TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.     

Metabolite profiling of 14C-omacetaxine mepesuccinate in plasma and excreta of cancer patients

1. Omacetaxine mepesuccinate (hereafter referred to as omacetaxine) is a protein translation inhibitor approved by the US Food and Drug Administration for adult patients with chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors.

2. The objective was to investigate the metabolite profile of omacetaxine in plasma, urine and faeces samples collected up to 72?h after a single 1.25-mg/m² subcutaneous dose of ¹⁴C-omacetaxine in cancer patients.

3. High-performance liquid chromatography mass spectrometry (MS) (high resolution) in combination with off-line radioactivity detection was used for metabolite identification.

4. In total, six metabolites of omacetaxine were detected. The reactions represented were mepesuccinate ester hydrolysis, methyl ester hydrolysis, pyrocatechol conversion from the 1,3-dioxole ring. Unchanged omacetaxine was the most prominent omacetaxine-related compound in plasma. In urine, unchanged omacetaxine was also dominant, together with 4′-DMHHT. In feces very little unchanged omacetaxine was found and the pyrocatechol metabolite of omacetaxine, M534 and 4′-desmethyl homoharringtonine (4′-DMHHT) was the most abundant metabolites.

5. Omacetaxine was extensively metabolized, with subsequent renal and hepatic elimination of the metabolites. The low levels of the metabolites found in plasma indicate that the metabolites are unlikely to contribute materially to the efficacy and/or toxicity of omacetaxine.

     

Effect of cold conditions on manual performance while wearing petroleum industry protective clothing

The purpose of this study was to investigate manual performance and thermal responses during low work intensity in persons wearing standard protective clothing in the petroleum industry when they were exposed to a range of temperatures (5, -5, -15 and -25℃) that are relevant to environmental conditions for petroleum industry personnel in northern regions. Twelve men participated in the study. Protective clothing was adjusted for the given cold exposure according to current practices. The subjects performed manual tests five times under each environmental condition. The manual performance test battery consisted of four different tests: tactile sensation (Semmes-Weinstein monofilaments), finger dexterity (Purdue Pegboard), hand dexterity (Complete Minnesota dexterity test) and grip strength (grip dynamometer). We found that exposure to -5℃ or colder lowered skin and body temperatures and reduced manual performance during low work intensity. In conclusion the current protective clothing at a given cold exposure is not adequate to maintain manual performance and thermal balance for petroleum workers in the high north.     

Motivation in pediatric motor rehabilitation: A systematic search of the literature using the self-determination theory as a conceptual framework

Objective: Motivation is suggested as an important factor in pediatric motor rehabilitation. Therefore, we reviewed the existing evidence of (motivational) motor rehabilitation paradigms, and how motivation influences rehabilitation outcome using self-determination theory as conceptual framework. Methods: PubMed and Web-of-Science databases were systematically searched until June 2015. Data were independently extracted and critiqued for quality by three authors. Studies reporting motivational aspects were included. Most studies examined new technology (e.g., virtual reality [VR]). Results: Out of 479 records, three RCT, six case-control, and six non-comparative studies were included with mixed quality. Motivation was rarely reported. Training individualization to the child’s capabilities with more variety seemed promising to increase motivation. Motivation increased when the exercises seemed helpful for daily activities. Conclusions: Motivation in pediatric rehabilitation should be comprehensively assessed within a theoretical framework as there are indications that motivated children have better rehabilitation outcomes, depending on the aspect of motivation.     

Emerging Filoviral Disease in Uganda: Proposed Explanations and Research Directions

Outbreaks of Ebola and Marburg virus diseases have recently increased in frequency in Uganda. This increase is probably caused by a combination of improved surveillance and laboratory capacity, increased contact between humans and the natural reservoir of the viruses, and fluctuations in viral load and prevalence within this reservoir. The roles of these proposed explanations must be investigated in order to guide appropriate responses to the changing epidemiological profile. Other African settings in which multiple filoviral outbreaks have occurred could also benefit from such information.     

Normative comparisons for large neuropsychological test batteries: User-friendly and sensitive solutions to minimize familywise false positives

Introduction. In neuropsychological research and clinical practice, a large battery of tests is often administered to determine whether an individual deviates from the norm. We formulate three criteria for such large battery normative comparisons. First, familywise false-positive error rate (i.e., the complement of specificity) should be controlled at, or below, a prespecified level. Second, sensitivity to detect genuine deviations from the norm should be high. Third, the comparisons should be easy enough for routine application, not only in research, but also in clinical practice. Here we show that these criteria are satisfied for current procedures used to assess an overall deviation from the norm—that is, a deviation given all test results. However, we also show that these criteria are not satisfied for current procedures used to assess test-specific deviations, which are required, for example, to investigate dissociations in a test profile. We therefore propose several new procedures to assess such test-specific deviations. These new procedures are expected to satisfy all three criteria. Method. In Monte Carlo simulations and in an applied example pertaining to Parkinson disease, we compare current procedures to assess test-specific deviations (uncorrected and Bonferroni normative comparisons) to new procedures (Holm, one-step resampling, and step-down resampling normative comparisons). Results. The new procedures are shown to: (a) control familywise false-positive error rate, whereas uncorrected comparisons do not; (b) have higher sensitivity than Bonferroni corrected comparisons, where especially step-down resampling is favorable in this respect; (c) be user-friendly as they are implemented in a user-friendly normative comparisons website, and as the required normative data are provided by a database. Conclusion. These new normative comparisons procedures, especially step-down resampling, are valuable additional tools to assess test-specific deviations from the norm in large test batteries.     

Health-Related Quality of Life

Abstract

Background: Motor neurone disease (MND) remains universally fatal despite the introduction of disease-modifying therapy in the form of the glutamate inhibitor, riluzole. Caring for people with MND presents enormous challenges, many of which are particular to the disease complex. An understanding of the carer burden is required in order to inform the delivery of palliative care to MND patients and their carers.

Aim: To explore the experiences and perceptions of carers and former carers of people with MND with emphasis on the later stages of the disease.

Participants and Methods: Focus groups were conducted with two groups of former carers and one group of current carers recruited through the Motor Neurone Disease Association of NSW. Recruitment continued until no new themes emerged. The discussions were taped, transcribed verbatim and content analysed.

Results: There was a clear thematic trajectory from diagnosis through to death and bereavement with ramifications evident for the delivery of palliative care. Unmet emotional needs and the unremitting and all-encompassing nature of care were emphasised, as was the importance of love in sustaining the carer.

Conclusions: The experience of caring for a person with MND has a lasting psychological impact which may outweigh the physical and financial costs of care. This relatively unexplored area of enquiry lacks adequate models on which to base quantitative investigation. This qualitative study provides a starting point for future research.