Understanding barriers and facilitators to palliative and end-of-life care research: a mixed method study of generalist and specialist health, social care, and research professionals.

BACKGROUND: Palliative care provision should be driven by high quality research evidence. However, there are barriers to conducting research. Most research attention focuses on potential patient barriers; staff and organisational issues that affect research involvement are underexplored. The aim of this research is to understand professional and organisational facilitators and barriers to conducting palliative care research. METHODS: A mixed methods study, using an open cross-sectional online survey, followed by working groups using nominal group techniques. Participants were professionals interested in palliative care research, working as generalist/specialist palliative care providers, or palliative care research staff across areas of North West England. Recruitment was via local health organisations, personal networks, and social media in 2022. Data were examined using descriptive statistics and content analysis. RESULTS: Participants (survey n = 293, working groups n = 20) were mainly from clinical settings (71%) with 45% nurses and 45% working more than 10 years in palliative care. 75% were not active in research but 73% indicated a desire to increase research involvement. Key barriers included lack of organisational research culture and capacity (including prioritisation and available time); research knowledge (including skills/expertise and funding opportunities); research infrastructure (including collaborative opportunities across multiple organisations and governance challenges); and patient and public perceptions of research (including vulnerabilities and burdens). Key facilitators included dedicated research staff, and active research groups, collaborations, and networking opportunities. CONCLUSIONS: Professionals working in palliative care are keen to be research active, but lack time, skills, and support to build research capabilities and collaborations. A shift in organisational culture is needed to enhance palliative care research capacity and collaborative opportunities across clinical and research settings.

GC-MS Techniques Investigating Potential Biomarkers of Dying in the Last Weeks with Lung Cancer.

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making.

Palliative care clinical nurse specialists leading enhanced supportive care in hepatopancreatobiliary cancer.

BACKGROUND: Integration of care between palliative care and oncology can improve patient outcomes and is increasingly recommended. Enhanced supportive care (ESC), led and delivered by palliative care clinical nurse specialists, is a potential model to achieve this but evidence about it is lacking. AIM: This research aimed to evaluate a nurse-led integrated ESC model within hepatopancreatobiliary cancer care. METHOD: Some 101 patients with hepatopancreatobiliary cancer were supported by integrated ESC delivered in a co-located clinic. Data on symptoms and quality of life were collected prospectively. Survival data and chemotherapy use were retrospectively analysed following minimum follow-up, using a matched control technique. RESULTS: Patients receiving ESC exhibited less severe symptoms and better mood over time. They also had less aggressive treatment towards the end of life, receiving 31% less chemotherapy than controls with comparable survival. CONCLUSION: An integrated, nurse-led ESC model can be effective in improving outcomes for patients with hepatopancreatobiliary cancer.

Pridinol for cancer-related myofascial pain.

Myofascial pain is an important yet under recognised component of cancer pain. It has a prevalence of between 11.9 and 44.8% in cancer patients. Treatments for myofascial pain reduce the prevalence of myofascial trigger points therefore decreasing pain and improving range of motion. Pridinol is a nonbenzodiazepine antispasmodic licenced for the treatment of central and peripheral muscle spasms in adults. This paper describes two case histories where patients with myofascial pain were successfully treated with pridinol. These cases highlight the importance of treating myofascial pain and the potential of pridinol to treat cancer-related myofascial pain.

Multidisciplinary supportive care in cancer: cost analysis.

PURPOSE: Enhanced supportive care (ESC) is the early implementation of supportive care in cancer. In England, this model is being developed to support patients with treatable but not curable cancer and implements a multiprofessional approach. OBJECTIVE: To describe the workforce and cost-effectiveness of an outpatient ESC service in a tertiary cancer centre in England. METHODS: Workforce costs to deliver ESC to 265 patients was collected. Service impact on secondary care usage in the last year of life was compared against the regional and national average derived from the National Health Service Digital Secondary Uses Service dataset. RESULTS: Our ESC service required the input of seven professional groups and cost £125 542 for 12 months. ESC patients had an average of 1.72 fewer admissions per patient per last year of life than the national average. Length of stay was reduced from an average of 9.2 days to 4.78 days per admission in the last year of life. The reduced secondary care usage saved £2 398 537.68. CONCLUSIONS: Outpatient ESC in this cohort required an multidisciplinary team approach and saved money through secondary care use reduction.

Continuous subcutaneous infusion: is community anticipatory prescribing and administration safe?

OBJECTIVE: The anticipatory prescribing of pro re nata medications and continuous subcutaneous infusion (CSCI) medication is essential for the timely management of symptomatic patients at the end of life. There is no evidence to support the safety or appropriateness of anticipatory CSCIs. In 2013, in response to safety concerns about end of life prescribing in the community, we designed an educational intervention to improve prescribing practices among non-specialist prescribers in this area. METHODS HOW THE STUDY WAS PERFORMED: We performed a safety-focussed retrospective cohort analysis of end of life community prescriptions of anticipatory CSCIs over a 12-month period, 5 years after creating clinical guidelines and embedding a multiprofessional rolling education programme. Medications prescribed and administered for symptom control at the end of life are compared between specialist and non-specialist prescribers in terms of their adherence to best practice guidance. RESULTS: Medications prescribed were not universally administered and more commonly not administered without specialist input. Prescriptions of higher doses of opioids and benzodiazepines beyond those recommended by guidance were significantly greater within the cohort of patients receiving specialist oversight. The prescription of a dose range did not result in excessive dose escalation. For patients not receiving specialist palliative care, median morphine and midazolam doses did not escalate at all once a CSCI was commenced. All midazolam administrations were safe. CONCLUSIONS: The practice of anticipatory CSCI prescribing and administration can be safe in the community non-specialist setting when supported by clinical guidelines, specialist advice and ongoing multiprofessional education.

Optimisation of Urine Sample Preparation for Headspace-Solid Phase Microextraction Gas Chromatography-Mass Spectrometry: Altering Sample pH, Sulphuric Acid Concentration and Phase Ratio.

Headspace-solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) can be used to measure volatile organic compounds (VOCs) in human urine. However, there is no widely adopted standardised protocol for the preparation of urine samples for analysis resulting in an inability to compare studies reliably between laboratories. This paper investigated the effect of altering urine sample pH, volume, and vial size for optimising detection of VOCs when using HS-SPME-GC-MS. This is the first, direct comparison of H2SO4, HCl, and NaOH as treatment techniques prior to HS-SPME-GC-MS analysis. Altering urine sample pH indicates that H2SO4 is more effective at optimising detection of VOCs than HCl or NaOH. H2SO4 resulted in a significantly larger mean number of VOCs being identified per sample (on average, 33.5 VOCs to 24.3 in HCl or 12.2 in NaOH treated urine) and more unique VOCs, produced a more diverse range of classes of VOCs, and led to less HS-SPME-GC-MS degradation. We propose that adding 0.2 mL of 2.5 M H2SO4 to 1 mL of urine within a 10 mL headspace vial is the optimal sample preparation prior to HS-SPME-GC-MS analysis. We hope the use of our optimised method for urinary HS-SPME-GC-MS analysis will enhance our understanding of human disease and bolster metabolic biomarker identification.

Improved analgesia by correction of hypomagnesaemia?

The role of magnesium as an analgesic in patients is unclear. Hypomagnesaemia is a common electrolyte abnormality, in the chronic state symptoms are insidious and often non-specific. It is often undiagnosed and thus untreated. There is evidence from animal studies that magnesium is involved in pain control including an animal model of hyperalgesia induced by hypomagnesaemia. We report two cases of patients admitted for pain control which improved when hypomagnesaemia was treated. Each case had metastatic cancer. Both were found on admission to have asymptomatic hypomagnesaemia and were treated with intravenous magnesium. Treatment for hypomagnesaemia resulted in an improvement in pain control such that analgesia was decreased. The incidence of hypomagnesaemia in palliative patients is unknown although it is thought to be common. These cases suggest that treating hypomagnesaemia may improve pain control.

A systematically structured review of biomarkers of dying in cancer patients in the last months of life; An exploration of the biology of dying.

BACKGROUND: The Neuberger review made a number of recommendations to improve end of life care, including research into the biology of dying. An important aspect of the biology of dying is the identification of biomarkers as indices of disease processes. Biomarkers have the potential to inform the current, limited understanding of the dying process and assist clinicians in recognising dying, in particular how to distinguish dying from reversible acute deterioration. OBJECTIVES: To critically appraise the literature on biological factors that may be used as prognostic indicators in advanced cancer patients and to identify candidate biomarkers of the dying process that can be measured serially in cancer patients' bodily fluids. METHODS: A systematically structured review was conducted using three electronic databases. A hand search of six peer-reviewed journals and conference abstracts was also conducted. Studies reporting prognostic biomarkers in cancer patients with a median survival of ≤90 days and post-mortem studies were included. Final levels of evidence and recommendations were made using the Evidence Based Medicine modified GRADE system. RESULTS: 30 articles were included. Seven prognostic biological factors demonstrated Grade A evidence (lymphocyte count, white blood cell count, serum C-reactive protein, albumin, sodium, urea and alkaline phosphatase). An additional eleven prognostic factors were identified with Grade B evidence (platelet count, international normalised ratio, serum vitamin B12, prealbumin, bilirubin, cholesterol, aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, pseudocholinesterase and urate). A number of biomarkers were specifically identified in the last two weeks of life but limitations exist. No post-mortem studies met the inclusion criteria. CONCLUSION: The biology of dying is an important area for future research, with the evidence focused on signs, symptoms and prognostic factors. This review identifies a number of common themes shared amongst advanced cancer patients and highlights candidate biomarkers which may be indicative of a common biological process to dying.

Collecting biological material from palliative care patients in the last weeks of life: a feasibility study.

OBJECTIVE: To assess the feasibility of prospectively collecting biological samples (urine) from palliative care patients in the last weeks of life. SETTING: A 30-bedded specialist hospice in the North West of England. PARTICIPANTS: Participants were adults with a diagnosis of advanced disease and able to provide written informed consent. METHOD: Potential participants were identified by a senior clinician over a 12-week period in 2014. They were then approached by a researcher and invited to participate according to a developed recruitment protocol. OUTCOMES: Feasibility targets included a recruitment rate of 50%, with successful collection of samples from 80% who consented. RESULTS: A total of 58 patients were approached and 33 consented (57% recruitment rate). Twenty-five patients (43%) were unable to participate or declined; 10 (17%) became unwell, too fatigued, lost capacity, died or were discharged home; and 15 (26%) refused, usually these patients had distressing pain, low mood or profound fatigue. From the 33 recruited, 20 participants provided 128 separate urine samples, 12 participants did not meet the inclusion criteria at the time of consent and 1 participant was unable to provide a sample. The criterion for a urinary catheter was removed for the latter 6 weeks. The collection rate during the first 6 weeks was 29% and 93% for the latter 6 weeks. Seven people died while the study was ongoing, and another 4 participants died in the following 4 weeks. CONCLUSIONS: It is possible to recruit and collect multiple biological samples over time from palliative care patients in the last weeks and days of life even if they have lost capacity. Research into the biological changes at the end of life could develop a greater understanding of the biology of the dying process. This may lead to improved prognostication and care of patients towards the end of life.

Freeze-drying: an alternative method for the analysis of volatile organic compounds in the headspace of urine samples using solid phase micro-extraction coupled to gas chromatography - mass spectrometry.

BACKGROUND: Volatile organic compounds (VOCs) can be intermediates of metabolic pathways and their levels in biological samples may provide a better understanding about diseases in addition to potential methods for diagnosis. Headspace analysis of VOCs in urine samples using solid phase micro extraction (SPME) coupled to gas chromatography - mass spectrometry (GC-MS) is one of the most used techniques. However, it generally produces a limited profile of VOCs if applied to fresh urine. Sample preparation methods, such as addition of salt, base or acid, have been developed to improve the headspace-SPME-GC-MS analysis of VOCs in urine samples. These methods result in a richer profile of VOCs, however, they may also add potential contaminants to the urine samples, result in increased variability introduced by manually processing the samples and promote degradation of metabolites due to extreme pH levels. Here, we evaluated if freeze-drying can be considered an alternative sample preparation method for headspace-SPME-GC-MS analysis of urine samples. RESULTS: We collected urine from three volunteers and compared the performances of freeze-drying, addition of acid (HCl), addition of base (NaOH), addition of salt (NaCl), fresh urine and frozen urine when identifying and quantifying metabolites in 4 ml samples. Freeze-drying and addition of acid produced a significantly higher number of VOCs identified than any other method, with freeze-drying covering a slightly higher number of chemical classes, showing an improved repeatability and reducing siloxane impurities. CONCLUSION: In this work we compared the performance of sample preparation methods for the SPME-GC-MS analysis of urine samples. To the best of our knowledge, this is the first study evaluating the potential of freeze-dry as an alternative sample preparation method. Our results indicate that freeze-drying has potential to be used as an alternative method for the SPME-GC-MS analysis of urine samples. Additional studies using internal standard, synthetic urine and calibration curves will allow a more precise quantification of metabolites and additional comparisons between methods.Graphical abstractEnhancing VOC profiling from urine samples.

Notch 1 and 3 receptor signaling modulates vascular smooth muscle cell growth, apoptosis, and migration via a CBF-1/RBP-Jk dependent pathway.

Vascular smooth muscle cell (SMC) fate decisions (cell growth, migration, and apoptosis) are fundamental features in the pathogenesis of vascular disease. We investigated the role of Notch 1 and 3 receptor signaling in controlling adult SMC fate in vitro by establishing that hairy enhancer of split (hes-1 and -5) and related hrt's (hrt-1, -2, and -3) are direct downstream target genes of Notch 1 and 3 receptors in SMC and identified an essential role for nuclear protein CBF-1/RBP-Jk in their regulation. Constitutive expression of active Notch 1 and 3 receptors (Notch IC) resulted in a significant up-regulation of CBF-1/RBP-Jk-dependent promoter activity and Notch target gene expression concomitant with significant increases in SMC growth while concurrently inhibiting SMC apoptosis and migration. Moreover, inhibition of endogenous Notch mediated CBF-1/RBP-Jk regulated gene expression with a non-DNA binding mutant of CBF-1, a Notch IC deleted of its delta RAM domain and the Epstein-Barr virus encoded RPMS-1, in conjunction with pharmacological inhibitors of Notch IC receptor trafficking (brefeldin A and monensin), resulted in a significant decrease in cell growth while concomitantly increasing SMC apoptosis and migration. These findings suggest that endogenous Notch receptors and downstream target genes control vascular cell fate in vitro. Notch signaling, therefore, represents a novel therapeutic target for disease states in which changes in vascular cell fate occur in vivo.