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.

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.

Platelet regeneration time after aspirin ingestion and platelet survival time after labelling with 51chromium or 111indium oxine--a comparative study.

A simultaneous investigation of platelet regeneration time (PRT) based upon malondialdehyde (MDA) recovery after a single oral intake of 500 mg of aspirin and of platelet survival time (PST) after labelling with 51chromium or 111indium oxine was performed in 25 cancerous patients. A pilot study conducted with 9 healthy volunteers demonstrated that the MDA assay was highly reproducible and specific for the platelet cycloxygenase activity. The pattern of MDA recovery after aspirin ingestion was linear in the healthy volunteers and in the patients presenting both a normal and an accelerated platelet turnover. PST were calculated using the four mathematical models recommended by the International Committee for Standardization in Hematology; the best fit was given by the multiple hit model in 22 cases and by the linear regression model in 3 cases. The mean results obtained in the patients investigated with the 51chromium were consistently shorter than those obtained in the patients investigated with the 111indium oxine while the mean PRT were almost identical in the two groups. An excellent correlation between PRT and PST was observed after 111indium oxine labelling and using the weighted mean method for PST determination. These results suggest that the 111indium oxine technique is a better method for platelet labelling and that the results provided by the weighted mean method reflect more closely the in vivo platelet turnover than those provided by the multiple hit model.

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.

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.

[Thyroid trabecular carcinoma. A clinicopathological entity of poor prognosis? (author's transl)]. / L'epithélioma trabéculaire du corps thyroïde. Une entité anatomoclinique à pronostic défavorable?

The records of 32 patients with trabecular carcinomas of the thyroid gland were critically reviewed from a previously published serie of 138 thyroid cancers referred to the Centre Claudius Regaud, between 1952 and 1973. On the basis of clinico-pathological considerations, it seems possible to divide trabecular carcinomas into two groups. Pure trabecular carcinomas (moderately differenciated follicular carcinomas--WOH) which have a poor prognosis (5 years actuarial survival: 13%) related to high rate of local recurrences, fast metastatic spread to the lung, bad response to suppressive hormonotherapy and lack of 131 iode uptake by malignant tissue. Mixed trabeculo-vesicular carcinomas which have in comparison a fairly good prognosis (5 years actuarial survival: 63%) in keeping with a lower tendency to local recurrences and a useful concentration of radioactive iodine by metastases (most of them located in the skeleton) although dependent on the pourcentage of vesicles in the tumor process. Among differentiated thyroid carcinomas, distinction between pure trabecular and mixed trabeculo-vesicular carcinomas with quantitative determination of vesicules seems of great interest in relation to the therapeutic approach.

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.

[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).

[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.

[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.

[The phenomenon of relative resistance to heparin]. / Le phénomène de résistance relative à l'héparine.

In a prospective clinical study heparin half-life and in vitro and ex vivo heparin sensitivity, as assessed by activated partial thromboplastin time prolongation, was evaluated in 8 healthy volunteers and in 21 patients with malignant tumor. In the patients, coagulation activation was evaluated by determining the fibrinogen half-life and the level of the fibrin-fibrinogen degradation products. The results were comparable in the two groups of subjects, and in the patients there was no correlation with the degree of activation of the coagulation system. In both groups large interindividual variations were recorded. These results confirm those obtained in patients with deep venous thrombosis. They suggest that the relative heparin resistance phenomenon encountered in some patients during heparin therapy is unrelated to the presence of the thromboembolic disease (P.M.).

[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).

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.

Exhausted platelets in patients with malignant solid tumors without evidence of active consumption coagulopathy.

Twenty-four patients with various types of tumors and without evidence of consumption coagulopathy (normal routine coagulation tests) were investigated for intraplatelet ATP, ADP, serotonin, beta-thromboglobulin and platelet factor 4; the percentage of light circulating platelets was also determined. Evidence for an acquired storage pool defect was found in seven patients (29%) without any correlation with the clinical status, the presence of metastases, platelet count or fibrinogen level. These results show that exhausted platelets are commonly encountered in cancerous patients even in the absence of consumption coagulopathy. The precise mechanism of this abnormality remains to be established.

Further studies on the relationship between platelet buoyant density and platelet age.

The relationship between platelet buoyant density and platelet age was investigated in eight human subjects submitted to an autologous chromium labeled platelet survival study. Platelets were isolated after isopycnic centrifugation using eight discontinuous isoosmotic stractan gradients (five subjects), or various continuous and linear isoosmolar gradients (three subjects). A paradoxical radioactivity enrichment of the dense platelets and a premature loss of radioactivity in the light platelets were observed. These results are explained by a shift of the radioactivity distribution curve toward higher densities during the 3-4 days after platelet injection, while the standard deviation of the distribution was conserved throughout the platelet life span. These results suggest that young platelets are heterogeneous and slightly less dense than the total platelet population.

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.