Celebrating oncology nursing: from adversity to opportunity. The Global Power of Oncology Nursing Conference held virtually on the 15th November 2022.

The Global Power of Oncology Nursing held their 3rd annual conference on 'Celebrating Oncology Nursing: From Adversity to Opportunity'. The conference, held virtually, addressed three major nursing challenges: health workforce and migration, climate change and cancer nursing within humanitarian settings. Around the world, nurses are working in situations of adversity, whether due to the ongoing pandemic, humanitarian crises such as war or floods, shortage of nurses and other health workers, and high clinical demands leading to overwork, stress and burnout. The conference was held in two parts in order to take into account different time zones. Three hundred and fifty participants attended from 46 countries, with part of the conference being held in both English and Spanish. It was an opportunity for oncology nurses around the world to share their experiences and the realities for their patients seeking care and their families. The conference took the form of panel discussions, videos, and individual presentations from all six WHO regions and highlighted the importance of oncology nurses role in expanding beyond caring for individuals and their families, to tackle wider issues, such as nurse migration, climate change and care within humanitarian settings.

Climate change and oncology nursing: the African perspective.

Climate change is impacting the lives of millions around the world and exacerbating existing challenges in healthcare globally. Although Africa contributes only 2%-3% of global greenhouse gas emissions, it suffers a disproportionate share of the environmental impact. High-income countries dominate the global discourse on climate change, while their continued utilisation of extractive policies exacerbates climate hazards and impacts economies in regions not responsible for the damage. Cancer is on the rise and constitutes a significant public health burden in low- and middle-income countries, yet little is known about the impact of climate change on oncology nursing on the African continent. To address the ways that climate change is exacerbating existing challenges and adding new difficulties for oncology care, it is essential that the expertise of professionals working in settings that are most impacted by the threats of climate change is amplified if climate crisis risks are to be effectively mitigated. Seven African oncology nurses from across sub-Saharan Africa were reflexively interviewed by voice over internet protocol (VOIP) in English to learn about their understanding of climate change and experiences with its impact on nursing care. Using a conceptual framework to map the impact of climate change on health and considering the vulnerability and social capacity of patients with cancer, our findings show how existing challenges to oncology nursing care are exacerbated by climate change on the continent. Food insecurity, national economic dependency on the agricultural sector, economic inequality, social vulnerability and isolation, transportation challenges, and the immunocompromised status of patients with cancer are all key concerns for oncology nurses in this context. We also present the nurses' specific recommendations for governments, hospital authorities, and oncology nurses regarding climate change mitigation, adaptation, and event response strategies. With this work, we aim to lay a foundation for further investigation and action to mitigate the oncoming challenges of climate disaster for oncology nurses across sub-Saharan Africa and the patients and families they care for.

Testing for dihydropyrimidine dehydrogenase deficiency in New Zealand to improve the safe use of 5-fluorouracil and capecitabine in cancer patients.

Dihydropyrimidine dehydrogenase deficiency is a rare inherited disorder. Approximately 3% of people of European ancestry are likely to have a partial deficiency in this enzyme. These individuals are typically asymptomatic until exposed to 5-fluorouracil (5-FU) or capecitabine (which forms 5-FU) for treatment of gastrointestinal or breast cancer. These individuals are then at considerably increased risk of severe to life-threatening adverse events. There are four well established risk variants within the DPYD gene that encodes dihydropyrimidine dehydrogenase. Although consensus guidelines for genotype-guided dosing of 5-FU and capecitabine have existed for a number of years, the implementation of this type of personalised medicine has not been widely adopted. This viewpoint covers the current state of knowledge about both genotype and phenotype testing, as well as the reported cost-savings and clinical effectiveness of pre-screening patients followed by dose-adjustment. Recent recommendations by agencies and professional societies, both in Europe and the USA, highlight the need for New Zealand oncologists to begin an informed discussion about whether it is now an appropriate time to advocate for routine access to testing for this enzyme deficiency in New Zealand cancer patients.

A systematic review of inter-individual differences in the DNA repair processes involved in melphalan monoadduct repair in relation to treatment outcomes.

PURPOSE: Melphalan is a bifunctional alkylating agent that elicits its cytotoxic activity by rapidly forming an initial DNA monoadduct, which then produces an inter-strand crosslink. Most studies exploring the role of inherited differences in DNA repair and melphalan outcomes focus on inter-strand crosslink repair, however, monoadduct repair likely plays a key role since it minimises the ultimate production of these crosslinks. The purpose of this systematic review was to assess evidence of an association between variation in monoadduct repair pathways and melphalan response. METHODS: A literature search was undertaken using Medline, Embase, Scopus and PubMed databases. Duplicates were removed and only full-text articles were included. To be included for critique in this systematic review, articles were assessed for relevance using strict inclusion/exclusion criteria. RESULTS: Fourteen studies were identified that involved patients treated with melphalan, however, in 3, only a minority of the cohort received melphalan. Across the remaining 11 studies, 61 genes/proteins in DNA monoadduct repair pathways were assessed. Both germline SNP (CDKN1A, ERCC1, ERCC2, ERCC4, ERCC6, EXO1, MLH1, MNAT1, MUTYH, PARP4, PCNA, POLE, POLR1G, RAD23B, RFC1, RFC3, RPA1, RPA3, TREX1, UNG, XPC, XRCC1) and somatic expression (CDKN1A, PARP1, PCNA, MGMT, RECQL, RFC5) were associated with melphalan outcomes in ≥ 1 study. CONCLUSION: It appears that inherited germline differences in monoadduct repair genes may be a risk factor for poor outcomes. However, the diversity of study design, patient cohorts, genes assessed and lack of replication, preclude any meta-analysis. Further prospective studies are required to validate these findings.

Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients.

PURPOSE: Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients. METHODS: CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug. RESULTS: We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing. CONCLUSION: Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

Comparison of a thymine challenge test and endogenous uracil-dihydrouracil levels for assessment of fluoropyrimidine toxicity risk.

PURPOSE: Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity. METHODS: Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC-MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases. RESULTS: There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), Unorm p = 0.0004; U/DHUnorm p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%). CONCLUSIONS: The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

Oncology nursing in the Global South during COVID-19.

In mid-2020, a call was made to oncology nurses in the Global South to share their experiences managing patient care during the coronavirus disease 2019 (COVID-19) pandemic. Eighteen submissions were received from 16 countries across Latin America, Africa, Europe and Asia. Three were research-based and 15 were personal narratives on the psychosocial impact of COVID-19 on the nurses, colleagues, patients and families. Three narratives were from oncology nurses working with cancer-related non-governmental organisations locally or, in one case, internationally. A simultaneous literature search for publications (including grey literature) was performed to identify themes of COVID-19's impact in these 16 countries and specifically on oncology nurses and patients/families. Four themes were identified: a) interruptions to care; b) support/resource shortages; c) psychosocial impact on nurses and patients and d) staffing and nursing role impacts. The three research-based studies describe oncology nursing in-depth efforts to explore the impact of COVID-19. Findings in the 15 narratives are briefly presented according to the four themes identified in the literature. Due to the severe shortage of physician adult and paediatric oncology specialists, oncology nurses in the Global South often shoulder much of the care for patients with cancer and even more so during COVID-19 with attendant oncology nursing shortages due to reassignment to COVID-19 units. It is important to hear from these critical members of the oncology nursing workforce who often lack the time, resources or training to publish in peer-reviewed journals in English, particularly in the middle of a pandemic. Giving voice to these nurses documents the reality of their work and ability to continue to provide care despite the chaos and rapidly changing guidelines and government action. Lessons learned by these nurses to improve mental health and psychosocial support of the nurses as well as their patients/families will be essential for the next global pandemic.

A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity.

AIMS: A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case-control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5-fluorouracil or capecitabine. METHODS: Patients (n = 37) received a 250 mg (per os) dose of THY and a cumulative urine sample was collected for 0-4 h. The urinary amounts of THY and metabolite dihydrothymine (DHT) were determined by liquid chromatography/mass spectrometry. Genomic DNA was analysed for DPYD gene variants. Renal function was estimated from blood creatinine levels. Cases (n = 9) and noncases (n = 23) of severe (grade ≥ 3) gastrointestinal toxicity were defined based on Common Terminology Criteria for Adverse Events. RESULTS: The median THY/DHT ratios were 6.2 (interquartile range 2.9-6.4) in cases, including the 2 patients who were DPYD heterozygous carriers. However, this was not significantly different (P = .07) from the THY/DHT in noncases (median 2.6, interquartile range 2.8-4.2). Although creatinine clearance was lower (P = .001) in cases, renal function could not discriminate cases from noncases. However, logistic regression analysis using both of these explanatory variables could discriminate most cases (receiver operating characteristic area 0.8792, 95% confidence interval 0.72-1.00). CONCLUSIONS: The THY challenge test combined with a patient's renal function may be useful as a phenotypic diagnostic test to detect risk of life-threatening fluoropyrimidine gastrointestinal toxicity.

A higher throughput assay for quantification of melphalan-induced DNA damage in peripheral blood mononuclear cells.

Inter-individual differences in DNA adduct formation and repair influence the response to melphalan treatment, however, further clinical investigation of this variability requires a logistically feasible and reproducible bioassay. Our improved fluorescence-based QPCR-block assay is robust, has good precision, and improved throughput. It also incorporates direct PCR amplification from melphalan exposed PBMC using commercially available blood tubes and extraction kits to maximise the utility of this assay for future clinical studies. Using this assay we have demonstrated reproducible inter-individual differences in melphalan-induced QPCR-block across individual PBMC donors. As proof-of-principle we assessed nine healthy donors and found a 7.8 fold range in sensitivity following exposure of PBMC ex vivo. This likely reflects differences in melphalan transport into cells as well as differences in DNA adduct repair proficiency. This improved bioassay may be useful for assessment of these processes in patients about to receive melphalan treatment.

A simple ex vivo bioassay for 5-FU transport into healthy buccal mucosal cells.

PURPOSE: Fluorouracil (5-FU), a chemotherapeutic agent widely used in the treatment of numerous common malignancies, causes oral mucositis in a proportion of patients. The contribution of drug transport processes to the development of this toxicity is currently unknown. This work aimed to establish and optimise a simple phenotyping assay for 5-FU uptake into primary buccal mucosal cells (BMC). METHODS: The uptake kinetics of radiolabelled 5-FU were determined in pooled BMC freshly collected from healthy volunteers. The inter- and intra-individual variability in 5-FU uptake was then assessed across a cohort that included both healthy volunteers and cancer patients. RESULTS: 5-FU uptake into pooled primary BMC was both time and concentration dependent. An Eadie-Hofstee analysis suggested two components; a high-affinity (KM = 3.3 µM) low-capacity ([Formula: see text] = 57.8 pmol min-1 105 viable cells-1) transporter, and a high-capacity ([Formula: see text] = 1230 pmol min-1 105 viable cells-1) low-affinity (KM = 3932 µM) transporter. There was 180-fold variation in the rate of 5-FU uptake into BMC (0.10-17.86 pmol min-1 105 viable cells-1) across the 34 subjects (healthy participants N = 24, cancer patients N = 10). Notably, retesting of a subset of these participants (N = 16) multiple times over a period of up to 140 days demonstrated poor stability of the uptake phenotype within individuals. CONCLUSION: The uptake of 5-FU into healthy oral mucosal cells is a highly variable process facilitated by membrane transporters at pharmacologically relevant concentrations. This bioassay is simple, minimally invasive, and suitable for phenotypic analysis of drug transport in healthy primary cells.

Indirect regulation of CYP2C19 gene expression via DNA methylation.

1. Despite speculation that the CYP2C19 gene may contain CpG islands, there has been little direct assessment of the role for epigenetics in the regulation of this pharmacogene. The effect of 5-aza-2'-deoxycytidine (5azaDC), a DNA methyltransferase inhibitor, and trichostatin A (TSA), an inhibitor of histone deacetylases, on the expression of CYP2C19 and five of its known transcription factors (TF) has been assessed in cell lines derived from neoplastic liver and intestine. 2. CYP2C19 mRNA was substantially up-regulated (>18-fold) after treatment with 5azaDC despite the fact that the two intronic CpG islands in this gene remained substantially methylated (>50%). The TF NR1I3 was also consistently up-regulated after treatment with 5azaDC. NR1I3 lacks CpG islands in the proximal promoter region and is therefore not likely to be directly regulated by DNA methylation. Therefore, it appears that 5azaDC treatment affects an unidentified upstream regulator of both CYP2C19 and/or NR1I3. This is supported by the fact that the relationships between TF for CYP2C19 and the expression of this target gene in human liver samples only accounted for ∼70% of the variability of CYP2C19 mRNA levels. These data suggest that an yet un-identified 'master regulator' of CYP2C19 transcription could itself be a target of epigenetic control.

Assessment of sediment hydrocarbon contamination from the 2009 Montara oil blow out in the Timor Sea.

In August 2009, a blowout of the Montara H1 well 260 km off the northwest coast of Australia resulted in the uncontrolled release of about 4.7 M L of light crude oil and gaseous hydrocarbons into the Timor Sea. Over the 74 day period of the spill, the oil remained offshore and did not result in shoreline incidents on the Australia mainland. At various times slicks were sighted over a 90,000 km(2) area, forming a layer of oil which was tracked by airplanes and satellites but the slicks typically remained within 35 km of the well head platform and were treated with 183,000 L of dispersants. The shelf area where the spill occurred is shallow (100-200 m) and includes off shore emergent reefs and cays and submerged banks and shoals. This study describes the increased inputs of oil to the system and assesses the environmental impact. Concentrations of hydrocarbon in the sediment at the time of survey were very low (total aromatic hydrocarbons (PAHs) ranged from 0.04 to 31 ng g(-1)) and were orders of magnitude lower than concentrations at which biological effects would be expected.

Summary results from a pilot study conducted around an oil production platform on the Northwest Shelf of Australia.

The Australian Institute of Marine Science (AIMS) conducted a pilot study around the Harriet A oil production platform on the Northwest Shelf of Australia. We evaluated hepatic ethoxyresorufin-O-deethylase (EROD) activity, fluorescent aromatic compounds (FACs) in bile and immunodetection of CYP1A-like proteins in two Australian tropical fish species, Gold-Spotted Trevally (Carangoides fulvoguttatus) and Bar-Cheeked Coral Trout (Plectropomus maculatus) to assess exposure to petroleum hydrocarbons associated with produced formation water (PFW). Additionally, the incidence of hydrocarbon-degrading bacteria isolated from the liver and bile of all fish captured was examined. Low EROD activity was found in both species, with EROD activity in C. fulvoguttatus showing significant site differences. FACs and CYP1A protein levels in C. fulvoguttatus showed a clear trend in hydrocarbon exposure consistent with hydrocarbon chemistry data: Harriet A>Harriet C>reference site. P. maculatus showed elevated levels of FACs at Harriet A as compared to the reference site and demonstrated detectable levels of CYP1A-like proteins at these two sites. Hydrocarbon-degrading bacteria were found in the liver and bile of both species, yet there was no correlation by sites. Our results demonstrate that C. fulvoguttatus and P. maculatus have potential as indicator species for assessing the effects from exposure to petroleum hydrocarbons. Both FACs and CYP1A are providing warning signs that there is potential for biological effects on fish populations exposed to PFW around the Harriet A production platform.