Novel germline RET mutation segregating with papillary thyroid carcinomas.

The RET proto-oncogene is responsible for inherited medullary thyroid cancer syndromes. RET is also found mutated in sporadic medullary thyroid cancer (MTC) and rearranged in sporadic papillary thyroid carcinomas. Here, we describe a previously unreported germline RET mutation at codon 603 in exon 10 associated with both MTC and nonmedullary thyroid cancer (NMTC) in a kindred. RET may thus not be excluded as a potential candidate for predisposition to some forms of NMTC.

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.

Improvement of the Cockcroft-Gault equation for predicting glomerular filtration in cancer patients.

In order to determine the morphological and biological covariables which better predict the glomerular filtration rate in cancer patients, we performed the present study in a population of 123 patients (78 men, 45 women) with various tumor types; 55 of these patients had previously received cisplatin, and 12 had undergone unilateral nephrectomy. The 51Cr-EDTA plasma concentration versus time data of 80 patients were analysed according to a population pharmacokinetic approach by using the Nonlinear Mixed Effects Model (Nonmem) program. The best fit for 51Cr-EDTA clearance estimation was given by the following formula: [formula: see text] (with ABW for actual body weight in kg, age in years, sex = 0 if male and sex = 1 if female, and Scr for serum creatinine in mumol/l). Actual body weight was the most predictive morphologic parameter, and the adjustment was not improved by taking into account the ideal body weight. The GFR of patients previously treated with cisplatin was 18% lower than that of untreated patients age for age. However, this covariable was not present in the final model because it was redundant with other covariables, likely Scr. The formula was then prospectively evaluated with the data of 43 other patients. The mean (+/- SD) ratio between GFR predicted according the Nonmem formula and the observed GFR was 0.95 +/- 0.23 which did not differ significantly from unity. Conversely, the mean ratio between creatinine clearance calculated according to the Cockcroft-Gault equation and the observed GFR (0.86 +/- 0.21) differed significantly from unity. This study shows that in cancer patients the formula to calculate GFR drawn from Nonmem analysis is more accurate than the Cockcroft-Gault equation. However, an accurate determination of GFR requires specific techniques as 51Cr-EDTA clearance investigation.

[Early therapeutic management of patients genetically predisposed to medullary thyroid cancer]. / Prise en charge thérapeutique précoce des sujets prédisposés génétiquement au cancer médullaire de la thyroïde. Le Groupe d'Etude des Tumeurs à Calcitonine.

STUDY: The aim of our study was to study therapeutic results after thyroidectomy in patients positive for predictive genetic analysis and with preoperative calcitonin (CT) response to pentagastlin (Pg) < 150 pg/ml. MATERIAL AND METHODS: 36 patients (13 F, 23 M) were selected: 13 F-MTC from 8 families, 22 MEN 2A from 15 families and 1 MEN 2B. They were positive for direct RET mutation analysis. CT was assayed by immunoradiometric method before and after Pg. Pg test results before and after thyroidectomy, age at operation and histologic results were analysed. RESULTS: Mean preoperative peak CT was 82.5 +/- 34.0 pg/ml (22-133): among these 36 patients preoperative basal and peak CT were normal in 16 and 2 patients respectively. F-MTC and MEN 2A patients were different according to their preoperative peak CT levels (58.1 +/- 24.0 vs 97.6 +/- 31.3) pg/ml, p < 0.01) and age at thyroidectomy (20.4 +/- 10.5 vs 11.6 +/- 7.6 years, p < 0.01 by Mann-Whitney test). Total thyroidectomy was performed in all patients at a mean age of 14.8 +/- 9.8 years (2.5-41.7) and was associated with lymph node dissection in 30 cases. The 2 F-MTC patients with normal preoperative peak CT levels had bilateral C-cell hyperplasia (CCH) associated with uni or bilateral micro-MTC. Other patients had uni or bilateral micro MTC except 4 who had isolated CCH without carcinoma. The age of two MEN-2A and 1 MEN 2B patients with micro-MTC ranged from 2.5 to 4.7 yr. Micro MTC was present in 100% of MEN-2A cases after the age of 10 yr. There were no lymph nodes metastases. During postoperative survey, the last PG tests (n = 33) were performed 27.5 months (1-92) after thyroidectomy: peak CT values were always < 10 pg/ml. IN CONCLUSION: Thyroidectomy should be performed at a very young age in RET mutation carriers, regardless of the plasma CT values. This choice is justified in NEM-2A and NEM-2B patients but must be discussed in F-MTC families with less aggressive forms of the disease.

Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine.

BACKGROUND: Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. OBJECTIVE: To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. DESIGN AND PATIENTS: Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. MEASUREMENTS: Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. RESULTS: Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage. CONCLUSION: Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

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.

Multiple endocrine neoplasia type 2: management of patients and subjects at risk. French Study Group on Calcitonin-Secreting Tumors (GETC).

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. The emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the protooncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons.

Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) type IIa is rare, occurring in 20% to 30% of the patients. The aim of this study was to evaluate clinical findings, surgical therapy, and outcome for 56 patients affected by PHPT among 249 MEN-IIa patients collected from 84 families assembled by the Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group). This retrospective study was based on cases registered by the GETC (20 participating centers) from 1969 to 1994. Characteristics of PHPT in 56 patients (31 women, 25 men) with MEN-IIa were reviewed. All but two underwent cervicotomy. The median age at diagnosis was 37.6 years. PHPT was found concomitantly with medullary thyroid carcinoma (MTC) or pheochromocytoma in 43 patients (77%). PHPT was asymptomatic in 68% of the patients. Serum calcium levels ranged from 2.20 to 3.70 mmol/L (median 2.82 mmol/L; normal 2. 10-2.60 mmol/L). The number of parathyroid glands removed at surgery was 0 (n = 2), 1 (n = 24), 2 (n = 5), > 2 (n = 12), 4 (n = 11). Pathology (initial surgery) consisted of 24 adenomas, 4 double adenomas, and 25 hyperplasia. Cure after initial surgery was obtained in 89%, including a 22% incidence of hypoparathyroidism. There were 6 cases (11%) with persistent PHPT. With a mean follow-up of 6.4 years, five patients (9%) had recurrent PHPT. The results indicate that MEN-IIa-related PHPT is generally associated with mild, often asymptomatic hypercalcemia. Despite recurrences encountered 5 to 15 years after the first cervicotomy, resection of only macroscopically enlarged glands generally appears sufficient. Subtotal or total parathyroidectomy with autotransplantation is associated with a high rate of hypoparathyroidism.

Metastatic neuroblastoma in children older than one year: prognostic significance of the initial metaiodobenzylguanidine scan and proposal for a scoring system.

BACKGROUND: Metaiodobenzylguanidine (mIBG) is a guanethidine analog that has demonstrated a high sensitivity and specificity in detecting bone metastases in about 90% of metastatic neuroblastomas. However, the predictive value of initial mIBG scan in neuroblastoma patients older than 1 year of age regarding response to initial chemotherapy has yet to be ascertained. Therefore, a scoring system for grading the positivity of mIBG scans was devised and applied in a retrospective study in an attempt to determine whether this score had a prognostic value in neuroblastoma patients older than 1 year of age at diagnosis. METHODS: Eighty-six children, older than 1 year of age, with metastatic neuroblastomas were homogeneously treated and had a mIBG scan performed at diagnosis and following the induction regimen to assess bone metastases. Each mIBG scan was assigned a reproducible score and the predictive value of the initial mIBG score was assessed in order to evaluate response to induction regimen. RESULTS: The relative risk of failing to achieve complete remission after four courses of induction therapy was 6.9 times higher in patients who had more than four mIBG spots at diagnosis. A multivariate analysis including the established prognostic factors revealed that the initial mIBG score was the only significant factor (P < 0.001). CONCLUSIONS: The initial mIBG scan is of prognostic significance to predict response to chemotherapy for metastatic neuroblastoma in children older than 1 year of age. A prospective study comparing this initial mIBG score with other recently established prognostic factors is warranted.

[Prediction of carboplatin clearance from morphological and biological patient characteristics]. / Prédiction de la clairance du carboplatine à partir des caractéristiques morphologiques et biologiques du patient.

Hematologic toxicity of carboplatin is largely dependent on its pharmacokinetics. Its seems likely that therapeutic efficacy is also related to plasma drug exposure. Dosage adjustments based on isotopic determination of glomerular filtration rate have been proposed but their ambulatory use is not conceivable. A population pharmacokinetic study was undertaken to determine a relationship between patient characteristics and carboplatin clearance. Plasma carboplatin pharmacokinetics were determined as ultrafilterable platinum in 70 patients (23 to 84 years old) treated with different combination regimens including carboplatin at doses ranging from 184 to 950 mg (1-hr i.v. infusion) for various tumor types. Data were analysed using Nonlinear Mixed Effects Model (NONMEM). The data from 34 patients (46 cycles) were used to obtain the most predictive formula for the carboplatin clearance (ml/min): [formula: see text] The obtained formula was prospectively evaluated with the data from 36 other patients (43 cycles) and compared to other methods available to predict carboplatin clearance. Prospectively this formula predicted the clearance with a good precision (median absolute percent error of 10% range 0-30%) and minimal bias (median percent error: 2% range--25-30%). This method of prediction was as accurate as the one which requires the glomerular filtration rate to be measured by 51Cr-EDTA injection. This formula should allow to individualize very easily the carboplatin dosage in adults by multiplying the calculated carboplatin clearance by the area under the curve desired for administration.

Prediction of carboplatin clearance from standard morphological and biological patient characteristics.

BACKGROUND: Hematologic toxicity of an antineoplastic drug, carboplatin, is largely dependent on its pharmacokinetics. Its therapeutic efficacy may be related to plasma drug exposure. Dosage adjustment based on isotopic determination of glomerular filtration rate has been proposed, but its ambulatory use is not yet conceivable. The dosage adjustment based on a patient's creatinine clearance relies on accurate measurement of urine volume per unit time and can be done with ease. PURPOSE: A population pharmacokinetics study was undertaken to determine a relationship between carboplatin clearance and patient characteristics. A predictive formula was derived that was then prospectively evaluated, and its outcome was compared with that obtained by other methods available to predict carboplatin clearance. METHODS: Plasma carboplatin pharmacokinetics determined as ultrafilterable platinum in 70 patients (age range, 23-84 years) treated with different combination regimens that included carboplatin at doses ranging from 184 mg to 950 mg (1-hour intravenous infusion) for various tumor types. Data were analyzed using the nonlinear mixed effects model (NONMEM). The data from 34 patients (46 cycles) were utilized to derive the most predictive formula. The reliability of the formula was subsequently evaluated by analyzing the data obtained from 36 other patients (49 cycles). RESULTS: Carboplatin clearance (mL/min) was found to be best predicted by the following formula: 0.134.weight + [218.weight.(1-0.00457.age).(1-0.314.sex)]creatinine expressed in micromolar concentration (with weight in kg, age in years, and sex = 0 if male and sex = 1 if female). Prospectively, this formula predicted the carboplatin clearance with good precision (median absolute percent error of 10% [range, 0% to 30%]) and minimal bias (median percent error of 2% [range, -25% to 30%]). This method of prediction was as accurate as the one derived from the measurement of glomerular filtration rate following the injection of 51 chromium-EDTA. CONCLUSION: This formula for the determination of carboplatin clearance can permit individualized determination of carboplatin dosage in adults by simply multiplying the calculated carboplatin clearance by the area under the curve for the desired dosage administration.

[Concomitant association of radiotherapy and chemotherapy (CDDP 4-6 mg/m2/daily in continuous i.v. administration) in locally advanced ORL tumors]. / Association concomitante radio-chimiothérapie (CDDP 4-6 mg/m2/j en i.v. continu) dans les tumeurs ORL localement avancées.

In order to enhance radiation effects in the treatment of unresectable Head and Neck squamous cell carcinoma, we initiated a phase I-II study in February 1991 with concomitant radiation and cisplatin in the treatment of resectable Head and Neck squamous cell carcinoma. The first patient was treated in a palliative intend for a cervical recurrence (cutaneous metastatic lymphangitis) of laryngeal cancer. The seven other patients had a Stage IV M0, previously untreated, oropharyngeal carcinoma. Standard external radiation was carried out up to a total dose of 60 Gy/6 weeks (7 MeV electron beam) for the 1st patient and 72 Gy/8 weeks (Co60 beam) for the 7 other patients. Cisplatin was given during the entire radiation treatment, by continuous infusion, 5 days a week, at doses of 4 mg/m2/d for the 1st patient, 5 mg/m2/d for the two following patients and 6 mg/m2/d for the last five patients. One patient with a poor initial performance status (three in the WHO scale) stopped his treatment on the 6th week due to a grade 3 mucositis with deglutition pneumonia. He died 2 months later with progressive carcinoma. For one other patient, treatment was discontinued for 1 week after 48 Gy, due to a grade 3 mucositis. The other patients completed the planned protocol without any interruption. Mucositis (grade 3 in two cases, grade 2 in four cases), dermitis (grade 3 in two cases, grade 2 in four cases) and neutropenia (grade 2 in two cases) were the most frequent acute toxicity. Of the seven patients treated with a curative intend, six are free of disease at 6 to 28 months after completion of treatment. A pharmacokinetic study showed a total platinum accumulation. The mean value at the end of treatment reached 1157 ng/ml. Only one patient experienced an accumulation of the ultrafilterable platinum (137 ng/ml at the end of treatment).

Biodistribution study of 99mTc-labeled LDL in B16-melanoma-bearing mice. Visualization of a preferential uptake by the tumor.

Since there is strong evidence of a preferential LDL accumulation in tumor cells, LDL might be of interest for tumor imaging. We have tested the ability of 99mTc-LDL in tumor imaging with B16-melanoma-bearing mice as a model for further applications in human studies. The LDL fixation rate was higher with 99mTc-labeled LDL than with 125I labeled LDL. Since technetium-99m remains trapped in the cells, 99mTc-LDL is a well-adapted radioligand because of information given by this radiotracer on the receptor metabolism. We observed that, at early growth stages, the tumor took up the LDL at a maximal rate, suggesting differences in cholesterol metabolism as a function of tumor growth. Accumulation of label in the tumor area was perfectly observable in tumor-bearing mice on scintigraphic images. Computerized quantification of the regions of interest (as well as biodistribution studies including killing of the animals) showed a 1.81-fold increase in uptake by the tumor as compared to the liver and a 28-fold increase as compared with corresponding normal tissue (muscle of the left leg) at day 8 of tumor growth. These data give strong support to the value of this non-invasive method in visualizing and quantifying the tissue LDL uptake in vivo, including the precise information provided by nuclear scintigraphy on the distribution of the radiolabeled LDL in the different tissues. 99mTc-LDL could be an efficient tool for further diagnostic or therapeutic exploration in cancer patients.

Anatomic changes in the abdominal cavity during intraperitoneal chemotherapy: prospective study using scintigraphic peritoneography.

Twenty-one patients undergoing either adjuvant or palliative intraperitoneal (ip) chemotherapy had repeated scintigraphic peritoneographies. Significant scintigraphic ip changes were recorded in 11 patients (52%). In patients without residual disease at the time of ip chemotherapy, the rate of ip mal-distribution reached 70%. These alterations did not correlate with clinical complications. Our study suggested that, independently of clinical assessment, scintigraphic peritoneography is a useful test for identifying patients who are no longer suitable for ip treatment, due to inadequate locoregional distribution.

Clinical pharmacokinetics of alpha 1-antitrypsin in homozygous PiZ deficient patients.

A pharmacokinetic study of alpha 1-antitrypsin (ATT) was performed in 2 groups of homozygous PiZ-deficient patients (treated and untreated) and 1 group of healthy volunteers. The distribution of the 131I-labelled protein corresponds to a 3-compartment model. The intravenously administered protein diffused quickly to the extravascular compartment where some retention occurred. No significant difference in AAT metabolism was observed between the 3 groups. The half-life of the injected protein is slightly longer than 2.5 days. The AAT protein was not stored. These results confirm the observations collected during the clinical trials. That is, a weekly infusion is necessary to obtain stable serum AAT concentrations. Monthly infusions are unable to maintain a 'plateau' phase. The periodicity may be limited to every 2 weeks.

[Multiple localization and lymphatic involvement of papillary micro-carcinoma of the thyroid. Results of total thyroidectomy with bilateral lymph node excision. Apropos of 38 patients]. / Multifocalité et lymphophilie des micro-carcinomes papillaires thyroidiens. Résultats de la thyroïdectomie totale avec évidement bilatéral, à propos de 38 patients.

This study involved 38 patients with occult papillary carcinoma of the thyroid gland treated by total thyroidectomy and bilateral prophylactic neck dissection. The histological results show the glandular multicentricity on either side, both in single nodule (65%) and in multinodular goiter (73.3%). High risk of cervical spreading clearly appears in papillary carcinoma (18.4% of the patients) even in these small foci (lower than 10 mm). Topography of involvement brings into prominence two main territories: paratracheal, mid and lower jugularly nodes (involved in 92.8% of the positive dissections).

Screening for multiple endocrine neoplasia type 2a with DNA-polymorphism analysis.

Multiple endocrine neoplasia type 2a has been shown to be genetically linked to a locus near the centromere of chromosome 10. The availability of polymorphic DNA probes for the region permits the use of restriction-fragment-length polymorphisms (RFLP) to identify carriers of the gene for this cancer syndrome. As part of a French national program, DNA probes were used in a genetic-linkage study of 130 members of 11 families of European and North African origin. In these families there was no recombination between the mutation causing multiple endocrine neoplasia type 2a and two of the three probes used. All 11 families were informative for at least one of the three markers, and linkage information was adequate to provide genetic counseling to 8 families. We found that RFLP analysis is much more useful in predicting the carrier state than conventional endocrine challenge, especially in younger people, but accuracy is maximal when both methods are employed. We conclude that genetic screening allows the identification of those who are at risk for multiple endocrine neoplasia type 2a at any age with a high level of certainty. After initial screening with DNA, tests for early neoplastic change may be directed toward those determined to be at high risk.