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In vivo anatomical and functional identification of V5/MT using high-resolution MRI: a technique for relating structure and function in the human cerebral cortex

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Post date April 1, 2015
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Previous in vivo neuroimaging studies have clearly demonstrated the functional specialisation of the human cerebral cortex. However, precise anatomical localisation of functionally defined cortical areas is an ongoing challenge due to the poor spatial resolution of functional imaging techniques and significant inter-individual differences in the complex morphological structure of the human cortex. The present study used high-resolution MRI to identify V5/MT in three subjects based on its distinctive MR-visible myeloarchitectonic structure. Consistent with previous studies, V5/MT was localised to the junction of the ascending limb of the inferior temporal sulcus and the lateral occipital sulcus. This anatomically defined location of V5/MT was shown to correspond with its functionally defined location, identified using fMR in one subject. Structural MR images with high spatial resolution were acquired in this study by combining increased MR field strength, a multi-channel phased-array head coil for image acquisition and signal averaging across a series of T1-weighted images. This study thus confirmed that MR contrast can be used to resolve intracortical lamination known to be present on a histological level, enabling cortical substructure to be visualised in vivo. It provided proof of concept in a single human subject; therefore, further validation of this novel technique for identification of V5/MT and other functionally defined cortical areas is required. Application of this methodology in its own right, or integrated with other MR-based neuroanatomical mapping techniques, will facilitate structure-function correlation throughout neocortex in living human subjects.

Functional specialisation of human cerebral cortex has been demonstrated in vivo using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) [e.g. 1]. Current research is aimed at precise anatomical localisation of functionally defined areas. However, accurate localisation of active regions is an ongoing challenge given the poor spatial resolution of functional imaging and inter-individual variability in the complex morphological structure of cerebral cortex [2,3]. Consequently, location of cortical areas must be examined within an individual to obtain precise structure-function information.

Various techniques have been developed to indirectly correlate structure and function in cerebral cortex. Post-mortem human brain analysis following functional imaging would be ideal for precise anatomical localisation of functional regions within an individual; however, this is not readily available. Consequently, novel techniques were required to enable structure-function correlation in living humans.

Early research relied on presumed homology between human and non-human primate brains. Unfortunately, comparative variations in brain size, complexity, orientation and potential rearrangement of cortical areas between species makes comparison of functional anatomy difficult [4].

Brain atlases developed using traditional histological techniques to provide standardised coordinates for neuroanatomical landmarks have also been widely used. However, significant inter-individual variation in brain topography limits their usefulness in precisely identifying functional regions. For example, Talairach and Tournoux’s [5] atlas is based on one brain’s structure, over which Brodmann’s cytoarchitectonic map [6] was projected. Given that functionally defined areas can vary in location by centimetres, such an atlas can provide only gross localisation. Additionally, Brodmann’s two-dimensional map contained no data about the intrasulcal surface, two-thirds of cortical surface, so we can only estimate these borders [7,8].

Humans who have had a stroke, tumour, or traumatic brain injury also provide localisation information. Correlation of lesion location and subsequent neurological deficits provides information about the damaged region’s role. However, this technique’s usefulness is limited because (1) lesions are often extensive so accurately locating the area responsible for the missing function is difficult and (2) rarely is only a single function lost, because lesions tend to incorporate areas performing a range of roles [9].

Recent studies have revealed a successful new method of achieving precise anatomical localisation of functionally identified areas. Co-registration of structural MR with functional images from the same individual enables functionally defined regions to be mapped onto the specific morphological structure of each subject [10,11,12,13]. This approach to structure-function correlation relies on distinct anatomical features, in particular MR-visible cortical myeloarchitecture, e.g. the densely myelinated stria of Gennari, which demarcates primary visual cortex [14,15]. These techniques were used here to identify the visual motion area, V5/MT.

V5/MT is readily identifiable histologically because of its characteristic myelination. Clarke and Miklossy [16] first identified putative V5/MT in post-mortem brains at the occipito-temporal junction featuring distinctive myelination. These MR-visible myelin bands in layers I, IV and V (the latter two, the external and internal bands of Baillarger) and radial fibres crossing layers VI to IV help anatomically localise putative V5/MT at the junction of ascending limb of inferior temporal sulcus (ALITS) and lateral occipital sulcus (LOS) in parieto-temporo-occipital cortex [11,13]. This is largely consistent with functional results, showing that this functionally defined area also has anatomical identifiers.

V5/MT has been studied in non-human and human primates. Its location and role in non-human primates is similar, although not identical, to humans [17,18], as expected given the limitations of such studies, discussed above. Research in brain-damaged humans also supports V5/MT’s role in visual motion detection [19,20,21,22]; however, lack of imaging or post-mortem analysis has prevented accurate lesion localisation. Even using transcranial magnetic stimulation to mimic deficits experimentally [23,24] is limited by the extensive area such lesions encompass, likely responsible for a range of functions. Thus, structure-function correlation based on MR imaging in healthy humans represents significant progress in the field.

Recent studies have produced a robust non-invasive method of identifying functionally defined cortical areas in living humans [e.g. 11]. However, acquiring MR images with sufficient spatial resolution to precisely characterise underlying microarchitecture is an ongoing challenge. Our approach focused on improving resolution by applying advanced technology and analysis now available.

Precise anatomical localisation of functionally defined cortical areas relies on correlation of functional and structural images. Visualisation of cortical lamination requires a minimum MR resolution of 200-300m, since the thickest myelin band is 250m thick [9]. Standard T1-weighted images are generally acquired at 1-1.5mm3 resolution – it would take several hours to acquire a single T1-weighted image of 200-300m3 with equivalent signal intensity and signal-to-noise ratio (SNR). It is clearly unfeasible to expect subjects to remain stationary within the scanner for this time.

Several ways of increasing spatial resolution of T1-weighted images without relying on long scan times were used here. Firstly, the scanner’s magnetic field strength was increased from 1.5 to 3 Tesla (T), nearly doubling available signal, producing a corresponding SNR improvement [25], thus enhancing resolution. Secondly, a multi-channel phased-array head coil was used for image acquisition, increasing SNR using radiofrequency coils and combining multiple coils with individual receiver channels into an array covering the same volume as a larger coil with slight sensitive volume overlap, producing signal of equivalent amplitude but greatly reduced noise [26]. This improvement in SNR is particularly evident in surface regions [27], such as V5/MT. Thirdly, averaging signal across a series of T1-weighted images significantly reduced noise, improving SNR and enhancing visibility of fine architectonic detail [27], a technique validated by Walters et al. [11]. Additionally, voxel oversampling during averaging due to jitter from small inter-scan head movements increased signal and reduced partial volume error of single scans, improving neuroanatomical detail [28].

The current study thus applied a well-established methodology of non-invasive in vivo structural identification of functionally defined cortical areas developed by Walters et al. [11] to the precise anatomical localisation of V5/MT. We aimed to (1) validate this technique and (2) use technological advances to enhance MR images and improve microarchitecture detection. We hypothesised that this would produce improved spatial resolution of structural MR images, enhancing visualisation of cortical lamination within V5/MT.

Methods

Experiment 1: Identification of cortical microarchitecture using high-resolution MRI

Subject recruitment

Ethical approval was obtained. Three healthy male subjects (mean age 52) participated with informed consent.

Structural MRI
Twelve to sixteen high-resolution T1-weighted part brain images and three to four whole brain images were acquired over several sessions on a Siemens Trio 3T scanner using a 32-channel phased-array head coil (Siemens AG, Germany). Part brain parameters: three-dimensional magnetisation prepared rapid gradient echo (3D MP-RAGE) sequence: slices=144; thickness=0.75mm; field of view (FOV)=220mm; in-plane resolution=0.5×0.5mm2; echo time (TE)=3.41ms; repeat time (TR)=1800ms; inversion time (TI)=900ms; flip angle (FA)=9º; number of excitations (NEX)=1. Whole brain parameters: 3D MP-RAGE sequence: slices=256; thickness=0.60 mm; FOV=265 mm; in-plane resolution=0.6×0.6mm2; TE=2.81ms; TR=1900ms; TI=900ms; FA=9º; NEX=1. Raw images were transferred via a DICOM client program (Digital Jacket, Hewlett-Packard, CA), composed into contiguous volumes, and saved in Analyze (Radiological) format (Biomedical Imaging Resource, Mayo Foundation, MN).

Data analysis
Images were analysed using tools from Oxford Centre for fMRI of the Brain (FMRIB) Software library [29,30] and Mricro [31]. T1-weighted images were cropped at rostral spinal cord using Mricro [31] and automatically segmented to remove non-brain tissue using the FMRIB Brain Extraction Tool (BET) [32]. Each image was resampled at half the acquired voxel dimensions, producing volumes with voxel dimensions of 0.25×0.38×0.25mm3 for part and 0.30×0.30×0.30mm3 for whole brain images.

One part brain with minimal motion artefact was made the template for each scanning session. All images obtained in that session were registered to the template using a rigid body model with six degrees of freedom with the FMRIB Linear Image Registration Tool [33]. Template images for each session were then registered to the template for session one. Transformation matrices were concatenated and applied to each image. Transformed images were averaged using fslmaths [29], producing a mean high-resolution image.

A single whole brain T1-weighted image was acquired in each scanning session. Each of these images was registered to that acquired in session one. Transformation matrices were applied to each and transformed images averaged using fslmaths, producing a mean high-resolution image. SNR was calculated prior to and following image co-registration with regional intensity measured using ImageJ version 1.45 [34].

V5/MT’s site was estimated based on its postulated location at the ALITS and LOS intersection. Slices through this region were identified and two-dimensional cortical lamination analysis conducted. Intensity line profiles were manually generated using ImageJ version 1.45 [34]. The number, intensity and relative location of each stationary point or point of inflection between cortical surface and grey-white matter boundary were calculated. These measurements were used to generate a cortical lamination map and enabled comparison of lamination between subjects.

Experiment 2: In vivo structural identification of V5/MT using high-resolution MRI

Subject recruitment

Subject 2 was previously involved in Walters et al. [11].

fMRI
fMR data for subject 2 was obtained from Walters et al. [11]. Images were acquired on a 1.5T scanner (Signa Echospeed, General Electric). Subjects observed a moving checkerboard stimulus [13]. Further details available in Walters et al. [11].

Data analysis

Functional analysis was carried out by Walters et al. [11] using FLIRT [33] and SPM99 [35,36]. High-resolution T1-weighted anatomical image obtained for subject 2 was aligned with the average greyscale-normalised surface coil T1-weighted image acquired by Walters et al. [11]. The functional activation map was overlaid and used to identify functionally defined V5/MT for comparison with the location of anatomically defined putative V5/MT from Experiment 1.

Results
Experiment 1: Identification of cortical microarchitecture using high-resolution MRI
Figure 1 shows three T1-weighted MR slices for subject 2. Figure 1(i) shows the raw T1-weighted MR image, prior to de-skulling. The second panel (Fig 1(ii)) is from a single T1-weighted MR image; the third panel (Figure 1(iii)) shows the effect of co-registering multiple T1-weighted MR images within and across scanning sessions. The significant increase in spatial resolution produced by averaging is clearly evident. Quantitatively, this reflects a 34% improvement in SNR due to co-registration.

Figure 1: The effect of de-skulling then signal averaging across multiple T1-weighted MR images for subject 2. (i) A coronally-oriented slice from a single T1-weighted image prior to de-skulling. (ii) The same coronally-oriented slice from a single T1-weighted image after de-skulling using BET. (iii) An equivalent coronally-oriented slice from subject 2’s average T1-weighted part brain image, derived by co-registering multiple T1-weighted MR images using a linear algorithm using FLIRT.

Slices through putative anatomically defined V5/MT in the co-registered high-resolution structural T1-weighted MR images for all subjects are shown in Figure 2 (left). Visual examination of the areas of interest (Figure 2, middle) showed two horizontally oriented bands within the cortical ribbon. Intensity line profile analysis through putative V5/MT at this point (AB) is also shown in Figure 2 (right). This enabled quantification of the location of these bands. The first was close to the cortical surface, at 30% grey matter depth while the second was at 65% cortical thickness. The intensity line profile for subject 2 (Figure 2 (vi)) also suggested a third band near the grey-white matter junction (90% depth), consistently identified as either a local maximum or point of inflection.

Figure 2: In vivo structural MR results from subjects 1 (left hemisphere), 2 (left hemisphere) and 3 (left hemisphere). The left column shows coronally-oriented slices through putative anatomically defined V5/MT in subjects 1 (i), 2 (iv) and 3 (vii). The region of interest has been highlighted (white boxes). The middle column shows an enlarged view of the highlighted area in (i), (iv) and (vii) for subjects 1 (ii), 2 (v) and 3 (viii) with a red line (AB) through the one of the banks of the sulcus indicating the site of cortical lamination analysis. The right column shows intensity line profiles along the red line AB of (ii), (v) and (viii) showing two intensity maxima for subjects 1 (iii), 2 (vi) and 3 (ix), with an additional point of inflection at 90% cortical depth for subject 2. Cortical depth is normalised to 0-100% from the outer cortical boundary to the grey/white matter junction.

Intensity line profiles of putative V5/MT are clearly different to surrounding cortex. The opposite sulcal bank is characterised by a single, wide peak at 45% cortical thickness (Figure 3).

Figure 3: In vivo structural MR results from subject 2 (left hemisphere). (i) Coronally oriented slice through putative anatomically defined V5/MT. The region of interest has been highlighted (white box). (ii) Enlarged view of the highlighted area in (i) with a red line (AB) through the upper bank of the sulcus indicating the site of cortical lamination analysis, as in Figure 2 (v). (iii) Intensity line profile along the red line AB of (ii), showing two intensity maxima, as in Figure 2 (vi). Cortical depth is normalised as described in Figure 2. (iv) The same coronally oriented slice as in (ii) with a yellow line (CD) through the lower bank of the sulcus indicating the site of cortical lamination analysis. (v) Intensity line profile along the yellow line CD of (iv), showing a single intensity maximum.

Experiment 2: In vivo structural identification of V5/MT using high-resolution MRI

Functionally-defined V5/MT for subject 2 was identified on the high-resolution structural T1-weighted MR image acquired in this study using functional data from Walters et al. [11]. This region sits at the junction of ALITS and LOS. Other areas of activation correspond largely with lower order visual areas; there are also areas of parietal activation. Figure 4(i) shows a high-resolution slice through subject 2’s brain with overlaid foci of functional activation. Figure 4(ii) is an enlarged view of the region, with functional activation overlying the location of putative V5/MT identified in Experiment 1. These functional results correlate strongly with the spatial location of putative V5/MT. Characteristic intensity line profiles are thus effective anatomical identifiers for V5/MT.

Figure 4: In vivo structural MR and fMR results from subject 2 (left hemisphere). (i) Coronally oriented slice through high-resolution MR image with overlaid functional activation map. The region of interest has been highlighted (white box). (ii) Enlarged view of the highlighted area in (i) showing co-localisation of functional activation and putative anatomically defined V5/MT identified in Experiment 1 (white arrow).

Discussion

This study employed a well-established methodology of non-invasive in vivo identification of functionally defined cortical areas to determine V5/MT’s precise location. Efficacy of the technique pioneered by Watson et al. [13] and extended to fMRI by Walters et al. [11] was confirmed. High-resolution structural MR images were successfully acquired and intensity line profiles drawn through putative V5/MT. Co-registration of functional data from Walters et al. [11] with new high-resolution structural data confirmed the putative anatomical location of V5/MT at the junction of ALITS and LOS in subject 2, consistent with previous studies [10,11,13].

Intensity line profile analysis has been used previously [37,11] to quantify cortical lamination. Current results are consistent with previous findings, demonstrating light-coloured bands at 30% and 65% cortical depth. Subject 2’s data suggest a third band near the grey-white matter junction. The first two likely correspond to the heavily myelinated internal and external bands of Baillarger identified in putative V5/MT in post-mortem brains [11]. The origin of the third band may correspond with radial fibres traversing lower cortical layers, also described in post-mortem specimens. These results thus confirm V5/MT’s characteristic T1-weighted MR appearance. Intensity line profiles distinguish putative V5/MT from surrounding cortex. Profiles of the opposite sulcal bank are characterised by a single, wide peak at 45% depth (Figure 3), consistent with lamination described by Walters et al. [11].

There is a strong correlation between putative V5/MT’s spatial location and functional results for subject 2. This confirms that the characteristic intensity line profiles from this region are distinctive anatomical identifiers for human V5/MT, verifying Walters et al. [11]. Quantitative comparison of the intensity of line profile maxima through V5/MT here and in Walters et al. was not possible due to different techniques used to derive cortical lamination maps. Qualitatively, however, the peaks of local maxima (Figure 2) are less well defined than those previously obtained. This reflects reduced SNR with the present paradigm.

On a whole brain level, high-resolution T1-weighted MR images acquired in this study clearly have superior spatial resolution compared to those in Walters et al. [11] However, this overall improvement in resolution is at the expense of reduced SNR at the site of interest i.e. putative V5/MT. This is reflected qualitatively as less well-defined maxima on intensity line profiles. In comparison, images obtained previously have high resolution at V5/MT, but lower resolution across remaining cortex. This represents a significant benefit of using surface coils placed directly over the cortex compared to the current paradigm. The potential for concurrent use of these techniques warrants exploration.

This novel approach to improving MR spatial resolution combined technological advances with innovative image analysis. MR scanning hardware is improving rapidly with improved access to high magnetic field strength scanners and multi-channel phased-array head coils. The technique of signal averaging across images from successive sessions is also relatively recent. We demonstrated that these new tools can be successfully applied to produce T1-weighted MR images with high SNR, enabling detection of cortical lamination.

The application of this new approach to in vivo structure-function correlation in the human cortex requires further validation. This study provides proof of concept in a single subject. High-resolution structural MR images obtained for two others clearly demonstrate the efficacy of this approach in enabling visualisation of cortical microarchitecture; unfortunately, functional identification of V5/MT in these subjects was not possible. Future extension of this study will help resolve this issue.

Imaging techniques used here significantly reduced analysis complexity. Twin surface coil arrangements used by Walters et al. [11] with narrow fields of view resulted in complicated signal attenuation requiring correction prior to registration. This processing step was not required here. Further, use of a multi-channel phased-array head coil also enabled examination of subcortical microarchitecture since high SNR is not restricted to cortical surface. Acquisition of images with high SNR over a larger field of view represents significant progress.

As suggested by Walters et al. [11], this technique can be broadly applied to identification of cortical architecture in living humans. Its usefulness has not yet been fully explored with studies restricted to V1 and V5/MT [14,11,12]. Given the strong contribution of myeloarchitecture to MR signal, further studies investigating non-visual cortex should focus on Flechsig’s37 fields of increased myelination to maximise initial success.

Development of imaging and analysis techniques enabling visualisation of cortical lamination opens up new research areas. For example, if functionally active areas are well-characterised microanatomically in vivo using high-resolution MR, major input and output cortical layers can be identified. This would require new task paradigms with multiple conditions activating a functional area in different ways, thus involving distinct pathways [39]. Additionally, anatomical localisation of functionally defined areas could guide medical therapy, like that achieved with deep brain stimulation in Parkinson’s disease [40]. Further research in these areas is required.

Conclusions

This study confirmed that MR contrast can resolve intracortical lamination present histologically, enabling visualisation of cortical substructure in vivo. It employed improved MR hardware and analysis to validate Walters et al. [11], including V5/MT’s characteristic MR profile, and identified further microarchitectonic detail. Further optimisation of techniques to improve lamination detection is required to maximise results. Application of this methodology alone, or integrated with other MR-based mapping, will facilitate structure-function correlation throughout the neocortex in living humans.

Acknowledgements

I am very grateful for the training in MR analysis provided by Jennifer Leech, Ayaka Ando, Alicia Dymowski and Dr Marcus Gray, technical support from Sina Sadeghi and Dr Neil Killeen, and assistance with MR imaging from Michael Kean. This research was supported by funds from the Florey Neuroscience Institutes, Melbourne. I was also grateful to receive the Dr Charlotte Last Memorial Scholarship for Honours in Medicine from the Sydney Medical School.

Conflict of Interest

None declared.

Correspondence

S Barnes: stephaniebarnes01@gmail.com

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Letters

Insights into the application of evolutionary and ecological concepts to cancer treatment via modelling approaches

Therapeutic resistance has been shown to result in poorer clinical outcomes in cancer treatment. It has been proposed that evolutionary adaptations of cancer cells to therapy result in the development of resistance with the rate of adaptive change correlating with the heterogeneity of the tumour. These concepts can help overcome therapeutic resistance and have been exploited by Gatenby and others in promising evolutionary double-bind simulations. It was further suggested that tumour vasculature contributes to intra-tumoural heterogeneity through the development of substrate gradients. Increasing analogy between natural ecosystems such as riparian habitats and the tumour environment may allow us to devise novel treatment strategies. This review will briefly examine some of these evolutionary and ecological concepts and how they can be applied to cancer treatment.

Introduction

Carcinogenesis is the process by which normal cells in the body acquire mutations and form tumours. In the 1970s, Peter Nowell characterized this transformation in terms of evolutionary change and this concept has been well accepted by the scientific community. [1] He proposed that genetic instability and mutations form the basis for heritable changes required for natural selection and clonal growth of single cancer cells. Cells are selected for desirable characteristics such as survival and proliferation in response to changes in their immediate environment. [1] Surprisingly, evolutionary principles have seldom been used in the treatment of cancer. Aktipis and colleagues did an analysis of over 6000 papers focusing on therapeutic resistance and cancer relapse and revealed that ‘evolution’ has been used in only 1% of all papers. [2]

As evolution is influenced by changes in the environment, it is possible to view the tumour microenvironment as an ecosystem consisting of heterogeneous populations of cancer cells interacting with one another, and with other cells of the microenvironment. These complex interactions have much in common with ecosystems in nature and consist of analogous abiotic and biotic components which provide novel treatment targets to circumvent therapeutic failure.

Failure of chemotherapy can be attributed to cancer resistance which can be inherent or acquired. Inherent resistance may occur due to over-expression of drug metabolism pathways such as the excision repair cross-complementing 1 gene (ERCC1 — a nucleoside excision repair gene) in resistance against platinum agents while acquired resistance can be caused by altered membrane transport as in the case of the P-glycoprotein transport protein encoded by the multi-drug resistance-1 gene (MDR-1). [3]

Evolutionary game theory

Hypoxia and acidosis within the tumour can exert selective pressures on individual cancer cell populations. These populations may adapt to these conditions through different phenotypic strategies arising from genetic instability and genotypic variations. Gilles and colleagues proposed that these interactions can be understood through the evolutionary game theory. In this theory, the evolutionary rate of a phenotypic strategy is dependent on the amount of phenotypic diversity and the fitness of cancer cell populations. [4] Cancer cell populations will evolve rapidly in the presence of a harsh tumour environment or when cell populations are phenotypically diverse. Selective pressures originating from perturbations outside the tumour microenvironment can also promote further phenotypic diversity. [4,5] Alteration of the tumor environment by chemotherapy can potentially encourage cancer cell populations to diversify and become heterogeneous via de novo mutations arising from therapy or selection of existing chemotherapy-resistant cells in the tumour. [5]

The evolutionary game theory therefore predicts that the probability of the existence and/or emergence of resistant cells correlates with the level of tumour heterogeneity. It also suggests that chemotherapy will inadvertently lead to resistance if chemo-resistant cells (such as cancer stem cells) are already present in the tumour. [4,5] These predictions appear to correlate with clinical findings as advanced cancers which are less responsive to therapies usually exhibit high levels of heterogeneity while the use of high-dose chemotherapy improves survival but seldom cures epithelial cancers. [6]

High-dose chemotherapy regimens were first conceptualized mathematically through the Norton-Simon model. It is hypothesised that administering the maximum tolerated dose (MTD) over a short time period would achieve a high cancer cell kill rate and a low probability of therapy-induced evolution of resistant clones. [7] This model, however, does not account for pre-existing chemo-resistant cells which clonally proliferate and result in cancer relapse after initial treatment. By recognising that resistant cells potentially pre-exist in tumours and that they correlate positively with tumour heterogeneity, certain strategies can be devised. These include controlling the heterogeneity of the tumour to prevent the occurrence of chemo-resistance and, exploiting our ability to predictably alter the adaptive strategies of cancer cells through various treatment modalities.

Controlling tumour heterogeneity: induction of evolutionary bottlenecks and achieving an evolutionary ‘double-bind’

Intra-tumoural heterogeneity is minimal in early neoplasms and the use of low-dose chemotherapy may be sufficient to eliminate early cancers with less risk of resistance. [7] This formed the basis of metronomic chemotherapy where low doses of chemo-drugs were given in frequent intervals. [8] However, intricate strategies involving circumvention of therapeutic resistance would be required as a cancer progresses.

Resistant cells favour tumour progression in a treatment setting but many forms of resistance incur phenotypic costs. If the phenotypic cost is low, for example, due to the ability of the cancer cell to adapt to therapy through up-regulation of xenobiotic mechanisms or usage of a redundant signaling pathway, control of cancer cell proliferation will be less effective. [9] Conversely, if the phenotypic cost is high, for example, due to competition from co-existing cancer cell populations with different proliferative characteristics and biological therapies, robust and long-lasting control may be achieved because cancer cells can only survive by diverting resources away from proliferation. The latter creates an evolutionary double-bind where the only way tumour cells can evade the deleterious effects of treatment is by compromising its fitness attributes, thereby inhibiting its proliferation or ability to develop resistance. [9]

An evolutionary double-bind in a combination therapy setting would require anticipating the adaptation of cancer cell populations to a specific treatment and then targeting the adapted phenotype by a follow-up treatment. [4] In a study by Hunter et al., treatment of glioblastoma multiforme tumours with the alkylating agent temozolomide (TMZ) resulted in hypermutations in the MSH6 mismatch repair gene. [5,10] These mutations were not present in untreated tumours and suggest that chemotherapy selected for MSH6-mutant cells. A clonal selection process was thought to create an evolutionary bottleneck where the majority of the cells were MSH-6 mutants while cancer cells with the wild-type MSH6 gene were eliminated. [5,11]

The transient decrease in genetic heterogeneity following TMZ administration provides a therapeutic window when cancer cells are most susceptible to a secondary treatment. [5] An in vivo study investigating the effects of the oral poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 on xenograft models of human tumours found that this PARP inhibitor not only synergistically maintains and potentiates the cytotoxic effects of TMZ on different tumours but also overcomes TMZ resistance. [12] ABT-888 and other similar PARP inhibitors may therefore have a role as a secondary treatment in combination therapies as they can eliminate most of the residual chemo-resistant cell populations. A schematic diagram of a two-step evolutionary double-bind is shown in Figure 1.

Figure 1. Evolutionary double-bind. For simplicity, tumour cells can be sensitive (neutral or susceptible) or resistant to a treatment. A two-step setup would involve the first treatment reducing heterogeneity of the tumour by imposing a high phenotypic cost on tumour cells. The second treatment works synergistically with the first treatment, such as in the case of PARP inhibitors and TMZ, to eradicate initially resistant cell populations.

Chemotherapy-based combination therapies

The widespread use of chemotherapy necessitates a scrutinisation of its synergistic and antagonistic effects in cancer treatment. Basanta and colleagues examined the use of an evolutionary double-bind in a combination therapy consisting of the p53 vaccine and chemotherapy. [13] Using a mathematical framework derived from the evolutionary game theory, they found that the p53 vaccine and chemotherapy work synergistically to exert robust anti-tumour effects. Interestingly, depending on whether the p53 vaccine or chemotherapy was used as the first treatment, different effects were observed.

Application of chemotherapy before the p53 vaccine was found to be more effective than using the p53 vaccine initially followed by chemotherapy. [13] This was attributed to a commensalistic relationship between vaccine-resistant cells and other cell populations. Eliminating vaccine-resistant cells in the first instance disrupts the protective effect and results in other cell populations (e.g. chemo-resistant and fully susceptible) being susceptible to immune mechanisms mediated by the p53 vaccine. In other words, ecological interactions between different cell populations of a tumour appear to determine the effectiveness of an evolutionary double-bind.

Although application of the p53 vaccine before chemotherapy had a diminished anti-tumour effect, the effectiveness of this approach can be increased with longer exposure to the p53 vaccine. [13] Indeed, both approaches appeared to be most effective when the first treatment was applied for a longer period. This reflects the importance of the first treatment as a limiting factor in combination therapy. Prolonged exposure to the first treatment widened the therapeutic window and acted as a barrier against therapeutic resistance most likely by reducing tumour heterogeneity through the creation of an evolutionary bottleneck.

Ecological interactions (e.g. commensalism or competition) between cancer cell populations are important and we can further characterize these interactions by considering the fitness of different cancer cell populations through phenotypic costs. [4] In the absence of treatment, resistant cells are likely to be less fit and have a slower rate of proliferation as compared to sensitive cells since they have to devote more resources to surviving. [4] These cells are most often found in the inner regions of a solid tumour where harsh conditions such as hypoxia and acidosis cause necrosis of tumour cells but favour the selection of resistant clones. Conversely, sensitive cells will be located at the outer rim of the tumour where a close proximity to the vasculature and expression of pro-survival proteins allow them to proliferate easily. [14] We can therefore predict that sensitive cells will be more susceptible to chemotherapy due to their proximity to the blood supply whereas resistant cells are highly affected by metabolic changes.

Silva and Gatenby proposed an evolutionary double-bind strategy consisting of the glucose competitor 2-deoxyglucose (2-DG) and chemotherapy. This was an attempt to reduce the fitness of both sensitive and resistant cell populations as well as stabilize tumour growth through competition via in silico simulations. [15] Different combinations of 2-DG and chemotherapy were modeled mathematically and the combination of 2-DG→chemotherapy was suggested to have the most potent anti-tumour effect. Efficacy was predicted to be lower in chemotherapy→2-DG and lowest in the synchronous administration of 2-DG and chemotherapy. The results become intuitive when we consider tumour cell populations in terms of inner region and outer rim populations. For the 2-DG→chemotherapy approach, the inner region populations are ‘pulverized’ by 2-DG due to their sensitivity to glucose depletion and this increases the surface area for chemotherapy to eliminate the outer rim cells. [15] Furthermore, 2-DG created a ‘pulverized’ morphology where a barrier of cells exists between the outer rim and inner region cells. This potentiates glucose depletion because glucose cannot diffuse effectively from the outer rim to inner region.

Interestingly, 2DG→chemotherapy mirrors the effectiveness of the p53 vaccine→chemotherapy approach. [13] This is probably attributed to the initial targeting of chemo-resistant cells and also the maintenance of a higher proportion of sensitive (and presumably fitter) cells as compared to resistant cells. The latter implies that sensitive cells can impede proliferation of resistant cells via competition for resources. Indeed, the chemotherapy→2-DG approach most likely had a better anti-tumour effect than synchronous administration because, even though the chemo-sensitive outer rim cells were targeted first, the introduction of a break or ‘drug holiday’ between chemotherapy sessions in the study’s protocol allowed the sensitive cells to recover and maintain a sizeable numerical advantage over resistant cells. [16] A similar effect was also noted in previous studies with different treatments. The chemotherapy→2-DG approach fared worse than 2-DG→chemotherapy as glucose can readily diffuse from the outer rim to inner (i.e. allowing chemo-resistant cells to survive) while the synchronous approach was least effective as the outer-rim was readily destroyed by chemotherapy; therefore reducing competition between sensitive cells and resistant cells. [15] Moreover, poor diffusion of chemotherapeutic drugs to areas deeper within the tumour meant that the inner region cells only received sub-lethal doses which favour the development of chemo-resistance.

Out of the three strategies, only the 2DG→chemotherapy approach managed to achieve an almost complete eradication of cancer cells when a bolus of MTD chemotherapy was applied while the other two strategies resulted in chemo-resistance. This result has two implications: firstly, it reflects the point that eradication of tumour cells is possible if tumour heterogeneity is targeted in the first instance and, specifically here, the chemo-resistant population. Secondly, it also implies that delineation of tumour cell populations into sub-groups based on location and proximity to key tumour structures such as the vasculature may be therapeutically significant. In fact, there is evidence that populations of tumour cells often exhibit a convergent phenotype despite genotypic differences between individual cells. [17] Thus, targeting this phenotype may be a more practical option since natural selection acts on phenotypes rather than genotypes.

Riparian ecosystems as an ecological framework for human tumours

Tumour vasculature can contribute to intra-tumoural heterogeneity by creating disparities in substrates such as oxygen and glucose through blood flow gradients, which then select for different populations of cancer cells. [17,18] Alfarouk and colleagues proposed that growth of cancer cell populations can be understood in the context of plant species in a riparian habitat. [18] A riparian habitat is the interface between land and a river stream and two distinct regions of plants can be identified depending on their distance from a river. The mesic region contains lush, tall vegetation which are adjacent to and well nourished by the nutrients from the river. This is followed by an abrupt transition to a xeric region containing sparse, short vegetation which, due to their relatively long distance away from the river, develop adaptations that allow them to conserve water and survive in arid conditions. [19] The rivers and regions of vegetation in a riparian habit are analogous to the vasculature and cancer cells in a tumour respectively.

Tumour cell populations can be broadly separated into ‘mesic’ and ‘xeric’ cells depending if they are adjacent or distal to a blood vessel. [18] Mesic tumour cells and their proximity to blood vessels would render them highly susceptible to angiogenesis inhibitors by systemic administration. Since the ‘lush’ mesic region is expected to contain many tumor cells, a drastic reduction in tumour volume can be achieved. [18] However, the elimination of mesic tumour cells favours unprohibited proliferation of xeric tumour cells and an early treatment directed against the xeric region would be necessary. Phase I and II trials have shown that pro-drug carriers (containing chemotherapeutic drugs) based on 2-nitromidazoles can target hypoxic regions of a tumor and have shown strong anti-tumour effects. [20,21] Combining pro-drug carriers with an intra-tumoural route of administration may improve the accuracy of this approach. Considering the scarcity of xeric tumour cells, prolonged early treatment may be extremely effective. A summary of the different strategies described above is shown in Figure 2.

Figure 2. Best predicted outcomes in evolutionarily and ecologically enlightened strategies. (i) In silico studies suggest that p53-resistant cells and p53-sensitive cells exist in a state of commensalism. The initial introduction of p53 eliminates vaccine-resistant cells and predisposes all remaining cells to destruction by chemotherapy. A greater effect is seen with prolonged p53 administration. (ii) 2DG targets and ‘pulverizes’ resistant cells, creating physical barrier between resistant cells but retains an outer-rim chemo-sensitive cells that inhibits cancer spread. (iii) Riparian-based therapy may achieve maximal tumour cell death through a localized targeting of mesic cells by hypoxia-based strategies followed by targeting of xeric cells by angiogenesis inhibitors.

Discussion and conclusion

Tumours are resilient in nature because they consist of a heterogeneous system of cells locked in a constant state of feedback. [22] Any perturbations in the environment of these cells may simply reinforce tumourigenic processes which restore overall tumour fitness. Although all therapies inherently disturb this fragile equilibrium, in silico studies have demonstrated proof of principle that a well-designed strategy such as an evolutionary double-bind can control and potentially eradicate most tumour cells. While modelling methods may not translate to immediate clinical benefits, they are an inexpensive way of exploring theoretical concepts in a controlled situation and provide a sound framework for further in vivo studies and clinical trials. The models described here can also readily be modified to study other forms of combination therapy, illustrating their flexibility and broad applicability to the clinical environment. One limitation, though, is that the parameters used in models have to be as realistic as possible and this can only occur through close cooperation between experimentalists and clinicians.

Key features highlighted here such as the need for prolonged initial treatment to reduce intra-tumoural heterogeneity, enhancing competition between resistant and sensitive cells and combining systemic and localized approaches are intuitive and feasible options that can be readily applied to existing treatment protocols. High-dose chemotherapy is no longer considered as a first-line approach except occasionally as salvage treatment for relapsed disease. This is not surprising in light of possible selection for chemo-resistance and increasing preference for low-dose maintenance and adaptive regimens. [6] The examples discussed in this review focused primarily on solid tumours due to easy visualisation and amenability to mathematical modelling. However, treatment of haematological malignancies would also benefit from a double-bind approach as evident from the restoration of drug sensitivity by second-generation tyrosine kinase inhibitors in treatment-resistant chronic myelogenous leukemia. [23]

There are several potential areas for further research. Firstly, we need to understand why natural selection appears to control cancers but does not eliminate them. In fact, a parallel exists with infectious diseases and high fitness costs and the tendency for organisms to evolve tolerance mechanisms may account for this phenomenon. Secondly, we should consider maximising the potential of new treatment modalities such as immunotherapy in evolutionary double-binds. [24] The limited efficacy of immunotherapy appears to contradict observations in natural ecosystems which indicate that biological control incurs higher phenotypic costs and achieves robust control of pests. This implies that inappropriate immune targets are being selected and, therefore, a true double-bind cannot be achieved. [4,23]

In conclusion, therapeutic resistance is a major obstacle to the optimisation of cancer treatment. Evolutionary and ecological principles may appear far-fetched concepts with little direct relevance to oncology but a closer inspection of the evolutionary origins and the spatial organisation of cancer cells reveal strategies that can improve clinical outcomes. Under-utilisation of these concepts is most likely a reflection of an inability to change our mindset rather than an issue of practicality. These encouraging modelling results provide a sound foundation for further translational research.

Conflict of interest

None declared.

Acknowledgments

None

References

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[2] Aktipis CA, Kwan VSY, Johnson KA, Neuberg SL, Maley CC. Overlooking evolution: a systemic analysis of cancer relapse and therapeutic resistance research. PLoS One. 2011;6(11): e26100. doi: 10.1371/journal.pone.0026100.

[3] Luqmani YA. Mechanisms of drug reistance in cancer chemotherapy. Med Princ Pract. 2005;14:35-48.

[4] Gillies RJ, Verduzco D, Gatenby RA. Evolutionary dynamics of carcinogenesis and why targeted therapy does not work. Nat Rev Cancer. 2012;12(7):487-93.

[5] Gerlinger M, Swanton C. How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine. BJC. 2010;103:1139-43.

[6] Gatenby RA, Silva AS, Gillies RJ, Frieden BR. Adaptive therapy. Cancer Res. 2009; 69(11):4894-903.

[7] Norton L, Simon R. Tumour size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep. 1977;61(7):1307-17.

[8] Gately S, Kerbel R. Antiangiogenic scheduling of lower dose cancer chemotherapy. Cancer J. 2001;7(5):427-36.

[9] Gatenby RA, Brown J, Vincent T. Lessons from applied ecology: cancer control using an evolutionary double bind. Cancer Res. 2009;69:7499-502.

[10] Hunter C, Smith R, Cahill DP, Stephens P, Stephens C, Teague J, et al. A hypermutation phenotype and somatic MSH6 mutations in recent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006;66(8):3987-91.

[11] Merlo LMF, Pepper JW, Reid BJ, Maley CC. Cancer as an evolutionary and ecological process. Nat Rev. 2006;6:924-35.

[12] Palma JP, Wang YC, Rodriguez LE, Montgomery D, Ellis PA, Bukofzer G, et al. ABT-888 confers broad in vivo activity in combination with temozolomide in diverse tumours. Clin Cancer Res. 2009;15(23):7277-90.

[13] Basanta D, Gatenby RA, Anderson ARA. Exploiting evolution to treat drug resistance: combination therapy and the double bind. Mol Pharm. 2012;9(4):914-21.

[14] Tannock I, Hill RP, Bristow TG, Harrington L. The Basic Science of Oncology. MacGraw-Hill Professional; 2005.

[15] Silva AS, Gatenby RA. A theoretical quantitative model for evolution of cancer chemotherapy resistance. Biol Direct. 2010;5(25):1-17.

[16] Labianca R, Sobrero A, Isa L, Cortesi E, Barn S, Nicolella D, et al. Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomized ‘GISCAD’ trial. Ann Oncol. 2011;22(5):1236-42.

[17] Yap TA, Gerlinger M, Futreal PA, Pusztai L, Swanton C. Intratumour heterogeneity: seeing the wood for the trees. Sci Transl Med. 2012;4(127): 127ps10. doi: 10.1126/scitranslmed.3003854.

[18] Alfarouk KO, Ibrahim ME, Gatenby RA, Brown JS. Riparian ecosystems in human cancers. Evol Appl. 2013;6(1):46-53.

[19] Helmlinger G, Yuan F, Dellian M, Jain RK. Interstitial pH and p02 gradients in solid tumours in vivo: high-resolution measurements reveal a lack of correlation. Nat Med. 1997; 3:177-82.

[20] Wilson WR, Hay MP. Targeting hypoxia in cancer therapy. Nat Rev Cancer. 2011;11(6): 393-410.

[21] Duan JX, Jiao H, Kaizerman J, Stanton T, Evans JW, Lan L, et al. Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem. 2008;51(8):2412-20.

[22] Cunningham JJ, Gatenby RA, Brown JS. Evolutionary dynamics in cancer therapy. Mol Pharm. 2011;8(6):2094-100.

[23] Thomas, F, Fisher D, Fort P, Marie JP, Daoust S, Roche BJ, et al. Applying ecological and evolutionary theory to cancer: a long and winding road. Evol Appl. 2013;6(1):1-10.

[24] Hochberg ME, Thomas F, Assenat E, Hibner U. Preventive evolutionary medicine of cancers. Evol Appl. 2013;6(1):134-43.

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Review Articles

A review of early intervention in youth psychosis

Post author By Website Publications Officer
Post date March 29, 2015
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Early intervention in youth psychosis has been a topic of contentious discussion. In particular, there is a lack of consensus regarding how early to treat patients with a psychotic disorder. There has been a recent push to provide treatment early in the development of psychosis, specifically to patients in an ultra-high risk or prodromal stage. There is also debate about the types of interventions that should be used, such as psychoeducation, psychotherapy and pharmacotherapy. In Australia, these uncertainties have been reflected by the production of conflicting guidelines by key stakeholders in this area. There are significant arguments both for and against the practice of early intervention. This article explores these arguments and reviews current practices in Australia. A number of updated recommendations are also set out in accordance with the findings of this article.

Introduction

Psychotic disorders are characterised by the presence of symptoms that reflect an excess or distortion of normal functions. For example, hallucinations, delusions, thought disorder and disorganised behaviour are symptoms characteristic of psychosis. Patients diagnosed with schizophrenia must demonstrate positive symptoms or severe negative symptoms (e.g. flattened affect, social withdrawal) in addition to deterioration in their social and vocational functioning. [1] Hence, the diagnosis is typically made after the onset of significant symptomology.

McGorry et al. [2] argue that late-stage diagnosis of a psychotic illness leads to delayed and inconsistent management of these patients. The concept of “early intervention” refers to appropriately managing patients in the early stages of psychotic disease, to minimise long-term negative social and psychological outcomes. As such, it represents a secondary prevention strategy and a paradigm shift in the way schizophrenia and other psychotic disorders are viewed; rather than being seen as illnesses with an inevitably poor social and functional outcome, they are viewed as conditions whose course can be altered
by recognition of the early warning signs and application of timely intervention. [2] The proponents of early intervention argue that many of the recognised risk factors for the development and progression of a psychotic disorder (e.g. disrupted peer and family networks, substance A review of early intervention in youth psychosis use, depression) are recognisable in advance and can be acted upon. [2]

The clinical staging model [3] proposes that psychiatric illnesses should be viewed as a sequence of stages that increase in disease severity. Employing the appropriate treatment modality at a particular stage would allow regression of the disease to an earlier stage. The clinical stages of early psychosis include the ‘ultra-high risk’ stage, the ‘first psychotic episode’ stage and the ‘first 5 years after diagnosis’ stage. [2]

The ‘ultra-high risk’ stage is the stage preceding the first psychotic episode. Although the first psychotic episode is often the first recognised sign of a psychotic illness, retrospective analysis reveals many changes occur in an individual’s thoughts and behaviour in the period preceding the psychotic episode. This is known as the ‘prodromal phase’. To intervene at this stage, it is clearly necessary to be able to identify this period in advance, and a considerable research effort is being focused on developing prospective criteria for this purpose. Two tools currently in use are the Positive and Negative Syndrome Scale (PANSS) or Attenuated Positive Symptoms (APS) approach and the Basic Symptoms (BS) approach. [4] The PANSS is a 30-point questionnaire with a 7-point rating for each question. It covers positive symptoms (e.g. delusions, hallucinations), negative symptoms (e.g. social withdrawal, blunted affect) and general symptoms of psychopathology (e.g. depression, poor insight, feelings of tension). [5] The Basic Symptoms approach focuses on subtler, self-experienced subclinical symptoms such as thought interference, disturbance of receptive language, inability to divide attention between tasks and derealisation. [6]

Intervention at the ‘first psychotic episode’ stage is largely aimed at reducing the duration of untreated psychosis (DUP), as a high DUP has been shown to result in poorer outcomes. Some authors have argued that untreated psychosis can lead to irreversible brain damage. [7,8] Although this theory has yet to receive widespread support, the personal, social and societal consequences of untreated psychosis can have a tremendous impact on the patient’s ability to recover from the episode. [2] Functional MRI brain imaging studies have shown decreased memory encoding in patients with schizophrenia and interestingly, decreased posterior cingulate activity in patients with ongoing first-episode psychosis compared to those showing remission at one year. [9] Such alterations in brain activity in patients more likely to proceed to a significant psychotic illness has exciting implications for the use of fMRI as a tool in screening for patients most likely to benefit from early intervention.

The ‘first 5 years after diagnosis’ stage is a crucial period that determines a patient’s long-term outcome. It is the time most likely to result in suicide, disengagement, relapse, [2] long-term treatment resistance and the break down and accumulation of disabilities in personal, social and occupational settings. [10] Mason et al. [11] suggest that the level of disability accumulated in the first 2 years of psychosis may in fact ‘set a ceiling for recovery in the long term’. Hence, intervention at this period is important. Maintaining a steady support structure especially tailored towards young people receiving a diagnosis of psychosis is likely to maximise chances of engagement with mental health care, life-style modifications, and adequate family involvement. [2]

Current Practice
There are currently a number of different practices/guidelines in Australia relating to early intervention in youth psychosis. The Royal Australian and New Zealand College of Psychiatrists (RANZCP) has produced clinical practice guidelines for schizophrenia, which include recommendations for patients at ultra-high risk (UHR). [12] Orygen Youth Health and headspace have also developed guidelines, called ‘The Australian Clinical Guidelines for Early Psychosis’, which are now in the second edition. [13]

Australia has established the first clinical and research clinic in the world for individuals considered to be at imminent risk of psychosis. The Personal Assessment and Crisis Evaluation (PACE) clinic was established by Orygen in Melbourne in 1994. [14] The clinic receives referrals from general practice, school counsellors and various health services. [14] They facilitate case management and provide a variety of in-house support services to families and carers including group programs, vocational and educational assistance, and occupational therapy. [15] Orygen, in conjunction with the Australian General Practice Network, the Australian Psychological Society and the Brain and Mind Research Institute also established headspace, which is a national youth mental health foundation. [16] The aim of headspace was to facilitate early intervention by increasing community awareness, clinician training and taking a youth-specific approach to management, as well as utilising multidisciplinary care. [16,17] Another service available is the Early Psychosis Prevention and Intervention Centres (EPPIC). In the 2010-11 and 2011-12 budgets, the Federal Government allocated $247m to the establishment of a network of 16 of these centres across Australia, modelled upon Orygen’s EPPIC centre in Melbourne. [18] A more detailed summary of the current guidelines/practices existing in Australia for youth psychosis is listed in Table 1.

Table 1. Current practice (guidelines and health services) in Australia for youth psychosis.

Guideline	Recommendation
RANZCP Clinical Practice Guidelines for the Treatment of Schizophrenia and Related Disorders (2005) [12]	Assessment and close monitoring every 2-4 weeks along with the provision of information to the patient and their family about the risk and likelihood of progression. Other techniques such as cognitive behavioural therapy (CBT), stress management and vocational rehabilitation should be employed depending on any concurrent psychosocial difficulties. Antipsychotics are only to be prescribed when the patient has been frankly psychotic for over a week, or in cases when milder symptoms are associated with a risk of self-harm or aggression (however, patients without such a history are often treated regularly with antipsychotics and the primary concern here is that they may have a delirium or physical illness, which should be excluded first). [12]
The Australian Clinical Guidelines for Early Psychosis [13]	Commencement of CBT for all patients identified as being at ultra-high risk is recommended. Family, vocational, educational and accommodation support should also be provided as required in a low stigma setting. Antipsychotic medication should only be considered once full threshold psychotic symptoms have been sustained for over a week, or if there is rapid deterioration accompanied by psychotic-like symptoms. [13]
Health Service	Nature of service provided
The Personal Assessment and Crisis Evaluation (PACE) clinic	PACE provides information to individuals and their families about what it means to be at risk of psychosis. [14] They facilitate case management and provide a variety of in-house support services to families and carers including group programs, vocational and educational assistance and occupational therapy. [15] Specific treatment is largely in the form of voluntary participation in clinical trials, such as those looking at antipsychotic use or CBT in ultra-high risk individuals. [14]
Headspace	These centres for 12-25 year olds combine specialist mental health, drug and alcohol and primary care services, vocational services and training, and employment support within a youth and family-friendly environment. [16,17] Headspace centres are also tasked with developing awareness campaigns for their local community and providing training for primary care and other workers using an evidence-based approach. [16]
Early Psychosis Prevention and Intervention Centres (EPPIC)	Provide comprehensive in-patient and mobile components and aim to identify patients as early as possible and deliver phase-specific bestpractice interventions to psychotic individuals between the ages of 15 to 24. [19] This model has also been adopted widely around the world, including in the UK [20] and the US. [21]

The early intervention model has also been subject to some criticism. The major basis for this is a lack of evidence, especially with regard to the use of anti-psychotics in the prodromal stages of psychotic illness and the significant cost associated with creating a clinical infrastructure for patients who may never proceed to a long-term psychotic illness.

Results and Discussion

Evidence for early intervention

There is evidence from several small studies that psychotherapy such as CBT [22] and pharmacotherapy [3,23] can reduce the progression of ultra-high risk individuals to first episode psychosis.

Wyatt et al. [8] reviewed 22 studies, of varying study designs, which included contemporaneous control group studies, cohort studies, mirror image studies and early intervention studies. In these studies, patients with schizophrenia were either given or not given neuroleptics at a specific time during the course of their illness. 19 of the studies, in particular, looked at patients who were experiencing their first psychotic episode. After re-analysing the data, Wyatt et al. [8] showed that early intervention with a neuroleptic in first-break schizophrenic patients improved the long-term course of the illness, commonly assessed based on re-hospitalisation and relapse rates. It was also shown that with the use of neuroleptics, the length of the initial psychotic period was reduced. In addition, when neuroleptics were discontinued, it resulted in poorer outcomes as the patients were not able to return to their previous level of functioning and relapses occurred more frequently. Neuroleptic medication has the strongest support for relapse prevention in schizophrenia and is the basis of most interventions.

It has been suggested that the duration of untreated psychotic episodes directly correlates with less complete recovery, a higher rate of relapse and increased levels of compromised functioning, since these episodes have a toxic effect on the brain. [7,8,24-26] These studies, both retrospective and prospective, suggest that a longer DUP in the early stage of schizophrenia is associated with a longer time to remission, a lower level of recovery, a greater likelihood of relapse and a worse overall outcome.

Studies have shown that raising public awareness and using mobile outreach detection teams to identify candidate patients [27] has significantly reduced DUP, leading to beneficial outcomes. In particular there has been a reduction in negative symptoms in schizophrenic patients.

Arguments against early intervention

There are certain groups who are against early intervention. One of the arguments against early intervention relates to whether it is cost effective, as resources may be diverted from treatment programs for patients who already have an established diagnosis of psychosis. In addition, they argue that the great majority of high-risk patients do not in fact progress to frank psychosis. There is also the argument that some patients seeking early intervention may not have ‘true prodromal’ features, thus inflating the numbers of those who actually require early intervention. These arguments are discussed in more detail below.

Economic cost of early intervention may be infeasible

Those against early intervention believe the increased attention and funding given to early intervention diverts funding away from treatment in those with established psychosis. [28-30] They also argue that proponents of early intervention have touted the cost-effectiveness of early intervention as such programs utilise more outpatient resources compared to inpatient resources, thus reducing overall healthcare costs (with outpatient services being much cheaper than inpatient treatment). However, critics of early intervention have pointed out that implementation of a cost-effective treatment actually increases total costs [31,32] since cheaper treatment would have a much higher uptake compared to an expensive alternative, thus raising the total cost of treatment. In addition, Amos argues that total healthcare costs are further increased since in-patient costs are not reduced with early intervention. [33] This is because 80% or more of hospital costs are fixed costs and by shifting psychosis treatment to largely outpatient settings in the community, community costs increase but hospital costs are not reduced. [33] This is corroborated by previous studies, which show an increase in total costs when hospitalisation rates had been reduced. [34,35]

Most high-risk patients do not progress to frank psychosis

One possible explanation for this is that a subset of adolescents whom are identified as being UHR may just be odd adolescents that become odd adults with few progressing to a frank psychosis. The prominent child psychiatrist Sula Wolff was the first to describe these odd adolescents in her book, Loners: The Life Path of Unusual Children. [36] Her research has shown that while odd qualities such as those found in schizoid and schizotypal disorders are found pre-morbidly in patients with schizophrenia, very few children with such personality traits/disorders go on to develop schizophrenia. For example, in 1995 Wolff undertook a records survey of all psychiatric hospital admissions in Scotland. Overall, 5% of schizoid young people were affected by schizophrenia in adulthood compared to a population prevalence rate in the UK of 0.31-0.49%. [36] These numbers suggest that while the risk for schizophrenia in schizoid children is higher than that of the general population, it is still low. To reiterate, there may be a proportion of patients who are flagged as being prodromal but whom actually have qualities consistent with schizoid personality disorder that will never progress to psychosis.

Recently, there has been a decline in the proportion of patients at high risk of psychosis actually progressing to frank psychosis

This decline has important ramifications for the practice of early intervention. A decline in the transition rate of patients identified as UHR has been reported within the PACE clinic (Melbourne, Australia) and in other UHR clinics as well. [37,38] As an example, The PACE clinic has reported that each successive year between 1995-2000 had a rate equal to 0.8 of the previous year. [38] The reported decline in transition rate was not due to differing patient characteristics across the years, such as gender, age, family history, baseline functioning and degree of psychopathology and psychiatric symptoms. [38] Additionally, the UHR criteria remained unchanged in the PACE clinic between 1995-2000. [38]

There are a number of possible explanations for the declining transition rate to psychosis. Firstly, UHR patients are being detected more quickly than in the past (the duration of symptoms prior to detection is getting shorter). [38] However, it is unclear whether the resulting decline in transition rate is due to earlier treatment (which may be more effective than delayed treatment), the identification of increased numbers of false positives (those who are not going to progress to psychosis) or a combination of both. [38] There may also be an effect from clinicians becoming better at managing UHR patients. [38] Additionally, it has been noted that the decline in transition rate was more prominent for patients who met two of the UHR inclusion criteria simultaneously compared to those who met only one of the criteria. [38] This could have been due to the increased emphasis which was placed on detection of patients who met both criteria, both in the UHR clinic and from referrers, thereby leading to earlier detection and treatment. [38] This is also in keeping with the wider community shift and preoccupation towards early psychosis and its recognition, and the increase in available referral pathways.

The decline in transition rate also raises questions about the validity of intervention approaches, such as pharmacotherapy and psychosocial treatment, on patients who may not ultimately transition to psychosis. [38] Such intervention may be harmful and therefore unjustified in this context. The UHR concept, which is used extensively in psychosis research, may also have to be re-visited if many of the identified patients are not transitioning. [38]

Due to the uncertainties regarding the basis for the declining transition rate, a review of the role of UHR clinics may be warranted. [38] It may be necessary to initially monitor patients and treat conditions such as depression, substance use problems and anxiety disorders while withholding antipsychotic treatment until features suggestive of transition occur, such as worsening of sub-threshold psychotic symptoms. [38] This may be prudent in the context of detecting increasing numbers of patients who were never destined to transition to psychosis. In any case, further research is needed to clarify the ongoing uncertainties in this area.

Bias in patient selection

Specialised teams set up to treat early psychosis engage with anyone who is seeking help. However, Castle [39] believes that this would skew the treatment group, as it would engage those with help-seeking behaviours rather than prodromal psychosis. Furthermore, it also raises the issue that those seeking help may have signs and symptoms of what is a normal developmental process or a ‘psychosis proneness’, which is part of a normal distribution within the general population. [40] Thus, these individuals may not require treatment for psychosis at all as they would either grow out of ‘psychotic proneness’ or would
stabilise and never develop psychosis.

Prescribing anti-psychotics to a population that is not psychotic: An ethical implication

The potential dangers of psychotropic drugs on young people are outlined in the United Nations Convention on the Rights of the Child, where children are recognised as being particularly deserving of protection from unnecessary exposure to psychotropic substances. [41] However, much of the research into early intervention includes administration of a low dose of antipsychotics as a crucial and efficacious treatment option. [42] Furthermore, antipsychotics are known to have serious side effects including sedation, weight gain, mild sexual dysfunction and disconcerting extrapyramidal symptoms (EPS) such as pseudoparkinsonism, akathisia, acute dystonia, and tardive dyskinesia. [43] While these effects have a stronger association with first generation antipsychotics, there is increasing evidence suggesting that second generation antipsychotics (SGA) are associated with significant side effects such as weight gain, hyperprolactinemia and EPS in the adolescent population.

Summary and recommendations

In view of the currently available literature, the authors make the following summary and recommendations with regards to early intervention in psychosis.

Psychosis is a highly disabling condition with detrimental impacts on patients’ relationships and occupational and social functioning
Possible interventions that delay or prevent transition from the prodromal period to psychosis are important, both clinically and economically
A systematic review by the Cochrane Database found limited evidence about interventions to prevent psychosis. Despite this, early intervention facilities such as headspace are widespread in Australia

Our recommendations

We do not recommend the use of antipsychotics in children and adolescents who have been identified as at increased risk but who have not yet progressed to frank psychosis. Exposing children and adolescents to the serious side effects of antipsychotics is both unethical and inappropriate considering a proportion of these patients will not progress to psychosis.
We recommend more research into safer, less harmful interventions such as omega-3 fatty acids and psychotherapy. For omega-3 fatty acids, evidence suggests a beneficial effect on transition rates compared to placebo. [44] However, this evidence comes from a single trial with few participants. A replication study with a larger sample size is needed to more definitively ascertain the merit of this intervention
As previously discussed, preliminary evidence shows that CBT may reduce the transition rate to psychosis. Further research should be undertaken to conclusively establish the benefit of psychotherapy in high-risk individuals. Further research should
include investigation of the cost-effectiveness of psychotherapy as an early intervention for youth psychosis. In addition, research should aim to identify any detrimental effects associated with providing psychotherapy to patients who do not progress to psychosis.
Patients identified as being at risk of developing psychosis should be monitored closely by a multi-disciplinary team. Team members may include a general practitioner, social worker, psychiatrist and psychologist. By closely monitoring at-risk patients, their progression into frank psychosis can be detected earlier and appropriate treatment given in a timely manner. Prompt detection and treatment of psychosis is crucial, as delayed untreated psychosis has been shown to result in poorer outcomes.

Table 2. Summary of the evidence supporting and arguments against early intervention in psychosis.

Evidence supporting early intervention

Evidence from small studies showing psychotherapy such as CBT and pharmacotherapy can reduce the progression
of ultra-high risk individuals to first episode psychosis.Studies show that raising public awareness and using mobile outreach detection teams to identify candidate patients significantly reduces the duration of psychosis.

Arguments not in favour of early intervention

The economic cost of early intervention may be infeasible.Most patients identified as being high risk do not progress to frank psychosis.Treatment teams for early psychosis may disproportionately target patients with “help
seeking behaviour” and thereby treat more patients who simply display signs and symptoms of a normal developmental process or “psychosis proneness”.The negative ethical implications associated with prescribing antipsychotics to a population that is not psychotic.

Acknowledgements

The authors would like to thank Professor Jeff Cubis and Professor David Harley for their guidance and expert opinion on the matter.

Conflict of interest

None declared.

Correspondence

H C Y Yu: u4788941@anu.edu.au

Tags University of New South Wales, University of Sydney, Australian National University

Feature Articles Articles

The B Positive Program as a model to reduce hepatitis B health disparities in high-risk communities in Australia

Post author By Website Publications Officer
Post date April 30, 2014

As the epicentre for the highest incidence of liver cancer diagnosis in New South Wales, southwest Sydney is simultaneously home to a large number of first generation migrants from Southeast Asia. Alarmingly, these individuals are six to twelve times more likely to be diagnosed with liver cancer than Australian born individuals. This article aims to explore some of the challenges in diagnosing and managing hepatitis B in culturally and linguistically diverse (CALD) communities as well as to introduce the B Positive Program, a health initiative by the Cancer Council of New South Wales, as a model to address chronic hepatitis B related health issues.

Challenges in Diagnosing and Managing Hepatitis B Infection in High Risk Communities in Australia
While hepatitis B vaccination is part of the immunisation program for infants and school-aged children in Australia, the incidence of hepatitis B induced hepatocellular carcinoma (HCC), the most common form of liver cancer, continues to be on the rise. This surge is largely attributed to chronic hepatitis B (CHB) infection amongst the migrant population from endemic areas such as Southeast Asia. [1] Alarmingly, these migrants are six to twelve times more likely to be diagnosed with liver cancer than Australian born individuals. [2] It is estimated that 90% of individuals acquire CHB at birth through mother-to-infant transmission. [3] Thus, most individuals suffering from CHB are unaware of their status due to the insidous nature of the disease in which individuals are asymptomatic until late adulthood. By the time CHB sufferers present for medical attention, a signifiant proportion of individuals have developed advanced HCC and treatment options are limited and survial rates are poor. In order to reduce the morbidity and mortality related to CHB related liver cancer, early screening, surveillance and treatment of high risk populations while in the asymptomatic phase are strongly indicated.

The National Cancer Prevention Policy for Liver Cancer recommend that hepatocellular carcinoma surveillance be based on abdominal ultrasound in high-risk groups at 6-month intervals. Blood tests screening for hepatitis B antigen and antibodies are used to diagnose CHB and individuals who are at high risk of hepatocellular carcinoma. If diagnosed early, antiviral agents and regular monitoring are extremely effective in preventing progression of CHB to HCC. As well, low grade HCC can be treated curatively by surgical resection, liver transplantation and percutaneous ablation.

Despite these guidelines and treatment options, it is well established that the culturally and linguistically diverse (CALD) communities in Australia remain undiagnosed or improperly managed due to difficulties in seeking equitable medical services. The following article aims to explore some of the challenges in diagnosing and managing hepatitis B in CALD communities as well as to introduce the B Positive Program, an ongoing health initiative by the Cancer Council of New South Wales, as a model to address chronic hepatitis B related health issues.

Language Barrier and Cultural Differences

Language barrier and cultural differences are often cited as two main challenges that adversely affect the diagnosis and management of hepatitis B infections in at-risk communities. [2,4] Due to language barriers, it is often difficult for patients to communicate with their healthcare providers unless the latter is well versed in the language. In these circumstances, an interpreter, often the patient’s family or friend, assumes the role of facilitating communication unless professional medical interpreters are available. This can be problematic because these novice interpreters might be unfamiliar with medical jargon and may misconstrue or censor physician messages. [4] In addition, the patient’s confidentiality and autonomy can be compromised when family or friends are involved. A systematic review study showed that patients benefit from professional interpreters instead of their family or friends. [5] At present, the prevailing solution for balancing patient confidentiality and autonomy while preserving cultural traditions for patients with limited English abilities is to consult language concordant healthcare providers. [6]

Stigmatization

Fear of stigmatization is a legitimate concern that individuals in CALD communities may experience. For example, a Chinese study conducted by Chao et al. showed that in China, healthcare professionals reported positive hepatitis B surface antigen (HBsAg) results to 38% and 25% of patients’ employers and schools respectively. [7] Although this sort of disclosure practice is considered a breach of patient confidentiality in Australia, migrants coming from hepatitis B endemic countries may be reluctant to seek testing because of the aforementioned practices in their home countries. As a consequence, failure to screen and intervene promptly may result in chronic hepatitis B sufferers seeking health professionals as a last resort and possibly present at more advanced disease states. Presentation at these late stages would confer a worse prognosis to the patient and also increase the burden and cost to the healthcare system.

Knowledge Gaps amongst Healthcare Professionals

Avoiding disease progression is largely dependent on early recognition, monitoring and intervention. Unfortunately, some health professionals have unsatisfactory levels of knowledge. A study conducted by Stanford University in collaboration with the Asian Liver Centre showed that 34% (n=250) healthcare professionals in China who attended the ‘China National Conference on the Prevention and Control of Viral Hepatitis’ failed to recognize the natural history of hepatitis B infection or that a vaccine can be used as a prophylaxis for individuals who are seronegative. [7]

Not surprisingly, within Australia, similar surveys have shown similar gaps in knowledge amongst general practitioners. [8] Due to lack of knowledge, general practitioners may neglect treatment for individuals suffering from chronic hepatitis B or make inappropriate referrals to specialists for patients who are seronegative. In a system that is already overstretched with long waiting periods, this can be highly problematic. In addition, a major concern is that healthcare professionals fail to recognise that effective therapies are available for chronic hepatitis B and that hepatocellular carcinoma diagnosed at an early stage can be effectively treated especially with timely diagnosis, surveillance and treatment using antiviral agents and Fibroscan. Fibroscan is an accurate noninvasive investigation that is used regularly to assess the degree of liver scarring based on ultrasound technology. All healthcare professionals should be aware that recent developments in hepatitis B management, like antiviral therapy and FibroScan, have been extremely effective in preventing, monitoring and controlling the disease to progress to cirrhosis, liver failure and liver cancer amongst chronically infected individuals. The concept of “healthy carriers” no longer holds true. Yet, if healthcare practitioners are not imparted with this important knowledge, the wellbeing and health of many individuals suffering from chronic HBV will continue to be in jeopardy.

An added layer of complexity lies in the frequent use of complementary and alternative medical therapies within CALD communities. A 2012 study conducted by Guirgis et al. indicated conflicting advice about hepatitis B management given by conventional and complementary medical practitioners within Sydney. [9] The contradictory information patients receive can negatively affect their screening or management intentions. Hence, it is important to reconcile any conflicting management strategies by not only educating conventional medicine practitioners but also complementary medicine practitioners about hepatitis B screening and management so as to allow the two systems to co-exist and complement one another.

B Positive Program – A Program to Reduce Health Disparities in Hepatitis B Care

Given the increased incidence of hepatocellular cancer is clustered within specific geographical and ethnic regions within Sydney, the B Positive program is a good model in reaching a vulnerable Southeast Asian audience within New South Wales. The program, spearheaded by the Cancer Council of New South Wales, employs various strategies to address access issues at the patient, community and health professional levels.

At the patient level, the program initiates numerous educational campaigns and materials to educate the at-risk population and to remove the stigmatization of hepatitis B. One of the strengths of the program is the use of educational materials that are culturally and language concordant. For example, one of the campaign posters features Andy Lau, a prominent Chinese entertainer within the Asian community, as an individual with hepatitis B. Placing a public figure in the spotlight helps to demystify the condition for the CALD community and can demonstrate to carriers that medical therapy is effective given proper management and timely diagnosis. This campaign was highly effective and recently garnered the NSW Multicultural Health Communication Award 2013.

Another educational strategy employed by the program was the distribution of chopsticks engraved with the phrase “one cannot spread hepatitis B by sharing food” in Vietnamese and Chinese to shed light on the mode of transmission for the virus. A further strategy that the Cancer Council NSW employed was to collaborate and engage with Asian community-based health organizations like CanRevive and Australian Chinese Medical Association during outreach programs to enhance their cultural authenticity and receptivity within the CALD community.

At the community level, the program has recently developed a pilot project in May 2013 to engage high-risk migrant communities by creating a high school certificate course for south-west Sydney students called “Animating Hepatitis B”. This course involves ten weeks of lessons on hepatitis B and animation production before the high school students create short animations to deliver hepatitis B health facts to their community.

At the health professional level, the program also assists general practitioners to better identify and screen patients belonging to high-risk groups. Community nurses visit medical clinics to remind general practitioners about enrolling at-risk patients into screening programs. The program also encourages regular monitoring programs of chronic hepatitis B patients for surveillance of hepatocellular carcinoma. General practitioners are also offered Hepatitis B seminars through the Continuing Medical Education Program, so that their knowledge is up to date.

Conclusion

With the appropriate use of cultural and language concordant educational campaigns and outreach programs for at-risk individuals, community healthcare workers to deliver these programs, community engagement and continuing medical education opportunities for healthcare professionals, the prospect of reducing the disparities in hepatitis B care within the CALD communities in Australia is highly positive.

Acknowledgements

Many thanks to Dr. Monica Robotin, Ms. Debbie Nguyen, Dr. Simone Strasser, Dr. Jacob George and Dr. Lilon Bandler for their guidance, mentorship and support.

Conflict of interest

None declared.

Correspondence

G Fong: gfon9247@uni.sydney.edu.au

References

[1] Robotin M, Patton Y, Kansil M, Penman A, George J. Cost of treating chronic hepatitis B: comparison of current treatment guidelines. World J. Gastroenterol. 2012 Nov; 14;18(42) :6106-13.

[2] Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004 Nov;127(5 Suppl 1):S5-S16.

[3] Gellert L, Jalaludin B, Levy M. Hepatocellular carcinoma in Sydney South West: late symptomatic presentation and poor outcome for most. Intern. Med. 2007 Aug;37(8):516-22.

[4] Ngo-Metzger Q, Massagli MP, Clarridge BR, Manocchia M, Davis RB, Iezzoni LI, et al. Linguistic and cultural barriers to care. J Gen Intern Med. 2003 Jan;18(1):44-52.

[5] Karliner LS, Jacobs EA, Chen AH, Mutha S. Do professional interpreters improve clinical care for patients with limited English proficiency? A systematic review of the literature. Health Serv Res. 2007 Apr;42(2):727-54.

[6] Wilson E, Chen AH, Grumbach K, Wang F, Fernandez A. Effects of limited English proficiency and physician language on health care comprehension. J Gen Intern Med. 2005 Sep;20(9):800-6.

[7] Chao J, Chang ET, So SK. Hepatitis B and liver cancer knowledge and practices among healthcare and public health professionals in China: a cross-sectional study. BMC Public Health. 2010 Feb;10:98.

[8] Guirgis M, Yan K, Bu YM, Zekry A. General practitioners’ knowledge and management of viral hepatitis in the migrant population. Intern. Med. 2012 May;42(5):497-504.

[9] Guirgis M, Nusair F, Bu YM, Yan K, Zekry AT. Barriers faced by migrants in accessing healthcare for viral hepatitis infection. Intern. Med. 2012 May;42(5):491-6.

Tags University of Sydney

Feature Articles Articles

Evidence based practice; keep it simple stupid

Post author By Website Publications Officer
Post date April 30, 2014

Learning and implementing evidence based practice is an expected component of good medical practice. Synthesising evidence in an effective and timely manner is a skill that is growing in importance and relevance. Evidence based practice is widely included in medical school curricula, and information literacy skills are known to be difficult to acquire. We provide a fresh look at a streamlined approach to evidence based practice, using a ‘real world’ case study.

Introduction

The importance of evidence based practice (EBP) is ever increasing. [1,2] However, the complexities of collecting, interpreting and synthesising information may be time consuming and laborious. [3] Information literacy skills are known to be difficult to learn. [4] In an effort to condense the process, a variety of models have been designed for evidence retrieval, including the 4S, [5] the 5S, [6] and more recently the 6S pyramid (Fig. 1). [7] In this article we will focus on the 6S pyramid and its application to a clinical case.

The technology explosion of the last decade has increased access to information for clinicians in almost all settings. The rapid development of handheld electronic devices, paired with the licenses to evidence based databases being held by many universities and institutions, results in information being easier to access. The problem then arises of how to find the best information for a clinical scenario in the swiftest manner. The 6S pyramid is useful as it provides a guide showing where to look first; additionally, it tracks the integration of research into clinical practice, with a decision support system at the pinnacle. An example of this is the ‘PrimaryCare Sidebar’ [8] integrating evidence based guidelines into the clinical data already in the patient record. Although the tip of the pyramid is not always readily available, as we step down the pyramid there are a variety of other evidence based tools available, including Dynamed, [9] BMJ Clinical Evidence, [10] and the Therapeutic Guidelines. [11] Further down the pyramid are reliable resources such as PubMed [12] and the Cochrane Database of Systematic Reviews, [13] which are freely available online.

This article presents a streamlined approach to EBP, demonstrating the multistep process via a clinical case. One of the most difficult aspects of evidence based practice, translating medical jargon and statistics into ‘layman’s terms’ with the goal of empowering the patient to make an informed decision, is demonstrated. Our aim is to demystify EBP and its application for medical students and practitioners, thereby encouraging a wider application in day-to-day clinical work.

Case Details

Mrs SJ is a 62yo Caucasian female who is fairly new to the practice; she presents to discuss the topic of her back pain. SJ reports a three year history of bilateral lumbar radiculopathy; MRI showed degenerative spinal canal stenosis at L5/S1 and nerve conduction studies confirmed neural involvement. Failing a period of conservative measures and continuing to report severe pain, SJ underwent an L5/S1 laminectomy and posterior fusion.

Postoperatively, SJ reported minor relief of her symptoms; she continues to have 6/10 bilateral leg pain on a daily basis. The surgeon advised SJ there was no role for further operative procedures and SJ confirmed she did not want to even consider another procedure. Following the surgery she trialled gabapentin, with minimal effect. Since then she has been attempting to manage her pain with paracetamol, which has only had a partial effect.

Although not under any major financial stress, SJ felt the benefit of the gabapentin did not justify the cost, contributing to cessation of the medication. As an adjunct to pharmacotherapy, SJ had five sessions of physiotherapy addressing postural correction and stretching. She felt there was no benefit from this treatment.

SJ has an otherwise unremarkable medical history, is not on any regular medication and has no allergies. She lives with her husband, who is well. Friends have mentioned other drugs that they found effective for their pain, and she asks why she shouldn’t use them.

Determining a specific, targeted question

Before we seek our answers, we need to define the question/s. [14] This will lead us to a more precise, relevant answer, and save time sifting through irrelevant information.

In patients with chronic lumbar neuropathic pain (radiculopathy), what are the pharmacological options? This question is really what the patient has asked; however, our clinical problem is: what are the pain management options (pharmacological and non-pharmacological) in a patient with radiculopathy who has failed surgical therapy. In practice, we may choose to enquire about the pharmacotherapy about which Mrs SJ has asked; however, a holistic approach to the longterm management of this patient would involve a review of all options, including those that are non-pharmacological. In order to stay focused on the purpose of this article, which is the process of EBP and not the best practice treatment for lumbar radiculopathy, we will focus on pharmacotherapy only.

PICO:

Population: Chronic radiculopathy, unsuccessful lumbar surgery, menopausal women
Intervention: Medication, not gabapentin
Comparator: No medication, paracetamol
Outcome: Pain reduction and quality of life improvement. [15]

Collecting the evidence

In order to approach this therapy question, we started as high up the pyramid as possible. When creating a search we used keywords that were defined during the formulation of our targeted (PICO) question. Boolean operators (AND, OR, NOT) are also useful and function well in most search engines. Dynamed contained a topic entitled ‘Lumbar spinal stenosis,’ and the treatment section covered some information about medications, but this was not complete. Using BMJ Clinical Evidence (a clinical guideline tool) we searched ‘chronic pain.’ That search led us to the topic ‘chronic pain syndromes,’ and, although there wasn’t a direct answer to our question, under the treatment section we found an international guideline dated 2007.

Now that we knew guidelines existed on the topic, we searched Medline for a more recent version. This led us to three international guidelines. We used the 2010 paper ‘Recommendations for the pharmacological management of neuropathic pain: an overview and literature update’ by Dworkin et al as the primary paper. [16] Unfortunately, as is often the case, evidence specific to our patient was not available.

Determining levels of evidence and strength of recommendation in order to deliver appropriate advice

In order to give valid advice we need to know the strength of the evidence it is based upon, and the size of effect in our population of interest. Various guides exist in order to systemise this process and various methods are commonly used in the literature. The Oxford Centre for Evidence-based Medicine [17] is a well established resource. More recently, The Grading of Recommendations Assessment, Development and Evaluation (GRADE) [18] has been developed with the aim of providing a comprehensive system for grading quality of evidence and strength of recommendations. The resources above provide quality instruction on how to perform the vital step of appraising evidence. Fortunately, this has often already been done for us by others who have summarised the literature, in guidelines or systematic reviews, but it is good to be familiar with the process.

Breaking down the evidence in a real world scenario

Evidence comes from a variety of communities worldwide, and as such, a patient’s specific situation always needs to be taken into account. [22] Various approaches for communicating evidence [23] and mediums for doing so have been evaluated. [24] The way we communicate with patients about risk and effectiveness of treatments can affect their perception and understanding of illness. Communicating with the aid of numerical data, absolute risk (instead of relative risk), both negative and positive perspectives, and with visual aids, all help to improve understanding. [25] Closed loop communication can be used in order to verify understanding. We need to start by translating the evidence into dialogue that would take place between two human beings. This can be helpful in conceptualising the information retrieved. Let’s try…

Doctor: Let’s start by talking about the type of pain you have.

The pain you have is a nerve pain, often called neuropathic pain. This can be due to a lesion or disease. In your case, structures in your lower back are directly irritating nerves. In a simple world you remove the ‘lesion or disease’ and the pain would go away.

Unfortunately, after chronic stimulation the pain message continues to be ‘switched on’ even without a stimulus. This pain can be treated with medications but is often more difficult to manage.

Patient: I totally agree, this pain has been really difficult to manage, and has been getting on top of me for a long time.

Doctor: So your friends have mentioned medications?

Patient: Yes, they have mentioned a few different ones. I’m not sure of the names.

Doctor: There’s a lot of research about medications for the treatment of neuropathic pain, [16] but not a lot have looked at your particular scenario. [26] Of the few medications that have been tested, the evidence suggests only a small amount of benefit. There are some medications that have a lack of efficacy and we should avoid these.

Patient: I am really interested in trying another medication, even if the improvement is only small. Anything that would help me get through the day would be positive.

Doctor: Studies have shown that there are a few main groups of medications that are considered first choice; gabapentin (the one you tried) was one of them. Alternatives include opioids and some antidepressants. We use the antidepressants not because we think you are depressed, but because they have good pain relieving properties for this type of pain. You should know that research found these medications gave meaningful pain relief to around 50 percent of the patients. [23] So, effectively one in two patients. Although this gives us an idea of what to expect, it doesn’t mean it will work for you.

Because of the unclear nature of the evidence, we need to approach the choice of medication carefully, considering your situation. [16]

Patient: So…what are the side effects and how much do these medications cost?

Doctor: Antidepressants, particularly an older group called ‘TCAs’ (tricyclic antidepressants) have been shown to be effective. We don’t fully understand how they work for pain, but do know they provide pain relief in patients who aren’t depressed. [28] On the positive side, they are cheap, are taken once a day and can help with sleep. On the negative side, there are some side effects including dry mouth and constipation. These are not harmful, but annoying, and often resolve with a change in dosage. Rarely, these drugs can cause disturbance to the heart rhythm, and an overdose of these medications is very dangerous to children, so they need to be kept out of reach at all times. Newer antidepressants called SNRIs have shown fewer side effects, but haven’t been studied as thoroughly. [16]

Patient: Besides the heart thing these sound pretty good. I don’t have children at home so that shouldn’t be an issue. Is there anything else on offer?

Doctor: Another group of medications work by slowing down pain impulses; gabapentin is one of these. Although they have proven effectiveness, side effects include dizziness and sedation. As you have mentioned, this is an expensive choice and hasn’t worked for you, so it’s probably not the best option for us at the moment.

Patient: Agreed!

Doctor: Finally, the opioid-like medications are an option. However, I would prefer if we could avoid these. Generally, individuals build tolerance to them and they can be addictive.

Patient: I don’t want to have to rely on it all the time, or have to keep using more of the medication. It sounds like the first option, the antidepressants, is the best, particularly if they are going to help me sleep.

Doctor: Yes, assisting with sleep is a great attribute of TCAs, but it takes a while for full effect, so let’s trial a medication called amitriptyline for six weeks and reassess after that. The medication will cost around A$30 a month. I would like to do an ECG to get an idea of your baseline heart rhythm, and for you to complete two questionnaires in order for us to keep track of your progress: the McGill pain questionnaire [29] and the Short form 36. [30]

Please come back and see me sooner if you have any concerns or develop the side effects we talked about. Also, I would like you to consider other ways this pain can be managed. There are many alternative approaches we should explore, most of which do not include medications.

Conclusion

So, that wasn’t too hard, was it? We defined the question, used a top down approach to the evidence pyramid, and accessed a synthesis of the best literature to answer our question. We made an assessment of the quality of the information available, and attempted to translate ‘doctor speak’ into lay terms. Implementation of the evidence will inevitably lead to further questions. The ongoing process of EBP is illustrated as a cycle (Fig. 2).

Gathering evidence based information should no longer be a chore. Using evidence at any level of the pyramid needs thoughtful consideration, requiring close scrutiny of the methods of evidence generation and the method of appraisal. Due to the increasing amount of evidence being published, synthesis and weighing of existing evidence can serve to provide a more comprehensive and relevant source of evidence based recommendations. The streamlined pyramid approach can be skimmed during consultations or scrutinised for assignments.

So the next time a patient (or an examiner!) throws you a curveball, use EBP to find the comprehensive answer they deserve.

Acknowledgements

The authors would like to thank Dr Morris Aziz for his contribution on the topic.

Conflict of interest

None declared.

Correspondence

J Dannaway: jdan9820@uni.sydney.edu.au

References

[1] Dawes M, Summerskill W, Glasziou P, Cartabellotta A, Martin J, Hopayian K, et al. Sicily statement on evidence-based practice. BMC Medical Education. 2005; 5(1):1.

[2] Sackett DL, Rosenberg WMC. On the need for evidence-based medicine. Journal of Public Health. 1995; 17(3):330 –334.

[3] Haynes B, Haines A. Barriers and bridges to evidence based clinical practice. BMJ. 1998 Jul 25;317(7153):273–6.

[4] Hofer AR, Townsend L, Brunetti K. Troublesome Concepts and Information Literacy: Investigating Threshold Concepts for IL Instruction. Portal: Libraries and the Academy. 2012; 12(4):387–405.

[5] Haynes RB. Of studies, syntheses, synopses, and systems: the “4S” evolution of services for finding current best evidence. ACP J. Club. 2001 Apr;134(2):A11–13.

[6] Haynes RB. Of studies, syntheses, synopses, summaries, and systems: the “5S” evolution of information services for evidence-based healthcare decisions. Evidence Based Medicine. 2006; 11(6):162–4.

[7] DiCenso A, Bayley L, Haynes RB. Accessing pre-appraised evidence: fine-tuning the 5S model into a 6S model. Evidence based nursing. 2009; 12(4):99–101.

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Tags University of Sydney

Review Articles Articles

Oncolytic Virotherapy: The avant-garde approach to oncological treatment via infectious agents

Post author By Website Publications Officer
Post date April 30, 2014

Over the past twenty years, advances in translational medicine have resulted in new and exciting treatments in the area of oncology. New modalities have arisen out of the need to address existing limitations in conventional treatments such as chemotherapy and radiotherapy. What started out as an outrageous idea in the 20^th century to use potentially dangerous infectious agents such as viruses to kill cancer cells has gradually evolved into a maturing field, which has the promising potential to incorporate conventional and immunological aspects of treatment within a microbial-based system. Finally, in 2006, the introduction of the world’s first approved oncolytic virus by China heralded a milestone in the clinical application of this approach. This article will examine use of oncolytic viruses in cancer treatment with emphasis on its current status and strategies, possible immune mechanism and future considerations.

Introduction

Oncolytic viruses are self-replicating viruses which can target and lyse cancer cells specifically. [1] Since the early 1900s, it was recognised that natural viral infections in cancer patients are sometimes associated with tumour regression. Indeed, case reports noted instances where influenza or measles infections in leukemia patients resulted in remissions. [2] Interest in utilising these ‘cancer-killing’ viruses peaked in the 1950-60s but the rise of chemotherapy and radiotherapy meant that progress in this field stagnated until the 1990s, when genetic engineering and better understanding of viruses and tumours revived the development of oncolytic viruses. [3] A breakthrough in the clinical translation of oncolytic viruses finally came in 2006 with the world’s first approved oncolytic virus- H101 (a genetically modified adenovirus) for head and neck cancers. [4]

Why oncolytic virotherapy?

Conventional treatments such as chemotherapy and radiotherapy have been the cornerstone of oncological management for many years. While we have achieved a considerable amount of success in many cancers, there are often criticisms against conventional treatments in terms of their limitations (e.g. transient effects against metastasis) and flaws (e.g. poor toxicity profile). [5] In recent years, gene therapy and immunotherapy have emerged as alternatives but results have been mixed. In 2002, the development of leukaemia in x-linked severe combined immunodeficiency (X-SCID) patients due to insertional mutagenesishas severely affected public confidence in gene therapy. [6] While immunotherapy remains promising, the current emphasis on specific targeting neglects the ability of tumour cells to mutate and change antigen profiles, resulting in variable clinical outcomes. [7]

In view of these insufficiencies, there has been renewed interest in oncolytic virotherapy, an interesting cross-disciplinary approach to treatment based virology, genetic engineering and immunology. The initial thinking behind this approach was simple- certain viruses exhibit tropism for cancer cells, which either express specific receptors for viral entry or lack anti-viral mechanisms that are normally intact in normal cells. [8] Once viral entry is achieved, replication of viruses continues until cell lysis occurs; allowing their progeny to infect other cancer cells. If viral spread is homogenous, the oncolytic effect can be amplified many times and this effectively destroys the whole tumour. [8] As therapeutic genes encoding pro-apoptotic and immune effectors can be incorporated into the viral genome, an effective anti-tumour response may be initiated and magnified with each replication. [9] The ingenuity of this idea is that it exploits the infectious nature of viruses and uses it as a carrier and amplifier of other therapeutic agents. The latter may be crucial in exploiting synergistic anti-tumour effects between distinct treatment modalities.

Current status of oncolytic virotherapy

A variety of natural occurring and genetically modified viruses have been tested in clinical trials (Table 1).

Natural occurring oncolytic viruses are chosen for their low pathogenicity and inherent specificity for tumour cells. [10] Conversely, genetically modified viruses are those that are modified to promote tumour specificity, for example through use of tumour-specific promoters and gene deletions, or reduce pathogenicity by serial passage through cell culture. [8] Based on clinical data, it has been shown that virotherapy has a favourable toxicity and safety profile as compared to conventional treatment; the most common side effects being fever,flu-like symptoms and safety issues mainly concerning viral shedding and mutation-induced pathogenesis. [1,11] For the latter, dosing limitations and use of pro-drug activating suicide genes have addressed many of these issues. [1,6]

A straightforward dose-response relationship is not often observed as viral replication occurs in a heterogeneous tumour microenvironment and depends on factors such as availability of cell surface receptors and anti-viral responses. [12] Efficacy varies between different viruses but is reasonable at this early stage of development. The clinical trial for H101 reported complete remissions and partial responses in three and eleven out of forty-six patients respectively while another modified adenovirus- ONYX-15 was also used in head and neck cancer trials and achieved tumour growth stabilisation in eight out of twenty-two patients and tumour necrosis in five out of twenty-two patients. [11,13]

It appears that limitations in efficacy were due to certain barriers. Firstly, viruses are not adept at surviving in the circulation. They are subjected to neutralising antibodies, complement and sequestration by the reticuloendothelial system. [8] In some cases, previous viral exposure may result in pre-existing anti-viral antibodies. For example, almost all individuals have antibodies to measles while reovirus infections are prevalent in about half the population. [14,15] Potent anti-viral responses such as type 1 interferons (IFNs) may also inhibit viral replication within the tumour. [8] Secondly, viruses have to endure acidotic and hypoxic conditions,transverse necrotic tumour regions and areas of poor vasculature in order to survive and infect tumour cells. [1] Thereafter, the availability of cell receptors may become a limiting factor in viral entry. [8] These obstacles are expected as viruses are foreign but this does not mean they are unsuitable therapeutic agents. On the contrary, viruses have the advantage of alerting the immune system to attack their infected target(s).

Enhancing oncolytic virotherapy via protective strategies

Protective strategies are aimed at improving delivery of viruses and avoiding viral clearance. The systemic delivery of viruses can be improved by preventing uptake of viruses by liver Kupffer cells (specialised macrophage cells). In mouse studies, viral delivery can be enhanced by clodronate-containing liposomes. [1] Clodronate is a selective macrophage-depleting agent that can temporarily inhibit viral uptake by Kuppfer cells, thereby allowing more virus particles to reach the tumour site. [1] Recent interest is focused on cell-carrier based delivery of oncolytic viruses, which aims to protect viruses from systemic and intra-tumoural barriers by packaging within a cell carrier that supports viral replication and targets tumour cells, its microenvironment or the tissue/organ in which the tumour resides. [16]

Cell-carriers targeting tumour cells include tumour-infiltrating lymphocytes (TILs) and cytokine-induced killer (CIK) cells. [16] TILs are T cells which accumulate in tumours and possess T cell receptors (TCRs) that recognise tumour-associated antigens (TAAs) in the context of major histocompatibility complex (MHC). [17] Since TILs are inherently cytotoxic to T cells, using such a carrier synergistically enhances the anti-tumour effects of oncolytic viruses. Highly-specific TAAs are rare and use of less-specific TAAs may lead to non-specific targeting of normal cells. [18] Production of TILs against TAAs is also an expensive and tedious process, which argues against its widespread clinical application. [16] Conversely, although cytotoxic lymphocytes like CIKs have a lower tumour-specificity, these cells are non-MHC dependent and can proliferate ex vivo without antigen stimulation. [18] Thorne et al. injected vaccinia virus-containing CIKs into nude mice and found that the VV/CIK combination was able to accurately target tumour cells and also improved the survival rate of mice as compared to VV administration alone. [19] To improve specificity, Yoon et al. engineered Her-2/neu expressing CIKs which can target ovarian cancer cells in nude mice with high affinity. Results suggest that this approach was more effective in killing cancer cells than administering Herceptin alone. [20] Nonetheless, mechanisms underlying the tumour-specificity of CIKs remain unclear and should be studied further.

In comparison, cell carriers targeting the tumour microenvironment have well-studied. Examples include mesenchymal stem cells (MSCs) and tumour-associated macrophages (TAMs). [18] MSCs are often attracted by inflammatory chemokines expressed in the microenvironment while TAMs tend to accumulate in hypoxic areas and regions of chronic inflammation in the tumour. [16] Mader et al. reported that in mouse studies, intra-peritoneal injection of a measles virus-MSC combination can prolong the survival period of mice with ovarian cancer. [21] Similarly, a clinical study found that intravenous injection of autologous MSCs carrying the modified adenovirus-ICOVIR 5 into four children with metastatic neuroblastoma was found to induce a complete clinical response in one child who also achieved complete remission within 3 years. [22] However, as MSCs are potentially tumourigenic, there is a trade-off between exploiting its propensity for tumour accumulation and the risk of enhancing tumour growth. The main criticism against targeting the tumour microenvironment relates to the inability of these cell carriers to deliver viruses directly into tumour cells. However, modifying the microenvironment through the engineering of viruses containing genes encoding pro-apoptotic and pro-inflammatory cytokines may circumvent this limitation by disrupting tumour-promoting interactions between the microenvironment and cancer cells. [16] Furthermore, the administration of proteases such as relaxin to degrade the extracellular matrix or fusogenic membrane glycoproteins to promote cell-to-cell fusion before oncolytic therapy may facilitate intratumoural spread of viruses. [23,34]

Lastly, the targeting of tumour-associated tissues and organs is also achieved by carriers such as dendritic cells (DCs) and peripheral blood lymphocytes (PBLs). [18] These carriers are attractive because they circulate through lymphoid organs such as the lymph nodes and spleen, which are sites of micrometastases and T-cell priming. [16] DC or PBL mediated delivery of VSV and reoviruses have been shown to purge metastases in lymphoid organs. Qiao et al. found that a VSV/PBL combination partially purged B16 metastases in mice 2-3 days after administration. [25] The oncolysis of metastatic cells by VSV also primed anti-tumour T cell responses effectively and probably contributed to fast purging. [16] Targeting of tissues/organs is the least specific but this negates the requirement for highly-specific tumour markers. In addition, the circulatory paths of these cell carriers are well-characterised, allowing better prediction of their tumour trafficking patterns. [18]

The mechanisms of viral loading, amplification and transfer are equally important in enhancing cell-carrier based strategies. Willmon et al. suggested that the loading of viruses depends on the multiplicity of infection (MOI), which is the ratio of infectious agent to infection target (i.e. cell carrier). [16] In high MOI loading, a higher viral loading density may be achieved but many viral particles will be stuck to the cell’s external surface and become susceptible to neutralising antibodies. [26] Conversely, in low MOI loading, most viral particles will be internalised although the viral loading density may be lower. [26] This approach may help avoid neutralisation and is suitable for individuals who have pre-existing antibodies against the oncolytic virus (e.g. measles and reovirus).

The carrier’s ability to support viral replication determines the amount of virus delivered. As viral replication can be affected by intact IFN responses in normal cells and also requires synchronous timing with carrier bursting, tumour cells have been implicated as possible carriers. [27] A successful example has been shown in the use of VSV-infected carcinoma cells to target lung metastases in mice but safety issues concerning the tumourigenity of tumour cell-based carriers remain. [28]

The transfer of virus from cell carrier to tumour cells is crucial as exposed viral particles are susceptible to neutralisation. In some viruses such human immunodeficiency virus (HIV), viral spread is mediated by a virological synapse (a specialised form of immunological synapse) between TCRs on T cells and MHC on adjacent cells. [29] By identifying viruses which utilises a virological synapse, oncolytic viruses can transfer safely between cells.

Besides cell-carrier based strategies, immunosuppression has been considered as a means of inhibiting anti-viral immunity. In rat glioma models, cyclophosphamide and cyclosporin A (CPA) have been shown to enhance HSV-mediated oncolysis by inhibiting tumour-mediated phagocyte infiltration. [30] However, recent studies suggest that such agents can be immunostimulatory and there is increasing recognition that anti-viral immunity also contribute to effective anti-tumour responses; implying that immune mechanisms of oncolytic virotherapy may need to be examined further. [31]

Immune mechanisms of oncolytic virotherapy

The direct oncolytic effects of oncolytic virotherapy are well appreciated. Successful infection and efficient spread of oncolytic viruses determine the extent of tumour lysis; leading to emphasis on developing viruses that replicated robustly and extensively. [31] However, the lack of a straightforward dose-response relationship suggests that other oncolytic mechanisms are present. The immune system may play paradoxical roles in enhancing or impeding anti-tumour responses mediated by oncolytic viruses. [32]

Innate immune responses have been shown to inhibit viral replication in rat glioma models as indicated by rapid decrease in HSV/VV titers with concomitant increase in natural killer (NK) cell infiltration following oncolytic virotherapy. [30,33] However, viral-mediated recruitment of NK cells is advantageous as NK cells are cytotoxic and associated with tumour regression. NK cells and DCs are also involved in reciprocal interactions. [31] In vitro experiments involving Mel888 melanoma cell lines showed that reovirus-infected DCs induced IFN-β production, which in turn activated NK cells. [34] Activation of NK cells resulted in cytotoxic effects against Mel888 cells and reciprocal maturation of DCs. [34] As DCs are involved in antigen presentation to T cells, DC maturation may also promote adaptive anti-tumour responses. However, DC functions are virus-dependent as studies showed that wild-type measles and adenoviruses are inhibitory and neutral respectively. [31] It appears that the timing of viral clearance is crucial and prolonging this therapeutic window by immunosuppression may be beneficial. This is because some immunosuppressive agents may suppress anti-viral responses while stimulating anti-tumour responses. For example, similar to HSV, rat glioma studies indicate that CPA may promote VV replication while inducing a cytokine storm, which enhances activity of tumour-associated cytotoxic lymphocytes. [35]

Adaptive anti-tumour responses may be shaped by two models of immune activation: the infectious non-self (INS) and ‘danger’ models. [31] The former refers to the provision of pathogen-associated molecular patterns (PAMPs) such as viral nucleic acids to pattern-recognition receptors (e.g. toll-like receptors) on antigen-presenting cells (APCs) while the latter refers to the release of endogenous ‘danger’ signals such TAAs to APCs. [31] In the INS model, the presence of viral PAMPs induces activation and proliferation of antibodies and T cells upon antigen presentation. Infection of tumour cells is therefore not a pre-requisite for anti-tumour responses, which may instead be due to bystander effects of anti-viral responses. This was illustrated by Breitbach et al. in a murine colorectal cancer model whereby administration of HSV and VV infected only a small number of cancer cells but triggered massive destruction of non-infected cancer cells. [36] Conversely, the ‘danger’ model is more in line with oncolysis of tumour cells. Greiner et al. showed that an attenuated VV was capable of lysing human melanoma cells with subsequent development of an anti-TAA response. [37] These two models are not mutually exclusive, suggesting that the actual anti-tumour effect may be mediated by both, with their relative contributions dependent on the immunogenicity of the oncolytic virus or the tumour. [31] It is therefore apparent from an immunological perspective that effective oncolyic virotherapy may capitalise on the use of highly immunogenic viruses in a bystander effect or alternatively, promoting efficient anti-TAA responses via engineering of TAA-expressing viral vectors in poorly immunogenic viruses. [31,38]

The mechanisms involved in oncolytic virotherapy are summarised in Figure 1.

Future work

The current development of oncolytic virotherapy is based on rational designing but this approach may not always lead to the most selective and potent viruses. Buazon and Hermiston suggested that directed evolution might help researchers identify viruses with these desired characteristics. This involves growing diverse viruses in conditions that enhance diversity and passaging them through conditions mimicking the tumour microenvironment. [39] Application of directed evolution to colon cancer cell lines resulted in the adenovirus ColoAd1, which was 2-3 logs more potent than the advanced ONYX-15 and also had a therapeutic window 3-4 logs greater than the standard Ad5. [4,40] Furthermore, ColoAd1 is more sensitive to the anti-viral cidofovir (CDV) than either of its parents (Ad11p and Ad3) and this was due to directed evolution. [41] Thus, such an approach has a promising safety profile.

Integrating oncolyic virotherapy with existing treatments must be considered. Current studies have indicated promising results with radiotherapy and chemotherapy. A combination of modified HSV and radiotherapy have shown additive cell-killing effects in colorectal cancer assays and increased tumour regression in human glioma xenograft models. [42,43] It was suggested that radiotherapy could have improved viral replication and spread through irradiation-induced cellular changes. Similarly, pre-clinical studies have indicated that combination of ONXY-15 with cisplatin and 5-flurouracil in oesophageal cancers had a 39% increase in response rate as compared to chemotherapy alone (79% versus 40%). [44] Although both radiotherapy and chemotherapy are immunosuppressive to some extent, synergistic effects can be achieved by selecting the right virus and radiation/drug dosage. Combination of immunotherapy and virotherapy is at an early stage but success has been seen with VSV therapy combined with IL-2 and regulatory T cell (Treg) depletion in terms of enhanced NK cell activity and increased viral delivery. [45]

In the short term, the conflict between intra-tumoural and intravenous/intra-peritoneal administration of oncolytic viruses needs to be resolved. Mastrangelo et al showed that intra-tumoural injection of a GM-CSF-modified VV was able to induce regression in distant non-injected metastatic sites in melanoma patients but systemic effects were absent in intra-tumoural injections of ONYX-15 or reovirus. [46] Intravenous administration of the latter viruses was efficacious but resulted in thrombocytopenia and transaminitis respectively. [47] Therefore, when deciding the route of administration, a clear clinical endpoint must be established (targeting primary tumour or metastatic sites) and this will guide the type of virus used and effects (beneficial and detrimental) observed, and eventually how the patient is managed.

To conclude, oncolytic virotherapy has its antecedent in early observations and experiments detailing viral-mediated tumour regressions. Despite being neglected for decades, its resurgence reflects a current trend towards exploring new oncological treatments and a genuine hope that it can deliver better clinical outcomes. Encouraging early results and the increasing availability of solutions to its problems suggest that it is well-poised to be the avant-garde of next-generation cancer therapeutics.

Conflict of interest

None declared.

Correspondence

K Ho: koho2292@uni.sydney.edu.au

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[46] Mastrangelo MJ, Maguire HC Jr, Eisenlohr LC, Laughlin CE, Monken CE, Mccue PA, et al. Intratumoural recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 1999; 6:409-22.

[47] Liu TC, Kirn D. Systemic efficacy with oncolytic virus therapeutics: clinical proof-of-concept and future directions. Cancer Res 2007; 67(2):429-32.

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Articles Review Articles

Spontaneous regression of cancer: A therapeutic role for pyrogenic infections?

Post author By Website Publications Officer
Post date November 5, 2012

Spontaneous regression of cancer is a phenomenon that is not well understood. While the mechanisms are unclear, it has been hypothesised that infections, fever and cancer are linked. Studies have shown that infections and fever may be involved in tumour regression and are associated with improved clinical outcomes. This article will examine the history, evidence and future prospects of pyrogenic infections towards explaining spontaneous regression and how they may be applied to future cancer treatments.

Introduction

Spontaneous regression of cancer is a phenomenon that has been observed since antiquity. [1] It can be defined as a reversal or reduction of tumour growth in instances where treatment has been lacking or ineffectual. [2] Little is known about its mechanism but two observations in cancer patients are of particular interest: first, infections have been shown to halt tumour progression while second, development of fever has been associated with improved prognosis.

Until recently, fever and infections have been regarded as detrimental states that should be minimized or prevented. However, in the era preceding the use of antibiotics and antipyretics, the prior observations were prevalent and were used as the basis of crude yet stunningly effective immunological-based treatments. The promise of translating that success to modern cancer treatment is a tempting one and should be examined further.

History: Spontaneous Regression & Coley’s Toxins

Spontaneous regression of cancers was noted as early as the 13th century. The Italian Peregrine Lazoisi was afflicted with painful leg ulcers which later developed into a massive cancerous growth. [3]The growth broke through the skin and became badly infected. Miraculously, the infection induced a complete regression of the tumour and surgery was no longer required. He later became the patron saint of cancer sufferers.

Reports that associated infections and tumour regression continued to grow. In the 18th century, Trnka and Le Dran reported cases of breast cancer regressions which occurred after tumour site infection. [4, 5] These cases are often accompanied by signs of inflammation and fever and gangrene are common. [3]

In the 19th century, such observations became the basis of early clinical trials by physicians such as Tanchou and Cruveillhier. Although highly risky, they attempted to replicate the same conditions artificially by applying a septic dressing to the wound or injecting patients with pathogens such as malaria. [1] The results were often spectacular and suddenly, this rudimentary form of ‘immunotherapy’ seemed to offer a genuine alternative to surgery.

Until then, the only option for cancer was surgery and outcomes were at times very disappointing. Dr. William Coley (a 19th century New York surgeon) related his anguish after his patient died despite radical surgery to remove a sarcoma of the right hand. [3] Frustrated by the limitations of surgery, he sought an alternative form of treatment and came across the work of the medical pioneers Busch and Fehleisen. They had earlier experimented with erysipleas, injecting or physically applying the causative pathogen, Streptococcus pyogenes, onto the tumour site. [6] This was often followed by a high fever which correlated with a concomitant decrease in tumour size in a number of patients. [3] Coley realized that using live pathogens was very risky and he eventually modified the approach using a mixture of killed S. pyogenes and Serratia marescens. [7] The latter potentiated the effects of S. pyogenes such that a febrile response can be induced safely without an ‘infection’, and this mixture became known as Coley’s toxins. [1]

A retrospective study in 1999 showed that there was no significant difference in cancer death risk between patients treated using Coley’s toxins and those treated with conventional therapies (i.e. chemotherapy, radiotherapy and surgery). [8] Data from the second group was obtained from the Surveillance Epidemiology End Result (SEER) registry in the 1980s. [3] This observation is remarkable given that Coley’s toxins were developed at a fraction of the cost and resources afforded to current conventional therapies.

Researchers also realized that Coley’s toxins have broad applicability and are effective across cancers of mesodermal embryonic origin such as sarcomas, lymphomas and carcinomas. [7] One study comparing the five-year survival rate of patients with either inoperable sarcomas or carcinomas found that those treated with Coley’s toxin showed had a survival rate as high as 70-80%. [9]

Induction of a high grade fever proved crucial to the success of this method. Patients with inoperable sarcoma who were treated with Coley’s toxins and developed a fever between 38-40 oC had a five-year survival rate three times higher than that of afebrile patients. [10] As cancer pain can be excruciating, pain relief is usually required. Upon administration of Coley’s toxins, an immediate and profound analgesic effect was often observed; allowing the discontinuation of narcotics. [9]

Successes related to ‘infection’ based therapies are not isolated. In the early 20th century, Nobel laureate Dr. Julius Wagner-Jauregg used tertian malaria injections in the treatment of neurosyphilis-induced dementia paralytica. [3]This approach relied on the induction of prolonged and high grade fevers. Considering the high mortality rate of untreated patients in the pre-penicillin era, he was able to achieve an impressive remission rate of approximately one in two patients. [11]

More recently, Bacillus Calmette-Guérin (BCG) vaccine has been used in the treatment of superficial bladder cancers. [12] BCG consists of live attenuated Mycobacterium bovis and is commonly used in tuberculosis vaccinations. [12,13] Its anti-tumour effects are thought to involve a localized immune response stimulating production of inflammatory cytokines such as tumour necrosis factor α (TNF-α) and interferon γ (IFN-γ). [13] Similar to Coley’s toxins, it uses a bacterial formulation and requires regular localized administration over a prolonged period. BCG is shown to reduce bladder cancer recurrence rates in nearly 70% of cases and recent clinical trials suggest a possible role in colorectal cancer treatment. [14] From these examples, we see that infections or immunizations can have broad and effective therapeutic profiles.

Opportunities Lost: The End of Coley’s Toxins

After the early success of Coley’s toxins, momentum was lost when Coley died in 1936. Emergence of chemotherapy and radiotherapy overshadowed its development while aseptic techniques gradually gained acceptance. After World War II, large-scale production of antibiotics and antipyretics also allowed better suppression of infections and fevers. [1] Opportunities for further clinical studies using Coley’s toxins were lost when despite decades of use, it was classified as a new drug by the US Food and Drug Administration (FDA). [15] Tightening of regulations regarding clinical trials of new drugs after the thalidomide incidents in the 1960s meant that Coley’s toxins were highly unlikely to pass the stringent safety requirements. [3]

With fewer infections, spontaneous regressions became less common. An estimated yearly average of over twenty cases in the 1960-80s decreased to less than ten cases in the 1990s. [16] It was gradually believed that the body’s immune system had a negligible role in tumour regression and focus was placed on chemotherapy and radiotherapy. Despite initial promise, these therapies have not fulfilled their full potential and the treatment for certain cancers remains out of reach.

In a curious turn of events, advances in molecular engineering have now provided us with the tools to transform immunotherapy into a viable alternative. Coley’s toxins have provided the foundations for early immunotherapeutic approaches and may potentially contribute significantly to the success of future immunotherapy.

Immunological Basis of Pyrogenic Infections

The most successful cases treated by Coley’s toxins are attributed to: successful infection of the tumour, induction of a febrile response and daily intra-tumoural injections over a prolonged period.

Successful infection of tumour

Infection of tumour cells results in infiltration of lymphocytes and antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs). Binding of pathogen-associated molecular patterns (PAMPs) (e.g. lipopolysaccharides) to toll-like receptors (TLRs) on APCs induces activation and antigen presentation. The induction process also leads to the expression of important co-stimulatory molecules such as B7 and interleukin-12 (IL-12) required for optimal activation of B and T cells. [17] In some cases, pathogens such as the zoonotic vesicular stomatitis virus (VSV) have oncolytic properties and selectively lyse tumour cells to release antigens. [18]

Tumour regression or progression depends on the state of the immune system. A model of duality in which the immune system performs either a defensive or reparative role has been proposed. [1, 3] During the defensive mode, tumour regression occurs and immune cells are produced, activated and mobilized against the tumour. In the reparative model, tumour progression is favoured and invasiveness is promoted via immunosuppressive cytokines, growth factors, matrix metalloproteinases and angiogenesis factors. [1, 3]

The defensive mode may be activated by external stimuli during infections; this principle can be illustrated by the example of M1/M2 macrophages. M1 macrophages are involved in resistance against infections and tumours and produce pro-inflammatory cytokines such as IL-6, IL-12 and IL-23. [19, 20] M2 macrophages promote tumour progression and produce anti-inflammatory cytokines such as IL-10 and IL-13. [19, 20] M1 and M2 macrophage polarization is dependent on transcription factors such as interferon response factor 5 (IRF5). [21] Inflammatory stimuli such as bacterial lipopolysaccharides induce high levels of IRF5 and this commits macrophages to the M1 lineage while also inhibiting expression of M2 macrophage marker expression. [21] This two-fold effect may be instrumental in facilitating a defensive mode.

Induction of febrile response

In Matzinger’s ‘danger’ hypothesis, the immune system responds to signals produced during distress known as danger signals, including inflammatory factors released from dying cells. [22] T cells remain anergic unless both danger signals and tumour antigens are provided. [23] A febrile response is advantageous as fever is thought to facilitate inflammatory factor production. Cancer cells are also more vulnerable to heat changes and elevated body temperature during fever may promote cell death and the massive release of tumour antigens. [24]

Besides a physical increase in temperature, fever encompasses profound physiological effects. An example of this is the induction of heat-shock protein (HSP) expression on tumour cells. [16] Studies have shown that Hsp70 expression on carcinoma cells promotes lysis by natural killer T (NKT) cells in vitro, while tumour expression of Hsp90 may play a key role in DC maturation. [25, 26] Interestingly, HSPs also associate with tumour peptides to form immunogenic complexes involved in NK cell activation. [25] This is important since NK cells help overcome subversive strategies by cancer cells to avoid T cell recognition. [27] Down regulation of major histocompatibility complex (MHC) expression on cancer cells results in increased susceptibility to NK cell attacks. [28] These observations show that fever is equally adept at stimulating innate and adaptive responses.

Route and duration of administration

The systemic circulation poses a number of obstacles for successful delivery of infectious agents to the tumour site. Neutralization by pre-immune Immunoglobulin M (IgM) antibodies and complement activation impede pathogens. [18] Infectious agents may bind non- specifically to red blood cells and undergo sequestration by the reticuloendothelial system. [29] In the liver, specialized macrophages called, Kupffer cells, can also be activated by pathogen-induced TLR binding and cause inflammatory liver damage. [29] An intratumoural route therefore has the advantage of circumventing most of these obstacles to increase the probability of successful infection. [18]

It is currently unclear if innate or adaptive immunity is predominantly responsible for tumour regression. Coley observed that shrinkage often occurred hours after administration whereas if daily injections were stopped, even for brief periods, the tumour continued to progress. [30] Innate immunity may therefore be important and this is consistent with insights from vaccine development, in which adjuvants enhance vaccine effectiveness by targeting innate immune cells via TLR activation. [1]

Although T cell numbers in tumour infiltrates are substantial, tolerance is pervasive and attempts to target specific antigens have been difficult due to antigenic drift and heterogeneity of the tumour microenvironment. [31] A possible explanation for the disproportionality between T cell numbers and the anti-tumour response is that the predominant adaptive immune responses are humoral rather than cell-mediated. [32] Clinical and animal studies have shown that spontaneous regressions in response to pathogens like malaria and Aspergillus are mainly antibody mediated. [3] Further research will be required to determine if this is the case for most infections.

Both innate and adaptive immunity are probably important at specific stages with sequential induction holding the key to tumour regression. In acute inflammation, innate immunity is usually activated optimally and this in turn induces efficient adaptive responses. [33] Conversely, chronic inflammation involves a detrimental positive feedback loop that acts reversibly and over-activates innate immune cells. [34] Instability of these immune responses can result in suboptimal anti- tumour responses.

Non-immune considerations and constructing the full picture

Non-immune mechanisms may be partly responsible for tumour regression. Oestrogen is required for tumour progression in certain breast cancers and attempts to block its receptors by tamoxifen have proved successful. [35] It is likely that natural disturbances in hormone production may inhibit cancerous growth and promote regression in hormone dependent malignancies. [36]

Genetic instability has also been mentioned as a possible mechanism. In neuroblastoma patients, telomere shortening and low levels of telomerase have been associated with tumour regression. [37] This may be due to the fact that telomerase activity is required for cell immortality. Other potential considerations may include stress, hypoxia and apoptosis but these are not within the scope of this review. [38]

As non-immune factors tend to relate to specific subsets of cancers, they are unlikely to explain tumour regression as a whole. They may instead serve as secondary mechanisms which support a primary immunological system. During tumour progression, these non-immune factors may either malfunction or become the target of subversive strategies.

A simplified outline of the possible role of pyrogenic infections in tumour kinetics is illustrated below (Figure 1).

Discussion

The intimate link between infections, fever and spontaneous regression is slowly being recognized. While the incidence of spontaneous regression is steadily decreasing due to circumstances in the modern clinical se

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Feature Articles Articles

The risks and rewards of direct-to-consumer genetic tests: A primer for Australian medical students

Post author By Website Publications Officer
Post date November 5, 2012

Introduction
Over the last five years, a number of overseas companies, such as 23andMe, have begun to offer direct-to-consumer (DTC) genetic tests to estimate the probability of an individual developing various diseases. Although no Australian DTC companies exist due to regulations mandating the involvement of a health practitioner, Australian consumers are free to access overseas mail-order services. In theory, DTC testing carries huge potential for preventing the onset of disease by lifestyle modification and targeted surveillance programs. However, the current system of mail-order genetic testing raises serious concerns related to test quality, psychological impacts on users, and integration with the health system. There are also issues with protecting genetic privacy, and ethical concerns about making medical decisions based on pre-emptive knowledge. This paper presents an overview of the ethical, legal and practical issues of DTC testing in an Australian context. The paper concludes by proposing five conditions that will be key for harnessing the potential of DTC testing technology. These include improved clinical utility, updated anti-discrimination legislation, accessible genetic counselling, Therapeutic Goods Administration (TGA) monitoring, and mechanisms for identity verification. Based on these conditions, the current system of mail-order testing is unviable as a scalable medical model. For the long term, the most sustainable solution is integration of pre-symptomatic genetic testing with the healthcare system.

The rise of direct-to-consumer testing
“Be on the lookout now.” This is the slogan of 23andMe.com, a Californian biotechnology company that has been offering personal genetic testing since late 2007. Clients mail a in a sample of their saliva and, for the humble fee of US$299, 23andMe will isolate their DNA and scan across key regions to estimate that individual’s risk of developing different diseases. [1] Over 200 different diseases in fact – everything from widespread, life-threatening conditions including breast cancer and coronary artery disease, to the comparatively obscure such as restless legs syndrome. Table 1 gives an example of the risk profile with which an individual may be faced.

Genetic testing has existed for decades as a diagnostic modality. Since the 1980s, clinicians have used genetic data to detect monogenic conditions such as cystic fibrosis and thalassaemia. [2] These studies were conducted in patients already showing symptoms of the disease in order to confirm a suspected diagnosis. 23andMe does something quite different: it takes asymptomatic people and calculates the risk of diseases emerging in the long term. It is a pre-emptive test rather than a diagnostic one.

23andMe is not the only service of its kind. There is a growing family of these direct-to-consumer (DTC) genetic tests: Navigenics (US), deCODEme (Iceland) and Genetic Health (UK) all offer a comprehensive disease screen for under $1000 AUD. There are currently no Australian companies that offer DTC disease scans due to regulations that require the involvement of a health professional. [3] However, Australian consumers are still free to access overseas services. Although no Australian retail figures exist, the global market for pre-symptomatic genetic testing is growing rapidly: 23andMe reported that 150,000 customers worldwide have used their test, [4] and in a recent European survey 64% of respondents said they would use a genetic test to detect possible future disease. [5] The Australian market for DTC testing, buoyed by increasing public awareness and decreasing product costs, is also set to grow.

Australian stakeholders have so far been divided on the issue of DTC testing. Certain parties have embraced it. In 2010 the Australian insurance company NIB offered 5000 of its customers a half-price genetic test through the US company Navigenics. [6] However, controversy arose over the fine-print at the end of NIB’s offer letter: “You may be required to disclose genetic test results, including any underlying health risks and conditions which the tests reveal, to life insurance or superannuation providers.” [6]

Most professional and regulatory bodies have expressed concern over the risks of DTC testing in an Australian context. In a 2012 paper, the Australian Medical Association argued that health-related genetic testing “should only be undertaken with a referral from a medical practitioner.” [7] It also highlighted issues surrounding the accreditation of overseas laboratories and the accuracy of the test results. Meanwhile, the Human Genetics Society of Australasia has stressed the importance of educating the public about the risks of DTC tests: “The best way to get rid of the market for DTC genetic testing may be to eliminate consumer demand through education … rather than driving the market underground or overseas.” [8]

Despite the deficiencies in the current model of mail-order services, personal genetic testing carries huge potential benefits from a healthcare perspective. The 2011 National Health and Medical Research Council (NHMRC) publication entitled The Clinical Utility of Personalised Medicine highlights some of the potential applications of genetic tests: targeting clinical screening programs based on disease risk, predicting drug susceptibility and adverse reactions and initiating preventative therapy before disease onset. [9] Genetic risk analysis has the potential to revolutionise preventative medicine in the 21st century.

The question is whether free-market DTC testing is a positive step towards an era of genetically-derived preventative therapy. Perhaps it creates more problems than it solves. What is the clinical utility of these tests? Is it responsible to give untrained individuals this kind of risk information? Could test results get into the wrong hands? These are the practical issues that will directly impact Australian medical professionals as genetic data infiltrates further into daily practice. This paper aims to grapple with some of these issues in an attempt to tease out how we as a healthcare community can best adapt to this new technology.

What is the clinical utility of these tests?
In 2010, a Cambridge University professor sent his own DNA off for analysis by two different DTC testing companies – 23andMe and deCODEme. He found that for approximately one third of the tested diseases, he was classed in a different risk category by the two companies. [10] A similar experiment carried out by a British journalist also revealed some major discrepancies. In one test, his risk of a myocardial infarction was 6% above average, while on another it was 18% below. [11]

This variability is a reflection of the current level of uncertainty about precisely how genes contribute to many diseases. Most diseases are polygenic, with an array of contributing environmental and lifestyle factors also playing a role in disease onset. [12] Hence, in all but a handful of diseases where robust genetic markers have been identified (such as the BRCA mutations for breast and ovarian cancers), these DTC test results are of questionable validity. An individual’s risk of Type 2 Diabetes Mellitus cannot simply be distilled down into a single numerical value.

Even for those diseases where isolated genetic markers have been identified in the literature, the findings are specific to the population studied. The majority of linkage analyses are performed in North American or European populations and may not be directly applicable to an Australasian context. Population bias aside, there is also a high level of ambiguity in how various genetic markers interact. As an example, consider two alleles that have each been shown to increase the risk of macular degeneration by 10%. It is not valid to say that the presence of both alleles signifies a 20% risk increase. This relates to the concept of epistasis in statistical genetics – the combined phenotypic effect of two alleles may differ from the sum of the individual effects. The algorithms currently used by DTC testing companies do not account for the complexity of gene-phenotype relationships.

For these reasons, the NHMRC states in its guide to the public about DTC testing: “At this time, studies have yet to prove that such susceptibility tests give accurate results to consumers.” [12] At best, current DTC testing is only valid as a rough guide to identify any risks that are particularly high or low. At worst, it is a blatantly misleading risk estimate based on insufficient molecular and clinical data. However, as our understanding of genetic markers improves, so too will the utility of these tests.

Can customers handle the results?
Assuming test quality improves, the next question is whether average individuals can deal with this type of risk information. What may the psychological consequences be if a healthy 25-year-old discovered that they had a 35% chance of developing ischaemic heart disease at some time during their life?

One risk is that people with an unfavourable prognosis may become discouraged from caring about their health at all, because they feel imprisoned within an immutable ‘genetic destiny.’ [13] As disease is written into their genes, they may as well surrender and accept it. Even someone with an average disease risk may feel an impending sense of doom when confronted with the vast array of diseases that may one day debilitate them. Could endless accounting of genetic risks overshadow the joy of living?

It is fair to say that DTC testing will only be useful if individuals have the right attitude – if they use this foreknowledge to take preventative measures. But do genetic test results really cause behaviour modification? A fascinating study in the New England Journal of Medicine in 2011 analysed the behavioural patterns of 2037 patients before and after a DTC genetic test. [14] They found no difference in exercise behaviour or dietary fat intake, suggesting that the genetic risk analysis did not translate into measurable lifestyle modification.

In order for individuals to interpret and use this genetic information effectively, they will need advice from healthcare professionals. Many of the DTC testing companies offer their own genetic counselling services; however, only 10% of clients reported accessing these. [15] The current position of the Australian Medical Association is that patients should consult a general practitioner when interpreting the results of a DTC genetic test. [7] However, a forced marriage between commercial sequencing companies and the healthcare system threatens to create problems of its own.

How should the health system adapt?
A 2011 study in North Carolina found that one in five family physicians had already been asked a question about pre-symptomatic genetic tests, yet 85% of the surveyed doctors reported that they were not sufficiently prepared to interpret test data [16]. In Australia, the healthcare system needs to adapt to this emerging trend. The question is – to what extent?

One controversial issue is whether it should be mandatory for doctors to be consulted when an individual orders a genetic test. Australia currently requires the involvement of a health practitioner to perform a disease-related genetic test. [3] Many countries, with the notable exception of the United States, share this stance. The German government ruled in early 2010 that pre-symptomatic testing could only be ordered by doctors trained in genetic counselling. [11] However, critics argue that mandatory doctor involvement would add medical legitimacy to a technology still in its infancy. [17] There is also an ethical argument that individuals should have the right to know about their own genes independent of the health system. [18]

Then there is the issue of how DTC genetic data should influence treatment. For example, should someone genetically predisposed to Type 2 Diabetes Mellitus be screened more regularly than others? Or, in a more extreme scenario: should those with more favourable genetic outlooks be prioritised for high-demand procedures such as transplant surgery?

These are serious ethical dilemmas; however, the medical community has had to deal with such issues before, whenever a new technology has arisen. With appropriate consultation from ethics committees (such as the NHMRC-affiliated Human Genetics Society of Australasia) and improved genetic literacy among healthcare professionals, it is possible to imagine a symbiotic partnership between the health system and free-market genetic testing.

How do we safeguard genetic privacy?
If DTC testing is indeed here to stay, a further concern is raised: how do we protect genetic privacy? Suppose a potential employer were to gain access to genetic data – the consequences could be disastrous for those with a poor prognosis. The outcome may be even worse if these data were made available to their insurance company.

In Australia, the disclosure of an individual’s genetic data by third parties (such as a genetic testing company) is tightly regulated under the Privacy Act 1988, which forbids its use for any purpose beyond that for which it was collected. [19] The only exception, based on the Privacy Legislation Amendment Act 2006, is for genetic data to be released to ‘genetic relatives’ in situations where disclosure could significantly benefit their health. [19]

In spite of the Privacy Act, individuals may still be forced to disclose their own test results to a third party such as an insurer or employer. There have been numerous reports of discrimination on the basis of genetic data in an Australian context. [20-22] The Australian Genetic Discrimination Project has been surveying the experiences of clients visiting clinical geneticists for ‘predictive or pre-symptomatic’ genetic testing since 1998. The pilot data, published in 2008, showed that 10% of the 951 subjects reported some negative treatment as a result of their genetic results. [23] Of the alleged incidents of discrimination, 42% were related to insurance and 5% to employment.

The use of genetic data by insurance companies is a complex issue. Although private health insurance in Australia is priced purely on basic demographic data, life and disability insurance is contingent on an individual’s prior medical record. This means that customers must disclose the results of any genetic testing (DTC or otherwise) they may have undergone. This presents a serious disincentive for purchasing a DTC test. The Australian Law Reform Commission, in its landmark report Essentially Yours: the Protection of Human Genetic Information in Australia, discusses the possibility of a two-tier system where insurance below a specific value would not require disclosure of any genetic information. [22] Sweden and the United Kingdom have both implemented such systems in the past; however insurers have argued that the Australian insurance market is not sufficiently large to accommodate a two-tiered model. [22]

As genetic testing becomes increasingly widespread, a significant issue will be whether insurance companies should be allowed to request genetic data as a standard component of insurance applications. Currently, the Investment and Financial Services Association of Australia, which represents all major insurance companies, has stated that no individual will be forced to have a genetic test. [24] But how long will this moratorium last?

Suffice to say that the privacy and anti-discrimination legislature needs to adapt to the times. There needs to be careful regulation of how these genomics companies use and protect sensitive data, and robust legislation against genetic discrimination. Organisations such as the Australian Law Reform Commission and the Human Genetics Society of Australasia will continue to play an integral role in this process.

However, there are some fundamental issues that even legislation cannot fix. For example, with the current system of mail-order genetic testing, there is no way of verifying the identity of the person ordering the test. This means that someone could easily send in DNA that is not their own. In addition, an individual’s genetic results reveal a great deal about their close family members. Consequently, someone who does not wish to know their genetic risks might be forcibly confronted with this information through a relative’s results. We somehow need to construct a system that preserves an individual’s right of autonomy over their own genetic data.

What does the future hold?
DTC genetic testing is clearly a technology still in its infancy, with many problems yet to be overcome. There are issues regarding test quality, psychological ramifications, integration with the health system and genetic privacy. On closer inspection, this risk-detection tool turns out to be a significant risk in itself. So does pre-symptomatic genetic testing have a future?

The current business platform, wherein clients mail their DNA to overseas companies, is unviable as a scalable medical model. This paper proposes that the following five conditions are necessary (although not sufficient) for pre-symptomatic genetic testing to persist into the future in an acceptable form:
• Improved clinical utility
• Updated anti-discrimination legislation pertaining to genetic test data
• Accessible genetic counselling facilities and community education about interpreting genetic results
• Monitoring of DTC companies by regulatory bodies such as the Therapeutic Goods Administration (TGA)
• Mechanism for identity verification to prevent fraudulent DNA analysis

Let us analyse each of these propositions. Condition (i) will be gradually fulfilled as our understanding of genetic markers and bioinformatics develops. A wealth of new data is emerging from large-scale sequencing studies spanning diverse populations, with advanced modeling for gene-gene interactions. [25,26] Condition (ii) is also a likely future prospect – the report by the Australian Law Reform Commission is evidence of a responsive legislative landscape. [22] Condition (iii) is feasible, contingent on adequate funding for publicly accessible genetic counselling services and education programs. However, given that the clinical utility of DTC risk analysis is currently low, it would be difficult in the short term to justify any public expenditure on counselling services targeted at test users.

Conditions (iv) and (v) are more difficult to satisfy. Since DTC companies are all located overseas, they fall outside the jurisdiction of the Australian TGA. Given that consumers may make important healthcare choices based on DTC results, it is imperative that this industry be regulated. We have three options. First, we could rely on appropriate monitoring by foreign regulatory bodies. In the US, DTC genetic tests are classed as an ‘in vitro diagnostic device’ (IVD), meaning they fall subject to FDA regulation. However, in a testimony before the US government’s Subcommittee on Oversight and Investigations in July 2010, the FDA stated that it has “generally exercised enforcement discretion” in regulating IVDs. [27] It went on to admit that “none of the genetic tests now offered directly to consumers has undergone premarket review by the FDA to ensure that the test results being provided to patients are accurate, reliable, and clinically meaningful.” This is an area of active reform in the US; however, it seems unwise for Australia to blindly accept the standards of overseas regulators.

The second option is to sanction overseas DTC testing for Australian consumers. Many prescription medicines are subject to import controls if they are shipped into Australia. In theory, the same regulations could be applied to genetic test kits. However, it is not difficult to imagine ways around this ban, e.g. simply posting an oral swab and receiving the results online.

A third option is to open the market for Australian DTC testing companies, which could compete with overseas services while remaining under TGA surveillance. In other words, we could cultivate a domestic industry. However, it may not be possible for fledgling Australian companies to compete on price with the large-scale US operations. It would also be hard to justify the change in policy before conditions (i) to (iii) are fulfilled. That said, of the three options discussed, this appears to be the most viable in the long term.

Finally, condition (v) presents one of the fundamental flaws with DTC testing. If the health system was formally involved in the testing process, the medical practitioner would be responsible for identity verification. However, it is simply not possible to reliably check identity in a mail-order system. The only way DTC testing can verify identity is to have customers come in person to a DTC facility and provide proof when their DNA is collected. However, such a regulation would make it even more difficult for any Australian company to compete against online services.

Conclusion
In summary, it is very difficult to construct a practical model that addresses conditions (iv) and (v) in an Australian context. Hence, for the short term, DTC testing will likely remain a controversial, unregulated market run through overseas websites. It is the duty of the TGA to inform the public about the risks of these products, and the duty of the health system to support those who do choose to purchase a test.
For the longer term, it seems that the only sustainable solution is to move towards an Australian-based testing infrastructure linked into the healthcare system (for referrals and post-test counselling). There are many hurdles to overcome; however, one might envisage a situation, twenty years from now, where a genetic risk analysis is a standard medical procedure offered to all adults and subsidised by the health system, and where individuals particularly susceptible to certain conditions can maximise their quality of life by making educated lifestyle changes and choosing medications that best suit their genetic profiles. [28]
As a medical community, therefore, we should be wary of the current range of DTC tests, but also open-minded about the possibilities for a future partnership. If we get it right, the potential payoff for preventative medicine is huge.

Conflict of interest
None declared.

Correspondence
M Seneviratne: msen5354@uni.sydney.edu.au

References
[1] 23andMe. Genetic testing for health, disease and ancestry. Available from: www.23andme.com.
[2] Antonarakis SE. Diagnosis of genetic disorders at the DNA level. N Engl J Med. 1989;320(3):153-63.
[3] Trent R, Otlowski M, Ralston M, Lonsdale L, Young M-A, Suther G, et al. Medical Genetic Testing: Information for health professionals. Canberra: National Health and Medical Research Council, 2010.
[4] Perrone M. 23andMe’s DNA test seeks FDA approval. USA Today Business. 2012.
[5] Ramani D, Saviane C. Genetic tests: Between risks and opportunities EMBO Reports. 2010;11:910-13.
[6] Miller N. Fine print hides risk of genetic test offer. The Age. 2010.
[7] Position statement on genetic testing – 2012. Australian Medical Association, 2012.
[8] Human Genetic Society of Australia. Issue Paper: Direct to consumer genetic testing. 2007.
[9] Clinical Utility of Personalised Medicine. NHMRC. 2011.
[10] Knight C, Rodder S, Sturdy S. Response to Nuffield Bioethics Consultation Paper ESRC Genomics Policy and Research Forum. 2009.
[11] Hood C, Khaw KT, Liddel K, Mendus S. Medical profiling and online medicine: The ethics of personalised healthcare in a consumer age. Nuffield Council on Bioethics. 2010.
[12] Direct to Consumer Genetic Testing: An information resource for consumers. NHMRC. 2012.
[13] Green SK. Getting personal with DNA: From genome to me-ome Virtual Mentor. 2009;11(9):714-20.
[14] Bloss CSP, Schork NJP, Topol EJM. Effect of Direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med. 2011;364(6):524-34.
[15] Caulfield T, McGuire AL. Direct-to-consumer genetic testing: Perceptions, problems, and policy responses. Annu Rev Med. 2012;63(1):23-33.
[16] Powell K, Cogswell W, Christianson C, Dave G, Verma A, Eubanks S, et al. Primary Care Physicians’ Awareness, Experience and Opinions of Direct-to-Consumer Genetic Testing. J Genet Couns.1-14.
[17] Frueh FW, Greely HT, Green RC. The future of direct-to-consumer clinical genetic tests Nat Rev Gene. 2011;12:511-15.
[18] Sandroff R. Direct-to-consumer genetic tests and the right to know. Hastings Center Report. 2010;40(5):24-5.
[19] Use and disclosure of genetic information to a patient’s genetic relatives under section 95AA of the Privacy Act 1988 (Cth). NHMRC / Office of the Privacy Commissioner, 2009.
[20] Barlow-Stewart K, Keays D. Genetic Discrimination in Australia. Journal of Law and Medicine. 2001;8:250-63.
[21] Otlowski M. Investigating genetic discrimination in the Australian life insurance sector: The use of genetic test results in underwriting, 1999-2003. Journal of Law and Medicine. 2007;14:367.
[22] Essentially Yours: The protection of human genetic information in Australia (ALRC Report 96). Australian Law Reform Commission, 2003.
[23] Taylor S, Treloar S, Barlow-Stewart K, Stranger M, Otlowski M. Investigating genetic discrimination in Australia: A large-scale survey of clinical genetics clients. Clinical Genetics. 2008;74(1):20-30.
[24] Barlow-Stewart K. Life Insurance products and genetic testing in Australia. Centre for Genetics Education, 2007.
[25] Davey JW, Hohenlohe PA, Etter PD, Boone JQ, Catchen JM, Blaxter ML. Genome-wide genetic marker discovery and genotyping using next-generation sequencing. Nat Rev Genet. 2011;12(7):499-510.
[26] Saunders CL, Chiodini BD, Sham P, Lewis CM, Abkevich V, Adeyemo AA, et al. Meta-Analysis of Genome-wide Linkage Studies in BMI and Obesity. Obesity. 2007;15(9):2263-75.
[27] Food and Drug Administration CeLnter for Devices and Radiological Health. Direct-to-Consumer Genetic Testing and the Consequences to the Public. Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, US House of Representatives; 2010.
[28] Mrazek DA, Lerman C. Facilitating Clinical Implementation of Pharmacogenomics. JAMA: The Journal of the American Medical Association. 2011;306(3):304-5.

Tags University of Sydney

Feature Articles Articles

The history of abdominal aortic repair: from Egypt to EVAR

Post author By Website Publications Officer
Post date November 5, 2012

Introduction

An arterial aneurysm is defined as a localised dilation of an artery to greater than 50% of its normal diameter. [1] Abdominal aortic aneurysm (AAA) is common with an incidence five times greater in men than women. [2] In Australia the prevalence of AAAs is 4.8% in men aged 65-69 years rising to 10.8% in those aged 80 years and over. [3] The mortality from ruptured AAA is very high, approximately 80%, [4] whilst the aneurysm-related mortality of surgically treated, asymptomatic AAA is around five percent. [5] In Australia AAAs make up 2.4% of the burden of cardiovascular disease, contributing 14,375 disability adjusted life years (DALYs), ahead of hypertension (14,324) and valvular heart disease (13,995). [6] Risk factors for AAA of greater than four centimetres include smoking (RR=3-5), family history (OR=1.94), coronary artery disease (OR= 1.52), hypercholesterolaemia (OR= 1.44) and cerebrovascular disease (OR= 1.28). [7] Currently, the approach to AAA management involves active surveillance, risk factor reduction and surgical intervention. [8]

The surgical management of AAAs dates back over 3000 years and has evolved greatly since its conception. Over the course of surgical history arose three landmark developments in aortic surgery: crude ligation, open repair and endovascular AAA repair (EVAR). This paper aims to examine the development of surgical interventions for AAA, from its experimental beginnings in ancient Egypt to current evidence based practice defining EVAR therapy, and to pay homage to the surgical and anatomical masters who made significant advances in this field.

Early definition

The word aneurysm is derived from the Greek aneurysma, for ‘widening’. The first written evidence of AAA is recorded in the ‘Book of Hearts’ from the Eber Scolls of ancient Egypt, dating back to 1550 BC. [9] It stated that “only magic can cure tumours of the arteries.” India’s Sushruta (800 ~ 600 BC) mentions aneurysm, or ‘Granthi’, in chapter 17 of his great medical text ‘Sushruta Samhita’. [10] Although undistinguished from painful varicose veins in his text, Sushruta shared a similar sentiment to the Egyptians when he wrote “[Granthi] can be cured only with the greatest difficulty”. Galen (126-c216 AD), a surgeon of ancient Rome, first formally described these ‘tumours’ as localised pulsatile swellings that disappear with pressure. [11] He was also first to draw anatomical diagrams of the heart and great vessels. His work with wounded gladiators and that of the Greek surgeon Antyllus in the same period helped to define traumatic false aneurysms as morphologically rounded, distinct from true, cylindrical aneurysms caused by degenerative dilatation. [12] This work formed the basis of the modern definition.

Early ligation

Antyllus is also credited with performing the first recorded surgical interventions for the treatment of AAA. His method involved midline laparotomy, proximal and distal ligation of the aorta, central incision of the aneurysm sac and evacuation of thrombotic material. [13] Remarkably, a few patients treated without aseptic technique or anaesthetic managed to survive for some period. Antyllus’ method was further described in the seventh century by Aetius, whose detailed paper ‘On the Dilation of Blood Vessels,’ described the development and repair of AAA. [14] His approach involved stuffing the evacuated sac with incense and spices to promote pus formation in the belief that this would aid wound healing. Although this belief would wane as knowledge of the process of wound healing improved, Antyllus’s method would remain largely unchanged until the late nineteenth century.

Anatomy

The Renaissance saw the birth of modern anatomy, and with it a proper understanding of aortic morphology. In 1554 Vesalius (1514-1564) produced the first true anatomical plates based on cadaveric dissection, in ‘De Humani Corporis Fabrica.’ [15] A year later he provided the first accurate diagnosis and illustrations of AAA pathology. In total, Vesalius corrected over 200 of Galen’s anatomical mistakes and is regarded as the father of modern anatomy. [16] His discoveries began almost 300 years of medical progress characterised by the ‘surgeon-anatomist’, paving the way for the anatomical greats of the sixteenth, seventeenth and eighteenth centuries. It was during this period that the great developments in the anatomical and pathological understanding of aneurysms took place.

Pathogenesis

Ambroise Pare (1510-1590) noted that aneurysms seemed to manifest following syphilis, however he attributed the arterial disease to syphilis treatment rather than the illness itself. [17] Stress on the arteries from hard work, shouting, trumpet playing and childbirth were considered other possible causes. Morgagni (1682-1771) described in detail the luetic pathology of ruptured sacular aortic aneurysms in syphilitic prostitutes, [18] whilst Monro (1697-1767) described the intima, media and adventitia of arterial walls. [19] These key advances in arterial pathology paved the way for the Hunter Brothers of London (William Hunter [1718-1783] and John Hunter [1728-1793]) to develop the modern definitions of true, false and mixed aneurysms. Aneurysms were now accepted to be caused by ‘a disproportion between the force of the blood and the strength of the artery’, with syphilis as a risk factor rather than a sole aetiology. [12] As life expectancy rose dramatically in the twentieth century, it became clear that syphilis was not the only cause of arterial aneurysms, as the great vascular surgeon Rudolf Matas (1860-1957) stated: “The sins, vices, luxuries and worries of civilisation clog the arteries with the rust of premature senility, known as arteriosclerosis or atheroma, which is the chief factor in the production of aneurysm.” [20]

Modern ligation

The modern period of AAA surgery began in 1817 when Cooper first ligated the aortic bifurcation for a ruptured left external iliac aneurysm in a 38 year old man. The patient died four hours later; however, this did not discourage others from attempting similar procedures. [21]

Ten further unsuccessful cases were recorded prior to the turn of the twentieth century. It was not until a century later, in 1923, that Matas performed the first successful complete ligation of the aorta for aneurysm, with the patient surviving seventeen months and dying from tuberculosis. [22] Described by Osler as the ‘modern father of vascular surgery’, Matas also developed the technique of endoaneurysmorrhaphy, which involved ligating the aneurysmal sac upon itself to restore normal luminal flow. This was the first recorded technique aiming to spare blood flow to the lower limbs, an early prelude to the homograft, synthetic graft and EVAR.

Early Alternatives to Ligation

Despite Matas’ landmark success, the majority of surgeons of the era shared Suchruta’s millennia-old fear of aortic surgery. The American Surgical Association wrote in 1940, “the results obtained by surgical intervention have been discouraging.” Such fear prompted a resurgence of techniques introducing foreign material into the aneurismal lumen with the hope of promoting thrombosis. First attempted by Velpeau [23] with sewing needles in 1831, this technique was modified by Moore [24] in 1965 using 26 yards of iron wire. Failure of aneurysm thrombosis was blamed on ‘under packing’ the aneurysm. Corradi used a similar technique, passing electric current through the wire to introduce thrombosis. This technique became known as fili-galvanopuncture or the ‘Moore-Corradi method’. Although this technique lost popularity for aortic procedures, it marked the beginning of electrothrombosis and coiling of intracranial aneurysms in the latter half of the twentieth century. [25]

Another alternative was wrapping the aneurysm with material in an attempt to induce fibrosis and contain the aneurysm sac. AAA wrapping with cellophane was investigated by Pearse in 1940 [26] and Harrison in 1943. [27] Most notably, Nissen, the pioneer of Nissen fundoplication for hiatus hernia, famously wrapped Albert Einstein’s AAA with cellophane in 1948. [28] The aneurysm finally ruptured in 1955, with Einstein refusing surgery: “I want to go when I want. It is tasteless to prolong life artificially.” [28]

Anastomosis

Many would argue that the true father of modern vascular techniques is Alexis Carrel. He conducted the first saphenous vein bypass in 1948, the first successful kidney transplant in 1955 and the first human limb re-implantation in 1962. [13,29] Friedman states that “there are few innovations in cardiac and vascular surgery today that do not have roots in his work.” [13] Perhaps of greatest note was Carrel’s development of the triangulation technique for vessel anastomosis.

This technique was utilised by Crafoord in Sweden in 1944, in the first correction of aortic coarctation, and by Shumacker [30] in 1947 to correct a four centimetre thoracic aortic aneurysm secondary to coarctation. Prior to this time, coarctation was treated in a similar fashion to AAA, with ligation proximal and distal to the defect. [31] These developments would prove to be great milestones in AAA surgery as the first successful aortic aneurysm resection with restoration of arterial continuity.

Biological grafts

Despite this success, restoration of arterial continuity was limited to the thoracic aorta. Abdominal aneurysms remained too large to be anastomosed directly and a different technique was needed. Carrel played a key role in the development of arterial grafting, used when end-to-end anastomosis was unfeasible. The original work was performed by Carrel and Guthrie (1880-1963) with experiments transplanting human and canine vessels. [32,33] Their 1907 paper ‘Heterotransplantation of blood vessels’ [34] began with:

“It has been shown that segments of blood vessels removed from animals may be caused to regain and indefinitely retain their function.”

This discovery led to the first replacement of a thrombosed aortic bifurcation by Jacques Oudot (1913-1953) with an arterial homograft in 1950. The patient recovered well, and Oudot went on to perform four similar procedures. The landmark first AAA resection with restoration of arterial continuity can be credited to Charles Dubost (1914-1991) in 1951. [35] His patient, a 51 year old man, received the aorta of a young girl harvested three weeks previously. This brief period of excitement quickly subsided when it was realised that the long-term patency of aortic homografts was poor. It did, however, lay the foundations for the age of synthetic aortic grafts.

Synthetic grafts

Arthur Voorhees (1921-1992) can be credited with the invention of synthetic arterial prosthetics. In 1948, during experimental mitral valve replacement in dogs, Voorhees noticed that a misplaced suture had later become enveloped in endocardium. He postulated that, “a cloth tube, acting as a lattice work of threads, might indeed serve as an arterial prosthesis.” [36] Voorhees went on to test a wide variety of materials as possible candidates from synthetic tube grafts, resulting in the use of vinyon-N, the material used in parachutes. [37] His work with animal models would lead to a list of essential structural properties of arterial prostheses. [38]

Vinyon-N proved robust, and was introduced by Voorhees, Jaretski and Blakemore. In 1952 Voorhees inserted the first synthetic graft into a ruptured AAA. Although the vinyon-N graft was successfully implanted, the patient died shortly afterwards from a myocardial infarction. [39] By 1954, Voorhees had successfully implanted 17 AAAs with similar grafts. Schumacker and Muhm would simultaneously conduct similar procedures with nylon grafts. [40] Vinyon-N and nylon were quickly supplanted by Orlon. Similar materials with improved tensile strength are used in open AAA repair today, including Teflon, Dacron and expanded Polytetrafluoroethylene (PTFE). [41]

Modern open surgery

With the development of suitable graft material began the golden age of open AAA repair. The focus would now be largely on the Americans, particularly with surgeons DeBakey (1908-2008) and Cooley (1920) leading the way in Houston, Texas. In the early 1950s, DeBakey and Cooley developed and refined an astounding number of aortic surgical techniques. Debakey would also classify aortic dissection into different types depending on their site. In 1952, a year after Dubost’s first success in France, the pair would perform the first repair of thoracic aneurysm, [42] and a year later, the first aortic arch aneurysm repair. [43] It was around this time that the risks of spinal cord ischaemia during aortic surgery became apparent. Moderate hypothermia was first used and then enhanced in 1957, with Gerbode’s development of extracorporeal circulation, coined ‘left heart bypass’. In 1963, Gott expanded on this idea with a heparin-treated polyvinyl shunt from ascending to descending aorta. By 1970, centrifuge-powered, left-heart bypass with selective visceral perfusion had been developed. [44] In 1973, Crawford simplified DeBakey and Cooley’s technique by introducing sequential clamping of the aorta. By moving clamps distally, Crawford allowed for reperfusion of segments following the anastomoses of what had now become increasingly more complex grafts. [45] The work of DeBakey, Cooley and Crawford paved the way for the remarkable outcomes available to modern patients undergoing open AAA repair. Where once feared by surgeons and patients alike, in-hospital mortality following elective, open AAA now has a 30-day all-cause mortality of around five percent. [58]

Imaging

It must not be overlooked that significant advances in medical imaging have played a major role in reducing the incidence of ruptured AAAs and the morbidity and mortality associated with AAAs in general. The development of diagnostic ultrasound began in the late 1940s and 50s, with simultaneous research by John Wild in the United States, Inge Elder and Carl Hertz in Sweden and Ian Donald in Scotland. [46] It was the latter who published ‘Investigation of Abdominal Masses by Pulsed Ultrasound,’ regarded as one of the most important papers in diagnostic imaging. [47] By the 1960s, Doppler ultrasound would provide clinicians with both a structural and functional view of vessels, with colour flow Doppler in the 1980s allowing images to represent the direction of blood flow. The Multicentre Aneurysm Study showed that ultrasound screening resulted in a 42% reduction in mortality from ruptured AAAs over four years to 2002. [48] Ultrasound screening has resulted in an overall increase in hospital admissions for asymptomatic aneurysms; however, increases in recent years cannot be attributed to improved diagnosis alone, as it is known that the true incidence of AAA is also increasing in concordance with Western vascular pathology trends. [49]

In addition to the investigative power of ultrasound imaging, computed tomography (CT) scanners became available in the early 1970s. As faster, higher-resolution spiral CT scanners became more accessible in the 1980s, the diagnosis and management of AAAs became significantly more refined. [50] CT angiography has emerged as the gold standard for defining aneurysm morphology and planning surgical intervention. It is crucial in determining when emergent treatment is necessary, when calcification and soft tissue may be unstable, when the aortic wall is thickened or adhered to surrounding structures, and when rupture is imminent. [51] Overall operative mortality from ruptured AAA fell by 3.5% per decade from 1954-1997. [52] This was due to both a significant leap forward in surgical techniques in combination with drastically improved imaging modalities.

EVAR

The advent of successful open surgical repair of AAAs using synthetic grafts in the 1950s proved to be the first definitive treatment for AAA. However, the procedure remained highly invasive and many patients were excluded due to medical and anatomical contraindications. [53] Juan Parodi’s work with Julio Palmaz and Héctor Barone in the late 1980s aimed to rectify this issue. Parodi developed the first catheter-based arterial approach to AAA intervention. The first successful EVAR operation was completed by Parodi in Argentina on seventh September 1990. [54] The aneurysm was approached intravascularly via a femoral cutdown. Restoration of normal luminal blood flow was achieved with the deployment of a Dacron graft mounted on a Palmaz stent. [55] There was no need for aortic cross-clamping or major abdominal surgery. Similar non-invasive strategies were explored independently and concurrently by Volodos, [56] Lazarus [57] and Balko. [58]

During this early period of development there was significant Australian involvement. The work of Michael Lawrence-Brown and David Hartley at the Royal Perth Hospital led to the manufacture of the Zenith endovascular graft in 1993, a key milestone in the development of modern-day endovascular aortic stent-grafts. [59] The first bifurcated graft was successfully implanted one year later. [60] Prof James May and his team at the Royal Prince Alfred Hospital in Sydney conducted further key research, investigating the causes of aortic stent failure and complications. [61] This group went on to pioneer the modular design of present day aortic prostheses. [62]

The FDA approved the first two AAA stent grafts for widespread use in 1999. Since then, technical improvements in device design have resulted in improved surgical outcomes and increased ability to treat patients with difficult aneurysmal morphology. Slimmer device profiles have allowed easier device insertion through tortuous iliac vessels. [63] Furthermore, fenestrated and branched grafts have made possible the stent-grafting of juxtarenal AAA, where suboptimal proximal neck anatomy once meant traditional stenting would lead to renal failure and mesenteric ischaemia. [64]

AAA intervention now and beyond

Today, surgical intervention is generally reserved for AAAs greater than 5.5cm diameter and may be achieved by either open or endoluminal access. The UK small aneurysm trial determined that there is no survival benefit to elective open repair of aneurysms of less than 5.5cm. [8] The EVAR-1 trial (2005) found EVAR to reduce aneurysm related mortality by three percent at four years when compared to open repair; however, EVAR remains significantly more expensive and requires more re-interventions. Furthermore, it offers no advantage with respect to all cause mortality or health related quality of life. [5] These findings raised significant debate over the role of EVAR in patients fit for open repair. This controversy was furthered by the findings of the EVAR-2 trial (2005), which saw risk factor modification (fitness and lifestyle) as a better alternative to EVAR in patients unfit for open repair. [65] Many would argue that these figures are obsolete, with Criado stating, “it would not be unreasonable to postulate that endovascular experts today can achieve far better results than those produced by the EVAR-1 trial.” [53] It is undisputed that EVAR has dramatically changed the landscape of surgical intervention for AAA. By 2005, EVAR accounted for 56% of all non-ruptured AAA repairs but only 27% of operative mortality. Since 1993, deaths related to AAA have decreased dramatically, by 42%. [53] EVAR’s shortcomings of high long-term rates of complications and re-interventions, as well as questions of device performance beyond ten years, appear balanced by the procedure’s improved operative mortality and minimally invasive approach. [54]

Conclusion

The journey towards truly effective surgical intervention for AAA has been a long and experimental one. Once regarded as one of the most deadly pathologies, with little chance of a favourable surgical outcome, AAAs can now be successfully treated with minimally invasive procedures. Sushruta’s millennia-old fear of abdominal aortic surgery appears well and truly overcome.

Conflict of interest

None declared.

Correspondence

A Wilton: awil2853@uni.sydney.edu.au

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The only medical science textbook you need to buy?

Post author By Website Publications Officer
Post date May 24, 2012

Wilkins R, Cross S, Megson I, Meredith D. Oxford Handbook of Medical Sciences, Second Edition. Oxford: Oxford University Press; 2011.

RRP: $47.95

A complete guide to the medical sciences that fits in your pocket? Including anatomy? It sounds like something you’d find on the bookshop shelf between Refl exology at Your Fingertips and Sex Explained. But The Oxford Handbook of Medical Sciences (OHMS) is probably one of the few serious books that handles this enormous topic and can still be picked up with one hand. The first edition was published in 2006, and it’s been a fairly constant companion since I started graduate medicine at Sydney University. The dense but well written text often feels more conducive to medical school than authoritative textbooks – if you’re asked to explain a concept in a tutorial, the 30 second answer is better than the five minute dissertation. Compiling principles and systems also means you can flip from say anatomy to immunology without piling up your desk with resources. Unfortunately, the more I’ve used the first edition the more niggling errors I’ve come across. Granted most are just typos, but others were more frustrating. Including a colour DNA sequencing output that seems more CSI-prop than medical text, at least to someone with a molecular biology background. And errors like labelling the muscles of mastication as supplied by cranial nerve VIII are inexcusable (instead of V3 mandibular – so presumably type-setting error). So OHMS1e – a great book in serious need of a revision, but could the second edition be the last medical science book you ever buy?

The OHMS second edition was published September 2011 from $35 in online bookshops. On first impression it has not transformed into a full colour extravaganza like the latest Oxford Handbooks of Clinical Medicine/Specialties. It is 40 pages longer than the original, 962 in total, and still small enough for a big pocket. Much of the first edition worked well and it is good to see that the layout remains the same, with each topic generally covered in two pages or less, with plenty of room for annotation. The first three chapters cover the essentials: cells, molecules and biochemistry – with some good looking new figures. The ten systems-based chapters are now followed by a chapter on medicine and society. The final chapter – techniques of medical sciences – has had a timely rewrite, it won’t make you a lab scientist but at least you’ll be able to have an intelligent conversation with someone who is. The best addition, in my opinion, are the blue boxes succinctly summarising relevant treatments and drug therapies in all the sections.

The cross-referencing to the most recent clinical Oxford Handbooks is a welcome update (in spite of a couple that refer to OHCM8p.000). I would have liked to see a more thorough reworking of the anatomy section; the diagram of the muscles of the hand remains duplicated a few pages apart. The molecular biology chapter, the one I feel semi-qualified to comment on, is my major complaint. There is no mention of new sequencing technologies and of non-coding RNAs that we are frequently told are the future of the field. Instead Maxam-Gilbert sequencing, a technique probably last done in the 1980s is still covered. Furthermore, ‘junk DNA’, a term surely killed off by the ENCODE project, makes a vampirelike appearance here. [1]

In summary, if you’ve already built a reasonable understanding of the medical sciences and are looking for a one-stop book for reference or revision on the run then this book is a good option. For its convenience and conciseness it is hard to beat OHMS2e. The USMLE crammers like First Aid, offer analogous coverage at an equivalent price but carrying one in your pocket isn’t an option. But beware – as far as OHCM2e is concerned the muscles of mastication are still innervated by CNVIII. Now where is my anatomy book?

References

[1] Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, et al. A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 2011 Apr;9(4):e1001046.

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