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M Schlumberger

Publications and source records attributed to M Schlumberger.

At least 37 records · Page 2Linked to original sources
PubMed2002

Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma.

BACKGROUND: Complete responses are rare after medical treatment of adrenocortical tumors. We performed a single center prospective study of the antitumor effect of irinotecan (CPT-11) in patients with metastatic adrenocortical cancer. PATIENTS AND METHODS: Since 1999, all patients with advanced progressive adrenocortical carcinoma, referred to the Institut Gustave-Roussy, have been enrolled prospectively in this study. CPT-11 (250 mg/m(2)) was administered intravenously on day 1 in a 2-h infusion, every 14 days. World Health Organization (WHO) criteria were used to evaluate tumor response and toxicity. RESULTS: During treatment, no dose or schedule modifications were made. A median of three courses were given (range 1-8), and all but two patients received at least three complete chemotherapy courses. No objective or complete responses were observed. The best response achieved was stabilization in three patients, lasting from 1.5 to 4 months. Significant toxicity occurred in two patients. CONCLUSIONS: Our results do not support a major role of CPT-11 in adrenocortical carcinoma.

Adrenal Cortex Neoplasms↗
PubMed2001

Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with adrenocortical carcinoma.

BACKGROUND: It has been suggested recently that 1,1-dichlorodiphenildichloroethane (o,p'DDD) elicits a dose effect relation in the treatment of patients with adrenocortical carcinoma (ACC). The authors performed a single-center, prospective study with two major objectives: 1) to confirm the interest of plasma o,p'DDD level measurement as a prognostic factor of response to o,p'DDD therapy; and 2) to look for parameters associated with a therapeutic plasma o,p'DDD level, especially the daily o,p'DDD dose. METHODS: Since 1995, patients with ACC who were referred to the Gustave-Roussy Institute have been enrolled prospectively in the study. Therapy with o,p'DDD was given as first-line therapy in 13 patients with metastatic disease or as adjuvant therapy in 11 patients. Oral o,p'DDD was given in three separate doses up to at least 6-12 g per day together with substitutive adrenal therapy. Plasma o,p'DDD levels were measured using high-performance liquid chromatography every 2 months. The o,p'DDD therapy was monitored to achieve plasma o,p'DDD levels within 14-20 mg/L. World Health Organization criteria were used to evaluate tumor response and toxicity. RESULTS: Twenty-four patients with ACC were studied, and a plasma o,p'DDD level > 14 mg/L was achieved in 14 patients (58%). An objective tumor response was observed in four patients with metastatic lesions (31%): One was response was complete, and three were objective hormonal responses. These tumor responses were observed among the six patients who achieved therapeutic plasma o,p'DDD levels. In contrast, no response was observed among the seven patients with plasma o,p'DDD levels that remained consistently low. Eight of 11 patients who received o,p'DDD as adjuvant therapy had disease recurrence, although the plasma o,p'DDD level was > 14 mg/L in 6 patients. Grade 3 or 4 neurologic toxicity was observed in three patients (12%), all with an o,p'DDD level > 20 mg/L. The daily o,p'DDD dose was the only parameter associated with the highest plasma o,p'DDD trough levels: It explained 35% of the variability in the plasma o,p'DDD level. A median interval of 3.7 months was found necessary to achieve the highest o,p'DDD trough levels. CONCLUSIONS: The results confirm the prognostic impact of the plasma o,p'DDD level in patients with metastatic ACC and its interest in avoiding toxicity.

Adrenal Cortex Neoplasms↗
PubMed2001

Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors.

Genetic alterations, such as loss of heterozygosity (LOH) at the 17p13 and 11p15 loci and overexpression of the insulin-like growth factor (IGF)-II gene, are associated with the malignant phenotype in sporadic adrenocortical tumors. A high risk of recurrence after surgery for adrenocortical tumors is predicted in cases with regional invasion or distant metastases. However, patients with localized tumors also have a high risk of recurrence. Reliable prognostic markers are required to identify subjects at high risk of recurrence. The aim of this study was to assess the prognostic value of three molecular markers (17p13 LOH, 11p15 LOH, and overexpression of the IGF-II gene) by assessing disease-free survival in a large series of adult patients with sporadic adrenocortical tumors. Adult patients (114) were prospectively followed up from diagnosis of the disease to June 1999 or to death. Malignancy was initially diagnosed in 18 patients (McFarlane stage III: n = 1 and stage IV: n = 17). The remaining 96 patients with localized adrenal disease at diagnosis (stage I: n = 60 and stage II: n = 36) were at risk of recurrence. Histological grade was assessed according to Weiss criteria, and tumors were classified into two groups (Weiss score or=4). Tumor samples were analyzed for LOH at the 17p13 and 11p15 loci and for IGF-II gene mRNA content. 17p13 LOH was a strong predictor of shorter disease-free survival in univariate analysis (P = 0.001; relative risk, 27), as were histological grade (Weiss score >or=4; P = 0.00001; relative risk, 15), 11p15 LOH (P = 0.004; relative risk, 9), tumor size (size >5 cm; P = 0.006; relative risk, 18), and overexpression of the IGF-II gene (P = 0.01; relative risk, 5). In a Cox proportional hazards regression model, histological grade (P = 0.04; relative risk, 4.2) and 17p13 LOH (P = 0.009; relative risk, 21.5) were independently associated with recurrence. Molecular markers, particularly 17p13 LOH, are predictive of long-term outcome in patients with sporadic adrenocortical tumors. In patients who have undergone curative surgery, routine assessment of these tumor markers is a useful complement to histological scoring for predicting recurrence and guiding decisions for subsequent follow-up and management.

Adolescent↗
PubMed2001

Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21.

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Carcinoma, Papillary↗
PubMed2001

A C3 convertase assay for nephritic factor functional activity.

C3 nephritic factor (C3NeF) is an autoantibody against the C3 convertase which stabilizes this otherwise inherently labile neoenzyme and induces a continuous activation of the alternative pathway with C3 depletion. NeF is found in patients with membranoproliferative glomerulonephritis and/or partial lipodystrpohy. NeF activity is usually detected in plasma by hemolytic tests. In order to obtain reproducible data for the functional activity of purified C3NeF IgG a solid phase assay was developed. C3 convertase was generated on immobilized C3b by incubation with factors B and D in the presence of Ni(2+). Convertase sites were left to decay in the presence of normal IgG or NeF IgG. Residual convertase activity was measured by adding 125I-C3 and capturing nascent 125I-C3b on the plate surface via covalently coupled NH2-Glu-Tyr dipeptide. In the presence of factor H during C3 convertase decay, a dose dependent stabilizing activity was shown for NeF IgG including NeF IgG purified from urine. A second format of the assay was developed in which C3 convertase was assembled on C3b(2)-IgG complexes in the presence of Mg(2+). Since these complexes are more efficient as convertase precursors the signal was five-fold higher than with C3b. Convertase decay, on the other hand, was not influenced by the nature of the precursor and in both systems the stabilizing activity of NeF IgG was similar.

Adult↗
PubMed2001

Chromogranin A and the alpha-subunit of glycoprotein hormones in medullary thyroid carcinoma and phaeochromocytoma.

Using specific immunoradiometric assays, we evaluated the clinical usefulness of chromogranin A and the alpha-subunit of glycoprotein hormones in neuroendocrine tumours of neuroectodermic origin. The serum alpha-subunit of glycoprotein hormones was only slightly increased in 2 out of 44 medullary thyroid carcinoma or phaeochromocytoma patients with increased calcitonin or 24-hour urinary metanephrine levels. Serum chromogranin A was increased in 12 of 45 (27%) medullary thyroid carcinoma patients with an elevated calcitonin level and in 4 of 16 medullary thyroid carcinoma patients (25%) with an undetectable calcitonin level, in 5 of 7 phaeochromocytoma patients with increased urinary catecholamine and metabolite excretion, and in 2 of 3 patients with a non-functioning phaeochromocytoma. During follow-up, the course of chromogranin A was found to parallel that of tumour burden and/or 24-hour urinary metanephrine in 5 phaeochromocytoma patients. We conclude that chromogranin A measurement is not recommended for the diagnosis of medullary thyroid carcinoma patients. It may be useful in patients with functioning and non-functioning phaeochromocytomas as a follow-up marker. In neuroendocrine tumour patients with elevated calcitonin secretion, the serum alpha-subunit of glycoprotein hormone measurement may help differentiate medullary thyroid carcinoma or phaeochromocytoma patients from other endodermal-derived neuroendocrine tumour patients in whom it is frequently elevated.

Adolescent↗
PubMed2001

Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours.

A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly (an increase of 50% or more in the lesion surface area in 3 months) and in Group 2, tumours were progressing more slowly (an increase of less than 50% in the lesion surface area in 3 months but greater than 25% in 6 months). Treatment consisted of subcutaneous (s.c.) octreotide, 100 microg thrice daily for 17 patients, intramuscular lanreotide, 30 mg/every 14 days for 11 patients and for 7 patients both somatostatin analogues were used successively during the follow-up. Primary tumour sites were the small intestine (n=12), pancreas (n=13), lungs (n=5), and other sites (n=5). 18 patients had the carcinoid syndrome with flushing and/or diarrhoea. The median duration of treatment was 7 months. Treatment was discontinued in 3 patients due to side-effects. One patient (3%) achieved a partial response and the disease was stabilised in 20 patients (57%) for a median duration of 11 months (6-48 months). Stabilisation of patients in Group 1 was significantly less frequent at 6 months than that of patients in Group 2 (4/12 and 13/17 respectively, P<0.02). Somatostatin analogue treatment resulted in one partial response (3%) and 20 cases of stabilisation (57%) in 35 patients with progressive NET. A slow tumour growth rate before treatment is predictive of a good response to somatostatin analogues which could be considered an option for first-line treatment.

Adult↗
PubMed2001

Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: trends for future evaluations.

BACKGROUND: As shown in a previous study, the knowledge of the genetic risk in individuals belonging to families at risk of medullary-thyroid carcinoma (MTC) could be associated with impaired quality of life (QoL). PATIENTS AND METHODS: In the present study, we compared the QoL scores obtained in the same period with the subjective quality of life profile (SQLP): in 82 individuals at risk of MTC who had been tested for Ret-mutations; in 200 women at risk of familial breast/ovarian cancer syndrome (BOC); and in a control population of 3,501 healthy volunteers. RESULTS: Significant differences were observed in favour of healthy volunteers as well as individuals at risk of MTC, over women at risk of BOC (mean scores: 0.89, 0.85, and 0.64, respectively, P < or = 0.001), but QoL scores were not statistically different between individuals at risk of MTC and the control population (P = 0.2). However, they were significantly inferior in the subgroup of germline Ret-mutation carriers, as compared to the control population (mean scores: 0.73 and 0.89, P = 0.04). In the latter, the relationships with the children and the family were the most important facets of their QoL. CONCLUSION: Our results confirm the potentially negative impact of the knowledge of the genetic risk of cancer and its consequences in terms of morbidity and follow-up, on the QoL in people followed at oncogenetic visits.

Adolescent↗
PubMed2001

Sodium iodide symporter and pendrin expression in human thyroid tissues.

Thyroid cells synthesize thyroid hormones through a multistep process during which iodide is transported through the basolateral and the apical membranes of thyrocytes. Two genes that participate in these transports and the corresponding proteins, namely sodium iodide symporter (NIS) and pendrin, the product of the Pendred syndrome gene, have recently been characterized. We studied NIS and pendrin expression at the mRNA and protein levels by a quantitative reverse transcription-polymerase chain reaction (RT-PCR) method and by single and double immunostaining in normal and pathological human thyroid tissues. In normal tissue, NIS and pendrin were detected in about 20% and 40%-60% of thyrocytes, respectively. The number of NIS- and pendrin-positive cells was much higher in hyperfunctioning tissue from Graves' disease or toxic adenoma. In hypofunctioning adenomas and carcinomas, the number of NIS- and pendrin-positive cells was low or nonexistent. Three types of follicular cells were observed in positive tissues: NIS-negative/pendrin-negative cells, NIS-positive/pendrin-positive cells, and NIS-negative/pendrin-positive cells. The first two types of cells appear to be resting and active cells, respectively, but the functional status of NIS-negative/pendrin-positive thyrocytes remains to be determined.

Adenocarcinoma, Follicular↗
PubMed2001

Absence of sodium/iodide symporter gene mutations in differentiated human thyroid carcinomas.

Decrease or loss of the sodium iodide (Na+/I-) symporter (NIS) activity influences the suitability of using radioiodine to detect and treat metastatic thyroid tissues. In previous studies, the presence of the NIS transcript, albeit at lower expression levels, has been shown in most thyroid differentiated carcinomas. In this study we searched for point mutations or other genetic alterations that may be responsible for an altered function of the NIS protein in tumors that still express NIS transcripts. Tumoral cDNAs derived from seven differentiated thyroid carcinomas (DTC), five papillary and two follicular, were analyzed by direct sequencing after polymerase chain reaction (PCR) amplification of the structural gene of the Na+/I- symporter. Neither mutations nor other genetic abnormalities were detected in any tumor sample examined. The data indicate that mutations or other genetic alterations of the NIS structural gene are not a major cause of the reduced iodide uptake in DTC.

Adenocarcinoma, Follicular↗
PubMed2001

Expression of nicotinamide adenine dinucleotide phosphate oxidase flavoprotein DUOX genes and proteins in human papillary and follicular thyroid carcinomas.

Duox2, and probably Duox1 are glycoflavoproteins involved in the thyroid H2O2 generator functionally associated to thyroperoxidase (TPO). We investigated both DUOX1 and DUOX2 gene expressions using quantitative reverse transcription-polymerase chain reaction (RT-PCR) in 47 thyroid carcinomas, including 10 paired normal/tumoral tissues. In carcinomas, variations of DUOX1 and DUOX2 mRNA levels were parallel, indicating that control mechanisms of both gene expressions operate in tumors as well as in normal thyroid tissues; DUOX1 expression was in the normal range in 20, was decreased up to 50-fold in 8, and increased up to 7-fold in 19 samples. DUOX2 expression was in the normal range in 15, was decreased up to 200-fold in 10, and increased up to 5-fold in 22 samples. In the 10 paired samples, variations of DUOX and TPO gene expressions were not correlated. We analyzed Duoxl/2 protein expression in 86 tumor samples using an antipeptide antiserum reacting with both Duox proteins. In normal tissue, Duox proteins are localized at the apical pole of thyrocytes, with 40% to 60% of thyrocytes being stained. In the 86 cancer tissues, immunostaining was absent in 19 samples, was low in 32, and normal or even slightly increased in the other 35 samples. The expression of Duox proteins was related to tumor differentiation, being more frequently found in neoplastic tissues that were able to pick up radioiodine, and in those with a detectable expression of sodium iodide symporter (NIS), pendrin and TPO.

Adolescent↗
PubMed2001

Impact of chromogranin A measurement in the work-up of neuroendocrine tumors.

Since the development of the first immunoassay for circulating chromogranin A in 1984, a lot of studies have evaluated its clinical impact in neuroendocrine tumors. Initially studied in pheochromocytoma patients, the clinical impact of chromogranin A has rapidly extended to most neuroendocrine tumours, sometimes in combination with other eutopic or ectopic secretions. In our experience, CgA demonstrates a variable sensitivity between NET primary and a high specificity. Our results suggest that CgA should be routinely screened in foregut-derived NET and abandoned in the routine screening of medullary thyroid carcinoma. In addition, in phaeochromocytoma and ileum-NET patients, CgA demonstrates a comparable sensitivity with urinary reference markers and its impact on the follow-up will form a key point when recommending routine screening. Both tumor burden and secretory activity should be taken into account when interpreting CgA results.

Biomarkers, Tumor↗
PubMed2001

Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase (ThoX, LNOX, Duox) genes and proteins in human thyroid tissues.

The large homolog of NADPH oxidase flavoprotein LNOX2, and probably LNOX1, are flavoproteins involved in the thyroid H(2)O(2) generator. Western blot analysis of membrane proteins from normal human thyroid, using antipeptide antibodies, indicated that LNOX1,2 are 164-kDa glycoproteins and that N-glycosylated motifs account for at least 10-20 kDa of their total apparent molecular mass. Northern blot analysis of 23 different human tissues demonstrated that LNOX2 messenger RNA (mRNA) is strongly expressed only in the thyroid gland, although blast analysis of expressed sequence tags databases indicated that LNOX genes are also expressed in some nonthyroid cells. We investigated LNOX1,2 gene and protein expressions in normal and pathological human thyroid tissues using real-time kinetic quantitative PCR and antipeptide antibodies, respectively. In normal tissue, LNOX1,2 are localized at the apical pole of thyrocytes. Immunostaining for LNOX1,2 was heterogeneous, inside a given follicle, with 40-60% of positive follicular cells. Among normal and pathological tissues, variations of LNOX1 and LNOX2 mRNA levels were parallel, suggesting a similar regulation of both gene expressions. Whereas LNOX mRNAs seemed slightly affected in benign disease, the expression of protein was highly variable. In multinodular goiters, 40-60% of cells were stained. In hypofunctioning adenomas, LNOX immunostaining was highly variable among follicles, whereas sodium/iodide (Na+/I-) symporter immunostaining was decreased. In hyperfunctioning thyroid tissues, only few cells (0-10%) were weakly stained, whereas sodium/iodide symporter staining was found in the majority of follicular cells. In conclusion, LNOX proteins are new apical glycoproteins with a regulation of expression that differs from other thyroid markers.

Adenoma↗
PubMed2001

Evaluation of plasma insulin-like growth factor binding protein-2 as a marker for adrenocortical tumors.

OBJECTIVE: Recent studies have pointed to the role of the IGF system in the pathogenesis of adrenocortical tumors, and it was shown recently that malignant adrenocortical tumors exhibit a high insulin-like growth factor binding protein (IGFBP)-2 content. Circulating markers specific for adrenocortical carcinoma are needed and the aim of this study was to evaluate plasma IGFBP-2 as a marker for these malignant tumors. METHODS: Plasma IGFBP-2 was determined in 51 patients referred to our institutions for adrenocortical tumors. Fifteen patients were in complete remission (group 1), eight patients had preoperative localized tumors (group 2) and 28 patients had metastatic tumors (group 3). Thirty-six healthy volunteers constituted a control group. RESULTS: There was no significant difference in plasma IGFBP-2 concentration between healthy controls and patients with complete remission or localized tumors. In contrast, patients with metastatic disease had significantly higher IGFBP-2 plasma levels than the control group (P<0.001). IGFBP-2 levels in patients with metastatic disease were inversely correlated with survival (R2=0.308; P=0.0026). In patients with localized tumors, there was no correlation between plasma IGFBP-2 concentration and tumor size or histological features. Analysis of individual IGFBP-2 concentrations showed that five patients (17.8%) with metastatic tumors had normal IGFBP-2 levels and two patients (13.3%) in complete remission had high plasma IGFBP-2 levels. The influence of nutrition, hormone secretion and treatment on IGFBP-2 levels was examined. Nutritional status was evaluated by determining IGF-I levels and was found to be normal in 16 patients (61.5%) with high IGFBP-2 levels, suggesting that malnutrition was not responsible for the high IGFBP-2 concentrations in these patients. IGFBP-2 levels did not differ significantly according to tumor secretion or mitotane treatment. In a follow-up study, plasma IGFBP-2 concentration remained stable in patients with complete remission or stabilized disease and was a late marker of tumor progression in patients with progressive metastatic disease. CONCLUSIONS: These results indicate that plasma IGFBP-2 is elevated in patients with malignant adrenocortical tumors and that the major factor affecting IGFBP-2 levels in these patients is tumor stage. However, plasma IGFBP-2 was less sensitive than expected for a tumor marker, which may limit its value in the diagnosis and follow-up of adrenocortical carcinoma.

Adolescent↗
PubMed2001

Na(+)/I(-) symporter and Pendred syndrome gene and protein expressions in human extra-thyroidal tissues.

OBJECTIVE: 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 in a series of various extra-thyroidal human tissues, and especially in those known to concentrate iodide. METHODS: To this end, we used real-time kinetic quantitative PCR to detect NIS and PDS transcripts and immunohistochemistry for the analysis of their protein products. RESULTS: NIS gene and protein expression was detected in most tissues known to concentrate iodine, and particularly in salivary glands and stomach. In contrast, PDS gene expression was restricted to a few tissues, such as kidney and Sertoli cells. Interestingly, in kidney, pendrin immunostaining was detected at the apical pole of epithelial cells of the thick ascending limb of the Henle's loop and of the distal convoluted tubule. CONCLUSION: This study provides new insights on the localization and expression of two genes involved in iodide transport and emphasizes the interest of combining real-time quantitative PCR and immunohistochemistry for the comparison of gene and protein expression in tissues.

Biological Transport↗
PubMed2001

Expression pattern of the pendrin and sodium/iodide symporter genes in human thyroid carcinoma cell lines and human thyroid tumors.

OBJECTIVE: In the present study we analyzed the pattern of pendrin (PDS) and sodium/iodide symporter (NIS) gene expression in some thyroid carcinoma cell lines and a series of thyroid tumoral tissues. METHODS: Total RNA was extracted from all cell lines and from 53 tissues, and gene expression was examined by RT-PCR. Semiquantitative 'multiplex' RT-PCR was used to assess variations in PDS gene expression among various thyroid pathologies. Pendrin expression was determined in the thyroid cell lines by Western blot analysis. RESULTS: PDS mRNA was expressed in all the cells investigated; conversely, NIS mRNA was detectable only in the B-CPAP cells. Pendrin protein was expressed in B-CPAP and WRO cell lines, reduced in FRO and absent in ARO cells. PDS gene expression was not detected in 5 of 25 differentiated thyroid carcinomas (DTC) while NIS gene was not expressed in six carcinomas. A concordance expression of both PDS and NIS transcripts was found in 20 DTC. In contrast, 2 neoplastic thyroid tissues carrying undetectable PDS mRNA maintained NIS transcript, and 3 thyroid carcinomas negative for NIS mRNA retained the expression of PDS gene. A semiquantitative analysis showed that the mean PDS mRNA levels were significantly decreased in DTC tissues. CONCLUSIONS: Our data demonstrate that pendrin expression: (i) is present in the more differentiated thyroid carcinoma cell lines studied; (ii) is reduced or absent in DTC tissues; (iii) may not correlate with the NIS expression. These alterations may contribute to the loss of iodine concentration ability detected in thyroid tumors.

Adenocarcinoma, Follicular↗