HOX transcription factors are potential targets and markers in malignant mesothelioma

YesBackground The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos. Methods We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model. Results We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival. Conclusion HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.The authors gratefully acknowledge the support of the British Lung Foundation, grant number ICAPPG10-1. KJH acknowledges support from the ICR/RM NIHR Biomedical Research Centre

Traumatic brain injury: An objective model of consent

The aim of this paper was to explore the issue of consent when considering the use of a life saving but not necessarily restorative surgical intervention for severe traumatic brain injury. A previous study has investigated the issue amongst 500 healthcare workers by using a two-part structured interview to assess opinion regarding decompressive craniectomy for three patients with varying injury severity. A visual analogue scale was used to assess the strengths of their opinions both before and after being shown objective outcome data. Opinions were assessed in a number of scenarios, one of which was that the participants themselves were the injured party. The implication, which was clearly stated, was whether they would provide consent for the procedure to be performed. The study demonstrated that participants were relatively risk aversive in regards to survival with severe disability especially when the injury was severe and there was high probability of that outcome occurring. This finding was not however universal and a minority of participants would provide consent even when the possibility of survival with severe disability was very high. The obvious difficulty comes when considering consent in patients who are unable to express their wishes. In order to address this issue we propose a model of consent based on a balance of the various factors that seem to be of material relevance. These include the severity of the injury, the willingness or otherwise to accept survival with severe disability and the willingness to "risk" the possibility of an unacceptable outcome in order to achieve an acceptable outcome

Futility in neurosurgery: A patient-centered approach

The concept of futility has been a source of discussion for many years. Even though it is tempting to propose that an action or clinical intervention should be deemed futile if it does not achieve the goals of that action, further clarification is needed in terms of the nature of the likely outcomes of an intervention and the probabilities of various outcomes being achieved. The outcome, in an age of balance between autonomy and necessity, should, at a minimum, be acceptable to the person on whom the intervention is to be performed. This is especially the case when considering outcome following decompressive craniectomy for severe traumatic brain injury, in which certain outcomes are likely to be severely impaired states that the patient would consider unacceptable. In this article, we use some key ethical concepts such as substantial benefit and the risk of unbearable badness to explore the concept of futility in severe traumatic brain injury and, by linking that to recent advances in neurosurgical science, propose a pragmatic patient-centered approach to deal with the concept of futility

Reconsidering the role of decompressive craniectomy for neurological emergencies

Objective There is little doubt that decompressive craniectomy can reduce mortality. However, there is concern that any reduction in mortality comes at an increase in the number of survivors with severe neurological disability. Method Over the past decade there have been several randomised controlled trials comparing surgical decompression with standard medical therapy in the context of ischaemic stroke and severe traumatic brain injury. The results of each trial are evaluated. Results There is now unequivocal evidence that a decompressive craniectomy reduces mortality in the context of “malignant” middle infarction and following severe traumatic brain injury. However, it has only been possible to demonstrate an improvement in outcome by categorizing a mRS of 4 and upper severe disability as favourable outcome. This is contentious and an alternative interpretation is that surgical decompression reduces mortality but exposes a patient to a greater risk of survival with severe disability. Conclusion It would appear unlikely that further randomised controlled trials will be possible given the significant reduction in mortality achieved by surgical decompression. It may be that observational cohort studies and outcome prediction models may provide data to determine those patients most likely to benefit from surgical decompression

Uncertainty, conflict and consent: revisiting the futility debate in neurotrauma

The concept of futility has been debated for many years, and a precise definition remains elusive. This is not entirely unsurprising given the increasingly complex and evolving nature of modern medicine. Progressively more complex decisions are required when considering increasingly sophisticated diagnostic and therapeutic interventions. Allocating resources appropriately amongst a population whose expectations continue to increase raises a number of ethical issues not least of which are the difficulties encountered when consideration is being given to withholding “life-preserving” treatment. In this discussion we have used decompressive craniectomy for severe traumatic brain injury as a clinical example with which to frame an approach to the concept. We have defined those issues that initially lead us to consider futility and thereafter actually provoke a significant discussion. We contend that these issues are uncertainty, conflict and consent. We then examine recent scientific advances in outcome prediction that may address some of the uncertainty and perhaps help achieve consensus amongst stakeholders. Whilst we do not anticipate that this re-framing of the idea of futility is applicable to all medical situations, the approach to specify patient-centred benefit may assist those making such decisions when patients are incompetent to participate

Interactive Intelligent Remote Operations

NRC publication: Ye

Decompressive craniectomy for diffuse cerebral swelling after trauma: Long-term outcome and ethical considerations

BACKGROUND: There is currently much interest in the use of decompressive for the management of diffuse cerebral swelling after trauma. Although the use of the procedure may improve survival, some of those survivors may be left severely disabled. The aim of this study was to see whether severe disability can be predicted and discuss the difficult ethical issue that this raises. METHODS: This was a retrospective cohort subgroup analysis of those patients with severe head injury in Western Australia between 2004 and 2008 who had had a decompressive craniectomy for intractably raised intracranial pressure despite maximal medical management. RESULTS: Among a total of 1,786 adult neurotrauma patients admitted between 2004 and 2008, 74 patients required a bifrontal decompressive craniectomy for intractably raised intracranial pressure. After the application of Corticosteroid Randomization After Significant Head Injury (CRASH) trial collaborators? prediction model, predicted and observed outcomes were compared. The mean timing and median timing of surgery were 42 hours and 30 hours after hospital admission, respectively. The timing of decompressive craniectomy was inversely correlated to the severity of the head injury (Spearman's correlation coefficient = -0.251, p = 0.031). At 18-month follow-up, 16 patients were deceased, 3 were in a persistent vegetative state, and 10 were severely disabled. In contrast to these unfavorable outcomes, 35 patients had a good outcome and 10 were moderately disabled at 18 months. The discrimination of the CRASH prediction model was excellent (area under receiver-operating characteristic curve, 0.905; 95% confidence interval, 0.829-0.982; p = 0.001). CONCLUSION: Our data provide some evidence that the CRASH prediction model may help clinicians and families to make informed decision about the benefits and risks of decompressive craniectomy for diffuse cerebral swelling

Decompressive craniectomy for neurotrauma: the limitations of applying an outcome prediction model

Background There is currently much interest in the use of decompressive craniectomy for patients with severe head injury. A number of studies have demonstrated that not only can the technique lower intracranial pressure but can also improve outcome. Whilst many patients who would otherwise have died or had a poor outcome now go on to make a good recovery, there is little doubt that complications can have a very significant impact on long term outcome. Methods By using the corticosteroid randomisation after significant head injury (CRASH) collaborators outcome prediction model, three patients were selected who had a similar outcome prediction. All three patients developed intracranial hypertension following trauma and had a decompressive craniectomy. Results Despite having a similar outcome prediction only one patient made an uneventful recovery. The remaining two patients suffered significant complications. Conclusions This report illustrates the potential clinical applications and limitations of an outcome prediction model and demonstrates the impact that complications can have on eventual outcome

Neurotrauma and the RUB: where tragedy meets ethics and science

Decompressive craniectomy is a technically straightforward procedure whereby a large section of the cranium is temporarily removed in cases where the intracranial pressure is dangerously high. While its use has been described for a number of conditions, it is increasingly used in the context of severe head injury. As the use of the procedure increases, a significant number of patients may survive a severe head injury who otherwise would have died. Unfortunately some of these patients will be left severely disabled; a condition likened to the RUB, an acronym for the Risk of Unacceptable Badness. Until recently it has been difficult to predict this outcome, however an accurate prediction model has been developed and this has been applied to a large cohort of patients in Western Australia. It is possible to compare the predicted outcome with the observed outcome at 18 months within this cohort. By using predicted and observed outcome data this paper considers the ethical implications in three cases of differing severity of head injury in view of the fact that it is possible to calculate the RUB for each case