Series: Volume 8, Issue 1 2017

Read online or Download the issue

Categories
Review Articles

Imatinib resistance in chronic myeloid leukaemia caused by Bcr-Abl kinase domain and non-Bcr-Abl mutations: a comparison and review.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder caused by BCR-ABL1 igureusion encoding for a tyrosine kinase oncoprotein. Since the introduction of the tyrosine kinase inhibitor (TKI), imatinib, in 2000, CML survival rates have increased, to the point where life expectancy is equal to that of the general population. One obstacle patients face is imatinib resistance. Literature about resistance has mainly focussed on mutations in the Bcr-Abl kinase domain (KD), which have been well described. Areas that have not been as well established include the origin of KD mutations and resistance from mechanisms outside of KD mutations. This review focuses on how KD mutations arise and their mechanisms of resistance and the roles of BCR-ABL1 gene amplification, Erk1, and Lyn kinase in creating resistance outside of the KD. Experimental therapies to combat imatinib resistance are also mentioned. Using database searches to obtain the current literature, this review attempts to determine the current consensus on these topics and highlight areas where research could be beneficial. While the origin of KD-mutations and non-KD resistance is not entirely clear, the many possible causes that have been elucidated thus far have already paved the way for new therapies.

 

Introduction

Chronic myeloid leukaemia (CML) was the first cancer where the pathological chromosomal abnormality was identified, and is one of the most understood and well-managed cancers [1,2]. CML is a clonal disorder of pluripotent stem cells that results in over-proliferation of mature myeloid cells [3]. Constitutive and aberrant tyrosine kinase activity is responsible for pathological cell proliferation in CML [4].
Before the advent of tyrosine kinase inhibitors (TKIs), 5-year survival rate for patients aged 20-44 was 40%, and less than 20% for patients over 65 years. For patients aged 15-44 diagnosed in 2000, this jumped to 71.6%, increasing to 86.4%, if diagnosed in 2005 [5]. Responsible for these leaps in survival was imatinib mesylate, a TKI approved in 2001 [6]. Imatinib antagonises tyrosine kinase activity by competing with ATP binding to the Bcr-Abl protein, reducing unchecked cell-cycle progression [3]. Imatinib resistance undermines therapy, putting patients at risk, and occurs in approximately 25% of patients [1]. Hence, it is important for doctors and medical students alike to understand that resistance occurs, some of the mechanisms behind resistance and how new pharmacotherapies can combat these. This review summarises the pathophysiology of CML and synthesises the literature around competing theories of imatinib resistance.

 

Pathophysiology of CML

CML is a myeloproliferative disease caused by a reciprocal translocation between chromosome 9 and 22 (9;22)(q34;q11.2)[1,7]. This creates an abnormal chromosome 22 called the Philadelphia (Ph) chromosome, named after the city it was discovered in in 1960 [2,8]. The oncogenic effects of this translocation are caused by 5’ exons of the BCR (breakpoint cluster region) gene fusing to the 3’ exons of ABL1 (Abelson tyrosine protein kinase 1) [3]. This creates the BCR-ABL1 oncogene on the Ph chromosome encoding for Bcr-Abl tyrosine kinase, or p210BCR/ABL [9-11].  Retroviral insertion of p210BCR-ABL in murine models induces a myeloproliferative disorder similar to CML [11]. However, in less than 10% of cases, gene fusion occurs in different exons creating kinases p190 or p230 depending on where the fusion occurs [12,13]. Bcr-Abl has constitutive tyrosine kinase activity, causing modulated gene transcription, proliferation, and enforced survival of myeloid progenitor cells [14]. Unregulated cells grow and enter the S-Phase of the cell cycle independently of physiological growth factors and avoid apoptosis [8,14,15]. Abl and Bcr-Abl are non-receptor tyrosine kinases that travel between the nucleus and the cytoplasm and phosphorylate proteins via SH2 and SH3 domains [16].

Figure 1. Intracellular pathways influenced by Bcr-Abl Kinase [24,25,26].
A synthesis and simplification of selected pathways (JAK/STAT, Gab2, Lyn kinase, IGF-1 and β-1 integrin) showing the leukaemogenic downstream effects of Bcr-Abl signalling. Imatinib is shown solely inhibiting Bcr-Abl, however, research shows imatinib therapy also affects Lyn kinase expression and activity.
Targets of increased phosphorylation that have proliferative effects include insulin-like growth factor receptor 1 (IGF-1R) [17], Ras [16], p27Kip [18], and others. This review will focus on a selection of the most well-known pathways (Figure 1). Bcr-Abl regulates IGF-1R expression via Stat5, which enhances IGF-1R gene expression [19,20]. IGF-1R tyrosine kinase stimulates haematopoietic stem cells and CML patients show higher than normal levels of IGF-1R mRNA [17]. When CML cells were treated with an inhibitor of tyrosine kinase phosphorylation of IGF-1R, the cells underwent apoptosis, cell-cycle arrest, and decreased cell proliferation, illustrating how IGF-1R and CML are linked [17]. One protein both IGF-1R and Bcr-Abl stimulate is Ras [21]. Ras is a well-studied oncoprotein that regulates several downstream pathways that increase cell proliferation including PI3/AKT and JAK/STAT [16]. The importance of Ras in CML pathophysiology was confirmed when association of Bcr-Abl and Ras was blocked and subsequent attempts to induce a CML-like disorder failed [22]. P27Kip is a cyclin dependent kinase (cdk) inhibitor and decreases cdk2 activity, thus inhibiting G1/S-phase progression. In CML, while the amount of P27Kip is unchanged, 80% of P27Kip is relocated to the cytoplasm, where it cannot interact with nucleic cdk2, allowing unregulated cell-cycle progression [18].  This is caused by Bcr-Abl interfering with cytoskeletal proteins such as 1-integrins [23]. These three pathways highlight that Bcr-Abl is central to CML pathology[11]. As a consequence, pharmacotherapy targeting Bcr-Abl has been developed in the form of imatinib.

 

Imatinib

Imatinib is a TKI hailed as a conceptual breakthrough in targeted chemotherapy, and is the first line treatment in CML, while also being used in Ph+ acute lymphocytic leukaemia and some gastric cancers [27]. In early evaluation studies, it was found to specifically inhibit cellular proliferation and tumour formation of Bcr-Abl expressing cells by 92%-98% [28]. Imatinib is effective when compared to other early treatments for CML, increasing the likelihood of survival at ten years by 20% when compared to the closest alternative therapy (Figure 2) [29]. The current parameters to measure successful treatment outcomes are listed with definitions in Table 1. In the International Randomized Study of Interferon and STI571, it was found that complete haematological response (CHR), complete cytogenetic response (CCyR), and major molecular response (MMR) scores were superior in imatinib-treated patients compared with interferon-treated patients [30]. Additionally, in the original trials for imatinib approval, three phase II studies involving 1027 patients showed over 90% of patient leukocyte counts returned to normal, and when combined with interferon, 100% of evaluable patients achieved CHR [31].

Figure 2. Survival with CML over time [29].
This figure from the German CML-Study group shows patient survival probability as a function of time after diagnosis in five consecutive randomised treatment optimisation studies.

 

 

Table 1. Measurements of CML therapy outcome [1,32]

Mechanism of action

Bcr-Abl has an activation loop, a P-loop with an ATP binding site (in the kinase domain) and substrate anchoring SH2 and SH3 domains [33,34,35]. Imatinib binds specifically to the ATP-binding sites of Bcr-Abl, c-kit, and platelet-derived growth factor receptors, and inhibits their tyrosine kinase activity by both preventing ATP binding and stabilising the activation loop in an inactive conformation [34,36,37]. When Bcr-Abl tyrosine kinase activity is inhibited, there is no downstream signalling and treatment is successful in 77% of all patients [1] and virtually 100% of patients treated in the early stages of the disease [34]. The European LeukemiaNet (ELN) 2013 guidelines use MMR as the marker to indicate success of TKI therapy [32], however, Thompson et al. [1]. have argued that MMR overestimates the number of patients with treatment failure.

 

Treatment considerations and mechanisms of Imatinib resistance in CML

Failure of TKI therapy is caused by a number of factors, including inappropriate drug choice, patient non-adherence, and drug resistance. There are a number of opinions as to what constitutes treatment failure, but the definition used by this paper is the one put forward by the ELN and European Society for Medical Oncology. Treatment failure depends on which measurement is used; using haematological parameters (testing peripheral leukocyte counts), treatment failure is defined as no haematological response by three months, or any loss of CHR. Using cytogenetic response, however, treatment failure is no cytogenetic response within six months, no CCyr by 18 months, or any loss of CCyr, as detected by CBA [38]. Finally, a sub-optimal molecular response is defined as no MMR by 18 months or loss of MMR at any point using PCR for BCR-ABL1 transcripts [38]. While this review focuses on imatinib (the gold standard in CML therapy) [30], second generation TKIs such as nilotinib, ponatinib, and dasatinib are now also used, both as first line agents and for use in imatinib resistant patients [1,27].  Which TKI to use and at what dose depends on a number of factors, including imatinib sensitivity and which disease phase the patient is in. CML is staged into chronic phase (CP), accelerated phase (AP), and blast phase (BP) (Table 2) [39]. For instance, a patient in AP who has never had a TKI is still treated with imatinib, but if they have taken imatinib and then progressed to AP, a second generation TKI is used [1]. Using imatinib inappropriately could cause treatment failure, while immediately using a second generation TKI or increasing TKI dosages has been found to limit adherence, as well as side effects (Table 2), especially for patients who require more potent TKIs and higher doses [40].

Table 2. Stages of CML with respective treatment options and side effects[1,27,41,42].
The most serious complication in CML treatment is resistance to therapy. This occurs most frequently in the AP and BP stages of the disease22.  Traditionally, resistance is thought to occur from point mutations in the Bcr-Abl kinase domain (KD) [1,15,34,43]. There are several mutations that can cause mutations in this setting (Table 3). Bcr-Abl KD mutations can be intrinsic (primary) or acquired (secondary) and interfere with TKI therapy in a number of ways [1]. The most common mechanisms are by directly interfering with TKI binding via amino acid substitutes in the ATP binding site or by preventing the activation loop from adopting the inactive conformational state [34]. Although Abl KD mutations causing TKI resistance were first induced in laboratory cell lines in 2000 [44], and detected in vivo clinically in 2001 [45], novel mutations are continually being discovered, with two new mutations conferring resistance sequenced in 2014 [46]. The discovery and sequencing of mutations has led to individualised therapy and a more accurate prognosis for specific mutations, for instance the T315I mutation. In this common mutation, threonine-315 is replaced with isoleucine, effectively removing a hydrogen-bonding site required for TKI binding resulting in enormous treatment difficulty [34]. Only one TKI has any activity in T315I+ patients and that is the highly potent ponatinib. However, this drug is not used as a front line therapy as it has a higher rate of arterial thrombosis and pancreatitis when compared to imatanimb [1]. A novel drug that binds to a nearby site not affected by the mutation, HS-438, is being investigated for use in T315I+ CML and has shown success in pre-clinical trials [47]. Another drug, ABL001, also acts at another molecular site and thus avoids the resistance caused by KD mutations. ABL001 mimics the autoregulating region of ABL1 that is lost upon fusion of BCR, restoring negative regulation, and has been shown to remain effective against clinically significant mutations in an in vivo model [48]. This example highlights how sequencing mutations can provide valuable, individualised prognostic information and guide future research.

Table 3. Sample of p210BCR/ABL kinase domain mutations known to cause resistance [1,34,49-51].  *Incidence based off Ursan et al.’s meta-analysis of a total of 1,698 patients. Overall mutation rate for imatinib was 9.7% [50].
How these mutations arise is not clear; in some patients with secondary resistance pre-therapeutic samples revealed the same KD mutation detected at relapse, consistent with selection of pre-existing resistant clones during therapy giving an evolutionary advantage [52,53]. There is some contention as to whether these stem cell mutations can cause primary resistance or whether KD point mutations can only cause secondary resistance and relapse. Previous studies have concluded that Bcr-Abl KD mutations are a rare cause for primary resistance, however, more recent research found KD mutations in 56% of patients with primary resistance [54,55]. This discrepancy may be explained by the more recent study utilising more sensitive technology and patients who had CML for a longer period of time, which has been linked to mutagenicity [28]. KD resistance in Bcr-Abl1 CML differs from other diseases in that unlike traditional drug resistance, where treatment resistance arises via positive selection of tumour cells with mechanisms to avoid DNA damage, in CML resistant cells there is a tendency to accumulate more rather than less DNA damage [56]. The mechanism behind this is unknown, but it is an example of how the malignancy directly causes resistance. Nevertheless, the evidence suggests that pre-existing KD mutations in cancer stem cells are more likely to be responsible for secondary resistance.

Other research suggests that BCR-ABL1 has the ability to cause self-mutagenesis.  Mutation rate and advanced disease phase were correlated, consistent with mutations being related to exposure time to Bcr-Abl activity [34]. One suggested mechanism is production of reactive oxygen species causing genomic instability, shown in vitro and in murine models, but beyond the original studies, no further research has been undertaken [34,57]. While KD mutations are a highly researched area in CML therapy (over 60 unique point mutations have been identified), there remains an information deficit, for example, the prevalence of mutations in specific populations, or randomised controlled trials for TKI choice following imatinib failure [1,58].

 

Non Bcr-Abl kinase domain mediated resistance

Recent research adds complexity by suggesting there are a number of mutations and events occurring outside of Bcr-Abl KD that impact drug resistance [43].This includes mutations of Bcr-Abl1 outside of the kinase domain, such as BCR-ABL1 amplification, and causes outside of the Bcr-Abl1 protein altogether, such as mesenchymal cells, drug transporters and bypass molecular pathways. Increased BCR-ABL1 expression via gene amplification is found in most TKI resistant cells, whether the mutations are primary, secondary, KD, or non-KD, implying a link between increased expression and resistance [59]. However, increased expression is not the sole cause of non-KD mediated resistance as studies have shown that increasing imatinib concentration in non-mutated, sensitive cells with induced BCR-ABL1 amplification still reduces Bcr-Abl activity, whereas some resistant cells without KD mutations remain resistant at any dose [60].

Extracellular Signal-Regulated Kinase 2 (Erk2) is a Mitogen Activated Protein Kinase (MAPK) and has been implicated in both primary and secondary resistance (i.e. immediate resistance to therapy and resistance that builds over time)[60,61]. In a study of non-KD mutated resistant cells treated with imatinib, Erk2 was found in the nucleus of resistant cells only, and inhibiting Erk2 caused damage to resistant cells [60]. Mechanisms for how Erk2 could cause primary resistance were then elucidated. To achieve this, mutated Ras (which activates Erk2), was virally transduced into sensitive cells that were cultured and treated with imatinib. Using proliferation assays to determine cell survival, it was discovered activating Erk2 gave previously sensitive cells resistance without any prior exposure to imatinib. Erk2 is a key regulator of the pro-apoptotic molecule Bim and it is proposed interactions between Erk2 and Bcr-Abl over-stimulate Erk2 and reduce CML cell apoptosis [62]. Research in 2016 by Wong et al. [63] extended these results to create a pharmacotherapy inhibiting Erk2, showing areas outside of the KD can cause primary and secondary resistance and can be targeted.

 

Lyn kinase

Lyn kinase is a non-receptor tyrosine kinase regulated by Bcr-Abl. Imatinib resistant but Bcr-Abl KD-mutation negative cells were found to overexpress Lyn kinase following treatment with imatinib [64]. In cell lines from these patients, while imatinib effectively inhibited Bcr-Abl activity, Lyn kinase phosphorylation continued, allowing proliferation to continue. Interestingly, prior to imatinib therapy, there was no consistent difference in Lyn expression between sensitive and resistant cells, but afterward there were consistent distinctions in their control of phosphorylation. This implies imatinib treatment uncouples Lyn expression from Bcr-Abl, leading to resistance. Lyn overexpression can induce a three to fourfold resistance, equal to some KD mutations, yet the mechanisms of its overexpression and how it worsens CML are not yet known [65]. One theory is that because silencing of Lyn kinase induces apoptosis in CML cells, overexpression causes cell survival, signalled through via Gab2 [66,67]. The fact that this effect is not seen in imatinib-naïve CML patient cells supports the idea that Lyn kinase only causes acquired resistance, leaving the mechanisms behind primary resistance a mystery.

 

Drug transporters

Alterations in drug transporters are yet another mechanism by which medication resistance can occur and will be mentioned briefly. A drug must both reach the target organ in sufficient amounts and be present at an effective therapeutic concentration for it to exert and effect, and both influx and efflux transporters can interfere with these pharmacokinetics [27]. Radiolabelled imatinib assays have determined that the level of kinase inhibition is dependent on the level of uptake and retention of imatinib achieved [68]. Imatinib enters the circulation from the gastrointestinal tract by a member of the organic cation transporter (OCT) family, OCT-1, thus mutations in OCT-1 are thought to contribute to treatment failure [68]. Conversely, imatinib leaves the cell via the p-glycoprotein multidrug resistance protein-1 (MDR1 or ABCB1) [69]. In other drugs, MDR1 overexpression has been confirmed to cause drug resistance by increasing efflux before a therapeutic concentration can be reached, and this is a relationship currently under investigation in CML.

Non-Bcr-Abl KD resistance is not a well-studied area and much research is yet to be undertaken. Two recent CML mutation reviews by Jabbour et al. and O’Hare et al. only provide a brief mention of non Bcr-Abl mutations causing resistance, even though these mutations cause from 10%-40% of TKI resistance [3,70]. In addition, there was much disagreement among researchers concerning molecular pathways to resistance. Erk2 is part of a super-family of MAPKs, other members such as Erk1, Erk5, and P38MAPK, have been considered in imatinib resistance [71,72]. Aceves-Luquero et al. carried out knock-out studies of MAPKs, which identified only Erk2 as having a resistance-inducing effect [52]. Extremely resistant patients require potent TKIs or stem-cell transplantation, both of which greatly affect quality of life, which could be avoided if mechanisms behind resistance were uncovered and targeted treatment developed1.

 

Limitations

While p210BCR-ABL accounts for 90% of cases of CML, other Bcr-Abl variants were not examined despite their different treatment responses, limiting the applicability of this review. Furthermore, the diagram in Figure 1 is a simplified representation of the pathways associated with Bcr-Abl, especially in the case of JAK/STAT. Only pathways that have been clearly implicated in CML and imatinib resistance by research literature were included. Systematic database searches were used to carry out this review. Spelling and terminology variations that influence search results, for example, “myeloid” and “myelogenous”, were a limiting factor.

 

Clinical implications

This article holds a number of clinical implications for all medical students, not just the aspiring oncologist. For instance, the prevailing view in oncology is that mutations that confer imatinib resistance occur in the kinase domain. With the explosion of advances in genome sequencing, it is becoming possible to prospectively genetically screen patients to determine whether resistance will occur. If the current wisdom regarding CML resistance prevails, then mutations outside the kinase domain (that have been reported to cause between 10% – 40% of resistance) could be ignored, potentially putting patients at risk of ineffective treatment which could cost them their lives [2]. By investigating and becoming aware of the role of non-KD mutations, doctors could also give more accurate prognoses to patients with these mutations and begin studies looking at the best treatment for these cases (for example, randomised controlled trials comparing current therapy to higher doses of imatinib, or new pharmacological agents altogether). This review also provides a general overview into CML pathophysiology, imatinib pharmacology and chemotherapy resistance, topics every medical practitioner should be very familiar with.

 

Conclusion

Imatinib is a TKI that revolutionised leukaemia treatment and increased the length and quality of life of CML patients. While it has been known for many years that primary and secondary resistance to imatinib exist, the mechanisms have not been fully explained. While mutations in the Bcr-Abl KD account for the majority of resistance and are well known, what remains unclear is the origin of these mutations, and how resistance occurs without KD mutations.  Stem cell mutations and self-mutagenesis are possible explanations for how KD mutation occurs, and gene amplification, Lyn kinase and Erk2 for resistance occurring outside of the KD. Further research identifying key events in downstream pathways will offer new approaches for overcoming all forms of imatinib resistance.

 

Acknowledgements

The author would like to thank and acknowledge A/Prof Peter Johnson and A/Prof Bill Warren of James Cook University School of Medicine and Dentistry who provided comments and feedback on this paper. The author would also like to thank Dr. Donna Rigano and Miss Shalisa Maisrikrod for their assistance and editing help.

 

Conflicts of interest

None declared

 

References

  1. Thompson PA, Kantarjian HM, Cortes JE. Diagnosis and treatment of chronic myeloid leukemia in 2015. Mayo Clinic proceedings. 2015;90(10):1440-54.
  2. Nowell P HD. A minute chromosome in human chronic granulocytic leukemia. Science. 1960;132:1497.
  3. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Haematol. 2014;89(5):547-56.
  4. An X, Tiwari AK, Sun Y, Ding PR, Ashby CR, Jr., Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leukemia research. 2010;34(10):1255-68.
  5. Brunner AM, Campigotto F, Sadrzadeh H, Drapkin BJ, Chen YB, Neuberg DS, et al. Trends in all-cause mortality among patients with chronic myeloid leukemia: a surveillance, epidemiology, and end results database analysis. Cancer. 2013;119(14):2620-9.
  6. Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research. 2002;8(5):935-42.
  7. JD R. A new consistent chromosomal abnormality in chromc myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-3.
  1. Holtz MS, Forman SJ, Bhatia R. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia. 2005;19(6):1034-41.
  2. Rafiei A, Mian AA, Doring C, Metodieva A, Oancea C, Thalheimer FB, et al. The functional interplay between the t(9;22)-associated fusion proteins BCR/ABL and ABL/BCR in Philadelphia chromosome-positive acute lymphatic leukemia. PLoS genetics. 2015;11(4):e1005144.
  3. McLaughlin J, Chianese E, Witte ON. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proceedings of the National Academy of Sciences of the United States of America. 1987;84(18):6558-62.
  4. Daley GQ, Van Etten RA, Baltimore D. Induction of Chronic Myelogenous Leukemia in Mice by the P210$^{bcr/abl}$ Gene of the Philadelphia Chromosome. Science. 1990;247(4944):824-30.
  5. Arana-Trejo RM, Ruiz Sanchez E, Ignacio-Ibarra G, Baez de la Fuente E, Garces O, Gomez Morales E, et al. BCR/ABL p210, p190 and p230 fusion genes in 250 Mexican patients with chronic myeloid leukaemia (CML). Clinical and laboratory haematology. 2002;24(3):145-50.
  6. Chan LC, Karhi KK, Rayter SI, Heisterkamp N, Eridani S, Powles R, et al. A novel abl protein expressed in Philadelphia chromosome positive acute lymphoblastic leukaemia. Nature. 1987;325(6105):635.
  7. Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, Toren A, Shomron N, Raanani P, et al. Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment. Cancer letters. 2015;360(2):245-56.
  8. Jonuleit T, Peschel C, Schwab R, van der Kuip H, Buchdunger E, Fischer T, et al. Bcr-Abl kinase promotes cell cycle entry of primary myeloid CML cells in the absence of growth factors. British journal of haematology. 1998;100(2):295-303.
  9. Bertacchini J, Ketabchi N, Mediani L, Capitani S, Marmiroli S, Saki N. Inhibition of Ras-mediated signaling pathways in CML stem cells. Cell Oncol. 2015;38(6):407-18.
  10. Shi P, Chandra J, Sun X, Gergely M, Cortes JE, Garcia-Manero G, et al. Inhibition of IGF-IR tyrosine kinase induces apoptosis and cell cycle arrest in imatinib-resistant chronic myeloid leukaemia cells. Journal of cellular and molecular medicine. 2010;14(6B):1777-92.
  11. Jiang Y, Zhao RC, Verfaillie CM. Abnormal integrin-mediated regulation of chronic myelogenous leukemia CD34+ cell proliferation: BCR/ABL up-regulates the cyclin-dependent kinase inhibitor, p27Kip, which is relocated to the cell cytoplasm and incapable of regulating cdk2 activity. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(19):10538-43.
  12. Lakshmikuttyamma A, Pastural E, Takahashi N, Sawada K, Sheridan DP, DeCoteau JF, et al. Bcr-Abl induces autocrine IGF-1 signaling. Oncogene. 2008;27(27):3831-44.
  13. Xie J, Chen X, Zheng J, Li C, Stacy S, Holzenberger M, et al. IGF-IR determines the fates of BCR/ABL leukemia. Journal of hematology & oncology. 2015;8:3.
  14. Zha J, Lackner MR. Targeting the insulin-like growth factor receptor-1R pathway for cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010;16(9):2512-7.
  15. Million RP, Van Etten RA. The Grb2 binding site is required for the induction of chronic myeloid leukemia-like disease in mice by the Bcr/Abl tyrosine kinase. Blood. 2000;96(2):664-70.
  16. Bhatia R, Verfaillie CM. Inhibition of BCR-ABL expression with antisense oligodeoxynucleotides restores beta1 integrin-mediated adhesion and proliferation inhibition in chronic myelogenous leukemia hematopoietic progenitors. Blood. 1998;91(9):3414-22.
  1. Sattler M, Mohi MG, Pride YB, Quinnan LR, Malouf NA, Podar K, et al. Critical role for Gab2 in transformation by BCR/ABL. Cancer Cell. 2002;1(5):479-92.
  2. Goss VL, Lee KA, Moritz A, Nardone J, Spek EJ, MacNeill J, et al. A common phosphotyrosine signature for the Bcr-Abl kinase. Blood. 2006;107(12):4888-97.
  3. O’Hare T, Deininger MW, Eide CA, Clackson T, Druker BJ. Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia. Clin Cancer Res. 2011;17(2):212-21.
  4. Rang HP RJ, Flower RJ, Henderson G. Anti-Cancer Drugs. Rang & Dale’s Pharmacology. 8th Edition ed. Philadelphia, Pennsylvania: Elsevier; 2015. p. 687-8.
  5. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature medicine. 1996;2(5):561-6.
  6. Hehlmann R. CML—where do we stand in 2015? Annals of Hematology. 2015;94(2):103-5.
  7. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. The New England journal of medicine. 2003;348(11):994-1004.
  8. Habeck M. FDA licences imatinib mesylate for CML. The Lancet Oncology. 2002;3(1):6.
  9. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84.
  10. Segaliny AI, Tellez-Gabriel M, Heymann MF, Heymann D. Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. Journal of bone oncology. 2015;4(1):1-12.
  11. O’Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110(7):2242-9.
  12. Ren SY, Xue F, Feng J, Skorski T. Intrinsic regulation of the interactions between the SH3 domain of p85 subunit of phosphatidylinositol-3 kinase and the protein network of BCR/ABL oncogenic tyrosine kinase. Experimental hematology. 2005;33(10):1222-8.
  13. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer research. 1996;56(1):100-4.
  14. Kantarjian HM, Cortes JE, O’Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003;101(1):97-100.
  15. Jabbour E, Cortes JE, Kantarjian HM. Suboptimal response to or failure of Imatinib treatment for chronic myeloid leukemia: what is the optimal strategy? Mayo Clinic proceedings. 2009;84(2):161-9.
  16. World Health Organization Classification of Tumors of Haematopoietics and Lymphoid Tissues. . In: Swerdlow SH CE, Harris NL, et al, editor. Lyon, France: IARC Press; 2008.
  17. Branford S, Yeung DT, Prime JA, Choi SY, Bang JH, Park JE, et al. BCR-ABL1 doubling times more reliably assess the dynamics of CML relapse compared with the BCR-ABL1 fold rise: implications for monitoring and management. Blood. 2012;119(18):4264-71.
  18. Australian public assessment report for Imatinib, Nilotinib and Dastinib. In: Administration TG, editor. Woden, ACT, Australia 2014.
  19. Song KW, Rifkind J, Al-Beirouti B, Yee K, McCrae J, Messner HA, et al. Subdural hematomas during CML therapy with imatinib mesylate. Leukemia & lymphoma. 2004;45(8):1633-6.
  20. Wei Y, Hardling M, Olsson B, Hezaveh R, Ricksten A, Stockelberg D, et al. Not all imatinib resistance in CML are BCR-ABL kinase domain mutations. Annals of Hematology. 2006;85(12):841-7.
  21. le Coutre P TE, Varella-Garcia M, et al. Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 2000;95(2):1758-66.
  22. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293(5531):876-80.
  23. Elias MH, Baba AA, Azlan H, Rosline H, Sim GA, Padmini M, et al. BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome. Leukemia research. 2014;38(4):454-9.
  24. Yun SM, Jung KH, Kim SJ, Fang Z, Son MK, Yan HH, et al. HS-438, a new inhibitor of imatinib-resistant BCR-ABL T315I mutation in chronic myeloid leukemia. Cancer letters. 2014;348(1-2):50-60.
  25. Wylie A, Schoepfer J, Berellini G, Cai H, Caravatti G, Cotesta S, et al. ABL001, a potent allosteric inhibitor of BCR-ABL, prevents emergence of resistant disease when administered in combination with Nilotinib in an in vivo murine model of chronic myeloid leukemia. Blood. 2014;124(21):398.
  26. Valent P. Imatinib-resistant chronic myeloid leukemia (CML): current concepts on pathogenesis and new emerging pharmacologic approaches. Biologics. 2007;1(4):433-48.
  27. Ursan ID, Jiang R, Pickard EM, Lee TA, Ng D, Pickard AS. Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors. J Manag Care Spec Pharm. 2015;21(2):114-22.
  28. Qin Y, Chen S, Jiang B, Jiang Q, Jiang H, Li J, et al. Characteristics of BCR-ABL kinase domain point mutations in Chinese imatinib-resistant chronic myeloid leukemia patients. Annals of hematology. 2011;90(1):47-52.
  29. Carella AM, Garuti A, Cirmena G, Catania G, Rocco I, Palermo C, et al. Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia. Leukemia & lymphoma. 2010;51(2):275-8.
  30. Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007;110(2):727-34.
  31. Gruber FX, Lundan T, Goll R, Silye A, Mikkola I, Rekvig OP, et al. BCR-ABL isoforms associated with intrinsic or acquired resistance to imatinib: more heterogeneous than just ABL kinase domain point mutations? Medical oncology. 2012;29(1):219-26.
  32. Willis SG, Lange T, Demehri S, Otto S, Crossman L, Niederwieser D, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005;106(6):2128-37.
  33. Skorski T. BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability. Oncogene. 2002;21(56):8591-604.
  34. Sallmyr A, Fan J, Rassool FV. Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair. Cancer letters. 2008;270(1):1-9.
  35. Nicolini FE, Corm S, Le QH, Sorel N, Hayette S, Bories D, et al. Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP). Leukemia. 2006;20(6):1061-6.
  36. Karimiani EG, Marriage F, Merritt AJ, Burthem J, Byers RJ, Day PJ. Single-cell analysis of K562 cells: an imatinib-resistant subpopulation is adherent and has upregulated expression of BCR-ABL mRNA and protein. Experimental hematology. 2014;42(3):183-91 e5.
  37. Aceves-Luquero CI, Agarwal A, Callejas-Valera JL, Arias-Gonzalez L, Esparis-Ogando A, del Peso Ovalle L, et al. ERK2, but not ERK1, mediates acquired and “de novo” resistance to imatinib mesylate: implication for CML therapy. PloS one. 2009;4(7):e6124.
  38. Hartel N, Klag T, Hanfstein B, Mueller MC, Schenk T, Erben P, et al. Enhanced ABL-inhibitor-induced MAPK-activation in T315I-BCR-ABL-expressing cells: a potential mechanism of altered leukemogenicity. Journal of cancer research and clinical oncology. 2012;138(2):203-12.
  39. Kuroda J, Puthalakath H, Cragg MS, Kelly PN, Bouillet P, Huang DC, et al. Bim and Bad mediate imatinib-induced killing of Bcr/Abl+ leukemic cells, and resistance due to their loss is overcome by a BH3 mimetic. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(40):14907-12.
  40. Wong SM, Liu FH, Lee YL, Huang HM. MPT0B169, a New Antitubulin Agent, Inhibits Bcr-Abl Expression and Induces Mitochondrion-Mediated Apoptosis in Nonresistant and Imatinib-Resistant Chronic Myeloid Leukemia Cells. PloS one. 2016;11(1):e0148093.
  41. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101(2):690-8.
  42. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, et al. Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. Journal of the National Cancer Institute. 2008;100(13):926-39.
  43. Ptasznik A, Nakata Y, Kalota A, Emerson SG, Gewirtz AM. Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells. Nature medicine. 2004;10(11):1187-9.
  44. Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z, et al. Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood. 2008;111(7):3821-9.
  45. White DL, Saunders VA, Dang P, Engler J, Zannettino ACW, Cambareri AC, et al. OCT-1–mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib. Blood. 2006;108(2):697.
  46. Illmer T, Schaich M, Platzbecker U, Freiberg-Richter J, Oelschlägel U, Bonin Mv, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18(3):401-8.
  47. Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA working party on chronic myeloid leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(24):7374-9.
  48. Buschbeck M, Hofbauer S, Di Croce L, Keri G, Ullrich A. Abl-kinase-sensitive levels of ERK5 and its intrinsic basal activity contribute to leukaemia cell survival. EMBO reports. 2005;6(1):63-9.
  49. Ozaki K, Kosugi M, Baba N, Fujio K, Sakamoto T, Kimura S, et al. Blockade of the ERK or PI3K-Akt signaling pathway enhances the cytotoxicity of histone deacetylase inhibitors in tumor cells resistant to gefitinib or imatinib. Biochemical and biophysical research communications. 2010;391(4):1610-5.
Categories
Review Articles

MicroRNA-34a: a novel treatment approach for hepatocellular carcinoma

Aim:  To ascertain the function of miRNA-34a in hepatocellular carcinoma (HCC) and to assess its use as a therapeutic agent through the analysis of pre-clinical and clinical trials.

 

Discussion:  Multiple studies found that miRNA-34a was down-regulated in the majority of human HCC samples and subsequently had a tumour suppressor role via the inhibition of a number of target genes essential for carcinogenesis. MRX34, a miRNA-34a mimic, is currently in an ongoing phase I clinical trial. Interim data has indicated that this therapy has a manageable safety profile, with a partial response observed in one patient. The combination of miRNA-34a with other agents has also proven to exert enhanced anti-tumour effects. Conversely, many studies have reported that miRNA-34a was up-regulated in HCC samples, particularly in those with activation of the beta-catenin pathway.

 

Conclusion: Pre-clinical studies have shown promising results in the use of a miRNA-34a mimic in HCC as a single agent or as a combination therapy, however, the results from the phase I trial are yet to be fully established. The mechanisms of miRNA-34a in HCC remain to be elucidated, with further research required into its proposed oncogenic role, especially relating to the clinical implications of this interaction.

 

Introduction

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related deaths worldwide and is the most common form of liver cancer, accounting for between 85% and 90% of primary liver cancers [1]. The major risk factors for hepatocellular carcinoma include hepatitis B (HBV) or C virus (HCV) infection, smoking, alcohol, and aflatoxin [2]. Currently the prognosis for HCC is poor with Australian statistics indicating that the five year relative survival rate for primary liver cancers is only 16% [3]. The non-specific tyrosine kinase inhibitor sorafenib currently represents the only effective treatment against HCC [4]. This poor prognostic outlook and the limited availability of targeted molecular agents for HCC has led to the development of new therapies such as microRNAs (miRNAs).

miRNAs are short (19-24 nucleotides), non-coding RNA molecules that are post-transcriptional regulators of gene expression. Initially, miRNA is transcribed as primary miRNA (pri-miRNA), which is processed into precursor miRNA (pre-miRNA). This is then transported from the nucleus into the cytoplasm where it is processed into its mature form by the enzyme Dicer. The mature miRNA forms part of the RNA-induced silencing complex (RISC), which is responsible for regulating the output of protein-coding genes. These miRNAs interact with the 3’ untranslated regions (UTRs) of the protein-coding genes to result in a decrease in protein output via mRNA degradation or translational repression [5]. Alternatively, miRNAs can result in post-transcriptional stimulation of gene expression via a multitude of direct and indirect mechanisms [6]. It is estimated that a single miRNA can target hundreds to over one thousand different mRNAs, ultimately resulting in miRNAs being responsible for the regulation of around 20-30% of all protein-encoding genes [7]. These miRNAs have been reported to have key roles in cancer initiation, progression, and metastasis [8]. Oncogenic miRNAs are miRNAs that are up-regulated in cancer cells and promote carcinogenesis via the inhibition of tumour suppressor genes. Conversely, the miRNAs that are decreased in cancer cells are known as tumour suppressor miRNAs, as they normally inhibit proto-oncogenes to prevent cancer from developing [9].  The mammalian miRNA-34 family consists of miRNA-34a, which is encoded via its own individual transcript, and miRNA-34b and miRNA-34c, which possess a common primary transcript [10]. Due to the promising and extensive research conducted on miRNA-34a, this review article focused specifically on this particular isoform. Dysregulation of miRNA-34a has been implicated in a wide variety of cancers, including prostate, colon [11], and HCC [12]. The purpose of this review is to analyse the specific role of miRNA-34a in HCC, including addressing contradictory findings and investigating the recent clinical trials.

Table 1. Percentage of human HCC samples with decreased miRNA-34a expression compared to surrounding non-cancerous liver tissue.

The tumour suppressor role of miRNA-34a in hepatocellular carcinoma

A range of studies established that in the majority of human HCC samples, miRNA-34a expression was decreased in comparison to the surrounding non-cancerous liver tissue (Table 1) [12-16]. A murine model of hepatocarcinogenesis induced by a methyl-deficient diet also resulted in the down-regulation of miRNA-34a [17]. Low expression of miRNA-34a in HCC samples has been correlated with a shorter overall [13-15] and disease-free survival [14], as well as higher recurrence rates [13] when compared with samples that displayed up-regulation of miRNA-34a. The decreased expression of miRNA-34a is thought to be caused by genetic alterations such as deletions, point mutations, or chromosomal translocations of its genomic region 1p36 [18], which is common in HCC [19, 20]. Alternatively, this decreased expression has been linked to inactivating mutations of the p53 gene [18], as the induction of miRNA-34a is correlated with p53 status [21]. Furthermore, epigenetic silencing of miRNA-34a has been implicated with these decreased expression levels in multiple forms of cancer, via abnormal CpG methylation in its promoter region [22].

The administration of a miRNA-34a mimic (MRX34) has been shown to cause inhibition of a number of genes within multiple oncogenic pathways such as Wnt/ beta-catenin, c-MET, VEGF, hedgehog, and MAPK (all of which have been implicated in hepatocarcinogenesis), as well as stimulating multiple genes of the p53 pathway [23]. Daige et al. explored a diverse range of HCC related pathways, demonstrating how miRNA-34a exerts its anti-cancer effects by modulation of a number of genes responsible for processes such as metastasis, cellular proliferation, cell cycle regulation, apoptosis, and cellular senescence [23].

 

miRNA-34a and cellular proliferation, cell cycle regulation, and apoptosis

A number of cell culture studies investigated the effects of ectopic expression of miRNA-34a in the HepG2 cell line, with contradicting results [12,16,18]. Ectopic expression of miRNA-34a caused significant inhibition of cellular proliferation at 72 hours [18] and 96 hours [16] post- transfection. In addition, miRNA-34a was demonstrated to regulate the cell cycle via inducing G1 arrest [18]. Furthermore, it has been found that miRNA-34a can induce apoptosis, as determined by increased caspase 3/7 activity [16]. In contrast, other reports claimed that there was no effect on cellular proliferation, G1 arrest, or apoptosis, [12,18], highlighting the conflicting information within the current literature. The discrepancies between these three studies could partially be explained by the varying methods used to express miRNA-34a, and the different measurement times post-transfection (48, 72 or 96 hours) [16]. Additional research has found that miRNA-34a induces apoptosis in HCC cells via binding to the 3’ UTR of the Bcl-2 mRNA, causing inhibition of its translation [15]. Over-expression of miRNA-34a has also been correlated with a decreased expression of Bcl-2 in a number of other HCC studies [14,24].

 

miRNA-34a and metastasis

Down-regulation of miRNA-34a expression has been associated with metastatic HCC [12,16,25]. Multiple studies have established that the ectopic[1] expression of miRNA-34a in the HepG2 cell line inhibits tumour cell migration and invasion via silencing of the c-Met gene, which subsequently decreases the c-Met-induced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) [12,16]. Cheng et al. also proposed that miRNA-34a prevents tumour migration, invasion, and metastasis by decreasing cathepsin D [18], a protease that contributes to the degradation of the basement membrane [26]. Furthermore in the HCC cell line Hca-F (high lymphatic metastatic potential) it was determined through in vitro and in vivo studies in mice that the ectopic expression of miRNA-34a caused a reduction in the metastatic potential [27].

 

miRNA-34a and cellular senescence

Earlier studies showed that miRNA-34a induced cellular senescence via cell cycle arrest in pathways that were telomere-independent [13, 28]. Recently, miRNA-34a over-expression has been shown to induce senescence in HCC cells in a telomere-dependent manner, regulated by p53.  This cellular senescence occurs by the inhibition of FoxM1 and c-Myc, which causes the inactivation of telomerase activity, resulting in telomere shortening (Figure 1) [13].

Figure 1. Telomere dependent pathway of miRNA-34a induced cellular senescence (adapted from Xu et al. [13]). High levels of miRNA-34a, which is regulated by p53, results in the inhibition of FoxM1 and c-Myc, causing the inactivation of telomerase, leading to telomere shortening and subsequently cellular senescence.

miRNA-34a delivery methods

There is a vast array of delivery systems, both viral and non-viral, that are used to increase miRNA expression. Both mechanisms are associated with advantages and disadvantages [29]. Rubone and MRX34 are two prominent non-viral delivery methods that have been investigated in HCC studies [23,24].  Rubone is a small molecular modulator of miRNA-34a that was shown to induce miRNA-34a expression selectively in HCC cells (although only those with wild-type or mutant p53, not with p53 deletion), causing inhibition of tumour growth both in vitro and in vivo in the HepG2 xenograft mouse model.  Xiao et al. also found that this miRNA-34a modulator displayed similar or even greater anti-HCC activity than sorafenib, the current treatment for advanced HCC [24]. MRX34 is a double-stranded miRNA-34a mimic that is delivered by liposomes [30]. The systemic delivery of this molecule resulted in tumour regression during in vivo studies in two different xenograft mouse models (Hep3B and HuH7) of liver cancer [23]. An oncolytic adenoviral vector that co-expressed miRNA-34a and IL-24 has also been studied in a HCC model. This was found to cause increased anti-tumour activity both in vitro and in vivo, predominantly via the downregulation of SIRT1 and Bcl-2 [14].

 

Clinical trials

Currently there is an ongoing phase I trial of MRX34 [31], which commenced in April 2013 and was originally indicated for patients with primary liver cancer or cancers with metastasis to the liver [32]. It was then gradually expanded to include patients with other advanced solid tumours (with or without liver metastasis) and haematological malignancies (lymphoma and multiple myeloma) [31]. There were 75 patients with advanced solid tumours enrolled in this study and 30 of these had HCC [33]. This trial’s data revealed that partial responses to the treatment, as per the RECIST guidelines (Table 2) [34], were observed in one patient with HCC, one with melanoma, [33] and one with advanced renal cell carcinoma [35]. Furthermore a number of patients in this trial were found to have attained a stable disease state [35]. This interim phase I data also determined that MRX34 has a manageable safety profile [33]. A recent press release from MIRNA therapeutics has indicated that phase II clinical trials will commence by the end of 2016 and will consist of two studies, one on renal cell carcinoma and the other on melanoma [35]. In terms of HCC-specific trials with MRX34, the future direction is currently unclear and with limited data available at the present time it is difficult to draw any definitive conclusions.

Table 2. Revised RECIST guidelines [34]

Combination therapy

Yang et al. demonstrated that ectopic expression of miRNA-34a resulted in the sensitisation of HCC cells to sorafenib-induced apoptosis and toxicity via inhibiting expression of Bcl-2 [15]. Additionally, the administration of miRNA-34a was found to sensitise HCC cells to chemotherapy (cisplatin) in vitro through the AXL pathway [36]. The combination of a miRNA-34a mimic and C-met inhibitor also resulted in a greater inhibition of cell growth and induction of apoptosis in vitro than either of these two therapies alone [16]. However, to establish more definitive results, further research is required in this field, particularly in regards to clinical trials.

 

The oncogenic role of miRNA-34a in hepatocellular carcinoma

Conversely, a number of other studies have shown increased expression of miRNA-34a in both murine and human HCC tissues [37-41], suggesting it may have an oncogenic role in addition to its tumour suppressor role. A recent article has investigated these claims and found that miRNA-34a displays oncogenic properties in liver tumours with beta-catenin activation [40]. Increased beta-catenin activation is most commonly caused by mutations in the CTNNB1 gene (the gene encoding  beta-catenin), and this is estimated to occur in 20-40% of HCCs [42]. Gougelet and colleagues demonstrated using ApcKO mice (ApcKO causes activation of the Wnt/beta-catenin pathway [43]) that administration of a miRNA-34a inhibitor (LNA-34a) caused increased expression of hepatocyte nuclear factor 4a. This leads to increased apoptosis predominantly via caspase 2 activation and decreased cell proliferation through inhibition of cyclin D1 (Figure 2).  This theory was then postulated to complement the data of the studies listed in Table 1, by accounting for those samples that showed up-regulation of miRNA-34a expression. The disparity in results between studies is thought to be due to the varying causes of HCC [40]. For example, the majority of HCC samples from the studies in the Table 1 were HBV+, and this was found to be associated with a lower frequency of CTNNB1 mutations [44]. Conversely HCC resulting from HCV infection has been shown to have a higher rate of CTNNB1 mutations [45].  However, these findings contradict the theory that miRNA-34a has a tumour suppressor function, and with relatively limited research on this oncogenic pathway, further investigation is required. Studies investigating the concept of miRNA-34a having a tumour suppressor or oncogenic function depending on the cause of the tumour would also be important, as well as an investigation of the clinical implications of this relationship.

Figure 2. Role of miRNA-34a inhibitor in counteracting the oncogenic action of miRNA-34a in HCC with beta-Catenin activation (Adapted from Gougelet et al. [40]). The miRNA-34a inhibitor LNA-34a causes a reduction in β-catenin induced miRNA-34a expression which leads to an increased expression of HNF-4α. Subsequently cyclin D1 levels are reduced, leading to decreased cell proliferation and increased caspase 2 levels, leading to increased apoptosis. The combined effects of these two actions then leads to the decreased progression of the hepatocellular carcinoma.

Limitations

A number of limitations were identified within this review, particularly relating to the conflicting information and the limited availability of clinical trial results. Contradictory information was noted on a number of occasions, especially with the use of a miRNA-34a inhibitor for HCC, making it difficult to evaluate a clear clinical benefit to this potential therapy. The data surrounding the clinical trial was also restricted as the trial is ongoing.  Subsequently, all the data had to be sourced from press releases and abstracts from presentations at conferences, which were all funded by MIRNA therapeutics; thus a potential conflict of interest was noted.

 

Conclusion

Results have indicated that miRNA-34a has a tumour suppressor function in HCC and is responsible for the down-regulation of a number of genes involved in carcinogenesis. There is, however, contradicting information described in studies investigating these parameters, highlighting the complexity of this topic. Rubone and MRX34 are two prominent miRNA-34a delivery systems that were shown to exert anti-tumour activity in pre-clinical models. Additionally, MRX34 has been commenced in a clinical phase I trial that is still currently ongoing, with a partial response already observed in one patient. However, the future of HCC-specific MRX34 trials remains unclear as limited information is currently available. Based on the promising results of miRNA-34a as a combination therapy, this is an area that requires further investigation through clinical trials. Conversely, other sources have found that miRNA-34a plays an oncogenic role in HCC, particularly in those with beta-catenin activation. Subsequently, it was demonstrated that miRNA-34a inhibitors should be used in these instances. Further research is necessary in order to ascertain the clinical implications of using a miRNA-34a mimic or inhibitor depending on the beta-catenin mutation status of the patient.

 

Conflicts of interest

None declared.

 

References

  1. Park J-W, Chen M, Colombo M, Roberts LR, Schwartz M, Chen P-J, et al. Global patterns of hepatocellular carcinoma management from diagnosis to death: the BRIDGE Study. Liver Int. 2015;35(9):2155-66.
  2. Chuang S-C, Vecchia CL, Boffetta P. Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection. Cancer Lett. 2009;286(1):9-14.
  3. Australian Institute of Health and Welfare. Cancer in Australia: an overview 2014 [Internet]. Canberra: Australian Institute of Health and Welfare; 2014 [updated 2015 Apr 16; cited 2016 Apr 2]. 220p. Available from: http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=60129550202
  4. Yim HJ, Suh SJ, Um SH. Current management of hepatocellular carcinoma: an Eastern perspective. World J Gastroenterol. 2015;21(13):3826-42.
  5. Ling H, Fabbri M, Calin GA. MicroRNAs and other non-coding RNAs as targets for anticancer drug development. Nat Rev Drug Discov. 2013;12(11):847-65.
  6. Vasudevan S. Posttranscriptional upregulation by microRNAs. Wiley Interdiscip Rev RNA. 2012;3(3):311-30.
  7. Felekkis K, Touvana E, Stefanou C, Deltas C. MicroRNAs: a newly described class of encoded molecules that play a role in health and disease. Hippokratia. 2010;14(4):236-40.
  8. Lin S, Gregory RI. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 2015;15(6):321-33.
  9. Misso G, Di Martino MT, De Rosa G, Farooqi AA, Lombardi A, Campani V et al. Mir-34: a new weapon against cancer? Mol Ther Nucleic Acids. 2014;3(9):e195.
  10. Hermeking H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 2010;17(2):193-9.
  11. Saito Y, Nakaoka T, Saito H. MicroRNA-34a as a therapeutic agent against human cancer. J Clin Med. 2015;4(11):1951-9.
  12. Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y et al. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer Lett. 2009;275(1):44-53.
  13. Xu X, Chen W, Miao R, Zhou Y, Wang Z, Zhang L et al. miR-34a induces cellular senescence via modulation of telomerase activity in human hepatocellular carcinoma by targeting FoxM1/c-Myc pathway. Oncotarget. 2015;6(6):3988-4004.
  14. Lou W, Chen Q, Ma L, Liu J, Yang Z, Shen J et al. Oncolytic adenovirus co-expressing miRNA-34a and IL-24 induces superior antitumor activity in experimental tumor model. J Mol Med. 2013;91(6):715-25.
  15. Yang F, Li QJ, Gong ZB, Zhou L, You N, Wang S et al. MicroRNA-34a targets Bcl-2 and sensitizes human hepatocellular carcinoma cells to sorafenib treatment. Technol Cancer Res Treat. 2014;13(1):77-86.
  16. Dang Y, Luo D, Rong M, Chen G. Underexpression of miR-34a in hepatocellular carcinoma and its contribution towards enhancement of proliferating inhibitory effects of agents targeting c-MET. PLoS ONE. 2013;8(4):e61054.
  17. Tryndyak VP, Ross SA, Beland FA, Pogribny IP. Down-regulation of the microRNAs miR-34a, miR-127, and miR-200b in rat liver during hepatocarcinogenesis induced by a methyl-deficient diet. Mol Carcinog. 2009;48(6):479-87.
  18. Cheng J, Zhou L, Xie QF, Xie HY, Wei XY, Gao F et al. The impact of miR-34a on protein output in hepatocellular carcinoma HepG2 cells. Proteomics. 2010;10(8):1557-72.
  19. Herath NI, Kew MC, Whitehall VL, Walsh MD, Jass JR, Khanna KK et al. p73 is up-regulated in a subset of hepatocellular carcinomas. Hepatology. 2000;31(3):601-5.
  20. Midorikawa Y, Yamamoto S, Tsuji S, Kamimura N, Ishikawa S, Igarashi H et al. Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis. Hepatology. 2009;49(2):513-22.
  21. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol. 2007;17(15):1298-307.
  22. Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H et al. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle. 2008;7(16):2591-600.
  23. Daige CL, Wiggins JF, Priddy L, Nelligan-Davis T, Zhao J, Brown D. Systemic delivery of a miR34a mimic as a potential therapeutic for liver cancer. Mol Cancer Ther. 2014;13(10):2352-60.
  24. Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y et al. A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. Cancer Res. 2014;74(21):6236-47.
  25. Budhu A, Jia HL, Forgues M, Liu CG, Goldstein D, Lam A et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897-907.
  26. Khalkhali-Ellis Z, Hendrix MJC. Elucidating the function of secreted maspin: inhibiting cathepsin D–mediated matrix degradation. Cancer Res. 2007;67(8):3535-9.
  27. Guo Y, Li S, Qu J, Wang S, Dang Y, Fan J et al. MiR-34a inhibits lymphatic metastasis potential of mouse hepatoma cells. Mol Cell Biochem. 2011;354(1-2):275-82.
  28. Chen F, Hu SJ. Effect of microRNA-34a in cell cycle, differentiation, and apoptosis: a review. J Biochem Mol Toxicol. 2012;26(2):79-86.
  29. Zhang Y, Wang Z, Gemeinhart RA. Progress in microRNA delivery. J Control Release. 2013;172(3):962-74.
  30. Agostini M, Knight RA. miR-34: from bench to bedside. Oncotarget. 2014;5(4):872-81.
  31. Mirna Therapeutics Inc; Cancer Prevention Research Institute of Texas. A multicenter phase I study of MRX34, microRNA miR-RX34 liposomal injection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2013 [cited 2016 Apr 3]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT01829971?view=results. NLM Identifier: NCT01829971
  32. Bouchie A. First microRNA mimic enters clinic. Nat Biotech. 2013;31(7):577.
  33. Beg MS, Brenner A, Sachdev J, Ejadi S, Borad M, Kang Y-K et al. Safety, tolerability, and clinical activity of MRX34, the first-in-class liposomal miR-34 mimic, in patients with advanced solid tumors [Abstract]. Mol Cancer Ther. 2015;14(12 S2):C43.
  34. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.
  35. MIRNA Therapeutics. Mirna therapeutics provides operational update & reports financial results for fourth quarter and full year ended December 31, 2015 [Internet]. Austin Texas: MIRNA Therapeutics; 2016 Mar 29 [cited 2016 Apr 3]. Available from: http://investor.mirnarx.com/releasedetail.cfm?ReleaseID=962545.
  36. Li X-Y, Wen J-Y, Jia C-C, Wang T-T, Li X, Dong MIN et al. MicroRNA-34a-5p enhances sensitivity to chemotherapy by targeting AXL in hepatocellular carcinoma MHCC-97L cells. Oncol Lett. 2015;10(5):2691-8.
  37. Pineau P, Volinia S, McJunkin K, Marchio A, Battiston C, Terris B et al. miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci USA. 2010;107(1):264-9.
  38. Sukata T, Sumida K, Kushida M, Ogata K, Miyata K, Yabushita S et al. Circulating microRNAs, possible indicators of progress of rat hepatocarcinogenesis from early stages. Toxicol Lett. 2011;200(1-2):46-52.
  39. Zhu L, Gao J, Huang K, Luo Y, Zhang B, Xu W. miR-34a screened by miRNA profiling negatively regulates Wnt/β-catenin signaling pathway in Aflatoxin B1 induced hepatotoxicity. Sci Rep. 2015;5:16732.
  40. Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G et al. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut [Internet]. 2015 Mar 19. Available from: http://gut.bmj.com/content/65/6/1024.long [Epub ahead of print].
  41. Pok S, Wen V, Shackel N, Alsop A, Pyakurel P, Fahrer A et al. Cyclin E facilitates dysplastic hepatocytes to bypass G1/S checkpoint in hepatocarcinogenesis. J Gastroenterol Hepatol. 2013;28(9):1545-54.
  42. Tornesello ML, Buonaguro L, Tatangelo F, Botti G, Izzo F, Buonaguro FM. Mutations in TP53, CTNNB1 and PIK3CA genes in hepatocellular carcinoma associated with hepatitis B and hepatitis C virus infections. Genomics. 2013;102(2):74-83.
  43. Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A et al. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci USA. 2004;101(49):17216-21.
  44. Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet. 2012;44(6):694-8.
  45. Li M, Zhao H, Zhang X, Wood LD, Anders RA, Choti MA et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet. 2011;43(9):828-9.
Categories
Review Articles

Effects of subchorionic haematoma on pregnancy outcomes

Introduction: Subchorionic haematoma (SCH) is the most common ultrasound abnormality found in women with symptoms of threatened miscarriage. It refers to a collection of blood between the chorionic membrane and the uterine wall. Depending on the time the haematoma is formed, it may appear as either hypoechoic or hyperechoic on the ultrasound. The cause of SCH may be related to poor placentation. Although SCH is common, the effects of SCH on pregnancy outcomes are unclear. The review aims to provide an overview of the effects of SCH on pregnancy outcomes and identify prognostic factors that may predict adverse pregnancy outcomes in women with SCH.

 

Methods: To identify the relevant literature, electronic databases (PubMed and EMBASE) were searched using the search terms: “subchorionic haematoma” and “subchorionic hemorrhage”. Exclusion criteria include multiple pregnancy, ectopic pregnancy, Breus mole, review articles, case reports, and studies that did not focus on the effects of SCH on pregnancy outcomes.

 

Results and conclusion: Women with SCH have an increased risk of placental abruption. Studies are conflicting on the risk SCH poses on pregnancy loss. There are only limited studies on other adverse pregnancy outcomes such as preterm delivery, small for gestational age, pre-eclampsia, and chorioamnionitis. Factors that may predict an increased likelihood of adverse pregnancy outcomes in SCH include: large haematoma size, fundal or retroplacental location, early gestational age of diagnosis (before 9 weeks), and severity of symptoms. Persistent SCH is rare but it carries a high risk of complications, including chorioamnionitis.

 

Introduction

Up to 25% of pregnant women experience symptoms of threatened miscarriage, namely first trimester per vaginum (PV) bleeding with or without uterine contractions [1]. The most common ultrasound abnormality in these women is a subchorionic haematoma (SCH) [2]. SCH is a collection of blood between the chorionic membrane and the uterine wall [2]. Typically, it appears as a crescenteric hypoechoic lesion around the gestational sac [2]. According to a 2014 retrospective cohort study from Turkey, the reported incidence of SCH in women with symptoms of threatened abortion is 18.2% [3]. In the general obstetric population, the incidence of SCH varies between 1.7% to 3.1% [4,5].

 

Pathophysiology

The exact pathophysiology of SCH is still unknown. Nevertheless, the underlying cause of SCH is believed to be poor placentation [3,6]. Poor placentation can impair angiogenesis and lead to the formation of weak vessels that tear easily [3,6]. In SCH, it is postulated that the marginal utero-placental veins tear and cause low pressure bleeding [7]. The blood then tracks around the gestational sac to form a cresenteric haematoma between the chorionic membrane and the uterine wall [7]. In contrast, the bleeding in placental abruption is usually high pressure bleeding from ruptured spiral arterioles [8]. Results from a recent Japanese study appear to support the theory that SCH is caused by poor placentation [9]. The study found that SCH is more common in women with risk factors for poor placentation such as multiparity and pregnancies conceived through in-vitro fertilisation, especially those using a frozen-thawed embryo transfer [9].

 

Clinical presentation

While some SCH are asymptomatic, most can present with first trimester PV bleeding with or without uterine contractions [5,10]. In most cases (up to 70%), PV bleeding of varying degree, ranging from spotting to heavy bleeds, can continue intermittently for 1 – 3 months after the diagnosis of SCH [11]. The symptoms usually resolve spontaneously during the second trimester [11]. However, a small minority of women (0.46% of all obstetric patients) can have a persistent SCH that remains symptomatic until delivery [11].

 

Diagnosis

SCH is diagnosed using ultrasound (Figure 1). The characteristic sonographic finding is a hypoechoic cresenteric lesion between the chorionic membrane and the uterine wall [2]. The haematoma may appear hyperechoic initially but with time, it becomes hypoechoic [2]. Possible differential diagnoses for this sonographic finding include chorioamniotic separation and twin gestational sac [2].

Figure 1. First trimester subchorionic haematoma.

Rationale and aims

Although SCH is very common in women with symptoms of threatened miscarriage, the effects of SCH on pregnancy outcomes are unclear. This review aims to provide an overview of the effects of SCH on pregnancy outcomes. It also aims to identify prognostic factors that may predict adverse pregnancy outcomes in women with SCH.

 

Methods

To identify the relevant literature, electronic databases (PubMed and EMBASE) were searched using the search terms: subchorionic haematoma and subchorionic hemorrhage. The search was limited to English-language human studies published between January 1981 and June 2016. A total of 192 studies were identified from the database search and an additional 14 studies were identified from manual review of bibliographies. After removing the duplicates, studies were excluded for reasons such as multiple pregnancy (n = 2), ectopic pregnancy (n = 2), Breus mole (n = 11), review articles (n = 2), case reports (n = 4) and different study focus (n = 82) (Figure 2). For this review, 28 studies discussing the effects of SCH on pregnancy outcomes were included.

Figure 2. PRISMA study flow diagram.

Effects on pregnancy outcomes 

Adverse pregnancy outcomes that may be associated with SCH include early and late pregnancy loss, placental abruption, preterm delivery (PTD), preterm premature rupture of membrane (pPROM), small for gestational age (SGA) and chorioamnionitis. The pathophysiological mechanisms behind how SCH might contribute to these adverse pregnancy outcomes remains unclear. It is thought that SCH may cause pregnancy loss through either a direct mechanical effect or an indirect inflammatory response [12]. As for placental abruption, studies suggest that the underlying cause of SCH – poor placentation –  also predisposes the patients to placental abruption [5,13].

 

Early and late pregnancy loss

In several studies, SCH is associated with an increased risk of miscarriage (pregnancy loss before 20 weeks) and stillbirth (pregnancy loss after 20 weeks). In a recent study, Sukur et al. [3] reported that the miscarriage rate was significantly higher in women with SCH compared to those without (29.5% versus 12.6%). A similar finding was obtained by Kurjak et al. [14]. According to Ozkaya et al. [15], the risk of miscarriage was six times higher in women with SCH (OR = 6.29, 95% CI 1.43 – 37.7). In a separate study, the risk of miscarriage remained significantly higher in cases of SCH even after PV bleeding has stopped [16]. Stillbirths are also more common in women with SCH compared to women without SCH [13]. Ball et al. [13] found that the risk of stillbirth was significant when compared to women both with and without PV bleeding. From a meta-analysis performed in 2011, SCH doubled the risk of miscarriage and stillbirth (OR = 2.18, 95% CI 1.29 – 3.68 and OR = 2.09, 95% CI 1.20 – 3.67, respectively) [6]. Based on the meta-analysis, for every 11 women with SCH, there was one additional miscarriage [6].

However, some studies had contrasting results. Two small studies (n = 22, n = 62) of SCH did not find that SCH increases the miscarriage rate [17,18]. In one of these studies, there were no miscarriages in all 22 cases of SCH studied [17]. Tower and Regan [19] studied the effect of SCH in a population with recurrent miscarriages. They found that SCH did not increase the miscarriage rate for these patients [19]. Based on a 2003 prospective study, women with SCH also did not have a significantly higher risk of stillbirth [5]. In a large retrospective study, the risk of stillbirth in women with SCH was not significant after adjusting for ethnicities, PV bleeding, chronic hypertension, pregestational diabetes, and smoking [4].

The mixed results from different studies suggest that the effect of SCH on pregnancy loss is complicated. Not all cases of SCH have an equal risk of miscarriage and stillbirth. The likelihood of pregnancy loss in SCH may depend on several prognostic factors, such as the size and location of haematoma.

 

Placental abruption

Unlike the risk of pregnancy loss, the risk of placental abruption in women with SCH is well established. When SCH is present, the risk of placental abruption increases from 0.6% to 3.6% (aOR = 2.6, 95% CI 1.8 – 3.7) [4]. This finding is echoed by several other studies [5,13,20]. From a meta-analysis that pooled together the results of four different studies, SCH increased the risk of placental abruption by more than fivefold (OR = 5.70, 95% CI 3.91 – 8.33) [6]. The number needed to harm was only 34 [6]. Given that studies have consistently reported that women with SCH have a higher risk of placental abruption, SCH most likely has a true effect on the risk of placental abruption.

 

Preterm delivery (PTD)

Studies also found that women with SCH have a significantly higher risk of PTD [4,5,20,21]. In 2003, Nagy et al. [5] reported that SCH doubled the risk of PTD (RR = 2.3, 95% CI 1.6 – 3.2). In their study, 43% of these PTD cases occurred before 34 weeks and 10% occurred before 28 weeks [5]. This result was corroborated by a large retrospective cohort study from 2010, which included more than 1000 cases of SCH [4]. More recently, Palatnik and Grobman [20] carried out a multivariable regression analysis and showed that SCH increased the risk of PTD independent of mid-trimester cervical length. There were several studies that did not find a correlation between SCH and preterm delivery [3,13,14,18,19]. However, these studies were smaller in size, with only one of the studies having more than 100 cases of SCH [13]. Nevertheless, more studies are required to confirm the risk of PTD in women with SCH.

 

Chorioamnionitis

Chorioamnionitis is a rare but severe complication in pregnancy that can cause life-threatening neonatal sepsis. Currently, the risk of chorioamnionitis in women with SCH is still unknown. There was only one study that extensively investigated the risk of chorioamnionitis in SCH [11]. In that study, Seki et al. [11] reported that chorioamnionitis was particularly common amongst women with persistent SCH. Six out of 22 women (27.3%) with persistent SCH had chorioamnionitis [11]. Half of these women had a miscarriage, while the other half delivered preterm [11]. In the study, persistent SCH was defined as a haematoma with clinical symptoms that lasted until delivery [11]. Recently, a study found that women with SCH had significantly different vaginal swab culture results [22]. Women with SCH had significantly higher prevalence of coagulase-negative Staphylococcus and Gardnerella vaginalis and lower prevalence of Lactobacillus on vaginal swabs [22]. The culture result is suggestive, though not diagnostic of bacterial vaginosis, a condition that has been associated with chorioamnionitis, pPROM, and PTD [22]. However, in that study, the swabs were only collected in the second trimester, which was temporally distant from the time SCH was diagnosed [22]. Hence, a direct cause and effect relationship could not be confirmed through the study [22]. The risk of chorioamnionitis in women with SCH warrants further investigation.

 

Small for gestational age (SGA) and pre-eclampsia

Given that SCH may be associated with poor placentation, it is important to also consider other adverse pregnancy outcomes typically associated with poor placentation such as SGA and pre-eclampsia. SCH was associated with a significantly higher risk of SGA in two studies [5,15] and and pre-eclampsia in one study [5]. However, the majority of the studies did not support a significant relationship between SCH and SGA [3,4,12,13,19,20]. SCH was also not associated with pre-eclampsia in multiple studies [4,12,19,20]. More importantly, in the two largest controlled studies on SCH (n = 512 and n = 1,081), SCH did not increase the risk of SGA or pre-eclampsia [4,20].

 

Preterm premature rupture of membrane (pPROM)

Limited studies recorded the incidence of pPROM in women with SCH. In a study by Palatnik and Grobman [20], pPROM was significantly more common in women with SCH compared to women without SCH (6.4% versus 4.0%). However, this finding was not reciprocated in two other studies [4,12].

 

Other adverse pregnancy outcomes

Interestingly, Nagy et al. [5] noted that women with SCH had significantly higher rates of an abnormally adherent placenta that required manual removal (13.9% versus 4.9%). Previously, two uncontrolled studies also noted that manual placenta removal was required in 7% and 11.1% of women with SCH [10, 23]. More controlled studies are needed to provide information about the risk.

 

Prognostic predictors  

The likelihood of adverse pregnancy outcomes in SCH may depend on several prognostic factors. Differences in the size, location, and persistency of SCH, as well as, the gestational age of diagnosis and the severity of symptoms can all change how SCH affects pregnancy [24]. Examining these factors in closer detail can help clinicians clarify the risk of SCH.

 

Size of haematoma

The risk of adverse outcomes may be increased with larger haematoma size. In the original case series on SCH, Mantoni and Pederson [25] noted that SCH > 50mL occurring after 16 weeks gestation increased the risk of spontaneous abortion and PTD but SCH < 35 mL had a good prognosis. In one study, all women had SCH < 16 mL and none of them had a miscarriage [17]. In contrast, another study found that 81% of the pregnancies with SCH > 60 mL did not continue to term [21]. The rate of miscarriage appeared to be vastly different depending on the size of the SCH. Ozkaya et al. [15] used a receiver operating characteristic curve analysis (ROC) and determined that haematoma > 32 mL was 81% sensitive and 80% specific for predicting the risk of miscarriage. The size of haematoma was also shown to be an important factor for miscarriage in several other studies [23,26-29]. However, many studies did not observe an association between size and pregnancy loss [1,13,14,16,18,30,31]. Predicting the risk of miscarriage with the size of haematoma is controversial because of the mixed evidence. It has been suggested that size is not the best indicator of the extent of subchorionic bleeding [24]. This is because a larger haematoma can be caused by either an increase in subchorionic bleeding and a decrease in cervical drainage as PV bleeding [24]. This may explain why several studies did not find the size to be predictive of poor prognosis. While size may not correlate linearly with increased risk of miscarriage, haematoma above a certain volume may still confer a higher risk. This is because regardless of the cause, a larger haematoma can have more direct pressure-volume effect on the pregnancy. A significantly larger haematoma may also have greater placental involvement. Currently, the size of haematoma remains a controversial predictor of poor outcome.

 

Location of haematoma

 Haematomas in certain locations may have a worse prognosis. Most SCH are located on the anterior aspect of the uterus and at the peripheries of the placenta [5,17]. Haematomas that were retroplacental or fundal had significantly higher rates of pregnancy loss according to several studies [14,29,30]. A fundal haematoma was four times more likely to cause a miscarriage compared to supra-cervical haematoma (27.5% versus 6.6%) [14]. While retroplacental location was a significant risk factor, Nyberg et al. [29] found that ultimately, it was the degree of placental involvement that best predicted foetal mortality. Using a multiple logistic regression analysis, Nyberg et al. [29] showed that the location was no longer significantly associated with foetal mortality after adjusting for placental involvement. Without any placental involvement, foetal mortality was only 8% [29]. When 20 – 50% of the placenta was involved, foetal mortality climbed to 20%. Greater than 50% of placental involvement resulted in a 75% foetal mortality rate [29]. Based on the current evidence, greater placental involvement and retroplacental or fundal location of haematoma may all be important risk factors for the poorer prognosis amongst women with SCH.

 

Persistency of haematoma

Most SCH will self-resolve in the second trimester but some can remain symptomatic until the delivery. This persistent SCH is rare and was only present in 0.46% of the general obstetric population [11]. Persistent SCH may carry a worse prognosis. Seki et al. [11] studied 22 cases of persistent SCH and found that while the miscarriage rate was not particularly high (13.6%), most women with persistent SCH experienced preterm labor (77.3%), half of which occurred before 32 weeks. There was also a high prevalence of chorioamnionitis amongst women with persistent SCH (27.3%) [11]. Aoki et al. also found that there is a higher rate of complications, including PTD, SGA, and neonatal lung disease in ten cases of persistent SCH [32]. Although there were no other studies on haematoma that persisted until delivery, several studies observed that haematoma that was slow to resolve or was associated with prolonged PV bleeding had higher rates of pregnancy loss [1,10,23,27]. The evidence is limited but persistent SCH appears to be associated with higher complication rates.

 

Gestational age of diagnosis 

An earlier gestational age of diagnosis of SCH has been found to be a risk factor for worse outcomes in several studies. From a 2005 observational study, SCH diagnosed before 9 weeks has a significantly higher risk of pregnancy loss and an adverse outcome compared to SCH diagnosed after 9 weeks (aOR = 18.29, 95% CI 2.36 – 41.46 and aOR = 2.22, 95% CI 1.13 – 4.40, respectively), even after adjusting for other factors such as haematoma size and maternal age [33]. The study also showed that the risk of pregnancy loss increased from less than 2% to 20%, if the diagnosis occurred before 9 weeks [33]. Similar results were obtained by Bennett et al. [26]. However, the studies were not clear on when the symptoms of PV bleeding occurred in relation to the diagnosis of SCH. Furthermore, many other studies did not agree that an earlier gestational age of diagnosis was a significant prognostic factor [16,27,29,34]. In one study, an earlier gestational age of diagnosis was strongly associated with preterm labor but not pregnancy loss [29]. Yet, according to a 2003 study, there was no significant correlation between gestational age of diagnosis and risk of PTD [34]. Based on the current evidence, gestational age of diagnosis is not a clear risk factor for worse outcomes. A probable mechanism on how an earlier gestational age of diagnosis leads to adverse outcomes is also lacking in the existing studies.

 

Severity of symptoms

Asymptomatic SCH are common and benign [13,23,35]. In women with SCH, those that experienced PV bleeding were more likely to have PTD than those who were asymptomatic (OR = 4.8, 95% CI 1.2 – 15.9) [34]. Based on a study by Abu-Yousef et al. [27], most women (83%) with moderate-to-heavy PV bleeding had an unfavorable outcome. In contrast, most women (75%) with light PV bleeding had a favorable outcome [27]. The risk of an adverse pregnancy outcome is higher with more severe symptoms in SCH.

 

Management

Despite the effects SCH might have on pregnancy, there is no specific management guideline for SCH. This is partly because there are only limited studies on how to manage SCH. Currently, most women with SCH are regularly monitored using ultrasound until the haematoma resolves. Otherwise, women with SCH are managed similarly to other women with threatened miscarriage, with advice on bed rest and supplementary progestogen. However, bed rest is not considered to be beneficial for women with threatened miscarriage based on the results of a Cochrane review [36]. There was one non-randomised controlled trial that showed a lower miscarriage rate in women with SCH that had bed rest (6.5% versus 23.3%) [37]. However, given that the study lacked randomisation and was performed retrospectively, the evidence is weak and inconclusive. In terms of progestogen, a Cochrane review of four randomised controlled trials found that it reduced the rate of spontaneous abortion in women with threatened miscarriage significantly (RR = 0.53, 95% CI 0.35 – 0.79) [38]. The beneficial effects of progestogen may be related to its immunomodulatory properties. Progestogen increases the production of progesterone-induced blocking factor, which favors T-helper cell type 2 response [39-41]. Besides that, progestogen may also help by promoting implantation and inhibiting uterine contraction and cervical dilation [39,41]. In several trials, progestogen was beneficial for women with SCH [40,41]. Pandian reported that dydrogesterone given as 40 mg/day stat. followed by 10 mg twice daily until 16 weeks gestation reduced the miscarriage rate by 15.9% (OR = 0.36, 95% CI 0.172 – 0.756) [41]. In another study, taking 40 mg of oral dydrogesterone daily until 16 weeks gestation resulted in maintenance of pregnancies for 93% of women with SCH [40]. Although the results are encouraging, more studies are needed to confirm the benefits of progestogen. Patients and clinicians should weigh the cost and benefits carefully, before starting on progestogen treatment.

A novel drug, called vaginal alpha lipoic acid (ALA), is currently being investigated for its potential use in SCH management [42]. A randomised controlled trial has shown that women taking 10 mg of vaginal ALA had faster resorption of SCH compared to women taking 400 mg progesterone and women without any medication [42]. ALA is thought to be beneficial because of its immunomodulatory properties [42]. However, the trial was a small pilot study with only 76 patients [42]. It is not powered to detect a change in the clinical outcome of miscarriage rate (3/27 in ALA group and 6/27 in progesterone group) [42]. It is still unclear whether faster resorption of SCH would improve clinical outcomes.

 

Learning points for medical students

For women with symptoms of threatened miscarriage, SCH is the most common ultrasound abnormality detected. It has been suggested that the cause of SCH may be poor placentation, which leads to formation of weak marginal uteroplacental veins that tear and bleed. SCH significantly increases the risk of placental abruption but studies are still conflicting on whether it increases the risk of pregnancy loss and other adverse outcomes including PTD, SGA, pre-eclampsia, and chorioamnionitis. Predictors of poor outcomes include the size of haematoma, location with greater placental involvement, persistency of haematoma, earlier gestational age of diagnosis, and severity of symptoms. Management of SCH involves regular ultrasound monitoring. There are potential benefits with bed rest and supplementary progestogen in some studies but the evidence is still limited. Vaginal ALA is a novel treatment option that is still under investigation. In the future, larger controlled studies that measure all the various prognostic factors will help provide better information on the risk posed by SCH.

 

Acknowledgements

I would like to thank Dr. Shavi Fernando for his advice and the Monash Diagnostic Imaging Department for providing the ultrasound image of the subchorionic haematoma.

Conflicts of interest

None declared

 

References

[1] Goldstein SR, Subramanyam BR, Raghavendra BN, Horii SC, Hilton S. Subchorionic bleeding in threatened abortion: sonographic findings and significance. AJR Am J Roentgenol. 1983;141(5):975-8.

[2] Trop I, Levine D. Hemorrhage during pregnancy: sonography and MR imaging. AJR Am J Roentgenol. 2001;176(3):607-15.

[3] Sukur YE, Goc G, Kose O, Acmaz G, Ozmen B, Atabekoglu CS, et al. The effects of subchorionic hematoma on pregnancy outcome in patients with threatened abortion. Journal of the Turkish German Gynecological Association. 2014;15(4):239-42.

[4] Norman SM, Odibo AO, Macones GA, Dicke JM, Crane JP, Cahill AG. Ultrasound-detected subchorionic hemorrhage and the obstetric implications. Obstet Gynecol. 2010;116(2 Pt 1):311-5.

[5] Nagy S, Bush M, Stone J, Lapinski RH, Gardo S. Clinical significance of subchorionic and retroplacental hematomas detected in the first trimester of pregnancy. Obstet Gynecol. 2003;102(1):94-100.

[6] Tuuli MG, Norman SM, Odibo AO, Macones GA, Cahill AG. Perinatal outcomes in women with subchorionic hematoma: a systematic review and meta-analysis. Obstet Gynecol. 2011;117(5):1205-12.

[7] Hertzberg BS, Middleton WD. Placenta, Umbilical cord, and cervix.  Ultrasound: The Requisites. Third ed: Elsevier Health Sciences; 2015. p. 469-95.

[8] Goldstein C, Hagen-Ansert SL. First-trimester complications.  Textbook of Diagnostic Sonography. Seventh ed: Mosby; 2011. p. 1081-102.

[9] Asato K, Mekaru K, Heshiki C, Sugiyama H, Kinjyo T, Masamoto H, et al. Subchorionic hematoma occurs more frequently in in vitro fertilization pregnancy. Eur J Obstet Gynecol Reprod Biol. 2014;181:41-4.

[10] Jouppila P. Clinical consequences after ultrasonic diagnosis of intrauterine hematoma in threatened abortion. J Clin Ultrasound. 1985;13(2):107-11.

[11] Seki H, Kuromaki K, Takeda S, Kinoshita K. Persistent subchorionic hematoma with clinical symptoms until delivery. Int J Gynaecol Obstet. 1998;63(2):123-8.

[12] Johns J, Hyett J, Jauniaux E. Obstetric outcome after threatened miscarriage with and without a hematoma on ultrasound. Obstet Gynecol. 2003;102(3):483-7.

[13] Ball RH, Ade CM, Schoenborn JA, Crane JP. The clinical significance of ultransonographically detected subchorionic hemorrhages. Am J Obstet Gynecol. 1996;174(3):996-1002.

[14] Kurjak A, Schulman H, Zudenigo D, Kupesic S, Kos M, Goldenberg M. Subchorionic hematomas in early pregnancy: clinical outcome and blood flow patterns. J Matern Fetal Med. 1996;5(1):41-4.

[15] Ozkaya E, Altay M, Gelisen O. Significance of subchorionic haemorrhage and pregnancy outcome in threatened miscarriage to predict miscarriage, pre-term labour and intrauterine growth restriction. J Obstet Gynaecol. 2011;31(3):210-2.

[16] Borlum KG, Thomsen A, Clausen I, Eriksen G. Long-term prognosis of pregnancies in women with intrauterine hematomas. Obstet Gynecol. 1989;74(2):231-3.

[17] Stabile I, Campbell S, Grudzinskas JG. Threatened miscarriage and intrauterine hematomas. Sonographic and biochemical studies. J Ultrasound Med. 1989;8(6):289-92.

[18] Pedersen JF, Mantoni M. Prevalence and significance of subchorionic hemorrhage in threatened abortion: a sonographic study. AJR Am J Roentgenol. 1990;154(3):535-7.

[19] Tower CL, Regan L. Intrauterine haematomas in a recurrent miscarriage population. Hum Reprod. 2001;16(9):2005-7.

[20] Palatnik A, Grobman WA. The relationship between first-trimester subchorionic hematoma, cervical length, and preterm birth. Am J Obstet Gynecol. 2015;213(3):403.e1-4.

[21] Sauerbrei EE, Pham DH. Placental abruption and subchorionic hemorrhage in the first half of pregnancy: US appearance and clinical outcome. Radiology. 1986;160(1):109-12.

[22] Yamada T, Atsuki Y, Wakasaya A, Kobayashi M, Hirano Y, Ohwada M. Characteristics of patients with subchorionic hematomas in the second trimester. J Obstet Gynaecol Res. 2012;38(1):180-4.

[23] Mandruzzato GP, D’Ottavio G, Rustico MA, Fontana A, Bogatti P. The intrauterine hematoma: diagnostic and clinical aspects. J Clin Ultrasound. 1989;17(7):503-10.

[24] Xiang L, Wei Z, Cao Y. Symptoms of an intrauterine hematoma associated with pregnancy complications: a systematic review. PLoS One. 2014;9(11):e111676.

[25] Mantoni M, Pedersen JF. Intrauterine haematoma. An ultrasonic study of threatened abortion. Br J Obstet Gynaecol. 1981;88(1):47-51.

[26] Bennett GL, Bromley B, Lieberman E, Benacerraf BR. Subchorionic hemorrhage in first-trimester pregnancies: prediction of pregnancy outcome with sonography. Radiology. 1996;200(3):803-6.

[27] Abu-Yousef MM, Bleicher JJ, Williamson RA, Weiner CP. Subchorionic hemorrhage: sonographic diagnosis and clinical significance. AJR Am J Roentgenol. 1987;149(4):737-40.

[28] Dongol A, Mool S, Tiwari P. Outcome of pregnancy complicated by threatened abortion. Kathmandu Univ Med J (KUMJ). 2011;9(33):41-4.

[29] Nyberg DA, Mack LA, Benedetti TJ, Cyr DR, Schuman WP. Placental abruption and placental hemorrhage: correlation of sonographic findings with fetal outcome. Radiology. 1987;164(2):357-61.

[30] Glavind K, Nohr S, Nielsen PH, Ipsen L. Intra-uterine hematoma in pregnancy. Eur J Obstet Gynecol Reprod Biol. 1991;40(1):7-10.

[31] Bloch C, Altchek A, Levy-Ravetch M. Sonography in early pregnancy: the significance of subchorionic hemorrhage. Mt Sinai J Med. 1989;56(4):290-2.

[32] Aoki S, Inagaki M, Kurasawa K, Okuda M, Takahashi T, Hirahara F. Retrospective study of pregnant women placed under expectant management for persistent hemorrhage. Arch Gynecol Obstet. 2014;289(2):307-11.

[33] Maso G, D’Ottavio G, De Seta F, Sartore A, Piccoli M, Mandruzzato G. First-trimester intrauterine hematoma and outcome of pregnancy. Obstet Gynecol. 2005;105(2):339-44.

[34] Sharma G, Kalish RB, Chasen ST. Prognostic factors associated with antenatal subchorionic echolucencies. Am J Obstet Gynecol. 2003;189(4):994-6.

[35] Dickey RP, Olar TT, Curole DN, Taylor SN, Matulich EM. Relationship of first-trimester subchorionic bleeding detected by color Doppler ultrasound to subchorionic fluid, clinical bleeding, and pregnancy outcome. Obstet Gynecol. 1992;80(3 Pt 1):415-20.

[36] Aleman A, Althabe F, Belizan J, Bergel E. Bed rest during pregnancy for preventing miscarriage. The Cochrane database of systematic reviews. 2005(2):Cd003576.

[37] Ben-Haroush A, Yogev Y, Mashiach R, Meizner I. Pregnancy outcome of threatened abortion with subchorionic hematoma: possible benefit of bed-rest? Isr Med Assoc J. 2003;5(6):422-4.

[38] Wahabi HA, Fayed AA, Esmaeil SA, Al Zeidan RA. Progestogen for treating threatened miscarriage. The Cochrane database of systematic reviews. 2011(12):Cd005943.

[39] Carp H. A systematic review of dydrogesterone for the treatment of threatened miscarriage. Gynecol Endocrinol. 2012;28(12):983-90.

[40] Pelinescu-Onciul D. Subchorionic hemorrhage treatment with dydrogesterone. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2007;23 Suppl 1:77-81.

[41] Pandian RU. Dydrogesterone in threatened miscarriage: a Malaysian experience. Maturitas. 2009;65 Suppl 1:S47-50.

[42] Costantino M, Guaraldi C, Costantino D. Resolution of subchorionic hematoma and symptoms of threatened miscarriage using vaginal alpha lipoic acid or progesterone: clinical evidences. Eur Rev Med Pharmacol Sci. 2016;20(8):1656-63.

Categories
Original Research Articles

Educational outcomes for children with moderate to severe acquired brain injury

Background: Acquired brain injury (ABI) in childhood can have serious physical, cognitive, and social consequences, although its specific impact on schooling attendance and provision of aid for children is often uncertain. We described educational and neuropsychological outcomes for a population of children with moderate to severe ABI.

 

Methods: A retrospective cohort study of children with moderate to severe ABI attending a paediatric brain injury service at The Children’s Hospital at Westmead between January 2003 and December 2007 was performed. The children were aged 8-16 at time of injury and information on school attendance, provision of aide, and neuropsychological test results were collected at 6, 18, and 30 months post-injury. Children with previous moderate to severe ABI, neurological disorders or learning difficulties were excluded.

 

Results: 104 children were included (mean age 12.4, 62.5% male). 48 had severe ABI (Glasgow Coma Scale ≤ 8 or Post Traumatic Amnesia ≥ 7 days). The proportion having returned to full time schooling improved from 56% to 89.7% between the 6 and 30-month follow-up. A majority of children had an impairment recorded on neuropsychological testing. Regression analysis found that severity of injury and language deficit were predictors of attendance in the first six months post-injury. During the 30-month follow-up, 18% of children attended special classes or received a classroom aide.

 

Conclusion: Time is important in recovery from ABI in children. Neuropsychological deficits influence delivery of classroom aides or modified curricula. Children with severe injury are more likely to have poorer cognitive and educational outcomes.

 

What is already known about this topic

  • Acquired brain injury can lead to serious physical, mental, and social problems for school-aged children
  • These deficits can often extend years after the initial injury
  • Severity of injury is correlated with poorer outcomes

 

What this paper adds

  • An Australian perspective of educational outcomes for children with moderate to severe brain injury
  • Information on deficits experienced by children over two-and-a-half years of follow-up
  • A better understanding of the importance of time, neuropsychological deficits, and physical injuries in transition back to school

 

Introduction

Acquired brain injury (ABI) includes a range of disabilities affecting the brain after birth including traumatic brain injury and haemorrhage. Children with moderate to severe ABI often experience long-term physical, cognitive, or behavioural impairments [1,2]. During discharge planning for these children, families often want to know what to expect from the future. In particular, they worry about the transition from hospital to the home and school environment [3]. Schooling is an important forum for childhood learning, as well as emotional and social development [4]. As such, parents often worry about how and when their children may return to school [5]. These concerns are important to address but are difficult to answer due to the great heterogeneity of outcomes following ABI.

Research has indicated that transition of children with ABI back into school is a challenging time for families. After brain injury, students may need to change their educational and vocational goals to accommodate changes in their abilities [6]. Interviews with children returning to school after ABI raise many issues, including social isolation, missed schoolwork, difficulties adjusting to physical and cognitive changes, and the support provided by schools [7]. Children find it more challenging to participate in school activities than at home and this may be due to the familiarity and greater support provided by the home environment [8].

It has been clearly established by prospective longitudinal studies that severity of injury is associated with poorer physical or cognitive outcomes [1,9-11]. Younger children are also more vulnerable to ongoing consequences of brain injury due to their larger head-to-body ratio, ongoing brain tissue myelination, and their thinner cranial bones [12]. Other factors such as type of injury, socioeconomic status, and provision of family support are also known to affect outcomes following childhood ABI [1,5,7]. Time plays a particularly important role in recovery from ABI however it is useful to note that some deficits may also become more apparent over time.

Neuropsychological testing may also be an early predictor of educational performance and special education requirements: in a study by Kinsella et al., severity of injury and verbal memory and fluency at three months post-injury was a predictor for requirement of special education at 24 months post-injury, Similar findings of the importance of verbal memory influencing educational performance at two years post-injury were made by Catroppa and Anderson as well as Miller and Donders [13,14]. Arnett also found that measures of executive functioning and verbal memory predicted educational competency but did not find these measures predictive of provision of special education [15]. Many studies regarding educational and schooling outcomes for children with ABI do not look specifically at school attendance. Studies of educational outcomes are also limited by small patient numbers and limited follow-up [16].

This study aims to use retrospective data to provide a better understanding of specific neuropsychological and schooling outcomes for children with moderate to severe ABI over a two-and-a-half-year period of follow-up. In particular, the study looks at providing a picture of time for return to schooling and the likelihood of requirement for an aide in the classroom or special education. It also seeks to explore whether neuropsychological factors such as attention, memory, information processing, and executive function, and whether co-morbidities such as fatigue and motor capacity may influence return to school and provision of an aide. This information may enable parents of children with ABI to have a better understanding of what to expect and could improve school engagement in the rehabilitation process [7].

 

Methods

Participants

Eligible cases were identified from the 2003-2007 database of a paediatric brain injury service at The Children’s Hospital at Westmead, New South Wales, Australia.

Inclusion criteria were age at injury of 8-16 years, moderate or severe ABI, and admission to hospital for ABI. Moderate ABI was defined as Glasgow Coma Scale (GCS) ≤ 12 or Post Traumatic Amnesia (PTA) ≥ 1 day. Severe ABI was defined as GCS ≤ 8 or PTA ≥ 7 days [17]. There were eight cases which were judged as representing moderate or severe ABI but there was unclear GCS and PTA data. These cases were included in order to more accurately represent the patient population and were classified as “undefined” in severity.

Exclusion criteria were previous moderate or severe ABI, previously documented behavioural or developmental difficulties, or previously documented special education support.

Medical records were searched and data extracted from neuropsychological and brain injury clinic reports, discharge summaries, and other hospital records. Data were collected for 0-6, 6-18, and 18-30 months post-injury. Data on educational outcomes of school attendance, provision of classroom aide, and whether children changed school were collected. Data on neuropsychological outcomes was taken from reports written by clinical neuropsychologists at the service. Patient demographics were taken from medical notes. Information on co-morbidities was collected primarily from brain injury clinic reports.

 

Measures

The neuropsychological testing variables measured were attention, memory, information processing, and executive functioning. Neuropsychological profile was considered intact when reported as “low average” or above. Where terms such as “difficulty”, “reduced”, “borderline”, or “impaired” were used as descriptors in reports they were coded as a deficit. In cases where children had no deficit on initial neuropsychological testing and were subsequently discharged without further testing, it was assumed that they would not develop deficit later on.

This research also collected data on variables concerning other sequelae of ABI including mood/behavior, fatigue, gross and fine motor deficit, receptive and expressive language deficit, visual impairment, and hearing impairment. These deficits were determined by whether they were mentioned as ongoing issues in clinical letters and other medical notes during the set follow-up periods.

 

Statistical analysis

Quantitative analysis was undertaken using STATA 11 SE.  Where possible, variables were coded dichotomously for analysis using Fisher’s Exact Test to look for a relationship with attendance at school or provision of aide. Ordered logistical regression examined which variables (severity, neurological findings, or co-morbidities) were predictive of school attendance.

 

Ethics approval

Ethics approval was obtained from the Services Improvement Unit at The Children’s Hospital at Westmead, NSW, Australia, approval number: QIE-2011-02-09.

 

Results

Participant demographics (Table 1)

Of the 158 identified cases, 104 cases met the inclusion criteria.  Age at time of injury was between 8-16 years, with the mean age at time of injury being 12.4 years. There were 48 children with severe injury, 48 with moderate injury and 1Table 1.)vehicle accidents. CT/8 with non-traumatic injury, mostly haemorrhage from rupture of arteriovenous malformations. 62.5% were male and three quarters came from urban residencies. 37.5% of injuries were due to falls and 31.7% of children were involved as passengers or pedestrians in motor vehicle accidents. CT and MRI data was collected for 85.6% patients, of which 82% showed abnormalities.

Table 1. Patient demographics of children with moderate to severe acquired brain injury.†
† Note that information is only reported for those cases where it was available.
Undefined cases are cases that were clinically moderate to severe but GCS and PTA were not clearly recorded.

Outcomes

Neuropsychological deficit (Table 2)

Sex and age at onset were not associated with any significant differences in neuropsychological outcomes. As expected, severe ABI has a trend towards more deficits as compared to moderate ABI. Children often had deficits in more than one domain, and children with severe injuries had higher rates of reported deficits. Almost all cases of children who had no deficits on neuropsychological testing were children with moderate ABI. Over time, there was improvement in the numbers of children with reported deficits across attention, memory, information processing, and executive functioning. There was no increase in incidence of deficits over time. Many children with deficits recorded at 0-6 months recovered by 18 or 30 months of follow-up.

Table 2. Number of children with moderate to severe acquired brain injury with neuropsychological deficits at follow up. †Non-traumatic cases had consequences considered to reflect moderate to severe ABI but there was insufficient information on GCS for status to be clearly defined. Note that information is only reported for those cases where it was available. This table therefore does not report on the entire sample of 104. Undefined cases are cases that were clinically moderate to severe but GCS and PTA were not clearly recorded.

Co-morbidities

The most common complaints reported were headache, fatigue, and dizziness. From 0-6 months, 62 children reported fatigue. Mood and behavioural problems were also common, with 61 children reporting problems between 0-6 months, 38 at 6-18 months, and 25 at 18-30 months. Persistence of mood and behavioural problems discussed by parents and children at rehabilitation clinics even two-and-a-half years after injury reflects the ongoing difficulties faced by children with ABI even after physical injuries have healed.

Fine motor deficits were slightly more common than gross motor deficits. For gross motor deficits, from 0-6 months, there were a greater number of children with impaired mobility requiring aid, than those without aide, but between 6-30 months, the majority of children with impaired mobility were able to walk without an aide. Over a fifth of children had initial reports from brain injury clinic reviews describing receptive or expressive language problems, but two thirds of these were resolved by 30 months follow-up. Between 2-8% of children experienced vision or hearing problems after ABI. Except for fine motor deficits, co-morbidities were most frequently recorded during the first 6 months. The frequencies of co-morbidities were recorded at each of the follow-up time points (Table 3).

Table 3. Frequency of co-morbidities reported for children with moderate to severe ABI at follow-up.†
†Note that information is only reported for those cases where it was available for all co-morbidities. This table therefore does not report on the entire sample of 104.

School attendance

Attendance improved over time; most part-time students transitioned into full-time schooling by 18 months (Figure 1). At the end of 18-30 months follow up, 6.9% (n = 87) remained unable to return to full-time schooling.

Figure 1. School attendance for 104 children with moderate to severe brain injury over follow up.

Ordered logistic regression was performed to identify predictors of school attendance. As expected, injury severity was negatively associated with full-time school attendance at 0-6 months post-injury. A child with severe ABI was five times less likely to attend school within six months post-injury than a child with moderate ABI (Table 4). There was a significant difference in school attendance at 18 months post-injury for children with moderate versus severe injury (p < 0.05). No relationship was found at 30 months (p > 0.2). No significant statistical impact of individual neuropsychological measures and attendance of schooling was found.

Table 4. Ordered logistical regression of attendance 0-6 months for 63 children with moderate to severe ABI.†
†SE= Standard Error.
Likelihood Ratio chi2(2) = 24.58 Prob > chi2 = 0.0000
Log likelihood = -52.060058 Pseudo R2= 0.191

Of the co-morbidities measured, it was found that injury severity and language deficit (independently and in combination) were negatively associated with full-time school attendance at 0-6 months post-injury. A child with a receptive or expressive language deficit was ten times less likely to attend school within six months post-injury than a child without a known language deficit.

 

School aide and change of school

Classroom aide was received by 3.3% of children at 0-6 months follow-up, by 12.8% at 6-18 months, and by 13.4% at 18-30 months. There was a significant difference according to injury severity for provision of a teaching aide at 18-30 months (p < 0.03). Special classes or educational programs were provided for 1.1% of children at 0-6 months follow-up, by 5.3% at 6-18 months, and by 7.2% at 18-30 months. There was some overlap with children receiving both aide assistance and attending a special class. During follow-up, seven children required a change of school for reasons relating to their ABI. Of these children, five had experienced severe ABI.

 

Discussion

This study describes the pattern of children in accessing schooling and special education or aide support following ABI.  Extended absences from school are one of the initial challenges facing children after ABI; 17.6% of children in our study population did not attend school in the first six months post-ABI. Whilst hospital and home schooling were sometimes available, this represents a considerable time difference in which children with ABI may fall behind their peers.  This study found that a combination of severity of injury and language deficit were found to be predictive of attendance in the first six months after injury. The involvement of language as a predictive factor is important, as it is modifiable. Language is important to complex learning and adaptation and contributes to understanding shared meanings in contexts such as school [18,19]. Language intervention programs may be able to facilitate earlier transition back to school. This study shows that the great majority (93%) of children with moderate or severe ABI will be able to return to full-time schooling. It also shows that the majority of these children are not given provision of classroom aides, special classes, or educational programs.

Attention to classroom instructions, reasoning and expression of ideas, and self-monitoring are all important features of good reintegration to schooling [20]. Children with severe ABI accounted for a greater proportion of neurological deficits in every domain measured (intellect, attention, memory, executive function, and information processing), and 44 of the 45 children with no reported neuropsychological deficits on testing had only moderate ABI. Our study reinforces that there is great variability in the way that ABI affects children, but severe ABI generally has a poorer prognosis and such children may experience greater challenges when returning to school. It is reassuring to note that time can help reduce the burden of ABI, with prevalence of neuropsychological deficits generally improving during follow-up. Longer-term studies suggest that intellect and personality problems may resolve by adulthood, but that reduced quality of life in relation to education and employment can persist [1]. Further long-term follow-up of these patients may be valuable in investigating this. Our study also found that attendance also improves with time, as 89.7% of children were able to resume full-time schooling by 30 months post-injury.

The presence of a classroom aide and modified learning programs is important in exploring whether the ongoing needs of children with ABI are met by schools. Our study found that 13% were provided with classroom aide during 30 months of follow-up. The provision of aid was found to increase over time. This may be accounted for by the inability of children with severe injuries to return to school early but another possible explanation is that there is a delay in the processing and provision of aid.

Quality of aide provision and the satisfaction children and their families had with the schooling system were not measured in this study. This is a possible avenue for future research, as general school educators and also special education teachers often do not have specialised training for working with children with ABI.  TBI Consulting Team and BrainSTARS are two promising models currently available for improving professional development of educators in caring for children with ABI, but both require further studies to show objective improvement [21].

In our study, some children reported needing to repeat a year of school. Grade repetition is known to be a de-motivating process that can affect homework completion and predict greater amounts of school absence [22]. A possible direction for future research would be to examine how common grade repetition is amongst the ABI population.

 

Strengths and limitations of this study

This study addresses the need for a better understanding of educational outcomes for children with moderate to severe ABI. The follow-up time of 30 months also provides a clearer understanding of how outcomes change over time. Additionally, this study deals specifically with school attendance and provision of aide time, two outcomes which are often overlooked in studies describing participation of children in the community following ABI.

The study also provides important information regarding predictors of attendance in the first six months of schooling. Whilst severity has been a known predictor, language has not been a focus for research previously. This new information may help guide health and education professionals in providing appropriate resources to ensure the best educational outcomes for children with ABI [23].

This study had a number of methodical limitations. Due to the highly variable nature of ABI and the small sample size, subgroup analysis was limited. As the study was retrospective there were a number of missing data fields. The results may underestimate true incidence of neuropsychological deficits as standard clinical practice does not comprehensively test children at all points of follow-up if no changes are expected or testing is not necessary. A larger, prospective study of educational outcomes would provide more data for studies with larger patient cohorts to be undertaken in order to confirm our results [24].

The study did not include a control group so confounders were minimised by excluding children with previous intellectual deficits, moderate to severe brain injury, schooling problems, or behavioural difficulties.

This study was unable to detect differences for children who were previously above average, but dropped into an average category on neuropsychological testing. Unfortunately, pre-morbid capabilities are difficult to quantify without formal testing. This study would not consider these children to have a deficit even though they have experienced a change in abilities. Any changes in abilities should not be discounted as they can still negatively impact the expectations and lifestyle of children and their families.

 

Conclusion

Children with moderate to severe ABI experience a wide range of neuropsychological and physical co-morbidities that can persist for at least 30 months following injury. Greater severity of injury and presence of language deficit are predictive of school attendance of children in the first six months following ABI. 13% of children required additional aide support or involvement in special classes. Over a third of children still reported fatigue and behavioural problems at 30 months follow-up. This study shows that whilst patients and families experience a long and difficult process of recovery, they may be able to expect improvements over time, and children are very likely to have returned to full-time schooling by 30 months post-injury.

 

Acknowledgements

I would like to thank Dr Angela Morrow for her supervision and guidance throughout this research project. I would further wish to express my gratitude to Dr Barzi for great assistance with the statistics and to Julie-Anne Macey, who came up with the research concept. I would also like to thank Dr Patrina Caldwell for her encouragement and invaluable feedback during the editing process.

 

References

[1] Anderson V, Brown S, Newitt H, Hoile H. Long-term outcome from childhood traumatic brain injury: intellectual ability, personality, and quality of life. Neuropsychology. 2011;25(2):176-84.

[2] Anderson V, Le Brocque R, Iselin G, Eren S, Dob R et al. Adaptive ability, behavior and quality of life pre and posttraumatic brain injury in childhood. Disabil Rehabil. 2012.

[3] Aitken ME, Mele N, Barrett KW. Recovery of injured children: parent perspectives on family needs. Arch Phys Med Rehab. 2004;85(4):567-73.

[4] Catalano RF, Oesterle S, Fleming CB, Hawkins JD. The importance of bonding to school for healthy development: findings from the social development research group. J School Health. 2004;74(7):252-61.

[5] Beaulieu CL. Rehabilitation and outcome following pediatric traumatic brain injury. The Surgical Clinics of North America. 2002;82(2):393-408.

[6] Stewart-Scott AM, Douglas JM. Educational outcome for secondary and postsecondary students following traumatic brain injury. Brain Injury. 1998;12(4):317-31.

[7] Sharp NL, Bye RA, Llewellyn GM, Cusick A. Fitting back in: adolescents returning to school after severe acquired brain injury. Disabil Rehabil. 2006;28(12):767-78.

[8] Galvin J, Froude EH, McAleer J. Children’s participation in home, school and community life after acquired brain injury. Aust Occup Ther J. 2010;57(2):118-26.

[9] Anderson V, Catroppa C, Morse S, Haritou F, Rosenfeld J. Functional plasticity or vulnerability after early brain injury? Pediatrics. 2005;116(6):1374-82.

[10] Anderson VA, Catroppa C, Haritou F, Morse S, Rosenfeld JV. Identifying factors contributing to child and family outcome 30 months after traumatic brain injury in children. J Neurol Neurosur PS. 2005;76(3):401-8.

[11] Catroppa C, Anderson VA, Morse SA, Haritou F, Rosenfeld JV. Outcome and predictors of functional recovery 5 years following pediatric traumatic brain injury (TBI). J Pediatr Psychol. 2008;33(7):707-18.

[12] Catroppa C, Anderson V. Recovery in memory function, and its relationship to academic success, at 24 months following pediatric TBI. Child Neuropsychol. 2007 May; 13(3):240-61.

[13] Miller LJ, Donders J. Prediction of educational outcome after pediatric traumatic brain injury. Rehabil Psychol. 2003;48:237–241

[14] Neuroimaging. 2012;22(2):e1-e17.

Arnett AB, Peterson RL, Kirkwood MW, Taylor HG, Stancin T et al, Behavioral and cognitive predictors of educational outcomes in pediatric traumatic brain injury. J Int Neuropsychol Soc. 2013;19(8):881-9.

[15] Pinto PS, Poretti A, Meoded A, Tekes A, Huisman TA. The unique features of traumatic brain injury in children. Review of the characteristics of the pediatric skull and brain, mechanisms of trauma, patterns of injury, complications and their imaging findings–part 1. J Neuroimaging. 2012;22(2):e1-e17.

[16] Welfare AIoHa. Disability in Australia: trends in prevalence, education, employment and community living. Canberra: AIHW, 2008.

[17] Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet. 1974;2(7872):81-4.

[18] Marlowe WB. An intervention for children with disorders of executive functions. Dev Neuropsychol. 2000;18(3):445-54.

[19] Ewing-Cobbs L, Barnes M. Linguistic outcomes following traumatic brain injury in children. Semin Pediat Neurol. 2002;9(3):209-17.

[20] Semrud-Clikeman M. Pediatric Traumatic Brain injury: rehabilitation and transition to home and school. Appl Neuropsychol. 2010;17(2):116-22.

[21] Glang A, Todis B, Sublette P, Brown BE, Vaccaro M. Professional development in TBI for educators: the importance of context. J Head Trauma Rehab. 2010;25(6):426-32.

[22] Martin AJ. Holding back and holding behind: grade retention and students’ non-academic and academic outcomes. Brit Educ Res J. 2010;37(5):739-63.

[23] Hawley CA, Ward AB, Magnay AR, Mychalkiw W. Return to school after brain injury. Arch Dis Child. 2004;89(2):136-42.

[24] Slomine B, Locascio G. Cognitive rehabilitation for children with acquired brain injury. Dev Disabil Res Rev. 2009;15(2):133-43.

Categories
Feature Articles

Perspectives on Alzheimer’s disease

Alzheimer’s disease is a commonly encountered pa ent case by medical students. However, many students struggle to see the person beyond the disease. This essay o ers a di erent perspec ve into Alzheimer’s disease, a deeper understanding that is crucial towards fostering more empathe c, a en ve and compassionate pa ent interac ons.

Since the start of my medical studies, I have found the disease process of Alzheimer’s disease an emotional and physiological enigma. However, it is the case of Clarice that profoundly impacted a deeper insight into the complexity of a life lived with Alzheimer’s disease.

Clarice has been living with Alzheimer’s disease since the death of her husband eleven years ago. Her family helplessly witness as she gradually loses any semblance of order and familiarity in her life. At first, she disguised her confusion through a veil of phrases, covering up her forgetfulness with laughter “Of course I knew that, I was only joking.” Alzheimer’s disease drowned Clarice within waves of confusion, muddling up her thoughts and blending the faces she was surrounded by all of her life with faces of strangers as she tried to tread water in the relentless current. She always wore a smile and came accompanied with jokes and quirky musings. She became known by eccentric catch phrases “How do you spell nachas (happiness)?” that she asked of her grandchildren. To which they answered melodiously “C L A R I C E”. At every family gathering, she tapped her glass with a fork and announced, “with tears in my eyes, I just want to say how special it is to be here, no itching or bitching, just all together, as a family.” As she left, she gathered everyone together and departed with famous final words “Go well, go shell, but don’t go to hell”.

“Go well, go shell, but –“,
“Don’t ring the bell!”
“Don’t say farewell!” her family tried to interject.
“No.” she confirmed with a cheeky grin, “Don’t go to hell!”

At Friday night meals, Clarice’s thirteen grandchildren said the Jewish blessing over food in chronological order from eldest to youngest. With much humour, Clarice would exclaim “Our Father, the holy spirit…” and proceed to tap out the cross on her body, reminding them of her rich childhood. Having attended a Catholic boarding school as a young Jewish girl, the daily prayers and hymns have stayed with her into old age. Her family loved her Zulu exclamations “saqua bona wena”, to which they replied in their own made up language, matching the sounds of her youth.

As her cognition declined, her honesty and humour sharpened and the kindness, love, and compassion that overflowed from her heart amplified. At times, her honesty was brutal, revealing hidden layers about the people surrounding her. No longer aware of social cues or the importance of privacy, she pointed out the sad man sitting by himself, or the distressed woman lost in thought. While sometimes uncomfortable, such honesty only exposed her caring and sensitive nature. She was apt at identifying someone’s hidden sadness, unbeknownst to anyone else, and quick to enquire why, offering her ear and heart.

If her family had visitors at their weekly Shabbat meals who showed signs of fragility, Clarice was the first to get up and help. “Can I help you up from the table?” “You stay put and I’ll get your food for you, what would you like?” The irony of such moments was heartrending, her ability to help those who were physically unwell when she wasn’t able, nor was anyone else, to help the illness that overwhelmed her mind.

As time gradually undid the threads that held together the clarity of Clarice’s mind, her sentences slipped into nonsensical musings. Moments of her childhood featured more frequently as she lost track of time. She referred to herself as a little girl, telling her adult children that she had to go home lest her parents worry where she was.

Yet, there were moments of pure happiness that peaked out occasionally. Her genuine awe as she watched the sunsets that showered her balcony and the raw happiness and surprise she had when her granddaughters kissed her on the cheek for a ‘selfie’, were moments of bliss. Her family learnt what made her happy and was able to tap into such experiences to change solemn moments into happier ones. The more they became desensitised to the tragedy of her illogical talk and the more they learnt how to laugh with her rather than cry, the more they were able to find joy and beauty in her quirky musings and disjointed sentences. The more they distanced themselves from her disease, the more they appreciated her presence, her warmth, and her unconditional love.

Clarice is not and never has been my patient. She is my grandmother, my Bobba. At the same time that I was dealing with the sudden deterioration of my Bobba’s cognition, I started my geriatrics placement at the hospital. The internal struggle that I felt as I grappled with my Bobba’s decline gave me a new perspective of the patients I met during that term.

Patient labels transitioned from ‘the demented old lady with delirium secondary to constipation’ to ‘the retired teacher and grandmother of seven suffering with …’. I found myself with a newfound depth of empathy and patient centered care. This gave me a greater understanding of the underlying disease processes of the patients as my passion for their wellbeing led me to deeper investigations of their conditions. The lessons I learnt from communicating with my Bobba, especially in her moments of stress and confusion, enabled me to connect to the geriatric patients with greater patience, tolerance, and appreciation. I found that I was able to implement the ‘tricks’ I learnt from soothing my Bobba to soothing distressed, agitated, and scared patients. The timing of my geriatrics placement was no coincidence but a treasured journey that transformed the blanket of grief, loss, and regret that plagued my mind, with acceptance, gratitude, and understanding. It was emotionally draining to be confronted with the exact challenges that I tried to distance myself from in my personal life every day at placement. Nonetheless, witnessing so many people in the same circumstance as my Bobba and my family also brought solace and comfort.

One moment I will never forget was walking into a very disorientated woman’s room; she was 63 years old and had early onset Alzheimer’s disease. She lay in bed with her 40-year-old daughter, who cuddled her while stroking her hair and placating her with kind words “Don’t worry mum, I’m here, everything’s going to be alright”. I left hospital that day and went straight to my Bobba’s home. Although I sensed that she didn’t know exactly who I was that day, I felt her love for me and as we sat together cuddled up on the couch, I found pleasure in the complex simplicity of love and togetherness that persists, and perhaps even strengthens, in the face of suffering and adversity.

Just like the 40-year-old daughter, I remember my own mother placating my Bobba by likening her confusion to a car ride, telling her that she can simply shut off, relax, and enjoy the ride, knowing with confidence that she was being looked after. That although she was in the passenger seat, she could trust in the fact that the driver had planned the journey meticulously ahead with love and care.  When my mother suffered herself, overwhelmed by hopelessness and pain, I remember my aunty, my mother’s younger sister, telling her that it was better to laugh, to simply shut off, relax, and enjoy the ride herself. As my aunty so aptly put it, “we have to laugh, for if we don’t laugh, then we’ll just cry.”

We chose to ignore the ugliness of the disease and to find joy in the benevolent absurdity of my Bobba’s behaviour. We laughed in the lift of crowded people when my Bobba interrupted the silence singing ‘Ba Ba Black Sheep’. We laughed when my Bobba plaited my friends’ hair together as they sat on the couch. We laughed when my Bobba walked up to the stranger engrossed in her book to sit down beside her and engage in conversation as if they were lifelong friends. We laughed so much with my Bobba until we laughed so much that we cried. And I thought of all those times we ran around as small children, my Bobba warning us “too much laughter ends in crying”. Yet, now we reversed this, we turned all our crying into laughter. And we were so much happier.

Alzheimer’s disease teaches us to savour every minute spent with those we love. It sensitises us to those extraordinary moments of pure joy. It clears out the complexity of the recent past and future to make way for the serenity of the present. It peels away the shell of the mind only to reveal the perfection of the soul – what a beautiful force to be around.

Conflicts of Interest

None declared.

This article was first published in the Australian Journal of Dementia Care (www.journalofdementiacare.com) Vol 5 No 6 December/January 2016-2017. Reprinted here with the permission of Hawker Publications Australia Pty Ltd.

 

Categories
Feature Articles

The changing face of cancer in Australian medical schools

A multitude of changes are revolutionising the study and practice of oncology worldwide.   Despite the undeniable importance of cancer education, there is currently no consensus amongst Australian medical schools as to what should be taught regarding oncology practice, nor have the best ways of teaching and learning about cancer been fully elucidated in the literature, or in the clinical realm. There is a lack of important cancer knowledge amongst graduating medical students and variation exists amongst individual Australian medical faculties, between states as well as individual universities from the same state. Furthermore, there is very little teaching here in Australia in relation to emerging genomic technologies within oncology, and in particular, the ever-increasing role of personalised and preventative medicine in cancer care today. Ultimately, there is a clear need for an integrated, overarching national oncology curriculum, embracing a patient-centred approach; national evaluation and assessment; supplementary courses; utilisation of self-directed learning and reflective practice activities; and greater emphasis on emerging technologies. With more research focus on this area, in future there may be a larger evidence-base targeted at providing improvements in Australian Oncology education, assisting graduates in gaining adequate understanding and appreciation of cancer-related scenarios and cancer care. More effective teaching and learning facilitation, with better overall Australian training outcomes, will lead to advancement in cancer diagnosis, treatment, and management as well as ensuring more insightful and valuable patient interactions in the future.

Introduction

A multitude of changes are revolutionising the study and practice of oncology worldwide.  The ways in which oncology and cancer care are incorporated into medical school curricula in Australia is thus of particular interest. Despire the undeniable importance of cancer education, there is currently no consensus amongst Australian medical schools as to what should be taught in regards to oncology practice, nor have the best ways of teaching and learning about cancer and cancer care been fully elucidated in the literature or in the clinical realm [1-4].

In Australia, there is considerable variation in undergraduate and postgraduate teaching of oncology amongst individual medical faculties [8,9] and a lack of important cancer knowledge amongst graduating medical students, between states and between individual universities from the same state [8,9,10]. This inconsistency is compounded by the nature of oncology as a multidisciplinary specialty, with overlap in numerous fields including pathology, surgery, histology, radiology, anatomy, genetics, communication skills, and palliative care [1].

Further, there is very little teaching here in Australia in relation to emerging technologies within oncology and in particular, the ever-increasing role of personalised and preventative medicine in cancer care today. Educators are now presented with the inevitable task of addressing all foundational educational needs in our generation of medical graduates. They must also ensure to incorporate pertinent aspects of such a rapidly progressive field of medicine as it relates, for example, to genetic testing and counselling, the rise of personalised or ‘precision’ medicine, and ongoing development in cancer immunotherapies [11-14].

Variation in oncology education in Australia is compounded by the lack of literature on this subject, which is predominantly qualitative in nature and overall, more difficult to evaluate [30].  Whilst cancer is the number one cause of death in Australia, oncology itself is still not a subscribed part of the medical curriculum, nor is an oncology rotation compulsory in Australian medical schools. There is an ongoing lack of literature regarding oncology-specific teaching and learning methods, as well as a lack of evidence in the effective implementation of compulsory curricula or rotations to engage with foundational and emerging aspects of oncology or palliative care.

The importance of this issue resonates with students, recent graduates, and educators as all medical students will at some point in their career play a role in the management of a cancer patient [5], whether as a resident on an oncology rotation, as a general practitioner at the stage of diagnosis, during long-term follow-up of a cancer survivor [6], as a fully-qualified oncologist, or as a clinical geneticist. Furthermore, with our ageing Australian population, there will be greater numbers of individuals diagnosed with and treated for cancer than ever before as well as an increased number of survivors, making cancer a chronic illness to be managed by a multidisciplinary team [7].

 

How did we get here?

In 1993, the General Medical Council published a detailed review of medical education [15], which led to a major overhaul of medical school oncology training in the United Kingdom, and worldwide [1,16].  A survey of European universities showed that 95% indicated the need for increased cancer education and there was an overwhelming interest in a common European oncology curriculum [17].

In 1999, and again in 2007, the Ideal Oncology Curriculum (IOC) for Medical Students was released here in Australia [18], produced by the Oncology Education Committee of the Cancer Council Australia and endorsed by the Union for International Cancer Control (UICC). It provides an unparalleled example of the evidence-based recommendations required for medical school cancer education, including prescribed clinical experiences and knowledge attainment, which necessitate a patient-centred approach to training methods. In each section, there is detail of prerequisite knowledge, as well as a list of representative questions that illustrate the ‘required depth of knowledge’ for graduating medical students, with attached example answers and multiple-choice question-answer options.

Focus is on the patient rather than the discipline, with topics ranging from public health and cancer biology, to patient management, diagnosis, communication skills, and clinical experiences [18]. More recently, it has been supplemented by a detailed e-Book entitled “Clinical Oncology for Medical Students”, which may be utilised alongside the recommended experiential learning, and acquisition of technical oncology skills, for a more robust understanding of the prescribed IOC material [19].

Moreover, the World Health Organisation and UICC recommend that cancer education be incorporated into oncology modules within an undergraduate curriculum and that medical students spend a minimum of two weeks in oncology training [4,5]. However, despite the superlative example given by the IOC, there has been minimal uptake in Australia, which may be linked to the current lack of a national curriculum, the dearth of literature on effective educational strategies, or the historical absence of oncology content in Australian medical school curricula. This lack of implementation and an inadequate evidence-base makes the feasibility and effectiveness of oncology rotations or uptake of the IOC guidelines incredibly difficult to ascertain, let alone, achieve.

 

Oncology teaching and learning methods

Internationally, there has been a push for an overarching pre-clinical oncology curriculum for medical students incorporating medical knowledge, psychosocial aspects, communication skills training, and utilisation of a variety of teaching methods such as interviews, discussion, reflection, and lectures [1,2,7,20].

There is increased emphasis on a patient-centred approach to teaching [11,13] and learning in oncology education [22,23]. This should extend from the use of standardised patients teaching examination skills to medical students, to the involvement of cancer patients in communication skills teaching and portfolio learning [1,24].

Self-directed learning (SDL) is the educational strategy considered most likely to produce medical graduates who are prepared for lifelong learning and who are able to meet the needs of their patients [26,30]. SDL activities include problem-based learning (PBL), discovery learning, task-based learning, experiential and reflective learning, portfolio-based learning, small group or project-based learning, and peer evaluation with learning contracts [26]. Results from numerous studies have indicated a trend towards improved student performance from SDL assessment, as with the follow-up of a cancer patient over an extended period of time [1,21,23-25]. The use of portfolio assessment and learning journals is also championed as a tool of successful oncology training and for lifelong education [25]. An array of methods may thus be employed in undergraduate oncology training whilst utilising the SDL approach [26-27].

The PBL approach, more specifically, as one of the major aspects of SDL, facilitates a deeper learning style [28] and involves an active search for understanding based on a given scenario. This technique is linked to better clinical problem-solving skills in medical students with higher levels of motivation and stimulation found [27] and superior outcomes in students tested [9,29].

Regarding format, some have argued that an independent block style is more effective in presenting an oncology curriculum [20]. This is as opposed to an integrated model of teaching into other system modules and would be relevant within an Australian-based system. In block format, the curriculum may be presented through oncology-specific technology-based lectures, team-based communication, and clinical skill exercises supplemented by lectures paired with relevant clinically-based scenarios and other activities posted online to be worked through independently [20].

Computer-aided learning [1,21,22,30] may itself have a role to play as supplementation to oncology study though technology-based approaches are not necessarily superior to other learning techniques [1]. Here in Australia, a number of medical schools are already utilising the e-Learning Undergraduate Modules for Australian Medical Schools, accessible via The e-Learning Portal, which is provided by The Australasian College of Dermatologists [31]. This is highly applicable on a national level when considering skin cancer rates in Australia [32]. Overseas, an ‘eDerm’ online curriculum [33] provided to 252 medical students in the United States significantly improved the diagnosis and management of pigmented skin lesions by medical students [33].

In regards to communication skills, suboptimal communication can lead to adverse psychological effects in patients. It can compromise a physician’s ability to treat patients, as well as impacting patient satisfaction, medication compliance and overall clinical outcomes [34]. The use of group presentations, small-group communication skills practice [35], and reflective self-awareness exercises have been shown to improve communication skills. This is particularly true with the use of patient-actors in simulated clinical situations as opposed to role-play alone. There is overwhelming proof that communication skills can be taught and should be delivered through experiential learning methods, which are ultimately more effective than instructional modes to address communication skills development in oncology [36].

Moreover, a primary skill that any medical student can bring to an oncology experience, or rotation is their presence and their time. Medical student training in this burgeoning field [11] must facilitate the development of essential communicative abilities: to be able to listen to a cancer patient’s story during their clinical journey, to be able to connect with this experience, and communicate effectively in response to this scenario [18,34-36].

 

Lessons from abroad

At the University of Wales’ College of Medicine, medical students followed a patient along their cancer journey over a six-month period and were assessed during patient interactions and through a final portfolio. Overall, students found the project rewarding and reported gaining unparalleled insight into the cancer experience [22].

A three-day intensive oncology course has been piloted in Israel, with students feeling more comfortable with cancer-related issues, less afraid of dealing with death, and better able to cope with uncomfortable cancer-related emotional situations as a result [7]. Psychosocial and ethical aspects were presented through student-led presentations and discussions, a psycho-oncology session led by a psychologist, and two presentations by cancer patients describing their personal experiences and offering advice on aspects such as the doctor-patient relationship [7].

In Poland, attempts have been made to improve cancer education through the National Program for Combating Neoplastic Diseases [16]. This was done with a course incorporating computer-learning modules, online tests, portfolio learning, summer school, modules taught by cancer patients, and attachments in oncology and palliative care. Observations highlighted that the introduction of these courses better prepares students for delivering cancer care [16].

Finally, in a novel Brazilian experience, students staffed an oncology clinic, with 77% of students involved in this approach over a ten-year period rating it as the best activity of their course. Findings suggested that attendance at an oncology outpatient clinic can contribute significantly to the cancer education of medical students [24].

 

Future directions for Australian oncology education

There is a clear need for the following in cancer education:

  1. An integrated, overarching national curriculum, with a patient-centred approach
  2. National evaluation and assessment
  3. Summer schools and supplementary courses
  4. Embracing SDL & PBL, with reflective practice activities
  5. Greater emphasis on emerging technologies

 

  1. An oncology curriculum, with a patient-centred approach

 A relevant, integrated oncology curriculum as detailed by the IOC [15,18] should be embraced by all Australian medical schools, with the aim of bringing together requirements regarding essential knowledge, skills, and attitudes about cancer and cancer-related care [2,8,9,10,17]. It should be well-rounded and ideally supported by a coordinating body, with an academic basis of professorships [2].

 As detailed by the IOC [18], there is a need for increased emphasis on clinical interaction and greater time spent with patients [1,2,5,21,37]. As suggested [18], medical students need at least five cancer clinical experiences before graduating:

  • Talking with and examining people affected by all stages of cancer;
  • Talking with and examining people affected by all common cancers;
  • Observing all components of multidisciplinary cancer care;
  • Seeing shared decision-making between cancer patients and their doctors; and
  • Talking with and examining dying people [2,15,18].

 

  1. Assessment

As shown in Australian medical schools, assessment drives performance [2]. Thus, having decided upon a particular patient-centred approach, carrying out formal evaluation of student learning and course content is vital for enhancing training outcomes [18,38], and should inform the prescribed curriculum [2]. In future, this might include the introduction of national assessment, such as a national exit examination [40], with oncology-related scenarios aimed at testing core knowledge levels and ensuring standardisation is maintained across the country [9,39,40].

 

  1. Supplementary courses 

Regarding adjuncts to a proposed national curriculum and module [20] of oncology teaching, summer schools and extra courses [7,16] may be of great use here in Australia [1]. The Vienna Summer School, for example, receives high levels of praise and acceptance rates from European medical students. These students note that these supplementary courses provide them with a greater understanding of oncology and an appreciation of its’ multidisciplinary character [15]. Summer schools may offer educational activities that fill the gaps of an otherwise disjointed oncology training program, as shown by the example of oncology summer schools in Europe [4].

 

  1. Self-directed learning, problem-based learning and reflective practice

Learning in medical school is rarely fully autonomous, with students valuing pedagogic support and often relying on teachers as coordinators and facilitators of their learning environment [41]. Students should be encouraged to recognise the importance of evidence-based medicine, how to critically appraise literature, and the need to constantly update one’s knowledge based on high-quality evidence and guidelines [18]. Furthermore, team-based learning through small scenario or discussion groups has a role to play in the application of basic science knowledge to real-world oncology-related scenarios [35]. This could lead to greater engagement with lecture content and its’ application in daily medical practice.

There is increasing necessity for our medical curriculum to foster the development of sound communication skills. Furthermore, providing students at every level of their education with an opportunity for reflective practice, as individuals and in smaller groups, is also a must. This may serve as an important tool in supporting students who emotionally encounter negative experiences as a result of difficult or uncomfortable clinical encounters. Mentoring, as an extension of this pathway, may be of use in allowing reflection following hospital experiences. It may be of use for medical students to attach themselves to ‘mentor’ clinicians on rotation, staff whom they perceive to be effective teachers for coaching purposes, development of reflective practice, and consolidation of learning [42].

Moreover, students learn more effectively by being actively involved in a PBL strategy, as it facilitates epistemic curiosity through activation and elaboration of prior knowledge [22]. Reflection on experience, followed by evaluation, analysis, and appropriate action, may facilitate further learning and appreciation of curriculum content in the Australian context [1,4,18,21,22,23,25]. Portfolio learning [1,22,23] should thus be employed in a set teaching program [16,23], with reflective exercise  and a compulsory portfolio-based experience, or assessment. This would to facilitate reflection and exploration of the patient experience along their cancer trajectory.

 

  1. Emphasis on emerging technologies

Dramatic advances in genomic technology stand to revolutionise clinical cancer care [13,14]. Personalised (or ‘precision’) medicine is a banner term, describing the use of molecular tools to individualise healthcare through genetic testing, whole genome sequencing, exome, or transcriptome sequencing [13]. While there has been ample research in the area of genetic testing and its’ implications for our future, very little is known about how best to encourage development in understanding of such technologies at the level of medical students or recent graduates.

In the realm of breast cancer in Australia, for example, an individualised cancer care approach is evidenced in the case of genetic testing for BRCA1/2 mutations, which reflect a specific predisposition toward breast and ovarian cancer [43]. About 5% of cases of breast cancer and 10% of ovarian cancer cases, are due to such inherited predisposition [44,45]. With progress towards a more personalised, family-centred model of oncological care in Australia, knowledge of ones’ genetic and genomic information plays a crucial role, from screening and prevention, to individualised surgical treatment, and utilisation of targeted therapies based on a tumours’ molecular signature [46].

In order to fully realise the effective application of personalised medicine into routine Australian cancer care, students and clinicians need a more comprehensive understanding of emerging technologies. In addition, an appreciation of the experiences, and attitudes of cancer patients, and their families is required. Evidence suggests that the majority of cancer patients are willing to undergo genetic and genomic testing during, or following, cancer treatment [11]. More work is needed in this area to provide graduates with a more refined appreciation of how best to communicate genomic concepts to a broad range of patients [11]. Medical graduates must have greater awareness of foundational genetics-based and personalised medicine pathways. This will allow them to alleviate patient misconceptions and ultimately, to empower patients to make more informed cancer care decisions [12-14]. Without this, there may be failure to adequately deliver genetically-guided cancer care, treatment, and management in the future. The issue our educators will now face is how to best integrate this information into a feasible medical student curriculum.

 

Conclusion

More effective teaching and learning strategies in oncology should be aimed at producing Australian medical graduates with adequate and relevant cancer-related knowledge, skills, and attitudes that best meet the needs of their society [2]. The IOC [18] does an exceptional job of demonstrating the requirements and expected knowledge to be attained through a prescribed oncology curriculum here in Australia.

Australian medical students need a well-rounded understanding of oncology concepts and appropriate examination and communication techniques to facilitate aspects of cancer diagnosis, referral, and management in future clinical practice [20]. There must be focus given to developing an awareness of emerging technologies in the realm of cancer care with emphasis on basic concepts related specifically to genetic testing, genetic counselling, and personalised medicine.

The foundational experiences provided by medical school training serve to shape one’s entire career as a doctor. Those students more engaged in their learning through SDL, PBL and reflective practice strategies [26,27], and who have a greater understanding of key concepts are more likely to achieve superior assessment outcomes [2]. They are also more likely to be involved in successful clinical interactions overall [1].

With greater research focus on this area in future, there may be a larger evidence-base targeted at providing overarching improvements in Australian oncology education. This will assist graduates in gaining an adequate understanding and an appreciation of cancer-related scenarios and cancer care. More effective teaching and learning facilitation with better overall Australian training outcomes will ultimately lead to advancement in cancer diagnosis, treatment, and management outcomes as well as ensuring more insightful and valuable patient interactions in our futures [5,12].

 

Conflicts of interest

None declared.

 

References

  1. Gaffan J, Dacre J, Jones A. Educating undergraduate medical students about oncology: a literature review. Journal of clinical oncology. 2006;24(12):1932-9.
  2. Barton MB, Bell P, Sabesan S, Koczwara B. What should doctors know about cancer? Undegraduate medical education from a societal perspective. The Lancet Oncology. 2006;7(7):596-601.
  3. Fromm-Haidenberger S, Pohl G, Widder J, Kren G, Fitzal F, Bartsch R, et al. Vienna international summer school on experimental and clinical oncology for medical students: an Austrian cancer education project. Journal of Cancer Education. 2010;25(1):51-4.
  4. Pavlidis N, Vermorken JB, Stahel R, Bernier J, Cervantes A, Audisio R, et al. Oncology for medical students:: A European School of Oncology contribution to undergraduate cancer education. Cancer Treatment Reviews. 2007;33(5):419-26.
  5. Payne S, Burke D, Mansi J, Jones A, Norton A, Joffe J, et al. Discordance between cancer prevalence and training: a need for an increase in oncology education. Clinical Medicine. 2013;13(1):50-6.
  6. Practitioners RACoG. The RACGP Curriculum for Australian General Practice: RACGP 2016 Curriculum. Melbourne: The Royal Australasian College of General Practitioners. 2016.
  7. Granek L, Mizrakli Y, Ariad S, Jotkowitz A, Geffen DB. Impact of a 3-Day Introductory Oncology Course on First-Year International Medical Students. Journal of Cancer Education. 2016:1-7.
  8. Smith WT, Tattersall MHN, Irwig LM, Langlands AO. Undergraduate education about cancer. European Journal of Cancer and Clinical Oncology. 1991;27(11):1448-53.
  9. McGrath BP, Graham IS, Crotty BJ, Jolly BC. Lack of integration of medical education in Australia: the need for change. Medical journal of Australia. 2006;184(7):346.
  10. Tattersall MHN, Langlands AO, Smith W, Irwig L. Undergraduate education about cancer. A survey of clinical oncologists and clinicians responsible for cancer teaching in Australian medical schools. European Journal of Cancer. 1993;29(11):1639-42.
  11. Gray SW, Hicks-Courant K, Lathan CS, Garraway L, Park ER, Weeks (2012). Attitudes of patients with cancer about personalized medicine and somatic genetic testing. Journal of Oncology Practice; 8(6): 329-35.
  12. McGowan ML, Settersten RA Jr, Juengst ET, Fishman JR. (2014). Integrating genomics into clinical oncology: ethical and social challenges from proponents of personalized medicine. Urologic Oncology; 32(2): 187-92.
  13. Tian Q, Price ND, Hood L. (2012). Systems cancer medicine: towards realization of predictive, preventive, personalized and participatory (P4) medicine. Journal of Internal Medicine; 271(2): 111-21.
  14. Ward RL. (2014). A decade of promises in personalised cancer medicine: is the honeymoon over? The Medical Journal of Australia; 200(3): 132-3.
  15. General Medical Council. Education C. Tomorrow’s doctors: recommendations on undergraduate medical education: General Medical Council London; 1993.
  16. Matkowski R, Szelachowska J, Szewczyk K, Staszek-Szewczyk U, Kornafel J. Improvements in undergraduate oncology education introduced at Polish Medical Universities between 2004 and 2010 under Poland’s “National Program for Combating Neoplastic Diseases”. Journal of Cancer Education. 2014;29(3):428-33.
  17. Robert KH, Einhorn J, Kornhuber B, Peckham M, Zittoun R. European undergraduate education in oncology: a report of the eortc Education Branch. Acta Oncologica. 1988;27(4):423-5.
  18. Oncology Education Committee. Ideal oncology curriculum for medical schools. The Cancer Council Australia. 2007.
  19. Sabesan S, Olver I, editors. Clinical Oncology for Medical Students. Sydney: Cancer Council Australia. [Version URL:http://wiki.cancer.org.au/oncologyformedicalstudents_mw/index.php?title=Clinical_Oncology_for_Medical_Students&oldid=1656, cited 2016 Oct 4]. Available from:http://wiki.cancer.org.au/oncologyformedicalstudents/Clinical_Oncology_for_Medical_Students.
  20. DeNunzio NJ, Joseph L, Handal R, Agarwal A, Ahuja D, Hirsch AE. Devising the Optimal Preclinical Oncology Curriculum for Undergraduate Medical Students in the United States. Journal of Cancer Education. 2013;28(2):228-36.
  21. Matkowski R, Szelachowska J, Szewczyk K, Staszek-Szewczyk U, Kornafel J. Improvements in undergraduate oncology education introduced at Polish Medical Universities between 2004 and 2010 under Poland’s “National Program for Combating Neoplastic Diseases”. Journal of Cancer Education. 2014;29(3):428-33.
  22. Maughan TS, Finlay IG, Webster DJ. Portfolio learning with cancer patients: an integrated module in undergraduate medical education. Clinical Oncology. 2001;13(1):44-9.
  23. Finlay IG, Maughan TS, Webster DJT. A randomized controlled study of portfolio learning in undergraduate cancer education. MEDICAL EDUCATION-OXFORD-. 1998;32:172-6.
  24. Abrão MN, Bensi CG, Gonçalves MS, Narahara JL, Otsuka FC, Ranzatti RP, et al. A medical student-staffed outpatient oncology clinic: a 10-year Brazilian experience. Journal of Cancer Education. 2008;23(1):63-4.
  25. Orr B. Learning in oncology: lessons from the 20th century, learner-centred education for the 21st century: part II. Clinical oncology. 2004;16(6):435-8.
  26. Spencer JA, Jordan RK. Learner centred approaches in medical education. British Medical Journal. 1999;318(7193):1280.
  27. Barrows HS. Problem-based learning in medicine and beyond: A brief overview. New Directions for Teaching and Learning. 1996;1996(68):3-12.
  28. Newble DI, Entwistle NJ. Learning styles and approaches: implications for medical education. Medical Education. 1986;20(3):162-75.
  29. Newble DI, Clarke RM. The approaches to learning of students in a traditional and in an innovative problem-based medical school. Medical Education. 1986;20(4):267-73.
  30. Coles CE, Spooner D. Lifelong learning in clinical oncology editorial series: introduction and overview. Clinical Oncology. 2011;23(5):309-11.
  31. The Australasian College of Dermatologists. 2016. ACD e-Learning Portal. Australia: The Australasian College of Dermatologists.
  32. Australian Institute of Health and Welfare. AIoHaWC. Cancer in Australia: an overview, 2014. . Cancer series no 78 Cat no CAN 75 2014.
  33. Dolev JC, O’Sullivan P, Berger T. The eDerm online curriculum: a randomized study of effective skin cancer teaching to medical students. Journal of the American Academy of Dermatology. 2011;65(6):e165-e71.
  34. Back AL, Arnold RM, Tulsky JA, Baile WF, Fryer-Edwards KA. Teaching Communication Skills to Medical Oncology Fellows. Journal of Clinical Oncology. 2003;21(12):2433-6.
  35. Haidet P, O’Malley KJ, Richards B. An Initial Experience with “Team Learning” in Medical Education. Academic Medicine. 2002;77(1):40-4.
  36. Aspegren K. BEME Guide No. 2: Teaching and learning communication skills in medicine-a review with quality grading of articles. Medical teacher. 1999;21(6):563-70.
  37. Cave J, Woolf K, Dacre J, Potts HWW, Jones A. Medical student teaching in the UK: how well are newly qualified doctors prepared for their role caring for patients with cancer in hospital? British journal of cancer. 2007;97(4):472-8.
  38. Dennis KEB, Duncan G. Radiation oncology in undergraduate medical education: a literature review. International Journal of Radiation Oncology* Biology* Physics. 2010;76(3):649-55.
  39. Koczwara B, Tattersall MHN, Barton MB, Coventry BJ. Achieving equal standards in medical student education: is a national exit examination the answer? Medical journal of Australia. 2005;182(5):228.
  40. Lawson-Smith C. Achieving equal standards in medical student education: is a national exit examination the answer? The Medical journal of Australia. 2005;183(3):167.
  41. Dornan T, Hadfield J, Brown M, Boshuizen H, Scherpbier A. How can medical students learn in a self‐directed way in the clinical environment? Design‐based research. Medical education. 2005;39(4):356-64.
  42. Norman GR, Vleuten C, Newble D. (2002). International handbook of research in medical education. Boston: Kluwer Academic.
  43. Komatsu H, Yagasaki K. Are we ready for personalized cancer risk management? The view from breast-care providers. International Journal of Nursing Practice 2014; 20(1): 39-45.
  44. Di Prospero LS, Seminsky M, Honeyford J, et al. Psychosocial issues following a positive result of genetic testing for BRCA1 and BRCA2 mutations: Findings from a focus group and a needs-assessment survey. Cmaj 2001; 164(7): 1005-9.
  45. Doherty GMW, L.W. Current Diagnosis & Treatment: Surgery (14th ed.). New York: McGraw-Hill Medical; 2015.
  46. Fashoyin-Aje L, Sanghavi K, Bjornard K, Bodurtha J. Integrating genetic and genomic information into effective cancer care in diverse populations. Annals of Oncology 2013; 24 Suppl 7: vii48-54.
Categories
Feature Articles

Opening the “die-logue” about palliation

He was just about my age, but his face was pale, his cheeks cavernous, and there was a weariness in his every movement; he was too weak to speak or even swallow well. It was as if he had been drained of all his youth.

We spent the next three hours helping him get through a bowl of porridge, and I will forever remember it. He struggled with every spoonful, and watching that made me sad and angry at life for being so unfair to someone as young as him. There was also an odd sense of relief whenever he did not choke on a swallow, warmth whenever he mustered enough energy to smile at me, and the type of calm you feel when you watch the ocean waves. But instead, I was watching his bony ribcage heave up and down with every breath.

That was the first day of my first job as a teenager, as a carer at St Joseph’s Hospice and Home in Singapore. I continued that job for four years and it inspired me to attend medical school. More importantly, however, those three hours were when I first discovered hospice and palliative care. Or rather, when it discovered me.

Since then, an aging population has become a major demographic trend worldwide and the topic of how to die well has garnered growing attention. Moreover, much focus has been directed to removing the taboo on death, a significant hurdle to the routine integration of palliative care into medicine [1]. As a fourth year medical student now, some deaths have inevitably left their marks on me, leading me to consider whether the palliative care we are offering to patients now really is the best. After all, in death, as in life, quality matters.

One of these deaths was that of a patient, Maggie[1], to whom I had provided care for a long time at St Joseph’s. Maggie was a retired dance teacher. She was chatty and had always proudly shared the stories of her students with me. Even after I left Singapore to attend medical school in Sydney, I would visit her whenever I made a trip back home. Unfortunately, with each visit she grew frailer, and she was eventually placed in a wheelchair, where she was spent most of her time. Her frailty took away much of her independence, but she remained cheerful, nonetheless.

At this time, St Joseph’s had begun working with a Singaporean philanthropic house, Lien Foundation, which conceptualised and pioneered the “Happy Coffin” palliative movement. The antithesis in the name of the movement captures its objective – to transform the coffin from a negative representation of death to a canvas for positive celebrations of life and expression of art. It is part of an initiative to lift the death taboo, encouraging hospice patients to share their lives, dreams, and wishes, which are interpreted and painted on a custom coffin by commissioned artists to liberate mind sets and open the “die-logue” [2]. Maggie was thus enrolled with Happy Coffin.

On my last visit to see Maggie, she showed me pictures of her coffin and described the drawings on them with a bright smile on her face. She said the lively children painted on it – her students – were the pride of her life. She seemed at peace with her condition and I felt genuinely happy for her. This seemed to reinforce what medical school had been teaching me: talking and planning for your death through palliative care really is the gold standard of dying.

A year later, I received news that Maggie has passed on. As one of the pioneer participants of the Happy Coffin experience, her death was highly publicised in the media, where she was positioned as the brave individual who confronted death optimistically, almost as the role model for all future deaths. Indeed, the moral strength of character of a patient who faces up to or denies death is always at stake whenever telling the story of death, and perhaps this is why we are fixated with open discussion of death and palliative integration [3]. They say she had a beautiful death.

However, the news of Maggie’s passing arrived in my first clinical year of medicine, during my oncology placement, a time where I was becoming increasingly aware that not every death is – or can be like Maggie’s.

There were many deaths in oncology, and thus many opportunities for palliative medicine to step in. While there were cases where palliation was seamlessly introduced into the care of terminally ill patients, I also witnessed many instances where palliative care implementation brought much distress and dilemmas in terms of medication choice, truth-telling, autonomy, and other treatment practises. Unlike what I had imagined, many patients were offended whenever death and palliation were mentioned, as some cultures believe that to speak of death is to invite it. In terms of pain management, different patients also had very different attitudes. Most doctors I met genuinely believed that pain relief is always the best option, although this can be quite controversial as many ethnic groups view pain tolerance as a form of strength. I particularly recall a Buddhist patient with staunch Confucian beliefs. Decision-making  for his treatment was relinquished to his children, whose filial piety was, in turn, measured by their perseverance, both financially and emotionally, through curative therapies for their sick parent, even when efforts are futile. Such perseverance was a form of devotion and love. Palliation for this patient was, therefore, almost out of the question. On another occasion, I also observed a family get upset when the doctor had suggested for advanced care directives to be established – they saw it as prolonging autonomy when autonomy was not sought.

This set me thinking about the current model of palliation in medicine.

In medicine, we believe palliative medicine is the gold standard for dying, with the 2014 World Health Assembly prioritising the assimilation of palliative care and death planning into national healthcare systems [4]. The surge in this global palliative movement is understandably so, as palliation offers awareness and open communication,  gradual acceptance of death, provision of pain relief, and continuity of a person’s essence till death in the form of autonomy in decision-making and control in the dying process. Patients who have been palliated thus approach end-of-life with symptomatic pharmacological care, spiritual, and psychosocial relief to them and their family, abundant knowledge of their disease’s natural history to manage expectations, and having their resuscitation status, medical proxies and advanced care directives established. Above all, confronting mortality empowers people to make the most of their time left, view life in wider perspectives, and live life it to the fullest [5].

However, amidst today’s palliative hype, I wonder if the medical community may have created a singular definition of a “good death”, forgetting that this definition may vary for different patients. Maggie’s death was the first death I had encountered in a healthcare setting, and I had the privilege of understanding her and her palliation process; death was openly discussed with her, she had her advanced care directives prepared, curative therapies were stopped in place of symptomatic ones, and as a Catholic, she was attending weekly prayer support sessions from the church associated with the hospice. I saw how comfortable she was even in her last months, and I am convinced that this was the best possible death for her. However, is this enough reason for deaths like hers to be touted as the role model for all other deaths, especially in today’s multicultural societies?

As our world becomes increasingly globalised and culturally diverse, our definitions of a “good” death will also diversify. This will inadvertently lead to provision of inappropriate end-of-life care to patients from diverse backgrounds and cultural misunderstandings. For example, a doctor’s concept of a “good” death, which is likely to be influenced by their culture as well as their personal and professional experiences, may conflict with the desires of the patient [6].

In Australia, while we are a multi-cultural society, our ethical paradigm remains firmly rooted in Western philosophical traditions. This becomes apparent when examining the medical school curriculum- the dominant paradigm through which ethics is being taught is the Western bioethical framework. Medical students are taught to keep diagnoses confidential to the patient only, and to prolong patient autonomy as much as possible. Although, doctors may reflect the diverse cultural demographics of Australia, they are educated to uphold the Western set of ethical principles even whilst caring for patients from diverse cultural backgrounds [6]. Such education might have unintentionally created a culture of marginalising other modes of death in the pursuit of what we were taught is a “good” death.

Perhaps more flexibility in models of end-of-life care might allow us as a medical community to better accommodate the care preferences of people from diverse backgrounds. This can be achieved through a wider appreciation of different cultural notions of death. While it is not realistic for health professionals to understand the breadth of cultural beliefs in relation to illness, it is necessary to have a fundamental level of cultural competence and to understand when, and how, to consult further expertise when caring for people of different backgrounds.

It is as much the professional responsibility of the doctor as it is the moral responsibility of friends and family to ensure that a patient’s death is in line with his/her wishes. Therefore, it really is time to open up this “die-logue” and examine how the different ideals of death seep through our current framework of palliative medicine, to decrease disparity in quality of death delivered to everyone. And who better to lead this “die-logue” than the medical community itself?

 

Conflicts of interest

None declared.

 

References

[1] Gardner DB. Quality in life and death: can we have the conversations? Nurs Econ. 2012;30(4):224.

[2] Lee PW. A Happy Coffin before you die. Singapore: Lien Foundation; 2011.

[3] Frith H, Raisborough J, Klein O. Making death ‘good’: instructional tales for dying in newspaper accounts of Jade Goody’s death. Sociol. Health Illn. 2013;35(3):419-33.

[4] Unit EI. The quality of death: ranking end of life care across the world. London: Economist Intelligence Unit; 2011.

[5] Sepúlveda C, Marlin A, Yoshida T, Ullrich A. Palliative care: the World Health Organization’s global perspective. J Pain Symptom Manage. 2002;24(2):91-6.

[6] Chater K, Tsai CT. Palliative care in a multicultural society: a challenge for western ethics. Aust J Adv Nurs. 2008;26(2):95.

 

Categories
Feature Articles

The strengths and shortcomings of empathy in medicine

Every day medical students and doctors are faced with challenging, ethical, and moral dilemmas. Caring for patients can be draining and bearing witness to their suffering can often take a toll on the mental and emotional health of practitioners. A key psychological component affecting how we react to these situations is empathy. Here, the effects of empathy on our health and relationships with patients as well as the benefits and challenges of using empathic practice are examined.

“Not even one’s own pain weighs so heavy as the pain one feels with someone, for someone, a pain intensified by the imagination and prolonged by a hundred echoes.”

― Milan Kundera, The Unbearable Lightness of Being [1]

 

Several times a day, if not more often, I see prescriptions for metformin on patient charts. Diabetes in hospital patients is almost as common as perfectionism in medical students; over 900,000 hospitalisations – or 9% of all hospitalisations – in Australia in 2013 were for management of diabetes as the principal or additional diagnosis [2]. Having lived with type 1 diabetes now for over 16 years, I have heard innumerable lectures on the pitfalls of chronic hyperglycaemia. With my last HbA1c falling in the “dangerously high” region at 12.9%, I am all too aware of how this can affect my long-term health. Yet, I cannot in good conscience stand at the bedside of patients with diabetes and lecture them on adherence to medication or better sleeping and eating habits when I myself struggle everyday with poor results. I often find myself torn between judging patients – and myself – for poor control, or letting poor control slide in acceptance of the human capacity for error. Rather than simply ruminating on my own shortcomings, the aim of this essay is to use my own as well as other patients’ experiences to highlight the all-too-real dilemma of allowing empathy to guide us while still separating personal feelings from professional agendas in medicine.

Empathy is a complex phenomenon, involving cognitive and affective processes that affect our capacity to understand and respond to other people’s emotional and mental states. Cognitive empathy can be defined as the awareness and understanding of another’s emotion. Affective empathy refers to the vicarious experience of emotions consistent with those of the observed person and often results in empathic concern, which involves feelings of compassion or concern for another. A more problematic form of affective empathy is personal distress: personal feelings of discomfort and anxiety in response to another’s suffering [3].

A recent popular article published in Scientific American explored the idea of empathy as being a double-edged sword [4]. The authors discussed the psychological construct of empathy’s ability to overwhelm their clinical judgment, however they also underlined its importance in relating to patients and being a well-adjusted human being. The article concluded, “[the] key is knowing when empathy is called for and when it is detrimental. It should not be the goal of physicians, then, to be more empathetic. They should aim instead to find the right balance, the golden mean that optimises care.”

Several studies have demonstrated that as clinical reasoning and experience in medicine widens, empathy decreases [5,6]. Reasons for this change are uncertain, however I question whether the inverse relationship between experience and empathy may be linked to the x-axis of time: the longer medical students spend exposed to the realities of medicine, the less able they become to expose their emotions to the harsh realities of patients’ lives. We can’t save everyone and often we can’t even eliminate much of their burden of disease – so losing the ability to empathise so as to limit emotional and psychological burden is likely a factor here as well. The evidence for this decrease in empathy over time is elegantly demonstrated in a study by Newton and colleagues which revealed that medical students’ empathy scores drop significantly between their first and third years [5]. This study used a standardised empathy scale to evaluate the same class of students every year between first and fourth year, and they found overall medical education was a determinant differentially affecting the vicarious empathy of students, with the greatest impact on male surgical specialties. The authors concluded, “the significant decrease in vicarious empathy is of concern, because empathy is crucial for a successful physician–patient relationship.” Another study of American medical students demonstrated the drop in empathy scores to be most significant across the third year (their first clinical year), with no significant drop during basic sciences teaching [6]. They also reported greater feelings of psychological distress in students over this same period, which is consistent with Australian statistics from Beyond Blue that report one in five medical students have had suicidal thoughts in the past year [7].

While it is undoubtedly true that empathy is necessary for healthy doctor-patient relationships, I question whether there is an element of self-preservation involved in the gradual loss of empathy over the course of our clinical years. Throughout my childhood, my younger sister was in and out of hospital for neurosurgeries involving a hard-to-access cyst in the pineal recess of her third ventricle. I was able to recite these words as a nine-year-old, and as a ten-year-old, I decided I wanted to be a doctor so that I could fix people like her. The problem was that I also hated hospitals; a normally well-mannered child, I would become hysterical after going to see her. In hindsight, I think that paediatric neurosurgery wards do this to a lot of people and in my case this was certainly caused by a vicarious empathetic response of personal distress. The immense suffering you see on these wards can make a bright day seem sombre, and it takes a special kind of nurse and surgeon to work in that environment day-in-day-out. If these people had not distanced themselves from their patients to a degree, the suffering they witnessed would almost certainly cause significant psychological distress. To preserve the emotional well-being of the medical staff on such wards, coping strategies such as intellectualisation, humour, and team support are essential [8].

There was one moment of kindness in that hospital which remains etched in my mind to this day. My sister was a bright child, and on the day before her surgery, unbeknownst to any of us, she secretly wrote a letter outlining her fears and questions for her surgeon. This man was the extremely busy head of neurosurgery and that morning, as usual, he charged into her room for rounds with his trailing procession of residents hanging on every word. After he had checked her over and turned to leave, my sister in a tiny voice announced she had something for him and thrust a piece of coloured paper at him. It was her list, carefully written out in crayon, of questions she wanted answered, number one being “Am I going to die?” He took it from her hand, glanced quickly at it, frowned, and left the room. My mother was appalled at his perceived indifference, while my father tried to soothe the situation with platitudes about how busy the man was. My sister was quiet and said little. Half an hour later we were surprised by the return of the surgeon, this time alone and with his white coat thrown over his shoulder. He walked in, nodded at my mother, and said to my sister, “Now that we’ve gotten rid of all those yucky doctors, let’s take a look at this list.” For the next ten minutes, he carefully went through each question with her and he told her the truth about everything. She calmly listened, occasionally asking more and when finished he rubbed his hands together and asked, “Are we good to go?” After she nodded, he smiled towards my parents and me and strode out of the room. Whether or not he was motivated by empathy I can only speculate, but it seems likely the surgeon recognised the suffering of my parents and sister and he demonstrated empathic concern: sympathy and compassion for others in response to their suffering. Whatever the case, I am thankful that this man was able to control his emotions without losing his humanity and I can only aspire to one day be able to do so as well.

I will conclude by making a case for using empathy in medicine. Empathy is derived from humanity and according to Hippocrates, “Wherever the art of medicine is loved, there is also a love of humanity” [9]. When a patient feels comfortable with a doctor, they are more likely to come forward with their true feelings and admit to forgetting to take prescription medications or to having sex without a condom, whatever the case may be. It is true that as future doctors we need to protect ourselves from feeling too deeply, but if we forget to open our hearts to the people we aim to help, we will risk losing their confidence altogether. Additionally, quite apart from the physician’s need to take a patient’s history to understand their affliction, the process of telling one’s story can be therapeutic for patients [10] and may help facilitate the healing process. Finally, empathy is beneficial to physicians – other physicians have noted that doctors who are more attuned to the psychosocial needs of their patients are less likely to experience burnout [11].

As for myself, I no longer fear going into the hospital but there are still many days where, as a result of connecting with a patient, I feel the urge to cry on my walk home. I try to balance this by looking forward to the time when, as a doctor, I can improve patients’ lives, just as the neurosurgeon did for my sister. I believe that empathy is a good tool to improve listening and understanding of the patient’s perspective. Ultimately my goal is to have the attributes of an excellent physician and a compassionate human being without letting my awareness of the pain of others pain destroy my soul.

 

Conflicts of interest

None declared.

 

References

[1] Kundera M. The unbearable lightness of being. New York: Harper & Row; 1984. 38 p.

[2] Diabetes (AIHW) [Internet]. Aihw.gov.au. 2016 [cited 2016 5 Jul]. Available from: http://www.aihw.gov.au/diabetes/

[3] Davis, M. H. Measuring individual differences in empathy: Evidence for a multidimensional approach. J Per Soc Psychol. 1983;44: 113–126.

[4] Haque OS, Waytz A. Why doctors should be more empathetic – but not too much more. Sci Am[Internet]. 2011 Apr 25 [cited 2016 7 Jul]. Available from: http://www.scientificamerican.com/article/doctors-and-dehumanization-effect/

[5] Newton BW, Barber L, Clardy J, Cleveland E, O’Sullivan P. Is there hardening of the heart during medical school? Acad Med. 2008;83(3):244–9.

[6] Hojat M, Vergare M, Maxwell K, Brainard G, Herrine S, Isenberg G et al. The Devil is in the Third Year: A Longitudinal Study of Erosion of Empathy in Medical School. Acad Med. 2009;84(9):1182-1191.

[7] Urgent action needed to improve the mental health and save the lives of Australian doctors and medical students [Internet]. Beyondblue.org.au. 2016 [cited 5 Jul 2016]. Available from: https://www.beyondblue.org.au/docs/default-source/media-release-pdf/urgent-action-needed-to-improve-the-mental-health-and-save-the-lives-of-australian-doctors-and-medical-students-october-2013.pdf?sfvrsn=0

[8] Meadors P, Lamson A. Compassion fatigue and secondary traumatization: Provider self care on intensive care units for children. J Pediatr Health Care. 2008;22(1) 24–34.

[9] Khan Z. Airway management. 1st ed. New York: Springer International Publishing; 2014. 5 p.

[10] Adler HM. The history of the present illness as treatment: who’s listening, and why does it matter? J Am Board Fam Pract. 1997;10(1):28-35.

[11] Anfossi M, Numico G. Empathy in the doctor-patient relationship. J Clin Oncol. 2004;22(11):2258-2259.

Categories
Feature Articles

Meditate to Medicate: Mindfulness Meditation as a Complementary Therapy for Surgical Patients

Mind-body therapies such as mindfulness meditation (MM) are increasingly being studied and applied as legitimate medical therapies. Since becoming popular in the 1970s, MM has been shown to improve psychological states such as anxiety and depression. The scope of MM has expanded in recent years, and MM has been shown to have positive effects on pain, recovery time, and even wound healing after surgery. The number and types of surgery are increasing with the ageing population, and MM has potential as a non-surgical therapy to help hasten recovery, minimise analgesic consumption, and improve overall satisfaction after surgery. Training patients in MM before surgery may be implemented at low cost and up to 24 hours before admission. Given these benefits, complementary mind-body therapies such as MM have potential to improve a patient’s surgical experience and outcomes. Despite the potential benefits, MM is not currently used routinely for patients undergoing surgery. The literature shows that there is a perceived suspicion of the practice’s effectiveness, which appears to hamper its clinical acceptance. Critics cite concerns about patients’ perception of meditation given its religious connotations and whether they would be encouraged to accept MM as a valid therapy. This essay explores the application of MM as a complementary therapy to expedite recovery from surgical admission and concludes that meditation may be as effective as medication in some circumstances.

 

Introduction

“The part can never be well unless the whole is well.” This epithet offered by Plato 2300 years ago refers to the symbiotic relationship between mental and physical health, and has increasingly been embraced by Western society [1]. The concept that psychological state can influence physical well-being has contributed to the acceptance and use of mind-body therapies and motivated research into their health benefits. Recent scientific enquiry has noted diverse benefits of meditation such as reduced anxiety and depression levels, improved cardiac health, heightened immunity, and fewer post-chemotherapy adverse symptoms among cancer patients [2-4]. Researchers have also established a strong link between mind-body therapies and pain attenuation [5]. These findings suggest that these therapies may have potential as treatment for elective surgery inpatients.

With the increased number and types of surgical procedures required by an ageing population, meditation has been proposed as a means of improving post-operative outcomes, particularly after elective surgery [6]. Despite reported benefits and potentially low implementation costs [7], traditional medicine has been slow in adopting these alternatives. Critics remain sceptical of the efficacy and practicality of meditation, whereas advocates suggest that the analgesic qualities indicate clinical potential. To reconcile these opposing views, one must consider the logistical, psychosocial, and therapeutic aspects of meditation in the surgical context.

 

Mindfulness meditation

Meditation is often defined as mental exercises and techniques designed to calm the mind through physiological processes [8-10]. Mindfulness meditation (MM) sometimes referred to as ‘Vipassana practice’ or ‘insight meditation’, was thought to have been conceived by Buddhist scholars over 2000 years ago in India and is inextricably linked with Buddhist theology [11]. It involves cultivating a focused psychological attention to the internal and external experiences occurring in the present moment [12,13]. In practice, MM requires attentiveness to simple physical sensations such as breathing, eating, or sitting. Technical applications of this approach vary. One popular methodology in a clinical setting involves using one’s imagination to mentally scan the entire body for awareness of physical sensations without judgment, beginning with the head and progressing to the toes. This can be used for any duration and in many circumstances. MM may also incorporate ‘guided imagery’ techniques in a clinical context, in which the patient visualises his or her own healing process and affirms thoughts of positivity regarding the management of illness [14].

 

MM as a form of therapy

Despite its origins in antiquity, MM has recently been adopted by Western society [15], and today’s incarnation is mostly secular [16]. One of the first occasions of mindfulness being introduced to Western medicine occurred in 1979 by Kabat-Zinn’s Mindfulness Based Stress Reduction (MBSR) program at the Stress Reduction Clinic at the University of Massachusetts Medical Center [3,17]. The inaugural program described reduced self-reported scores for depression and anxiety in participants with psychological problems [11].

To implement MM as a therapeutic tool, Kabat-Zinn adapted the methodology. He anticipated that the introduction of an alternative medicine, particularly one with religious associations, would be denounced by orthodox medical practitioners as the work of charlatans or mystics [17]. Overcoming this prevailing medical stigma was integral to the wider acceptance of mindfulness today. Accordingly, Kabat-Zinn distinguished MBSR from its religious counterpart by exploring the curative potential of meditation and designed it to be used as a clinical tool that complemented rather than replaced conventional medical therapies.

The scope of clinical mindfulness has expanded greatly with wider acceptance of MM by the wider scientific community. Current programs include mindfulness-based cognitive therapy, acceptance and commitment therapy, and mindfulness-based relapse prevention [18,19]. There are now even smart phone applications, DVDs, and self-help books, which have propelled mindfulness concepts into the public domain.

The acceptance of mindfulness by the medical community is also evidenced by the recent interest in the scientific evaluation of mindfulness as a health promotion tool. For example, in the 2008-09 fiscal year, the US government funded hundreds of studies concerning the clinical applications of various meditative practices, at a cost of US $51 million [17].

 

MM and surgical outcomes

By influencing psychological states, MM may help address post-surgical complications such as pain and reduced functioning [20]. A systematic review of studies that evaluated psychological variables and surgical outcomes found that psychological state strongly correlates with early recovery, although differences in study design restrict the ability to confidently pool results [20]. Psychological factors have also been shown on occasion to be superior predictors of post-operative outcomes than the surgical intervention itself [14]. Despite continued technological innovation, today many patients endure moderate to severe negative post-operative outcomes [21]. For example, up to 40% of patients who undergo elective joint replacement surgery report suboptimal functional improvement, pain relief, and overall satisfaction after their procedure [22]. These issues suggest that there is a need for complementary therapies to support existing therapies in a surgical setting.

Mind-body therapies such as MM are being increasingly evaluated for their effects on post-operative psychological variables. The use of mind-body therapies as a nonpharmacological adjunct has been well studied in cardiac, abdominal, and orthopaedic surgeries [14]. In these contexts, MM is associated with improved levels of pain, anxiety, fatigue, and distress [14]. Reduced systolic blood pressure has been reported during the post-operative period in patients who have practised a guided-imagery protocol [23]. Other benefits include shorter hospital stay and promotion of wound healing in some studies [14,24].

MM has been shown to be useful for reducing reliance on analgesia in the post-operative period and beyond [14]. Analgesia consumption levels can be used as a proxy for pain control. Although analgesic use is essential for promoting surgical recovery, too great a reliance on pharmaceuticals increases the risk of adverse side effects such as nausea, respiratory depression, and lethargy [25]. Some analgesics can also predispose to long-term dependency if their use is not appropriately stewarded. Palmaro et al. [26] observed that one-third of patients undergoing orthopaedic surgery for carpal tunnel syndrome had persistent and increased consumption of anti-neuropathic and/or opioid analgesics for more than two months after surgery. Among this population, psychiatric disorders and subjective levels of pre-operative pain explained this increased use [26]. MM may positively affect these two variables and reduce medication use. An estimated 234.2 million surgeries are performed worldwide each year, many of these necessitating pain medications [27]. It would therefore make fiscal sense to reduce the amount of pharmaceuticals required after surgery through the use of nonpharmacological therapies such as MM.

 

Proposed mechanisms to explain the effects of MM on post-operative pain

Meditative practice has been shown to change brain structure and function [28]. These effects may be seen both immediately and from chronic practice as demonstrated via brain imaging modalities such as fMRI, SPECT and PET [28]. Firstly, the prefrontal cortex (PFC) is intensely active during meditation, specifically the lateral prefrontal regions [28,29]. The ventromedial areas of the PFC are responsible for the affective integration of sensory input, whilst the posterolateral regions are concerned with sensory appraisal without self-referential value [29]. It is proposed that a neuronal shift away from the ventromedial prefrontal regions to the posterolateral centres supports a more self-detached analysis of interoceptive and exteroceptive sensory events [29]. Secondly, additional neural correlates such as modulation of the limbic system contribute to meditative effects [28]. MM practice has been shown to reduce the activity of the amygdala, and broader limbic structures concerned with emotional reactions [28].  For example, after eight weeks of an MM intervention, arterial spin labelling functional MRI showed neuroarchitectural changes such as increasing grey matter concentration within the left hippocampus an amygdala [16]. These regions are associated with emotional regulation, which may account for reduced anxiety and improved coping reported after programs of a similar duration [30]. In addition to this, MM has been posited to exert influence on the hypothalamus, which by extension shifts autonomic nervous system function towards increased parasympathetic activity [28]. This hypothesis attempts to explain physiological reductions in heart rates, blood pressure and serum cortisol levels which all evidence relaxation experienced during MM [28].

Another potential benefit of MM as a surgical therapy is pain modulation. However the exact mechanisms through which MM regulates pain are unknown [3,31]. Zeidan et al. [5] suggested MM can attenuate post-operative pain, reporting a 40% reduction in pain intensity and 57% reduction in pain unpleasantness following mindfulness intervention in a laboratory setting. The authors posited that this phenomenon results from synergistic interactions of improved attentional control, expectation modulation, and a placebo effect. By exerting attentional control on physical sensations other than discomfort, MM is thought to dampen the saliency of nociceptive stimuli.

Although this explanation seems to be reductive at face value, it is consistent with knowledge about complex neurobiology. The influence of MM on neurological pain-modulating networks is only now being explored. The cognitive inhibition of pain has traditionally been attributed to opioidergic mechanisms [32,33]. This model proposes that endogenous opioids are secreted by regions of the brain with an abundance of opioid receptors [33] and that these natural opioids elicit analgesic effects. Opioid receptors are found in high concentrations in the anterior cingulate cortex, orbitofrontal cortex (OFC), and insula [34]. Pain relief attributed to a placebo effect, conditioned pain modulation, and attentional control mechanisms such as those involved in MM rely on opioidergic pain relief [35-37]. These analgesic effects can be reversed after administration with opioid antagonists such as naloxone [34]. Imaging studies have shown that MM-induced analgesia is associated with increased activation in these regions of the brain [34]. This suggests that opioidergic mechanisms may account for some of the analgesic effects associated with MM.

Pain attenuation by MM may be supplemented by non-opioidergic mechanisms because opioidergic and non-opioidergic brain regions work synergistically. In MM, the OFC projects synapses to the thalamic reticular nuclei (TRN) which, via further projections exerts inhibitory control over the thalamus, an area considered to be the ‘gatekeeper’ through which all sensory information must pass [38]. When the TRN is active (either through the OFC or distinct mechanisms) ascending information such as nociception may be filtered from triggering conscious awareness [38]. MM therapy responses might therefore be mediated by the interaction between the OFC and the TRN, which appears to inhibit nociception from reaching the conscious part of the brain, the cerebral cortex. Self-facilitated pain modulatory systems seem to be engaged by non-evaluative recognition of an unpleasant physical sensation such as nociception [38]. Pain reduction experienced during MM is also associated with thalamic deactivation, which suggests a pain-gating effect may be exerted by the limbic system [5]. This suggests that nociception is influenced by the complex interaction of expectations, emotions, and cognitive appraisals, and may be modulated by the meta-cognitive task of focusing on the present moment [5].

 

Delivery of MM therapy to elective surgical patients

MM-based interventions vary in format and administration. Group mindfulness interventions are often preferable in clinical and research settings, and have been shown to expedite improved socialisation, program participation, and skill acquisition [14].

Group therapy with a set number of sessions of prescribed length may be more cost-effective than individual one-to-one interventions [14]. In group formats, a health professional such as a psychologist, physician or nurse instructs participants and distributes supporting material such as books and audiotapes to reinforce the program rationale and encourage independent practice outside standardised sessions.

It may not be practical to offer group sessions for patients undergoing elective surgery because of the nature of elective admissions, which are typically non-emergency procedures and can be delayed or rescheduled at short notice. Patients requiring more urgent surgery would not have sufficient advance notice to begin preoperative group therapy. Therefore, viable program methodologies should be flexible in terms of participant admission or delivered on an individualised basis as part of pre-operative patient care.

Personalised instruction or a single session with a psychologist can be tailored to the patient’s level of comprehension. Patients could also be given the opportunity for follow-up sessions to consolidate skills learned before admission.

Regardless of the mode of delivery, the rationale, advantages, and disadvantages of MM should be explained to the patient before surgery. The patient’s cognitive capacity and psychological state should be assessed by the physician or psychologist to evaluate his or her suitability for MM intervention and provide baseline psychological scores for comparison.

The benefits of regular MM practice in clinical practice have been well documented, and these skills can be consolidated for life [17]. In the context of pre-operative MM programs, optimum duration and timing of MM programs should be considered. The MBSR program developed by Kabat-Zinn [13] spans an 8-week course involving a 20-minute intervention each day. Many clinical programs use a similar program design, which has shown to be adequate to elicit desired benefits [17].

However it does not seem to be necessary for pre-operative programs to be as long as eight weeks to elicit desired effects. MM therapy given for the first time 24 hours before an operation has been shown to be beneficial. For example, Manyande et al. [39] reported reduced scores for post-operative pain and distress, and ward analgesic consumption for surgical patients given a 15-minute audio recording 1 day before elective abdominal surgery. Other studies have reported similar results [18,34,40]. Thus, although the benefits of MM are generally associated with regular practice (which may discourage some from taking up the practice), these findings imply that MM therapy involving short mental training may produce benefits even when undertaken in the days before surgery.

 

Limitations to MM therapy in the surgical context

There are potential limitations to MM as a pre- and post-operative therapy for surgical patients. The success of MM programs can be limited by surgery type and patient attributes, such as physical or cognitive impairment [14]. The stress associated with a hospital admission and surgery may impair a patient’s ability to learn a new skill such as MM [41].

Implementation of standardised programs across healthcare providers may require additional funding, development of standardised educational material, and targeted training for healthcare professionals. Estimates of the resources needed would also vary according to differences between practices and institutional infrastructure. However, the cost of implementing MM programs may be recovered at least in part by improved recovery, reduced length of stay, reduced complication rates and reduced analgesic consumption [14,24,39,42]. Further cost-benefit analysis of MM programs for surgical patients may be warranted to better understand the organisational fiscal advantages associated with the use of MM therapies.

The effect size of MM intervention on post-operative outcomes has been subject to debate. Some studies investigating the use of pre-operative mind-body therapies in the surgical context failed to establish changes to post-operative outcomes such as pain and duration of hospital stay [14]. For example, Scott and Clum [43] observed no significant effects of treatments on outcome measures such pain, anxiety and analgesic intake after an attentional control regimen initiated 24hr prior to abdominal surgery. Other studies described mixed outcomes of such protocols [14,39]. It has been suggested that heterogeneity in study design and differences in the surgical context in which they are examined restrict generalizations being formed into the effectiveness of individual protocol design [14]. This is additionally hampered by fluid definitions of ‘mind-body therapies’ and noted methodological flaws consistent throughout much of existing literature, such as reduced sample size, inadequate controls and insufficient study duration [14,17]. Additionally, it is difficult to account for the influence of external factors on broader research outcomes. Factors such as insurance coverage may exert control on measures such as duration of hospital stay which may distort findings [14]. Further research may need to be conducted to reconcile these considerations and establish the clinical scope of MM.

It is unknown how receptive patients would be to learning MM around the time of surgery. Patients may be sceptical of or uninformed about mind-body therapies [17]. It is also unclear if the religious connotations associated with MM would promote or hinder patient participation [17]. Some patients may be discouraged by anything resembling a religious practice or indeed the opposite may be true [17]. Such phenomena may be subject to many individual patient factors and could be difficult to predict in the absence of empirical data. Future enquiry may seek to better understand the influence of individual patient preferences and values on MM adherence. It may be reasoned that patient education and evidence-based practice could also help dispel misconceptions about MM therapy and foster its adoption amongst the wider community, but research would be needed to corroborate this.

 

Conclusion

Since its adoption by Western society, MM has become increasingly used as a clinical tool. With an ageing population and increased demand for surgical interventions, complementary therapies such as MM should be considered. In the surgical setting, MM may reduce pain, anxiety, and distress, improve contentment, psychological state, and recovery time, and could decrease the need for high levels of medication and the risks associated with polypharmacy. Beyond its physiological effects, MM may also benefit those seeking relief from mental and physical stresses encountered during their hospital admission. Further research and development are needed to establish viable standardised treatment programs. Despite the mixed opinions about MM, it is likely that future medical practitioners will regard MM as a powerful therapeutic option in addition to its pharmacological counterpart.

 

Conflict of interest

None.

 

Acknowledgements

The authors wish to acknowledge Laurel Mackinnon, PhD, ELS, and Sharon Johnatty, PhD, for their invaluable assistance in editing this article.

 

References

[1] Wright J. Psychosomatic Interactions. Int J Adv Couns. 1986;9(1):47-60.

[2] Davidson RJ, Kabat-Zinn J, Schumacher J, Rosenkranz M, Muller D, Santorelli SF et al. Alterations in brain and immune function produced by mindfulness meditation. Psychosom Med. 2003; 65(4):564-70.

[3] Ditto B, Eclache M, Goldman N. Short-term autonomic and cardiovascular effects of mindfulness body scan meditation. Ann Behav Med. 2006;32(3):227-34.

[4] Henderson VP, Clemow L, Massion AO, Hurley T, Druker S, Hébert J. The effects of mindfulness-based stress reduction on psychosocial outcomes and quality of life in early-stage breast cancer patients: a randomized trial. Breast Cancer Res Treat. 2012;131(1):99-109. [5] Zeidan F, Martucci KT, Kraft RA, Gordon NS, Mchaffie JG, Coghill RC. Brain mechanisms supporting the modulation of pain by mindfulness meditation. J Neurosci. 2011;31(14):5540-8.

[6] Bettelli G. Anaesthesia for the elderly outpatient: preoperative assessment and evaluation, anaesthetic technique and postoperative pain management. Curr Opin Anaesthesiol. 2010;23(6):726-31.

[7] Miller JJ, Fletcher K, Kabat-Zinn J. Three-year follow-up and clinical implications of a mindfulness meditation-based stress reduction intervention in the treatment of anxiety disorders. Gen Hosp Psychiat. 1995;17(3),192-200.

[8] May A, Gaser C. Magnetic resonance-based morphometry: a window into structural plasticity of the brain. Curr Opin Neurol. 2006;19:407-11.

[9] Grant JA. Meditative analgesia: The current state of the field. Ann N Y Acad Sci. 2014;1307(1):55-63.

[10] Lutz A, Slagter HA, Dunne JD, Davidson RJ. Attention regulation and monitoring in meditation. Trends Cogn Sci. 2008;12(4):163-9.

[11] Bauer-Wu S. Mindfulness meditation. Oncology. 2010;24(10):36-40.

[12] Baer RA. Mindfulness training as a clinical intervention: a conceptual and empirical review. Clin Psychol Sci Pract. 2003;10(2):125-43.

[13] Kabat-Zinn, J. An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results. Gen Hosp Psychistry. 1982;4:33-47.

[14] Nelson EA, Dowsey MM, Knowles SR, Castle DJ, Salzberg MR, Monshat K et al. Systematic review of the efficacy of pre-surgical mind-body based therapies on post-operative outcome measures. Complement Ther Med. 2013;21(6):697-711.

[15] Grossman P, Nieman,L, Schmidt S, Walach H. Mindfulness-based stress reduction and health benefits. A meta-analysis. Psychosom Res. 2004;57:35-43.

[16] Kristeller JL. Mindfulness meditation. In: P. Lehrer, R.L. Woolfolk, & W.E. Simes. Principles and Practice of Stress Management. 2nd Edition. New York: Guildford Press. 2007;393-427.

[17] Hickey WS. Meditation as medicine: a critique. Cross Curr. 2010;60(2):168-84.

[18] Segal Z, Williams M, Teasdale J. Mindfulness-based cognitive therapy for depression: A new approach to preventing relapse: Book review. Cogn Behav Ther. 2002;31:193-4.

[19] Bowen S, Chawla N, Collins SE, Witkiewitz K, Hsu S, Grow J et al. Mindfulness-based relapse prevention for substance use disorders: a pilot efficacy trial. Subst Abus. 2009;30:295-305.

[20] Mavros MN, Athanasiou S, Gkegkes ID, Polyzos KA, Peppas G, Falagas ME et al. Do psychological variables affect early surgical recovery? PLoS ONE. 2011;6(5):e20306.

[21] Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21(3):185-211.

[22] Hawker GA, Badley EM, Croxford R, Coyte PH, Glazier RJ, Guan JI et al. A population-based nested case-control study of the costs of hip and knee replacement surgery. Med Care. 2009;47(7):732-41.

[23] Lin PC. An evaluation of the effectiveness of relaxation therapy for patients receiving joint-replacement surgery. J Clin Nurs. 2012;21(5-6):601-8.

[24] Broadbent E, Kahokehr A, Booth RJ, Thomas J, Windsor JA, Buchanan CM et al. A brief relaxation intervention reduces stress and improves surgical wound healing response: A randomised trial. Brain Behav Immun. 2012;26(2):212-7.

[25] Spiller R, Aziz Q, Creed F, Emmanuel A, Houghton L, Hungin P et al. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut. 2007;56(12):1770-98.

[26] Palmaro A, Fuzier R, Serres I, Bourrel R, Lapeyre-Mestre M. Analgesic drug consumption increases after carpal tunnel surgery: a pharmacoepidemiological study investigating postoperative pain. Clin Ther. 2015;37(8):e64-5.

[27] Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008;372(9633):139-44.

[28] Wasi P. Brain and meditation. J Neurol Sci. 2009;285(1):s36.

[29] Farb NA, Segal ZV, Mayberg H, Bean J, McKeon D, Fatima Z et al. Attending to the present: mindfulness meditation reveals distinct neural modes of self-reference. Soc Cogn Affect Neur. 2007;2(4):313-322.

[30] Hoge EA, Metcalf CA, Morris LK, Simon NM. Mindfulness meditation for generalized anxiety disorder: effects on resilience, anxiety, and hypothalamic pituitary adrenal (HPA) axis. ‎Psychosom Med. 2013;75(3):A-2.

[31] Kahokehr A, Broadbent E, Wheeler BRL, Sammour T, Hill AG. The effect of perioperative psychological intervention on fatigue after laparoscopic cholecystectomy: a randomized controlled trial. Surg Endosc. 2012;26(6):1730-6.

[32] Wager TD, Scott DJ, Zubiet, J-K. Placebo effects on human mu-opioid activity during pain. Proc Natl Acad Sci USA. 2007;104(26):11056-61.

[33] Tracey I, Ploghaus A, Gati JS, Smith S, Matthews PM, Gati JS et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci. 2002;22(7);2748-52.

[34] Zeidan, F, Adler-Neal AL, Wells RE, Stagnaro E, May LM, Eisenach JC et al. Mindfulness-meditation-based pain relief is not mediated by endogenous opioids. J Neurosci. 2016;36(11):3391-7.

[35] Sprenger C, Eippert F, Finsterbusch J, Bingel U, Rose M, Büchel C. Attention modulates spinal cord responses to pain. Curr Biol. 2012; 22(11):1019-22.

[36] Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63(4):533-43.

[37] King CD, Goodin B, Kindler LL, Caudle R, Edwards R, Gravenstein N et al. Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing. J Behav Med. 2013;36(3):315-27.

[38] Zikopoulos B, Barbas H. Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates. Rev Neurosci. 2007;18(6):417-38.

[39] Manyande A, Berg S, Gettins D, Stanford SC, Mazhero S, Marks DF et al. Preoperative rehearsal of active coping imagery influences subjective and hormonal responses to abdominal surgery. Psychosom Med. 1995;57(2):177-82.

[40] Lin P-C. An evaluation of the effectiveness of relaxation therapy for patients receiving joint replacement surgery. J Clin Nurs. 2012;21(5-6):601-8.

[41] Jawaid M, Mushtaq A, Mukhtar S, Khan Z. Preoperative anxiety before elective surgery. Neurosciences. 2007;12(2):145-8.

[42] Manyande A, Salmon P. Effects of pre-operative relaxation on post-operative analgesia: immediate increase and delayed reduction. Br J Health Psychol. 1998;3(Pt 3):215-24.

[43] Scott LE, Clum GA. Examining the interaction effects of coping style and brief interventions in the treatment of postsurgical pain. Pain 1984;20(3):279-91.

Categories
Feature Articles

Management of chronic post-surgical pain: an overview

Chronic pain is an anticipated complication of any surgery despite comprehensive treatment modalities to combat it.  The development of chronic pain is attributable to a larger variety of inherent risks. Due to both the individual and social costs of chronic, unremitting pain, the value in preventing its development is paramount. Considering the complex pathophysiology of pain, chronic post-surgical pain (CPSP) development requires a multimodal understanding that involves understanding the physiological, psychological, and social circumstances of the patient.  Prevention and management of CPSP starts preoperatively, addressing the patient’s risk factors and expectations to anticipate and create a more personalised plan for pain control.  Intraoperative measures include local anaesthesia and pharmacological analgesic therapies.  postoperatively, a multidisciplinary approach utilising both pharmacological and non-pharmacological strategies can be used.  Pharmacological treatments include individualised opioid-based patient controlled analgesia in conjunction with prostaglandin inhibitors, central nervous system pain receptor modulators, and nerve blocks. Non-pharmacological management includes transcutaneous electrical stimulation and acupuncture.  A good understanding of how CPSP develops can aid in managing CPSP that can result in better control of chronic pain.

Pain in the perioperative period is a common and anticipated complication of surgery. Pain can be attributed in part to surgical factors such as nerve injury, inflammation, and infection. In addition, chronic pain development is dependent  on a larger variety of putative risks that include past medical history of chronic pain and perioperative anxiety (Table 1) [1]. Chronic post-surgical pain (CPSP) is classified by the International Classification of Disease 11, as persisting pain for at least three months after surgery or tissue trauma, with the exclusion of other or pre-existing causes (such as infection and malignancy) [1,2]. The presentation of CPSP is often variable and may occur in relation to deep tissue or skin trauma at the surgical site, referred from viscero-somatic convergence, or related to nerve injury during surgery [3,4].

While epidemiological accounts vary, the populations at risk of developing CPSP are variable depending on the types of surgery and the likelihood of nerve injury. Current literature indicates that CPSP occur in 10-50% of surgical cases. In orthopaedic surgery related CPSP, up to 5% of all surgical patients report severe disabling pain at one year postoperatively, and a further 10% report lesser pain [1,3,4]. In a UK study of 5000 patients considering frequency and cause of chronic pain in the secondary care setting, 22% of outpatients attributed surgery as the major cause of their chronic pain [3,5]. As chronic pain is difficult and costly to manage and has a major impact on quality of life and productivity, the socioeconomic health burden is potentially enormous considering the volume of surgeries performed annually [1,5].

Formerly, conceptualisation of chronic pain was limited to uni-factorial models of biomedical causality. These models sought to explain pain as corresponding directly to bodily damage with severity being a measurement of extent (for example, using a visual analogue scale or numeric pain rating scale), rather than patient interpretation of injury [1,6]. However, the lack of a clear relationship between extent of tissue/nerve damage and pain severity indicates there is a psychological and sociological component to pain, with the additional influences of motivation and secondary gains (family, work, and “the sick role”) [6]. These aspects were heavily enforced by operant learning factors, which develop into “pain behaviours” of avoidance, and cognitive factors based around beliefs and expectations of pain post-surgery [7]. Patients who have a past medical history including emotional or psychiatric stressors, have increased work-related injuries and claims, negative attitudes to treatments, and previous chronic pain diagnosis are at an increased risk of developing chronic pain syndromes [1,8]. To demonstrate this point, a large 2007 prospective surgical cohort study using preoperative psychological questionaries (Item-36 Short Form Health Survey) with postoperative acute pain scores for 625 patients undergoing minor, intermediate, and major surgeries, found that fear of the long-term consequences of surgery predicted increased pain in the six month postoperative follow-up period, independent of the type of procedure and other somatic factors [7].

Table 1. Risk factors for CPSP development.

Generally, surgical pain can be attributed to three main mechanisms: inflammation, direct nerve injury, and increased sensitisation [1,2]. Inflammatory pain arising from tissue trauma and ischaemia is an unavoidable aspect of most surgeries [4]. Although the release of local inflammatory mediators like tumour necrosis factor alpha and interleukins 1 and 6 are needed to a certain degree for healing, they can result in hyperalgaesia (augmented sensitivity) and allodynia (misperception of non-painful stimuli) long after the expected healing time from surgery [1,4]. These outcomes are attributed to peripheral nerve sensitisation and are often managed with anti-inflammatory medications both intraoperatively and on an outpatient basis [4]. In conjunction, pain developing from direct nerve injury (compression, stretch, or transection) can have a similar presentation in addition to hyperpathia (exaggerated pain), paraesthesia/dysaesthesia (abnormal sensation) and even hypoesthesia (decreased sensation) [1,4]. For example, nerve injury arising from fetal head descent through the birth canal during labour may result in compression or stretch of lumbosacral nerve roots resulting in radiculopathy from 8% elongation, while 15% elongation can result in axon disruption and axonotmesis [7].

Pain sensitisation is also a major precipitating factor for the transition from acute to chronic pain. The pathophysiology of sensitisation is attributed to increased excitability of both central and peripheral nerve fibres (in addition to decreased inhibition from dorsal horn spinal neurons) [1,10]. Centrally, sensitisation is linked to upregulation of N-methyl-D-aspartate (NMDA) receptors in the dorsal horn causing the “wind-up” phenomenon of pain, with peripheral changes from prolonged inflammation or opioid exposure linked to ‘hyperalgesic priming’ at the afferent sensory nerve level [1,2]. Ectopic activity in transected nerves has also been associated as the underlying cause for the spontaneous pain characteristics of some neuropathic states that involves maladaptive plasticity within the nerve nociceptive system post-injury [1]. It is predominantly owing to this sensitisation (with input from patient psychology) that the major risk factor for developing CPSP is severe acute post-surgical pain, making acute pain management of foremost importance for CPSP prevention [1,2].

Owing to its complexity, pain management warrants a comprehensive and surgery specific multimodal approach [5]. This starts preoperatively with patient risk factors and expectations addressed to anticipate potential complications and acceptable therapies. Furthermore, following procedure specific guidelines produces better clinical outcomes with appropriate discharge and rehabilitation planning incorporating a pain clinic follow-up [2]. For example, open colorectal procedures may benefit from thoracic epidurals to reduce postoperative pain, nausea, and vomiting, while laparoscopic abdominal procedures, with minimal tissue injury, often do not require the same cover [11]. These considerations should be made preoperatively with patient expectations taken into account and the risk of neuropathic/nerve injury considered for procedure appropriate analgesia [2].

Intraoperatively, local and systemic therapies can be used to target the aforementioned biomedical risks and can be further broken into nociceptive and neuropathic targets. Systemic therapies often involve opioid and limited non-opioid options for nociceptive pain, with opioid use being limited by adverse effects (such as respiratory depression and vomiting) [2].

Patient-controlled analgesia (PCA) remains a cornerstone of postoperative pain management, with early postoperative intravenous opioids providing better analgesia than conventional parenteral opioid regimens, with greater patient satisfaction particularly for nociceptive pain [2,11]. There is little evidence that any particular opioid delivered via PCA is superior to another in regard to analgesic or adverse effects in general, but individual patients may tolerate one opioid better than another, and safety of administration can be impacted by hospital staff education [12].

In regards to non-opioid analgesics, there is fair evidence to support their complementary use with opioid analgesics [2]. Medications in this category that target nociceptive pathways include non-steroidal anti-inflammatory drugs (NSAIDs) which are superior to paracetamol (although combining both increases efficacy), and selective COX-2 inhibitors (a subtype of NSAIDs) which offer further advantages over their non-selective counterparts in particular with regard to platelet dysfunction, blood loss, and renal impairment [2,11]. Other multimodal analgesic options that can assist in neuropathic pain management involve intravenous local anaesthetics (such as lignocaine), which has been shown to reduce opioid requirements after abdominal surgery and to decrease the risk of nausea, vomiting, and duration of postoperative ileus, and so decrease the length of hospital stay [12,13]. Locally, lignocaine can also be injected proximally to surgical sites intraoperatively as a preventative somatic analgesia, although a 2005 meta-analysis of 66 randomised controlled trials (comparing preoperative analgesic interventions with similar postoperative analgesic interventions via the same route) and a 2005 randomised controlled trial assessing pain relief in laparoscopic gynaecological surgery suggested the use of pre-emptive local infiltration was associated with a more limited, but still beneficial effect on post-surgical visceral pain [14,15].

The importance of multimodal approaches targeting not only the nociceptive, but also the neuropathic and central neurons can be seen in the prevention of wind-up phenomena and central sensitisation [6,12]. For this, therapies targeting not only opioid, but also substance P, calcitonin gene-related peptide, aspartate, glutamate, gamma-aminobutyric acid (GABA), and NMDA receptors can be used to target pain on multiple levels of the pain pathway [1,2]. Examples of neuropathic treatments include perioperative use of gabapentin and pregabalin, which have both been shown to decrease postoperative opioid requirements [13,16]. Similarly, a meta-analysis of 29 randomised controlled trials indicated a small yet significant decrease in CPSP with intra- and postoperative ketamine use [8]. Furthermore, peri-operative intravenous ketamine also reduces opioid use and postoperative nausea and vomiting compared with placebo, in addition to being cost effective and useful in opioid-tolerant patients [2,17].

Concurrently, the use of regional blocks or neuraxial methods such as femoral nerve blocks may reduce the use and side effects of systemic opioids whilst facilitating early mobilisation and recovery (thereby reducing the psychological impact of illness) [8]. Risk of infection exists, but is predominantly preventable by sterile precautions. Likewise, the risk of neuropathy from this procedure is low and countered generally by the use of ultrasound guidance [11]. Additionally, while regional blocks present an increased risk of procedural complications depending on the block used (for example, brachial plexus blocks risk pneumothorax), these are far rarer than complications of opioid use and often outweigh them on a clinical outcome basis for controlling neuropathic pain [11,18].

In terms of patient education, better pain relief is achieved by structured preoperative education and written information, rather than routine information with generalised verbal discussion [2]. Although identification of preoperative risk factors may assist in targeted patient education and expectation management (Table 1), other interventions, such as pre-surgical hypnosis and music therapy, have been found to be reliable for decreasing CPSP as an outcome indicated by six month follow-up surveys and postoperative pain surveys [1, 7]. Identification of factors that will make pain management more difficult, such as obesity, history of opioid abuse, and current opioid use may assist in appropriate pre and post-surgical management [1,2].

Finally, non-pharmacological methods including transcutaneous electrical stimulation and acupuncture have been shown to reduce postoperative pain, particularly in the setting of back surgery and ambulatory knee surgery when compared to placebo, with the aforementioned psychological methods (distraction, music, and video) being of potential use in paediatric populations. However, the evidence for these is limited and variable in the literature [2,11].

In conclusion, CPSP is a common, inherently complex, and costly complication of surgery. Managing chronic post surgical pain from a multimodal multidisciplinary approach may improve pain control.

 

References

  1. Mariano E, Fanciullo G, Crowley M. Management of acute perioperative pain. UpToDate Clinical Topic Reviews. 2016 Jun 13.
  2. Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J. Acute pain management: scientific evidence, 2015. Med J Australia. 2016;204(8):315-7.
  3. Bruce J, Quinlan J. Chronic post surgical pain. Rev Pain. 2011;5(3):23.
  4. Therapeutic Guidelines Ltd. The transition from acute to chronic pain: risk factors for postsurgical pain syndromes. eTG Complete: Analgesic. 2012, Mar.
  5. Macrae WA. Chronic post-surgical pain: 10 years on. Brit J Anaesth. 2008;101(1):77-86.
  6. Turk DC, Okifuji A. Interdisciplinary approach to pain management: philosophy, operations, and efficacy. In: Ashburn MA, Rice LJ, editors. The management of pain. Baltimore: Churchill-Livingstone; 1998.
  7. Peters ML, Sommer M, Rijke JM, Kessels F, Heineman E, Patijn J, et al. Somatic and psychologic predictors of long-term unfavorable outcome after surgical intervention. Ann Surg. 2007;245(3):487-94.
  8. Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: a systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain. 2012;28(9):819-41.
  9. Flores AJ, Lavemia CJ, Owens PW. Anatomy and physiology of peripheral nerve injury and repair. Am J Orthop. 2000;29(3):167-78.
  10. Johansen A, Romundstad L, Nielsen CS, Schirmer H, Stubhaug A. Persistent postsurgical pain in a general population: prevalence and predictors in the Tromsø study. Pain. 2012;153(7), 1390-6.
  11. Corke P. Postoperative pain management. Aust Prescr. 2013;36(6).
  12. Gilron I. Antidepressant drugs for postsurgical pain: current status and future directions. Drugs. 2016;76(2):159-67.
  13. Dualé C, Ouchchane L, Schoeffler P, Group EI, Dubray C. Neuropathic aspects of persistent postsurgical pain: a French multicenter survey with a 6-month prospective follow-up. J Pain. 2014;15(1):24-e1.
  14. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg. 2005;100(3):757-73
  15. Ghezzi F, Cromi A, Bergamini V, Raffaelli R, Crotti S, Segredini R, et al. Preemptive port site local anesthesia in gynecologic laparoscopy: a randomized, controlled trial. J Minim Invas Gyn. 2005;12(3):210-5.
  16. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg. 2012;115(2):428-42.
  17. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of chronic pain after surgery in adults. The Cochrane Library. 2013 Jan 1.
  18. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain. 2013;154(1):95-102.