Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients.

INTRODUCTION: Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. MATERIALS AND METHODS: Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. RESULTS: Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p < 0.0001) and a polymorphism in the ABCG2 transporter (421C>A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01-2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05-1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03-1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. CONCLUSIONS: This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.

Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. PATIENTS AND METHODS: From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. RESULTS: Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03). Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) without grade 3-4 events. CONCLUSION: Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity.

BACKGROUND: Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN). PATIENTS AND METHODS: The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied. RESULTS: Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03). CONCLUSION: We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Estimation of glomerular filtration rate in cancer patients with abnormal body composition and relation with carboplatin toxicity.

PURPOSE: Carboplatin clearance is correlated with glomerular filtration rate (GFR) and usually estimated with creatinine clearance using Cockcroft-Gault (CG) formula. Because plasma creatinine level is highly correlated with muscle mass, we hypothesized that an abnormal body composition with a low lean body mass (LBM) percentage [(LBM/weight) × 100] may result in inadequate carboplatin dosing. Serum cystatin C is an alternative marker of GFR, not affected by muscle mass. We aimed to investigate the influence of total LBM and LBM percentage on GFR calculation, using creatinine (CrCl) or cystatin C (GFRcysC-creat) in cancer patients. METHODS: Pretreatment serum creatinine and cystatin C were prospectively measured in consecutive patients. CrCl (CG formula), GFRcysC-creat (CKD-EPI creatinine-cystatin equation), and LBM (CT scan) were calculated. Severe thrombocytopenia post-carboplatin were analyzed. RESULTS: In 131 patients without renal insufficiency, LBM was correlated with creatinine (r = 0.30, p < 0.005) but not with cystatin C (r = -0.07, p = 0.43). In patients with the lowest LBM percentage, the CrCl was significantly higher than GFRcysC-creat indicating an overestimation of GFR with creatinine (p = 0.0004). In 24 patients treated with carboplatin AUC 5 (mg/ml min) ± paclitaxel, the risk of severe thrombocytopenia was associated with lower LBM percentage (p = 0.0002) and higher CrCl/GFRcysC-creat ratio (p = 0.006). By ROC analysis, the CrCl/GFRcysC-creat ratio threshold predicting severe thrombocytopenia was 1.23. CONCLUSIONS: A low LBM percentage increases the risk of inadequate GFR calculation by CG formula, and carboplatin overdosage with severe thrombocytopenia. High CrCl/GFRcysC-creat ratio allows the identification of these patients.

[West Nile virus infection: serological investigation among horses in France and in Africa]. / Infection par le virus West Nile: enquêtes sérologiques sur des chevaux en France et en Afrique.

This study was carried out in 2003 to detected serological evidence of West Nile virus infection in 190 Army horses kept nearby French troops stationed in Southeast France and in Africa (Chad, Côte d'Ivoire and Senegal). Both IgG and IgM antibodies were searched for using an ELISA assay. Specifiity of IgG antibodies was determined by western blot and plaque reduction seroneutraization. Finding showed that 79% of the Army horses (n=96) tested in Africa presented specific IgG antibodies. All horses that were seropositive for IgG were seronegative for IgM. None of the Army horses (n=94) tested in the Southeast France were seropositive for West Nile virus. This study indicates that West Nile virus has circulated in all three African countries but not recently. It also underscores the value of western blotting as a rapid, specific confirmation technique that could eliminate the need to use plaque reduction seroneutralization.

Cloning and expression of a thyroid hormone receptor alpha 1 in the perennibranchiate amphibian Proteus anguinus.

We demonstrated the presence of thyroid hormone receptor alpha mRNAs in tissues of the perennibranchiate amphibian Proteus anguinus, which is insensitive to thyroid hormone. From P. anguinus muscle we cloned and sequenced the 3' coding and untranslated region of a cDNA corresponding to a thyroid hormone receptor alpha 1. Using cDNA-PCR and in situ hybridization, we showed a tissue-specific expression of thyroid hormone receptor alpha genes, which was not upregulated by thyroid hormone as opposed to that observed in the TH-sensitive species, Xenopus laevis.

Seroepidemiological survey of HTLV-I infection among randomized populations of western central African countries.

Between 1987 and 1988, a survey to determine the distribution of HTLV-I infection was conducted in a representative population of adults, living in southern Chad, Cameroon, and Equatorial Guinea. Populations studied were selected by the cluster sampling technique. Sera were tested for IgG antibodies to HTLV-I by ELISA. ELISA-positive sera were retested by Western blot. The study comprised 2,301 adults, all apparently healthy. Crude prevalence rates range from 0.5 to 11.8%. We found three clearly different areas of HTLV-I seroprevalence rates. An area of low seropositivity in southern Chad and northern Cameroon (0.5-2.0%), an area of moderate seropositivity in the savannah region of Ngaoundere, Cameroon (4.2%) and in Bata, Equatorial Guinea (6.5%), and lastly an area of high seropositivity (8.6-11.8%) in the equatorial forest area of Equatorial Guinea and southern Cameroon. HTLV-I seroprevalence rates increased with age up to 12.6% after 40 years old in the areas of high seropositivity. There was no difference between male and female age-adjusted prevalence rates in all of the areas studied.

Studies of HLA-B27-associated disease.

Several rheumatic diseases were first shown to be associated with human leukocytic antigen (HLA)-B27 in 1973. Recent developments in understanding this association include the finding that there are at least six variants of HLA-B27 at the molecular level, with no one variant preferentially associated with disease. Detailed studies of the structure of the HLA-B27 molecular family are in progress in several laboratories. Mice expressing HLA-B27 and transmitting it to their offspring (transgenic mice) have been produced and are being studied for their response to bacteria that are known to trigger reactive arthritis in B27+ humans. A particular restriction fragment length polymorphism was recently claimed to be a genetic marker for an additional risk factor in ankylosing spondylitis, but two other laboratories have failed to confirm this finding.

PCR amplification of large genomic fragments from human and simian immunodeficiency virus infected cell lines.

Polymerase chain reaction (PCR) has been used to amplify the large fragments from viral genomic DNA of SIV from wild caught, asymptomatic Erythrocebus monkeys from Western Africa (Senegal) and also from HIV-2 infected cell lines. By using consensus primer sequences from highly conserved stretches of gag, pol and env genes, two halves of the viral genome of HIV-2 and SIV (isolated from west African Erythrocebus monkeys) have amplified by PCR. One half spans 5200 bp from within the U3 region of the 5' long terminal repeat (LTR) into pol gene and an overlapping fragment spans 3700 bp from the pol gene into U5 region of 3' LTR. Also fragments ranging from 1-2.3 kb from gag pol and env genes have been successfully amplified. Our data demonstrate that primers used to amplify large segments from viral DNA yield better results if they are derived from a consensus sequence of a highly conserved stretch of the viral genome.

Microcomputer software applied to corneal stromal biometry.

Here we report a new method for image analysis of the corneal stroma. To obtain the biometric characteristics of a given area, we perform three different treatments of the same image. These automated predictions closely match each parameter (length, surface area, etc.), as measured manually by a "blind investigator." Furthermore, to obtain quantifiable, average values, we have increased the number of successive image measurements, which has led to the development of a series of programs designed to optimize automated data handling. Finally, the acquired, calculated parameters are summarized in the form of intermediate tables for each series of images, and as a final summary table incorporating t-test values and permitting comparison between two stromas (e.g., normal and pathological). Multivariate analysis and an ascending hierarchical classification demonstrate the main trends in differences of pathological vs. normal stroma.

Ocular development and involution in the European cave salamander, Proteus anguinus laurenti.

The anatomy and development of the eye of Proteus anguinus are described. The relationships between organogenesis of the eye in embryos and larva and its involution in the young and the adult are discussed. The availability (in breeding cultures) of a significant number of Proteus embryos (which are normally rare) allowed experimental analysis of the effects of light, xenoplastic differentiation and thyroid hormones on the development of the eye. The results of this study suggest that development and involution of the eye of Proteus are controlled by genetic factors which are not greatly influenced by environment, and one can, therefore, consider the microphthalmy of Proteus as a relict characteristic which is the result of a specific development with disturbance of the normal ontogenic process.

Comparative study of the rheotaxis in the cave salamander Proteus anguinus and his epigean relative Necturus maculosus (Proteidae, Urodela).

The reaction to different water currents of the cave salamander Proteus anguinus and his epigean relative Necturus maculosus has been tested in a choice chamber. Both species showed a positive reaction which started in P. anguinus with a current of 35 cm/min and in N. maculosus 60 cm/min. These thresholds are within the range measured for different species of fish in the absence of visual stimuli. In addition, the rheotactic behaviour is less steady in N. maculosus . It seems that the differences found are not sufficient to be explained by adaptation to cave life.

[Not Available]. / Etude comparee de la detection chimique des proies par Proteus anguinus, cavernicole, et son parent de surface Necturus maculosus (proteidae, urodela).

Do the blind cave salamander Proteus and its epigean relative Necturus use the chemical sense in searching for prey? Proteus shows a significant, and Necturus only a weak, preference for water which passes living prey before entering a choice chamber. Prey which was frozen before the test also gave the same result in both species. However, with this immobilized prey the time for a decision in the test was much longer. The results of ten series of tests demonstrate the importance of chemoreception for prey detection in Proteus. The weaker reactions in Necturus can be explained probably by the different biotope. Six other series of tests have been conducted to show that our results are not influenced by stimuli relating to mechanoreception, thigmotaxis and rheotropism.

Predation in caves: the effects of prey immobility and darkness on the foraging behaviour of two salamanders, Euproctus asper and Proteus anguinus.

The behavioural responses of the blind cave salamander Proteus anguinus and the Pyrenean salamander Euproctus asper (a facultative cave dweller) to living and dead chironomids offered in light or in darkness were studied experimentally. Both species were able to detect and locate single prey items positioned at distances of 30 cm. Proteus responded to dead prey in light faster and captured live prey in darkness earlier than E. asper. E. asper captured live prey in light earlier than in darkness. Proteus is well equipped to search for non-visual information and used an active, mechanically and chemically guided approach in all experiments. E. asper showed a more directed, visually dominated approach behaviour with live chironomids in light, but used an active, widely foraging mode with live prey in darkness and dead prey in light. E. asper may forage successfully both in epigean and hypogean habitats.

[Oxygen requirements of the myocardium]. / Les besoins en oxygène du myocarde.

Myocardial oxygen consumption (MVO2) is defined by the equation: MVO2 = coronary blood flow x arteriovenous difference in O2 content. The average value for a heart of 300 g is 30 to 35 ml/min. In the absence of physiological variations in the arteriovenous difference in O2 content, MVO2 is related to coronary blood flow and the typical anti-anginal agent is one which prevents or reduces increases in MVO2. MVO2 depends on several factors: 1. intraparietal tension, which depends on intraventricular pressure and volume and in which the oxygen demands of pressure overload are much higher than those of volume overload; 2. contractility or myocardial inotropism: 50 per cent increase in the velocity of left ventricular contraction increases MVO2 by 40 per cent; 3. heart rate; 4. external cardiac work--the work accomplished during the ejection phase; this represents about 15 per cent of the MVO2; 5. the energy of electrical activation; this represents about 0,5 per cent of the MVO2; 6. the oxygen requirements of basal myocardial metabolism which represent about 20 per cent of the MVO2; 7. ventricular relaxation: is a factor to be added to those described above; this consumes about 15 per cent of the total energy of a cardiac beat; it may be increased with Isoproterenol or decreased by increasing the calcium concentration. This mechanism may explain the physiopathological impact of calcium inhibitors in effort angina or angina due to increased MVO2.

[Prognosis of asymptomatic or slightly symptomatic chronic aortic insufficiency. Apropos of 54 patients followed for an average of 36 months]. / Pronostic des insuffisances aortiques chroniques asymptomatiques ou paucisymptomatiques. A propos de 54 patients suivis en moyenne pendant 36 mois.

A series of 54 patients with chronic aortic insufficiency with little (38) or no symptoms (16) were studied. All had severe regurgitation leading to discussion of aortic valve replacement. All patients (44 male and 10 female) underwent clinical, radiological, electrocardiographic, hemodynamic and angiographic investigation with assessment of left ventricular volume by monoplane 30 degrees cineangiography on entry to the study. They were then followed-up for an average of 36 months and the data assessed in a prospective study. At the end of the 36 months period, 4 patients had been lost to follow-up but were still alive, 31 patients were unchanged (Group A) and 19 patients had deteriorated (Group B). The parameters characterising Group B (P less than 0.001) were: corrected cardiac surface area of 1,72 +/- 0,13, a Sokolow index of 60,1 +/- 18,8 mm an ejection fraction of 56.2 +/- 14 % and a left ventricular end diastolic value of 225,3 ml/m2. Therefore, in chronic asymptomatic aortic incompetence, the parameters of cardiac dilatation, cardiac surface area greater than 1,70 and left ventricular end diastolic volume greater than 170 ml/m2, would appear to be good indications for aortic valve replacement. However, the values are nor formal criteria because a discrepancy between symptoms and the volumetric measurements may be observed in some cases, and also large variations in these measurements may be observed in patients in the same functional class.

[Analysis of interobserver variations in the estimation of myocardial volume, thickness and mass in right anterior oblique monoplanar angiocardiography]. / Analyse des variations interobservateurs dans l'estimation des volumes, de l'épaisseur et de la masse myocardique dans l'incidence angiocardiographique monoplane oblique antérieure droite.

The parameter derived from right anterior oblique angiocardiography (end diastolic and end systolic volumes, stroke volume, ejection fraction, wall thickness and myocardial mass) are used to decide the most appropriate management of cardiac disease. It is important to assess their reliability especially as other clinical data may be underestimated and the objective results may play a prominent role in the decision. Therefore, good quality cinefilms of 31 patients were reinterpreted by three observers (A, B and C); the contours were traced on a Vanguard console with an electromagnetic pet and the data treated automatically by the SNIASS SYSCOMORAN program (Simpson's method, assimilating the left ventricle to an ellipsoid divided into n identical cylinders). The interobserver variability (A and B; A and C; B and C) was good in the assessment of end diastolic volume (R = 0,96; 0,98; 0,99), end systolic volume (R = 0,96; 0,96; 0,98). On the other hand, it was poor in the measurement of wall thickness (R = 0,63; 0,73; 0,69) and myocardial mass (R = 0,85; 0,83; 0,89). In addition, the ejection fraction and end systolic volume were perfectly reproducible from one observer to another whether or not the left ventricle was dilated. End diastolic volumes seemed to be more reproducible in dilated cavities (EDV greater than 104 ml/m2). These results confirm that monoplane RAO cineangiography remains a good method of assessing left ventricular performance.

[Pure arrhythmic form of the pre-infarction syndrome or spasm responsible for myocardial necrosis]. / Syndrome prémonitoire à forme rythmique pure ou spasme responsable d'une nécrose myocardique.

A 74 years old man was admitted as an emergency for syncopal attacks due to recurrent ventricular fibrillation (VF). These attacks were observed at the height of myocardial ischaemia as shown by ST elevation in Leads II, III and RV without associated anginal pain. Inferior myocardial infarction occurred during recurrent VF on the 4th day; the outcome was favourable. Coronary angiography was performed on the 10th day and showed double vessel disease; ergometrine (0.2 mg) induced anginal pain and ST elevation in Leads II, III and AVF. A good clinical result was obtained by calcium antagonists with an 18 months follow-up. Coronary spasm, documented in this case by the ergometrine provocation test, is now recognised as a cause of resting angina, effort angina and also some cases of myocardial infarction. This report suggests that coronary spasm may also induce apparently isolated severe ventricular arrhythmias without associated chest pain, which raises the question as to whether arrhythmias induced by spasm could play a primary role in aggravating myocardial ischaemia, leading to myocardial infarction.

[Rest and exercise angina caused by spasm of the left coronary artery. Apropos of a case with angiographically normal coronary arteries]. / Angor de repos et d'effort par spasme du tronc coronaire gauche. A propos d'un cas à artères coronaires angiographiquement normales.

A 42 year old woman presented with resting and effort angina. During an attack of chest pain, ST-T wave depression was recorded in the anterior chest leads. Coronary angiography showed spontaneous spasm of the left main stem, relieved by nitrate derivatives. The coronary arteries were angiographically normal between attacks of angina. Thallium 201 myocardial scintigraphy showed anterior wall hypofixation at maximal effort. A good therapeutic result was obtained with calcium antagonists. The site of coronary spasm is the special feature of this case, which may be grouped with other rare reported cases of spontaneous spasm or spasm on effort. We confirm that spasm-induced myocardial ischaemia may cause ST depression on the surface ECG.