Clinical benefit and quality of life in patients with advanced pancreatic cancer receiving gemcitabine plus capecitabine versus gemcitabine alone: a randomized multicenter phase III clinical trial--SAKK 44/00-CECOG/PAN.1.3.001.

PURPOSE: To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m(2) twice daily on days 1 through 14 plus Gem 1,000 mg/m(2) in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m(2) in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for >or= 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight. RESULTS: Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05). CONCLUSION: There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

Osteoporotic fracture risk in elderly women: estimation with quantitative heel US and clinical risk factors

PURPOSE: To derive a prediction rule by using prospectively obtained clinical and bone ultrasonographic (US) data to identify elderly women at risk for osteoporotic fractures. MATERIALS AND METHODS: The study was approved by the Swiss Ethics Committee. A prediction rule was computed by using data from a 3-year prospective multicenter study to assess the predictive value of heel-bone quantitative US in 6174 Swiss women aged 70-85 years. A quantitative US device to calculate the stiffness index at the heel was used. Baseline characteristics, known risk factors for osteoporosis and fall, and the quantitative US stiffness index were used to elaborate a predictive rule for osteoporotic fracture. Predictive values were determined by using a univariate Cox model and were adjusted with multivariate analysis. RESULTS: There were five risk factors for the incidence of osteoporotic fracture: older age (>75 years) (P < .001), low heel quantitative US stiffness index (<78%) (P < .001), history of fracture (P = .001), recent fall (P = .001), and a failed chair test (P = .029). The score points assigned to these risk factors were as follows: age, 2 (3 if age > 80 years); low quantitative US stiffness index, 5 (7.5 if stiffness index < 60%); history of fracture, 1; recent fall, 1.5; and failed chair test, 1. The cutoff value to obtain a high sensitivity (90%) was 4.5. With this cutoff, 1464 women were at lower risk (score, <4.5) and 4710 were at higher risk (score, >or=4.5) for fracture. Among the higher-risk women, 6.1% had an osteoporotic fracture, versus 1.8% of women at lower risk. Among the women who had a hip fracture, 90% were in the higher-risk group. CONCLUSION: A prediction rule obtained by using quantitative US stiffness index and four clinical risk factors helped discriminate, with high sensitivity, women at higher versus those at lower risk for osteoporotic fracture.

Brain energy consumption induced by electrical stimulation promotes systemic glucose uptake.

BACKGROUND: Controlled transcranial stimulation of the brain is part of clinical treatment strategies in neuropsychiatric diseases such as depression, stroke, or Parkinson's disease. Manipulating brain activity by transcranial stimulation, however, inevitably influences other control centers of various neuronal and neurohormonal feedback loops and therefore may concomitantly affect systemic metabolic regulation. Because hypothalamic adenosine triphosphate-sensitive potassium channels, which function as local energy sensors, are centrally involved in the regulation of glucose homeostasis, we tested whether transcranial direct current stimulation (tDCS) causes an excitation-induced transient neuronal energy depletion and thus influences systemic glucose homeostasis and related neuroendocrine mediators.METHODS: In a crossover design testing 15 healthy male volunteers, we increased neuronal excitation by anodal tDCS versus sham and examined cerebral energy consumption with (31)phosphorus magnetic resonance spectroscopy. Systemic glucose uptake was determined by euglycemic-hyperinsulinemic glucose clamp, and neurohormonal measurements comprised the parameters of the stress systems.RESULTS: We found that anodic tDCS-induced neuronal excitation causes an energetic depletion, as quantified by (31)phosphorus magnetic resonance spectroscopy. Moreover, tDCS-induced cerebral energy consumption promotes systemic glucose tolerance in a standardized euglycemic-hyperinsulinemic glucose clamp procedure and reduces neurohormonal stress axes activity.CONCLUSIONS: Our data demonstrate that transcranial brain stimulation not only evokes alterations in local neuronal processes but also clearly influences downstream metabolic systems regulated by the brain. The beneficial effects of tDCS on metabolic features may thus qualify brain stimulation as a promising nonpharmacologic therapy option for drug-induced or comorbid metabolic disturbances in various neuropsychiatric diseases.

Measuring brain perfusion with intravoxel incoherent motion (IVIM): Initial clinical experience.

PURPOSE: To evaluate the feasibility of intravoxel incoherent motion (IVIM) perfusion measurements in the brain with currently available imaging systems. MATERIALS AND METHODS: We acquired high in-plane resolution (1.2 × 1.2 mm(2) ) diffusion-weighted images with 16 different values of b ranging from 0 to 900 s/mm(2) , in three orthogonal directions, on 3T systems with a 32-multichannel receiver head coil. IVIM perfusion maps were extracted by fitting a double exponential model of signal amplitude decay. Regions of interest were drawn in pathological and control regions, where IVIM perfusion parameters were compared to the corresponding dynamic susceptibility contrast (DSC) parameters. RESULTS: Hyperperfusion was found in the nonnecrotic or cystic part of two histologically proven glioblastoma multiforme and in two histologically proven glioma WHO grade III, as well as in a brain metastasis of lung adenocarcinoma, in a large meningioma, and in a case of ictal hyperperfusion. A monoexponential decay was found in a territory of acute ischemia, as well as in the necrotic part of a glioblastoma. The IVIM perfusion fraction f correlated well with DSC CBV. CONCLUSION: Our initial report suggests that high-resolution brain perfusion imaging is feasible with IVIM in the current clinical setting. J. Magn. Reson. Imaging 2014;39:624-632. © 2013 Wiley Periodicals, Inc.

Correlation between microtensile bond strength data and clinical outcome of Class V restorations.

OBJECTIVE: To determine if the results of resin-dentin microtensile bond strength (µTBS) is correlated with the outcome parameters of clinical studies on non-retentive Class V restorations. METHODS: Resin-dentin µTBS data were obtained from one test center; the in vitro tests were all performed by the same operator. The µTBS testing was performed 8h after bonding and after 6 months of storing the specimens in water. Pre-test failures (PTFs) of specimens were included in the analysis, attributing them a value of 1MPa. Prospective clinical studies on cervical restorations (Class V) with an observation period of at least 18 months were searched in the literature. The clinical outcome variables were retention loss, marginal discoloration and marginal integrity. Furthermore, an index was formulated to be better able to compare the laboratory and clinical results. Estimates of adhesive effects in a linear mixed model were used to summarize the clinical performance of each adhesive between 12 and 36 months. Spearman correlations between these clinical performances and the µTBS values were calculated subsequently. RESULTS: Thirty-six clinical studies with 15 adhesive/restorative systems for which µTBS data were also available were included in the statistical analysis. In general 3-step and 2-step etch-and-rinse systems showed higher bond strength values than the 2-step/3-step self-etching systems, which, however, produced higher values than the 1-step self-etching and the resin modified glass ionomer systems. Prolonged water storage of specimens resulted in a significant decrease of the mean bond strength values in 5 adhesive systems (Wilcoxon, p<0.05). There was a significant correlation between µTBS values both after 8h and 6 months of storage and marginal discoloration (r=0.54 and r=0.67, respectively). However, the same correlation was not found between µTBS values and the retention rate, clinical index or marginal integrity. SIGNIFICANCE: As µTBS data of adhesive systems, especially after water storage for 6 months, showed a good correlation with marginal discoloration in short-term clinical Class V restorations, longitudinal clinical trials should explore whether early marginal staining is predictive for future retention loss in non-carious cervical restorations.

Coffee consumption attenuates short-term fructose-induced liver insulin resistance in healthy men.

BACKGROUND: Epidemiologic and experimental data have suggested that chlorogenic acid, which is a polyphenol contained in green coffee beans, prevents diet-induced hepatic steatosis and insulin resistance. OBJECTIVE: We assessed whether the consumption of chlorogenic acid-rich coffee attenuates the effects of short-term fructose overfeeding, dietary conditions known to increase intrahepatocellular lipids (IHCLs), and blood triglyceride concentrations and to decrease hepatic insulin sensitivity in healthy humans. DESIGN: Effects of 3 different coffees were assessed in 10 healthy volunteers in a randomized, controlled, crossover trial. IHCLs, hepatic glucose production (HGP) (by 6,6-d2 glucose dilution), and fasting lipid oxidation were measured after 14 d of consumption of caffeinated coffee high in chlorogenic acid (C-HCA), decaffeinated coffee high in chlorogenic acid, or decaffeinated coffee with regular amounts of chlorogenic acid (D-RCA); during the last 6 d of the study, the weight-maintenance diet of subjects was supplemented with 4 g fructose · kg(-1) · d(-1) (total energy intake ± SD: 143 ± 1% of weight-maintenance requirements). All participants were also studied without coffee supplementation, either with 4 g fructose · kg(-1) · d(-1) (high fructose only) or without high fructose (control). RESULTS: Compared with the control diet, the high-fructose diet significantly increased IHCLs by 102 ± 36% and HGP by 16 ± 3% and decreased fasting lipid oxidation by 100 ± 29% (all P < 0.05). All 3 coffees significantly decreased HGP. Fasting lipid oxidation increased with C-HCA and D-RCA (P < 0.05). None of the 3 coffees significantly altered IHCLs. CONCLUSIONS: Coffee consumption attenuates hepatic insulin resistance but not the increase of IHCLs induced by fructose overfeeding. This effect does not appear to be mediated by differences in the caffeine or chlorogenic acid content. This trial was registered at clinicaltrials.gov as NCT00827450.

Oral tongue squamous cell carcinoma (OTSCC): alcohol and tobacco consumption versus non-consumption. A study in a Portuguese population

There has been an increase in the incidence of carcinoma of the tongue, particularly among alcohol and tobacco non-users. However, the number of studies that would allow a better understanding of etiological factors and clinical features, particularly in the Portuguese population, is very limited. This study was based on patients with squamous cell carcinoma of the anterior two thirds of the tongue that were treated at the Department of Head and Neck Surgery of the ¿Instituto Portugues de Oncologia de Lisboa - Francisco Gentil" IPOLFG) in Lisbon, Portugal, between January 1, 2001 and December 31, 2009. The patients were divided in alcohol and tobacco users and non-users in order to evaluate the differences between these 2 groups based on gender, age, tumor location, denture use, and tumor size, metastasis and stage. Of the 354 cases, 208 were users and 146 were non-users. The main location in both groups was the lateral border of the tongue. Denture use showed no significant effect in both study groups. It was possible to conclude that patients who did not drink or smoke were older and presented with smaller tumor size, lower incidence of ganglion metastasis and lower tumor stage compared with alcohol and tobacco users.

Helical tomotherapy in the treatment of anal canal cancer: 3-year clinical experience

Objective: To report a single-center experience treating patients with squamous- cell carcinoma of the anal canal using helical Tomotherapy (HT) and concurrent chemotherapy (CT).Materials/Methods: From October 2007 to February 2011, 55 patients were treated with HT and concurrent CT (5-fluorouracil/capecitabin and mitomycin) for anal squamous-cell carcinoma. All patients underwent computed- tomography-based treatment planning, with pelvic and inguinal nodes receiving 36 Gy in 1.8 Gy/fraction. Following a planned 1-week break, primary tumor site and involved nodes were boosted to a total dose 59.4 Gy in 1.8 Gy/fraction. Dose-volume histograms of several organs at risk (OAR; bladder, small intestine, rectum, femoral heads, penile bulb, external genitalia) were assessed in terms of conformal avoidance. All toxicity was scored according to the CTCAE, v.3.0. HT plans and treatment were implemented using the Tomotherapy, Inc. software and hardware. For dosimetric comparisons, 3D RT and/or IMRT plans were also computed for some of the patients using the CMS planning system, for treatment with 6-18 MV photons and/or electrons with suitable energies from a Siemens Primus linear accelerator equipped with a multileaf collimator.Locoregional control and survival curves were compared with the log-rank test, and multivariate analysis by the Cox model.Results: With 360-degree-of-freedom beam projection, HT has an advantage over other RT techniques (3D or 5-field step-and-shot IMRT). There is significant improvement over 3D or 5-field IMRT plans in terms of dose conformity around the PTV, and dose gradients are steeper outside the target volume, resulting in reduced doses to OARs. Using HT, acute toxicity was acceptable, and seemed to be better than historical standards.Conclusions: Our results suggest that HT combined with concurrent CT for anal cancer is effective and tolerable. Compared to 3D RT or 5-field step-andshot IMRT, there is better conformity around the PTV, and better OAR sparing.

Wear of two denture teeth materials in vivo-2-year results.

OBJECTIVE: (1) To quantify wear of two different denture tooth materials in vivo with two study designs, (2) to relate tooth variables to vertical loss. METHODS: Two different denture tooth materials had been used (experimental material=test; DCL=control). In study 1 (split-mouth, 6 test centers) 60 subjects received complete dentures, in study 2 (two-arm, 1 test center) 29 subjects. In study 1 the mandibular dentures were supported by implants in 33% of the subjects, in study 2 only in 3% of the subjects. Impressions of the dentures were taken and poured with improved stone at baseline and after 6, 12, 18 and 24 months. Each operator evaluated the wear subjectively. Wear analysis was carried out with a laser scanning device. Maximal vertical loss of the attrition zones was calculated for each tooth cusp and tooth. A mixed linear model was used to statistically analyse the logarithmically transformed wear data. RESULTS: Due to drop-outs and unmatchable casts, only 47 subjects of study 1 and 14 of study 2 completed the 2-year recall. Overall, 75% of all teeth present could be analysed. There was no statistically difference in the overall wear between the test and control material for either study 1 or study 2. The relative increase in wear over time was similar in both study designs. However, a strong subject effect and center effect were observed. The fixed factors included in the model (time, tooth, center, etc.) accounted for 43% of the variability, whereas the random subject effect accounted for another 30% of the variability, leaving about 28% of unexplained variability. More wear was consistently recorded in the maxillary teeth compared to the mandibular teeth and in the first molar teeth compared to the premolar teeth and the second molars. Likewise, the supporting cusps showed more wear than the non-supporting cusps. The amount of wear did not depend on whether or not the lower dentures were supported by implants. The subjective wear was correct in about 67% of the cases if it is postulated that a wear difference of 100μm should be subjectively detectable. SIGNIFICANCE: The clinical wear of denture teeth is highly variable with a strong patient effect. More wear can be expected in maxillary denture teeth compared to mandibular teeth, first molars compared to premolars and supported cusps compared to non-supported cusps. Laboratory data on the wear of denture tooth materials may not be confirmed in well-structured clinical trials probably due to the large inter-individual variability.

Enteral nutrition and cardiovascular failure: from myths to clinical practice.

Cardiovascular failure and low flow states may arise in very different conditions from both cardiac and noncardiac causes. Systemic hemodynamic failure inevitably alters splanchnic blood flow but in an unpredictable way. Prolonged low splanchnic blood flow causes intestinal ischemia, increased mucosal permeability, endotoxemia, and distant organ failure. Mortality associated with intestinal ischemia is high. Why would enteral nutrition (EN) be desirable in these complex patients when parenteral nutrition could easily cover energy and substrate requirements? Metabolic, immune, and practical reasons justify the use of EN. In addition, continuous enteral feeding minimizes systemic and myocardial oxygen consumption in patients with congestive heart failure. Further, early feeding in critically ill mechanically ventilated patients has been shown to reduce mortality, particularly in the sickest patients. In a series of cardiac surgery patients with compromised hemodynamics, absorption has been maintained, and 1000-1200 kcal/d could be delivered by enteral feeding. Therefore, early EN in stabilized patients should be attempted, and can be carried out safely under close clinical monitoring, looking for signs of incipient intestinal ischemia. Energy delivery and balance should be monitored, and combined feeding considered when enteral feeds cannot be advanced to target within 4-6 days.

Comment diminuer son risque cardiovasculaire avec l'alimentation? Rôle des graisses consommées [Nutritional advice to help reduce the cardiovascular risk. Update of the Swiss Federal Office of Public Health's recommendations on fat consumption].

The Swiss Federal Office of Public Health's (FOPH) updated its recommendations on fat consumption in 2013. The report recommends that maximum 10% of the daily caloric intake should come from saturated fatty acids, and the total fat intake should account for 20-35%. There is no limitation to dietary cholesterol consumption. Recent studies have shown that replacing consumption of saturated fatty acids by unsaturated fatty acids is more beneficial in terms of cardiovascular prevention than a low fat diet. The purpose of this article is to review the FOPH recommendations on dietary fat as well as the current evidence about their cardiovascular benefit, and to provide a translation of these scientific recommendations into clinical advice.

Clinical effectiveness of direct class II restorations: a meta-analysis.

Purpose: More than five hundred million direct dental restorations are placed each year worldwide. In about 55% of the cases, resin composites or compomers are used, and in 45% amalgam. The longevity of posterior resin restorations is well documented. However, data on resin composites that are placed without enamel/dentin conditioning and resin composites placed with self-etching adhesive systems are missing. Material and Methods: The database SCOPUS was searched for clinical trials on posterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimum number of restorations at last recall = 20; (3) report on dropout rate; (4) report of operative technique and materials used; (5) utilization of Ryge or modified Ryge evaluation criteria. For amalgam, only those studies were included that directly compared composite resin restorations with amalgam. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. P-values under 0.05 were considered significant. Results: Of the 373 clinical trials, 59 studies met the inclusion criteria. In 70% of the studies, Class II and Class I restorations had been placed. The overall success rate of composite resin restorations was about 90% after 10 years, which was not different from that of amalgam. Restorations with compomers had a significantly lower longevity. The main reason for replacement were bulk fractures and caries adjacent to restorations. Both of these incidents were infrequent in most studies and accounted only for about 6% of all replaced restorations after 10 years. Restorations with macrofilled composites and compomer suffered significantly more loss of anatomical form than restorations with other types of material. Restorations that were placed without enamel acid etching and a dentin bonding agent showed significantly more marginal staining and detectable margins compared to those restorations placed using the enamel-etch or etch-and-rinse technique; restorations with self-etching systems were between the other groups. Restorations with compomer suffered significantly more chippings (repairable fracture) than restorations with other materials, which did not statistically differ among each other. Restorations that were placed with a rubber-dam showed significantly fewer material fractures that needed replacement, and this also had a significant effect on the overall longevity. Conclusion: Restorations with hybrid and microfilled composites that were placed with the enamel-etching technique and rubber-dam showed the best overall performance; the longevity of these restorations was similar to amalgam restorations. Compomer restorations, restorations placed with macrofilled composites, and resin restorations with no-etching or self-etching adhesives demonstrated significant shortcomings and shorter longevity.

Predictors for hospitalization and outpatient visits in patients with inflammatory bowel disease: results from the Swiss Inflammatory Bowel Disease Cohort Study.

OBJECTIVES: Patients with inflammatory bowel disease (IBD) have a high resource consumption, with considerable costs for the healthcare system. In a system with sparse resources, treatment is influenced not only by clinical judgement but also by resource consumption. We aimed to determine the resource consumption of IBD patients and to identify its significant predictors. MATERIALS AND METHODS: Data from the prospective Swiss Inflammatory Bowel Disease Cohort Study were analysed for the resource consumption endpoints hospitalization and outpatient consultations at enrolment [1187 patients; 41.1% ulcerative colitis (UC), 58.9% Crohn's disease (CD)] and at 1-year follow-up (794 patients). Predictors of interest were chosen through an expert panel and a review of the relevant literature. Logistic regressions were used for binary endpoints, and negative binomial regressions and zero-inflated Poisson regressions were used for count data. RESULTS: For CD, fistula, use of biologics and disease activity were significant predictors for hospitalization days (all P-values <0.001); age, sex, steroid therapy and biologics were significant predictors for the number of outpatient visits (P=0.0368, 0.023, 0.0002, 0.0003, respectively). For UC, biologics, C-reactive protein, smoke quitters, age and sex were significantly predictive for hospitalization days (P=0.0167, 0.0003, 0.0003, 0.0076 and 0.0175 respectively); disease activity and immunosuppressive therapy predicted the number of outpatient visits (P=0.0009 and 0.0017, respectively). The results of multivariate regressions are shown in detail. CONCLUSION: Several highly significant clinical predictors for resource consumption in IBD were identified that might be considered in medical decision-making. In terms of resource consumption and its predictors, CD and UC show a different behaviour.

Social Media in health. What are the safety concerns for healthcare consumers?

Recent literature has discussed the unintended consequences of clinical information technologies (IT) on patient safety, yet there has been little discussion about the safety concerns in the area of consumer health IT. This paper presents a range of safety concerns for consumers in social media, with a case study on YouTube. We conducted a scan of abstracts on 'quality criteria' related to YouTube. Five areas regarding the safety of YouTube for consumers were identifi ed: (a) harmful health material targeted at consumers (such as inappropriate marketing of tobaccoor direct-to-consumer drug advertising); (b) public display of unhealthy behaviour (such as people displaying self-injury behaviours or hurting others); (c) tainted public health messages (i.e. the rise of negative voices againstpublic health messages); (d) psychological impact from accessing inappropriate, offensive or biased social media content; and (e) using social media to distort policy and research funding agendas. The examples presented should contribute to a better understanding about how to promote a safe consumption and production of social media for consumers, and an evidence-based approach to designing social media interventions for health. The potential harm associated with the use of unsafe social media content on the Internet is a major concern. More empirical and theoretical studies are needed to examine how social media infl uences consumer health decisions, behaviours and outcomes, and devise ways to deter the dissemination of harmful infl uences in social media.

Biases on the administered parenteral doses of an experimental drug during phase I clinical trials

Introduction: The pharmaceutical aspects of drug administration in clinical trials receive poor consideration compared with the important attention devoted to the analytical and mathematical aspects of biological sample exploitation. During PK calculations, many researchers merely use for dose the nominal amount declared, overlooking the noticeable biases that may result in the assessment of PK parameters. The aim of this work was to evaluate the biases related to doses injected of a biosimilar drug in 2 Phase I clinical trials. Patients (or Materials) and Methods: In trial A, 12 healthy volunteers received different doses of a biosimilar of interferon beta-1a by either subcutaneous (SC) or intravenous (IV) injection. The doses were prepared by partially emptying 0.5-mL syringes supplied by the manufacturer (drop count procedure). In trial B, 12 healthy volunteers received 3 different formulations of the drug by IV injection (biosimilar without albumin [HSA], biosimilar with HSA and original brand [Rebif®]) and 2 different formulations as multiple SC injections (biosimilar HSA-free and original brand). In both trials, the actual dose administered was calculated as: D = C·V - losses. The product titer C was assessed by ELISA. The volume administered IV was assessed by weighting. Losses were evaluated by in vitro experiments. Finally, the binding of 125I-interferon to HSA was evaluated by counting the free and HSA complexed molecule fractions separated by gel filtration. Results: Interferon was not significantly adsorbed onto the lines used for its IV administration. In trial A, the titer was very close to the one declared (96 ± 7%). In trial B, it differed significantly (156 ± 10% for biosimilar with/without HSA and 123 ± 5% for original formulation). In trial A, the dose actually administered showed a large variability. The real injected volume could be biased up to 75% compared with the theoretical volume (for the lower dose administered [ie, 0.03 mL]). This was mainly attributed to a partial re-aspiration of the drug solution before withdrawing the syringe needle. A strict procedure was therefore applied in trial B to avoid these inaccuracies. Finally, in trial B, 125I-Interferon beta-1a binding to HSA appeared time dependent and slow, reaching 50% after 16-hour incubation, which is close to steady state reported for the comparator Rebif®. Conclusion: These practical examples (especially biases on actual titer and volume injected) illustrate that actual dose assessment deserves attention to ensure accuracy for estimates of clearance and distribution volume in the scientific literature and for registration purposes, especially for bioequivalence studies.