Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses as Support for Meropenem-Vaborbactam Dosing Regimens and Susceptibility Breakpoints.

Meropenem-vaborbactam is a fixed-dose beta-lactam/beta-lactamase inhibitor with potent in vitro and in vivo activity against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales. Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken using population pharmacokinetic models, nonclinical PK-PD targets for efficacy, in vitro surveillance data, and simulation to provide support for 2 g meropenem-2 g vaborbactam every 8 h (q8h) administered as a 3-h intravenous (i.v.) infusion, and dosing regimens adjusted for patients with renal impairment. Simulated patients varying by renal function measure (estimated glomerular filtration rate [eGFR], mL/min/1.73 m2 and absolute eGFR, mL/min) and resembling the clinical trial population (complicated urinary tract infection, including acute pyelonephritis) were generated. The PK-PD targets for meropenem, the percentage of time on day 1 that free-drug plasma concentrations were above the MIC (%T>MIC), and vaborbactam, the ratio of free-drug plasma area under the concentration-time curve (AUC) on day 1 to the MIC (AUC:MIC ratio), were calculated. Percent probabilities of achieving meropenem free-drug plasma %T>MIC and vaborbactam free-drug plasma AUC:MIC ratio targets were assessed. MIC distributions for Enterobacterales, KPC-producing Enterobacterales, and Pseudomonas aeruginosa were considered as part of an algorithm to assess PK-PD target attainment. For assessments of free-drug plasma PK-PD targets associated with a 1-log10 CFU reduction from baseline, percent probabilities of PK-PD target attainment ranged from 81.3 to 100% at meropenem-vaborbactam MIC values of 4 or 8 µg/mL among simulated patients. The results of these PK-PD target attainment analyses provide support for a dosing regimen of 2 g meropenem-2 g vaborbactam q8h administered as a 3-h i.v. infusion, with dosing regimens adjusted for patients with renal impairment and a meropenem-vaborbactam susceptibility breakpoint of ≤8 µg/mL (tested with a fixed vaborbactam concentration of 8 µg/mL) for Enterobacterales and P. aeruginosa based on these dosing regimens.

Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Noninfected Subjects and Infected Patients.

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma.

STUDY QUESTION: What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER: A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY: Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION: A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE: Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION: Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS: Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER: NCT01150318.

Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

Population pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials.

Oritavancin is a lipoglycopeptide antibiotic with activity against Gram-positive bacteria. Here we describe oritavancin population pharmacokinetics and the impact of patient-specific covariates on drug exposure variability. Concentration-time data were analyzed from two phase 3 clinical trials, SOLO I and SOLO II, in which oritavancin was administered as a single 1,200-mg dose to patients with acute bacterial skin and skin structure infections. A total of 1,337 drug concentrations from 297 patients (90% of whom had 4 or 5 pharmacokinetic samples) were available for analysis. A previously derived population model based on data from 12 phase 1, 2, and 3 oritavancin studies was applied to the SOLO data set. Alterations to the structural model were made, as necessary, based on model fit. Analyses utilized Monte Carlo parametric expectation maximization (S-ADAPT 1.5.6). The previous population pharmacokinetic model fit the data well (r(2) = 0.972), and population pharmacokinetic parameters were estimated with acceptable precision and lack of bias. Covariate evaluations revealed statistically significant relationships between central compartment volume and age and between clearance and height; however, these relationships did not indicate a clinically relevant impact on oritavancin exposure over the range of age and height observed in the SOLO studies. The mean (coefficient of variation [CV]) area under the plasma concentration-time curve from time zero to 72 h (AUC0-72) and maximum plasma concentration (Cmax) were 1,530 (36.9%) µg · h/ml and 138 (23%) µg/ml, respectively. The mean (CV) half-life at alpha phase (t1/2α), t1/2ß, and t1/2γ were 2.29 (49.8%), 13.4 (10.5%), and 245 (14.9%) hours, respectively. These analyses are the first to describe oritavancin pharmacokinetics following a single 1,200-mg dose. Covariate analyses suggested that no dose adjustments are required for renal impairment (creatinine clearance, >29 ml/min), mild or moderate hepatic impairment, age, weight, gender, or diabetes status.

Population pharmacokinetic analyses for BC-3781 using phase 2 data from patients with acute bacterial skin and skin structure infections.

BC-3781, a pleuromutilin antimicrobial agent, is being developed for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia. Data from a phase 2 study of patients with ABSSSI were used to refine a previous population pharmacokinetic (PK) model and explore potential predictors of PK variability. The previously derived population PK model based on data from three phase 1 studies was applied to sparse sampling data from a phase 2 ABSSSI study and modified as necessary. Covariate analyses were conducted to identify descriptors (e.g., body size, renal function, age) associated with interindividual variability in PK. All population PK analyses were conducted by using Monte Carlo parametric expectation maximization implemented in S-ADAPT 1.5.6. The population PK data set contained 1,167 concentrations from 129 patients; 95% of the patients had 5 or more PK samples (median, 11). The previous population PK model (three-compartment model with first-order elimination and nonlinear protein binding) provided an acceptable and unbiased fit to the data from the 129 patients. Population PK parameters were estimated with acceptable precision; individual clearance values were particularly well estimated (median individual precision of 9.15%). Graphical covariate evaluations showed no relationships between PK and age or renal function but modest relationships between body size and clearance and volume of distribution, which were not statistically significant when included in the population PK model. This population PK model will be useful for subsequent PK-pharmacodynamic analyses and simulations conducted to support phase 3 dose selection. (This study has been registered at ClinicalTrials.gov under registration no. NCT01119105.).

The localization of the distal perforators of posterior tibial artery: a cadaveric study for the correct planning of medial adipofascial flaps.

PURPOSE: The adipofascial flap, introduced by Lin in 1994, has many advantages compared to fasciocutaneous or free flaps. Its dissection is relatively easy and fast with low donor-site morbidity, and it does not alter the shape of the leg. The aim of this dissection study is to evaluate the anatomic localization of the most distal perforator of the posterior tibial vessels to provide an anatomical rationale for the safe harvesting of distally based medial adipofascial flaps of the leg. MATERIALS AND METHODS: 30 Lower limbs from 15 cadavers were used for this study. The most distal perforator from posterior tibial perforator artery, accompanied by at least one vein, was identified and its distance from the medial malleolus was noted. RESULTS: A distal perforator was found in all specimens; the mean caliber was 0.77 mm. In all cases, the perforator artery passed in the septum between flexor hallucis longus m. and flexor digitorum longus m. and was accompanied by two veins. In our series, the distance between the lowest perforator and the medial malleolus ranged from 3.5 to 8.2 cm. The median was 6.75 cm, the 5th percentile 4 cm and the 95th percentile 8.1 cm. The mean distance of the perforator from the medial tibial border was 1.23 cm. The mean ratio between the distance of perforator from the medial malleolus and the total leg length was 21%. CONCLUSION: Compared to all previous researches, our study has found more distal perforators from posterior tibial perforator artery. This fact may have important clinical consequences, because the anteromedial adipofascial flap would cover more distal soft tissue defects. Moreover, our data suggest some safety parameters to make the rising of a medial adipofascial leg flap safer in surgical practice.

A new contrast agent for radiological and dissection studies of the arterial network of anatomic specimens.

PURPOSE: The aim of the present study is to propose a new contrast agent that can be easily applied both to CT and dissection studies to replace lead oxide based formulas for comparative anatomical analyses of the vascularisation of cadaveric specimens. METHODS: The infusion material was an epoxy resin, especially modified by the addition of barium sulphate to enhance its radiopacity. The final copolymer was toxicologically safe. To test the properties of the new material, several cadaveric limb injections were performed. The injected specimens were both CT scanned to perform 3D vascular reconstructions and dissected by anatomical planes. RESULTS: There was a perfect correspondence between the image studies and the dissections: even the smallest arteries on CT scan can be identified on the specimen and vice versa. The properties of the epoxy allowed an easy dissection of the vessels. CONCLUSIONS: The new imaging techniques available today, such as CT scan, can evaluate the vascular anatomy in high detail and 3D. This new contrast agent may help realising detailed vascular studies comparing CT scan results with anatomical dissections. Moreover, it may be useful for teaching surgical skills in the field of plastic surgery.

A case series study on complications after breast augmentation with Macrolane™.

BACKGROUND: The use of Macrolane™ seems to have several advantages compared to the other standard methods for breast augmentation: it is faster, less invasive, and requires only local anesthesia. Nevertheless, various complications associated with the use of Macrolane™ have been described, e.g., encapsulated lumps in breast tissue, infection, and parenchymal fibrosis. We report the results of our case series study on the clinical and imaging evaluations of patients who came to our attention after breast augmentation with Macrolane™ injection and evaluate the effect of this treatment on breast cancer screening procedures. METHODS: Between September 2009 and July 2010, seven patients, treated elsewhere with intramammary Macrolane™ injection for cosmetic purposes, presented to our institution complaining of breast pain. In all patients, Macrolane™ had been injected under local anesthesia in the retromammary space through a surgical cannula. RESULTS: On mammography, nodules appeared as gross lobulated radiopacities with polycyclic contours. On breast ultrasound, the nodules showed hypo-anaechogenic cystlike features. In all cases, image analysis by the radiologist was hindered by the presence of the implanted substance, which did not allow the complete inspection of the whole breast tissue. CONCLUSIONS: From our experience, although safe in other areas, injection of Macrolane™ into breast tissue cannot be recommended at this time. Our study, along with other reports, supports the need to start a clinical trial on the use of injectable fillers in the breast to validate their safety and effectiveness. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Relation of risk of contralateral breast cancer to the interval since the first primary tumour.

BACKGROUND: There is no consensus on how to separate contralateral breast cancer (CBC) occurring as distant spread of the primary breast cancer (BC) from an independent CBC. METHODS: We used standardised incidence ratios (SIRs) to analyse the variations in the risk of CBC over time among 6629 women with BC diagnosed between 1954 and 1983. To explore the most appropriate cutoff to separate the two types of CBC, we analysed the deviance between models including different cutoff points as compared with the basal model with no cutoff date. We also performed a prognostic study through a Cox model. RESULTS: The SIR was much higher during the first 2 years of follow-up than afterwards. The best cutoff appeared to be 2 years. The risk of early CBC was linked to tumour spread and the risk of late CBC was linked to age and to the size of the tumour. Radiotherapy was not selected by the model either for early or late CBC risk. CONCLUSION: A clearer pattern of CBC risk might appear if studies used a similar cutoff time after the initial BC.

Impact of different factors on the probability of clinical response in tigecycline-treated patients with intra-abdominal infections.

Patients with intra-abdominal infections differ with regard to the type of infection and the severity of illness. However, the impact of these factors, together with differences in drug exposure, on clinical response is not well understood. Using phase 2 and 3 data for patients with complicated intra-abdominal infections, the relative importance of tigecycline exposure, host factors, and disease factors, alone or in combination, for the probability of clinical response was examined. Patients with complicated intra-abdominal infections who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for 5 to 14 days and who had adequate clinical, pharmacokinetic, and response data were evaluated. Multivariable logistic regression was used to identify factors associated with clinical response. A final multivariable logistic regression model demonstrated six factors based on 123 patients to be predictive of clinical success: a weight of <94 kg (P = 0.026), the absence of Pseudomonas aeruginosa in baseline cultures (P = 0.021), an APACHE II score of <13 (P = 0.029), non-Hispanic race (P = 0.005), complicated appendicitis or cholecystitis (P = 0.004), and a ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) of > or =3.1 (P = 0.003). The average model-predicted probability of clinical success when one unfavorable factor was present was 0.940. This probability was lower (0.855) when the AUC/MIC ratio was < 3.1 and the remaining five factors were set to the favorable condition. The average model-predicted probability of clinical success in the presence of two unfavorable factors was 0.594. These findings demonstrated the impact of individual and multiple factors on clinical response in the context of drug exposure.

Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults.

Pirfenidone is a small, synthetic molecule under investigation for treatment of idiopathic pulmonary fibrosis. In an open-label, single-dose crossover study, the pharmacokinetics (PK) of pirfenidone were investigated with or without food and antacids in healthy adult volunteers. Concentrations of pirfenidone and its metabolites in plasma and urine were determined by liquid chromatography with tandem mass spectrometry, and candidate pharmacokinetic models were fit to plasma data using weighted, non-linear regression. The effect of food and antacids on pirfenidone exposure was evaluated by determining 'equivalence' using FDA guidelines. Adverse events were recorded by site personnel and classified by investigators on the basis of severity and relationship to study drug. Sixteen subjects yielded 64 pharmacokinetic profiles. The best fit was achieved using a five-compartment, linear model with an allowance for direct conversion to the primary metabolite (5-carboxy-pirfenidone). Coadministration with food decreased the rate and, to a lesser degree, the extent of pirfenidone absorption of absorption. Analysis of adverse events revealed a correlation between pirfenidone C(max) and the risk of gastrointestinal (GI) adverse events, suggesting that food may reduce the risk of certain adverse events associated with pirfenidone. Administration of pirfenidone with food has a modest effect on overall exposure but results in lower peak concentrations, which may improve tolerability.

Effects of zafirlukast on capsular contracture: controlled study measuring the mammary compliance.

Capsular contracture is a highly distressing, difficult complication after breast augmentation for both the patient and the surgeon. Although capsular contracture is a multifactorial process, one common denominator in the successful treatment of this complication is believed to be the abatement of inflammation. Leukotriene antagonists have recently emerged as effective prophylactic agents in reactive airway diseases. Anecdotal reports have indicated that zafirlukast (Accolate, AstraZeneca) effectively reverses capsular contracture. A prospective study of capsular contracture in 120 female patients in whom a total of 216 prostheses were implanted was performed. The hardness of capsular contracture was assessed by means of the mammary compliance method (Anton Paar Mammacompliance system). The patients were divided into two groups: patients in group A received zafirlukast for a 6-month period, while those in group B received vitamin E. The results show a significant decrease of the values of breast compliance after 6 months in group A but not in group B and that the variation in compliance after 6 months in group A compared to group B is statistically significant. In zafirlukast-treated patients, we observed a reduction in mammary compliance of 7.69 percent after 1 month, 16.78 percent after 3 months and 24.01 percent after 6 months. The present study suggests that zafirlukast may be effective in reducing pain and breast capsule distortion in patients with longstanding contracture who are either not surgical candidates or who do not wish to undergo surgery.

The efficacy of a polyhydrated ionogen impregnated dressing in the treatment of recalcitrant diabetic foot ulcers: a multi-centre pilot study.

OBJECTIVE: Assessing the efficacy of a polyhydrated ionogen impregnated dressing in the treatment of recalcitrant diabetic foot ulcers. SUMMARY BACKGROUND DATA: Diabetic Foot Ulcers (DFU) continue to present a formidable challenge in terms of morbidity and health care costs. Increasing evidence ascertains the important role of Matrix MetalloProteinases (MMPs) and their tissue inhibitors, TIMPs, in wound healing. Imbalance of MMPs in the DFU microenvironment has been associated with poor wound healing. Current research is directed towards therapeutic agents that could redress the imbalance of MMPs/TIMPs. Poly Hydrated Ionogen (PHI) formulation is based on metallic ions and citric acid. PHI application aims to positively restore MMP ratios within chronic wounds. This initial multi-centre pilot study aimed to investigate the efficacy of the PHI formulation in achieving stable wound closure in recalcitrant DFUs. MATERIAL AND METHODS: Twenty patients with therapy resistant DFUs of at least 1 cm2 and 3 months duration were treated with PHI formulation in an acetate carrier dressing. Wound debridement, digital imaging and wound perimeter tracing was performed weekly. Off-loading was performed by the use of appropriate shoe-wear (cut-out sandals) and crutches. Patient satisfaction was assessed with a questionnaire. A detailed evaluation sheet was kept for every patient and updated at each visit. RESULTS: Stable wound closure with high patient satisfaction was achieved in 16 (80%) DFUs. The mean time to full closure was 18 weeks. A stable wound epithelization was seen in all full closure patients up to latest follow-up of one year. CONCLUSIONS: Encouraging results of this pilot study prompt us to further investigate the PHI efficacy in DFU treatment in a multi-centre, randomized controlled trial.

Cost-minimization analysis of prophylactic granulocyte colony-stimulating factor after induction chemotherapy in children with non-Hodgkin's lymphoma.

BACKGROUND: Colony-stimulating factors promote the proliferation of certain bone marrow cell populations. The primary objective of treating patients with these factors prophylactically following chemotherapy is to reduce the risk of infection, thereby minimizing the need for hospitalization and parenteral antibiotics. The use of colony-stimulating factors in children is widespread, despite the absence of conclusive supportive data and the high cost of these drugs. Consequently, the cost-benefit ratio of using prophylactic colony-stimulating factors is an important issue in cancer therapy. METHODS: During the period from January 1994 through June 1996, 149 afebrile children with newly diagnosed non-Hodgkin's lymphoma were randomly assigned either to receive granulocyte colony-stimulating factor (G-CSF) (lenograstim; 5 microg/kg body weight per day subcutaneously) or not to receive it (the control) at the end of the first two courses of induction chemotherapy with cyclophosphamide, vincristine, prednisone, doxorubicin, and methotrexate. A cost-minimization analysis was performed to assess the cost of chemotherapy in each group and to quantify how much could be economized by prescribing G-CSF. RESULTS: The total cost for induction chemotherapy was $29,765 in the G-CSF-treated group and $30,774 in the control group, indicating that the treatment strategy with G-CSF was slightly less expensive than the strategy without G-CSF (mean difference = $1009; 95% confidence interval = -$1474 to $3492). CONCLUSION: Treatment with G-CSF following chemotherapy in children with non-Hodgkin's lymphoma--previously shown to be of limited clinical benefit--also does not appear to reduce the costs of chemotherapy.

[Relationship between lipid profile and body mass index. Five-year follow-up in children aged 6-11 years old. The Rivas-Vaciamadrid study]. / Relación entre el perfil lipídico y el índice de masa corporal. Seguimiento de los 6 a los 11 años. Estudio Rivas-Vaciamadrid.

BACKGROUND: To study the relationship between lipid profile and body mass index (BMI) in children after a 5-year follow-up. METHOD: A total of 281 children were evaluated at the ages of 6 and 11 years. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and apoproteins A1 (Apo A) and B100 (Apo B) were measured. Low-density lipoprotein cholesterol (LDL-C) was determined and the Apo B/Apo A, TC/HDL-C, LDL-C/HDL-C indexes, and the atherogenic index were calculated. BMI was also calculated (BMI 5 kg/m2). Evolution parameters were calculated (EVO 5 value 11 years - value 6 years). Associations between BMI and lipid profile were studied. RESULTS: The prevalence of obesity (according to the criteria of the International Obesity Task Force) was 4.98 % (6 years) and 16,72 % (11 years). In children who were in the fourth BMI quartile at the age of 11 years, LDL-C/HDL-C and TC/HDL-C levels were significantly higher and than those in children in the first quartile but HDL-C and Apo A levels were lower. A significant positive correlation was found between the evolution of BMI and the four indexes studied and TG, but this correlation was negative for HDL-C and Apo A. The evolution of the indexes was positive in 11-year-old obese children and negative in nonobese children. CONCLUSIONS: Lipid profile was worse in 11-year-old children in the fourth BMI quartile than in the remaining children. Obese children had higher values of the indexes studied, supporting the importance of obesity as a cardiovascular risk factor.

A large lower eyelid reconstruction: nasojugal flaps plus V-Y advancement flap.

Lower eyelid reconstruction still represents one of the finest expressions in oculoplastic surgery. A 76-year-old male presented with a basal cell carcinoma (BCC) of the lateral canthus, involving the inferior eyelid. After ablative surgery, the resulting full-thickness defect was reconstructed with a mucosal graft from the buccal sulcus and a nasolabial flap subcutaneously pedicled on a V-Y advancement flap. The above techniques, joined together, allow better nasojugal transposition and should be considered when lateral half of the lower eyelid and lateral canthus reconstruction are performed.