Gene expression signatures and molecular markers associated with clinical outcome in locally advanced head and neck carcinoma.

The purpose of this study was to identify molecular markers associated with tumor recurrence and survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). We studied the expression profile of 63 pre-treatment tumor biopsies obtained from locally advanced HNSCCs treated with standard treatments. Cluster analysis identified three tumor subtypes associated with significant differences in local recurrence-free survival (LRFS) (P<0.001), progression free-survival (PFS) (P<0.009) and overall survival (OS) (P<0.004). Tumor subtype 1, associated with short LRFS, PFS and OS, showed features of epithelial-mesenchymal transition and undifferentiation. It also overexpressed genes involved in cell adhesion, NF-κB and integrin signalling. Tumor subtype 3, associated with longer LRFS, PFS and OS, showed a high degree of differentiation and overexpressed genes located in chromosomal regions 19q13 and 1q21. Tumor subtype 2, which had an intermediate clinical outcome between subtype 1 and subtype 3, overexpressed genes involved in branching morphogenesis. Finally, we validated the association between gene cluster classification and patient survival using Gene Set Enrichment Analysis and two HNSCC data sets obtained from two independent patient cohorts. In conclusion, we generated a gene prognostic signature associated with survival in locally advanced patients using the expression profile of the pre-treatment tumor biopsy. Independent prospective studies would be necessary to assess if the proposed survival signature could help to guide clinical management of HNSCC.

Massive thyroxine intoxication: evaluation of plasma extraction.

Six patients were admitted after erroneous massive intake of levothyroxine (70-1200 mg over an interval of 2-12 days). All patients developed classical symptoms of thyrotoxicosis within 3 days of the first dose; five patients presented grade II-III coma and one became stuporous (days 7-10). Two patients developed left ventricular failure and three had arrhythmias (days 8-11). Total thyroid hormone levels in serum on admission ranged 935-7728 nmol/l for T4 (TT4) and 23-399 nmol/l for T3 (TT3). All patients received treatment with hydrocortisone and Propranolol. Propylthiouracil was also given in 3 cases. Extractive techniques (charcoal haemoperfusion and/or plasmapheresis) were initiated 8-14 days after the first dose of L-T4. The plasma disappearance rate (K) of TT4 with plasmapheresis was 30 times higher, on average, than under standard medical treatment (M). Also, K of TT4 under haemoperfusion was about five times higher than K under M. K changes for TT3 were higher under haemoperfusion than under plasmapheresis. Furthermore, extractive procedures shortened the average half life of TT4, (from 106.5 +/- 44.6 to 59.7 +/- 20.2 h, p less than 0.05).

[Relation between the viscosity of enteral diets and mechanical complications in their administration according to the nasogastric catheters]. / Relación entre la viscosidad de las dietas enterales y las complicaciones mecánicas en su administración según el diámetro de la sonda nasogástrica.

OBJECTIVE: The use of enteral nutrition has increased enormously over the last few years and at the same time the standard indications for parenteral nutrition, whether in hospitals or at home, have gradually been defined. The most common way to administer enteral nutrition is intermittently and using gravity, through a nasogastric catheter or through gastrostomy. In our daily practice it has been observed that there was at times a considerable delay in the administration of the diet by means of a nasogastric catheter and the tube was sometimes blocked due to its small calibre and/or the excessive viscosity of the formula. It was therefore proposed to study the viscosities of polymeric enteral diets with and without fibre at this hospital to identify the relationship with the time taken for their intermittent, gravity-driven administration through different calibres of nasogastric catheter at the maximum flow rate. RESULTS: Some of the enteral diets under study exceeded the recommended time for intermittent administration by gravity (20-40 minutes). CONCLUSIONS: We feel it is essential for the product label to provide information on the optimal calibre of the nasogastric catheter required for administration of the product.

[Contrast vision in patients with aphakia and pseudophakia]. / Etude sur la vision de contraste chez les aphakes et les pseudophakes.

A study was carried out on contrast vision in 26 aphakic patients (48 operated eyes) and 37 pseudophakic patients (37 operated eyes); in some cases an intraocular PMMA lens had been implanted, in others an IOGEL (polimacon) had been implanted. The level of sensitivity to contrast in both cases was found to be lower than expected by the Vistech company for aphakics. At the same time a comparative study was carried out of the results obtained for sharpness of vision in aphakic and pseudophakic patients, with the traditional tests of Snellen (long sightedness) and Parinaud (short sightedness) and those obtained with the Contrast Sensitivity Test System (VCTS-6500 for long sightedness and VCTS-6000 for short sightedness). The former tests were found to overestimate the visual results. Corrected aphakia was found to affect the sensitivity to contrast more than in pseudophakic cases. Nevertheless no significant differences were found between contrast vision in eyes with PMMA lens implantation and eyes with IOGEL (polimacon) lens implantation. Summing up, alterations in the sensitivity to contrast undetected by the simple measurement of visual sharpness were found.

[Viscosity changes in thickened water due to the addition of highly prescribed drugs in geriatrics]. / Cambios en la viscosidad del agua con espesantes por la adición de fármacos altamente prescritos en geriatría.

INTRODUCTION: Dysphagia is a swallowing disorder with a high incidence in the geriatric patient related with an increased risk for undernutrition and pneumonia due to bronchial aspiration. In this condition, it is usual to add commercial thickeners in liquids, as well as the addition of drugs in this mixture to improve their administration. However, there are no studies regarding the possible change in viscosity produced by their addition. OBJECTIVES: To assess the change in viscosity of water thickened with commercial products by adding the drugs frequently used in elderly patients. METHODS: Samples of water mixed with the commercial thickener Resource (modified corn starch) or Nutilis (modified corn starch, maltodextrin, and gums: tara, xhantan, and guar) to achieve an intermediate consistence as "honey". The viscosity of these samples was measured as well as for similar samples to which one of the following drugs was added: galantamine, rivastigmin, ciprofloxacin, cholecalciferol, memantine, fosfomycin, calcium, and amoxicillin/clavulanic acid. RESULTS: In the samples with Resource thickener we observed decreased viscosity by adding galantamine, memantine, fosfomycin or calcium, and increased viscosity with amoxicillin/clavulanic acid. The viscosity of the samples with Nutilis® decreased with galantamine, rivastigmine, amoxicillin/clavulanic acid, fosfomycin and calcium. CONCLUSION: The viscosity of water with commercial thickeners may be affected by some drugs or their preservatives, which may influence the swallowing capability. It is recommended to perform further in vitro and in vivo studies in order to adjust these formulations if necessary.

Absence of veno-occlussive disease in a cohort of multiple myeloma patients undergoing autologous stem cell transplantation with targeted busulfan dosage.

BACKGROUND: Plasma concentrations of oral busulfan (BU) were measured in multiple myeloma (MM) patients undergoing autologous peripheral blood stem cell transplantation (ASCT) with a double alkylating conditioning protocol in order to individualise doses of BU based on individual pharmacokinetic parameters and to reduce toxicities related to BU exposure. PATIENTS AND METHODS: Forty-four consecutive patients with MM participating in the co-operative Spanish protocol were prospectively evaluated. Conditioning regimen prior to autologous infusion consisted of BU followed by melphalan. BU pharmacokinetic parameters were estimated for each patient after the first dose based on measured concentrations and subsequent doses were modified as necessary to achieve target exposure. RESULTS: Mean BU exposure (AUCss) (+/-DS) before dosage modification range from 3192 to 12 180 ng h/mL. Twenty-six out of 44 (59%) patients required dose adjustment. None of the patients developed hepatic veno-occlusive disease (VOD). Grade > or = II oropharyngeal mucositis was observed in the majority of patients (95%) and the severity of mucositis increased with increasing average steady-state BU plasma concentration. There were four treatment-related deaths: two patients died from multiorgan failure and two of respiratory infections. Of the remaining 40 patients, 15 were in complete remission with negative immunofixation, 21 in partial remission and four in stable disease 3 months after ASCT. CONCLUSIONS: The results of the present study show the variability in BU pharmacokinetic parameters and suggest the possible relationship between toxicities and BU exposure. Individualising BU dosage in MM patients undergoing ASCT we observed the absence of VOD.

Algorithms for dosage and therapeutic monitoring of theophylline.

Theophylline is widely prescribed in Spain. Because this drug has a narrow therapeutic range and high interindividual pharmacokinetic variability, it is essential to adapt the dosage to each patient. In order to simplify the drug individualization we are proposing three algorithms to apply to intravenous loading and maintenance doses and to oral doses. The initial recommended dosages have been established using the pharmacokinetic parameters obtained from patients treated with theophylline in our hospital. Because the pharmacokinetic behavior of theophylline may be different in other populations, dosage requirements may not be the same. A minimum number of blood sample collections is proposed in an attempt to improve the cost-benefit relationship in theophylline therapy.

Serum levels of G-CSF, IL-3, IL-6 and GM-CSF after a single intraperitoneal dose of rhG-CSF in lethally irradiated B6D2F1 mice.

The objective of this study was to assess the pharmacokinetics of rhG-CSF after a single intraperitoneal injection 2 h post-TBI in B6D2F1 lethally irradiated mice and to analyze the effect of rhG-CSF on the endogenous response of interleukin-3 (IL-3), interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in these animals. For comparison, these cytokine serum levels have also been measured in nonirradiated mice. The serum concentrations of rhG-CSF in irradiated mice were higher than in nonirradiated mice at all time points during the first 60 min after injection. Furthermore, rhG-CSF administration failed to induce detectable endogenous serum levels of IL-3, IL-6 and GM-CSF, at least in the 72-hour period after administration of the rhG-CSF. The radioprotective effect of rhG-CSF in lethally irradiated mice is not mediated by an increase in endogenous serum levels of these three cytokines.

[Effectiveness of rectal metromidazole in acute infantile appendicitis]. / Eficacia del metronidazol rectal en la apendicitis aguda infantil.

Thirty two consecutive children who underwent surgery for suspected acute appendicitis, were treated with prophylactic metronidazole suppositories. A serum sample was taken at surgery to determine the serum concentration of the drug. After a preoperative dose of 15-20 mg/kg the minimal bactericidal concentration was achieved in almost all cases at the time of anesthetic induction. This drug showed an optimal biodisponibility when used rectally and no side-effects was noted. Neither a wound-infection, nor a wound-sepsis was reported and a satisfactory outcome was registered. We conclude that rectal dosing with metronidazole is effective for prophylactic wound infection in acute appendicitis.

Determination of imipenem in plasma by high-performance liquid chromatography for pharmacokinetic studies in patients.

A rapid and simple HPLC method is described for the determination of imipenem in human plasma. After blood collection, plasma was separated by centrifugation and immediately stabilized with 3-morpholinopropanesulfonic acid (MOPS) and ethylene glycol solution (1:1). The sample preparation, before injection into HPLC, was ultrafiltration. The mobile phase was boric acid buffer. The imipenem was detected at 300 nm and cilastatin sodium, coadministered, did not interfere. Calibration curves in human plasma were linear from 0.1 to 100 microg/ml. The limit of detection was 0.030 microg/ml. Inter-day precision at 0.1 microg/ml, determined as the coefficient of variation, was 6.26%. Only 250 microl of plasma was required in our assay. Due to the limited stability of imipenem [G.B. Smith et al., J. Pharm. Sci., 79 (1990) 732], stability studies in plasma were done to establish appropriate storage conditions. The assay was applied to pharmacokinetic studies in patients.