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P Fragu

Publications and source records attributed to P Fragu.

At least 19 recordsLinked to original sources
PubMed1992

Quantitative mapping of 4'-iododeoxyrubicin in metastatic squamous cellcarcinoma by secondary ion mass spectrometry (SIMS) microscopy.

Secondary ion mass spectrometry microscopy enables quantitative mapping of chemical elements in tissue sections. It was used for the detection of 127I contained in 4'-iododeoxyrubicin (IDX). Metastatic cutaneous squamous cell carcinoma from 7 patients participating in a phase I study (IDX dose, 80 mg/m2, 10-min i.v. infusion) were biopsied 10 min after drug administration and compared to 3 controls who did not receive any treatment (one squamous cell carcinoma and 2 gastric carcinomas). Biopsy specimens were fixed and embedded in methacrylate resin. Then, serial semithin sections (3 microns) were analyzed simultaneously with ionic and optimal microscopes in order to identify the histological structures given by the 31P distribution in which 127I in IDX was mapped. The iodine signal was undetected in controls and found mainly in the nuclei of tumor cells of the treated patients. Its concentration, measured in at least 30 nuclei of each specimen, was undetectable in 8% of the nuclei and 91% of them were within 1 and 16 ng/mg. The mean concentration of each specimen ranged from 5 to 23 ng/mg. This study demonstrates the capacity of ion microscopy to localize a cytotoxic drug (IDX) in a human biopsy specimen without the need for radioactive labeling and enables the evaluation of drug penetration in cancer cells which is critical for its activity.

Carcinoma, Squamous Cell↗
PubMed1992

SIMS microscopy in the biomedical field.

We attempted to indicate the requirements for biomedical applications of SIMS microscopy. Sample preparation methodology should preserve both the structural and the chemical integrity of the tissue. Furthermore, it is often necessary to correlate ionic and light microscope images. This implies a common methodological approach to sample preparation for both microscopes. The use of low or high mass resolution depends on the elements studied and their concentrations. To improve the acquisition and processing of images, digital imaging systems have to be designed and require both ionic and optical image superimposition. However, the images do not accurately reflect element concentration; a relative quantitative approach is possible by measuring secondary ion beam intensity. Using an internal reference element (carbon) and standard curves the results are expressed in micrograms/mg of tissue. Despite their limited lateral resolution (0.5 microns) the actual SIMS microscopes are very suitable for the resolution of biomedical problems posed by action modes and drug localization in human pathology. SIMS microscopy should provide a new tool for metabolic radiotherapy by facilitating dose evaluation. The advent of high lateral resolution SIMS imaging (less than 0.1 microns) should open up new fields in biomedical investigation.

Animals↗
PubMed1992

Significance of SIMS microscopy for the radioiodine detection in animal and human thyroid tissue.

We defined the SIMS conditions for radioiodine detection in animal and man thyroid follicles, in tissue sections (3 microns) chemically fixed and resin embedded. Two radioisotopes were tested: 125I and 129I, of high (14 mCi 125I micrograms-1) and low specific activity (1.07 10(-6) mCi 129I micrograms-1). In animal study, Wistar rats fed a normal iodine diet (10 micrograms 127I day-1) were injected ip 24 h before sacrifice either with 125I (7 10(-3) micrograms) or with 129I at a dose identical to iodine diet (10 micrograms) or 3 times higher (30 micrograms). No SIMS signal of 125I was obtained in vivo due to its too low concentration, while radioiodine distribution was evidenced with both doses of 129I. Local concentration of previously stored 127I in follicular lumen was not modified, when compared to control (4.14 +/- 0.03 micrograms/mg, m +/- SE), by 125I or 129I at a dose of 10 micrograms, but was nearly doubled with 129I at a dose of 30 micrograms, proof of a pharmacological effect on thyroid iodine regulation. In human study 129I was excluded due to its long half-life (1.6 10(7) years), and 125I was tested only in vitro on two surgical specimens of normal perinodular thyroid tissue maintained in mini-organ culture for 48 h in presence of 100 microCi/ml of 125I. The 125I was detectable, its concentration was 1,000-fold higher than that of 127I (1.5 +/- 0.004 micrograms/mg). For both in vivo and in vitro studies, a positive correlation exists between newly organified radioiodine (125I or 129I) and previously stored iodine (127I).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Macroscopic and microscopic imaging of stable iodine (127I) in the thyroid.

The purpose of this review is to describe the two imaging methods which allow direct estimation of stable iodine (127I) within thyroid gland either in vivo by X-ray fluorescence or in vitro by secondary ion mass spectrometry (SISM) microscopy. X-ray fluorescence of thyroid is mainly used for the estimation of thyroid iodine content (TIC) in human pathophysiology. Although its measurement has little revelance for routine explorations of thyroid function, this is a valuable method for understanding complex pathophysiological conditions such as hyperthyroidism without radioactive uptake, the fate of irradiated glands or the thyroid adaptation to iodine overload. On the other hand, SIMS microscopy which combines the phenomena of secondary ion emission and mass spectrometry, makes possible the quantitative mapping of 127I on tissue section. This technique is able to characterize the functional activity of thyroid tissue without prior administration of radioiodine by measuring 127I concentration within the thyroid follicles. Furthermore, SIMS microscopy can be used to determine the extent to which exogeneous iodine affects the regulation of iodine within the thyroid follicles. Both methods were used to evaluate the quantitative changes in thyroid 127I induced by amiodarone overload. TIC measurements shows that hyperthyroidism occurred only in patients who increased their iodine stores, while the patients who developed hypothyroidism had low iodine stores. These data demonstrate that the mechanisms by which subjects who become hypothyroid under amiodarone iodine overload differ from those of subjects who remain euthyroid or become hyperthyroid: iodine organification is blocked in hypothyroid patients and increased in the euthyroid and hyperthyroid patients. The SIMS microscopy data obtained in mice demonstrated that the thyroid response to amiodarone is related to dietary iodine intake leading to an increase in iodine stores in iodine deficient mice and a decrease in iodine supplemented mice. These results could explain that hyperthyroidism with high thyroid iodine content occurred in areas with low thyroid iodine intake and hypothyroidism with low thyroid iodine content in areas with a supplemented iodine diet.

Animals↗
PubMed1992

[Direct evaluation of thyroid I-127 in an iodine overload situation: in vivo study by X-ray fluorescence and in vitro by analytical ion microscopy].

This review describes the two methods which allow direct estimation of stable iodine (127I) within thyroid gland either in vivo by X-ray fluorescence or in vitro by secondary ion mass spectrometry (SIMS) microscopy on tissue section. Although the measurement of thyroid iodine content (TIC) by X-ray fluorescence has little relevance for routine explorations of thyroid function, this is a valuable method for understanding complex pathophysiological conditions such as the thyroid adaptation to iodine overload. On the other hand, SIMS microscopy which is able to characterize the functional activity of thyroid tissue by measuring 127I concentration within the thyroid follicles, can be used to determine the extent to which exogenous iodine affects the regulation of iodine within the thyroid follicles. Both methods were used to evaluate the quantitative changes in thyroid 127I induced by amiodarone iodine overload. TIC measurements shows that hyperthyroidism occurred only in patients who increased their iodine stores, while the patients who developed hypothyroidism had low iodine stores. The SIMS microscopy data obtained in mice demonstrated that the thyroid response to amiodarone is related to dietary iodine intake leading to an increase in local iodine concentration in iodine deficient mice and to a decrease in iodine supplemented mice. This response is specific and different from that induced by an iodide overload. These results could explain that hyperthyroidism with high thyroid iodine content occurred in areas with low thyroid iodine intake and hypothyroidism with low thyroid iodine content in areas with a supplemented iodine diet.

Amiodarone↗
PubMed1992

Significance of secondary ion mass spectrometry microscopy for technetium-99m mapping in leukocytes.

Secondary ion mass spectrometry (SIMS) microscopy is the only method potentially capable of mapping all the elements in the periodic table including stable and radioactive isotopes. We used this method to study 99mTc distribution by detecting and localizing of 99Tc, a daughter product which has the same mass and the same chemical properties. It was combined with albumin macroaggregates or with Hexamethylpropylene-amine oxime (HMPAO) in leukocytes. The efficiency of 99Tc ionization under Cs+ bombardment was higher than with an O2+ beam. By using high mass resolution we succeeded in detecting and localizing 99Tc in cell sections by eliminating polyatomic ions that arise from this biological matrix. The 99Tc specific signal was obtained with a mass resolution of 2000 for labeled albumin macroaggregates, and 5000 for HMPAO-labeled leukocytes. In the latter, the labeling varied from one cell to another and 99Tc was present in both the nucleus and the cytoplasm. The results indicate that SIMS microscopy can provide new insights into 99mTc dosimetry.

Humans↗
PubMed1992

[Influence of the distribution of the dose on carcinogenic effects of ionizing radiations of low lineal energy transfer on the thyroid tissue].

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.

Adolescent↗
PubMed1991

Demonstration of a heterogeneous transcription pattern of thyroglobulin mRNA in human thyroid tissues.

Previous reports on human thyroglobulin (hTg) modifications in thyroid carcinomas prompted us to study hTg mRNA in thyroid adenomas and carcinomas. The quantification of hTg mRNA showed a decrease in its levels of expression in both pathological conditions which differed by a factor of 2 between adenomas and carcinomas. Furthermore, PCR was used to analyse the characteristics of hTg mRNA by amplifying 4 regions of the hTg mRNA. When applied to 2 normal, 17 benign and 13 malignant pathological tissue specimens, PCR showed no modification in the size of Tg mRNA. However, abnormal sized cDNAs appeared in all tissues with no distinction between the pathologies; the Restriction Fragment Length Polymorphism study of these cDNAs suggests the existence of alternate splicing patterns in thyroglobulin mRNAs.

Adenoma↗
PubMed1991

A new immunoradiometric assay (IRMA) system for thyroglobulin measurement in the follow-up of thyroid cancer patients.

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.

Follow-Up Studies↗
PubMed1991

Long-term effects in skin and thyroid after radiotherapy for skin angiomas: a French retrospective cohort study.

To evaluate the long-term effects of skin angioma irradiation, a recall programme was established which included the systematic recalculation of the radiation dose to the skin and the thyroid. 22% of the 6229 patients contacted had a dermatological examination which revealed cutaneous dystrophy in 81% of the 1137 exposed angiomas and in 39% of the 208 unexposed angiomas. The risk of dystrophy (telangiectasia, hypopigmentation, superficial and subcutaneous atrophy) was 12.1 higher (P less than 0.0001) among patients who had received a surface skin dose above 30 Gy than among those who had received a dose of 10 Gy or less. The relative risk for each dystrophy component increased significantly (P less than 0.001) with surface skin dose. Furthermore, 14 basal cell carcinomas (BCC) were observed in 12 patients from the exposed group for all quantities of radiation, with a mean latency period of 22 years. No BCC was observed for a surface skin dose below 10 Gy. Thyroid testing was done on a subgroup of 431 patients whose thyroid gland had been particularly exposed during angioma irradiation. After recalculation, the dose delivered to the gland was below 1 Gy in 98% of patients. Only 13 thyroid nodules were discovered (1 hot and 12 cold). 1 patient with a cold nodule had a malignant thyroid tumour 21 years after irradiation. He belonged to the group of 7 patients who had received a thyroid dose above 1 Gy. Although no morphological abnormality was found in 98% of the tested patients, most (92%) had a thyroid iodine content below 15 mg (the standard French value), while a raised serum thyroglobulin level (greater than 30 ng/ml) was observed in 17%. This might confer a higher risk of subsequently developing thyroid nodules.

Adolescent↗
PubMed1991

Study of calcitonin and thyroglobulin gene expression in human mixed follicular and medullary thyroid carcinoma.

mRNAs were isolated from 2 patients suffering from a familial form of a rare variant of medullary carcinoma of the thyroid (MTC), called mixed follicular and medullary carcinoma. The presence of calcitonin (CT) and thyroglobulin (Tg) mRNAs was checked by northern and in situ hybridization and compared with immunohistochemical results. In each case, mRNAs hybridizing to probes specific for CT and Tg were detected. Both proteins were quantified by radioimmunoassay determination in tissue extracts. Patient 1 had 20 ng Tg and 68 ng CT per micrograms total protein, and patient 2 had 0.4 ng Tg and 1.7 ng CT per micrograms total protein. Northern analysis showed that mixed carcinoma expressed several species of both CT mRNAs and Tg mRNAs. The main Tg transcripts present in neoplastic cells (8.5 and 4.8 kb for patient 1 and patient 2) were identical to or smaller than those of normal thyroid tissue (8.5 kb). The tumor CT mRNA (1 kb) was identical to that of normal tissue. In situ hybridization confirmed the presence of CT and Tg mRNA in the great majority of tumor cells. Furthermore, the presence of small amounts of organified iodine was evidenced by analytical ion microscopy in 35% of these cells. This raises an important question regarding the histogenesis of this tumor.

Adenocarcinoma↗
PubMed1991

Image registration and distortion correction in ion microscopy.

We present a method whereby the geometric registration of a series of ion microscopic images is performed by applying a two-step procedure. After applying a global linear transformation that corrects for geometric differences, a non-linear elastic transform is used in order to match local properties and structures of the images. Transformation parameters are computed on the basis of shape-specific points in the images. Distortion correction is achieved by relating ion images to the optical image of the same field and by using the two-step algorithm to register the images. This methodology is evaluated on synthetic misaligned objects and on thyroid tissue images.

Animals↗
PubMed1991

[Functional microscopic imaging of the thyroid gland with the help of analytical ion microscopy].

Secondary ion mass spectrometry (SIMS) microscopy provides a direct mapping of 127I in thyroid follicles. Thyroid tissue should be fixed and embedded in methacrylate resin, then cut in 3 microns-thick sections which are placed on a gold coverslip. The histological structure of the tissue is determined by the phosphorus ion (31P) which is present in large amounts in nuclei and phosphorylated molecules in the cytoplasm. An image processing system is used to superimpose images of 127I and 31P: this system allows measurement of local concentration of 127I in the follicular cell and follicular lumen compartments. A study in 8 subjects with normal thyroid glands showed that the level of 127I within follicular cells (430 +/- 250 micrograms/g; m +/- SE) was 6 to 7 times lower than the level in the follicular lumen (2.780 +/- 230 micrograms/g). In simple goiter (9 patients with macrofollicular adenomas), follicular lumen (346 +/- 17 micrograms/g) and cellular (68 +/- 6 micrograms/g) concentrations of 127I were decreased fivefold but the ratio of concentrations remained similar to that seen in normal tissue. In hyperfunctioning nodules (2 microfollicular and 3 macrofollicular adenomas), follicular cell and follicular lumen 127I levels varied widely and showed considerable overlap (2 to 16,000 micrograms/g and 1-21,000 micrograms/g, respectively). In benign cold nodules (1 microfollicular adenoma and 2 macrofollicular adenomas), follicular cell and follicular lumen 127I levels were barely detectable (3 +/- 0.6 micrograms/g and 6 +/- 0.7 micrograms/g respectively). In the 9 malignant nodules studied, no difference in 127I level profile was found with benign nodules.(ABSTRACT TRUNCATED AT 250 WORDS)

Goiter, Nodular↗
PubMed1991

[Chemical mapping of normal and tumorous gastric mucosa by analytical ion microscopy].

The analytical ion microscopy (AIM) makes possible quantitative mapping of chemical elements on tissue section this method was applied to the study of chlorine (Cl-) and sulfur (S-) distributions on chemically fixed stomach sections obtained by biopsy. The Cl- and S- images were correlated with the histological structure of the tissue obtained by the phosphorus distribution on the same field or by the photonic image of a serial section. In normal tissue, Cl- and S- were evidenced in cytoplasm with accumulation at the apical cell border while in gastric adenocarcinoma both elements were distributed without precise topography. The use of cryo-prepared specimens should offer the possibility to study the changes of chlorine and sulfur content in functional pathology of stomach.

Gastric Mucosa↗
PubMed1990

Correlated autoradiographic and ion-microscopic study of the role of iodine in the formation of "cold" follicles in young and old mice.

The role of iodine in the formation of "cold" follicles (not labeled on autoradiograms after radioiodine administration) was analysed in ICR female mice during aging and involution of thyroid hyperplasia, by use of light and electron microscopy and by comparing autoradiographic and analytical ion-microscopic images for the same follicle in serial sections. The proportion of "cold" and "partly cold" (displaying a patchy or ring labeling pattern on autoradiograms) follicles increased significantly during aging. This increase was more pronounced in old mice fed an iodine-rich diet as compared to mice fed a moderate iodine diet. Similarly, during goiter involution produced by refeeding iodine, the follicular heterogeneity of iodine metabolism was more accentuated with a high dose of iodine, regardless of the age of the mice. The follicular lumina of "hot" and "cold" follicles had the same concentration of stable iodine, as shown by analytical ion microscopy, and the cells of both types of follicles formed colloid droplets in response to TSH. Furthermore, when a goitrogenic treatment was induced in aged mice, some "cold" follicles persisted after 8 days, but all follicles resumed "hot" after 16 days. By analytical ion microscopy, 127iodine was also found inside thyroid cells of old mice, but the cytoplasmic patches of 127iodine were not labeled with 125iodine. They corresponded to lipofuscin pigments and secondary lysosomes, as observed in serial sections at the electron-microscopic level. This intracellular stable iodine could constitute a slow turnover compartment not used for hormone synthesis.

Aging↗
PubMed1990

Thyroid iodine content and serum thyroglobulin level following external irradiation to the neck for Hodgkin's 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.

Adolescent↗