Impact of renal impairment on dihydropyrimidine dehydrogenase (DPD) phenotyping.

BACKGROUND: The chemotherapeutic agent 5-fluorouracil (5-FU) is catabolized by dihydropyrimidine dehydrogenase (DPD), the deficiency of which may lead to severe toxicity or death. Since 2019, DPD deficiency testing, based on uracilemia, is mandatory in France and recommended in Europe before initiating fluoropyrimidine-based regimens. However, it has been recently shown that renal impairment may impact uracil concentration and thus DPD phenotyping. PATIENTS AND METHODS: The impact of renal function on uracilemia and DPD phenotype was studied on 3039 samples obtained from three French centers. We also explored the influence of dialysis and measured glomerular filtration rate (mGFR) on both parameters. Finally, using patients as their own controls, we assessed as to what extent modifications in renal function impacted uracilemia and DPD phenotyping. RESULTS: We observed that uracilemia and DPD-deficient phenotypes increased concomitantly to the severity of renal impairment based on the estimated GFR, independently and more critically than hepatic function. This observation was confirmed with the mGFR. The risk of being classified 'DPD deficient' based on uracilemia was statistically higher in patients with renal impairment or dialyzed if uracilemia was measured before dialysis but not after. Indeed, the rate of DPD deficiency decreased from 86.4% before dialysis to 13.7% after. Moreover, for patients with transient renal impairment, the rate of DPD deficiency dropped dramatically from 83.3% to 16.7% when patients restored their renal function, especially in patients with an uracilemia close to 16 ng/ml. CONCLUSIONS: DPD deficiency testing using uracilemia could be misleading in patients with renal impairment. When possible, uracilemia should be reassessed in case of transient renal impairment. For patients under dialysis, testing of DPD deficiency should be carried out on samples taken after dialysis. Hence, 5-FU therapeutic drug monitoring would be particularly helpful to guide dose adjustments in patients with elevated uracil and renal impairment.

Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children.

BACKGROUND: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. OBJECTIVE: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. METHODS: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. RESULTS: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. CONCLUSION: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

[Efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) on the neuropathic manifestations in POEMS syndrome]. / Efficacité à moyen terme de l'autogreffe de cellules souches hématopoïétiques périphériques sur la polyneuropathie du syndrome POEMS: expérience chez 5 cas.

INTRODUCTION: POEMS syndrome (polyneuropathy, organomegaly, endocrynopathy, M-protein, and skin changes) is a rare multisystem disease associated with plasma cell dyscrasia. The efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) reported in case series has been mainly based on hematologic criteria and clinical recovery of peripheral neuropathy dysfunctions but has not been specifically evaluated. This retrospective study aimed to analyze the efficacy of auto-PBSCT on disability and electrophysiological patterns in patients with POEMS syndrome. METHODS: Five patients presenting with POEMS syndrome received auto-PBSCT. Disability was evaluated before treatment and at 6 and 12 months using the Overall Neuropathy Limitation Scale (ONLS) and MRC sumscore of 28 muscles. Nerve conduction studies were performed before and one year after treatment, on median, ulnar, fibular and tibial nerves. RESULTS: Mean age was 60.6 years (49-70). Disease duration between first symptoms and auto-PBSCT was 15.4 months (2-33). Before auto-PBSCT, mean ONLS score was 4.2 (1-10) and mean MRC sumscore 115.8/140 (74-140). At M6, mean ONLS score decreased and mean MRC sumscore increased; both were improved in all patients at M12: mean ONLS score 3 (range 0-8) at M6 and 2.2 (range 0-7) at M12; mean MRC sumscore 118/140 (77-140) at M6 and 122.4/140 (80-140) at M12. Significant recovery in electrophysiological patterns was observed in all patients on ulnar and median nerves: before-after treatment differences were observed for motor conduction velocities (34.41 vs. 45.47 m/s; P<0.001), distal CMAP amplitudes (5.04 vs. 5.96 mV; P=0.004), and sensory conduction velocities (43.20 vs. 49.20 m/s; P=0.001). Distal CMAP amplitude remained low in fibular and tibial nerves (0.41 vs. 0.17 mV). CONCLUSIONS: Clinical and electrophysiological improvement is obvious in POEMS syndrome peripheral neuropathy within one year after treatment with auto-PBSCT, undoubtedly resulting from extensive remyelinisation and axonal regeneration. Further studies are required to examine long-term outcome in patients with POEMS syndrome given auto-PBSCT.

[Identifying addictive behaviors among adolescents: a school-based survey]. / Repérer les comportements addictifs chez les adolescents : enquête en milieu lycéen.

French epidemiological data show that adolescents today experiment with tobacco at an earlier age than in the 1990s. Half of them combine tobacco consumption with other psychoactive products such as alcohol or cannabis. Tobacco consumption usually begins in adolescence and early smoking initiation is related to stronger nicotine dependence and problems quitting in adulthood. Occasional tobacco consumption rapidly leads to nicotine dependence. The national smoking cessation questionnaire is a tool to assess addictive behaviors among adolescents. It includes validated scales such as the loss of autonomy over tobacco and psychological evaluation. The aim of this school-based study was to assess addictive behaviors among adolescents (specifically loss of autonomy over tobacco) and psychological profile. Data were collected from a cross-sectional study conducted in a high school in the Paris metropolitan area (Nogent-sur-Marne) in 2007 by the smoking cessation team of the Albert-Chenevier Hospital. Three hundred adolescents filled in a questionnaire concerning tobacco, alcohol, and cannabis consumption as well as their psychological profile. Loss of autonomy over tobacco use was evaluated with the Hooked on Nicotine Checklist (HONC). Anxiety and depressive disorders were identified using the Hospital Anxiety and Depression scale (HAD). Self-administered questionnaires were anonymously completed in the classroom by 151 girls and 149 boys aged 15-16 years (mean, 15.4 years): 34% of the adolescents smoked and most of them smoked at least one cigarette a day; 38% had used cannabis at least once in their life and one-third of them smoked more than 10 cannabis joints per month. Adolescents who frequently smoked cannabis had started smoking tobacco earlier than the other smokers (mean, 11.7 years versus 13.2 years). Adolescents often used different tobacco products. Manufactured cigarettes were the most frequently used, followed by shisha (waterpipe) and hand-rolled cigarettes. Among those who only smoked shisha, 76% had declared being non-smokers. Alcohol was the first psychoactive drug experimented by these adolescents; 73% had used alcohol at least once in their life and 10% used alcohol several times a week. According to the HONC, 94% of the smokers had lost control of their tobacco consumption. Concerning anxiety and depressive disorders, anxiety and depression scores were higher among smokers than non-smokers. Less than 6% of never-smokers had a depression score greater than 8 compared to 26% of adolescents smoking cannabis more than 10 times a month. The rapidity of the loss of autonomy among young smokers emphasizes the need for early interventions for tobacco prevention and cessation among adolescents. Tobacco use was often associated with anxiety and depressive symptoms, suggesting a need for professional support. The national smoking cessation questionnaire may be helpful in pediatric wards and consultations.

Comparative evaluation of in vitro parameters of tamoxifen citrate loaded poly(lactide-co-glycolide), poly(epsilon-caprolactone) and chitosan nanoparticles.

Tamoxifen (TAM), the clinical choice for the antiestrogen treatment of advanced or metastatic breast cancer, was formulated in nanoparticulate carrier systems in the form of poly(lactide-co-glycolide) (PLGA), poly-epsilon-caprolactone (PCL) and chitosan (CS) nanoparticles. The PLGA and PCL nanoparticles were prepared by a nanoprecipitation technique whereas the CS nanoparticles were prepared by the ionic gelation method. Mean particle sizes were under 260 nm for PLGA and PCL nanoparticles and around 400 nm for CS nanoparticles. Polydispersity indices were less than 0.4 for all formulations. Zeta potential values were positive for TAM loaded nanoparticles because of the positive charge of the drug. Drug loading values were significantly higher for PCL nanoparticles when compared to PLGA and CS nanoparticles. All nanoparticle formulations exhibited controlled release properties. These results indicate that TAM loaded PLGA, PCL and CS nanoparticles may provide promising carrier systems for tumor targeting.

[Anti-MAG paraproteinemic demyelinating polyneuropathy: a clinical, biological, electrophysiological and anatomopathological descriptive study of a 13-patients' cohort]. / Les polyneuropathies avec IgM monoclonale anti-MAG : étude descriptive clinique, biologique, électrophysiologique et anatomopathologique d'une cohorte de 13 patients.

INTRODUCTION: Polyneuropathies associated with IgM paraproteinemia and anti-myelin associated glycoprotein (MAG) antibodies (MAG-PN) have to be differentiated from chronic inflammatory demyelinating polyneuropathies. METHODS: In a retrospective study, we have analyzed clinical, electrophysiological, biological and pathological data from MAG-PN patients. RESULTS: Seven male and six female patients were followed in the department for a mean 2 years (0.5-6.5 years). Mean age at diagnosis was 61 years (44.5-85.5 years). Patients had symmetrical bilateral paresthesia (11/13) and hypoesthesia (11/13) prominent in the lower limbs. Nine patients developed gait ataxia and four patients had moderate distal weakness in the lower limbs. Mean Overall Neuropathy Limitation Scale was 2.3 (0-5). Nerve conduction study showed demyelinating features though delayed distal motor latency on median (206 % of normal value) and ulnar nerves (150% of normal value). Seven out of thirteen patients had at least two nerves with terminal latency index below 0.25. IgM paraproteinemia was of undetermined significance in ten cases and three patients had non-Hodgkin lymphoma. IgM deposits and widening of the peripheral myelin were observed in 5/7 sural nerve biopsies. Anti-MAG antibodies were detected in the sera of all patients using enzyme-linked immunosorbent assay and in 8/12 patients using western blot analysis. CONCLUSIONS: MAG-PN have distinctive clinical, electrophysiological and pathological features. It is a chronic, slowly progressive, predominantly sensory and ataxic neuropathy. Disability is usually moderate. Electrophysiological study shows distal demyelinating process and is highly suggestive of MAG-PN in more than one half of our patients. Several techniques may detect anti-MAG antibodies, they have to be associated to improve sensitivity and specificity of the test.

[Paraneoplastic limbic encephalitis with positive anti-RI antibodies and mediastinal seminoma]. / Encéphalite limbique paranéoplasique avec anticorps anti-RI et séminome médiastinal.

We report the case of a 49-year-old man who was admitted for progressive behaviorial disorders with frontal elements. There was no sensorial nor motor deficiency. Clinical examination revealed android obesity, cutaneous and mucous paleness, pubic and axillary depilation and gynecomastia. Encephalic MRI found a lesion of the left amygdalian region with high T2 intensity and low T1 intensity associated with gadolinium-enhancement. Cerebrospinal fluid analysis showed a lymphocytic meningitis. Panhypopituitarism was found on the endocrine investigations. Anti-RI antibodies were positive, leading to the diagnosis of paraneoplastic limbic encephalitis. The CT-scan showed a node of the lower part of the thymic area. Surgical resection revealed an ectopic mediastinal seminoma. The evolution consisted of paraneoplastic fever and crossed-syndrome with right hemiparesia and left common oculomotor nerve paralysis. Treatment was completed by two cycles of carboplatin, corticosteroids and substitutive opotherapy. Paraneoplastic fever disappeared, but behavioral disorders and palsy remain unchanged. The patient died two years later in a bedridden state. This case of paraneoplastic limbic encephalitis associated with positive anti-RI antibodies and mediastinal seminoma is exceptional and has not to our knowledge been described in the literature. Cancers usually associated with anti-RI antibody are breast and lung cancer. Paraneoplastic limbic encephalitis is not the classical clinical presentation, which usually is brainstem encephalitis. Hypothalamic involvement, uncommon in paraneoplastic limbic encephalitis is mainly associated with positive antineuronal anti-Ma2 antibodies. Finally, the gadolinium enhancement on encephalic MRI is unusual in paraneoplastic limbic encephalitis.

[Post-traumatic cholesteatoma of the ear: medicolegal aspect]. / Les cholestéatomes post-traumatiques de l'oreille: intérêt médico-légal.

Post-traumatic cholesteatomas pose the medicolegal problem of determining the causal link between trauma and cholesteatoma. The author reports on an observation of an antro-attical cholesteatoma that occurred ten years after a fracture of the pars petrosa. The pathogeny of the different types of post-traumatic cholesteatoma is discussed. From a study of the literature, it is possible to distinguish between cholesteatomas of the external auditory canal which are revealed relatively soon after the trauma (less than 5 years), and cholesteatomas of the middle ear that can be revealed more than 10 years after the trauma.

[Spinal and spinal cord injuries. Therapeutic approach in Gabon]. / Traumatismes vertébro-médullaires. Attitudes thérapeutiques au Gabon.

The authors present their experience with 81 cases (66.4%) of acute cervical spine injuries (C.S.I.) and 41 cases (33.6%) of acute thoracolumbar spine injuries (T.L.S.I.) treated by a multidisciplinary approach, at Jeanne Ebori Hospital (Libreville, Gabon) between the years 1981 and 1987. Traffic accidents were the leading cause of injury. The largest group consisted of patients in their third decade. The anatomic localizations were: upper cervical spine: 22 cases (27%); lower cervical spine: 56 (69%); upper thoracic spine: 11 (26.8%); lower thoracic spine or thoracolumbar area: 19 (46.3%); lumbar spine: 7 (17%). There were osteoligamental lesions in 3 cases (3.7%) of C.S.I. and 4 (9.7%) of T.L.S.I. Clinically, 44 patients (54.3%) with C.S.I. and 37 (90.2%) with T.L.S.I. had neurological deficits. Surgical indications depended upon the osseous as well as neurologic lesions. There were five important steps in the treatment of spinal injuries associated with neurological deficit: (1) immobilization, (2) medical stabilization, (3) spinal alignment (skeletal traction), (4) operative decompression if there was proven cord compression, and (5) spinal stabilization. Twenty patients (24.6%) with cervical injuries were treated conservatively (traction, collar, kinesitherapy); 53 (65.4%) underwent a surgical intervention (anterior approach - 21, posterior fusion - 30, combined approach - 2); and in 8 patients (9.8%) refraining from surgery seemed the best alternative. After lengthy multidisciplinary discussion, the authors elected not to operate on tetraplegic patients with respiratory problems that necessitated assisted ventilation, because of its fatal outcome. Of injuries to the thoracolumbar spine, 13 (31.7%) were treated conservatively (bedrest, orthopedic treatment). Twenty-eight patients (68.2%) with unstable thoracic and lumbar fractures associated with neurologic deficit required acute surgical intervention (stabilization with or without decompression of the neural elements). Laminectomy alone was performed in 5 cases, laminectomy with graft in 2, stabilization by Roy-Camille plates in 16 and by Harrington rods in 5. Most upper thoracic spine fractures were treated conservatively. Surgical intervention was increasingly possible with the availability of more material and qualified staff. There were 17 patients (21%) who died from C.S.I. (15 were tetraplegic), and 6 (14.6%) from T.L.S.I. In general, osteoligamental consolidation was satisfactory. Neurological recovery was observed only in patients with partial deficits. Most cases posed socioeconomic problems.

[Radio-anatomy of the infratemporal fossa. Pterygo-maxillary region]. / Radio-anatomie de la fosse infra-temporale. Région ptérygo-maxillaire.

The modern imaging techniques (computed tomography, MRI), allow a new approach of the limits and contents of the infratemporal fossa. This better anatomical knowledge allows distinguishing three distinct subregions, hence providing better interdisciplinary understanding.

[Transzygomatic approach of the infratemporal fossa. Value and limits]. / Voie d'abord transzygomatique de la région infra-temporale. Intérêts et limites.

We report about one case of neurofibroma in the infratemporal fossa, which was treated surgically through a transzygomatic approach. Lowering the zygomatic arch with the masseter muscle and raising the coronoid process with the temporalis muscles provides a wide access to the infratemporal region without any mutilation. This way of approach can be widened anteriorly towards the orbital frame in order to reach lateral orbital lesions, and posteriorly towards the mastoideum to resect large tumors extending into the base of the skull. The transzygomatic approach seems to be particularly appropriate for the exeresis of benign tumors in the infratemporal region.

[Nervous tumors of the infratemporal fossa]. / Les tumeurs nerveuses de la fosse infra-temporale.

Six cases of neurogenic tumors developing in the infratemporal fossa are reported. These are neuromas or neurofibromas in 5 cases and meningioma in 1 case only. The first 4 cases are primary tumors of the infratemporal fossa, while the last 2 tumors have developed into the temporal fossa from neighboring lesions. Computed tomography and RMI are irreplaceable techniques to assess the extension of such tumors and their connection with the neighboring organs, and to guide the treatment, which must be surgical whenever possible. Complete exeresis of the tumor is difficult. These examinations are also essential for follow-up and for the early detection of possible recurrence.

High-dose cytosine arabinoside and mitoxantrone in previously-treated acute leukemia patients.

35 patients with refractory or relapsed acute leukemia received salvage chemotherapy using high-dose cytosine arabinoside 2 g/m2 intravenously for 3 hours every 12 h, in 8 doses, followed by continuous infusion of mitoxantrone 12 mg/m2/day for 2 d. 9 patients had acute myeloblastic leukemia (AML), (4 relapsed, 5 refractory), 20 had acute lymphoblastic leukemia (ALL) (11 relapsed, 9 refractory) and 6 had chronic myelogenous leukemia (CML) in the blastic phase (BP). 4 out of 9 AML and 16 out of 20 ALL achieved complete remission. Median survival was 6 months for all patients and 10 months for responders. A short (1.5 months) chronic phase was achieved in 3 patients with CML. The main toxic effect was hematologic. A pharmacokinetic study was performed on mitoxantrone. No correlation was found with clinical response. The combination of mitoxantrone and ara-C is an effective antileukemic regimen, especially in ALL.

[Surgical treatment of lumbar spinal stenosis in Gabon]. / Traitement chirurgical des canaux lombaires étroits au Gabon.

The authors report their experiences based on 41 cases operated on for lumbar spinal stenosis between 1981 and 1988. The series included 28 men and 13 women aged between 23 and 63 years (mean age: 48 years). Neurogenic intermittent claudication was the presenting symptom in only 12% of the cases, as opposed to lumbago-sciatica in 78%. Clinical examination did not provide any specific elements. The key to diagnosis was lumbar myelography. Laminectomy was the most important aspect of treatment which, in certain cases, was associated with vertebral stabilization by arthrodesis (3 cases). There were ten minor operative complications. Further surgery was necessary in five cases (12%). Therapeutic results in patients followed from one to eight years (35 cases) were satisfactory. The discussion covers nosologic, clinicoradiologic and therapeutic aspects.

Population pharmacokinetics of mitoxantrone performed by a NONMEM method.

To date, the pharmacokinetics of mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2- hydroxyethyl)amino]ethyl]amino]anthraquinone) has been described either by an open two- or three-compartment model, showing high interindividual variability. In order to evaluate this variability, residual intraindividual variability, and measurement error, we carried out a population study. A sensitive HPLC method allowed analysis of blood samples drawn from 21 patients with breast cancer or acute nonlymphocytic leukemia. Individual data treatment (22 kinetics) using weighted nonlinear least squares regression confirmed the huge interindividual variability whatever the administration protocol of mitoxantrone: bi- or tri-exponential models fitted the data. The NONMEM population method used herein describes all concentration-time curves by a single three-compartment model, considering biphasic kinetics as fragmentary data. Residual intraindividual variability was 21.4%. Population mean values (+/- interindividual SD) of clearance, terminal half-life, and total volume of distribution were, respectively, 23.40 (+/- 10.76) L/h, 46.87 (+/- 12.18) h, and 385.49 (+/- 196.60) L. These results are of particular interest in clinical routines to calculate dosage regimens by Bayesian estimation methods.

A limited sampling procedure for estimating adriamycin pharmacokinetics in cancer patients.

The aim of this study was to find a procedure allowing estimation of individual pharmacokinetic parameters for adriamycin with minimal cost and disturbance for the patient. Twenty-five patients with breast cancer were treated by short infusion of adriamycin at a dose of 12 mg m-2 week-1 (41 courses). Population characteristics were determined on 15 randomly chosen courses (10 patients, group I) in order to define two optimal sampling times (26 min and 24 h) and to perform Bayesian estimation on the remaining 26 courses (17 patients, group II). For patients of group II, Bayesian estimation (BE) associated with a reduced sub-optimal sampling protocol (20 min and 24 h) was compared with maximum likelihood estimation (MLE), the classical procedure. Regression analysis of clearance values obtained after BE versus MLE indicated a high correlation coefficient (r = 0.969) with the slope (a = 0.991 +/- 0.085) and the intercept (b = 2.271 +/- 4.810) close to 1 and 0 respectively. This original method is thus valid to measure accurately adriamycin clearance; it improves patient comfort and can be used routinely.