Practice review: Evidence-based and effective management of fatigue in patients with advanced cancer.

BACKGROUND: Fatigue affects most patients living with advanced cancer and is a symptom that healthcare professionals can find difficult to manage. AIM: To provide healthcare professionals with a pragmatic overview of approaches to management of fatigue in patients with advanced cancer that are commonly recommended by guidelines and to evaluate evidence underpinning them. DESIGN: Scoping review methodology was used to determine the strength of evidence supporting use of interventions recommended in management of fatigue in patients with advanced cancer. DATA SOURCES: National or international guidelines were examined if they described the management of fatigue in adult cancer patients and were written within the last 6 years (2015-2021) in English. The Cochrane Database of Systematic Reviews (January 2011-December 2021) was searched for 'cancer' AND 'fatigue' in title, abstract or keywords. A PubMed search was also made. RESULTS: Evidence indicates physical exercise interventions are effective and patients may benefit from energy conservation tactics. Evidence does not support use of psychostimulants such as methylphenidate. Limited data were found on efficacy of corticosteroids, psychological interventions, nutritional intervention, sleep optimization or complementary therapies for management of fatigue in advanced cancer. CONCLUSION: We recommend regular assessment, review and acknowledgement of the impact of fatigue. Exercise and energy conservation should be considered. Pharmacological interventions are not endorsed as a routine approach. Many interventions currently recommended by guidelines are not supported by a robust evidence base and further research on their efficacy is required.

Identifying associations between dental arch relationship scores, relative deprivation and other cleft audit outcomes. Part 1.

OBJECTIVES: To assess whether dental arch relationship scores are associated with speech, audiological and psychology outcomes in patients with complete unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP). SETTING AND SAMPLE POPULATION: One hundred 5-year-old children with non-syndromic complete UCLP and forty-two 5-year-olds with non-syndromic complete BCLP from the United Kingdom. MATERIAL AND METHODS: Data were collected from five-year audit clinics for dental arch relationships, speech, hearing and psychology outcomes. Associations were assessed between ordinal prognostic covariates and the dental arch relationship outcome using a Cochrane-Armitage test for trend and comparisons with binary prognostic covariates using chi-square/Fisher's exact test. This was extended to assess associations between five-year audit outcomes and a measure of deprivation. RESULTS: There was no evidence of associations between dental arch relationships and outcomes for audiology and speech. Individual domain analysis of the psychology outcomes within the UCLP cohort reported a poor outcome for Pro-social score to be associated with a poor 5-year-old index score (P = .018). For the BCLP sample, a good outcome for the BCLP Deciduous Dentition Yardstick was associated with a good conduct score (P = .01). CONCLUSION: There was no association with the 5-year-old index/BCLP Deciduous Dentition Yardstick score and outcomes reported for audiology and speech. For the UCLP and BCLP cohorts, a poor dental arch relationship outcome may be associated with issues with some aspects of psychological well-being, associated with peer interactions and conduct. The deprivation index of samples had no association with the outcomes assessed.

Conceptualising effective symptom management in palliative care: a novel model derived from qualitative data.

BACKGROUND: Pain, breathlessness and fatigue are some of the most challenging symptoms to manage in patients with advanced disease. Specialist palliative care leads to better symptom management, but factors contributing to successful symptom management in this context have not been explored. Our aim was to understand what facilitates effective symptom management in specialist palliative care within UK hospices and investigate what barriers are experienced. METHODS: This was a grounded theory study using qualitative semi-structured focus groups and interviews. Participants were recruited from multidisciplinary specialist palliative care teams (doctors, nurses, healthcare assistants, physiotherapists, occupational therapists, complementary therapists, social workers and chaplains) working in inpatient, outpatient and community services provided by five hospices in the United Kingdom. RESULTS: We present a novel qualitative data-derived model of effective symptom management in specialist palliative care. We describe a co-ordinated, multi-faceted, sequential approach involving a process of engagement, partnership, decision-making, and delivery. Interventions to manage symptoms are less effective in psychologically distressed patients. Our data highlights that families of patients have a key role in determining effectiveness of symptom management interventions A holistic approach by a co-ordinated, multi-disciplinary team, including support to recognise and minimise psychological distress might facilitate more effective symptom management. Barriers to symptom management include team discordance and lack of understanding about symptom management by patient and families. CONCLUSIONS: Shared decision-making between patients and professionals and co-ordination of care by a multi-disciplinary team are key components of effective symptom management. Actions to address psychological distress and evaluate the understanding and expectations of patients and their families would enable more effective symptom management. A more effective multi-disciplinary approach would be facilitated by discussion within teams about role competencies and boundaries.

Practice review: Evidence-based and effective management of pain in patients with advanced cancer.

BACKGROUND: Pain of a moderate or severe intensity affects over half of patients with advanced cancer and remains undertreated in at least one-third of these patients. AIM: The aim of this study was to provide a pragmatic overview of the evidence supporting the use of interventions in pain management in advanced cancer and to identify where encouraging preliminary results are demonstrated but further research is required. DESIGN: A scoping review approach was used to examine the evidence supporting the use of guideline-recommended interventions in pain management practice. DATA SOURCES: National or international guidelines were selected if they described pain management in adult cancer patients and were written within the last 5 years in English. The Cochrane Database of Systematic Reviews (January 2014 to January 2019) was searched for 'cancer' AND 'pain' in the title, abstract or keywords. A MEDLINE search was also made. RESULTS: A strong opioid remains the drug of choice for treating moderate or severe pain. Bisphosphonates and radiotherapy are also effective for cancer-related bone pain. Optimal management requires a tailored approach, support for self-management and review of treatment outcomes. There is likely a role for non-pharmacological approaches. Paracetamol should not be used in patients taking a strong opioid to treat pain. Cannabis-based medicines are not recommended. Weak opioids, ketamine and lidocaine are indicated in specific situations only. CONCLUSION: Interventions commonly recommended by guidelines are not always supported by a robust evidence base. Research is required to evaluate the efficacy of non-steroidal anti-inflammatory drugs, anti-convulsants, anti-depressants, corticosteroids, some invasive anaesthetic techniques, complementary therapies and transcutaneous electrical nerve stimulation.

Achieving Consensus in the Measurement of Psychological Adjustment to Cleft Lip and/or Palate at Age 8+ Years.

BACKGROUND: Consensus regarding optimal outcome measurement has been identified as one of the most important, yet most challenging developments for the future of cleft lip and/or palate (CL/P) services. In 2011, a process began to adopt a shared conceptual framework and to identify a set of core outcome measures for the comprehensive assessment of psychological adjustment. OBJECTIVES: The aim of the current article is to outline the collaborative process used to achieve consensus in the academic and clinical measurement of psychological adjustment to CL/P from the age of 8 years onward. RESULTS: A conceptual framework and corresponding parent- and self-reported outcome measures for use at ages 8, 10, 12, 15, 18, 20, and 25 years have been agreed upon by clinicians, researchers, and patient and parent representatives. All measures have been evaluated according to their psychometric properties, clinical utility, ability to produce meaningful longitudinal data, and a range of pragmatic considerations. CONCLUSIONS: Although the collaborative process has been challenging and has required ongoing dedication from multiple stakeholders, consistency in data collection over time will allow for key research questions in CL/P to be addressed, both in the United Kingdom (UK) and internationally. The process has also demonstrated the clinical utility of the measures and the potential for the gradual integration of the measures into clinical practice. UK progress has sparked global interest, and the adaptation of the framework and its corresponding measures for worldwide use is now a prominent focus.

Exploring stakeholder experiences of interprofessional teamwork in sex development outpatient clinics.

Adopting an interprofessional team approach to care of the child with rare conditions that can affect sex development (DSD) has been advocated by a consensus document within the last decade. In the United Kingdom, the approach appears orientated towards an interprofessional model with the integration of separate professions working in single consultations with families working collaboratively to focus on care using a person and family-centred lens. This concurrent mixed-methods UK study using questionnaires, observation, and interviews aimed to examine professionals', patients', and parents' expectations and interactions during DSD clinic. In adapting a model of patient and family-centred care, we were able to analyse the dimensions of care at the micro-, meso-, and macro-level. The micro captured the unique nature of the bio-psychosocial aspects of DSD, professional capabilities, and communication. The meso examined shared learning and objective setting as well as aspects of knowledge translation. The macro focused on the operational aspects and the emancipatory knowing embedded within DSD care. Complete data from participants (n = 105) were analysed from 47 outpatient clinical consultations and are reported as numerical data, tables, and participants' voices. Interestingly, all participants identified topics or concerns that were absent in the dialogues during consultation. Our findings informed the adaptation of a patient-focused model, thereby supporting the development of the concept of patient-centeredness, integration, and collaboration. This framework may serve as a platform, embedding existing evaluative tools and acknowledging the patient and professional partnership necessary in DSD care.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015).

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in lung cancer.

Approximately 70% of patients with non-small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ~50% of non-small-cell lung cancers remain unknown. Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells. Genomic profiling of patients with lung cancer is ushering in an era of personalized medicine; however, lack of actionable mutations presents a significant hurdle. Our study indicates that targeted genetic dependency screens will be an effective strategy to elucidate somatic variants that are essential for lung cancer cell viability.

The Effectiveness of Psychosocial Intervention for Individuals With Cleft Lip and/or Palate.

OBJECTIVE: The aim of this review was to assess the effectiveness of different psychological interventions for children and adults with cleft lip and/or palate and their parents. DESIGN: We searched six databases including MEDLINE and EMBASE to June 2013 and checked bibliographies. We included research that evaluated any psychological intervention in studies in which at least 90% of the participants had cleft lip and/or palate or were parents of those with cleft lip and/or palate. Studies containing less than 90% were excluded unless they reported results separately for those with cleft lip and/or palate, or raw data were available upon request from the authors. Inclusion assessment, data extraction, and risk of bias assessment were carried out independently by two reviewers. RESULTS: Seven studies were identified as inclusions, with only two studies being included in the full data analysis (one of which failed to meet the full inclusion criteria). The five remaining studies were included only in a narrative synthesis because data were available for people or parents of those with cleft lip and/or palate only. This highlights a distinct dearth of research into psychological intervention within the field of cleft lip and/or palate. CONCLUSIONS: The review found no evidence to support any specific intervention. Key uncertainties need to be identified and addressed. Adequately powered, methodologically rigorous randomized controlled trials are needed to provide a secure evidence base for psychological intervention techniques in participants with cleft lip and/or palate and their parents.

UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development.

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional DSD team acts as the first point of contact. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents are as fully informed as possible and have access to specialist psychological support. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

A national survey of hospice pharmacists and a comparison with international models.

BACKGROUND: Pharmacists can contribute to improved patient outcomes, improve medicine knowledge, reduce drug costs and minimise errors. However, their role within hospice-based services is not well described. OBJECTIVE: The objective of this paper was to explore the role of pharmacists within UK hospices. METHODS: Methods include an online survey and follow-up telephone contact of pharmacists working in UK hospices assessing pharmacist provision, duties, communication, medicine sourcing and training. RESULTS: Eighty-nine responses were received from 82 hospices (response rate 50%). Pharmacists had a role in 75% of hospices providing between 6.6 min and 5.5 hrs of pharmacist support per bed per week. The most frequent duty reported was provision of medicines information to the clinical team. Access to patient records varied considerably: 13% had full read and write access to GP records while 29% had no access. Job-specific training had not been received by 36% of the respondents and 47% reported training needs including basic training in palliative care. CONCLUSIONS: Three-quarters of UK hospices have pharmacy provision, although this falls below the recommended levels in the majority. Hospice pharmacists lack access to training and records. Medicines sourcing for hospices is variable and could provide opportunities for efficiencies with further research.

Understanding the role of hospice pharmacists: a qualitative study.

Background Pharmacists are important members of multidisciplinary teams but, despite surveys of provision, the role of the hospice pharmacist is not well described. Objective To explore the role of the hospice pharmacist and identify barriers and facilitators to the role. Setting Hospices offering in-patient services caring for adults towards the end of life in one geographical area of northern England. Method Pharmacists providing services to hospices were invited to take part in qualitative semi-structured interviews asking about experience, patient contact, team working and barriers and facilitators to the role. These were recorded verbatim and data were analysed thematically using framework analysis. Main outcome measure The hospice pharmacist's perceptions of their role and barriers and facilitators to it. Results Fifteen pharmacists took part. Two themes and ten subthemes were identified focused on tasks and communication. Practise was varied and time limited the quantity and depth of services carried out but was often spent navigating complex drug supply routes. Participants found methods of communication suited to the hours they spent in the hospice although communication of data was a barrier to effective clinical service provision. Participants identified the need for appropriate training and standards of practice for hospice pharmacists would enable better use of their skills. Conclusion Barriers to the role of hospice pharmacist include time, access to role specific training, access to clinical information and complex medicines supply chains. The role would benefit from definition to ensure that hospices are able to use hospice pharmacists to their greatest potential.

A community pharmacist medicines optimisation service for patients with advanced cancer pain: a proof of concept study.

Background Patients with advanced cancer commonly experience pain and it is least controlled in community settings. Community pharmacists in the UK already offer medicines optimisation consultations although not for this patient group. Objective To determine whether medicines consultations for patients with advanced cancer pain are feasible and acceptable. Setting Community-dwelling patients with advanced cancer pain were recruited from primary, secondary and tertiary care using purposive sampling in one UK city. Methods One face-to-face or two telephone delivered medicines optimisation consultations by pharmacists were tested. These were based on services currently delivered in UK community pharmacies. Feedback was obtained from patients and healthcare professionals involved to assess feasibility and acceptability. Main outcome measure Recruitment, acceptability and drug related problems. Results Twenty-three patients, (range 33-88 years) were recruited, 19 completed consultation(s) of whom 17 were receiving palliative care services. Five received face-to-face consultations and 14 by telephone during which 47 drug related problems were identified from 33 consultations (mean 2.5). Advice was provided for 34 drug related problems in 17 patients and referral to other healthcare professionals for 13 in 8 patients, 2 patients had none. Eleven patients returned questionnaires of which 8 (73%) would recommend the consultations to others. Conclusion The consultations were feasible as patients were recruited, retained, consultations delivered, and data collected. Patients found the 20-30 min intervention acceptable, found a self-perceived increase in medicines knowledge and most would recommend it to others. Community pharmacists were willing to carry out these services however they had confidence issues in accessing working knowledge. Most drug related problems were resolved by the pharmacists and even among patients receiving palliative care services there were still issues concerning analgesic management. Pharmacist-conducted medicines consultations demonstrate potential which now needs to be evaluated within a larger study in the future.

Evaluating recruitment methods of patients with advanced cancer: a pragmatic opportunistic comparison.

BACKGROUND: Recruitment of patients with advanced cancer into studies is challenging. OBJECTIVE: To evaluate recruitment methods in a study of pharmacist-led cancer pain medicine consultations and produce recommendations for future studies. METHOD: Two methods of recruitment were employed: (1) community-based (general practitioner computer search, identification by general practitioner, community pharmacist or district nurse and hospital outpatient list search) and (2) hospice-based (in and outpatient list search). Patients identified in method 1 were invited by post and in method 2 were invited face-to-face. Information was designed in collaboration with patients and carers. RESULTS: A total of 128 patients were identified (85 from the community and 43 from the hospice), and 47 met the inclusion criteria. Twenty-three agreed to take part and 19 completed the study, 17 of whom were already under specialist palliative care. Recruitment rates were 7% for community-based methods and 40% for hospice. The recruitment methods differed in intensity of resource use. Recruitment via letter and a lack of engagement by healthcare professionals were found to be barriers. Facilitators included the researcher having personal involvement in recruitment. CONCLUSION: The overall recruitment rate was in line with other studies for this patient cohort. Attempts to identify and engage patients through community-based postal contact were less effective than where personal contact with patients was both possible and occurred. Methods were less successful at recruiting patients who were not already engaged with hospice services.

Pharmacist educational interventions for cancer pain management: a systematic review and meta-analysis.

OBJECTIVES: Educational interventions by pharmacists for patients with cancer pain aim to improve pain management, but little is known about the different components of interventions and their effectiveness. Our aim was to assess the benefit of pharmacist delivered educational interventions for patients with cancer pain. A systematic review and meta-analysis of experimental trials testing pharmacist delivered educational interventions for cancer pain was carried out to identify the components of interventions and effectiveness at improving pain-related outcomes for patients with cancer. A literature review was conducted in EMBASE, MEDLINE, CINAHL, PsycINFO, ASSIA, Web of Science and CENTRAL from inception until January 2018 searching for educational interventions involving a pharmacist for patients with cancer pain. Four studies were included involving 944 patients. Meta-analysis was carried out where possible. KEY FINDINGS: Meta-analysis of three of the four studies found that mean pain intensity in the intervention group was reduced by 0.76 on a 0-10 scale (95% confidence interval), although only two of the studies used validated measures of pain. Improvements in knowledge, side effects and patient satisfaction were seen although with less reliable measures. SUMMARY: Pharmacist educational interventions for patients with cancer pain have been found to show promise in reducing pain intensity. Studies were few and of varying quality. Further, good quality studies should be carried out in this area and these should be comprehensively reported. Trials measuring patient self-efficacy and patient satisfaction are needed before the impact of the pharmacist delivered interventions on these outcomes can be established.

How do patients with cancer pain view community pharmacy services? An interview study.

Pain experienced by many patients with advanced cancer is often not well controlled and community pharmacists are potentially well placed to provide support. The study objective was to explore the views and experiences of patients with advanced cancer about community pharmacies, their services and attitudes towards having a community pharmacist pain medicines consultation. Purposive sampling of GP clinical information systems was used to recruit patients with advanced cancer, living in the community and receiving opioid analgesics in one area of England, UK between January 2015 and July 2016. Thirteen patients had a semi-structured interview which was audio-recorded and transcribed verbatim. Data were analysed deductively and inductively using Framework analysis and incorporating new themes as they emerged. The framework comprised Pain management, Experiences and expectations, Access to care and Communication. All patients reported using one regular community pharmacy citing convenience, service and staff friendliness as influential factors. The idea of a community pharmacy medicines consultation was acceptable to most patients. The idea of telephone consultations was positively received but electronic media such as Skype was not feasible or acceptable for most. Patients perceived a hierarchy of health professionals with specialist palliative care nurses at the top (due to their combined knowledge of their condition and medicines) followed by GPs then pharmacists. Patients receiving specialist palliative care described pain that was better controlled than those who were not. They thought medicines consultations with a pharmacist could be useful for patients before referral for palliative care. There is a need for pain medicines support for patients with advanced cancer, and unmet need appears greater for those not under the care of specialist services. Medicines consultations, in principle, are acceptable to patients both in person and by telephone, and the latter was perceived to be of particular benefit to patients less able to leave the house.

Survival of Head and Neck Cancer Cells Relies upon LZK Kinase-Mediated Stabilization of Mutant p53.

Head and neck squamous cell carcinoma (HNSCC) includes epithelial cancers of the oral and nasal cavity, larynx, and pharynx and accounts for ∼350,000 deaths per year worldwide. Smoking-related HNSCC is associated with few targetable mutations but is defined by frequent copy-number alteration, the most common of which is gain at 3q. Critical 3q target genes have not been conclusively determined for HNSCC. Here, we present data indicating that MAP3K13 (encoding LZK) is an amplified driver gene in HNSCC. Copy-number gain at 3q resulted in increased MAP3K13 mRNA in HNSCC tumor samples and cell lines. Silencing LZK reduced cell viability and proliferation of HNSCC cells with 3q gain but not control cell lines. Inducible silencing of LZK caused near-complete loss of colony-forming ability in cells harboring 3q gain. These results were validated in vivo by evidence that LZK silencing was sufficient to reduce tumor growth in a xenograft model of HNSCC. Our results establish LZK as critical for maintaining expression of mutant stabilized p53. Cancer Res; 77(18); 4961-72. ©2017 AACR.

Mixed lineage kinases activate MEK independently of RAF to mediate resistance to RAF inhibitors.

RAF inhibitor therapy yields significant reductions in tumour burden in the majority of V600E-positive melanoma patients; however, resistance occurs within 2-18 months. Here we demonstrate that the mixed lineage kinases (MLK1-4) are MEK kinases that reactivate the MEK/ERK pathway in the presence of RAF inhibitors. Expression of MLK1-4 mediates resistance to RAF inhibitors and promotes survival in V600E-positive melanoma cell lines. Furthermore, we observe upregulation of the MLKs in 9 of 21 melanoma patients with acquired drug resistance. Consistent with this observation, MLKs promote resistance to RAF inhibitors in mouse models and contribute to acquired resistance in a cell line model. Lastly, we observe that a majority of MLK1 mutations identified in patients are gain-of-function mutations. In summary, our data demonstrate a role for MLKs as direct activators of the MEK/ERK pathway with implications for melanomagenesis and resistance to RAF inhibitors.

Elective caesarean section: a case study.

Caesarean section as a means of delivering babies has been around for centuries with numerous references to the procedure appearing in ancient writings (Simm & Matthew 2008). It is now the most common major surgical intervention carried out on women in the world, with between 23% and 30% of deliveries in the UK performed by caesarean section (Beech 2004). This rate is all the more surprising when one considers that caesarean section accounted for just 5.3% of UK births in 1973 (Kitzinger 1998). This rising rate has many implications for both clinical practice and the NHS. An Audit Commission report (1997) suggested that each 1% rise in the caesarean section rate would cost the NHS five million pounds per year. However, the increased rate also has clinical implications, with some studies suggesting that maternal mortality is three to seven times greater following abdominal rather than vaginal birth and maternal morbidity is proportionately even greater, even with elective procedures (McCourt et al 2004).