[Hematopoiesis regulating factors. Important therapeutic future].
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Biomedical subjects
Publications and source records attributed to C Parmentier.
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Short-term cultures from 19 papillary thyroid adenocarcinomas revealed clonal numerical and/or structural chromosomal changes in 13 tumors, nonclonal abnormalities in one tumor, and only normal karyotypes in five tumors. Clonal abnormalities of chromosome 10 were present in three tumors, two of which had the translocation t(7;10)(q35;q21). Numerical abnormalities of chromosome 17 were detected in two tumors.
Immunoscintigraphy (IS) using the HRS-3 Hodgkin associated monoclonal antibody (MoAb) was performed in 18 patients with Hodgkin's Disease (HD) at staging or restaging. Either F(ab')2 fragments (14 patients) or whole HRS-3 (4 patients) labeled with 77-260 Mbq 131-I were used. Whole body images, including anterior and posterior views, were taken from a digital gamma camera, within 4 to 8 hours after injection and then daily for 5 days. In one patient IS was discontinued due to iodine intolerance. Seventeen patients were evaluable: 14 showed a true positive result including 2 cases which were reviewed as anaplastic large cell lymphoma (ALCL). Nodal, splenic, bone marrow and muscle involvements were imaged, many of these sites were previously unsuspected. In 7 patients with true positive findings the Pressman Specificity Index, as measured from biopsied material, ranged from 1.5-3 in 4 patients and from 5 to greater than 100 in 3 patients. Imaging was equivocal or failed in 1 patient (lymph nodes). In 2 patients, IS imaging was truly negative due to the absence of active HD, and a false negative result occurred once (inguinal node). In none of the patients a false positive image was observed. In order to rule out non-specific iodine uptake a control, anti-ACE MoAb, labeled with 125-Iodine was injected simultaneously in 10 patients. The evaluation of the study gave a sensitivity of 87% and a good specificity. IS using radioiodine labeled MoAbs is feasible and represents a reliable non-invasive diagnostic method for the staging and follow-up of HD and ALCL.
The frequency of thyroid nodules has been studied among 396 children irradiated for a hemangioma, from 1946 to 1973. 226Ra, 192Ir, 90Y, 32P, 90Sr, as well as X-rays had been used for treatments. The doses of radiation received by the thyroid of each child have been estimated retrospectively. The irradiations have been classified in two categories based on their duration: less than 30 min., and more than 30 min. The doses received with each of these two types of irradiation were summed for each patient. The risk of thyroid nodule increased as a function of the dose to thyroid only for the dose delivered with the short duration. This study emphases the importance of the role of the dose rate in the risk of radio-induced tumour.
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Fourteen patients with progressive metastatic adrenal cortical carcinoma were treated with a combination of 5-fluorouracil (5-FU), doxorubicin, and cisplatin (FAP). All had a large tumor burden. Six patients had a hormone-producing tumor; mitotane treatment was given to five of them during chemotherapy for its possible antihormonal effects. Treatment could be evaluated in 13 patients. The overall response rate was 23% (95% confidence interval [CI], 5% to 54%). A complete remission, which lasted for 42 months, was achieved in one patient. Partial remissions, which lasted for 6 and 11 months, were achieved in two patients. Cardiotoxicity appeared in three patients, myelotoxicity in four, and nephrotoxicity in one. This confirms that this regimen is an active combination for the treatment of metastatic adrenal cortical carcinoma.
Since 1981, 20 patients with anaplastic giant cell carcinoma of the thyroid have been prospectively treated according to a combination regimen of chemotherapy and external beam radiation therapy. Two types of chemotherapy were used every 4 weeks, depending on the patient's age. For those younger than 65 years, a combination of doxorubicin (60 mg/m2) and cisplatin (90 mg/m2) was given, and for older patients mitoxantrone (14 mg/m2) was used. Radiotherapy was carried out between Day 10 and Day 20 of the first four cycles of chemotherapy. It delivered 17.5 Gy in 7 fractions to the neck and the superior mediastinum. Survival exceeding 20 months was observed in three patients. Complete neck tumor response was observed in five patients, among whom four had undergone previous operations. No response was seen in distant metastases, which were the cause of death in 14 patients. These treatment modalities are effective in some patients, both in terms of survival and of local control, avoiding death from local invasion. Gross tumor resection should be performed whenever possible but should not delay the commencement of this protocol. Toxicity was high and remains the main limiting factor.
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A new commercially available kit for thyroglobulin (Tg) measurement [immunoradiometric assay (IRMA) system based on monoclonal antibodies] was used in 479 patients with thyroid carcinoma. The effective working range was 1 ng/ml, and results were strongly correlated with our homemade radioimmunoassay (RIA). This IRMA method is less susceptible to interferences of auto-antibodies than our RIA. During thyroxine (T4) treatment, the Tg level was undetectable in 98% of patients after total thyroid ablation, in 91% after total thyroidectomy and in 42% after lobectomy only. In this situation, Tg was found in all patients with large metastases and in 88% of those with small metastases. Following T4 withdrawal, Tg was detectable in all patients with neoplastic disease and in 13% of those in complete remission after total thyroid ablation. In conclusion, Tg measured with this IRMA method appears to be a reliable marker of differentiated thyroid carcinoma.
Cytogenetic investigations using short-term cultures are reported in six thyroid adenomas. Clonal and nonclonal numerical chromosomal changes were present in two tumors. In two of the four remaining, nonclonal numerical and structural abnormalities were observed, whereas only normal karyotypes were found in the other two. Chromosome 10 and 17 were involved in several cases, although no common clonal changes could be detected. The present studies show that thyroid adenomas, benign tumors of an endocrine gland, may have chromosomal abnormalities, as described for other benign tumors.
OBJECTIVE: To investigate whether the addition of 3,5,3'-triiodothyroacetic acid (TRIAC) to thyroxine (T4) treatment can suppress TSH secretion without inducing thyrotoxicosis at the periphery. DESIGN: Thyroid cancer patients were studied with different treatment modalities: T4 at supraphysiologic dose (2.5 +/- 0.3 micrograms/kg/day) and after reduction to a physiologic dose (1.8 +/- 0.3 micrograms/kg/day); then with the addition of TRIAC 500 or 1000 micrograms/day to the physiologic T4 treatment dose. PATIENTS: Twenty-two patients who had total thyroid ablation for differentiated thyroid carcinoma. MEASUREMENTS: Clinical and biological parameters of thyroid hormone action studied included heart rate, serum creatine phosphokinase, testosterone-oestradiol binding globulin, procollagen III and osteocalcin levels. RESULTS: The addition of TRIAC induced a significant and dose-dependent decrease in serum TSH levels and parallel effects on peripheral tissues. Compared to the suppressive T4 treatment dose, the addition of TRIAC to the physiologic T4 dose resulted in greater inhibition of TSH secretion in only 50% of the patients. The effects at the periphery of both treatment modalities were similar for a comparable level of TSH suppression. CONCLUSIONS: Even at low dose and when combined with T4, TRIAC has parallel effects on the pituitary and peripheral tissues. There is no justification for the use of TRIAC as suppressive treatment in thyroid cancer patients.
We describe a biodistribution study using a radiolabelled anti-tumor murine monoclonal antibody F(ab')2 in XF-8 in 6 patients with colorectal carcinoma. One patient had an isolated rectal carcinoma. Five patients had hepatic metastasis of colorectal carcinoma. Among them three had also the primary colorectal carcinoma. Double-label method using simultaneous injection of 131-Iodine monoclonal antibody XF-8 F(ab')2 and 125-Iodine control monoclonal antibody was performed to evaluate the specificity of monoclonal antibody localization in the tumor. Each patient received 4-8 mCi of 131-I XF-8 F(ab')2 infused at doses 0.5-5 mg. Simultaneously 200 microCi of 125-I non relevant antibody were infused. Before each administration, immunoreactivity of antibodies preparations was checked before labelling by immunohistological methods and, after labelling, by cell-binding tests. In biodistribution studies, patients were scanned with a scintillation camera each day since the infusing day to the surgery day (3-6 days). To study specificity of XF-8 F(ab')2 antibody localization we measured by means of scintillation counting in tumors and normal tissues recovered after surgery. In vitro immunoreactivity of monoclonal antibody batches was safe. All our data in vivo are negative but correlated. We concluded that criteria for screening the monoclonal antibodies considered for detection of human tumors are not really known.
The presence of gsp mutations at codons 201 and 227 in the gene coding for the alpha subunit of the GTP-binding Gs protein which stimulates adenylyl cyclase (AC) has been investigated in 31 samples of differentiated thyroid tumours, which had been previously characterized with respect to their adenylyl cyclase activity (ACA) before and after stimulation by thyroid-stimulating hormone (TSH). Polymerase chain reaction (PCR) amplification of DNA extracted from these tumours, followed by high stringency oligonucleotide probing, enabled the detection of mutations in three samples originating from tumours with high constitutive ACA, which was not significantly further stimulated by TSH. Two mutations were at codon 227 and replaced Gln227 by His or Lys, and one was at codon 201, with the substitution of Arg201 by Ser. Because thyrocytes belong to the subset of differentiated cells which are programmed to proliferate in response to elevated cAMP levels, the gsp mutations observed in some differentiated thyroid carcinomas probably contributed to their tumorigenic phenotype.
Forty-nine patients with metastatic nonanaplastic thyroid carcinoma were treated over a 10-year period. Five successive chemotherapeutic protocols were used: a combination of doxorubicin, etoposide, 5-fluorouracil and cyclophosphamide; elliptinium acetate; doxorubicin; cisplatin; and the combination of doxorubicin and cisplatin. Results obtained with the different protocols were very disappointing, with only two objective responses (3%). Phase II trials with new chemotherapeutic agents are warranted in selected cases of nonanaplastic metastatic thyroid carcinoma.
The authors report the case of a 41-year old man who presented simultaneously with phaeochromocytoma, paraganglioma and renal carcinoma. The postoperative finding of metaiodobenzylguanidine uptake foci showed that the phaeochromocytoma was malignant. The patient's son had a phaeochromocytoma and a pancreatic cyst. The phaeochromocytoma had no clinical manifestations and had been discovered by systematic assays of urinary catecholamines and their derivatives. These abnormalities are those of Von Hippel-Lindau disease.
Fifty-four clinically euthyroid patients were evaluated 1 up to 17 yr after external irradiation to the neck for Hodgkin's disease. T4 level was decreased in 6%, while basal TSH level was increased in 44%, and TSH response to TRH was increased in 66% of the patients with normal basal TSH level. Thyroid iodine content (TIC), measured in 50 patients, was below 5 mg in 18. The 29 patients with normal basal TSH level had a mean TIC (6.8 +/- 2.7 mg) significantly lower (p less than 0.01) than the control population (14.6 +/- 5 mg). A significant positive correlation was found between log T4 and log TIC (r = 0.55, p less than 0.01). Thyroglobulin (Tg) level was increased in 53% of the patients with no palpable thyroid abnormality. It was not related to TSH level but was related to younger age at irradiation. T4 treatment decreased Tg level to the normal range in 5 of 8 patients. These facts suggest subclinical thyroid abnormalities and patients with elevated Tg levels should be considered at risk for developing a thyroid tumor.
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