Pegylated asparaginase in combination with high-dose methotrexate for consolidation in adult acute lymphoblastic leukaemia in first remission: a pilot study

The German Multicentre acute lymphoblastic leukaemia (ALL) study group (GMALL) performed a pilot study using pegylated asparaginase (PEG-ASP) in combination with high-dose methotrexate as consolidation therapy in the 05/93 protocol. The aim of the study was an intra-individual comparison of two different doses of PEG-ASP in 26 patients, with regard to the depletion of asparagine in serum and toxicity. 'Pharmacokinetic' monitoring was performed to evaluate the effect of an intra-individual dose escalation of PEG-ASP from 500 to 1000 U/m2 intravenously in successive doses. Serum asparaginase activity was targeted at > or =100 U/l for 1 week and > or =50 U/l for 10 d. The second course of PEG-ASP was administered to 23 patients. Due to hypersensitivity reactions in five patients, only 18 patients were evaluable for pharmacokinetic monitoring. With respect to the PEG-ASP activity, an effective depletion of asparagine could be postulated in the majority of patients during 10 d after the first administration. The effect of an intraindividual dose escalation form 500 to 1000 U/m2 was evaluable in 17 of 22 patients. An increment in peak PEG-ASP activity >70% was observed in 65% of the patients. PEG-ASP was well tolerated. Despite the long half-life of PEG-ASP, neither pancreatic nor central nervous toxicities occurred among the 26 adult patients treated in this pilot study.     

Systematic review of cardiac output measurements by echocardiography vs. thermodilution: the techniques are not interchangeable

Purpose

Echocardiography is frequently used in the hemodynamic evaluation of critically ill patients, but inaccurate measurements may lead to wrong clinical decisions. The aim of our systematic review was to investigate the interchangeability of echocardiography with thermodilution technique in measuring cardiac output and its changes.

Methods

In August 2015 we systematically searched electronic databases and included studies investigating the echocardiographic measurement of cardiac output compared with thermodilution technique using the Bland–Altman method. Two authors independently reviewed the studies and extracted data on type of measurements, clinical setting and characteristics, and those of the Bland–Altman and trending ability analyses.

Results

We identified 13,834 citations and included 24 studies in the final analysis. The median number of participants was 32 (range 8–65). Most of the studies assessed left-sided heart structures and the majority had small bias, wide limits of agreement, and high percentage error between echocardiography and thermodilution. In only two of the 24 studies the precision of each technique (echocardiography and thermodilution) was assessed before comparing them. In the single study evaluating trending ability using valid methodology, agreement was observed between echocardiography and thermodilution in detecting the directional changes in cardiac output, but the magnitude of changes varied considerably.

Conclusions

The majority of studies comparing echocardiography with thermodilution were difficult to interpret, but current evidence does not support interchangeability between these techniques in measuring cardiac output. The techniques may be interchangeable in tracking directional changes in cardiac output, but this has to be confirmed in large high-quality studies.

     

Social cognitive bias and neurocognitive deficit in paranoid symptoms: evidence for an interaction effect and changes during treatment

Persistent paranoid symptoms are best understood as having multiple causal mechanisms. An enhanced multidimensional understanding of paranoia may result from the convergence of two distinct measurement paradigms, experimental psychopathology and social cognitive research. This study investigated the role of neurocognitive deficits and emotion misperception bias as they relate to paranoid symptoms at two different time points in a sample of individuals with severe mental illness (primarily schizophrenia spectrum disorders [N=91]) undergoing intensive psychosocial rehabilitation. Before intensive rehabilitation (but after initial stabilization), paranoid symptoms were related to a tendency to misperceive emotion as disgust. The impact of this social cognitive bias was amplified by perseveration (as measured by the COGLAB Card Sorting Task). Perseverative errors were associated with paranoid symptoms at both time points. After 6 months of treatment, there were significant reductions in paranoid symptoms and perseverative errors but no significant changes in emotion misperception biases. This study is one of few to date to evaluate the contribution of both neurocognitive deficits and social cognitive biases to paranoid symptoms. The results demonstrate how social cognitive biases can interact with neurocognitive deficits in expression of paranoid symptoms, and how these relationships change during treatment.     

Spectral morphometric characterization of breast carcinoma cells

The spectral morphometric characteristics of standard haematoxylin and eosin breast carcinoma specimens were evaluated by light microscopy combined with a spectral imaging system. Light intensity at each wavelength in the range of 450-800 nm was recorded for 10(4) pixels from each field and represented as transmitted light spectra. A library of six characteristic spectra served to scan the cells and reconstruct new images depicting the nuclear area occupied by each spectrum. Fifteen cases of infiltrating ductal carcinoma and six cases of lobular carcinoma were examined; nine of the infiltrating ductal carcinoma and three of the lobular carcinoma showed an in situ component. The spectral morphometric analysis revealed a correlation between specific patterns of spectra and different groups of breast carcinoma cells. The most consistent result was that lobular carcinoma cells of in situ and infiltrating components from all patients showed a similar spectral pattern, whereas ductal carcinoma cells displayed spectral variety. Comparison of the in situ and the infiltrating ductal solid, cribriform and comedo carcinoma cells from the same patient revealed a strong similarity of the spectral elements and their relative distribution in the nucleus. The spectrum designated as number 5 in the library incorporated more than 40% of the nuclear area in 74.08% of the infiltrating lobular cells and in 13.64% of the infiltrating ductal carcinoma cells (P < 0.001). Spectrum number 2 appeared in all infiltrating ductal cells examined and in none of the lobular cells. These results indicate that spectrum number 5 is related to infiltrating lobular carcinoma, whereas spectrum number 2 is characteristic for infiltrating ductal carcinoma cells. Spectral similarity mapping of central necrotic regions of comedo type in situ carcinoma revealed nuclear fragmentation into defined segments composed of highly condensed chromatin. We conclude that the spectral morphometric features found for lobular and ductal cell populations may serve future automated histological diagnostics.     

Improved assessment of bioactive erythropoietin in human sera using a modified tritiated-thymidine-incorporation assay

The reproducibility and utility of an in vitro bioassay for erythropoietin were evaluated, and modifications, including the use of frozen target cells, were made. The assay, based on 3H-thymidine incorporation into phenylhydrazine-treated mouse spleen cells, showed a dose-response curve from 0.2 to 20 mU of sheep plasma or human urinary erythropoietin, with a 50-100-fold increase in 3H-thymidine incorporation. The dose-response curve, using purified, recombinant erythropoietin was identical to that from material obtained from other sources. The use of frozen cells simplified the methodology, reduced the time for assay preparation, and lowered costs. The freezing process resulted in 15% attrition of the cells, but after one year of storage, this level was not increased nor was the response to erythropoietin diminished. The nonspecificity of the assay was reduced by supplementing the cells with critical nutrients, depleting fetal bovine serum of endogenous erythropoietin, and reducing solute variability by ultrafiltration and reconstitution of samples with culture medium. Heat inactivation diminished inhibitors in sera samples, but affinity chromatography using wheat-germ lectin-Sepharose was most effective for extracting erythropoietin and reducing nonspecific effects. The assay is sensitive, can be used to measure multiple samples rapidly, and should prove useful for complementing immunoassay techniques.