Faculty of Radiation Oncology Position Paper on the use of Image–Guided Radiation Therapy

The development of technology such as intensity‐modulated radiotherapy (IMRT), volumetric arc therapy (VMAT) and stereotactic ablative body radiotherapy (SABR) has resulted in highly conformal radiotherapy treatments. While such technology has allowed for improved dose delivery, it has also meant that improved accuracy in the treatment room is required. Image‐guided radiotherapy (IGRT), the use of imaging prior to or during treatment delivery, has been shown to improve the accuracy of treatment delivery and in some circumstances, clinical outcomes. Allied with the adoption of highly conformal treatments, there is a need for stringent quality assurance processes in a multidisciplinary environment. In 2015, the Royal Australian and New Zealand College of Radiologist (RANZCR) updated its position paper on IGRT. The draft document was distributed through the membership of the Faculty of Radiation Oncology (FRO) for review and the final version was endorsed by the board of FRO. This article describes issues that radiotherapy departments throughout Australia and New Zealand should consider. It outlines the role of IGRT and reviews current clinical evidence supporting the benefit of IGRT in genitourinary, head and neck, and lung cancers. It also highlights important international publications which provide guidance on implementation and quality assurances for IGRT. A set of key recommendations are provided to guide safe and effective IGRT implementation and practice in the Australian and New Zealander context.     

Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials

There is an urgent need for an improved vaccine against tuberculosis. Heterologous prime-boost immunization regimes induce higher levels of cellular immunity than homologous boosting with the same vaccine. Using BCG as the priming immunization in such a regime allows for the retention of the beneficial protective effects of BCG against disseminated disease in childhood. Recombinant poxviruses are powerful boosting agents, for both CD4+ and CD8+ T cells. Here we review the preclinical data from a BCG prime-recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A) boost strategy. MVA85A is now in clinical trials in the UK and Africa and the design of these trials, including the ethical and regulatory issues are discussed.     

Use of intranasal corticosteroids in sinonasal infection and after surgery

The use of intranasal steroids by otolaryngologists in the treatment of patients with infective rhinosinusitis and after endonasal surgery, particularly endoscopic sinus surgery, is unlicensed, as stated in the British National Formulary and in the manufacturers' leaflets supplied with nasal steroid medications. However, despite this, nasal steroids continue to be prescribed in these circumstances. Debate continues as to the exact role of intranasal steroids in sinonasal infection and after sinonasal surgery and whether their use in these circumstances should still be unlicensed. This article reviews the current medical literature regarding this topic and aims to clarify whether intranasal steroid usage in these circumstances should be recommended.     

The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.On sexual transmission, HIV-1 infects CD4⁺CCR5⁺ T cells and remains localized in genital/rectal mucosa and draining lymph nodes for ∼10 d (1). Virus then spreads via the blood to other lymphoid tissue, especially that in the gut (2). There, it replicates profusely and the level of free virus in the blood rises exponentially to reach a peak, often millions of virus copies per milliliter of plasma, 21–28 d after infection. Virus level then falls, rapidly at first, until a stable level is reached (3, 4). This set point varies across patients and is partially predictive of the later course of disease in the absence of antiretroviral drugs; patients with low set points progress to AIDS more slowly (5).It is uncertain how the peak viremia of acute HIV-1 infection is controlled. Some mathematical models (6–8) suggest that the rampant early infection simply destroys so many CD4 T cells in the gut (2, 9) and elsewhere that the cell substrate becomes limiting. However, reduction of peak viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) was dependent on the presence of CD8 cells (10), either T or NK cells, or both. In HIV-1 infection, virus-specific CD8 T cells first appear in the blood just before the viremia peaks and then expand and contract as virus load falls (11–13). HIV-1–specific CD8 T cells are detectable before seroconversion and long before neutralizing antibodies (NAbs) (14). However, the mere presence of such T cells does not prove that they control virus. Indirect evidence for their importance comes from HLA class I allelic associations with low virus set point and with delayed progression to AIDS (15), but these effects, which are probably mediated by HLA class I–restricted T cells, could occur after the initial drop in viremia. Overall, this leaves the relative importance of CD8 T cells and the loss of infectable target cells to the decline of viremia of acute HIV-1 infection unresolved.Further clues for a role of CD8 T cells in HIV-1 containment comes from studies demonstrating that they select virus escape mutations as early as 30–54 d after the peak viremia of acute infection (16, 17) and continue to select mutations throughout chronic infection (18–26). Nearly all these observations have been made after the steep decline from peak viremia, as the virus is stabilizing at its set point, or later. Few studies have directly measured T cell escape; it is more often argued that changes in virus sequence in regions that correspond to CD8 T cell epitopes matching the HLA type of the patient are selected by T cells (e.g., see reference 28). However, this approach can be confounded by the many overlapping epitopes, that are presented by different HLA types (27). Approaches based on sequence alone also miss T cell responses to invariant epitopes as well as mutants selected by other immune responses.In this paper, a comprehensive study was made of the ontogeny of the primary T cell response in acute HIV-1 infection. The single genome amplification (SGA) sequencing technique (28, 29) identified the single transmitted/founder virus sequence in each of four preseroconversion patients, before the immune response had made a discernable imprint on the virus quasispecies. The adaptive immune responses to the transmitted virus proteome were then followed using peptides matched to autologous founder virus and to subsequent mutants, to capture responses that might otherwise be missed because of virus variability (30). This approach identified the first T cell responses in HIV-1–infected humans and showed that virus escape mutants were rapidly selected as viremia fell from its peak in acute infection. A mathematical model quantified the downward pressure exerted by these CD8 T cell responses on the virus, showing that they contributed to the concurrent reduction of viremia. These data imply that vaccines that stimulate strong and broad early CD8 T cell responses to HIV-1 should be valuable.     

Greater benefits of multisensory integration during complex sensorimotor transformations

Multisensory integration enables rapid and accurate behavior. To orient in space, sensory information registered initially in different reference frames has to be integrated with the current postural information to produce an appropriate motor response. In some postures, multisensory integration requires convergence of sensory evidence across hemispheres, which would presumably lessen or hinder integration. Here, we examined orienting gaze shifts in humans to visual, tactile, or visuotactile stimuli when the hands were either in a default uncrossed posture or a crossed posture requiring convergence across hemispheres. Surprisingly, we observed the greatest benefits of multisensory integration in the crossed posture, as indexed by reaction time (RT) decreases. Moreover, such shortening of RTs to multisensory stimuli did not come at the cost of increased error propensity. To explain these results, we propose that two accepted principles of multisensory integration, the spatial principle and inverse effectiveness, dynamically interact to aid the rapid and accurate resolution of complex sensorimotor transformations. First, early mutual inhibition of initial visual and tactile responses registered in different hemispheres reduces error propensity. Second, inverse effectiveness in the integration of the weakened visual response with the remapped tactile representation expedites the generation of the correct motor response. Our results imply that the concept of inverse effectiveness, which is usually associated with external stimulus properties, might extend to internal spatial representations that are more complex given certain body postures.     

Validation of a within-trial measure of the oculomotor stop process

The countermanding (or stop signal) task requires subjects try to withhold a planned movement upon the infrequent presentation of a stop signal. We have previously proposed a within-trial measure of movement cancellation based on neck muscle recruitment during the cancellation of eye-head gaze shifts. Here, we examined such activity after either a bright or dim stop signal, a manipulation known to prolong the stop signal reaction time (SSRT). Regardless of stop signal intensity, subjects generated an appreciable number of head-only errors during successfully cancelled gaze shifts (compensatory eye-in-head motion ensured gaze stability), wherein subtle head motion toward a peripheral target was ultimately stopped by a braking pulse of antagonist neck muscle activity. Both the SSRT and timing of antagonist muscle recruitment relative to the stop signal increased for dim stop signals and decreased for longer stop signal delays. Moreover, we observed substantial variation in the distribution of antagonist muscle recruitment latencies across our sample. The magnitude and variance of the SSRTs and antagonist muscle recruitment latencies correlated positively across subjects, as did the within-subject changes across bright and dim stop signals. Finally, we fitted our behavioral data with a race model architecture that incorporated a lower threshold for initiating head movements. This model allowed us to estimate the efferent delay between the completion of a central stop process and the recruitment of antagonist neck muscles; the estimated efferent delay remained consistent within subjects across stop signal intensity. Overall, these results are consistent with the hypothesis that neck muscle recruitment during a specific subset of cancelled trials provides a peripheral expression of oculomotor cancellation on a single trial. In the discussion, we briefly speculate on the potential value of this measure for research in basic or clinical domains and consider current issues that limit more widespread use.