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1.
Cancer Chemother Pharmacol ; 80(1): 45-53, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28508095

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/administration & dosage , Body Composition/physiology , Carboplatin/administration & dosage , Glomerular Filtration Rate , Neoplasms/drug therapy , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Carboplatin/adverse effects , Carboplatin/pharmacokinetics , Creatinine/blood , Cystatin C/blood , Female , Humans , Male , Middle Aged , Neoplasms/pathology , Paclitaxel/administration & dosage , Prospective Studies , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology
2.
Invest New Drugs ; 33(1): 257-68, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25344452

ABSTRACT

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.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Angiogenesis Inhibitors , Body Weight , Indoles , Neoplasm Proteins/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors , Pyrroles , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , Aged , Angiogenesis Inhibitors/adverse effects , Angiogenesis Inhibitors/pharmacokinetics , Angiogenesis Inhibitors/therapeutic use , Constitutive Androstane Receptor , Cytochrome P-450 CYP3A/genetics , Female , Humans , Indoles/adverse effects , Indoles/blood , Indoles/pharmacokinetics , Indoles/therapeutic use , Male , Middle Aged , Neoplasms/genetics , Neoplasms/metabolism , Pharmacogenetics , Polymorphism, Genetic , Protein Kinase Inhibitors/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrroles/adverse effects , Pyrroles/blood , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Receptors, Steroid/genetics , Sunitinib , Treatment Outcome
5.
Ann Oncol ; 23(1): 200-205, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21427067

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/adverse effects , Cyclohexanols/therapeutic use , Neurotoxicity Syndromes/prevention & control , Organoplatinum Compounds/adverse effects , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/drug therapy , Double-Blind Method , Female , Humans , Male , Middle Aged , Oxaliplatin , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/prevention & control , Venlafaxine Hydrochloride
6.
Bull Cancer ; 96(10): 951-60, 2009 Oct.
Article in French | MEDLINE | ID: mdl-19734117

ABSTRACT

For the past two decades, significant developments have been made in supportive care for the management of chemotherapy-induced nausea and vomiting (CINV). A better understanding of the pathophysiology of vomiting and the introduction of two new classes of antiemetic agents with a high therapeutic index (serotonin type 3 receptor antagonists [anti-5HT3 or setrons] in the 1990s and neurokinin type 1 receptor antagonists [anti-NK1] in 2000), possibly combined with corticosteroids, have helped to improve the management of this distressing side effect, constantly feared by patients. It is essential to distinguish between the anticipatory, acute (first 24 hours) and delayed phases of CINV, to take into account the emetogenic potential of the different chemotherapy protocols (very low, low, moderate and high) together with individual risk factors. The authors would like to propose methodological and therapeutic recommendations for the primary and secondary prophylaxis of the acute and delayed phases of CINV, based on recent publications by international learned societies.


Subject(s)
Antiemetics/therapeutic use , Antineoplastic Agents/adverse effects , Nausea/prevention & control , Practice Guidelines as Topic , Vomiting/prevention & control , Adrenal Cortex Hormones/therapeutic use , Antiemetics/adverse effects , Antiemetics/classification , Antineoplastic Agents/classification , Humans , Nausea/chemically induced , Nausea/drug therapy , Neurokinin-1 Receptor Antagonists , Quality of Life , Risk Factors , Serotonin 5-HT3 Receptor Antagonists , Societies, Medical/standards , Vomiting/chemically induced , Vomiting/drug therapy
7.
Ann Oncol ; 20(4): 736-40, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19223573

ABSTRACT

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.


Subject(s)
Antineoplastic Agents, Phytogenic/adverse effects , Glutathione Transferase/genetics , Isoleucine/genetics , Oxidative Stress , Peripheral Nervous System Diseases/chemically induced , Polymorphism, Genetic , Taxoids/adverse effects , Valine/genetics , Aged , Docetaxel , Female , Humans , Male , Middle Aged
10.
Med Trop (Mars) ; 65(5): 439-43, 2005 Nov.
Article in French | MEDLINE | ID: mdl-16465812

ABSTRACT

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.


Subject(s)
Horse Diseases/virology , West Nile Fever/veterinary , West Nile virus/immunology , Africa , Animals , Antibodies, Viral/analysis , Blotting, Western , Enzyme-Linked Immunosorbent Assay , France , Horse Diseases/blood , Horse Diseases/transmission , Horses , Immunoglobulin G/analysis , Serologic Tests , West Nile Fever/blood , West Nile Fever/transmission
11.
J Med Virol ; 74(2): 277-82, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15332277

ABSTRACT

The resurgence of Chikungunya virus is described during an urban epidemic in Kinshasa Democratic Republic of the Congo, after 39 years without any isolation of the virus. Chikungunya virus was isolated in sera from nine patients with clinical symptoms. A 1,200 bp long partial sequence of the E1/3'UTR genomic region was determined for each isolate. All sequences clustered in the central African lineage. They constitute Chikungunya virus reference sequences for the Democratic Republic of the Congo.


Subject(s)
Alphavirus Infections/epidemiology , Communicable Diseases, Emerging/epidemiology , Disease Outbreaks , Alphavirus Infections/virology , Antibodies, Viral/blood , Chikungunya virus/classification , Chikungunya virus/genetics , Chikungunya virus/immunology , Chikungunya virus/isolation & purification , Communicable Diseases, Emerging/virology , Democratic Republic of the Congo/epidemiology , Humans , Malaria, Falciparum/complications , Molecular Epidemiology , Molecular Sequence Data , Phylogeny , Sequence Analysis, DNA
12.
Med Trop (Mars) ; 64(1): 81-8, 2004.
Article in French | MEDLINE | ID: mdl-15224565

ABSTRACT

Only six of the many alphavirus known to affect humans can cause articular manifestations. They are the Ross River and Barmah Forest viruses from the South Pacific, the Chikungunya, O'Nyong Nyong and Sindbis viruses from tropical Africa, and the Mayaro virus from South America. In most cases, articular manifestations involve arthralgia or transient arthritis and are usually minor. However in some cases especially involving Ross River virus acute polyarthritis may be the most prominent clinical feature and even develop before fever. Although these joint symptoms may be severe and persist for weeks or months in a subacute mode with slightly inflammatory episodes that can be relieved using analgesics, they never cause permanent damage. Differential diagnosis of alphavirsus-related polyarthritis is simple to diagnosis especially in epidemic outbreaks as is frequently the case for Ross River virus epidemics in Australia. Imported cases should be suspected in patients presenting acute or subacute polyarthritis after a recent stay of any length of time in a tropical country and can be confirmed by ordering serology from a specialized reference laboratory.


Subject(s)
Alphavirus Infections/complications , Alphavirus/pathogenicity , Arthritis, Infectious/virology , Alphavirus Infections/diagnosis , Arthritis, Infectious/diagnosis , Arthritis, Infectious/pathology , Diagnosis, Differential , Humans , Tropical Medicine
15.
Med Trop (Mars) ; 62(3): 291-4, 2002.
Article in French | MEDLINE | ID: mdl-12244928

ABSTRACT

For three years the arbovirus surveillance unit of the Tropical Medicine Institute of the French Army Medical Corps (French acronym IMTSSA) in Marseille, France has been investigating causes of benign non-malarial febrile syndromes in French military personnel serving outside mainland France. The methodology used in N'Djamena consisted of sending frozen specimens collected concomitant with viremia, to Marseille for culture. During the rainy season of 2001, specimens were collected from a total of 50 febrile soldiers. Cultures allowed isolation and identification of two strains of Rift Valley virus. The risk of contamination exists not only in the field but also in mainland hospital departments treating infected patients. Routine serological diagnosis for Rift Valley fever must be DISCUSSED for all patients in the field or returning from Africa.


Subject(s)
Disease Outbreaks , Military Personnel , Rift Valley Fever/epidemiology , Adult , Africa , France , Hospitals, Military , Humans , Rift Valley Fever/diagnosis , Serologic Tests
17.
Emerg Infect Dis ; 7(4): 692-6, 2001.
Article in English | MEDLINE | ID: mdl-11585534

ABSTRACT

On September 6, 2000, two cases of equine encephalitis caused by West Nile (WN) virus were reported in southern France (Hérault Province), near Camargue National Park, where a WN outbreak occurred in 1962. Through November 30, 76 cases were laboratory confirmed among 131 equines with neurologic disorders. The last confirmed case was on November 3, 2000. All but three cases were located in a region nicknamed "la petite Camargue," which has several large marshes, numerous colonies of migratory and resident birds, and large mosquito populations. No human case has been confirmed among clinically suspected patients, nor have abnormal deaths of birds been reported. A serosurvey has been undertaken in horses in the infected area, and other studies are in progress.


Subject(s)
Communicable Diseases, Emerging/veterinary , Disease Outbreaks , Horse Diseases/epidemiology , Sentinel Surveillance/veterinary , West Nile Fever/veterinary , West Nile virus/isolation & purification , Age Factors , Animals , Antibodies, Viral/analysis , Communicable Diseases, Emerging/epidemiology , Communicable Diseases, Emerging/immunology , Communicable Diseases, Emerging/virology , France/epidemiology , Horse Diseases/immunology , Horse Diseases/virology , Horses , Humans , Immunoglobulin M/analysis , Phylogeny , RNA, Viral/analysis , Serologic Tests/methods , West Nile Fever/epidemiology , West Nile Fever/immunology , West Nile virus/classification , West Nile virus/genetics , West Nile virus/immunology
18.
Arch Mal Coeur Vaiss ; 94(9): 1001-7, 2001 Sep.
Article in French | MEDLINE | ID: mdl-11603062

ABSTRACT

The authors present the results of a retrospective national enquiry which took place in 1999 and was mailed and faxed to the 3,800 cardiologists practising in the private sector in order to assess the different types of continuous, individual and collective postgraduate training which they had benefited from in the preceding 12 months. The data was analysed by comparison with that obtained from an individualized representative sample in a panel of private sector cardiologists. The results were then compared with the criteria of a yardstick proposed by the National Committee of Continuous Medical Education of 1997, according to the April 25th 1996 decree. The meeting of these criteria would require carrying out 114,000 to 76,000 hour-equivalents of continuous education whereas the present offer is about 100,000 hour-equivalents. The different forms of individual or collective training were compared in the 327 questionnaires which were exploitable following adhesion to the French Society of Cardiology, to the Cardiologists' Union, to local cardiological societies, by age, gender and type of practice. The average number of annual hours of collective education was 52.2 +/- 60.1 hours (25% quartile = 25 hours, 75% = 60 hours). The average value of hours of individual education was 89.7 +/- 89.3 hours (25% quartile = 25 hours; 75% = 120 hours). This evaluation indicates that about 15% of cardiologists practising in the private sector have inadequate continuous medical education and that 68% would satisfy the criteria laid down in 1997. Moreover, the present offer would seem to be adequate providing the criteria of accreditation have been met.


Subject(s)
Cardiology/education , Education, Medical, Continuing , Adult , Female , France , Humans , Male , Middle Aged , Private Sector , Retrospective Studies
19.
J Gen Virol ; 82(Pt 6): 1283-1290, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11369871

ABSTRACT

Recombination events are known to occur in non-segmented RNA viruses like polioviruses or alphaviruses. Analysis of the subgenomic sequences of dengue virus type 1 (DENV-1) structural genes has recently allowed the identification of possible recombination breakpoints. Because DENV is a major human pathogen, this discovery might have important implications for virus pathogenicity, vaccine safety and efficiency, or diagnosis and, therefore, requires clear confirmation. We report the complete sequence determination of one Asian and two African strains of DENV-1 isolated from human patients. Rigorous sequence analysis provided strong evidence for the occurrence of intragenomic recombination events between DENV-1 strains belonging to different lineages. Singapore S275/90 strain appears to be the evolutionary product of a recombination event between viruses belonging to two distinct lineages: one lineage includes an African strain isolated in Abidjan (Ivory Coast) and the other includes isolates from Djibouti and Cambodia. The 'Recombination Detection Program', bootscanning and analysis of diversity plots provided congruent results concerning the existence of a two-switch recombination event and the localization of recombination breakpoints. Thus, the 5' and 3' genomic ends of the Singapore S275/90 strain were inherited from a Djibouti/Cambodia lineage ancestor and an internal fragment located in the envelope/NS1 region originated from an Abidjan lineage ancestor.


Subject(s)
Dengue Virus/classification , Dengue Virus/genetics , Genome, Viral , Recombination, Genetic/genetics , Base Sequence , Cambodia , Cote d'Ivoire , DNA, Complementary/genetics , Dengue Virus/pathogenicity , Evolution, Molecular , Genetic Linkage/genetics , Humans , Male , Molecular Sequence Data , Phylogeny , RNA, Viral/genetics , Sequence Alignment , Singapore , Viral Vaccines/adverse effects , Viral Vaccines/genetics
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