Category: Articles

A review of the resistance mechanisms underlying dabrafenib/trametinib combined therapy in the treatment of BRAF mutant metastatic melanoma

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Background: BRAF mutant metastatic melanoma treatment is most effective when it targets the changes induced within the mitogen-activated protein kinase (MAPK) cas-cade. However, due to the cancer’s heterogeneous nature, drug resistance predictably develops within 9-10 months, reducing treatment efficacy and producing poor patient outcomes. Understanding the mechanisms behind this acquired resistance is vital in de-vising optimal therapeutic regimens and ultimately improving the survival rate of this widespread disease.

Methods: This review examines the different resistance mechanisms that develop in BRAF mutant metastatic melanoma to prevent the durable efficacy of combined BRAF and MEK inhibitors as a treatment method. Subsequently, it evaluates possible changes that can be made to ensure therapy is made more effective in future disease management.
Results: Currently recognised resistance mechanisms include: alterations to BRAF (commonly through gene amplification), eIF4F complex mutations, changes activating the upstream regulator N-RAS or downstream effectors MEK1/2, and non-genomic al-terations. Together, these factors reactivate the MAPK cascade, despite dual MAPK in-hibition, and allow the tumour to continue to grow and metastasise unimpeded by inter-vention.

Conclusion: The ease at which contemporary treatment is being made redundant high-lights the requirement for further research into the underlying molecular aberrations, and from this, the development of new, more effective therapies into the future.

Introduction

Despite representing only 4% of all possible skin cancers, cutaneous melanoma has shown to be the most aggressive type, contributing to approximately 80% of all skin cancer related deaths (65,000 per year) [1]. It is the most common form of cancer diag-nosed in Australians aged 15-29 years, and its incidence in Caucasian populations has been increasing faster than any other malignancy over the last 30 years [2]. Five-year survival is poor for disseminated disease, from 15% to 60% in patients with either dis-tant or local metastases respectively [1,2]. Until 2011, treatment for patients with meta-static melanoma was largely ineffective, with chemotherapy having no effect on either median progression-free or overall survival [3,4]. However, an improved understanding of the underlying molecular aberrations in melanoma tumour cells led to the development of new targeted therapies, which have fortunately shown a significant clinical effect [2,5].

The genetic analysis of melanomas has revealed the clinical importance of BRAF, a pro-tein kinase that plays an essential role in activating the mitogen-actived protein kinase (MAPK)/extracellular signal related kinase (ERK)-signalling pathway [6]. Approximate-ly 40-50% of all cutaneous melanomas harbour activating BRAF mutations, although this aberration is rare in mucosal melanomas, and non-existent in the uveal form [7]. The mutation most commonly occurs in valine at codon 600, causing an increase in enzyme activity, which leads to angiogenesis, unchecked replication of cells and an ability to me-tastasise — all essential factors in tumour growth and spread [8,9]. As such, it is a vital target for drugs in reducing melanoma progression (and thus morbidity and mortality) when the diagnosis is made too late for simple excision. However, whilst treatments tar-geting a single aspect in the MAPK pathway were previously employed as a first-line defence, resistance to these therapies nearly invariably developed within 5-7 months of commencement [2,9-11].

Combined MAPK inhibition using both selective BRAF and allosteric MEK inhibitors as a method of circumventing these resistance mechanisms was subsequently consid-ered, and in 2014 met the approval of the Australian Therapeutic Goods Administration for disease treatment [3,10,12]. Initial clinical trials merging the BRAF inhibitor dabraf-enib, with MEK inhibitor trametinib, demonstrated an increased durability against drug resistance, thereby improving response rate, and enhancing progression-free and overall survival compared to single agent BRAF inhibition [7]. Following therapy initiation, 50% of patients experienced disease progression after 9-10 months, and long-term clini-cal outcomes were again impeded by the development of resistance [13,14].

Understanding of these resistance mechanisms is currently improving, however com-plete comprehension is vital if a significant reduction in melanoma mortality rates is to be achieved [5,15]. This review thus aims to provide readers with a thorough understand-ing of the resistance mechanisms that develop to the combined therapy of dabraf-enib/trametinib, and what improvements can be made to make treatment more effective in the future.

Discussion

Mechanism of action of dabrafenib/trametinib combined therapy in BRAF mu-tant metastatic melanoma

Normal MAPK function
The MAPK pathway (Figure 1) is a highly-conserved signalling cascade, essential for various cellular functions such as proliferation, differentiation and migration of cells [16-18]. Its activation is a complex process to ensure pathway regulation, and is often initiat-ed via RAS (a guanosine triposphate (GTP)-hydrolysing enzyme) binding to a GTP molecule, and leading to phosphorylation and activation of the RAF kinases [2]. These in turn phosphorylate the MEK1/2 kinases, which consequently enable ERK 1 and 2 ac-tivation [6,19,20]. ERK then proceeds to phosphorylate a plethora of cytoplasmic and nuclear substrates, which subsequently mediate the pathway’s pleiotropic effects. These include: cell cycle protein expression, proapoptotic and antiapoptotic regulation and function, and nuclear transcription factor activation [6,19-21].

Figure 1. The effect deregulation of the MAPK signalling pathway (left) and PI3K/AKT/mTOR pathway (right) has on melanoma tumourigenesis, and the various sites of intervention that occur with dabrafenib/trametinib dual therapy [21].

BRAF mutation in melanomas
The RAF protein has three isoforms: ARAF, BRAF and CRAF [6,20,21]. As dis-cussed earlier, BRAF mutations occur at the highest frequency within most cutaneous melanomas (commonly as a V600E point mutation) and create a constitutively active BRAF molecule [23]. This subsequently leads to increased MEK and ERK function, which not only completely deregulates the cell cycle, but also increases transcription and inhibits apoptosis, thus inducing the cancer phenotype [23].

Mechanism of action of dabrafenib and trametinib
Dabrafenib is a highly potent, reversible adenosine triphosphate (ATP) competitive in-hibitor that selectively inhibits the kinase domain of mutant BRAF (Figure 1) [5,20,21]. This leads to reduced proliferation through subsequent reductions in phosphorylated ERK and thus, increased expression of apoptotic proteins and G1-phase cell cycle arrest [21]. Alternatively, trametinib is an allosteric inhibitor of MEK 1 and 2, that selectively binds and stabilises the closed, inactive conformation of the MEK enzymes, thereby re-ducing phospho-ERK concentrations and the downstream effects it has on cell prolifera-tion, growth and senescence (Figure 1) [18,24,25]. Ultimately, the combination of these two inhibitors significantly improved progression-free survival and response duration for metastatic melanoma patients when compared to monotherapy [12,14].

Mechanisms behind combined therapy resistance

The mechanisms involved in MAPK inhibitor resistance still largely require further in-vestigation. However, given the nature of combination therapy and the fact it was devel-oped to address many of the mechanisms causing acquired resistance in single target treatment, the culpable genetic aberrations are not as diverse as those seen in monothera-py [10,13,26].

There are currently several categories of mutations consistently identified as the source of MEK/ERK signalling reactivation: BRAF gene amplification, MEK1/2 mutation, and NRAS alteration [10,18,27]. There have also been a number of melanoma phenotypes recognised as possessing innate resistance, the mechanics of which are still under heavy investigation and only briefly covered within this report.

Resistance mechanism of BRAF gene amplification
BRAF copy number gains were most common, affecting 36% of all melanomas treated with combined therapy [10]. Notably, the extent of this amplification was significantly higher than seen in monotherapy resistance. Not only is this reflective of the upsurge in MAPK signalling required to overcome dual treatment, it is also indicative of increased tumour reliance on this resistance mechanism due to inhibition of other avenues [10,11,14]. Ultimately, gene amplification leads to augmented BRAF kinase concentra-tion within the cell, drastically elevating MAPK signalling by creating an excess of acti-vated MEK [8,14]. This has two vital consequences:

1. An increase in the basal level of phosho-ERK and thus increased activation of nuclear transcription factors, anti-apoptotic and cell cycle regulation proteins to cause proliferation, metastasis, and apoptosis resistance in melanoma cells [21,24].
2. An increase in the IC50 (the concentration of drug required to inhibit a biological process by half) of both trametinib and dabrafenib for inhibition of ERK phos-phorylation [6].

The latter point is explained by the mechanism of action of trametinib [14]. The drug has a significantly lower affinity for activated, phosphorylated MEK than it does for inactive MEK [10,14]. The presence of BRAF amplification and the resulting MEK hyperactiva-tion induces an excess of phosphorylated MEK, with little remaining in the drug’s fa-voured inactive conformation [10,24,25]. Overcoming this decreased affinity and ade-quately inhibiting MEK hence requires higher concentrations of trametinib [14]. Fur-thermore, because of the increased BRAF kinase concentration, therapeutic levels of dabrafenib cannot compete, and thus have an insufficient effect in inhibition [10].

Resistance mechanism of MEK1/2 mutation
Further implicated in resistance development were de novo mutations in MEK1/2, with an incidence of 26% in treatment-insensitive tumours [10,13]. The majority of MEK mu-tations employ a similar mechanism of action, with the alterations tending to occur within, or proximal to, a negative regulatory region of MEK; helix A/C sub structure [9,10,13,17]. The helix sits against the area of the kinase that binds both ATP and allos-teric inhibitors (such as trametinib). Whilst the mutations are usually located too far from the ligand to directly interact with it, they are close enough to alter the ATP binding site in a way that allosterically increases the intrinsic kinase activity of MEK [14,27]. As a result, ERK levels can be up to 20-fold higher compared to wild type MEK, increasing proliferation and apoptotic inhibition and ultimately creating an environment conducive to tumour growth [10,14]. Furthermore, over-expression of MEK causes a greater than ten-fold decrease in sensitivity to trametinib (due to mechanisms explained above), thereby increasing the concentrations required for MAPK inhibition and abrogating the effects of dabrafenib (which acts immediately upstream), and thus conferring acquired resistance to the combination therapy [10,13,27].

Coexisting NRAS mutation development
The emergence of coexisting BRAF and NRAS de novo mutations are also a possible cause for dual therapy resistance [28]. The NRAS gene encodes for the protein N-Ras, whose primary function involves regulating cell division. Its relatively high mutation rate means it contributes to the development of 15-20% of all non-uveal melanomas, and is subsequently the second most common oncogenic stimulus for cutaneous metastatic melanomas [7,28]. In around 80% of cases, these genetic aberrations involve a gain-of-function point mutation occurring at codon 61 of the NRAS gene, with the remaining alterations either affecting codons 12 or 13 [28]. This leads to a subsequent hyperactiva-tion of the RAS-RAF-MAPK and P13KT-AKT cascades, thereby increasing pro-survival protein expression, cellular proliferation, and cell cycle dysregulation [29]. The resulting synergistic effect of having two gain-of-function mutations within both NRAS and BRAF means a tumourigenic environment that supports metastasis quickly devel-ops, and the efficacy of trametinib/dabrafenib therapy is limited by the need to increase their required levels above what is therapeutically appropriate [28].

eIF4F eukaryotic translation initiation complex hyperactivation
Finally, it is important to consider downstream pathways and their influence on dual therapy drug resistance. MAPK and PI3K/AKT/mTOR signalling converge to influence the eIF4F eukaryotic translation initiation complex, a molecule nexus consisting of the eIF4G scaffolding protein, the eIF4E cap-binding protein and the eIF4A ribonucleic acid (RNA) helicase [30,31]. Its normal function involves modulating specific mitochondrial RNA translation to produce a plethora of proteins that potently regulate cell growth, pro-liferation, migration, and survival [31]. As such, excessive stimulation of the complex can alter the proteome, and ultimately give rise to the phenotypic heterogeneity of cells essential for drug resistance development, as well as tumour progression and metastasis [31,32]. There are three main mechanisms that have been identified in producing this augmented state, the first of which involves MAPK signalling reactivation through mechanisms described earlier [30]. Persistent phosphorylation of 4EBP1 (a protein that normally inhibits eIF4E binding) to permit increased translation initiation can also insti-gate hyperactivity, as can increased degradation of eIF4G through raised levels of pro-apoptotic BMF [30]. Ultimately, it is unsurprising that the enhanced formation and acti-vation of the eIF4F complex has been associated with dual therapy resistance in BRAF mutant metastatic melanoma, due to its propensity to produce the intratumoural hetero-geneity that helps enable drug resistance development [30-32].

Non-genomic resistance mechanisms
However, clinically acquired resistance to MAPK inhibition therapies cannot be fully explained through acquired genomic mechanisms, given that up to 10-20% of BRAF mutant metastatic melanoma patients never achieve a meaningful treatment response [7,27,33]. Rather, divergent transcriptional profiles exist between drug responsive cell lines and those which are intrinsically resistant, indicating that certain transcription fac-tors are innately present which can modulate melanoma response to MAPK inhibitors [7,29,33].

Differing tumour cell phenotypes and MITF
The significance of the microphthalmia-associated transcription factor (MITF) and its expression levels in treatment outcomes was one such identified transcription factor [34-36]. MITF plays a key role in the survival and differentiation of melanocytes by regulat-ing the expression of a variety of crucial melanogenic genes [35]. Whilst the majority of drug sensitive cells show high levels of MITF, both its expression and function were notably reduced within resistance lines. These cells instead tended to display elevated Nuclear Factor-κB (NF-κB) transcriptional activity, which in itself promotes melanoma progression and metastasis through pro-survival signalling [35,36]. The synergistic ef-fect of these phenotype factors creates a global transcriptional state that induces intrinsic indifference to intervention throughout all three levels of the RAF/MEK/ERK cascade. This was evidenced by the fact that, subsequent to dabrafenib/trametinib therapy, pro-gression-free survival of MITF-low/NF-κB-high melanomas was significantly shorter than the MITF-high/NF-κB-low group (median 5.0 months versus 14.5 months respec-tively) [35,36]. It should be noted however, that although this transcriptional state is cer-tainly associated with innate resistance, it can also be induced through MAPK hyperacti-vation, NF-κB induction and MITF dysregulation, thus becoming a mechanism of ac-quired resistance [36]. Ultimately, this transcriptional class distinction between BRAF mutant metastatic melanomas will aid future efforts in predicting treatment outcome and subsequently developing new therapeutic approaches for those patients unresponsive to RAF/MEK inhibition.

Further transcriptional alterations
There are a plethora of other transcriptional alterations that develop in treatment resistant tumours, frequently as the result of differential methylation of tumour cell-intrinsic cyto-sine-phosphate-guanine sites [7,28,37]. However, only the most recurrent molecular ab-errations will be discussed within this article: c-MET up expression, infra-physiologic LEF1 down expression, and YAPI signature enrichment [7,28]. Of the three, up expres-sion of c-MET not only remains the most consistently altered gene throughout treatment resistant melanomas, its degree of expression also greatly predicts patient outcomes via the mediation of MAPK-redundant survival signalling [37]. It is a receptor tyrosine ki-nase that reacts with its hepatocyte growth factor (HGF) ligand and stimulates an array of signalling pathways, ranging from proliferation to migration and invasion through activation of RAS and PI3K [37]. Evidently, its resultant hyperactivation of these path-ways ensures the level of BRAF and MEK inhibitors required to adequately control such a situation are too high to be within safe administration limits, thereby ensuring that melanoma cells carrying this mutation never respond to dual therapy [7,28].

Recurrent β-catenin-LEF1 down regulation has also shown to promote dual therapy in-sensitivity as its normally pro-apoptotic induction to MAPK inhibition is subsequently decreased [7]. Whilst this feature is essential for survival of metastatic cells, primary be-nign melanoma cells do not depend on this signalling cascade for survival. YAP1, a pro-survival factor that alters cell function through post transitional regulation, was also no-ticed to be harboured in increased quantities within MAPK inhibitor resistant tumours [7]. Given the history of known interactions between these two pathways in other bio-logical contexts, simultaneous deregulation of both β-catenin-LEF1 and YAP1 signal-ling is common, thereby resulting in an increased apoptotic threshold within melanomic cells, and thus reduced sensitivity to dual MAPK inhibition [7,28]. Given that the high-lighted transcriptional mutations are only a few of many in inducing therapy resistance, it is evident that current genomic diversity is severely limiting the long-term efficacy of dual medication.

Potential mechanisms to overcome acquired resistance in dabrafenib/trametinib combined therapy
Further MAPK pathway inhibition

MAPK-independent mechanisms of resistance were not conferred at a higher frequency in combined therapy compared to single-agent BRAF inhibitors [4,10,13]. This insinu-ates that BRAF mutant metastatic melanomas remain highly dependent on MEK/ERK signalling for tumour growth and survival, highlighting a potential avenue to increase combined treatment durability in the future and thus improve patient outcomes [10,14]. To elaborate, if other aspects of the pathway can be targeted along with BRAF and MEK inhibition, and thus the potency of MAPK inhibition further increased, it may help cir-cumvent the acquired resistance mechanisms which otherwise increase the concentration of activated MEK to levels dabrafenib/trametinib can no longer inhibit [10,12,13]. Ex-ample therapies include those targeting ERK through inhibition [4,26,27]. A preclinical study investigating this phenomenon found that BRAF/MEK/ERK inhibitor combina-tions not only delayed the emergence of acquired resistance, but they could also be used to overcome it in desensitised BRAF mutant tumours [27]. Whilst the exact reason for this is not yet clear, it is hypothesised that the ATP-competitive ERK inhibitors are less sensitive to altered conformation dynamics of activated ERK in the context of upstream oncogene amplification, and thus remain effective in inhibiting its downstream tumour-igenic effects on the cell [27]. Evidently, further refined investigation is needed into the area before more conclusive implications can be drawn, but current results allude to a hopeful future for a disease with such a poor survival rate.

Dual pathway inhibition
Furthermore, new studies have recently been released examining dual pathway inhibition [29,33]. The PI3K/AKT/mTOR pathway is an important cascade involved in signalling cellular growth, metabolism, and translation initiation (Figure 1). Along with MAPK, it is one of the most commonly altered signalling pathways in solid malignancy [33]. In melanoma cells, PI3K/AKT/mTOR has been shown to interact extensively with the MAPK pathway and potentially lead to its activation via phosphoionsitide 3-kinase (PI3K)-RAS interaction [29]. Whilst alone, it is not sufficient to completely confer re-sistance to combined therapy, PI3K has shown to contribute to earlier resistance devel-opment by modulating tumour responses to MAPK inhibitors [26,28]. Current evidence suggests that PI3K/mTOR pathway inhibition via ATP, and to a lesser extent, non-ATP competitive inhibitors can have a modest impact on both primary melanoma tumours and metastasis, diminishing the growth and proliferation of cells [29]. Therefore, the efficacy of PI3K and MAPK is being trialled in the hope it will ultimately improve patient out-comes [26,27]. Dual PI3K and MEK inhibition, the most common combination under-going investigation, currently results in only modest success and a number of relatively frequent adverse effects that include diarrhoea, nausea, pyrexia, rash, and fatigue. How-ever, this does not discount the feasibility of this dual pathway approach, but merely highlights the requirement for further investigation to improve tolerability [29]. This in-volves discerning the most optimal dosing schedule, perhaps targeting other members of the P13K/AKT/mTOR pathway, or augmenting patients with predictive factors [29].

Furthermore, the eIF4F complex (discussed earlier) sits at the junction of multiple onco-genic pathways and plays an essential role in producing the intratumoural heterogeneity that ultimately assists drug resistance development [32]. As such, its combined inhibi-tion with the MAPK pathway may provide a formidable effect in improving treatment efficacy [30]. There is currently work being done to target all three components of the complex, including: blocking eIF4E-cap interaction, interfering with eIF4E-eIF4G inter-action, inhibiting eIF4A helicase activity, and suppressing eIF4E levels — all with vary-ing degrees of success [31,32]. For example, eIF4A inhibitions (such as silvestrol) have a more potent effect compared to eIF4E in reducing global protein synthesis and thus the capability of tumour cells in developing treatment resistance, largely because cellular translation requires persistently high eIF4A concentrations, but not eIF4E, to be main-tained [30,31]. Whilst silvestrol therefore appears an advantageous agent to combine with MAPK inhibitors, it too is vulnerable to drug resistance due to overexpression of ABCB1/P-glycoprotein, thereby hampering its use in in vivo studies [30]. Ultimately, the introduction of eIF4F complex and MAPK doublet inhibitors as a possible treatment avenue is only a recent occurrence, and significantly more research is required before any definite conclusion can be established [31]. However, it theoretically can provide a potent influence in the seemingly insurmountable barrier of resistance in metastatic mel-anoma treatment, and thus provides hope for future patient outcomes [30].

Incorporation of immunomodulation in treatment
The potential of immunotherapy in treatment of metastatic melanoma has also been rec-ognised. Metastatic melanoma patients commonly display tumour-mediated immune suppression, and in the past, treatment with immunomodulatory therapies such as inter-feron alpha and high dose interleukin-2 has shown positive results [38]. With greater understanding of the immune system and its interaction with tumour cells, further inter-ventional therapies have now been developed with varying degrees of efficacy. These include monoclonal antibodies that inhibit essential immune checkpoints, such as ipili-mumab (an anti-cytotoxic T-lymphocyte-associated protein 4 inhibitor), and pembroli-zumab (an anti-programmed cell death 1 inhibitor), as well as other methods involving adoptive cell transfer [38]. Whilst it is hoped that a combination between these im-munomodulatory therapies with MAPK inhibition will improve clinical outcomes in metastatic melanoma patients, the toxic effects of such combinations currently remain unpredictable [38]. This only indicates the need for further, careful study into the dosing and timing of these dual treatments, as their potent anti-tumour activity and synergistic properties have high potential for improving patient outcomes.

Conclusion

Melanoma remains one of three cancers with an increasing mortality rate, despite exten-sive clinical investigation and the recent introduction of various novel and specific drugs into its treatment regimen [12]. This is primarily because long-term efficacy of these pharmaceuticals has been limited by the emergence of resistance in targeted cancer cells [3,5,6]. Given that the presence of BRAF mutations in metastatic melanoma has been associated with reduced survival in the absence of specific treatment, it is essential that these mechanisms are overcome to increase drug durability and thus improve patient outcomes [11]. It has been found that dabrafenib/trametinib associated resistance was primarily the result of BRAF gene amplification, MEK1/2 changes, the development of co-existing NRAS mutations, and eIF4F complex hyperactivation, as well as non-genomic alterations [10,13,14]. Together, they abrogate the effects of both drugs and cause resistance within 9-10 months of treatment commencement [21]. Possible solu-tions to overcome this include further inhibition of kinases downstream of RAF and MEK in the MAPK cascade such as ERK, as well as targeted inhibition of the heavily associated PI3K/ATK/mTOR cascade or eIF4F complex [10,26,28]. Incorporating im-munomodulatory therapies into current regimes is also a major point of consideration [36]. Ultimately, full comprehension of the factors influencing combination therapy re-sistance is fundamental, for only with understanding can solutions be developed, and the currently pitiable patient outcomes for BRAF mutant metastatic melanoma be improved.

As medical students enter the workforce, combination therapies will likely be the fore-front of metastatic melanoma treatment and only the beginning of the trend towards mu-tation-specific cancer management. As such, is it essential to have not only a strong un-derstanding of the basic pathways affected by these cancers, but the clinical relevance the short-term efficacy of these drugs have for patients. This need to be informed is only further augmented by the increasingly high incidence of melanoma in Australia.

Limitations of review
The major limitation of this literature review relates to the contemporary nature of the topic. With primary journal and review articles assessing the efficacy of dabrafenib/ tra-metinib still being released, investigations into the resistance mechanisms behind these results, and methods to overcome them, have only recently commenced. Consequently, there were a restricted number of articles available to examine which may affect the va-lidity of conclusions within this review when further information is made available. Fur-thermore, the sample sizes within the available primary journal articles were small [10]. Whilst the overlap in implicated mutations and possible solutions suggests valid results, it is possible that further vital mechanisms were missed because of the small sample size. Finally, it should be noted that whilst this review only focuses on dabrafenib/trametinib dual therapy, in actuality there are three BRAF/MEK doublets that have shown clinical benefit (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib) [39].

Conflict of interest
None declared.

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[35] Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C. Low MITF/AXL ratio predicts resistance to multiple targeted drugs in melanoma. Nat Commun. 2014;5:5712. doi:10.1038/ncomms6712
[36] Konieczkowski D, Johannessen C, Abudayyeh O, Kim J, Cooper Z, Piris A. A mela-noma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Dis-cov. 2014;4(7):816-27. doi:10.1158/2159-8290.CD-13-0424
[37] Organ S, Tsao M, de Bono J. An overview of the c-MET signalling pathway. Ther Adv Med Oncol. 2011;3(1):S7-19. doi:10.1177/1758834011422556
[38] Kirkwood J, Tarhini A, Panelli M, Moschos S, Zarour H, Butterfield L. Next genera-tion of immunotherapy for melanoma. J Clin Oncol. 2008; 26(20):3445-55. doi:10.1200/JCO.2007.14.6423
[39] Sullivan R, LoRusso P, Boerner S, Dummer R. Achievements and challenges of mo-lecular targeted therapy in melanoma. Am Soc Clin Oncol Educ Book. 2015:177-86. doi: 10.14694/EdBook_AM.2015.35.177

Tags BRAF mutant, metastatic, melanoma, dabraf-enib, trametinib

Review Articles

Sickle Cell Disease and Hydroxyurea Treatment

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Introduction: Sickle cell disease (SCD) is a genetic disorder impacting the patient’s haemoglobin. This condition is accompanied by many dangerous phenotypes, which are the result of pathological haemoglobin polymerisation within the red blood cell (RBC). The primary aim of this piece is to review the accepted literature on the SCD pathophysiology and its pharmacological treatment option, hydroxyurea.

Summary: Hydroxyurea has multiple posited mechanisms of action but most importantly it is the only SCD treatment that targets the underlying pathology. It was found that hydroxyurea significantly decreases the frequency of hospitalisations, vaso-occlusive events and blood transfusions required. In summary, SCD is a complex hereditary disorder in which for a medical practitioner to effectively manage requires a comprehensive understanding of both normal haemoglobin physiology and its pathophysiology.

Introduction

Sickle cell disease (SCD) is a common monogenic autosomal recessive disorder of haemoglobin, occurring in approximately 1-2% of Europeans and Americans of African descent and has a prevalence of 4% or higher in West Africa [1]. The primary role of haemoglobin is the transport of oxygen from highly oxygenated areas, such as the lungs, to the comparatively poorly oxygenated tissues. However, in SCD, low oxygen conditions result in the polymerisation of the pathological haemoglobin which downstream leads to the SCD signs and symptoms, including vaso-occlusive events, chronic haemolytic anaemia, organ dysfunction, and increased infections.

To extensively investigate SCD, this review will first address normal RBC physiology, the SCD pathophysiological models, and finally a treatment option for the condition. Regarding SCD treatment, this review will examine the pharmacological use of hydroxyurea, an antineoplastic agent. Finally, this topic is relevant and of considerable importance as it frequently leads to patient hospitalisations, life-threatening characteristics, and significant global prevalence.

Materials and Methods

A comprehensive review of literature was conducted using the computerised search databases, PubMed and Ovid MEDLINE. The obtained articles were then filtered and case reports and articles written in languages other than English were excluded. The review was conducted during September of 2016, with the most recent literature used where appropriate.

Normal physiology

The primary function of the RBC is O2 delivery from the lungs to the body’s tissues, mainly to allow oxidative phosphorylation in the mitochondria [2]. Within the RBC it is the chromo-protein haemoglobin that allows for the loading and unloading of O2. Haemoglobin contains four globin chains, with a corresponding haem molecule for which each has the ability to reversibly bind oxygen [3]. As haemoglobin binds O2 to its haem groups, its affinity for oxygen increases due to the alteration of the haemoglobin molecular structure. However, haemoglobin has more functions, those being; CO2 transport to the lungs from tissues as carbaminohaemoglobin, buffering of H+ via the carbamoyl anhydrase reaction within the RBC, and nitric oxide (NO) metabolism [3,4].

There are two types of adult haemoglobin, those being the major haemoglobin HbA and minor haemoglobin HbA2, comprising of two α-globin and two β-globin chains and two α-globin and two δ-chains, respectively [3]. These differing globin chains make HbA2 a considerably poorer oxygen carrier. Each of the α-chains are made of 141 amino acids, and β-chains of 146 amino acids. Chromosome 16 contains the genes for the α-chain and chromosome 11 has those for the β-chain [3].

The other type of haemoglobin is foetal haemoglobin (HbF) and is clinically and therapeutically significant in SCD, as discussed below. Structurally, HbF comprises of two α-globin and two γ-globin chains. Studies have shown that after 6 months, HbF begins to disappear from infant RBCs, however, the signalling mechanism of this is not known [5,6].

Pathophysiology

SCD is defined by the presence of sickle haemoglobin (HbS) in the RBCs, which causes the distinctive sickle RBC shape. SCD is an inherited disease done so in an autosomal recessive fashion. The carriers for the disease are heterozygous for the mutation and are said to have the sickle cell trait [7]. Patients that are disease compound heterozygous or homozygous have SCD and will exhibit some level of symptoms. In the U.S., the common SCD genotypes include: sickle cell anaemia (HbSS), HbS/β° thalassaemia, and HbS/β+ thalassaemia [7]. There are, however, many more compound heterozygous sickle cell genotypes, though most are rare.

HbS occurs due to a single nucleotide β-globin gene mutation, causing the 6th amino acid to be changed from glutamic acid to valine [8]. The mutation results in the binding of β1 and β2 chains of two deoxygenated HbS tetramers. This crystallisation process continues within the RBC, growing until the flexibility and structure is disturbed. Disease severity is dependent upon the degree of HbS polymerisation, which relies on the degree of haemoglobin deoxygenation and the concentration of intracellular HbS. For HbS, this deoxygenation results in the exposure of the mutated valine residue on the molecule surface, this causes hydrophobic interactions with surrounding chains. The consequently formed polymers develop into bundles, causing RBC distortion into its distinguishing sickle appearance. This reduces flexibility which impairs the flow of sickled RBCs through narrow vasculature.

The signs and symptoms of SCD can be understood via the three mechanisms: vascular occlusion, haemolytic anaemia, and increased infection tendency (Figure 1).

**Figure 1. Sickle cell disease pathophysiology.** The pathophysiological effects of sickled haemoglobin (HbS) polymerisation can be seen, being; vaso-occlusion, ischemia, haemolysis and decreased nitric oxide (NO) bioavailability. HbS polymerisation develops following RBC deoxygenation which consequently gives the RBC the characteristic sickle shape. Vaso-occlusion is the effect of interactions between the rigid sickled RBCs and the endothelial surface, causing downstream necrosis, organ dysfunction, acute pain and oxidative reperfusion stress. Haemolysis results in the release of haemoglobin into the plasma which removes bioavailable NO.

Vaso-occlusion most frequently occurs in the bones – but can occur anywhere – which is the result of sickled cells blocking blood vessels. Venous blockage results due to the physiological requirement for haemoglobin deoxygenation at the tissues which then allows for the formation of the pathological sickled RBC shape. Subsequent systemic disturbances and pain can be felt downstream from the blockage, caused by ischemia, necrosis and organ dysfunction. Fat embolisms can occur secondary to a bone marrow infarct which could exacerbate the vascular occlusion issue, especially in the respiratory and neurological systems [9].

Initially, it was thought that only the less soluble deoxygenated polymerised HbS caused the sickled RBCs to be ridged and dense, resulting in vaso-occlusion [10,11]. However, the process is multifaceted and dynamic incorporating stimulatory interactions of the vascular endothelium to increase numerous adhesion molecules, such as integrin. This produces an inflammatory response, RBC and leukocyte adhesion to vessel walls, as well as, tissue damage predisposing the patient to vaso-occlusion [12-14]. Such vaso-occlusion causes interrupted blood flow, oxidative reperfusion stress, thrombus formation, stroke, and potentially severe ischemia [15-18]. The later mentioned endothelial dysfunction which occurs due to decreased NO levels causing vasoconstriction, also contributes to this dangerous vaso-occlusive state [19].

Haemolytic anaemia is another marked pathology in sickle-cell disease, which too is promoted by HbS polymerisation. It is accepted that such haemolysis results in fatigue, anaemia, and cholelithiasis, and now is also being linked to the advancement of progressive vasculopathy. As patients with SCD age, their vasculopathy risk increases, primarily distinguished by pulmonary and systemic hypertension, as well as vascular intimal and smooth muscle proliferative modifications [20-22]. Clinically, the severity of intravascular haemolysis in SCD patients is determined by measuring the serum levels of lactate dehydrogenase [23].

Epidemiological studies have proposed a positive correlation to both low levels of non-polymerised haemoglobin and significant intravascular haemolysis with increased rates of the SCD manifestations, some of which include; cholelithiasis, cutaneous leg ulceration, priapism, and pulmonary hypertension [24,25]. Furthermore two prospective cohort studies have reported a relationship between pulmonary hypertension and haemolytic anaemia severity [24,26].

One pathophysiological basis for pulmonary hypertension in SCD is through the effect of haemolysed cells on NO and arginase. NO regulates vasodilation via the stimulation of cGMP dependent protein kinases, it also decreases platelet aggregation, and inhibits the release of endothelin-1, the powerful vasoconstrictor [27,28]. RBC haemolysis causes haemoglobin and the arginase enzyme to enter plasma circulation. This free haemoglobin is a potent NO scavenger, hence acting to impede the vaso-protective qualities of NO. Additionally, arginase catabolises arginine which is required for NO synthesis, hence perpetuating the decreased NO bioavailability [29]. Downstream arginase metabolites further increases vascular proliferation, inflammatory stress, and overall endothelial dysfunction [30]. These homeostatic changes will produce pulmonary vascular endothelial remodelling and constriction, hence resulting in pulmonary hypertension.

Another danger to SCD patients is their increased susceptibility to many encapsulated bacterial infections and is a major cause of mortality and morbidity [31,32]. The primary factors allowing this predisposition to encapsulated bacteria are: post-infarct hypo- or asplenia, abnormal opsonin phagocytosis due to potential defects in the alternative complement pathway, and deficiencies of particular circulating antibodies [33]. Common SCD infections are from Haemophilus influenza, non-typhi Salmonella, and Streptococcus pneumoniae [31,34,35]. The polysaccharide capsule of these bacteria acts to prevent the binding of complement or inhibits complement communication with macrophage receptors [36].

Treatment

As previously described, the underlying mechanism in SCD pathology is the polymerising of deoxygenated HbS, all stemming from the single nucleotide mutation of the β-globin gene.

Numerous management and treatment options are described in medical literature such as RBC exchange transfusions, however, hydroxyurea – an antineoplastic agent – is the only approved pharmacological intervention that treats the underlying SCD pathology and will be discussed at length for the remainder of this paper [37]. Hydroxyurea was approved for therapeutic use in 1998 by the US Food and Drug Administration in SCD patients suffering from frequent painful crises [38]. Despite much evidence supporting the clinical efficacy for SCD hydroxyurea treatment, its HbF induction mechanism of action continues to be largely unknown [39].

Hydroxyurea is a short-acting cytotoxic ribonucleotide reductase inhibitor which acts to arrest S-phase cells by impairing their DNA replication [40]. It may therefore enhance HbF production indirectly, by killing rapidly proliferating late erythroid cells [41,42]. The recurrent pharmacological injury to the erythropoietic marrow from repeated drug administration results in enhanced erythropoiesis, this increases primitive erythroid precursor recruitment, consequently raising HbF levels [43]. Most of the beneficial effects of hydroxyurea are attributed to the HbF induction, however, clinical improvement has been observed before a marked increase in circulating HbF, which has led to the postulation of additional mechanisms of action, including decreased intercellular adhesion enhancing blood flow and increased NO bioavailability. Hydroxyurea metabolism is the cause of this increase in NO levels [41].

It has been known for some time that the primary effect of hydroxyurea, increased HbF levels, can ameliorate SCD [8]. This works by its reduction of RBC sickling because HbF replaces the mutated β-globin with a γ-globin chain which is non-pathological, hence decreasing the number of vaso-occlusive events and infarction. Even if an infarct occurs, the decreased circulating neutrophils from hydroxyurea administration may regulate the degree of tissue damage and pain felt [44]. There is also evidence that hydroxyurea generates NO and increased cGMP levels which causes the induction of foetal γ-globin mRNA and HbF protein [45].

Hydroxyurea has been shown to downregulate the expression of specific adhesion molecules on vascular endothelium [46]. This phenomenon is evidently independent of any of the SCD β-globin gene effects. Considering the importance that exposure to hypoxic capillary bed venules has on sickling, and consequently vaso-occlusive events, any reduction in endothelial-sickled RBC adhesion would have salutary effects.

Pregnancy is contraindicated with the use of hydroxyurea because it is known to have mutagenic, carcinogenic, and teratogenic effects in animals [47]. However, this relationship was not observed in 94 pregnancy outcomes of the human SCD patients that participated in hydroxyurea drug trials that despite precautions became pregnant mid-trial [47]. This suggests the foetal exposure to therapeutic hydroxyurea may not be teratogenic. Conversely, another study indicated abnormal sperm parameters in males taking hydroxyurea that possibly could have teratogenic effects or cause infertility [48]. It is important to note, however, that most individuals in this study had abnormal sperm prior to commencing hydroxyurea treatment, thus it was difficult to establish the precise contribution of hydroxyurea. Therefore, considerably more research and follow up time should be allocated to pregnant SCD subjects exposed to hydroxyurea to determine definitive results.

At present, there have only been 5 randomised control trials conducted regarding the efficacy of hydroxyurea treatment in patients with sickle cell anaemia. Of these, all except the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial indicated benefit for hydroxyurea treatment over the standard of care [49-53]. Study sizes range between 44 and 299 participants. The results from these studies described reduced vaso-occlusive crises, pulmonary pathologies, and blood transfusion frequencies in those receiving hydroxyurea treatment (Table 1) [49,50,52,53].

**Table 1. SCD hydroxyurea randomised control trials.**
Abbreviations: HU = hydroxyurea, y = year, SCA = sickle cell anaemia, VOC = vaso-occlusive crisis, ACS = acute chest syndrome, Hx = history, mo = months, MTD = maximum tolerated dose.

The Belgian paediatric randomised control trial showed that hydroxyurea treatment resulted in statistically significant increases in levels of HbF and decreased both hospitalisations and vaso-occlusive events when compared to the placebo [49]. Wang and associates found that although changes in renal and splenic function were insignificant, there were statistically relevant decreases in vaso-occlusive events, hospitalisations, and the number of blood transfusions required [52]. A small Indian based study also reported that children treated with hydroxyurea experienced decreased numbers of vaso-occlusive events, hospitalisations, and blood transfusions required, despite the low doses of drug administered [50]. The findings from the Multicentre Study of Hydroxyurea, conducted by Charache et al [53], too demonstrated decreased incidents of vaso-occlusion, hospitalisations, and required transfusions compared to the placebo. However, in Charache et al [53], results were compromised by the substantial loss to follow up, with only 134 of the initial 299 participants completing the full 2-year trial.

At present no phase 3 randomised control trials are enrolling individuals with different genotypes to HbSS and HbS/β° thalassaemia [38]. However, two cohort studies from Italy and Greece have shown that hydroxyurea efficacy observed in HbSS individuals also extends to those with HbS/β+ thalassaemia [54,55]. However, this hydroxyurea recommendation is weak due to the limited sample population when likened to the size of HbSS data.

Conclusion

To conclude, this literature review has discussed the normal physiology of haemoglobin, pathogenesis of sickle cell disease as well as its course of treatment. It was found this haemoglobinopathy is responsible for vaso-occlusive crises, pulmonary pathologies, and increased susceptibility to infection. Nonetheless, hydroxyurea was reviewed as a potential treatment option. Hydroxyurea has multiple posited mechanisms of action but more importantly is the only SCD treatment that targets the underlying pathology. There is opportunity for future research into both the exact hydroxyurea mechanism of action in SCD patients and hydroxyurea efficacy and dangers when used to treat SCD patients expressing one of the rare genotypes. Thus, to summarise, SCD is a complex hereditary disorder in which for a medical practitioner to effectively manage requires a comprehensive understanding of both normal haemoglobin physiology and its pathophysiology.

Conflict of interest
None declared.

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Tags sickle cell disease, hydroxyurea, haematology

Undertaking a medical elective in Peru: a student’s perspective

Post author By Website Publications Officer
Post date April 16, 2018

I chose to undertake a Work the World placement as I wanted to get a feel for how healthcare operates in countries that have less funding and fewer resources than Australia. Like many students, I had also been bitten by the travel bug. I wanted to get out and see the world. A Work the World placement allowed me to experience Peruvian medicine in a supported way, and meant I could observe and interact with healthcare delivery without feeling like I was stepping outside my role or acting above my qualifications, which was very important to me.

I had already organised to travel to the USA from Australia with family over Christmas and the New Year, so I decided it would be a good time to visit South America. I’ve always been interested in history, so I was attracted to Peru’s Incan and pre-Incan ruins, like Machu Picchu. I also liked the idea of gaining some new language skills while overseas.

I’m also interested in women’s health as a career path, and I think part of what makes care in Australia so effective is that we are very secular in our healthcare delivery. Latin America is predominantly Catholic, and their healthcare is very much influenced by their religion, especially when it comes to women’s health interventions like contraception and termination. I wanted to discover how these beliefs affect health outcomes for women.

When I arrived in Peru, I was both excited and nervous. My previous travels around South America had introduced me to new people and places, but my actual time in these countries was limited. This time, I was spending six weeks in one place!

The first 24 hours in Arequipa were great. Raul, part of the local Work the World team, met me at the airport and we took a taxi back to the house. Another student had also flown in that day and was waiting at the house when we arrived. A further five people from the US were due to arrive an hour later. All the students who had started their placements earlier were away on weekend trips, as our placements were from Monday to Friday. I was then taken on a tour of the house, shown our rooms, a map of the city, and how to get to our local shopping centre. After a while, the additional new students arrived, and we met Mama Julia and Angelo, our in-house chefs. We all had a quiet night getting to know each other.

As I had booked to do the Work the World intensive Spanish course, the following morning Raul caught the bus to Spanish school with us. There we met Maria, the wonderful, patient, and friendly language teacher. We spent the morning getting to grips with Spanish before Raul returned to take us into the centre of Arequipa on our city orientation. He took us out for lunch and on a walking tour to help us get to know the beautiful ‘White City’.

The house was fantastic; it had all the amenities you could want. I always felt safe, as there was always a Work the World staff member onsite. But most importantly, the friends I made at the house were the highlight of my trip. I can now say I have friends on almost every continent! Everyone got along very well, and we enjoyed doing lots of different activities together, from cooking classes and white water rafting, to weekend hiking trips, late-night karaoke, and dancing in the town square. Some friends left the house sooner than others, as we didn’t all stay for the same amount of time, but I’m so glad to have met all my former housemates, even the ones I only lived with for a week.

When arriving at the hospital for the first time, my immediate reaction was, “it looks like a convent!” The hospital was old, and there weren’t any segregated rooms. All the patients in the obstetrics and gynaecology ward were in beds next to each other, without separating walls, or even dividing curtains for privacy.

I spent a week in oncology and cancer prevention, where I learnt about cervical cancer screening methods from the midwives, as well as seeing cases of cervical cancer. Screening in Peru involves pap smears, but also regular screening with acetic acid under colposcopy, which is not standard practice in my state in Australia. They also do a lot of ‘freezing’ of cervical lesions, whereas in Australia we’re more likely to favour lower loop excision of the transformation zone (LLETZ) procedures for recurrent or high-grade lesions. Screening techniques and the Gardasil vaccine (also available in Peru) have largely decreased cervical cancer morbidity and mortality in Australia, and cases are detected early.

In Peru, many women never undergo screening, as they do not have the means to attend clinics for preventative care. As such, women commonly present late in the disease process. Unfortunately I saw multiple cases of cervical cancer so advanced that the cervical appearance would not feature on a grading scale in Australia, because it would never go so long undetected. This was fascinating as a scholar, but hard to observe on a personal level.

In some situations I’d help with things like moving the light for the midwife during a birth, or passing equipment. Under supervision in oncology, I was able to palpate some lumps, discuss X-rays with the consultant, and assist with a cervical biopsy. The more enthusiasm you show, the more you’ll be able to do.

Being in the hospital in Peru made me realise how lucky Australia is to have things we consider disposable, like shoe covers and hair nets. Shoe covers are reused until they are falling apart in Arequipa. Everything is re-purposed there. In Arequipa, patients are required to pay for everything, right down to the sterile gloves the surgeon wears in the theatre, the needles required to cannulate and administer medicines and analgesia, even the saline drip!

We travelled almost every weekend, taking trips to Colca Canyon, Cuzco, Machu Picchu, Lake Titicaca, and the Nazca lines. Most things are just an overnight bus ride away. Colca Canyon was only three hours from the accommodation, and Lake Titicaca only six. The Work the World staff also gave us tips on how to organise cooking classes, chocolate-making sessions, and many other wonderful activities. What I loved most about Peru was the dancing and the music! Some of the food, like lomo saltado, was amazing. Other cuisine, such as Cuy (guinea pig), was not for me!

It’s too difficult to pick my favourite memory, but special mention has to go to our regular Taco Tuesday whole-house lunches at a restaurant near our house. And I will always remember the first time someone didn’t reply to me in English after I tried to order in Spanish — the ultimate ‘gringa’ compliment!

If you’re considering doing a Work the World placement in Peru, I say: do it! Prepare to have the time of your life. Everyone is so friendly and so happy to have you visiting their country. Oh, and make sure you haggle with the taxi drivers!

Work the World specialise in tailoring overseas healthcare electives and placements in Cambodia, Ghana, Tanzania, Peru, Nepal, Sri Lanka and the Philippines. Each of our destinations provide unique and exciting insight into healthcare in the developing world.

Enquire via www.worktheworld.com.au or chat to us on +61 3 7000 6007.

Book Reviews

Balanda: My Year in Arnhem Land

Post author By Website Publications Officer
Post date April 16, 2018

Book Review

Balanda: My Year in Arnhem Land

In a nation often eager to present a whitewashed version of Australian history, Mary Ellen Jordan gives us an uncomfortable, yet refreshingly honest account of her experiences living in a remote Indigenous community for 14 months. Balanda: My Year in Arnhem Land [1] follows her experience, highlighting the stark social and cultural divisions between Indigenous and non-Indigenous Australians. This book recounts Jordan’s time at the Community Art Centre in Maningrida, a 2,300 strong coastal Aboriginal community in the heart of Arnhem Land in the Northern Territory [2]. Having previously lived and worked as an editor in Melbourne, Jordan’s role in Maningrida is to organise the community art centre and work on a bilingual dictionary including English and the local Indigenous language.

One can only learn so much about Aboriginal culture in a medical school lecture theatre. Guest lecturers, workshops in Australia’s history, and explanations of Aboriginal culture as ‘deeply spiritual’ reward us with only a broad, generalised view of what is, in reality, a diverse collection of tribes, languages, and individuals. The impact of these diverse cultures on diagnosis and treatment is often only touched upon, or otherwise described only in general terms.

Despite accounting for 3.7% of total health expenditure, the Close The Gap initiative of 2008 is failing [3,4]. There is an average life expectancy gap of ten years between Indigenous and non-Indigenous Australians, a 2.5 times greater disease burden, and disproportionate incidences of preventable diseases such as rheumatic heart disease and trachoma in Aboriginal and Torres Strait Islander populations [5]. Furthermore, the ultimate goal of Closing the Gap between Aboriginal and non-Aboriginal Australia in terms of culture is not always clear. Is it a covert attempt to achieve Western assimilation? Or an endeavour to preserve a culture already re-shaped by the influences of a dominant white culture?

In remote Maningrida, a sense of cultural alienation results in a type of split community, where “there is very little crossover between the two cultures, although [they] live side-by-side [1].” Balanda aims to investigate the involvement of white Australians in Aboriginal communities as ‘modern day missionaries’, a resonant phrase for medical students considering placements or working in an Aboriginal community. While Jordan’s inability to offer a solution to the social determinants of health may frustrate readers, it reinforces her sense of helplessness regarding the complexity of the current situation for Indigenous people and cross-cultural communication.

Confronting and critical, Jordan’s recount lingers in the reader’s mind long after the covers are closed. Questions regarding what it means to be non-Indigenous in a country built on dispossession are raised and not always answered clearly. For medical students inexperienced with Indigenous cultures, these questions are unsettling. Jordan describes the healthcare system as an imposition of one culture onto another, in which health practices are taught based on the Western model of medicine rather than Aboriginal tradition. To her, the “unspoken…unintentional assimilation [1]” of healthcare delivery is often administered in a paternalistic fashion, in which Aboriginal people are prevented from taking responsibility for themselves and their community.

Integration and success have been noted, however, in the example of Aboriginal Community Controlled Health Services (ACCHS) [6]. These services, offering general practice, allied health, antenatal care, and support programs deliver holistic and culturally appropriate primary healthcare. ACCHS exist as autonomous organisations initiated by Indigenous communities and governed by a locally elected board. These services overcome trends of non-participation and tokenism by engaging the community through partnership, self-determination, and community ownership. For these services to succeed, building community capacity, addressing risk factors, and implementing evidence-based strategies to address social determinants is necessary.

Health practitioners and medical students may well feel intimidated by the candid accounts of the communication challenges faced by Jordan, such as differences in verbal and non-verbal language, and social organisation. Jordan’s recognition of her difficulties in cross-cultural communication highlights how bridging two disparate cultures can pose a major impediment to clinical practice.

Practitioners and students, however, should not to be dismayed or dissuaded by Jordan’s cynicism. Rather, this book encourages us to reflect on how our own beliefs and social milieu shape how we act towards others, and in turn, form partnerships that celebrate diversity. The author’s insights and experiences can be used to formulate inventive and novel approaches to addressing health disparities, and help prepare for both the inevitable frustrations and rewards experienced when working with such a unique and ancient culture.

Acknowledgements
Dr Tarun Sen Gupta, the Lynn Kratcha Memorial Bursary selection committee, and the staff of the University of Saskatchewan for making my placement in Canadian rural Indigenous communities a success.

Conflict of interest
None declared.

References

[1] Jordan ME. Balanda: my year in Arnhem Land. Australia: Allen & Unwin; 2005.

[2] Maningrida Demographics (NT) [Internet]. Australian Bureau of Statistics; 2011 [cited 2016 Jul 1]. Available from: http://maningrida.localstats.com.au/population/nt/northern-territory/darwin/maningrida

[3] Australian Government Department of the Prime Minister and Cabinet. Closing the gap: Prime Minister’s report 2017. In: Department of the Prime Minister and Cabinet, ed: Commonwealth of Australia 2017; 2017.

[4] Aboriginal and Torres Strait Islander Social Justice Commissioner. Close the gap: statement of intent [Internet]. 2008 [cited 2016 Jul 1]. Available from: https://www.humanrights.gov.au/publications/close-gap-indigenous-health-equality-summit-statement-intent

[5] Australian Institute of Health and Welfare. Indigenous health profile 2014 [Internet]. 2014 [cited 2017 Apr 11]. Available from: http://www.aihw.gov.au/australias-health/2014/indigenous-health/.

[6] Panaretto KS, Wenitong M, Button S, Ring IT. Aboriginal community controlled health services: leading the way in primary care. Med J Aust. 2014;200(11):649-652. doi:10.5694/mja.00005

Case Reports

The rare case of a pelvic abscess following caesarean section in a Sri Lankan woman: an argument for medical student electives

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Introduction: A pelvic abscess is a rare complication that can occur following gynaecological and obstetric procedures. Whilst the condition is not confined geographically, women in less developed countries are at an increased risk of developing this complication, due in part to low resource settings, socioeconomic status, and educational attainment.

Case: A 36 year old primigravid woman in rural Sri Lanka undergoing a non-emergency caesarean section delivery developed clinical signs of puerperal sepsis two days postpartum. Following transfer to a tertiary hospital, imaging and laparotomy confirmed the presence of a pelvic abscess associated with the caesarean section wound. Surgical drainage was performed and IV antibiotics were administered, ultimately resulting in the full recovery of the patient. The infant did not demonstrate clinical signs of sepsis at birth.

Discussion: Numerous factors contributed to the development of this serious complication in this patient, including increased maternal age at first pregnancy, caesarean section management, and the low resource setting of the patient’s care. This case also highlights the difficulties and barriers facing patients and doctors in less developed countries, including that of patient transfers from a rural setting and the availability of specific antibiotics recommended in clinical guidelines. The barriers to optimal care faced by this woman are largely disconnected from the experiences of patients that Australian medical students see in their day-to-day training. Overseas electives to low resource areas should be required and supported amongst all Australian medical students to facilitate greater appreciation for such barriers and to foster their skills in resourcefulness and empathy.

Introduction

As a demonstration of the public health issues and associated complications that arise in less developed countries, the following presents a rare case of pelvic abscess formation following caesarean section delivery. This is written from the perspective of an Australian medical student on an obstetrics and gynaecology elective in rural Sri Lanka.

Pelvic abscess is considered a rare complication of pelvic surgery, affecting less than 1% of women undergoing any obstetric or gynaecological procedure [1]. The implications of such a complication are more significant when they occur in a low resource setting, such as Sri Lanka [2]. Data suggest puerperal sepsis accounts for 11.6% of maternal mortality in such settings, compared with 2.1% in developed countries [3]. A range of factors contribute to the risk of puerperal sepsis and pelvic abscess, including increasing maternal age at first pregnancy, high caeserean section rates, and low socioeconomic and educational status, all well-documented factors present in this patient and their demographic [2,4,5]. Whilst pelvic abscess is a complication that has no geographical boundaries, women in less developed countries are at increased risk of dying from this complication [3]. This is likely compounded by sub-optimal infection control and limited access to resources, including trained midwifery and obstetric care [2]. This is reflected in the high rate of hospital-acquired infections, up to 50%, resulting from surgical site wounds [3]. Despite the high morbidity and mortality of pelvic abscesses and puerperal sepsis, the actual incidence of both conditions is poorly defined [3]. The following case exemplifies some of these challenges.

Case

A 36 year old primigravid woman underwent a caesarean section with no immediate surgical complications, in the setting of a reportedly uneventful pregnancy. Surgery was performed at a local rural hospital in Sri Lanka, approximately three to four hours by road transfer from the capital, Colombo. The reason for caesarean section was unclear; however, it was understood that the caesarean section was performed in a non-emergency setting. Two days postpartum, the woman developed fever (temperature not specified) and complained of a triad of foul-smelling and purulent lochia, abdominal distension, and dyspnoea, according to the patient and her family. The patient was denied transfer by the treating hospital, and so the family arranged private transportation to a tertiary centre in Colombo. She arrived in a state of septic shock: mildly hypothermic (36.0˚C), tachypnoeic (45 breaths/min), hypertensive (150/100 mmHg), tachycardic (150 beats/min), and cyanotic with significant generalised oedema. Computerised tomography of the abdomen and pelvis identified abscess formation anterior to the uterine sutures and significant fluid in the peritoneal cavity. An emergency laparotomy was performed. A dehiscence of her uterine scar was repaired and two litres of pus was drained. The fluid cultured positive for Group B beta-haemolytic Streptococcus, sensitive to vancomycin. The patient was subsequently commenced on intravenous antibiotics (vancomycin, metronidazole, and meropenem) post-operatively.

Following surgery, hyperglycaemia (180-250 mg/dL) and hypertension (160/110 mmHg) persisted for some weeks, with recovery complicated by a secondary wound infection requiring additional antibiotics (flucloxacillin and metronidazole) and a second laparotomy. Mother and baby ultimately recovered completely, with no clinical signs of postnatal sepsis reported in the child. Clinical guidelines for puerperal sepsis recommend a combination of broad-spectrum antibiotics, targeting the common polymicrobial sources, including anaerobic organisms (E. coli and S. pyogenes), and surgical abscess drainage [5,6]. This case failed to utilise the recommended first-line empirical antibiotics. Poor antibiotic practices, unreliable antibiotic supplies, and a lack of adequate medication delivery protocols are cited as common reasons for increasing rates of puerperal sepsis in the developing world, with one or more of these factors potentially influencing antibiotic choice in this case [2,4].

Discussion

Although the woman had a full recovery, this case serves as a reminder of the seriousness of obstetric complications, and how they may be compounded by geographical factors and a paucity of adequate medical resources. This case offered significant opportunity for learning and personal reflection. Primarily, I was able to recognise that the outcomes of childbirth and postnatal care in less developed countries may be vastly different to such events occurring in Australia. Some of the difficulties I observed included inadequate systems for medical documentation, and communication of results and information for clinical handover. The disparity in access to such basic resources is alarming, and I believe all medical professionals should be angry about such injustices. To fully understand this degree of inequality, however, it required the immersive experience of an elective term in Sri Lanka. Based on my own experience, I would strongly recommend an overseas elective as a mandatory component of any Australian medical degree. This could be a useful step in helping Australian graduates to become more resourceful. In addition, it will help our graduates recognise the importance of an effective and well-resourced, high-quality health system in achieving the best health outcomes for our patients.

Consent declaration
Informed consent was obtained from the patient for publication of this case report.

Acknowledgements
Dr Roshan Zaid (consultant obstetrician and gynaecologist, Nawaloka Hospital, Colombo, Sri Lanka), a senior consultant involved in the above patient’s care, who provided clinical advice and support in compiling this report.

Financial assistance for this elective was provided in the form of a bursary from the University of Melbourne.

Conflict of interest
None declared.

References

Mahdi H, Goodrich S, Lockhart D, DeBernardo R, Moslemi-Kebria M. Predictors of surgical site infection in women undergoing hysterectomy for benign gynecologic disease: a multicenter analysis using the national surgical quality improvement data. J Minim Invasive Gynecol. 2014;21(5):901-9.
Buddeberg BS, Aveling W. Puerperal sepsis in the 21st century: progress, new challenges and the situation worldwide. Postgrad Med J. 2015;91(1080):572-8
Hussein J, Walker L. Puerperal sepsis in low- and middle-income settings: past, present and future. In: Kehoe S, Neilson J, Norman J, editors. Maternal and infant deaths – chasing millennium development goals 4 and 5. Cambridge: Cambridge University Press; 2010.
Knowles S, O’sullivan N, Meenan A, Hanniffy R, Robson M. Maternal sepsis incidence, aetiology and outcome for mother and fetus: a prospective study. BJOG. 2015;122(5):663-71.
The World Health Organisation. Managing puerperal sepsis – midwifery education module 4: avoidable factors. 2nd ed. Geneva: The WHO Press; 2008.
The Royal College of Obstetrics and Gynaecology. Bacterial sepsis following pregnancy. Green-top Guideline No. 64B [Internet]. 2012 [cited 2016 Nov]. Available from: https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg64b/

Tags Pelvic Abscess, Puerperal Sepsis, Post-Partum Sepsis, International Health

Review Articles

Novel neuroprotective pathways of remote ischaemic post-conditioning in models of cerebral ischemia reperfusion injury

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Introduction: This article aims to provide a narrative review of the most recent primary literature on the pathways associated with the neuroprotective effects of remote ischaemic post-conditioning (RIPC) in stroke and discuss the prospect for application in the clinical setting.

Summary: This narrative review identified multiple pre-clinical in-vivo studies. These studies found that RIPC modulates a wide variety of pathways within the brain, including those associated with inflammation, reactive oxygen species (ROS) production, antioxidant regulation, and oedema development. Modulation of these pathways was associated with a significant reduction in the neuronal damage, a finding supported by measured reductions in cerebral infarct volume and apoptotic neuronal populations. Clinical research was limited; only one trial on RIPC in stroke was discovered. Whilst the results were positive the small sample size of the study does not make them definitive.

RIPC as an intervention for ischaemia reperfusion injury (IRI) in stroke has been found to be considerably effective in animal models, stimulating a wide variety of neuroprotective pathways. The limited clinical research has not yet been able to confirm RIPC efficacy in human stroke models but should be a catalyst for further research.

Introduction

Cerebrovascular disease constitutes the third greatest cause of mortality in the Australian population, with 23 people dying from a stroke every day [1]. Ischaemic stroke occurs when an artery, supplying a particular area of the brain, is blocked by an embolus, starving neuronal tissue of oxygen and resulting in permanent damage of the local area [2]. Treatment for ischaemic stroke usually involves thrombolysis which dissolves the embolus and restores blood supply to the ischaemic area [1]. Although reperfusion is a critical intervention, it is also associated with a spike in neuronal cell damage, in a phenomena known as ischaemia reperfusion injury (IRI) [2,3]. In recent years, considerable effort has gone into developing ways to limit the impact of IRI. One promising therapy is remote ischaemic conditioning (RIC) [4].

The principle of RIC is to expose the brain to a series of sub-lethal cycles of ischaemia and reperfusion through intermittent vascular occlusion of another distant and accessible organ such as the upper or lower limb [5]. Transient ischaemia performed in this manner is known to activate several endogenous neuroprotective pathways which reduce the damage associated with an IRI [5,6]. RIC can be performed before the onset of ischaemia (“pre-conditioning”), during the ischaemic event (“per-conditioning”), and after reperfusion (“post-conditioning”) [5]. By their very nature, both pre- and per-conditioning require pre-emptive action which is simply not practical in the health care setting. As such, this review focuses on remote ischaemic post-conditioning (RIPC) performed on the femoral artery in the time immediately following a stroke [7]. This review will explore and integrate the pre-clinical literature surrounding the neuroprotective pathways of RIPC and thus produce a narrative on how this novel intervention acts on a molecular level, and how it may translate to clinical medicine.

Ischaemia reperfusion injury

IRI is a multi-faceted process, in which reperfusion is associated with cellular death, rather than the restoration of normal function. This abnormal response is a consequence of the ischaemia induced dysregulation of cellular function [8]. One such example is the dysfunction of the Na+/K+ ATPase which triggers the accumulation of intracellular sodium. Sodium accumulation is an initiator for a series of events including calcium overload, excitotoxicity, acidosis, cellular swelling, and the initiation of apoptosis [4].

Another event which occurs during prolonged ischaemia is damage and dysregulation of the mitochondrial electron transport chain (ETC). Once a cell undergoes reperfusion, the ETC will again utilise oxygen to try to produce ATP. However, due to extensive damage, a high proportion of this oxygen will instead be metabolised to form reactive oxygen species (ROS) [9]. The excessive ROS production overwhelms the brain’s anti-oxidant system, resulting in lipid peroxidation, dysregulation of proteins, DNA damage, and alterations in transcription [8].

Ischaemia also has the effect of priming the endothelium for leukocyte recruitment through increasing adhesion molecules and the transcription of pro-inflammatory factors, such as NFκB. Upon reperfusion, these adaptations will stimulate the recruitment of neutrophils to the ischaemic area, where they will release ROS and further exacerbate oxidative damage and cell death [10].

**Figure 1. Basic inflammatory pathways resulting in apoptosis and necrosis of neuronal tissue in IRI [2-8].** ETC, Electron transport chain; ROS, Reactive oxygen species; NFκB, Nuclear factor κB.

Collectively, these effects of cellular dysfunction, ROS production and inflammation result in the death and destruction of neurons even after blood supply has been restored (Figure 1). Whilst little can be done about the tissue destroyed by the initial ischaemic event, a reduction in IRI may have the potential to prevent the death of otherwise salvageable neurons [2,3].

Discussion

HIF1a/TIM3 axis in the initiation of inflammation

Inflammation is a key contributor to the damage associated with IRI, with the recruitment of leukocytes responsible for the substantial production of ROS and cytokines [10]. The inflammatory response of cerebral IRI is thought to be mediated in part by Hypoxia Inducible Factor 1a (HIF1a), which is activated and up-regulated during and after cerebral ischaemia [11]. Zong et al [11] investigated the effects of RIPC on HIF1a, discovering that RIPC significantly reduced the expression of HIF1a when compared to the control group one day post reperfusion. These results correlated with a 10.3% reduction in cerebral infarct volume [11], suggesting that HIF1a is an important target in the neuro-protective effects of RIPC [11,12].

The mechanism in which HIF1a mediates its downstream effects is still a topic of some speculation [11,12]. Recent research by Koh et al [13] investigated how HIF1a interacts with another downstream signalling molecule, TIM3. It was found that in response to hypoxia, HIF1a binds to the TIM3 prompter region to increase its expression. Increased TIM3 up-regulates the inflammatory cytokines IL1b and CXCL1 (Figure 2) [13]. Blockage of TIM3 activity by monoclonal antibodies showed a significant reduction in the expression of both these cytokines as well as a substantial reduction in cerebral infarct volume. The findings of Zong et al [11] and Koh et al [13] suggest that RIPC exerts its neuro-protective effect via inhibition of HIF1a; subsequently resulting in down-regulation of TIM3 and reduction in cytokine and ROS production [10-13].

**Figure 2. Activation of the HIF1α/TIM3 axis producing inflammatory cytokines and neutrophil recruitment [11-13].** HIF1α, Hypoxia inducible factor 1α; TIM3, T-cell immunoglobulin and mucin domain protein 3; IL1-β, Interleukin 1β; CXCL1, Chemokine CXC ligand 1; ROS, Reactive oxygen species.

PKCd, JAK2/STAT 3 and P38 MAPK apoptotic pathways

Apoptosis is a process of organised cell death, triggered by an extensive number of signalling cascades. One well known example involves PKCd, an intracellular enzyme, activated by cell stress to initiate apoptosis [14]. It has been extensively reported that RIPC exerts an anti-apoptotic effect via reduction of PKCd expression [3,5,14]. However, recent research has investigated several additional pathways which may be involved in the anti-apoptotic effects of RIPC. One such pathway is the JAK2/STAT3 axis which has been found to attenuate apoptosis in multiple models of IRI [15,16]. Cheng et al [17] recently investigated the potential effects of RIPC on JAK2/STAT3, finding that it was associated with a significant increase in both JAK2 activity and STAT3 protein expression. The increase in STAT3 expression results in the transcription of anti-apoptotic Bcl2 family proteins, which inhibit the formation of Bax channels and the initiation of apoptosis [15-17].

As well as its effect on anti-apoptotic signalling, Cheng et al [17] also demonstrated that RIPC was potentially involved in the JAK2/STAT3 mediated inhibition of NFkB. The inhibition of NFkB results in the reduction of pro-inflammatory cytokines such as IL1b and TNFa; subsequently reducing recruitment of neutrophils and other leukocytes to the brain [3,17]. The collective effects of RIPC on JAK2/STAT3 mediated reduction of inflammation and apoptosis, resulted in a 13.2% reduction in rodent cerebral infarct volume when compared to the IRI control group (Figure 3) [17].

Figure 3. RIPC mediated activation of the JAK2/STAT3 pathway causing inhibition of pro-apoptotic and pro-inflammatory pathways [15-17]. LRIPC, Limb remote ischaemic post-conditioning; JAK2, Janus kinase 2; STAT3, Signal transducer and activator of transcription 3; IL1β, Interleukin 1β; TNFα, Tissue necrosis factor α.

Another recently investigated apoptotic pathway involves the p38MAPK enzyme, responsible for phosphorylation of downstream signalling molecules in response to cellular stress [18]. Li et al [19] investigated the effects of RIPC on p38MAPK on in vivo rodent models. They found that the RIPC intervention was associated with down-regulation of this enzyme as well as a reduction in IRI induced apoptotic neuron populations. Li et al [19] proposed that the attenuation of apoptosis occurred through the RIPC/p38 MAPK mediated reduction of the transcription factor ATF2. How this reduction in ATF2 results in an anti-apoptotic effect is, however, unclear. Other conflicting literature has found that it is the up-regulation of ATF2 which is associated with Bcl2 production, and hence a reduction in apoptosis [20,21]. Although the exact mechanism remains a topic of speculation, many studies do support this study’s conclusion that P38 MAPK down-regulation is associated with a reduction in apoptosis [18-21].

PI3k/Akt and eNOS uncoupling

Endothelial nitric oxide synthase (eNOS) is responsible for the physiological production of nitric oxide (NO), a key regulator of normal endothelial cell function. During IRI eNOS can become uncoupled and as a result transfer its electrons to an oxygen molecule to produce superoxide free radicals [22]. These superoxide radicals can cause direct cellular damage but can also combine with NO to produce peroxynitrite, a highly destructive reactive nitrogen species (RNS) which suppresses protein function in the same way as ROS [8,22].

The process of eNOS uncoupling is thought to result from both ROS mediated damage and the depletion of the eNOS substrate BH₄[22,23]. Chen et al [22] investigated the capacity of RIPC to attenuate these effects; finding that it was associated with both an increase in BH₄ availability, as well as a reduction in ROS (through inhibiting transcription of NADPH oxidase and xanthine oxidase). The RIPC mediated inhibition of eNOS uncoupling resulted in a significant reduction in peroxynitrite levels, as well as a 15.1% reduction in cerebral infarct volume when compared to the control group [22].

RIPC has also been found to directly increase the synthesis of the eNOS enzyme, leading to higher levels of NO during reperfusion [22,24,25]. It is thought that this effect may be associated with the RIPC induced up-regulation of the PI3k enzyme, which triggers phosphorylation of the protein kinase B (Akt) transcription factor. Akt is an important anti-apoptotic signalling factor, which is also thought to upregulate eNOS transcription [24,25]. The increased production of eNOS increases the quantity of NO produced within the ischaemic brain; this promotes vasodilation and reduces inflammation and thrombosis [22,24]. Furthermore, the reduction in eNOS uncoupling increases the proportion of NO to superoxide radicals produced [22]. Hence, it appears that RIPC works synergistically to upregulate eNOS transcription whilst reducing uncoupling, resulting in an increase in NO and reduction in ROS and RNS [8,22-25].

Nrf-Antioxidant response element (ARE) pathway

Small amounts of ROS are produced in normal physiological processes, but cause no damage because they are rapidly neutralised by cellular antioxidants. The excessive ROS production in IRI overwhelms the antioxidant system and leads to extensive cellular damage [8,26]. Li et al [26] investigated the effects of RIPC on the Nrf2-ARE pathway. It was found that RIPC increased the activity of Nrf2 which subsequently increased ARE transcription [26]. ARE increases the production of the antioxidant molecules SOD, HO1, and NQO1 which, through a range of different cellular processes, neutralise oxygen free radicals into less reactive substrates (Figure 4) [27,28]. RIPC mediated neutralisation of ROS correlated with a significant reduction in MDA (a lipid peroxidation marker), as well as a 16.9% reduction in cerebral infarct volume compared to the control group [26].

**Figure 4. RIPC mediated activation of Nrf2/ARE axis producing anti-oxidising agents to neutralise reactive oxygen species [26].** LRIPC, Limb remote ischaemic post-conditioning; SOD, Superoxide dismutase; HO1, Heme oxygenase 1; NQO1, NAD(P)H quinone dehydrogenase; Nrf2, Nuclear factor erythroid 2-related factor 2; ARE, Antioxidant response element.

AQP4 and ROS in formation of cerebral oedema

ATP deficiency during the period of ischaemic stroke triggers dysfunction of the Na+/K+ ATPase, accumulation of intracellular sodium, and influx of water into the astrocytes. Fluid accumulation within the astrocyte produces cytotoxic oedema, an event which results in death and destruction of nearby tissue [3,4]. Recent research has shown that this influx of water during IRI is likely mediated by the aquaporin 4 (AQP4) channels [29]. Li et al [30] has found that RIPC can reduce the expression of AQP4 channels in the brain following reperfusion, thus reducing the influx of water into the astrocytes. Reduction in astrocyte swelling was found to attenuate cytotoxic oedema formation, resulting in a 15.0% reduction in rodent cerebral infarct volume compared to the control group [30].

Cytotoxic oedema usually occurs in the earlier stages of IRI, when the blood-brain barrier (BBB) is still intact [3,4]. Later in disease progression, there is an increased production of ROS through the mechanisms which have previously been discussed [22,24,26,31]. ROS have been found to mediate BBB damage through oxidative damage, tight junction modification, and activation of matrix metalloproteinases (MMP) [32]. As a result of these events, BBB permeability increases, leading to influx of fluid into the neuronal extracellular space in an event called vasogenic oedema [31,32]. Li et al [30] demonstrated that RIPC may reduce BBB permeability and hence reduce vasogenic oedema: a finding supported by another study investigating RIPC in carotid stenosis [33]. RIPC most likely reduces BBB permeability through a variety of pathways targeting inflammation, ROS and antioxidant production that may all impact the integrity of the vascular endothelium or initiate endothelial dysfunction [29-33].

Integrating the pathways

RIPC is an expanding field with more pathways being discovered each year. As this occurs, it is important to know how each pathway relates to another (Figure 5).

**Figure 5. Interconnection of the neuroprotective pathways proposed for RIPC, ultimately leading to reductions in apoptosis, necrosis and neuronal cell death, post reperfusion [11-33].** LRIPC, Limb remote ischaemic post-conditioning; SOD, Superoxide dismutase; HO1, Heme oxygenase 1; NQO1, NAD(P)H quinone dehydrogenase; Nrf2, Nuclear factor erythroid 2-related factor 2; ARE, Antioxidant response element; JAK2, Janus kinase 2; STAT3, Signal transducer and activator of transcription 3; IL1β, Interleukin 1β; TNFα, Tissue necrosis factor α; HIF 1α, Hypoxia inducible factor 1α; TIM3, T-cell immunoglobulin and mucin domain protein 3; CXCL1, Chemokine CXC ligand 1; ROS, Reactive oxygen species; ETC, Electron transport chain; NFκB, Nuclear factor κB; GTPCH, GTP cyclohydrolase I; BH4, tetrahydrobiopterin; AQP4, aquaporin 4; P38MAPK, p38 mitogen-activated protein kinase; PI3K, phosphoinositide 3 kinase; Akt, Protein kinase B; PKCδ, Protein kinase C δ; eNOS, Endothelial nitric oxide synthase.

RIPC in the clinical setting

The application of RIPC in animal cerebral ischaemia models has been demonstrated to be safe and efficacious, reducing cerebral infarct volume and apoptotic neuronal populations substantially (Table 1) [5,7,34].

Table 1. Results from pre-clinical trials.

Whilst the preclinical evidence for RIPC is convincing, there is still a large gap in the translation to clinical trials. In May of 2017, the results of the RECAST trial were published. This phase I pilot blinded placebo controlled trial involved 26 patients with ischaemic stroke, 13 of whom were given the RIPC intervention within 24 hours of ischaemic stroke. Whilst small, this pilot study found that RIPC was very well tolerated, safe, and feasible in the clinical setting. Furthermore, RIPC was found to provide significant improvements in neurological function when compared to the control group [35]. As the only study published of its kind, the evidence for RIPC in stroke is still tentative, however, a recent meta-analysis on the use of RIPC in acute coronary syndrome has provided some more firm results. The analysis of 13 clinical trials demonstrated that RIPC was effective in reducing infarct size, reperfusion injury, and improving patient outcomes post myocardial infarction [36]. These recent publications provide a convincing argument for the further clinical exploration of how RIPC can be utilised in patients who suffer from ischaemic stroke.

Current gaps

Confusion surrounding the molecular mechanism of RIPC primarily pertain to a gap in understanding how an episode of ischaemia in the lower limb can result in an increased expression of neuro-protective factors within the brain [6]. Current research, predominantly conducted on cardiac models, suggests that this effect is likely achieved through multiple neurological, humoral, and immune events. How these mechanisms relate to ischaemic stroke and how they result in such diverse effects is still unknown [6,37-39]. Further research must be conducted, particularly in cerebral ischaemia models, before links can be made regarding the initiation of the RIPC neuroprotective pathways.

Conclusion

IRI is a major contributor to the death and destruction of the neuronal tissue after ischaemic stroke. The RIPC intervention aims to attenuate this damage through stimulation of neuroprotective pathways within the brain. Although clinical trials remain limited, RIPC has shown substantial efficacy in the pre-clinical setting: reducing cerebral infarct volume and apoptotic neuron populations. Research should continue to be conducted regarding the pathways involved in RIPC, however, a shift must also take place in translating this pre-clinical knowledge into clinical trials. The limited clinical data is positive thus far, but more must be done to determine whether this intervention is appropriate for the clinical setting.

Conflict of interest

None declared.

References

[1] Australian Institute of Health and Welfare. Stroke and its management in Australia: an update 2013 [Internet]. 2013 [cited 2016 Jun] Available from: http://www.aihw.gov.au/publication-detail/?id=60129543613.

[2] Nadel L. Stroke. Encyclopedia of cognitive science. Wiley; 2005.

[3] Sanderson TH, Reynolds CA, Kumar R, Przyklenk K, Hüttemann M. Molecular mechanisms of ischemia–reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol Neurobiol. 2013;47(1):9-23.

[4] Nour M, Scalzo F, Liebeskind DS. Ischemia-reperfusion injury in stroke. Interv Neurol. 2013;1(3-4):185-99.

[5] Wang Y, Reis C, Applegate nR, Stier G, Martin R, Zhang JH. Ischemic conditioning-induced endogenous brain protection: applications pre-, per- or post-stroke. Exp neurol. 2015;272:26.

[6] Ren C, Yan Z, Wei D, Gao X, Chen X, Zhao H. Limb remote ischemic postconditioning protects against focal ischemia in rats. Brain Res. 2009;1288:88-94.

[7] Hess DC, Hoda MN, Bhatia K. Remote limb perconditioning [corrected] and postconditioning: will it translate into a promising treatment for acute stroke? Stroke. 2013;44(4):1191-97.

[8] Dorweiler B, Pruefer D, Andrasi TB, Maksan SM, Schmiedt W, Neufang A, et al. Ischemia-reperfusion injury: pathophysiology and clinical implications. Eur J Trauma Emerg Surg. 2007;33(6):600-12.

[9] Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581-609.

[10] Boros P, Bromberg JS. New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant. 2006;6(4):652-8.

[11] Zong Y, Jiang L, Zhang M, Zhou F, Qi W, Li S, et al. Limb remote ischemic postconditioning protects cerebral ischemia from injury associated with expression of HIF-1α in rats. BMC Neurosci. 2015;16:97-105.

[12] Shi H. Hypoxia inducible factor 1 as a therapeutic target in ischemic stroke. Curr Med Chem. 2009;16(34):4593-608.

[13] Koh HS, Chang CY, Jeon S-B, Yoon HJ, Ahn Y-H, Kim H-S, et al. The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nat Commun. 2015;6:6340.

[14] Wang Q, Zhang X, Ding Q, Hu B, Xie Y, Li X, et al. Limb remote postconditioning alleviates cerebral reperfusion injury through reactive oxygen species-mediated inhibition of delta protein kinase C in rats. Anesth Analg. 2011;113(5):1180-7.

[15] Liu X, Zhang X, Zhang J, Kang N, Zhang N, Wang H, et al. Diosmin protects against cerebral ischemia/reperfusion injury through activating JAK2/STAT3 signal pathway in mice. Neuroscience. 2014;268:318-27.

[16] Zheng W-x, Wang F, Cao X-l, Pan H-y, Liu X-y, Hu X-m, et al. Baicalin protects PC-12 cells from oxidative stress induced by hydrogen peroxide via anti-apoptotic effects. Brain Inj. 2014;28(2):227-34.

[17] Cheng Z, Li L, Mo X, Zhang LU, Xie Y, Guo Q, et al. Non-invasive remote limb ischemic postconditioning protects rats against focal cerebral ischemia by upregulating STAT3 and reducing apoptosis. Int J Mol Med. 2014;34(4):957-66.

[18] Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15(1):11-8.

[19] Li H, Zhou S, Wu L, Liu K, Zhang Y, Ma G, et al. The role of p38MAPK signal pathway in the neuroprotective mechanism of limb postconditioning against rat cerebral ischemia/reperfusion injury. J Neurol Sci. 2015;357(1-2):270-5.

[20] Ma Q, Li X, Vale-Cruz D, Brown ML, Beier F, LuValle P. Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes. J Cell Biochem. 2007;101(2):477-87.

[21] Liu W-H, Chang L-S. Arachidonic acid induces Fas and FasL upregulation in human leukemia U937 cells via Ca 2+/ROS-mediated suppression of ERK/c-Fos pathway and activation of p38 MAPK/ATF-2 pathway. Toxicol Lett. 2009;191(2):140-8.

[22] Chen G, Yang J, Lu G, Guo J, Dou Y. Limb remote ischemic post-conditioning reduces brain reperfusion injury by reversing eNOS uncoupling. Indian J Exp Biol. 2014;52(6):597.

[23] Gulati P, Singh N. Pharmacological evidence for connection of nitric oxide-mediated pathways in neuroprotective mechanism of ischemic postconditioning in mice. J Pharm Bioallied Sci. 2014;6(4):233-40.

[24] Peng B, Guo Q-l, He Z-j, Ye Z, Yuan Y-j, Wang N, et al. Remote ischemic postconditioning protects the brain from global cerebral ischemia/reperfusion injury by up-regulating endothelial nitric oxide synthase through the PI3K/Akt pathway. Brain Res. 2012;1445:92-102.

[25] Gulati P, Singh N. Evolving possible link between PI3K and NO pathways in neuroprotective mechanism of ischemic postconditioning in mice. Mol Cell Biochem. 2014;397(1):255-65.

[26] Li P, Su L, Li X, Di W, Zhang X, Zhang C, et al. Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1, NQO-1 in mice. Int J Neurosci. 2015:1-28.

[27] Dinkova-Kostova AT, Talalay P. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys. 2010;501(1):116-23.

[28] Shah ZA, Nada SE, Doré S. Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection. Neuroscience. 2011;180:248-55.

[29] Akdemir G, Ratelade J, Asavapanumas N, Verkman AS. Neuroprotective effect of aquaporin-4 deficiency in a mouse model of severe global cerebral ischemia produced by transient 4-vessel occlusion. Neurosci lett. 2014;574:70-5.

[30] Li S, Hu X, Zhang M, Zhou F, Lin N, Xia Q, et al. Remote ischemic post-conditioning improves neurological function by AQP4 down-regulation in astrocytes. Behav Brain Res. 2015;289:1-8.

[31] Pun PBL, Lu J, Moochhala S. Involvement of ROS in BBB dysfunction. Free Radic Res. 2009;43(4):348-64.

[32] Freeman L, Keller J. Oxidative stress and cerebral endothelial cells: regulation of the blood-brain-barrier and antioxidant based interventions. Biochim Biophys Acta. 2012;1822(5):822-9.

[33] Yang F, Zhang X, Sun Y, Wang B, Zhou C, Luo Y, et al. Ischemic postconditioning decreases cerebral edema and brain blood barrier disruption caused by relief of carotid stenosis in a rat model of cerebral hypoperfusion. PLoS One. 2013;8(2):e57869.

[34] Ma XD, Song JN, Zhang M, An JY, Zhao YL, Zhang BF. Advances in research of the neuroprotective mechanisms of cerebral ischemic postconditioning. Int J Neurosci. 2015;125(3):161-9.

[35] England T, Hedstrom A, O’Sullivan S, Donnelly R, Barrett D, Sarmad S, et al. RECAST (Remote Ischemic Conditioning After Stroke Trial) a pilot randomized placebo controlled phase ii trial in acute ischemic stroke. Stroke. 2017;48:1412-5.

[36] Man C, Gong D, Zhou Y, Fan Y. Meta-analysis of remote ischemic conditioning in patients with acute myocardial infarction. Sci Rep. 2017;7:43529.

[37] Weber C. Far from the Heart: Receptor cross-talk in remote conditioning. Nat Med. 2010;16(7):760-2.

[38] Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation. 1996;94(9):2193-200.

[39] Kerendi F, Kin H, Halkos ME, Jiang R, Zatta AJ, Zhao ZQ, et al. Remote postconditioning: brief renal ischemia and reperfusion applied before coronary artery reperfusion reduces myocardial infarct size via endogenous activation of adenosine receptors. Basic Res Cardiol. 2005;100(5):404-12.

Tags Limb remote ischaemic post-conditioning, stroke, Ischaemia reperfusion injury, Neuroprotective pathways

Editorial Addendum

Oncology teaching in Australian medical schools: opportunities for patient-centred change

Post author By Website Publications Officer
Post date April 16, 2018

Within a poignant reflection and critical analysis of Australian medical school curricula, Bravery’s article ‘Oncology teaching in Australian medical schools: opportunities for patient-centred change’ brings to light the growing importance of cancer education for medical trainees and the need for meaningful integration with the existing curricula.

It has been nearly a decade since the publication of the Ideal Oncology Curriculum for Medical Students by the Oncology Education Committee (OEC), originally as part of the Cancer Council Australia (CCA) [1]. To date, multidisciplinary members of the OEC remain active and dedicated to improving oncology education across Australia and New Zealand with advocacy, collaboration with medical schools, and development of resources such as the free e-book “Clinical Oncology for Medical Students” [2].

Australia has been one of the first countries internationally to present a national framework for the standard of oncology education. The CCA discontinued its affiliation with the OEC in late 2016, and the Clinical Oncology Society of Australia has not taken responsibility of the OEC. Within this changing landscape of medical education, increasing medical schools and work-force shortages, a growing proportion of paediatric and adult populations continue to be affect-ed and at-risk of cancer. It becomes even more important for students, medical schools, clini-cians and bodies such as the Australian Medical Council alike to be cognisant and proactive in promoting a high standard of oncology education in foundational years of training.

References
[1] Oncology Education Committee. Ideal Oncology Curriculum for Medical Schools [Inter-net]. The Cancer Council Australia, 2007 [cited 2017 Jul 22]. Available from:

[2] Sabesan S, Olver I. Clinical Oncology for Medical Students [Internet]. Sydney: Cancer Council Australia; 2015 [cited 2017 Jul 22]. Available from: http://wiki.cancer.org.au/oncologyformedicalstudents/Clinical_Oncology_for_Medical_Students

Feature Articles

Multilevel approaches to optimising antenatal care: its delivery, uptake and the subsequent health outcomes

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Introduction:
The World Health Organisation recommends that all pregnant women receive at least four antenatal visits. However, nearly half of all women worldwide, particularly in less developed countries, do not receive this care. Antenatal care (ANC) provides an opportunity to improve the outcome of pregnancy and reduce maternal and fetal mortality rates, particularly in low- and middle-income countries.

Summary:
There is a critical need for evidence-based studies surrounding ANC and its provision and uptake, both in Australia and on an international level. This is to ensure that the care provided is specific to the needs of every woman the medical community serves. In this article, we examine a Cochrane review of a variety of community-based and health systems-related approaches that target determinants of reduced ANC coverage. The review aims to address the issues affecting antenatal care coverage, highlight the gaps in the care we currently provide, and discusses its implications for the current healthcare policies regarding ANC provision. While transport and cost remain the basic barriers to accessing ANC, woman-doctor partnerships, contextual care, women’s satisfaction, and cultural safety are also of paramount importance if ANC is to reach more women. The part clinicians play, particularly in delivering holistic and woman-centered care, must also be realised in order to restructure care to be more coordinated and effective.

Introduction

Michelle Obama once said, “Communities and countries and ultimately the world are only as strong as the health of their women [1].”

Antenatal care (ANC) plays an important role in assisting and preparing pregnant women mentally, emotionally, and physically for childbirth. ANC ensures that the well-being of both the mother and child is well monitored to ensure an ongoing pregnancy with an increased likelihood of a successful birth and a healthy baby. Despite the importance of ANC for both mother and child, globally only 82% of pregnant women have access to at least one ANC visit during their entire gestation period, and only 54% receive the recommended minimum of at least four antenatal visits [2,3]. It is important to discern and address the causes of this disparity. A 2015 systematic review by Mbuagbaw and colleagues analysed a variety of community-based and health systems-related interventions that targeted determinants of reduced ANC coverage, in order to ascertain their effectiveness in increasing the number of women who received ANC [4]. This article analyses and interprets the findings of the review, exploring its implications for women, clinicians, and the broader medical community.

Summary of the systematic review by Mbuagbaw et al. [4]

The review evaluated results from up to 400,000 women across 34 randomised controlled trials assessing different methods of optimising antenatal care. Of these trials, 29 used a cluster-randomised design. The trials tested two main types of interventions both aimed at improving the uptake of ANC: health system interventions that included home visits for pregnant women and provision of adequate equipment for clinics; and community-based interventions, such as media campaigns, provision of education, or financial incentives for pregnant women.

Using one intervention, as opposed to none, was found to be effective as demonstrated by an increase in the number of women who received four or more antenatal visits, an increase in the number of women who received at least one antenatal visit, and the number of births carried out in a health facility. There was no evidence of any change in the number of pregnancy-related deaths or any impact on the rates of low birth weight babies [4].

Using a combination of interventions in comparison to no intervention resulted in an increase in the proportion of pregnant women who obtained at least one antenatal visit. Combined interventions also resulted in a reduction in perinatal deaths and a reduction in underweight babies, compared with no intervention. There were no differences between single interventions and combined interventions for any outcome measured [4].

The findings revealed that regardless of the number of interventions used the implementation of at least one intervention led to a positive outcome. In view of this, it is important to evaluate the methods used and to understand and appreciate why the interventions were successful.

Interpretation of the findings

Two main categories of interventions were used in the systematic review, as detailed above. The first targeted the health system and involved the reorganisation of health services and patient-centred care. This proved effective as it addressed the woman’s sociocultural context and agenda, serving as an example of patient-centred care as defined by the Institute of Medicine [5]. Both personal and social environments play a role in influencing the experience of pregnancy. It is therefore essential to consider these factors when administrating health services to ensure that the best care is provided and the needs and expectations of the woman are met [6].

The majority of the trials were implemented in low and middle income countries. Most pregnant women in these populations are still unable to gain access to healthcare and thus experience poorer health outcomes [7]. In a similar study that evaluated the factors affecting ANC attendance across four sub-Saharan regions, the results showed that the way women described ANC was often vague: many of the women had very generalised descriptions about care during pregnancy, what it comprised of, what transpired when one was administered ANC, and the necessity of at least four visits [8].

Moreover, the women often only sought ANC when they faced problems or uncertainties with their pregnancies. How the ANC services responded to these uncertainties, together with their general interactions with the pregnant women, affected women’s ANC attendance [8].The attitudes and behaviours of healthcare workers has long been recognised to influence patient care. Poor interpersonal relationships may act as a barrier to the successful conveyance and interpretation of information, a key component of a successful patient-centred interview [9].

In view of these results, the second intervention that targeted the community proved to be highly effective. The methods used were aimed at helping women, particularly pregnant women, gain a greater understanding of the purpose of ANC. A study carried out in Pakistan’s Punjab province showed that women’s lack of awareness of ANC was also responsible for low ANC coverage [10]. With limited knowledge, the use of ANC services is reduced. As health professionals, it is important that we never assume a woman has any previous health knowledge. Provision of information regarding the services rendered and their usefulness can prompt more women to use the available services while ideally improving patient satisfaction [11]. In addition, the provision of education about health in pregnancy should be culturally appropriate, including supplying a local adaptation of the written materials, making them culturally and linguistically applicable to the target population [6].

The second intervention additionally offered financial incentives, which increased access to ANC for women who were previously deterred due to its cost. It also addressed social mobilisation, which consequentially actuated community initiatives and creativity in addressing the problem at hand. This intervention also included changes in behaviour, such as birth preparedness, aimed at modifying behaviour patterns that can cause low ANC uptake.

Implication of the systematic review findings

A woman-centred healthcare system involves the meaningful engagement of women and the formation of partnerships with the woman and their families. The trust that arises as a result of a strengthened woman-provider relationships has the power to drive change in healthcare delivery. Taking time to build rapport helps improve women’s experience of ANC. It requires effective communication as women who understand their healthcare providers are more likely to understand their treatment and adhere to follow-up recommendations [12].

“Put patients first” declared Harvey Fineberg, President of the Institute of Medicine. “When one has truly understood what the patient needs, they have truly put the patient first [13].” Both interventions used in this study involved reaching out to individual women. Findings revealed that the usage of ANC was considerably lower in women who lived far from the place ANC was delivered, as the long distances reduced access. This was largely the case for women living in rural and remote areas [14]. The use of mobile clinics and greater involvement of the healthcare system, such as requiring skilled attendants to make home visits to pregnant women in remote communities, would greatly reduce such problems. Mobile clinics in particular, as an integral part of the healthcare system, have proven to be highly beneficial in the provision of high-quality, low-cost care to vulnerable isolated populations. They offer a wide scope of services tailored to the community’s needs, thus removing the logistical constraints (transport and financial issues, long waiting periods, and complex and often tedious administrative practices) faced by many [15].

Adequate improvements in the utilisation of ANC and thus its coverage require much more than an increase in the health workforce or an increase in the number of health centres established. It demands a greater focus on a woman’s overall social, political, and economic determinants of health. When ANC provision is both theoretically and contextually opposed to local beliefs and experiences, its usage is diminished, especially when women experience any form of abuse in their care setting or when their attendance puts them at risk from their immediate family or community [16].

Implications within an Australian context

In 2002, Hunt published research aimed at improving ANC, its protocols, and practice in the Northern Territory in Australia [17]. He suggested that antenatal visits be prolonged in time, but less in number, thus making them more likely to be comprehensive and delivered in a more flexible woman-centred manner that makes no generalisations or assumptions about its patients. Likewise, the Daruk Aboriginal Community Controlled Medical Service in New South Wales succeeded in achieving earlier ANC attendance and increasing the number of ANC visits through a comprehensive primary healthcare program. This program incorporated a wide range of ANC services, including home visits and transport provision, both examples of strategies which could be extended to many other Aboriginal communities [18,19]. Conversely, a large proportion of Aboriginal and Torres Strait Islander people live in urban or inner regional areas and have their healthcare channelled through mainstream services. Therefore, it is imperative that we optimise the care we provide to these groups by applying the same principles of cultural competence in all healthcare services, in order to heighten the authentic involvement of women in decision-making. Such measures have the potential to see a greater proportion of this population gain access to the services available to them [19].

These interventions could prove to be very useful in many rural and remote regions, and specifically the Aboriginal community through the engagement of the wider community. The assistance from Aboriginal health workers facilitates communication and understanding between the woman and the healthcare provider, which may consequentially engender trust and responsiveness to ANC [20].

Recommendations

Therefore, when providing care as health professionals, we need to consider the woman’s context and establish a holistic approach that addresses the needs and concerns of that specific woman [17]. This is pertinent in places where culture plays a pivotal role. ‘Shame’ in Australian Aboriginal communities is a culturally-held belief that introduces behaviours and attitudes, evident in patient-doctor encounters, that can be easily misconstrued, resented, and/or disregarded by care providers who fail to appreciate its role in a woman’s life and family [18]. A basic yet appreciative understanding of the history and policies that have moulded the lives of Aboriginal women and their families may assist in the comprehension of some of their health behaviours. For example, the systematic removal of Aboriginal children from their families, the Stolen Generation, has been suggested as a prevailing source of distrust in the Aboriginal mothers’ community [19,20]. Provision of a healthcare service that is culturally equipped to provide holistic ANC is essential if we are to successfully reach out to all communities, including the Aboriginal community.

Conclusion

Based on the findings of this systematic review, it is evident that several interventions were effective in increasing ANC coverage and improving other pregnancy-related outcomes. Reported interventions addressed the common problems that affected the utilisation of ANC, which included maternal knowledge, accessibility to healthcare facilities, and financial difficulties. Accordingly, as doctors and future practitioners, it is imperative that as we provide maternal and antenatal care, we structure the healthcare services we provide around the woman and cater to their individual preferences, needs, and concerns. We are advised to accommodate the woman as much as we can, which means providing them with care that is specific to them and care that addresses the whole person [15-17]. The evidence obtained in Mbuagbaw’s review should be applied effectively in all areas, especially in those places with low ANC coverage [4]. This also serves as an indicator of the gaps in the current evidence that still require further research.

Therefore, instead of asking “Why do women not accept the service that we offer?” the important question should be “Why do we not offer a service that women will accept [22]?”

Conflict of interest

None declared.

References

[1] Obama M. A plea for education [Internet]. TED talks; 2009 [updated 2009 Apr 2; cited 2016 Apr 2]. Available from: http://www.ted.com/talks/michelle_obama?language=en

[2] Only half of women worldwide receive the recommended amount of care during pregnancy. UNICEF Data: Monitoring the Situation of Children and Women [Internet]. The United Nations Children’s Fund; 2015 [updated 2015 Jul; cited 2016 Mar 14]. Available from: http://data.unicef.org/maternal-health/antenatal-care.html

[3] Antenatal care: Global Health Observatory (GHO) data [Internet]. Switzerland: World Health Organization; 2017 [updated 2017; cited 2017 Mar 13]. Available from: http://www.who.int/gho/mdg/maternal_health/antenatal_care_text/en/

[4] Mbuagbaw L, Medley N, Darzi AJ, Richardson M, Habiba Garga K, Ongolo-Zogo P. Health system and community level interventions for improving antenatal care coverage and health outcomes. Cochrane Database Syst Rev. 2015;(12):CD10994. doi:10.1002/14651858.CD010994.pub2

[5] Institute of Medicine, Committee on Quality of Health Care in America: crossing the quality chasm. A new health system for the 21th century. Washington, D.C: National Academy Press; 2001:6

[6] Clinical practice guidelines antenatal care – module I: understanding the women’s context [Internet]. Australian Department of Health; 2013 [updated 2013 Apr 2; cited 2016 Mar 19]. Available from: http://www.health.gov.au/internet/publications/publishing.nsf/Content/clinical-practice-guidelines-ac-mod1~part-a~woman-centred-care~womans-context.

[7] Women’s health: the new national agenda: AWHN position paper [Internet]. Australia: Australian Women’s Health Network; 2008 [cited 2016 Mar 19]. Available from: http://whnsw.asn.au/wp-content/uploads/2016/01/AWHN_Position_Paper.pdf

[8] Pell C, Meñaca A, Were F, Afrah NA, Chatio S, Manda-Taylor, et al. Factors affecting antenatal care attendance: results from qualitative studies in Ghana, Kenya and Malawi. PloS One. 2013;18(1):e53747. doi:10.1371/journal.pone.0053747

[9] Holmes W, Goldstein M. “Being treated like a human being”: attitudes and behaviors of reproductive and maternal health care providers [Internet]. 2012 [cited 2016 Apr 14]. Available from: https://www.burnet.edu.au/system/asset/file/1408/Holmes_et_al_attitudes_review_sept2_final.pdf

[10] Majrooh MA, Hasnain S, Akram J, Siddiqui A, Memon ZA. Coverage and quality of antenatal care provided at primary health care facilities in the ‘Punjab’ province of ‘Pakistan’. PLoS One. 2014; 9(11):e113390. doi:10.1371/journal.pone.0113390

[11] Galle A, Van Parys AS, Roelens K, Keygnaert I. Expectations and satisfaction with antenatal care among pregnant women with a focus on vulnerable groups: a descriptive study in Ghent. BMC Womens Health. 2015;15(1):1-12. doi:10.1186/s12905-015-0266-2

[12] Frampton S, Guastello S, Brady C, Hale M, Horowitz S, Smith SB, Stone S. Patient-centered care improvement guide [Internet]. Picker Institute; 2008 [updated 2008 Oct; cited 2016 Mar 26]. Available from: http://www.patient-centeredcare.org

[13] Cooney E. Put patients first [Internet]. Harvard Medical School; 2013 [updated 2013 May 30; cited 2016 Mar 13]. Available from: http://hms.harvard.edu/news/put-patients-first-5-30-13

[14] Ye Y, Yoshida Y, Harun-Or-Rashid M, Sakamoto J. Factors affecting the utilization of antenatal care services among women in Kham district, Xiengkhouang province, Lao Pdr. Nagoya J Med Sci. 2010;72(1):23- 55.

[15] Hill CF, Powers BW, Jain SH, Bennet J, Vavasis A, Oriol NE. Mobile health clinics in the era of reform. Am J Manag Care. 2014;20(3):261-4.

[16] Finlayson K, Downe S. Why do women not use antenatal services in low- and middle-income countries? A meta-synthesis of qualitative studies. PLoS Med. 2013;10(1):e100373. doi:10.1371/journal.pmed.1001373

[17] Hunt J. How can routine antenatal care protocols and practice in the Northern Territory be improved? A discussion paper [Internet]. Centre for the Study of Mothers’ and Children’s Health, La Trobe University; 2002 [cited 2016 Apr 14]. Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.602.9270&rep=rep1&type=pdf

[18] Kildea S, Kruske S, Barclay L, Tracy S. ‘Closing the Gap’: how maternity services can contribute to reducing poor maternal infant health outcomes for Aboriginal and Torres Strait Islander women. Rural Remote Health. 2010;10(1383):1-18.

[19] Clarke M, Boyle J. Antenatal care for Aboriginal and Torres Strait Islander women. Aust Fam Physician. 2014;43(1):20-4.

[20] Simkhada B, Teijlingen ER, Porter M, Simkhada P. Factors affecting the utilization of antenatal care in developing countries: systematic review of the literature. J Adv Nurs. 2008;61(3):244-60. doi:10.1111/j.1365-2648.2007.04532.x

[21] Stolen Generations History. National Sorry Day Committee [Internet]. National Sorry Day Committee; 2015 [updated 2015 May 24; cited 2016 Apr 12]. Available from: http://www.nsdc.org.au/stolen-generations-history/

[22] Phumaphi J, Evans T, Van Lerberghe WV, Manuel A, Matthews Z, Wolfheim C, et al. Make every mother and child count: World Health Report 2005. WHO: Sexual and reproductive health [Internet]. Switzerland: World Health Organization; 2005 [updated 2005; cited 2016 Apr 2]. Available from: http://www.who.int/whr/2005/whr2005_en.pdf?ua=1

Tags outcomes, antenatal, multilevel, community, interventions

Feature Articles

Oncology teaching in Australian medical schools: opportunities for patient-centred change

Post author By Website Publications Officer
Post date April 16, 2018

Abstract

Introduction: Given the prevalence of cancer and its multidisciplinary and increasingly personalised treatments, this group of diseases is an ideal vehicle for teaching medicine and medical care. The teaching of oncology in medical school environments is of paramount importance to the skill sets and efficacy of future doctors. But do we do it well, and could we do it better?

Discussion: Oncology education in medical schools in Australia and abroad is explored through a personal lens, a qualitative survey, and a literature review in this article. First, the author reflects on his own experience of oncology education as a cancer survivor and third-year medical student. Qualitative data from a survey of medical students at one institution provide insight into the potential benefit of increased exposure to people living with cancer while in medical school. Australia’s andragogic oncological landscape is critically evaluated, and opportunities for change are proposed.

Introduction

As a cancer survivor, the frightening experience of a cancer diagnosis is something I intimately understand. Cancer remains the major cause of mortality in Australia and many cancers still have very high mortality rates [1]. One in two Australians will be diagnosed with a cancer before the age of 85. In 2016, it was estimated that 130,466 people were diagnosed with cancer [2] and 46,880 people died from cancer. In this same year, 384,593 Australians reported living with cancer [2].

Despite large volumes of research, it is a disease that continues to kill indiscriminately and its treatment inflicts harsh side effects during therapy and late toxicities in survivorship. The contradictory way that the causes of cancer are communicated and the complexity of the disease all contribute to a fear of cancer. Medical students are not immune to this fear and many develop additional anxiety about cancer throughout their university training. Cancer, for medical students, is a complex disease process, often of unfamiliar and unknown aetiology. It challenges our understanding of genetics, anatomy, physiology, therapeutics, psychology, and public health. As a major health burden, all doctors and medical students should possess a foundational understanding of cancer screening, the pathophysiology underpinning its signs and symptoms, principles of diagnosis and cancer treatment, and appreciate the importance of multidisciplinary care. Simultaneously, doctors require the confidence to effectively and empathetically facilitate conversations with patients and their families about the diagnosis of cancer, fear and grief, prognosis, side-effects, palliative care, and end-of-life planning [3-5].

Reflections from a cancer survivor and their learning community

During my first two years of medical school, I was surprised to not once encounter a cancer advocate or patient as part of my learning. This was surprising because patient narratives and engagement are regarded as central to medical education. Early exposure in preclinical years to cancer patients and oncology content has been shown to improve communication confidence and increase empathy towards cancer patients [6].

I am open about my stage-three colorectal cancer journey [7] and it felt natural to share my lived experience with my problem-based learning team of seven other students during first year. Learning about cancer within this context I believe benefited me and my colleagues. Their questions and knowledge allowed me to conceptualise my own experience in new ways, and helped me retain a greater amount of the material encountered during oncology cases. The prevalence of cancer and growing incidence of certain cancers in young adults means medical students will be increasingly confronted by cancer in some way during their learning. This should be embraced by medical curricula and extracurricular structures as a strategy to create more rewarding oncology learning environments that draw on lived experience within medical cohorts (when appropriate) and cancer groups in the wider community.

When in second year, I asked members of my first-year problem-based learning group to reflect on their experience of learning about cancer alongside me. At my medical school, we have traditional lectures, occasional workshops, and frequent tutorials with a problem-based learning group. Its membership remains the same for the academic year. Oncology is not taught as a block, but is weaved throughout the curriculum. There were no specific tutorials or workshops on oncology, but from time to time discussion in my tutorial group would turn to oncology and my experience and we would have involved discussions together.

An eight-item survey was distributed via SurveyMonkey to the seven other members (average age 24 years old; five females and two males) of the learning unit in April 2016 and data was anonymously collected from five respondents (two colleagues did not provide data for reasons I did not ascertain to protect anonymity). Closed questions concerned the quality of oncology teaching (for example: Do you believe the amount of oncology education provided by the school’s current curriculum is ideal? and Would you have liked more contact with cancer survivors last year?) and learning about cancer alongside a cancer survivor (for example: Was your cancer learning experience advantaged, disadvantaged or unaltered by the presence of someone in your problem-based learning group with direct lived experience with cancer?). Two questions asked students to list the topics they believed they would be most comfortable with when entering hospital and which format for learning about oncology was the most appreciated (for example: lectures, workshops, or tutorials). Two open questions asked for opinions on the role of cancer consumers in education and any other reflections related to oncology education.

Overall, students reported that contact with a colleague living with cancer was transformative, broadened their understanding of oncology, and helped form connections between the biological and humanistic aspects of cancer (Table 1). All five respondents indicated that their cancer learning experience had been positively influenced by the presence of a cancer survivor, and four of the five respondents indicated they would have preferred more contact with cancer survivors in their first year of medicine.

Table 1. Responses from five members of the same problem-based learning group reflecting on their cancer education experience learning alongside a cancer survivor.

This small sample is neither robust nor generalisable, but these qualitative impressions demonstrate that early exposure to cancer survivors in a medical education environment was a transformative experience for these preclinical students. Given the nature of this survey, sources of bias are numerous and include the sample size, familiarity between myself and the subjects, that the benefits are self-reported only, and that the survey was done several months after the problem-based group was dissolved. However, learning alongside me and hearing about my disease informally throughout the year created patterns of change seen in more robust assessments of oncology educational experiences discussed below.

Given the benefits of early patient contact, why is contact with cancer patients not standard practice in medical schools? To address this question, this article evaluates the historical development and current status of oncology teaching more broadly.

The evolution of oncology teaching

The education of medical students must change over time in response to the changing needs of patients, society, and governments. Cancer education for Australian medical students has a history of responding and adapting to external drivers of change. In 1988, Cancer Council Australia released guidelines for core competencies for medical graduates and called for compulsory oncology education in all medical schools [3]. These guidelines were reviewed and amended as the Ideal Oncology Curriculum for Medical Schools in 1999 and in 2007 by the Oncology Education Committee [3]. Over the same period, a call for a foundation oncology curriculum in Europe was made in 1989. The independent International Union Against Cancer released a paper on oncology curricula in 1994 and an Australian Government inquiry into breast cancer in 1995 concluded that medical schools should urgently develop curricula enabling students to better acquire knowledge about the diagnosis and management of cancer [3].

Medical schools have undergone significant changes in the last decade, including growth in graduate-entry medical degrees, problem-based curricula, student-directed learning, and integrated content. Despite the increasing agility of medical schools to adopt improved teaching and learning models for oncology [5,8-10], assessments of medical students’ understanding of oncology have consistently found knowledge and skill deficits [5,10-16]. The curriculum is crowded, medicine grows more complex, and the volume of information available about a given topic is now unmanageable. This is on a background of a general fear of cancer that many students likely possess. The disjunction between students’ knowledge of cancer and the knowledge they are expected to have remains an active and rich research space in Australia and globally.

What should medical students know about cancer?

While the diagnosis of cancer is usually confirmed by oncologists, the responsibility for facilitating screening and detection remains primarily in the domain of general practitioners (GPs). GPs also provide the majority of general health care for cancer-diagnosed patients [17]. The role of the GP in cancer care and long-term follow-up is growing due to increasing cancer incidence and survivorship, the shift towards defining cancer as a chronic disease, and proposed policy changes aimed at restoring GPs as the keystone of chronic disease management [17-19]. Although approximately half of Australian medical graduates go on to train as GPs, access to oncology training is limited outside of specialist oncologist training programs. Thus, effective oncology training during medical school is of paramount importance in establishing an appropriate skill set for internship and beyond. Further, as the numbers of cancer survivors and people living with cancer grow, cancer care and support issues will impact an increasing number of specialists outside of oncology.

The role of medical curricula is to prepare students for their first year after university as interns. However, what students should know by this point will differ depending on the views of various stakeholders. From a patient perspective, medical graduates need to be able to recognise and identify cancer, understand treatments, engage in discussion around the psychosocial implications of cancer, and appreciate the roles of different health professionals involved in cancer journeys. From a senior doctor perspective, medical graduates should understand history-taking and examination, red flag symptoms, screening and diagnosis, treatment modalities and goals, chronic care needs, communication, and ethics [5,20]. From a public health perspective, medical graduates should understand the principles and guidelines for cancer prevention, screening and detection, and the relationships between cancer prevalence, demography, and geography [5,20]. Last but not least, medical graduates have expectations of their own cancer knowledge: they expect to know about cancer prevention, patterns of cancer prevalence, and the signs and symptoms of cancer. They also strive to effectively communicate with cancer patients, and be up-to-date on the principles of surgery, chemotherapy, immunotherapy, and radiotherapy.

Trends in the cancer knowledge of medical graduates

Two major surveys of Australian medical graduates’ attitudes and understanding of cancer were conducted in 1990 and 2001 [4,13]. According to these samples, students in 2001 had more exposure to palliative care and radiation oncology and better knowledge about breast cancer over other cancer types [4]. Procedural-based skills such as performing a Papanicolaou smear and analysing a pigmented skin lesion worsened, but breast examination competency and an understanding of screening guidelines for cervical cancer improved [4]. In the eleven years between surveys, the number of students who felt dissatisfied with the teaching of curable versus non-curable cancer management grew, while the number of students reporting little or no skills in discussing death with dying patients fell [4].

Overseas, a survey of medical graduates in the UK in 2005 found that only 61% of students completed a clinical attachment or special module in oncology, three-quarters would have liked more teaching on oncology, namely radiotherapy, chemotherapy, and symptom management, and only 40% felt prepared to care for cancer patients [14]. Evaluation of American medical graduates found that many lacked knowledge on cancer prevention and history-taking, alongside an unpreparedness to care for cancer patients [5]. In Canada, a 2011 survey found that only half of medical schools taught oncology as a separate topic [11]. It also found that 67% of final-year students felt that oncology education was inadequate and the most poorly taught subject at medical school, a sentiment shared by curriculum committees, residents, and training program managers alike [11].

How can we better teach and learn about cancer?

Medical school oncology education has suffered, and in many places continues to suffer, from neglect, fragmentation, a narrow scope, under-resourcing, and inconsistency between curricula and schools [5,21]. Despite acknowledgement almost 30 years ago of the need for common oncology teaching based on shared principles and standardised learning objectives, disparity in oncology education remains the norm [21,22]. Debate persists around the role of oncologists as educators within medical schools, and how much focus there should be on oncology at medical school. The degree to which oncology should be integrated into curricula [22] or taught as blocks of content is also disputed [23]. Despite a lack of congruence amongst medical oncology teaching, methods to improve oncology teaching have emerged from medical schools around the world.

Standardisation of objectives and curricula
Guidelines for cancer education by medical schools have existed in Australia since 1999 [3]. While these are criticised for not presenting specific learning objectives according for each stage of a medical degree [5], the guidelines are an excellent summary of cancer education objectives that are both patient-centred and skills-oriented. Indeed, Australia should be proud of its national oncology education framework for medical school teaching, as this has yet to be achieved in the United Kingdom [20], Canada [11], or the United States [24].

Teaching methods and resources
Active learning techniques such as problem-based and team-based learning [9] and information technologies are now a common feature of many medical schools. A recent assessment of oncology education across 130 medical schools in the United States found widespread use of case-based learning, online resources, and virtual laboratories; lectures continued to be the dominant form of teaching in all schools [12]. This and other studies demonstrate that medical schools are modernising the methods they use to teach oncology, albeit slowly and despite the predominately online learning styles of medical students [25,26]. Whether newer teaching methods result in improved learning outcomes for medical graduates remains under-evaluated. However, examples of high-yield oncology education strategies are growing and include e-learning oncology modules [27], short clinical oncology modules [28], cancer centre-hosted research programs [8], and summer schools [21].

Use of an oncology textbook remains variable across medical schools. In a Canadian survey of the oncology learning needs of final-year medical students, 89% would have preferred a textbook or web book dedicated to oncology learning objectives [11]. A standard oncology textbook is not recommended across Australian medical schools. However, Clinical Oncology for Medical Students, an e-book produced by faculty representatives across Australian and New Zealand medical schools, is recommended by some institutions and accessible for all medical students to download online [29].

While most Australian medical schools have adopted the concept of learning communities [9], Brazil has expanded student-led and team-focused learning and developed a system of academic leagues with implications for oncology education [30]. The oncology leagues are designed to instil broad knowledge and foster leadership, entrepreneurialism, and learning by engaging in research days, outreach, fundraising, and charitable work [30].

Contact with people living with cancer
Contact with cancer patients is defined as a core clinical experience in the Ideal Oncology Curriculum [3]. However, in Australia, medical student exposure to cancer patients declined from 1990 to 2001 [13]. This is concerning because the need for greater engagement with cancer patients consistently emerges as a theme in surveys of medical graduates, and exposure to cancer patients and hospices is correlated with self-assessments of preparedness for internship [14]. Further, from my small sample of fellow students in my problem-based learning group, contact with me while learning about cancer was beneficial and transformative.

Exposure to patients and advocates is essential to medical school education, and this is particularly the case with oncology because of its complexity, interdisciplinary nature, chronicity, and psychosocial impacts. Solid preclinical and clinical exposure to cancer patients directly assists in the acquisition of skills such as communication, and indirectly via contextualisation and personalisation of the disease [6]. While consumer engagement can be formal and didactic, other models like learning leagues provide the freedom to focus on patient-centred activities such as outreach, education, and support [30]. Since many of the skills needed to understand cancer and communicate with people living with cancer are transferable to other diseases and contexts, investing in better oncology teaching would likely yield benefits across the board for our junior doctors.

Conclusion

The growth in cancer incidence, treatment complexity, and survivorship has resulted in a large amount of discussion about the cancer education of medical students. Calls for medical curricula to remain agile to the shifting needs of cancer patients and communities have echoed widespread concern about the knowledge gaps and unpreparedness of medical graduates to examine, communicate with, and manage cancer patients. Early efforts to standardise oncology learning objectives have largely been resolved in Australia, and medical curricula are slowly adopting newer teaching and learning strategies. However, the exposure of medical students to cancer patients remains unsatisfactory in medical schools in Australia and around the world. In addition, data about what medical graduates understand about cancer should be updated nationally. Building on the existing case-based approach and role of narrative in medical education by drawing upon the well-developed networks of cancer consumers is one way of enhancing the learning outcomes of medical students, but it cannot take place in isolation. Any assessment of oncology education needs to occur alongside a larger discussion about curriculum inclusion, streamlining, and factors accounting for underperforming disciplines such as oncology. For example, there does not appear to be a good rationale for, say, the emphasis on cardiovascular diseases and interventions over cancer at medical school, when heart disease and cancer are both leading causes of mortality and morbidity. Future work will need to identify and then explain differences between subject domains for true medical curriculum reform to begin.
Acknowledgements
Thank you to Professor Alexander Heriot, Dr Ben Ticehurst and Annie Miller for constructive feedback on an earlier version of this article, and the reviewers for constructive suggestions during the review process.

Conflict of interest
None declared.

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Tags adult oncology, cancer, medical education

Original Research Articles

Symbiotic, medical student initiated community engagement on a rural longitudinal integrated clerkship

Post author By Website Publications Officer
Post date April 15, 2018

Background: Community engagement is an important aspect of a successful rural placement.

Materials and Methods: In this study, medical students undertaking longitudinal integrated clerkships at a rural clinical school instigated community engagement activities with a special school. Six health education sessions were delivered to eight adolescent special school students. This paper describes the perceptions of medical students and special school teachers in relation to the effect of this program on medical student personal and professional development, its acceptability by special school teachers, and the factors which contributed to the program outcomes. Two separate focus groups were conducted with seven medical students and two special school teachers.

Results: Theme 1: Symbiotic nature of the program. There was perceived improvement in the medical students’ communication, leadership and teaching skills, and their understanding of working with people with disabilities. Special school teachers noted benefits to their students from the health expertise and role modelling provided. The university experienced enhanced links with the community. Theme 2: Factors that contributed to the success of this community engagement activity. All parties wanted to engage in the program. Valuable time was spent developing relationships and preparing with all stakeholders. Constructive teamwork was paramount.

Discussion: Involvement in this program gave students a unique opportunity to develop skills in professionalism that are essential to working as health practitioners but difficult for universities to teach. The voluntary nature of the initiative was novel, promoting this skill development and enhancing the effectiveness of the program. The factors that contributed to the success of this program are potentially applicable to other settings.

Conclusion: This initiative was highly acceptable to the special school teachers involved and was perceived to have positive effects on medical student personal and professional development.

Introduction

Medical student rural clinical rotations are well established in Australia and internationally [1-7]. Typically, longitudinal rotations involve students being placed into a rural community where they undertake their year’s university curriculum. These placements provide unique educational opportunities and are an important way to attract future doctors to address increasing rural workforce shortages [8].

The symbiotic clinical education model developed from research conducted on medical students completing longitudinal integrated clerkships (LICs) [9,10]. This model proposes that clinical education is underpinned by relationships between key stakeholders and that a symbiotic curriculum can be achieved if these relationships lead to mutual benefit. One of these key stakeholders is the community in which medical students are placed. Community engagement by medical students can therefore be seen as an important aspect of a successful rural placement.

Community engagement is also important for the future of our rural medical workforce. Studies indicate it is a predictor of longer duration of stay for rural doctors and that positive community engagement experiences encourage students and doctors to undertake similar activities in the future [11,12].

Monash University’s East Gippsland Rural Clinical School (RCS) was established in 2001 [13]. One of their sites is in Bairnsdale (East Gippsland, Victoria, Australia). Bairnsdale and its surrounds are classified as RA3 on the Australian Standard Geographical Classification – Remoteness Area (ASGC-RA), defined as ‘Outer Regional’ [14]. At the time of this study an integrated, community-based curriculum was provided for a group of eight fourth-year medical students during their five-year Bachelor of Medicine, Bachelor of Surgery (MBBS) undergraduate degree. Students lived and studied in East Gippsland for the entire academic year, while studying the disciplines of paediatrics, obstetrics and gynaecology, psychiatry, and general practice.

Materials and Methods

Intervention

Seven fourth-year medical students from the East Gippsland RCS developed a community engagement program, which involved the delivery of six health education sessions to students at the East Gippsland Specialist School. This initiative developed after two special school teachers approached one medical student who had been volunteering at the school for assistance with health education, which they were required to deliver as part of the school curriculum. This medical student subsequently facilitated the development of links between the RCS and the special school, which led to the initiative growing and more medical students becoming involved.

The sessions were presented to one class of eight students, between 14 and 18 years of age, with autism, attention deficit hyperactive disorder, and learning disabilities. Various topics, content, and pedagogical approaches were used (Table 1). Each session was conducted by two to four medical students with the support of the two special school teachers. The sessions were developed by the medical students in consultation with the special school teachers. Resources were utilised from the local community health centre, East Gippsland RCS, and the local general practices, where the medical students were completing their clinical placements.

This paper describes the perceptions of the medical students and special school teachers in relation to the effects of the program on the personal and professional development of the medical students involved, the acceptability of the program to the special school teachers involved, and the factors which contributed to the program outcomes.

Evaluation

Data was collected at the conclusion of the program via two semi-structured focus groups; one with the seven medical students and another with the two special school teachers who had been involved in the program delivery. Informed consent was obtained from all participants. The focus groups were conducted by three of the authors (DGC, DCF, MAC), each of whom was employed by Monash University’s RCS in East Gippsland. These three researchers had existing relationships with the medical students whom they interviewed but had not previously met the special school teachers.

The focus group questions centred on three areas:

Perceptions of the program content and delivery methods
Perceived impact of the program on the special school students, medical students, institutions, and other groups or individuals
Challenges and future improvements

All information was audio recorded and transcribed. A mixed deductive and inductive analysis was completed. We hypothesised that the program impacted on the medical students, special school teachers, school students, and potentially other stakeholders, and thus used this as a framework to guide our analysis. Data coding was completed by hand. The initial data analysis was completed by AD, a staff member working with the East Gippsland RCS and was not involved in the program delivery. Three other authors (TAW, DCF, and DGC), one of whom (TAW) was a medical student involved in the program, coded sections of the data independently. The four authors (AD, TAW, DCF, and DGC) then cross-checked codes and subsequently came to a consensus on the themes.

Ethics approval

Ethics approval was obtained from the Monash University Human Research Ethics Committee (Approval Number: A8/2009 2009001726). Consent was obtained from study participants for publication.

Results

Two main themes were identified: the symbiotic nature of the program, and the factors that contributed to the success of this community engagement activity.

Symbiotic nature of the program

The program was perceived to have mutual benefits for all involved. Its symbiotic nature was reflected by one student stating “… it was a real reciprocal thing. It felt like you were really giving… [the special school students] an opportunity to learn, but at the same time it was a personal experience of growth and learning.”

Table 1. Descriptions of the six topics covered in the health education sessions.

Benefits to the medical students and university:

Development of communication, organisation, leadership, & teaching skills

The medical students reflected that “it [community engagement] really helped us grow as people and as future doctors.” They felt that they improved their communication, organisation, leadership, and teaching skills, with another medical student commenting, “It gave me the opportunity to teach… It was a challenge at times to keep [the special school students’]… attention… and you had to learn techniques to hold the audience.”

Insight into interacting with and caring for a person with a disability

The program encouraged the medical students to develop their understanding of developmental disability, as “…it was an opportunity for… [medical students] to appreciate what it was like to interact with these… children.” One medical student reflected on parallels with the medical curriculum by stating, “…the range of issues these… [special school students] face might not be as wide as the whole developmental disability curriculum encompasses… but the teaching gave us a much deeper insight than I think we would have got reading text or listening perhaps to a lecture, because you meet these kids one-on-one…” The medical students felt that they would be more comfortable in the future when seeing patients with a disability. One student commented: “…when we are interns… and someone with a disability comes in we might change the way we interact with them.”

A desire for future community engagement

Medical students were enthusiastic to continue their involvement in community engagement activities. They felt that the experience had opened their eyes to the possibilities to help in their community, with comments such as “it was a good example for me of how you can become engaged in a community [as a doctor].” Another stated, “the difference you can make as a clinician and as a teacher is really inspiring.”

Table 2. Themes and sub-themes identified from the focus groups.

Benefits to the special school teachers and students:

It was perceived that this program benefited the special school students and its teachers. The teachers were positive in their reflections, stating “…it has been very impressive…”

Health expertise and behaviour change

The teachers at the special school were positive about the impact on their students, saying “…I really do believe that they have got a lot out of it. It has been hugely beneficial.” It was not compulsory for special school students to attend these sessions, however “…[special school students] kept turning up and staying in the sessions… if they didn’t like it, they wouldn’t have stayed there.” The teachers were impressed by the focus shown by special school students during the sessions, which they believed indicated their level of engagement with the medical students.

This was reiterated in the reflections of the medical students, who also thought they had provided the special school students with a foundation to influence future decision-making. One medical student expressed, “They were actually responding and getting engaged in these issues. I hope that is a step in the right direction.” Another added, “It is not going to change massive things but it plants a seed, I think.”

The teachers felt they too gained a greater knowledge of the topics: “There were different terminologies and things that I learnt as well.” They believed an important factor was that the information presented was tailored to their students, acknowledging “…[the medical students] targeted everything very well in relation to the issues that… [special school students] are going through at the moment.”

Breaking down barriers

It was suggested that the program helped in breaking down barriers between the special school students and health professionals, making it more likely that these students would seek medical help when needed. One medical student reflected “… maybe it will make doctors seem less intimidating later if they need to see one.”

Links within the community

Overall, the medical students and special school teachers believed that the program had enhanced relationships between the East Gippsland Clinical School, the medical students, and the local community.

Factors that contributed to the success of this community engagement activity.

All parties wanted to engage:

It was suggested that the program would not be as successful if it was compulsory for the medical students. One student stated, “if anyone went there and didn’t really want to, it could be destructive both from our point of view and for the kids.”

Support from both organisations was essential for this engagement. In addition to permitting medical students to take time out of scheduled activities, the RCS gave them access to equipment and facilities. One student said, “We contacted people at the community health centre or we used equipment from … [East Gippsland RCS] …” The special school was equally supportive and accommodative of the program, providing staff, a workplace, equipment, and remaining very flexible with teaching times.

Taking time to develop relationships:

The trust and rapport established between the medical students, special school students, and teachers was perceived to be paramount to the program’s success. A special school teacher commented, “A big part with these kids is trust… They did so well to attend these sessions and ask questions and I think they felt comfortable enough to be able to ask questions.” The medical students also believed their relationship with the special school students grew over the course of the program. One student commented, “I was involved in three sessions… and definitely by the third one [engagement improved]. …I felt like I got to know… [the special school students] reasonably well …and the sessions got better.”

Teachers felt that the medical students’ contact with the specific special school class prior to beginning the program assisted in tailoring the sessions appropriately. They stated that the “… [medical students] knew what type of kids they were going to deal with, so that prior knowledge… definitely helped to make these sessions a success… If you were just sending medical students into a classroom you would really be running blind because you don’t know the personalities of the students…”

The medical students also stated that the prior knowledge of the school, students, and staff helped them feel comfortable and was integral to the success of the program. It was suggested that if the program were to be repeated in the future, “…you would need one or two people… to go into the school for a few months and just… get to know how things work.”

Collaborative input into the development of the program and activities:

Both medical students and the teachers agreed that cross-checking the content of each individual session helped both parties prepare for the sessions. One teacher stated, “…[the medical students] rang me before the sessions… [and] went over everything.” A medical student concurred, “…the teachers appreciated… the process of going back to them before a session and checking [the content] with them.”

Leadership:

Having one person dedicated to liaising with all the stakeholders and to delegating the planning and implementation of each session was seen to be important. A medical student stated, “[One of the medical students] …has put in a huge amount of work and unless someone is prepared to be that person then I don’t think it will work as well [in the future].”

Facilitators worked as a team:

Knowing each other was perceived to help the medical students facilitate the sessions effectively as a team. One medical student observed, “…we really tried to look at the strengths of different people in the group… As a group of students running the sessions we need to be comfortable with each other as well.” The teachers reiterated that “…[medical students] worked as a team” and “…were well organised.”

Preparation of teaching sessions:

Both the teachers and medical students frequently mentioned the need for well-prepared sessions. There were however difficulties for the medical students, with one stating that “…one of the downsides is the time it takes to prepare for it, on top of everything else we are doing.”

Special school teachers felt it would be helpful to have a set schedule, noting “There were a couple of times where the sessions had to be changed… That is the only drawback… [some special school students] don’t take change very well.”

The medical students reflected that the best way to run the sessions was to plan activities and refresh their knowledge of the topic, but to also be flexible and to adjust the sessions as they proceeded. One medical student commented, “…for me it was about having as much information in my mind ready for the session and just sort of letting the group go with it a bit and still bringing it back on track… it was really quite fluid.” The teachers were impressed by this approach, stating that “… [medical students] prepared the lessons but they would also get a feel for what …[the special school students] knew.”

Non-didactic facilitation techniques:

Hands-on activities and discussions were reportedly preferable to didactic lessons. One special school teacher recalled, “There was only one session… that didn’t really have a lot of visuals. You could tell when they didn’t have the hands–on activities and visuals that… [special school students] weren’t as attentive.” Special school teachers went on to say that more hands-on activities would make sessions even more effective at engaging the special school students. They also suggested that having the key session content in writing would be beneficial.

One important aspect of the medical students’ approach to teaching was said to be a focus on informing special school students about consequences of their behaviour, rather than simply telling them that it is wrong. One student said, “The sessions… [were about] educating and saying ‘look, these are the risks and these are the issues’…rather than saying… ‘you shouldn’t do this because it is wrong.’ That helped with the engagement.”

Intra-generational education

The teachers thought that having medical students conduct the sessions was particularly beneficial, as their ages and experiences were more identifiable to their students. It was noted, “… [special school students] connect with that … [medical students are] not old, they’re still cool!”

Discussion

The results reflect our hypothesis that the program impacted stakeholders in positive ways, as well as presenting challenges for those involved. Of particular note was the perceived importance of the symbiotic nature of the program in contributing to its success. We had not foreseen the enhanced relationship that was thought to develop between the East Gippsland RCS and the local community. This was an important institutional benefit, as relationships of this nature are essential for the success of the LIC model in East Gippsland. Furthermore, universities have community engagement responsibilities and need to remain ‘socially accountable’ [15].

We also noted the responses of the medical students in relation to the perceived impact of the program on their personal and professional development. The skills in communication, teamwork, leadership, and organisation that the medical students were reported to have developed were important outcomes of the program. These are key skills highlighted in the Australian Curriculum Framework for Junior Doctors [16], and are difficult skills for a university to teach.

Determining the impact of this program on the special school students is beyond the nature of this research. Our paper does however highlight how this program provided an innovative and engaging way for the special school teachers to deliver areas of their health education curriculum.

A number of potential limitations must be considered when interpreting the results. Pre-existing relationships existed between the researchers conducting the focus groups and the medical student participants. This, along with a lack of anonymity within a focus group format, may have prevented participants from discussing concerns they had with the program. The results are also potentially limited by small participant numbers. Including additional stakeholders in the focus group discussions, most particularly the special school students, would have been beneficial but was difficult due to ethical considerations around interviewing a potentially vulnerable group.

We consider the East Gippsland RCS’ role and the fact that this was a voluntary, student-driven initiative to be of key importance. This is highlighted through the comparison of our program with a similar program where medical students based at a RCS (in NSW, Australia) were placed at a special school as part of their paediatric studies [17]. The main difference between both initiatives was that the program in NSW was designed and implemented by the university whereas our program was student initiated and directed. In both cases benefits were experienced by all stakeholders. There were however drawbacks to the NSW program. Its compulsory nature may have forced some medical students to engage against their will, which, as highlighted by one of the respondents in our focus groups, could have negative ramifications. Furthermore, the medical students in our study had far greater opportunities to develop their leadership, teamwork, communication, and organisation skills as they were the drivers of the initiative. There were also drawbacks to our program. The medical students found it challenging at times to balance their existing curricular commitments with this extra activity. Furthermore, the non-compulsory nature of our program means that its future is uncertain and depends on the motivation of subsequent medical student groups. Overall, we consider the positive aspects of this voluntary, student-driven model to outweigh the negative aspects.

Conclusion

This voluntary, medical student-initiated community engagement activity which took place during LICs was perceived to impact positively on the personal and professional development of the medical students involved, as well as being acceptable to the special school teachers. The factors that contributed to the perceived success of this program could be applied to other settings where students have the opportunity to engage with their local community. We encourage universities to play a supportive role by linking students with the local community and fostering any constructive opportunities that arise.

Conflict of interest

None declared.

References

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Tags medical student, Rural rotation, Community engagement, Health education, Symbiosis

Abstract

Introduction

Discussion

Mechanism of action of dabrafenib/trametinib combined therapy in BRAF mu-tant metastatic melanoma

Mechanisms behind combined therapy resistance

Potential mechanisms to overcome acquired resistance in dabrafenib/trametinib combined therapy Further MAPK pathway inhibition

Conclusion

References

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Introduction

Materials and Methods

Normal physiology

Pathophysiology

Treatment

Conclusion

References

Book Review

Abstract

Introduction

Case

Discussion

References

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Introduction

Discussion

Conclusion

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Introduction

Summary of the systematic review by Mbuagbaw et al. [4]

Conclusion

References

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Introduction

Reflections from a cancer survivor and their learning community

The evolution of oncology teaching

What should medical students know about cancer?

Trends in the cancer knowledge of medical graduates

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Conclusion

References

Introduction

Materials and Methods

Results

Discussion

Conclusion

References

Potential mechanisms to overcome acquired resistance in dabrafenib/trametinib combined therapy
Further MAPK pathway inhibition