Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors.

Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m² twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.

Monitoring intracellular redox potential changes using SERS nanosensors.

Redox homeostasis and signaling are critically important in the regulation of cell function. There are significant challenges in quantitatively measuring intracellular redox potentials, and in this paper, we introduce a new approach. Our approach is based on the use of nanosensors which comprise molecules that sense the local redox potential, assembled on a gold nanoshell. Since the Raman spectrum of the sensor molecule changes depending on its oxidation state and since the nanoshell allows a huge enhancement of the Raman spectrum, intracellular potential can be calculated by a simple optical measurement. The nanosensors can be controllably delivered to the cytoplasm, without any toxic effects, allowing redox potential to be monitored in a reversible, non-invasive manner over a previously unattainable potential range encompassing both superphysiological and physiological oxidative stress.

Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells.

Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34(+)38(lo)) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells in vitro. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34(+) cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease.

Positioning long lines: contrast versus plain radiography.

AIM: To assess the value of contrast versus plain radiography in determining radio-opaque long line tip position in neonates. METHODS: In a prospective study, plain radiography was performed after insertion of radio-opaque long lines. If the line tip was not visible on the plain film, a second film with contrast was obtained in an attempt to visualise the tip. RESULTS: Sixty eight lines were inserted during the study period, 62 of which were included in the study. In 31, a second radiographic examination with contrast was necessary to determine position of the tip. In 29 of these, the line tip was clearly visualised with contrast. On two occasions, the line tip could not be seen because the contrast had filled the vein and obscured the tip from view. Eight of the lines that required a second radiograph with contrast were repositioned. CONCLUSION: Intravenous contrast should be routinely used in the assessment of long line position in the neonate.

Recommendations for a mammography quality assurance program.

In 1989 the ACPSEM published a position paper entitled "A Quality Assurance Programme for Mass Screening in Mammography". This paper described test parameters and performance specifications for the equipment related aspects of a mammography quality assurance program. Advice on test equipment selection was also provided. In the intervening period of time there have been considerable advances in mammography technology creating a need to review a number of the paper's recommendations. There have also been considerable developments in the mammography quality assurance (QA) field, not the least of which includes the American College of Radiology Mammography Accreditation Program (ACR-MAP) and the similarly structured Royal Australian and New Zealand College of Radiologists' Mammography Accreditation Program (RANZCR-MAP). In light of these developments it was decided by the Radiology Interest Group to review the ACPSEM position on those aspects of mammography QA that fall within the medical physicist's area of expertise. This document represents the outcome of those deliberations.

Automated homogeneous immunoassay for gentamicin on the dimension clinical chemistry system.

BACKGROUND: Monitoring of the concentration of gentamicin in serum and plasma during therapy is widely recommended and practiced in hospitals. Our aim was to develop a homogeneous immunoassay based on particle-enhanced turbidimetric inhibition immunoassay technology to quantify gentamicin on the Dimension clinical chemistry system. METHODS: Assay performance was assessed on each of the Dimension models in a 15-instrument interlaboratory comparison study. A split-sample comparison (n = 1171) was also performed between the gentamicin methods on the Dimension system and the Abbott TDx analyzer, using multiple reagent and calibrator lots on multiple instruments. RESULTS: The Dimension method was linear to 25.1 micromol/L (12.0 microg/mL) with a detection limit of 0.63 micromol/L (0.3 microg/mL). Calibration was stable for 30 days. The within-run imprecision (CV) was <1.3%, and total imprecision ranged from 1.8% to 3.2% between 4.2 micromol/L (2.0 microg/mL) and 16.7 micromol/L (8.0 microg/mL) gentamicin. Linear regression analysis of the results on the Dimension method (DM) vs the Abbott TDx yielded the following equation: DM = 0.98TDx - 0.42; r = 0.987. Minimal interference was observed from structurally related compounds such as sagamicin, netilmicin, and sisomicin. CONCLUSION: The monoclonal antibody used in this method has similar reactivities toward the individual gentamicin subspecies C1, C1a, and C2, thus providing analytical recovery not significantly dependent on relative subspecies concentrations.

Immunizing against depression and anxiety after spinal cord injury.

OBJECTIVE: To further report on the effectiveness of early psychological intervention in reducing anxiety and depressive mood in persons with spinal cord injury 2 years after injury. DESIGN: A nonrandomized, longitudinal, controlled trial. SETTING, OUTCOME MEASURES, AND INTERVENTION: Twenty-eight spinal cord injured persons participated in group cognitive behavior therapy during hospital rehabilitation. They were assessed for depressive mood and anxiety before, immediately after, and 12 and 24 months after treatment. The intervention group's responses on the measures were compared with a control group of 31 spinal cord injured persons who only received traditional rehabilitation services during their hospitalization. RESULTS: Subjects in the treatment group with high depression and anxiety scores before treatment were significantly less depressed and reduced their anxiety to a greater extent 2 years after the injury in comparison with similar persons in the control group. CONCLUSIONS: Group cognitive behavior therapy for spinal cord injured persons who are abnormally depressed and anxious appears to reduce depressive mood and anxiety in the short and long term.

Development and validation of a particle-enhanced turbidimetric inhibition assay for urine albumin on the Dade aca analyzer.

The measurement of urine albumin now has a well-established role in the monitoring of patients with diabetes mellitus. We have developed a particle-enhanced immunoturbidimetric inhibition assay for urine albumin on the Dade aca analyzer. The inhibition approach removes any of the potential antigen excess difficulties that could be expected from the wide clinical range of urine albumin, but retains the sensitivity advantages of latex-enhanced immunoturbidimetry. Human serum albumin (HSA) is covalently attached to 40-nm poly(chloromethyl)styrene-modified latex particles. This reagent, along with monoclonal antibody to HSA, is aliquoted into the aca reagent pack along with polyethylene glycol 8000 in a tablet form (giving a final reaction concentration of 15 g/L). A 150 mmol/L phosphate buffer, pH 7.8, is used to fill the reagent pack in the instrument and the agglutination reaction is monitored at 340 nm. The sample volume is 100 microL and the calibration curve covers the range 2-250 mg/L. Evaluation of commercial scale reagents against the Beckman Array nephelometric immunoassay system gave a Deming regression correlation of aca = 0.87 x Beckman + 8.5, r = 0.995, n = 145. Mean analytical recovery was 104+/-4.5%, n = 20, and there was no evidence of a lack of parallelism. Interassay precision was 8.8% at 10.0 mg/L and <2.5% at >65 mg/L. Calibrator stability was in excess of 60 days. A small reference range study (24-h urine collections, n = 27) gave a mean of 5.6 mg/L with a range of 0.5-16.2 mg/L. Analytical sensitivity (2.5 SD from zero) was 0.40 mg/L.

Long-term psychological outcomes in spinal cord injured persons: results of a controlled trial using cognitive behavior therapy.

OBJECTIVE: Although there are many anecdotal reports that psychological intervention is effective in enhancing adjustment to spinal cord injury (SCI), there are little data to support this assertion. To date, reports of few longitudinal-based controlled trials that assessed psychological outcomes for SCI persons have been published. This study was conducted to determine long-term efficacy of cognitive behavior therapy during rehabilitation. DESIGN: The study employed a nonrandomized controlled trial, and measures were taken on three occasions: before, immediately after, and 12 months after treatment. SETTING, OUTCOME MEASURES, AND INTERVENTION: Anxiety, depressive mood, and self-esteem were assessed in 28 SCI persons consecutively selected on admission to hospital, who participated in specialized group cognitive behavior therapy (CBT) during rehabilitation. CONTROLS: The intervention group's responses on the measures were compared with a control group of 41 SCI persons who only received traditional rehabilitation services during their hospitalization. RESULTS: There were no overall group differences on anxiety, depressive mood, and self-esteem, although there was a trend for the treatment group to have greater levels of improvement in depression scores across time in comparison to the control group. However, those in the treatment group who reported high levels of depressive mood before the CBT treatment were significantly less depressed 1 year after injury, compared to similar persons in the control group. CONCLUSIONS: While it appears not everyone who experiences SCI needs CBT, at least in the hospital phase of their rehabilitation, those who report high levels of depressive mood benefited greatly from CBT.

Kinetics and proposed mechanism of the reaction of an immunoinhibition, particle-enhanced immunoassay.

We report kinetic studies on the reaction of a latex agglutination immunoassay used to quantify phenytoin in serum. In this assay, polystyrene particles with a covalently attached analog of phenytoin react with an antiphenytoin monoclonal antibody to form light-scattering aggregates, with the rate of this reaction being decreased by addition of phenytoin from sample. In the absence of free (sample) phenytoin, this reaction did not exhibit a maximum rate of agglutination in the presence of excess antibody, i.e., an equivalence point. Furthermore, agglutination was inhibitable by free phenytoin even when the latter was added after agglutination of particles with antibody had begun. Most significantly, the immunoagglutination proceeded in an identical fashion with monovalent F(ab) fragment. These data are consistent with low-affinity immunospecific particle-antibody complexation, which then induces colloidal aggregation, without requiring immunospecific bridging by antibody molecules. The described mechanism is not generalizable to all latex agglutination immunoassays, although disturbance of colloidal stability may be a component in most assays.

Validation of a particle enhanced immunoturbidimetric assay for serum beta 2-microglobulin on the Dade aca.

We describe the development and validation of a fully automated homogeneous immunoassay for serum beta 2-microglobulin on the Dade aca clinical analyzer. The assay employs latex enhanced immunoturbidimetry, with an affinity purified polyclonal antibody covalently coupled to a 40 nm latex particle. The assay working range is < 0.5 to 20 mg/l with no evidence of loss of signal due to antigen excess at concentrations up to 120 mg/l. The assay sensitivity is 0.2 mg/l; within run and between run imprecision showed coefficients of variations of < 7%, across the assay range 1-20 mg/l. A method comparison with an established RIA procedure gave a regression equation of (aca) = 1.14 (RIA)-0.26, r = 0.996, n = 109. Good analytical recovery (98-101%), no evidence of a lack of parallelism and no interference from rheumatoid factor (tested up to 1.2 x 10(6) U/l) were observed. The low method to be considered as an effective means of monitoring seroconversion in HIV infected subjects and treatment of patients with myelomatosis.

Mean glandular dose and the standard breast.

Mean glandular dose limits in mammography are defined in terms of a "standard breast". However, accrediting bodies do not always use the same standard breast. In this study, dose was measured following the guidelines of the National Program for the Early Detection of Breast Cancer (NPEDBC) and the Royal Australasian College of Radiologists (RACR). The RACR dose was found to be 32% less than the NPEDBC dose. This highlights the need for breast characteristics to be included in any statement of mean glandular dose.

Results of a traditional acupuncture intervention for stuttering.

It is important that researchers investigate alternative strategies for treating stuttering, as contemporary treatments are not entirely successful in reducing stuttering with all people. Furthermore, many who have been "successfully" treated suffer from high relapse rates in the long term. Acupuncture has been shown to be a promising treatment for several diverse disorders, so a pilot investigation into its effectiveness for stuttering was considered worthwhile. This study investigated traditional acupuncture-based treatments for two adult males who had stuttered since childhood. A single-case experimental ABAB multiple baseline design was employed to test for treatment effectiveness. Subjects were followed up for a further 12 weeks to evaluate maintenance (C phase) of possible improvements. No significant ABAB reversal effects were observed, and stuttering frequency through the treatment phases remained at baseline levels for the two subjects. Speech rate also remained at baseline levels throughout the treatment phases, as did naturalness of speech and anxiety levels. This research is important as claims that acupuncture may successfully reduce stuttering need to be tested, and the scope and usefulness of treatments like acupuncture for a wide variety of problems needs to be determined. However, the low subject numbers involved suggest caution in concluding acupuncture is not a successful intervention for stuttering. Perhaps alternative acupuncture points need to be evaluated and a wider variety of persons who stutter need to be involved in any future research.

A longitudinal investigation into anxiety and depression in the first 2 years following a spinal cord injury.

This study is a 1 year extension of a controlled 1 year follow up study of spinal cord injured persons. The study assessed the extent of spinal cord injury (SCI) persons' depression and anxiety in comparison to an able bodied control group matched for age, sex, education and as far as possible, occupation. Psychological adjustment to SCI was assessed in terms of scores on the Trait Anxiety Inventory and the Beck Depression Inventory. Results obtained at the 2 year follow up were not significantly changed from those obtained over the first year. There was no significant improvement in anxiety and depression scores in the SCI group 2 years post injury. Examination of the SCI scores suggest that psychological morbidity was confined to a group of approximately 30% of persons, whilst the remaining persons were not severely anxious or depressed. Traditional stage models of adjustment to SCI which suggest that the passage of time is associated with better adjustment were not supported by the present data.

The influence of spinal cord injury on coping styles and self-perceptions two years after the injury.

This study is a two year follow-up of previous longitudinal research which investigated the effects of spinal cord injury (SCI) on perceptions of control, self-esteem and coping styles over the first year of SCI. Persons with SCI and a demographically matched able-bodied control group completed standardised questionnaires on four occasions over two years. The instruments included the Locus of Control of Behaviour Scale (LCB), Rosenberg's Self-Esteem Scale, and an adapted Mental Adjustment to Cancer Scale (MAC), which measures coping styles, including fighting spirit, helplessness/hopelessness and fatalism. Results obtained in the first year were replicated in the two year data, except for the LCB Scale. After one year, the SCI group were found to perceive their life to be externally controlled, to be lower in self-esteem, and have more helpless/hopeless and fatalistic attitudes than the controls. There were no differences in self esteem and coping styles after two years for the SCI group. However, locus of control fluctuated over the two years, though there was a trend for the SCI group to be more externally focussed. There were no significant interactions between group and time. Implications for the adjustment of SCI persons are discussed.

Spinal cord injury: a search for determinants of depression two years after the event.

A prospective longitudinal study employing repeated measures was used to isolate factors which might predispose a person to depression two years after sustaining spinal cord injury (SCI). Thirty-one subjects who suffered acute spinal injuries resulting in permanent loss of movement, and who had no head injuries or any pre-existing psychopathology, were at least 17 years of age, and who were able to speak English, participated in the study. Using the Beck Depression Inventory (BDI) as a measure of depression, a regression analysis demonstrated that the experience of pain two years post-injury and feeling out of control of one's life prior to hospital discharge were predictive of depression two years post-injury. No demographic variables or injury characteristics such as level of lesion or completeness of lesion were related to long-term depression. Pain management and rehabilitation techniques that enhance the individual's belief of control over their lives are therefore recommended as interventions that could act to reduce depression in the long term in persons with spinal cord injury.

Anxiety and depression over the first year of spinal cord injury: a longitudinal study.

The literature concerning the psychological consequences following spinal cord injury (SCI) indicates a discordance between clinical impressions and empirical research. Although many studies report that psychological morbidity is not an inevitable consequence of SCI, much of this research is characterised by methodological inadequacies and the conclusions are therefore tenuous. The present study assessed 41 persons with SCI for depression and anxiety using objective psychological measures on three occasions over the first year of SCI and compared them with 41 able bodied controls matched for age, sex, education and, as far as possible, occupation. Results demonstrated significant differences between the two groups, with the SCI group being more anxious and depressed. However, psychological morbidity was not an inevitable consequence of SCI, with group means reflecting mild levels of depression and anxiety. No significant differences were found across time and no interactions between groups and time were detected. Implications for the treatment of SCI are discussed.

Stabilization of turbidimetric immunoassay by covalent coupling of antibody to latex particles.

Turbidimetric immunoassay is commonly used to quantify serum proteins. Latex-particle enhancement of this type of assay has been primarily associated with increasing assay sensitivity. However, covalent coupling of an antibody to a latex particle can offer other advantages that are also pertinent in measurement of high concentrations of analytes. By using a common antibody with IgG as a model analyte, we describe the development of a nonenhanced and a latex-particle-enhanced turbidimetric assay for measuring serum IgG. Both assays show adequate analytical recovery and parallelism, and results compare well with those by rate nephelometry. The latex-enhanced assay has equivalent sensitivity, working range, and interassay precision, but much greater signal change and calibration stability than the nonenhanced assay. In addition, with latex particles, less antiserum is needed. Coupling antibodies to latex particles offers considerable advantages, even when an improved assay detection limit is not required.