A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer

Purpose OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma. Method A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity. Results Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m², oxaliplatin 130 mg/m²) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients. Conclusions The recommended regimen for further investigation is OSI-7904L 9 mg/m² and oxaliplatin 130 mg/m².     

Early postoperative complications in primary cleft lip and palate surgery

We studied the occurrence of early complications of cleft lip and palate surgery by the retrospective study of 132 consecutive cases (160 procedures) operated between three and six months of age. Three children presented with major complications within the immediate postoperative period. All were treated successfully. A local complication directly related to the operation occurred in 7.5% of the cases within the first six postoperative days. In 17%, a general complication not directly related to the operation was observed. The majority of these general complications were cross infections during the hospital stay. These observations led us to reduce the hospital stay to one day for cleft lip and five days for cleft palate and cleft lip and palate operations without compromise to safety but with a reduction of the morbidity and hence the treatment costs and of the child-family disturbance.     

Analysis of the receptor specificity of tolerance induction in stress versus opioid-related prolactin secretion in rats

The effects of restraint stress and opiates on prolactin secretion in male rats have been measured. Both induced a short-lived increase in prolactinaemia. Experimental evidence indicates that both opioids and restraint stress bring about their actions by the activation of opioid receptors. When restraint stress was followed by administration of the specific kappa-agonist bremazocine, a second prolactin peak was observed. In contrast, morphine (predominantly a mu-agonist) lost its prolactin-stimulating capacity when given after a period of restraint stress. This indicates cross-tolerance between restraint stress and morphine. Tolerance was overcome when the dose of morphine was doubled, and an increase in prolactin secretion could again be obtained. The cross-tolerance phenomenon argues that a common opioid receptor is involved in morphine- and restraint stress-stimulated prolactin release. In another set of experiments, in which morphine administration replaced restraint stress as a means of inducing tolerance, a second rise in prolactinaemia was seen only with bremazocine and not with a further administration of morphine. This suggests a morphine (mu) receptor-specific development of tolerance. Two consecutive administrations of bremazocine also produced tolerance, in this case for the kappa-receptor. This illustrates the rapid and receptor-specific development of tolerance for the prolactin-releasing capacity of opioid compounds.     

Frequent discordance of the light‐chain isotypes expressed by serum monoclonal components and leukaemic B‐cells

In B‐cell malignancies, it is generally held that the monoclonal components (MC) are produced by the malignant clones. Genetic relatedness implies the concordant expression of light‐chain (LC) isotypes in the MC and at the surface of the malignant lymphocytes. We reviewed a series of 91 B‐cell leukaemias, immunophenotyped by flow cytometry in our laboratory. A serum MC had been sought in 75 of these patients, and had been found in 23 (31%). Biclonal serum components were detected in three cases. LC concordance could not be assessed in three cases of surface LC‐null lymphocytes. Of the 23 MC studied in 20 patients, light‐chains were discordant in 39%, mostly due to κ MC in λ leukaemias. The origin of LC discordance remains speculative. It could be due to the emergence of subclones with the same primal VDJ gene rearrangement or, alternatively, to the development of new B‐cell clones escaping immune surveillance from deregulated T‐cells.     

Immunologic Response of Unvaccinated Workers Exposed to Anthrax, Belgium

To determine immunologic reactivity to Bacillus anthrax antigens, we conducted serologic testing of workers in a factory that performed scouring of wool and goat hair. Of 66 workers, ≈10% had circulating antibodies or T lymphocytes that reacted with anthrax protective antigen. Individual immunity varied from undetectable to high.     

Reliability of narrative assessment data on communication skills in a summative OSCE

ObjectiveTo quantitatively estimate the reliability of narrative assessment data regarding student communication skills obtained from a summative OSCE and to compare reliability to that of communication scores obtained from direct observation.MethodsNarrative comments and communication scores (scale 1–5) were obtained for 14 graduating pharmacy students across 6 summative OSCE stations with 2 assessors per station who directly observed student performance. Two assessors who had not observed the OSCE reviewed narratives and independently scored communication skills according to the same 5-point scale. Generalizability theory was used to estimate reliability. Correlation was used to evaluate the relationship between scores from each assessment method.ResultsA total of 168 narratives and communication scores were obtained. The G-coefficients were 0.571 for scores provided by assessors present during the OSCE and 0.612 for scores from assessors who provided scores based on narratives only. Correlation between the two sets of scores was 0.5.ConclusionReliability of communication scores is not dependent on whether assessors directly observe student performance or assess written narratives, yet both conditions appear to measure communication skills somewhat differently.Practice implicationsNarratives may be useful for summative decision-making and help overcome the current limitations of using solely quantitative scores.