[An ophthalmologic diagnostic error leading to a rare systemic diagnosis: Erdheim-Chester disease]. / Une errance diagnostique ophtalmologique aboutissant à un diagnostic systémique rare: la maladie d'Erdheim-Chester.

INTRODUCTION: Erdheim-Chester disease is a rare systemic disease. The diagnosis is difficult due to significant clinical and morphological polymorphism. Orbital involvement is rare, but constitutes a classic means of detection. OBSERVATION: We report the case of a 60-year-old man, who consulted for evaluation of bilateral retro-orbital tumors. These tumors had been discovered on head CT two years previously during work-up of proptosis. Two biopsies were performed. The first one revealed polymorphous inflammatory tissue. The second one revealed intense granulomatous reaction, rich in non-specific foamy histiocytes. Thoracic-abdominal-pelvic CT scan detected peri-aortic and retroperitoneal infiltration. The association of these signs pointed to a diagnosis of Erdheim-Chester disease, confirmed by the re-examination of the histological samples. DISCUSSION: Erdheim-Chester disease is a rare non-Langerhans histiocytosis with a specific tropism for perivascular and fatty connective tissue. The cause is not known. The diagnosis of this systemic disease is histological. CONCLUSION: In the case of bilateral intra-orbital tumors, the diagnosis of Erdheim-Chester disease must be considered.

[Granular corneal dystrophy treated with deep anterior lamellar keratoplasty: comparing histological analysis and optical coherence tomography]. / Dystrophie granuleuse de type Groenouw 1 traitée par kératoplastie lamellaire antérieure profonde: analyses histologique et tomographique par cohérence optique.

Granular corneal dystrophy is a rare autosomal dominant disease. It is characterized by breadcrumb-like granular opacities in the central corneal stroma. The mutation has been localized in the TGFßI gene, which codes for keratoepithelin, an adhesion protein found in corneal epithelium and stroma. We report the case of granular corneal dystrophy in a 60-year-old man complaining of reduced visual acuity. Slit-lamp examination revealed multiple opacities in the central stroma of his left eye, and recurrent deposits in his other eye 13 years after penetrating keratoplasty. An anterior segment optical coherence tomography (Visante(®) OCT) was used to determine the location of deposits, then a deep anterior lamellar keratoplasty was performed in his left eye. The depth of the deposits revealed by Visante(®) OCT correlated well with the postsurgical histological findings. Visante(®) OCT can therefore help choose between phototherapeutic keratectomy and lamellar keratoplasty, techniques that are less invasive than penetrating keratoplasty, which is advantageous since this dystrophy is known to recur after surgery.

Exposure equivalence between IV (0.8 mg/kg) and oral (1 mg/kg) busulfan in adult patients.

OBJECTIVE: This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. METHODS: Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu (n = 71, 1 mg/kg) and those of IV Bu (n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. RESULTS: Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. CONCLUSION: This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu.

Clinical, sonographic and manometric characteristics and impact on quality of life of fecal incontinence in 92 men referred for endoanal ultrasonography.

UNLABELLED: Anal incontinence (AI) is a frequent symptom with considerable impact on quality of life. The aim of this study was to describe the clinical, sonographic and manometric characteristics of a male population with AI. MATERIALS AND METHODS: Endoanal ultrasonography (EAU) was performed in 92 men referred for exploration of AI. Anal incontinence severity was evaluated by the Jorge and Wexner score (JW). The gastrointestinal quality-of-life index (GIQLI) was determined in 57% of patients. Anorectal manometry was performed in 62.6% of patients. RESULTS: The average JW score was 11+/-1. Anal incontinence had considerable impact on quality of life: average GIQLI=81+/-4. Seventeen patients presented an anal sphincter defect on EAU, 16 of whom had a history of coloproctological surgery. Prior surgery was significantly more common among patients who had a defect on ultrasonography; manometry showed significantly lower resting anal pressure. CONCLUSION: Our study confirms the severity of AI in a male population and its impact on quality of life. It also highlights the high prevalence of anal sphincter defects in patients with a history of anal surgery.

Vinorelbine/docetaxel combination treatment of metastatic breast cancer: a phase I study.

PURPOSE: The aim of this study was to investigate the combination of vinorelbine (VRL) alternating intravenous (i.v.) and oral in combination with docetaxel (DCT) as first-line chemotherapy of patients with metastatic breast cancer. PATIENTS AND METHODS: Tested doses were 60 or 70 mg m(-2) given on day 1 for DCT, 20 to 25 mg m(-2) for i.v. VRL on day 1, 60 mg m(-2) on day 8 or day 15 for oral VRL. Day 1 was administered every 3 weeks. Three to six patients were treated per dose level. RESULTS: The median age of the 30 treated patients was 60 years. Four patients were non evaluable for the maximum tolerated dose (MTD) and were replaced. Reported dose-limiting toxicities were 11 omissions of oral VRL for neutropenia, two cases of febrile neutropenia and two grade 4 neutropenia >or=7 days. Dose levels using DCT doses >60 mg m(-2) and/or i.v. VRL doses >20 mg m(-2) met the criteria for MTD. Most frequent toxicities were febrile neutropenia in seven patients and neutropenic infection in four patients (one fatal). Therefore, the recommended schedule was established at i.v. VRL 20 mg m(-2) with DCT 60 mg m(-2) on day 1 and oral VRL 60 mg m(-2) given on day 15 every 3 weeks. At this recommended schedule, only one of six patients experienced febrile neutropenia. Among 22 patients evaluable for tumour response, 2 complete and 10 partial responses were reported. Pharmacokinetics of combined VRL and DCT demonstrated the absence of mutual interaction. CONCLUSIONS: This phase I study established the recommended doses and schedules of the combination alternating i.v. and oral VRL with DCT, this recommended regimen being further explored in a phase II study.

Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study.

An IV form of busulfan (IV Bu) has recently become available for high dose conditioning regimen before haematopoietic stem cell transplantation (HSCT). This IV form is expected to reduce the high pharmacokinetic variability exhibited with oral busulfan and as a result, to better target the plasma area under the curve (AUC). Pharmacokinetics (PK) of IV Bu was investigated on 127 adult patients (333 PK administrations) who received 0.8 mg.kg-1 of Bu as a 2-h infusion every 6 h over 4 days, followed by cyclophosphamide (60 mg.kg-1 day-1x2). A retrospective population PK analysis was carried out to search for important predictive factors of IV Bu PK and to develop a limited sampling strategy (LSS) through Bayesian methodology. The analysis was conducted using the Non Linear Mixed Effect methodology and included a validation process on an independent data set. Adjusted Ideal Body Weight (AIBW) and Body Surface Area (BSA) were the best covariates to explain the inter-patient variability. The final inter-patient variability (CV=16%) in IV Bu clearance (Cltot) was estimated close to the intra-patient variability (CV=13%). There was neither age-dependency nor gender effect. IV Bu Cltot was not affected by elevated hepatic enzymes or by co-administration of either fluconazole or acetaminophen, and was not altered in heavily pre-treated or pre-transplanted patients. Normalised Cltot based on either AIBW or BSA was comparable between normal and obese patients (BMI=18-26.9 kg.m-2, >26.9 kg.m-2, respectively) whereas significant differences existed when based on either actual (ABW) or ideal body weight (IBW). As a consequence, no dose adjustment is required in obese patients when using a AIBW- or BSA-based dose calculation. A fixed dose of 0.80 mg.kg-1 of AIBW or 29 mg.m-2 of BSA yielded an average AUC of 1,200 microM.min, with 80% of patients within the "therapeutic" AUC range of 900-1,500 microM.min. Alternatively, 0.80 mg.kg-1 based on either ABW or IBW for normal patients and on AIBW for obese patients would achieve the same performance. A limited sampling strategy based on a Bayesian methodology was developed and validated on an independent dataset: AUCs obtained from one to two samplings were demonstrated to be reliably estimated.

[Advantages and disadvantages of the femtosecond laser microkeratome]. / Avantages et inconvénients du microkératome laser femtoseconde.

Laser in situ keratomileusis (LASIK) complications are mainly attributable to imperfect cutting with the mechanical microkeratome. The femtosecond laser is an important challenger because it can provide extremely precise cutting beginning at any corneal point. We analyze the potential of this new tool from the results reported in the literature. The optomechanical control of the impact position provides freer and more effective intrastromal cutting than the blade. The best cutting matrix is obtained with the postage stamp method. If the plasma quality is not perfectly under control, side effects such as tissue streaks and secondary ultraviolet radiations can be observed. For LASIK surgery, femtolaser cutting can offer greater safety, reproducibility, predictability and flexibility. The risk of incomplete or irregular cutting and the free cap risk are reduced. Striae, epithelial defects and interface deposits should be minimized. A better flap congruence can limit the risk of secondary displacement and epithelial ingrowth. The results of making thinner flaps should be more predictable. Other than the high cost of the procedure, laser cutting has very few disadvantages. In 1999, Intralase Corporation introduced the first femtolaser microkeratome on the American market. Approximately 120,000 intra-LASIK procedures have been carried out with fewer cutting complications than with the mechanic blade.

[Tissular and mechanical effects observed with an experimental femtosecond laser microkeratome for corneal refractive surgery]. / Effets tissulaires et mécaniques observés lors de l'expérimentation d'un microkératome laser femtoseconde pour la chirurgie réfractive cornéenne.

PURPOSE: Despite progress in mechanical microkeratomes used in refractive surgery, mechanical complications during cutting of the cornea still occur. Cutting by laser could reduce these complications and to date, the femtosecond laser is the only potential candidate for this purpose. Our study reports preliminary results with a femtosecond microkeratome for cutting porcine corneas ex vivo. METHODS: We first examined the fundamental principles of the interaction between the femtosecond laser and the corneal stroma, including the volume of tissue lesions, the laser breakdown threshold of the stroma and the laser ablation selectivity. We then analyzed the quality of cutting corneal flaps with the laser, focusing on collateral tissue effects and the roughness of the interfaces observed both histologically and with scanning electron microscopy. RESULTS: The photoablative and photodisruptive effects were very similar with the femtosecond laser. This characteristic is specific to ultrashort impulsion photodisruptor lasers and allows for a very precise surgical procedure. The laser-induced breakdown threshold of porcine corneal stroma was found to be 0.55 J/cm2. Collateral tissue lesions were on the submicrometer level. The roughness of the stromal bed was optimal for postage stamp cutting, providing very many contiguous points of impact which were as spherical as possible. CONCLUSION: Corneal photodisruption with a femtosecond laser is reproducible and extremely accurate. The optomechanical parameters involved with this technique require great technological skill and should be placed in experienced hands.

I.V. busulfan in pediatrics: a novel dosing to improve safety/efficacy for hematopoietic progenitor cell transplantation recipients.

A retrospective population pharmacokinetic (PPK) analysis was performed in 24 pediatric patients (PEDS) (0.45-16.7 years old) receiving i.v. busulfan/cyclophosphamide (i.v. Bu/Cy 4) regimen prior to allogeneic hematopoietic stem cell transplantation. I.V. Bu doses were given as a 2-hour infusion every 6 h over 4 days. Initial dosing of i.v. Bu was 1 mg/kg for children < or =4 years old and 0.8 mg/kg for patients >4 years old. Bu plasma concentrations at doses 1, 9 and 13 were analyzed through a multivariate NONMEM analysis. A close log-linear relationship between body weight (BW) and i.v. Bu clearance was demonstrated with no further age-dependency or gender effect. The interpatient coefficient of variation (CV) in Bu clearance significantly decreased from 56% (covariate-free model) to 19% (BW covariate model) and reproducible i.v. Bu exposure between doses was illustrated (intraindividual CV=9%). Based on the PPK model, a novel Bu dosing regimen (ie: doses in mg/kg adjusted to discrete weight categories) for a better AUC targeting was developed by simulation on 1000 patients. Age-based dosing was demonstrated not to be clinically relevant with i.v. Bu. Use of the new BW-based dosing appears to be more appropriate for the PEDS.

Factors affecting pharmacokinetic variability of oral topotecan: a population analysis.

The aim of this study was to characterise the pharmacokinetics of the anticancer agent topotecan, and explore the influence of patient covariates and interoccasion variability on drug disposition. Data were obtained from 190 patients who received the drug as a 30-min infusion (N=72) or orally (N=118). The population model was built with the use of NONMEM to identify candidate covariates, and obtain models for clearance (CL) and volume of distribution. The final models were based on first-order absorption with lag-time (oral data), and a two-compartment model with linear elimination from the central compartment. The Cockcroft-Gault creatinine clearance (CrCl) and WHO performance status (PS) were the only significant covariates: CL=(12.8+2.1 x CrCl) x (1-0.12 x PS). For the volume of distribution, a correlation was found between body weight and the central volume (V1)=0.58 x body weight. Based on the structural models, a limited-sampling strategy was developed with minor bias and good precision that can be applied a posteriori using timed samples obtained at 1.5, and 6 h after the administration of topotecan. In conclusion, a population pharmacokinetic model for topotecan has been developed that incorporates measures of renal function and PS to predict CL. In combination with drug monitoring, the limited sampling strategy allows individualised treatment for patients receiving oral topotecan.

Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance.

BACKGROUND: Carboplatin is the only cancer drug for which conventional doses are individually adjusted according to estimated clearance and target area under the curve (AUC). The aim of this prospective study was (i) to evaluate intra- and interpatient variability of ultrafilterable (UF) carboplatin AUC(0-)(infinity) and (ii) to test whether the prediction of carboplatin clearance according to the Chatelut formula established for conventional carboplatin doses was accurate for low carboplatin doses. MATERIALS AND METHODS: Thirty-one head and neck cancer patients (29 men, two women, mean age 55.9 years) received concomitant radiotherapy (Rgamma 2 Gy/day) and chemotherapy (carboplatin 50 mg/m(2)/day i.v.) for 7 weeks: Rgamma was administered 5 days/week (days 1-5) and carboplatin 2 days/week (days 1 and 4). Pharmacokinetics was performed once per week. A limited sample strategy based on Bayesian analysis was first validated and blood was subsequently taken 1 and 4 h after the end of carboplatin administration. RESULTS: A total of 143 cycles was analyzed. Ultrafilterable carboplatin AUC(0-)(infinity) ranged from 0.360 to 4.200 mg.min/ml (mean 0.830, median 0.670). As a corollary, UF carboplatin clearance ranged from 19.1 to 244.7 ml/min. Ultrafilterable carboplatin concentrations were very stable over time: AUC(0-)(infinity) variability due to treatment duration contributed to <1% of the total variance, while interpatient variability contributed to 68.6%. Accordingly, intrasubject effect was not significant (P = 0.38) whereas intersubject effect was highly significant (P <0.001). These results suggest that optimal dosage for targeting a given AUC may vary within a 13-fold range between patients. The Chatelut formula, based on creatininemia, body weight, age and sex, over estimates carboplatin clearance by 40% on average (bias 95% CI 29.6% to 51.1%). No significant relationship was observed between either bone marrow toxicity or creatinine clearance decrease and carboplatin pharmacokinetics. CONCLUSIONS: The Chatelut carboplatin clearance model established for conventional carboplatin dosages (>100 mg/m(2)) is not applicable for targeting low AUC (<1 mg x min/ml).

S/e-PTFE episcleral buckling implants: an experimental and histopathologic study.

To investigate tissue changes induced by the implantation of a silicone band coated with expanded polytetrafluoroethylene (S/e-PTFE) used as scleral buckling, an experimental and histopathological study was performed in rabbits. The right eyes of eight rabbits were implanted for 28-85 days with S/e-PTFE. No complications were encountered in any of the eyes, so histopathological examinations could be performed. Encapsulations combined with numerous giant cells were found to be surrounding the implants in seven eyes, and deposits from the mineral salts of calcium were found in three eyes, forming granulomas possibly caused by irregularities of the implant surface. The porous structure allowed a peripheral colonization by fibrovascular tissue. Taking into account the histological results, the use of this material does not appear suitable. However, this inflammation was limited and did not merge on surrounding tissues.

Impact of the biochemical assay for serum creatinine measurement on the individual carboplatin dosing: a prospective study.

We previously developed a formula to estimate the individual carboplatin clearance (CL) based on serum creatinine (Scr) determined by an enzymatic assay using creatinine amidohydrolase. An analytical comparison had shown systematic differences between this method and the commonly used Jaffé method (with Jaffé Scr (in microM)=1.08 x enzymatic Scr+1.6, as regression equation). We performed a pharmacokinetic prospective clinical study using the Jaffé assay to evaluate the impact of the method used for Scr measurement on the prediction of the carboplatin CL. In forty patients, carboplatin dosing was performed according to the Chatelut formula where the serum creatinine level was corrected according to the above equation. The population pharmacokinetics of carboplatin were analysed using the NONMEM program to determine the individual carboplatin CL from a limited sampling strategy. Thanks to the correction of the Jaffé Scr, no significant difference was observed between the administered and the optimal dose. In contrast, if no correction of the Scr was done, the patients would have been significantly under-dosed. Moreover, a covariate analysis using NONMEM gave a very consistent result showing that Scr should be decreased by 11.6% when the Jaffé value is used within the Chatelut equation. This study confirmed that differences in the Scr assay has consequences with regard to carboplatin dosing. The correction we propose for Scr obtained by the Jaffé method may help to standardise clinical practice.

[Histologic evaluation in rabbits of the biocompatibility of episcleral implant material: S-PTFEe (silicone core covered with expanded polytetrafluoroethylene)]. / Evaluation histologique chez le lapin de la biocompatibilité d'un matériel d'indentation épiscléral: le S-PTFEe (noyau en silicone recouvert de polytétrafluoro-éthylène expansé).

PURPOSE: To study the tolerance of a silicone band wrapped with expanded polytetrafluoroethylene (e-PTFE) in "fauve de Bourgogne" rabbits. METHODS: A 5.7mmx3.2mm band of S-PTFE (silicone-polytetrafluoroethylene, France Chirurgie Instruments) was used. A tight seal was produced between the two materials by silicone gluing. Eight eyes were implanted episclerally and fixed with Mersilene 5-0. One silicone band was used on a control eye. RESULTS: Three eyes were removed at 4 weeks, one at 8 weeks and four at 12 weeks. No extrusion was observed except for the silicone band rejected 2 weeks after implantation. On histopathologic examination, PTFE colonisation was present in all eyes with fibroblast, inflammatory cells, and neovascularization. CONCLUSION: The S-PTFE implant was colonized and well tolerated in rabbit eyes. Advantages of silicone band (quality, stability of indentation) are combined to the tolerance of PTFE.

Histologic findings in a series of 1,540 corneal allografts.

We present a series of 1,540 corneal allografts studied since 1982. Corneal edema was the major lesion in 439 corneal specimens (28.4%). Keratitis was the largest group with 378 cases (24.5%), including 134 cases of corneal scarring (8.7%). There were 113 cases of herpes simplex virus keratitis (7.3%), mostly of the disciform stromal type, and 60 cases of non herpetic interstitial keratitis (3.9%), 44 of superficial keratitis (2.8%) and 10 of ulcerative keratitis (0.6%). Among the 17 other cases (1.1%), there were 3 of fungal keratitis, 2 syphilitic keratitis and one case of acanthamoebic keratitis. The third group was formed by corneal dystrophies with 376 cases (24.4%). There were 192 keratoconus (12.5%), 121 Fuchs' dystrophies (7.9%), 28 calcific band keratopathies (1.8%), 18 had corneal dystrophies with amyloid deposits and 16 did not. There were 169 regrafts (11%) and 135 traumatic lesions (8,8%). Among the 43 miscellaneous cases (2,8%), there were 22 cases with previous refractive eye surgery, one corneal myxoma, 5 cases of dysplasia, 5 pterigia, 3 sclerocornea, one fish-eye disease, one floppy eyelid syndrome and 5 unclassifiable cases. The mechanisms of these lesions are mainly related to an autoimmune disease in most cases of herpes keratitis. Some rare forms of corneal dystrophies contain amyloid deposits produced by an abnormal kerato-epithelin. Cases of graft failure are not particulary frequent, due to the avascularity of the cornea and its particular immune status.