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Biomedical subjects

M Schlumberger

Publications and source records attributed to M Schlumberger.

At least 91 records · Page 5Linked to original sources
PubMed1998

Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

Adult↗
PubMed1998

Iodide symporter gene expression in human thyroid tumors.

Expression of the Na+/I- symporter (NIS) gene was investigated by RT-PCR in a selected series of 26 primary thyroid carcinomas (19 papillary, 5 follicular, and 2 anaplastic). Fifteen follicular adenomas (11 "cold" and 4 "hot" adenomas) were also studied. Five of 19 papillary thyroid cancer did not express NIS messenger ribonucleic acid (mRNA). In all but 1 follicular cancer, NIS transcript was fully detected. In anaplastic tissue, NIS mRNA was only barely detected in 1 case. All of the follicular thyroid adenomas except 1 expressed the NIS gene. In contrast, all tumors studied excluding the anaplastic histotype fully expressed thyroglobulin and thyroid peroxidase mRNA transcripts. In 2 patients, a lower expression (3- to 5-fold) of NIS mRNA was found in metastasis by dot blot analysis compared with those in both normal and primary neoplastic thyroid tissue. Four of 8 differentiated thyroid cancer patients selected for the presence of metastases with negative posttherapy 131I total body scan showed the lack of NIS gene expression in their primary cancer. This defect, at least in these cases, is a somatic and intrinsic lesion of the primary cancer cells and is not due to a dedifferentiation process in the metastatic tissue. The early detection of the loss of NIS gene expression in the primary cancer, therefore, may provide useful information for the management of differentiated thyroid cancer patients.

Adenocarcinoma, Follicular↗
PubMed1998

Combination of radioiodine (131I) and probe-guided surgery for persistent or recurrent thyroid carcinoma.

To improve the completeness of surgical excision of persistent or recurrent differentiated thyroid carcinoma, the following protocol was used for the treatment of 54 patients with functioning lymph node metastases: administration of 3.7 gigabecquerels (100 mCi) 131I; total body scintigraphy (TBS) on day 4; surgery on day 5, using an intraoperative probe (Gammed 2, Eurorad); and postoperative TBS with the remaining 131I activity on day 7. The 54 patients (35 women and 19 men presenting 47 papillary carcinomas, 2 well differentiated follicular carcinomas, and 5 poorly differentiated follicular carcinomas) had already undergone surgery for differentiated thyroid carcinoma: total thyroidectomy (51 patients) or lobectomy with isthmusectomy (3 patients), with lymph node dissection in 33. One to 7 131I treatments were performed before inclusion. Preoperative 131I-TBS with a high dose of 131I allowed accurate localization of previously suspected neoplastic foci and detection of yet unknown foci in 56%; it was the most sensitive tool for localizing neoplastic foci. The use of an intraoperative probe was considered decisive in 20 patients, as neoplastic foci were found inside sclerosis due to previous surgery (n = 9), at unusual sites behind vessels or in the mediastinum (n = 10), or both (n = 1). In 26 patients, it facilitated the preoperative detection of foci with 131I uptake already depicted at preoperative 131I-TBS. In all 46 patients, the completeness of excision was demonstrated by both the probe and the postoperative 131I-TBS and was confirmed during follow-up. Of note, lymph node metastases undetected by 131I-TBS or by the probe were found in 14 patients at histological examination. This clearly shows that en block dissection is the only recommended procedure. In four patients, no neoplastic foci were found and in four patients, uptake was either due to the thymus (in two) or to the salivary glands (in two).

Adenocarcinoma, Follicular↗
PubMed1998

[Von Hippel-Lindau disease: recent genetic progress and patient management. Francophone Study Group of von Hippel-Lindau Disease (GEFVH)].

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder, predisposing to the development of central nervous system (CNS) and retinal hemangioblastomas, endolymphatic sac tumors, renal cell carcinoma and/or renal cysts, pheochromocytomas, pancreatic cysts and/or tumors. Incidence of the disease is 1/36,000. CNS hemangioblastomas and renal cell carcinoma are the main causes of death. The VHL gene, located on 3p25-26, is a tumor-suppressor gene which plays a major role in regulation of VEGF expression. Germline mutations of the VHL gene are identified in about 70-99% of the patients. Mutations associated with VHL type 2 (with pheochromocytoma) are mainly missense mutations with hot-spot at codon 167. Somatic mutations of the VHL gene are found in both sporadic central nervous system hemangioblastomas and sporadic renal cell carcinoma. For endocrinologists search for VHL disease (as for MEN) should be imperative in presence of a patient with pheochromocytoma and neuroendocrine pancreatic tumor.

Carcinoma, Renal Cell↗
PubMed1998

[Isolated mandibular metastasis of cancer of the thyroid. Mandibulectomy and reconstruction using a free vascularized peroneal graft].

Isolated mandibular metastasis from a thyroid cancer is exceptional. In our observation, it was revealed 13 years after the thyroid cancer (papillo-vesicular carcinoma which was treated with total thyroidectomy, nodes resection and I 131). Treatment included interruptive mandibulectomy and reconstruction with a free composed vascularized fibular transplant. Follow-up was uneventful. Functional and morphological results were excellent. Isolated cases are reported in the literature. Surgical resection must be achieved. The originality of our observation is the mandibular reconstruction with a free vascularized fibular transplant.

Adenocarcinoma↗
PubMed1998

Biologic dosimetry in thyroid cancer patients after repeated treatments with iodine-131.

UNLABELLED: To estimate a cumulative dosimetric index that reflects the dose to the circulating lymphocytes after repeated treatments with 131I, biologic dosimetry was applied to 18 patients with differentiated thyroid carcinoma and neck relapse or lung metastases. METHODS: Chromosomal aberrations were scored in peripheral blood samples that were obtained before and 4 days after each administration of 3.7 GBq 131I according to two methods, conventional cytogenetics and chromosome 4 painting. RESULTS: The mean dosimetric index was equal to 0.5 Gy by both methods after the administration of 3.7 GBq 131I. Repeated administrations of 131I delivered the same dose each time, resulting in a cumulative dose from 1-3.5 Gy in the patients who had two to seven treatments. However, the estimated dose, based on the number of chromosomal aberrations on Day 4 and, above all, from the third treatment on, was considerably lower than the real dose absorbed by the lymphocytes. This may be linked to the phenomenon of apoptosis, which results in a loss of information during the course of repeated irradiation. CONCLUSION: Both chromosomal painting and conventional cytogenetics underestimate the cumulative dose after repeated 131I treatments. A complementary test measuring apoptosis may improve the dose estimates.

Apoptosis↗
PubMed1997

Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are two dominantly inherited disorders caused by germline mutations of the RET proto-oncogene. The RET gene codes for a receptor tyrosine kinase. The majority of MEN2A and FMTC mutations are clustered in the extra-cellular cysteine-rich domain and result in constitutive activation of the tyrosine kinase through the formation of disulfide-bonded RET homodimers. Recently, two novel point mutations have been identified in the germline of five distinct FMTC families. Both mutations occur within the catalytic domain of the RET kinase and lead to the substitution of either glutamic acid 768 or valine 804 by an aspartic acid and a leucine respectively. We have introduced each FMTC mutation in two RET isoforms: RET51 the long isoform (1114 aa) and RET9 the short isoform (1072 aa) which differ in the C-terminal region of the protein. The RET51 isoform carrying either E768D or V804L mutation was autophosphorylated, displayed a transforming activity upon expression in Rat1 fibroblasts and induced neuronal differentiation of PC12 cells. However, the transforming capacity of these RET51-FMTC mutants was found to be severalfold less potent compared to the same isoform carrying either the MEN2A mutation (C634R) or the MEN2B mutation (M918T). In contrast, RET9 containing mutations E768D or V804L was not autophosphorylated, exhibited a poor oncogenic potential in fibroblasts and did not promote neuritic outgrowth upon expression in PC12 cells. Overall, these findings demonstrate that mutations E768D and V804L are gain-of-function mutations that confer to the long RET isoform the capacity to exert a biological effect, although these mutations are more weakly activating than the MEN2A and MEN2B mutations. These results may provide a biochemical basis as to why the phenotypic consequences of these mutations are restricted to thyroid C-cells.

3T3 Cells↗
PubMed1997

Characterization and radiosensitivity at high or low dose rate of four cell lines derived from human thyroid tumors.

PURPOSE: This study attempted to establish cell lines derived from human differentiated thyroid tumors, and to characterize and evaluate the radiation dose-rate effect. METHODS AND MATERIALS: Two cell lines (K1 and K2) were derived from papillary carcinomas, one (K7) from a follicular less-differentiated carcinoma and one (A14) from a follicular adenoma. Cell-survival curves after irradiation were established by the in vitro colony method. Radiation doses were delivered either at a high (45.9 Gy/h) or low dose rate (0.6 Gy/h) by a 60Co source. The data were analyzed according to the linear quadratic and multitarget model of radiation action. RESULTS: Doubling times were around 24 h. All cell lines were positive for intracellular thyroglobulin. Cyclic adenosine monophosphate (cAMP) response to thyrotropin (TSH) was significant for the cell lines derived from the follicular adenoma and follicular carcinoma. The two cell lines derived from papillary carcinomas were tumorigenic after inoculation into nude mice. After high-dose-rate irradiation, the surviving fraction at 2 Gy (SF2) was not significantly different for the three malignant cell lines K1, K2, and K7, and ranged from 0.39 to 0.42. For the adenoma cell line A14, we found a higher radiosensitivity with a lower SF2 value and a higher alpha parameter. After low-dose-rate irradiation, only one cell line (K2) showed a significant low-dose-rate sparing with a dose reduction factor of 1.35. CONCLUSION: The major result of our study is the weak effect of the dose rate on the survival of thyroid cell lines.

Adenocarcinoma, Follicular↗
PubMed1997

Clinical immunogenicity and tolerance studies of liquid vaccines delivered by jet-injector and a new single-use cartridge (Imule): comparison with standard syringe injection. Imule Investigators Group.

A new needleless jet-injector, Mini-Imojet, was developed that administers liquid vaccines from a single-use, pre-filled cartridge named Imule, which avoids the risk of cross-contamination. We conducted clinical trials in several settings in France and West Africa to compare the immunogenicity and tolerance of five vaccines (influenza vaccine, Vi capsular polysaccharide typhoid vaccine, tetanus toxoid vaccine, diphtheria-tetanus-whole cell pertussis vaccine, and inactivated hepatitis A vaccine) administered with the Imule system vs standard syringe technique. In each vaccine study, all subjects of either group were tested for serum antibody titres to calculate the geometrical mean titres and seroconversion rates after complete vaccination. Immediate local-reactions were noted after each injection, and local and general reactions were evaluated during a predetermined period of follow-up. When delivered by the Imule technique, all the administered vaccines were of equivalent or superior immunogenicity, compared to the syringe technique. The tolerance to vaccines injected by the Imule system was acceptable in all studies. The most frequently observed reactions were mild (e.g. minor bleeding, superficial papules, erythema and induration) and could be considered to be inherent to the injection technique. The technical and safety advantages of the Mini-Imojet/Imule system, compared to sterilizable, standard disposable or autodestruct syringes and to classical multi-dose vial jet-injectors, reinforces the interest of this new injection technique for collective immunizations.

Adolescent↗
PubMed1997

Oncogenic rearrangements of the ret proto-oncogene in thyroid tumors induced after exposure to ionizing radiation.

A high frequency (approximately 60%) of ret rearrangements in Chernobyl papillary thyroid carcinomas (PTC) has been reported recently. The data suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In our study, we have analyzed for the presence of RET/PTC oncogenes using the RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors. Our results indicate that: 1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; 2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1; and 3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%: 3/20). Our data confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

Adenoma↗
PubMed1997

Leukaemias and cancers following iodine-131 administration for thyroid cancer.

We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received (131)I. The average (131)I cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80 Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of (131)I administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0.02). These findings were probably caused by the accumulation of (131)I in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of (131)I administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).

Adolescent↗
PubMed1997

High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation.

A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies (Fugazzola et al., 1995; Ito et al., 1994; Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to confirm the postulated link between irradiation and the role of the ret proto-oncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiation-associated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%:3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

Adenoma↗
PubMed1997

131I therapy for elevated thyroglobulin levels.

Assuming that the fractional uptake is the same, both after the administration of a diagnostic and a therapeutic activity, 131I uptake too low to be detected with 2-5 mCi may become detectable after the administration of 100 mCi. This should be performed routinely in patients with thyroglobulin levels above approximately 5 ng/mL during L-Thyroxine (LT4) treatment or 10 ng/mL off LT4 treatment for three main reasons: 1) in 80% of these patients, a post-therapy 131i total body scan showed foci of uptake in the neck or at distant sites, whereas in the other patients, metastases emerged clinically some years later; 2) 131I is not the only treatment modality, and, for instance, lymph node metastases may warrant further surgery; and 3) from a dosimetric point of view, the relevant parameter is the concentration of 131I, i.e., the ratio between the uptake and the mass of functioning tissue: a low uptake in a small metastasis may result in a higher 131I concentration than a higher uptake in a much larger metastasis.

Biomarkers, Tumor↗
PubMed1997

Digital superimposition of CT and positive SPECT tumor images. Phantom study and clinical applications.

Digital superimposition of SPECT and CT data was evaluated in a phantom and then applied to patient data. Seven patients were studied. Six patients had pheochromocytomas as evidenced by I-131 or I-123 MIBG localization and one had ovarian cancer imaged by In-111 OC125 MoAb. Anatomic or skin landmarks identified the level of each SPECT transaxial slice. Both SPECT and CT image data sets were transferred to a minicomputer connected to an image processor. Afterwards, a scaled, rotated and translated realignment was performed. Data for each modality were coded in different primary colors and then superimposed. Superimposition of phantom data was checked for the absence of distortion of pinpoint and large structures. For suspected tumor sites, superimposition of the patients' slices were allowed to check for matching SPECT and CT abnormalities to localize a SPECT abnormality without a corresponding CT lesion or to distinguish SPECT abnormalities from those seen on CT. In one case, the technique failed because of very low I-131 MIBG-tumor uptake. The superimposition decreases false positives in SPECT and both false negatives or false positives in CT.

Adolescent↗
PubMed1997

Targeted oncogenesis in the thyroid of transgenic mice.

We have developed mouse models for tumors affecting the epithelial cellular compartment of the thyroid which has been targeted using the bovine thyroglobulin (bTg) promoter. Transgenic mice expressing the human activated c-Ha-Ras gene developed papillary thyroid carcinomas demonstrating the oncogenic potential of activated Ras gene in the thyroid gland. Transgenic mice express the mutant form of the alpha subunit of the adenylate cyclase-coupled G alpha s with mutations at codon 201 (R201H). The expression of this mutant transgene is not by itself sufficient to produce benign tumors or even hyperplasia, but the transgenic mice have inherited a predisposition to develop thyroid adenomas.

Adenylyl Cyclases↗
PubMed1997

Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France.

After the Chernobyl nuclear accident (April 26, 1986), childhood thyroid carcinoma had a great increase in Belarus and Ukraine, as a consequence of the exposure to iodine radioactive fallout. The epidemiological and clinical features of the disease were studied in 472 patients less than 21 yr old at diagnosis, with differentiated thyroid carcinoma, representing 97.7% of all thyroid carcinomas diagnosed in Belarus between May, 1986, and December, 1995. The results were compared with those of 369 subjects of the same age group, with naturally occurring thyroid carcinoma, observed in Italy and France. Between 1986 and 1989, the number of thyroid cancer cases per year ranged from 3-8 and increased to 31 in 1990, to 66 in 1991, to 72 in 1992, to 93 in 1993, to 96 in 1994, and to 90 in 1995. The age at diagnosis was 14 yr or less in 78.8% (children group) and more than 14, but less than 21, yr in the remaining subjects (adolescents group). Mean (+/- SD) age at the time of the accident was 4.4 +/- 3.4 yr (3.2 +/- 2.3 in children and 8.9 +/- 2.7 in adolescents), the majority of the patients (62.9%) being 5 yr old or less. The time interval between the accident and the diagnosis (latency period) decreased progressively from 7.5 +/- 1.6 yr in children 0-2 yr old at the time of the accident to 6.0 +/- 1.6 yr in those 9-11 yr old. Since 1993, the yearly distribution of new cases showed a decrease in the subjects 9 yr old or more at the time of the accident but not in those 5 yr old or less. This could not be accounted for by a shift of exposed subjects to an age group at diagnosis not included in this study, because only subjects less than 12 yr of age at the time of the accident were considered in this analysis. Mean age at diagnosis in Belarus patients was 11.3 +/- 3.1 yr (10.1 +/- 2.3 in children and 15.7 +/- 1.4 in adolescents), whereas, among patients with naturally-occurring thyroid carcinomas from Italy and France, the majority of cases were diagnosed after 14 yr of age (mean age at diagnosis: 14.6 +/- 4.2 yr). The female-to-male ratio was significantly higher in Italy and France (2.5/1), compared with the ratio of patients from Belarus (1.6/1). Most of the tumors were papillary in both series, but a relatively high proportion of follicular carcinomas (P = 0.0001) was found in Italy/France (15.2%), as opposed to 5.3% in Belarus. Extrathyroidal extension and lymph node metastases were more frequent in Belarus (49.1%, P = 0.0001; and 64.6%, P = 0.002, respectively) with respect to Italy/France (24.9% and 53.9%, respectively). Thyroid lymphocytic infiltration and circulating antithyroperoxidase antibody were more frequent in Belarus patients. Our analysis of Belarus thyroid cancer patients less than 21 yr old showed that the post-Chernobyl increase in thyroid carcinomas involved both children and, to a much lesser extent, adolescents. Subjects 5 yr old or less at the time of the accident accounted for the majority of the patients. No evidence of a decrease in the number of new cases was observed in this age group, as opposed to older subjects. These data support the concept that subjects who were younger at the time of radiation exposure had, and continue to have, a greater risk of developing thyroid carcinoma and strongly suggest that this age group should be carefully monitored in the future. When compared with naturally occurring thyroid carcinoma of the same age group observed in Italy and France, the post-Chernobyl Belarus thyroid carcinomas affected younger subjects, were less influenced by gender, were virtually always papillary, had a greater aggressiveness at presentation, and were more frequently associated with thyroid autoimmunity.

Adenocarcinoma, Follicular↗