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.

Aspergillus spp. invasive external otitis: favourable outcome with a medical approach.

Aspergillus spp. invasive external otitis (IEO) is a rare infection. We performed a seven-year, single-centre retrospective study from 2007 to 2014 including all patients with proven Aspergillus spp. IEO. Twelve patients were identified. All patients had a poorly controlled diabetes mellitus and one underwent solid organ transplant. The most frequently isolated species was Aspergillus flavus (n = 10) and voriconazole was the first-line therapy in all cases, with a median length of treatment of 338.5 days (158-804 days). None of the patients underwent extensive surgery. The clinical outcome was excellent. However, otological sequelae were reported, including hearing impairment (n = 7) and facial palsy (n = 3).

Intraperitoneal clearance as a potential biomarker of cisplatin after intraperitoneal perioperative chemotherapy: a population pharmacokinetic study.

BACKGROUND: Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis. METHODS: Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM. RESULTS: Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity. CONCLUSION: This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context.

Pharmacokinetics and diffusion into sputum of oseltamivir and oseltamivir carboxylate in adults with cystic fibrosis.

Oseltamivir is a prodrug of oseltamivir carboxylate (OC), a neuraminidase inhibitor used for treatment and prevention of influenza. The pharmacokinetics of these 2 compounds were investigated after a single 75-mg oseltamivir dose in 6 patients with cystic fibrosis (CF). Means ± standard deviations of the area under the curve from time zero to infinity (AUC) were 173 ± 58 µg · h/liter for oseltamivir and 2,256 ± 394 µg · h/liter for OC. The concentrations of OC in sputum 4 to 6 h and 22 to 26 h after the intake ranged from 4.1 to 62.2 µg/liter. The AUC of OC was approximately 30% lower than and significantly different from published values for volunteers. On the basis of the present results and because the anti-A/H1N1 influenza virus efficacy of OC is related to its AUC/50% effective concentration (EC(50)) ratio, an increase in the oseltamivir unitary dose could be considered for the treatment of influenza in CF patients. This should nevertheless be confirmed by a controlled pharmacokinetic study performed on a larger number of patients.

FibroScan used in street-based outreach for drug users is useful for hepatitis C virus screening and management: a prospective study.

Although hepatitis C virus (HCV) infection prevalence is high among drug users, they do not commonly receive regular care in academic centres. The aim of this prospective study was to assess the influence of FibroScan use on HCV screening and management in street-based outreach. From January 2006 to January 2007, all consecutive drug users were offered noninvasive evaluation of liver fibrosis with FibroScan. After FibroScan, parameters were recorded with a structured, face-to-face questionnaire by outreach workers. All 298 subjects accepted FibroScan evaluation drug use was--ever injected heroin (69%), ever snorted or injected cocaine (89%), current chronic alcohol abuse (44%). The median FibroScan score was 5.3 kPa. Before blood sampling, 34% of subjects reported HCV positivity. HCV positivity was found in 83 cases. All these subjects had positive HCV-RNA. Forty-five subjects agreed to meet a hepatologist. By multivariate analysis, never snorted cocaine, consumed alcohol < 21 drinks per week, duration of injected heroin > 7 years, and FibroScan > 7.1 kPa were significantly associated with HCV positivity. Thus in a street-based outreach service for drug users, the acceptance of FibroScan is excellent. FibroScan with a hospital-based physician may facilitate screening and management of drug users for HCV infection.

[Noninvasive ventilation in palliative care and near the end of life]. / Place de la ventilation non invasive dans les soins palliatifs et en fin de vie.

INTRODUCTION: The occurrence of life threatening severe respiratory failure in patients with an incurable illness may be an indication for the use of noninvasive ventilation (NIV). STATE OF THE ART: Two approaches are associated with the use of NIV in palliative care settings. In the "palliative approach", NIV is proposed for patients with end stage of chronic respiratory failure and do-not-tracheostomize orders as a ceiling of care. In the "palliative and probably curative" approach, NIV may help patients with do-not-intubate orders or to forego endotracheal intubation. This review provides some guidelines for clinicians responsible for patients with incurable illness, to help to guide and anticipate the medical management if acute respiratory failure (ARF) develops. CONCLUSIONS AND PERSPECTIVES: NIV may palliate symptoms in patients near the end of life. In the case of severe ARF in patients with do-not-intubate orders, NIV may avoid the need for endotracheal mechanical ventilation, most often in patients with COPD or cardiogenic pulmonary oedema. NIV may help some patients to forego endotracheal intubation. Future studies are needed to examine the attitudes of patients and families to this intervention.

Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study.

BACKGROUND: We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity. PATIENTS AND METHODS: Advanced cancer patients with normal liver function, performance status (PS)<3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy. RESULTS: Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02). CONCLUSION: Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.

Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms.

OBJECTIVE: Patients initiating docetaxel chemotherapy were genotyped for CYP3A4, CYP3A5, MDR1, GSTM1, GSTT1, GSTM3, and GSTP1 to identify variability factors of docetaxel pharmacokinetics and toxicity. METHODS: Genotyping was performed by direct sequencing (CYP3A4), real-time polymerase chain reaction (CYP3A5), and polymerase chain reaction-restriction fragment length polymorphism (MDR1 and GST). The clearance and area under the curve of docetaxel were calculated by use of a Bayesian approach. Absolute neutrophil count was recorded twice weekly. RESULTS: With regard to the pharmacokinetic analysis, 58 patients were included. CYP3A4*1B carriers (*1A/*1B, n=4), who are also CYP3A5*1/*3 carriers, had a significantly higher clearance and lower dose-normalized area under the curve of docetaxel than those with the wild genotype (*1A/*1A, n=53): 55.2+/-13.5 L/h versus 37.3+/-11.7 L/h (P=.01) and 31.4+/-6.2 (microg . h/L)/(mg/m(2)) versus 52.7+/-18.2 (microg . h/L)/(mg/m(2)) (P=.005), respectively. No influence of MDR1 was evidenced. With regard to the pharmacodynamic analysis, febrile neutropenia occurred more frequently in GSTP1*A/*B carriers (31.6% versus 3.7% in *A/*A carriers and 0% in *A/*C, *B/*B, and *B/*C carriers) (P=.037). Grade 3 neutropenia occurred more frequently in 3435TT MDR1 genotype carriers: TT, 100%; CT, 77.3%; and CC, 54.5% (P=.046). No influence of GSTM1, GSTT1, or GSTM3 polymorphisms was evidenced on docetaxel toxicity. CONCLUSIONS: Patients carrying the CYP3A*1B allele may have enhanced docetaxel clearance and may be underexposed, whereas those carrying GSTP1*A/*B and 3435TT genotypes may have excessive hematologic toxicity. Further studies are warranted to determine the usefulness of genotyping before docetaxel treatment.

[Interstitial fibrosis in cryptogenic organizing pneumonia could be a predictive factor of relapses]. / La fibrose interstitielle pourrait être prédictive de rechute dans la pneumopathie organisée cryptogénique.

INTRODUCTION: Cryptogenic organizing pneumonia (COP) is a clinicopathologic syndrome characterized by a good prognosis with steroid therapy, but frequent relapses when the dose of corticosteroid is reduced or stopped. CASE REPORT: The purpose of this study was to identify histopathologic features related to the relapse of COP. Six cases of COP that had been diagnosed using open lung biopsy were selected for evaluation. The 6 cases were put into two groups composed of 3 patients who relapsed and 3 who did not relapse. Their pathologic features were examined and compared. CONCLUSIONS: Interstitial fibrosis of the lung parenchyma could correspond to histopathologic characteristics of relapses in COP.

[Alveolar hypoxemic interstitial pneumonia related to rituximab therapy]. / Une pneumopathie alvéolo-interstitielle hypoxémiante associée à la prise de rituximab.

INTRODUCTION: Rituximab is indicated for the treatment of low-grade lymphoma. Pulmonary toxicity related to rituximab is exceptional. CASE REPORT: Here we report a patient with non-Hodgkin lymphoma treated with "CHOP" chemotherapy (cyclophosphosphamide, adriamycin, vincristine and prednisolone) and rituximab who developed an interstitial pneumonia with acute respiratory failure. The differential diagnosis of this clinical and radiological diagnosis is discussed. CONCLUSION: Although cases of interstitial pneumonia associated with rituximab are rare, they may be severe and thus any patient experiencing respiratory symptoms on this therapy should be monitored closely.

[Bronchopulmonary cancer, antiphospholipid syndrome and coagulation disorders]. / Cancer bronchique, syndrome des antiphospholipides et pathologie de la coagulation.

INTRODUCTION: The antiphospholipid syndrome includes recurrent thrombotic manifestations related to antiphospholipid antibodies. Adrenal insufficiency is a rare complication of the antiphospholipid syndrome. EXEGESIS: We report a case of acute adrenal insufficiency secondary to bilateral adrenal hemorrhage in a 45-year-old man. The finding of antiphospholipid antibodies and 6 months later of a polymetastatic bronchopulmonary cancer led us to diagnose a paraneoplasic antiphospholipid syndrome. CONCLUSION: We discuss the role of coagulation disorders in the pathogenesis of tumor growth and rapid metastatic spread. Assessment of the high risk for thrombosis may be of prognostic and therapeutic value in patients with evolutive bronchopulmonary cancer. Early anticoagulation treatment in association with classical treatment of cancer may contribute to prevent malignant process from extending and avoid metastatic spread.