cerebrovascular pathology despite the setting up of an effective antihypertensive therapy.

[131I]metaiodobenzylguanidine therapy in advanced neuroblastoma.

Forty-two children with advanced neuroblastoma who either failed with first-line therapy or relapsed after achieving a complete remission, were considered for treatment with [131I]metaiodobenzylguanidine (131I-MIBG). We subdivided 42 cases into 5 groups, in accordance with the stage of disease at diagnosis, response to first-line therapy and relapse. A total of 99 courses of 131I-MIBG were administered with doses ranging from 2.8 to 6.0 GBq. One child received six courses, 3 four courses, 18 three courses, 6 two courses and 15 one course of 131I-MIBG. The total delivered dose in single measurable lesions ranged from 286 to 1691 cGy with an uptake factor ranging from 3% to 10%. We obtained a major response in primary tumors, and a long-term response was observed in 5 cases, lasting more than 2 years without further chemotherapy.

Treatment of advanced neuroblastoma with I-131 meta-iodobenzylguanidine.

From February 1986 to December 1988, 31 children with advanced pretreated neuroblastoma were treated with 131-I meta-Iodobenzylguanidine (131-MIBG). Thirteen children had been resistant to first-line therapy, three had suffered a local relapse, and fourteen had suffered a disseminated relapse without over bone marrow infiltration. One child was treated initially because of resistance to first-line therapy, and subsequently for a local relapse. A total of 72 courses of 131-MIBG was administered, with doses ranging from 2.8 to 6.0 GBq (median, 3.7 GBq). One child received five courses, two four courses, 13 three courses, four two courses, and 12 one course of 131-MIBG. The most common toxic effect was thrombocytopenia, with a platelet level of less than 50,000/cmm occurring after 19 of 60 evaluable courses. A leukocyte count less than 1000/cmm was seen only once. There were six major responses (two complete) lasting 4 to 9 months, and two minor responses lasting longer than 38 and 44 months. Responses were seen more commonly in children whose only lesion was a residual primary tumor and in children who had not been pretreated who experienced disseminated relapse. Further studies of the role of 131-I meta-Iodobenzylguanidine in treatment of neuroblastoma are needed.

[Double-blind controlled comparison of placebo and paracetamol in patients with G-6-PD deficiency]. / Confronto in doppio cieco controllato tra placebo e paracetamolo in soggetti carenti di G-6-PD.

In this study are reported 17 patients with G-6-PD deficiency. These subjects have been studied with double-blind trial between placebo and Paracetamol, looking for the possible hemolysis induced from drug in these children with G-6-PD deficiency. Hemolysis had been valued by various hematological parameters (Hb, erythrocyte count, reticulocytosis, bilirubinemia, haptoglobin, hemopexin, and survival of erythrocytes marked with Cr). The results (8 cases with placebo and 9 cases with paracetamol) demonstrate that paracetamol have not induced hemolysis in these G-6-PD deficient subjects.

Scintigraphy used to compare cemented and cementless prostheses: two-year follow-up.

Cemented and cementless total hip prostheses were followed up after two years, using computerized skeletal scintigraphy. The authors discuss the protocol used for the study, and compare the validity of this method with that of traditional radiography in monitoring the long-term results. They evaluated the degree of reorientation in the host bone and showed that there were significant differences between the two types of prosthesis.