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Biomedical subjects

M Schlumberger

Publications and source records attributed to M Schlumberger.

At least 55 records · Page 3Linked to original sources

Sodium/iodide symporter (NIS) and pendrin are expressed differently in hot and cold nodules of thyroid toxic multinodular goiter.

OBJECTIVE: The expression of two iodide transporters, the sodium/iodide symporter (NIS) and pendrin, was analyzed in thyroid tissues of patients with toxic multinodular goiter (TMNG) and non-toxic multinodular goiter (MNG). METHODS: The levels of NIS and pendrin proteins were analyzed in total protein extracts from nodular and non-nodular tissues by Western blot. RESULTS: In tissue samples from TMNG, we found an increased expression of NIS (2.5-fold) in the hot nodules, and similar levels between cold nodules and non-nodular tissues. In contrast, the levels of pendrin were slightly increased in both hot and cold nodules from TMNG, and decreased (about twofold) in cold nodules from MNG. We also noticed that there was no relationship between NIS and pendrin expression. CONCLUSIONS: Our data demonstrate that hot nodules from TMNG express a higher number of iodide transporters (mainly NIS), whereas cold nodules from TMNG, but not from MNG, show levels of the two proteins comparable with normal tissue, suggesting a role in vivo of TSH in maintaining the expression of NIS and pendrin protein in normal thyroid tissue. Finally, different mechanisms are involved in the regulation of NIS and pendrin expression.

Actins↗

[Pelvic and spinal giant metastases from thyroid carcinomas: report of 8 cases].

PURPOSE OF THE STUDY: We report 8 cases of giant metastases in 7 patients with a pelvis or spinal localization in patients with differentiated carcinoma of the thyroid gland. MATERIAL AND METHOD: Surgery was indicated for major functional disorders: pathological fracture, neurological complications. All patients were treated by embolization, tumor resection and reconstruction. All patients were given suppressive doses of thyroid hormones and 6 received complementary radiotherapy. Radioactive iodine, 100 mCu was also given in 5 cases. Outcome was analyzed retrospectively. RESULTS: Two postoperative infections were successfully treated by surgical cleaning in one operation. There were no surgery-related neurological complications. One patient died in the immediate postoperative period due to the cancer. Mean follow-up in the other patients was 4 years. Functional outcome was excellent without local recurrence or mechanical complications. DISCUSSION: These results suggest that surgical resection of giant bone metastases from thyroid carcinomas can provide favorable functional outcome similar to that achieved for small-sized metastases.

Adenocarcinoma, Follicular↗

Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy.

The Na+/I- symporter (NIS) present in the membranes of thyroid cells is responsible for the capacity of the thyroid to concentrate iodide. This allows treatment of thyroid cancers with 131I. We propose to enlarge this therapeutic strategy to nonthyroid tumors by using an adenoviral vector to deliver the NIS gene into the tumor cells. We constructed a recombinant adenovirus encoding the rat NIS gene under the control of the cytomegalovirus promoter (AdNIS). Infection of SiHa cells (human cervix tumor cells) with AdNIS resulted in perchlorate-sensitive 125I uptake by these cells to a level 125-225 times higher than that in noninfected cells. Similar results were obtained for other human tumor cell lines, including MCF7 and T-47D (mammary gland), DU 145 and PC-3 (prostate), A549 (lung), and HT-29 (colon), demonstrating that the AdNIS vector can function in tumor cells of various origins. In addition, AdNIS-infected tumor cells were selectively killed by exposure to 131I, as revealed by clonogenic assays. To assess the efficiency of this cancer gene therapy strategy in vivo, we injected the AdNIS vector in human tumors (SiHa or MCF7 cells) established s.c. in nude mice. Immunohistological analysis confirmed the expression of the NIS protein in the tumor. Three days after intratumoral injection, AdNIS-treated tumors could specifically accumulate 125I or 123I, as revealed by kinetics and imaging experiments. A quantitative analysis demonstrated that the uptake in AdNIS-injected tumors was 4-25 times higher than that in nontreated tumors. On average, 11% of the total amount of injected 125I could be recovered per gram of AdNIS-treated tumor tissue. Altogether, these data indicate that AdNIS is very efficient in triggering significant iodide uptake by a tumor, outlining the potential of this novel cancer gene therapy approach for a targeted radiotherapy.

Adenoviridae↗

Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation.

Rearrangements of NTRK1 proto-oncogene were detected in 'spontaneous' papillary thyroid carcinomas with a frequency varying from 5 to 25% in different studies. These rearrangements result in the formation of chimaeric genes composed of the tyrosine kinase domain of NTRK1 fused to 5' sequences of different genes. To investigate if the NTRK1 gene plays a role in radiation-induced thyroid carcinogenesis, we looked for the presence of NTRK1-activating rearrangements in 32 human thyroid tumours (16 follicular adenomas, 14 papillary carcinomas and two lymph-node metastases of papillary thyroid carcinomas) from patients who had received external radiation, using the reverse transcription polymerase chain reaction, Southern blot and direct sequencing techniques. These data were compared with those obtained in a series of 28 'spontaneous' benign and malignant thyroid tumours, collected from patients without a history of radiation exposure and four in vitro culture cell lines derived from 'spontaneous' thyroid cancers. Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas. All the radiation-associated adenomas were negative. In the 'spontaneous' tumours, only one of the 14 papillary carcinomas and one of the four in vitro culture cell lines, derived from a papillary carcinoma, presented a NTRK1 rearrangement also with the TPM3 gene. Twenty-five of this series of radiation-associated tumours were previously studied for the ras and RET/PTC oncogenes. In conclusion, our data: (a) show that the overall frequency of NTRK1 rearrangements is similar between radiation-associated (2/31: 6%) and 'spontaneous' epithelial thyroid tumours (2/32: 6%). The frequency, if we consider exclusively the papillary carcinomas, is in both cases 12%; (b) show that the TRK oncogene plays a role in the development of a minority of radiation-associated papillary thyroid carcinomas but not in adenomas; and (c) confirm that RET/PTC rearrangements are the major genetic alteration associated with ionizing radiation-induced thyroid tumorigenesis.

Adenoma↗

Establishment and characterization of a human adrenocortical carcinoma xenograft model.

Adrenocortical carcinomas are rare malignant tumors. They have a poor prognosis, as they are often diagnosed late and are usually resistant to chemotherapy. The lack of a suitable animal model for these tumors has been a major obstacle to the evaluation of new therapeutic agents. The aim of this study was to establish and characterize xenografts of the human adrenocortical carcinoma NCI H295R cell line as a model of adrenocortical carcinoma for future therapeutic trials. This cell line was sc injected (6 x 10(6) cells) into nude mice (n = 20). Solid tumors were locally measurable after 45 days at 90% of the inoculation sites. The xenografts were similar histologically to the original adrenocortical carcinoma from which the cell line was derived. The xenografts precisely reproduced the dysregulation of the insulin-like growth factor (IGF) system [overexpression of the IGF-II and IGF-binding protein-2 (IGFBP-2) genes] typical of adrenocortical carcinoma. Similarly to adrenocortical carcinomas, human IGFBP-2 (but not IGF-II) was secreted in mouse plasma. We analyzed steroid production (cortisol, 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, delta4-androstenedione, 11-deoxycortisol, corticosterone, and testosterone). Xenografts produced all three class of steroids, with the preferential production of androgens of the delta4 pathway. The H295R xenograft model is a good model of human adrenocortical carcinoma, as it mimics dysregulation of the IGF system usually found in these tumors. It also produces IGFBP-2 and steroids that can be used as tumor markers. This model may therefore be useful for evaluating therapeutic agents.

Adrenal Cortex Neoplasms↗

Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer?

A diagnostic iodine-131 (131I) total body scan (TBS) is usually recommended 6 to 12 months after thyroid ablation for differentiated thyroid carcinoma. Its usefulness was evaluated in 256 consecutive patients treated and followed up at the Institut Gustave Roussy for papillary (n = 200), well differentiated (n = 27), or poorly differentiated (n = 29) follicular thyroid carcinomas. All patients underwent a near-total or total thyroidectomy and 131I ablation with 3.7 GBq (100 mCi). No TBS was performed before 131I ablation. The TBS performed after the administration of 131I to destroy the thyroid remnants showed uptake (<2%) limited to the thyroid bed. A diagnostic 131I-TBS was obtained after withdrawal of T4 treatment, with either 74 MBq (2 mCi; n = 82) or 185 MBq (5 mCi; n = 174), 6 to 12 months after initial treatment, with serum thyroglobulin (Tg) determination. No interference in the Tg assay was found in these 256 patients. Uptake in the thyroid bed was not detected (total ablation) in 236 patients, was visible but too low to be measured in 19 patients, and attained 1% in only 1 patient. No uptake was found outside the thyroid bed. The serum Tg level, once thyroid hormone treatment had been withdrawn, was below 1 ng/mL in 210 patients, ranged from 1-10 ng/mL in 31 patients, and was above 10 ng/mL in 15 patients. A 131I-TBS performed with 3.7 GBq in nine patients with a Tg level above 10 ng/mL, showed foci of uptake outside the thyroid bed in three patients; lung metastases were demonstrated by a CT scan in another patient, and palpable lymph node metastases were found in one patient. In conclusion, a diagnostic 131I-TBS with 74-185 MBq performed 1 yr after thyroid ablation demonstrated no abnormal uptake; it did not correlate with results of Tg determination and only confirmed the completeness of thyroid ablation. The serum Tg level obtained after withdrawal of T4 treatment permits the selection of patients with a Tg level exceeding 10 ng/mL, for scanning with 3.7 GBq (100 mCi).

Adolescent↗

Expression of Na+/I- symporter and Pendred syndrome genes in trophoblast cells.

Placental iodide transport is critical for the fetal thyroid function, but the molecular mechanisms of this transport are not understood. The expression of two recently identified iodide transporters, namely the sodium/iodide symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS), was studied using real-time kinetic quantitative PCR and immunohistochemistry 1) in placental tissues collected at different gestational ages and 2) in primary cultures of villous cytotrophoblast cells (VCT) that differentiate and fuse over 2-3 days in vitro to form villous syncytiotrophoblast (VSCT) cells. Both NIS and PDS genes are expressed in placenta, albeit at low levels compared with those in thyroid tissue. NIS gene expression in placental samples from first trimester and term pregnancies was similar. In contrast, the expression of PDS gene was higher in term than in first trimester pregnancy samples. In vitro, NIS gene was expressed at a high level in VCT obtained from first trimester pregnancy, and its expression decreased by 3- to 4-fold during the differentiation of VCT in VSCT. Expression of NIS was lower (up to 30-fold) in VCT obtained in placental samples from third trimester than from first trimester pregnancy. In contrast, the expression of PDS gene was low in VCT and increased by 5- to 10-fold during VSCT formation; this was observed in cells isolated from placental samples of both first trimester and term pregnancies. Immunohistochemical analysis showed that NIS protein was present on the entire membrane of VCT, whereas pendrin was mainly located at the brush border membrane of VSCT, facing the mother. In conclusion, 1) NIS and PDS genes are differently expressed in the placenta during gestation; and 2) whereas pendrin is expressed at the brush border membrane of syncytiotrophoblast cells, NIS protein is mainly located in the cytotrophoblast layer.

Carrier Proteins↗

Expression of pendrin and the Pendred syndrome (PDS) gene in human thyroid tissues.

The gene recently cloned that is responsible for the Pendred syndrome (PDS), an autosomal recessive disease characterized by goiter and congenital sensorineural deafness, is mainly expressed in the thyroid gland. Its product, designated pendrin, was shown to transport chloride and iodide. To investigate whether the PDS gene is altered during thyroid tumorigenesis, PDS gene expression and pendrin expression were studied using real-time kinetic quantitative PCR and antipeptide antibodies, respectively, in normal, benign, and malignant human thyroid tissues. The results were then compared to those observed for sodium/iodide symporter (NIS) expression. In normal tissue, pendrin is localized at the apical pole of thyrocytes, and this in contrast to the basolateral location of NIS. Immunostaining for pendrin was heterogeneous both inside and among follicles. In hyperfunctioning adenomas, the PDS messenger ribonucleic acid level was in the normal range, although immunohistochemical analysis showed strong staining in the majority of follicular cells. In hypofunctioning adenomas, mean PDS gene expression was similar to that detected in normal thyroid tissues, but pendrin immunostaining was highly variable. In thyroid carcinomas, PDS gene expression was dramatically decreased, and pendrin immunostaining was low and was positive only in rare tumor cells. This expression profile was similar to that observed for the NIS gene and its protein product. In conclusion, our study demonstrates that pendrin is located at the apical membrane of thyrocytes and that PDS gene expression is decreased in thyroid carcinomas.

Adenoma↗

Clinical use of recombinant human TSH in thyroid cancer patients.

Recombinant human TSH (rhTSH) is an effective and safe alternative to thyroid hormone withdrawal during the post-surgical follow-up of papillary and follicular thyroid cancer. Its clinical efficiency for the detection of persistent and recurrent disease is similar to that of thyroid hormone withdrawal. The main purpose for its use is to avoid hypothyroidism.

Humans↗

Sodium-iodide symporter (NIS) gene expression in lymph-node metastases of papillary thyroid carcinomas.

OBJECTIVE: To investigate the molecular mechanisms underlying the influence of alteration of iodine trapping on the prognosis of metastatic papillary thyroid carcinomas, focusing on the expression of the Na+/I(-) symporter (NIS). DESIGN: We evaluated the expression of the NIS gene in a series of 11 enlarged neck lymph-node metastases of papillary thyroid carcinomas, including four patients in whom an enlarged lymph node represented the first sign of the tumoral disease. Nine lymph nodes, either reactive or metastatic for non-thyroid tumors, were also investigated. METHODS: Expression of the NIS gene was evaluated by RT-PCR in material obtained by fine-needle aspiration biopsy. RESULTS: The NIS gene was expressed in eight (73%) of 11 differentiated thyroid cancer metastatic lymph nodes examined. Five of these metastatic lymph nodes were positive at the post-treatment total-body iodine-131 scan; in the other three, the total-body scan showed no uptake in the metastatic tissues, indicating an alteration downstream to the NIS mRNA synthesis causing the loss of iodide uptake. As expected, when the NIS mRNA expression was absent, total-body (131)I scan showed no uptake in the metastatic lymph nodes. CONCLUSIONS: Our study demonstrates that NIS gene expression may be absent in metastatic differentiated thyroid carcinomas and that different mechanisms, other than loss of NIS transcription, may also be involved in the loss of iodide uptake in metastatic thyroid cells. Study of NIS gene expression in the metastatic lymph nodes, therefore, may provide useful information in the management of patients with thyroid carcinoma.

Adolescent↗

[Radiation-induced thyroid cancers].

Human epithelial thyroid radiation-induced tumorigenesis is the most frequent radiation-induced tumorigenic process in man. Results of different studies, concerning the molecular mecanism(s) of epithelial thyroid radiation-associated tumorigenesis show : 1) that there is not a significant difference in the frequency of activation of ras, gsp and trk proto-oncogenes between radiation-associated and < > thyroid tumors; 2) the relevant role played by RET/PTC ret proto-oncogene activating rearrangements, in the development of radiation-associated thyroid tumors originated after therapeutic radiation (mainly PTC 1) or the atomic accident of Chernobyl (mainly PTC 3) and 3) suggest that the patients who develop thyroid tumors after a history of irradiation, show a genomic instability consisting in a DNA repair defect.

Drosophila Proteins↗

[Neuro-endocrine tumors and von Hippel-Lindau disease. 3 cases].

BACKGROUND: Neuroendocrine tumors can occur in patients with hereditary syndromes predisposing to multiple endocrine neoplasia (MEN) and Von Hippel-Lindau disease (VHL). CASE REPORTS: We report the cases of three men with pheochromocytomas, one with an associated neuroendocrine tumor of the pancreas. In one case, diagnosis was suggested by the familial context of VHL in the patients father. In the two other cases, the bilateral character of the pheochromocytoma, and in one case the associated pancreatic neuroendocrine tumor led to the diagnosis of VHL. Systematic biological surveillance gave the diagnosis of contralateral pheochromocytoma in two cases. Search for associated tumoral lesions led to the diagnosis of hemangioblastoma of the cerebellum in two patients and pancreatic cyst in the third. No renal or retinal lesions were observed. Molecular study of the VHL gene evidenced point nonsense mutation of the gene in all three patients, involving codon 184 in two and codon 167 in the third (identical to the proband case). Systematic investigations in the families of the two other patients remains to be completed. CONCLUSION: The diagnosis of HVL disease should be suggested in case of familial pheochromocytoma and/or bilateral localizations, but also in case of neuroendocrine tumors of the pancreas associated with another cardinal lesion of the disease. Early screening and treatment of this potentially fatal disease is essential.

Adolescent↗

Comparison of the safety and immunogenicity of the lyophilized Mérieux seed and the World Health Organization working reference BCG vaccines in school-aged children in Senegal.

In order to validate two new lots of Mérieux BCG vaccine (Mérieux seed derived from strain 1072), a calibration study was performed to compare their safety and immunogenicity to a full dose of the WHO-reference BCG vaccine (Tokyo strain 172) as well as the WHO-reference vaccine given at 1/10 of its normal concentration, in an open, randomized, four-arm, multicenter study in Senegal. A total of 1041 healthy Senegalese children aged 8-10 years were screened for participation in this study, of whom 548 had a negative Mantoux test and complied with inclusion and exclusion criteria. These children were randomly allocated a single dose of one of the following vaccines: full-dose Mérieux BCG vaccine (lot E0650); full-dose Mérieux BCG vaccine (lot E0624); full-dose WHO-reference vaccine (Tokyo strain 172); or 1/10 dose WHO-reference vaccine. A follow-up examination, including a tuberculin test, was performed 10-12 weeks after BCG vaccination for 465 (85%) children: 236 Mérieux BCG vaccine (117 lot E0650; 119 lot E0624); 115 full-dose WHO; 114 1/10 dose WHO. The percentage of subjects with a positive tuberculin test after vaccination was significantly lower (P < 0.001) in the 1/10 dose group (81.5%) compared to the other three groups (> 96%). The mean induration diameter was significantly smaller in subjects who received the low-dose of WHO vaccine compared to the others, according to analyses considering all subjects vaccinated, as well as only those subjects with a positive tuberculin test after vaccination. More children in the low-dose group did not have a vaccination scar, and the mean diameter of scars was smaller in this group. The rate of tuberculin reactions, the classification of reactions (Palmer and Edwards), and the characteristics of the vaccinal lesion were similar for the Mérieux BCG vaccines and the full-dose WHO-reference vaccine. All vaccines were safe, as evidenced by the absence of adenitis or suppurative adenitis during the course of the study. Results from this trial show that the two lots of Mérieux BCG vaccine behave equally as well as the full-dose WHO-reference BCG vaccine. The WHO-reference vaccine, given at 1/10 of its normal concentration was significantly less immunogenic, according to all parameters evaluated.

BCG Vaccine↗

Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation.

BACKGROUND: Many crucial problems are associated with the diagnosis of inherited cancer susceptibility. One of the most important is related to the psychosocial consequences of the knowledge by the patients and their relatives of their own genetical status. Little data are available in the literature, mainly from studies including small numbers of selected and motivated patients. PATIENTS AND METHODS: From January till December 1997, we studied the psychometric and quality of life parameters of 77 subjects followed in two French specialized centers. These subjects had been treated for either sporadic or familial or were at risk for medullary thyroid carcinoma. All patients had previously attended genetic counselling with detection of germline Ret-mutations, were informed on their own genetic risk, had good short-term prognosis and performance status and did not receive recent cancer treatment. Each patient was invited to answer two questionnaires, the hospital anxiety and depression scale (HADS) and the subjective quality of life profile (SQLP). RESULTS: We report herein the descriptive results of this study (HADS and SQLP scores and distributions) and describe the individual clinical covariates that might explain the observed differences between subgroups of individuals. Although psychometric scores appeared similar in these subgroups, quality of life scores were lower in Ret-mutation carriers. Genetically-predisposed patients were less satisfied and expressed more expectations for favourable change in their quality of life. CONCLUSION: This finding suggests a high level of frustration and latent unsatisfaction related either to the management of the genetic information given by the clinicians and its psychosocial consequences or simply to the knowledge of the genetic risk of cancer. Further studies on the individual consequences of genetic testing, information delivery and when necessary psychotherapeutic interventions, are needed to insure the quality of presymptomatic genetic testing in this field of oncology.

Adult↗

Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin.

The purpose of this study was to evaluate by a retrospective analysis of 53 patients the efficacy of chemotherapy combining etoposide and cisplatin in the treatment of neuroendocrine tumours. The regimen was a combination of etoposide 100 mg m(-2) day(-1) for 3 days and cisplatin 100 mg m(-2) on day 1, given by 2-h intravenous infusion, administered every 21 days. Twelve patients had a well-differentiated and 41 a poorly differentiated neuroendocrine tumour. Toxicity of treatment was assessed in 50 patients and efficacy in 52 patients. Among the 11 patients with a well-differentiated tumour evaluable for tumoural response, only one (9.4%) had a partial response for 8.5 months. Forty-one patients with a poorly differentiated tumour showed an objective response rate of 41.5% (four complete and 13 partial responses); the median duration of response was 9.2 months, the median overall survival 15 months and the median progression-free survival 8.9 months. Haematological grade 3-4 toxicity was observed in 60% of the cases with one treatment-related death, digestive grade 3-4 toxicity in 40% and grade 3 alopecia was constant. No severe renal, hearing and neurological toxicities were observed (grade 1 in 6%, 14%, 72% respectively and no grade >1). We confirm that poorly differentiated neuroendocrine tumours are chemosensitive to the etoposide plus cisplatin combination. However, the prognosis remains poor with a 2-year survival lower than 20% confirming that new therapeutic strategies have to be developed.

Adult↗

Screening for multiple endocrine neoplasia type 1 and hormonal production in apparently sporadic neuroendocrine tumors.

Screening was performed in 130 consecutive patients with apparently sporadic neuroendocrine tumors (NET) to assess the prevalence of multiple endocrine neoplasia type 1 (MEN1) and hormonal production. Screening for MEN1 included measurement of serum calcium and PTH [PTH-(1-84)], gastrin, PRL, and insulin-like growth factor type I (IGF-I) levels. MEN1 genetic testing was performed in patients with two components of the MEN1 syndrome. Screening for hormonal production included measurement of serum neuron-specific enolase (NSE), calcitonin (CT), glycoprotein alpha-subunit (GP alpha), hCG beta-subunit (free hCG beta), and somatostatin levels. Twenty-four-hour urinary free cortisol (UFC) and 5-hydroxyindolacetic acid (5-HIAA) determinations were also performed. Four patients had hyperparathyroidism, none of whom had pituitary or familial disease. Hyperprolactinemia was compatible with a pituitary disease in one patient. No acromegalic feature or any increase in IGF-I was found. Hypergastrinemia, compatible with an associated pancreatic NET, was found in one patient. Genetic screening of the MEN1 gene was performed in five of the six patients with two components of the MEN1 syndrome. A nonsense mutation (Arg108stop) was identified in the tumor of one patient. Elevated NSE, 5-HIAA, CT, GP alpha, free hCG beta, SMS, and nonsuppressible UFC were found in 47%, 46%, 14%, 19%, 12%, 3%, and 6% of NET patients, respectively. Production of CT, GP alpha, and free hCG beta was highly related to the primary site: all but two of these secretions originated in foregut NET. 5-HIAA secretion was found in 27% of foregut-derived and 85% of midgut-derived NET. In conclusion, MEN1 is a rare event in patients presenting with apparently sporadic NET. It occurred mainly in foregut NET and should be screened for by serum calcium and PTH-(1-84) measurements. Routine hormonal measurements should depend on the primary site. NSE, 5-HIAA, CT, and alphaGP should be routinely measured in foregut-derived NET; only serum NSE and 5-HIAA measurements are recommended in midgut-derived NET.

Adult↗