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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., (© 2024. The Author(s).)

Background: Orthopaedic surgical helmet systems (SHS) rely on an intrinsic fan to force clean external air over the wearer. Carbon dioxide (CO 2 ) is produced through aerobic metabolism and can potentially accumulate inside the SHS. Levels above 2500 ppm have previously been shown to affect cognitive and practical function. Maximum Health and Safety Executive (HSE) 8-h exposure limit is 5000 ppm. There is a paucity of data on real-world CO 2 levels experienced during arthroplasty surgery whilst wearing a SHS., Objectives: To determine intra-operative levels of CO 2 experienced within SHS., Methods: CO 2 levels were continuously recorded during 30 elective arthroplasties, both primary and revision. Data was recorded at 0.5Hz throughout the procedure utilising a Bluetooth CO 2 detector, worn inside a surgical helmet worn with a toga gown. Five surgeons contributed real time data to the study., Results: The average CO 2 level across all procedures was 3006 ppm, with 23 of the cases measured within the surgeons' helmets having a mean above 2500 ppm, but none having a mean above 5000 ppm. For each procedure, the time spent above 2500 and 5000 ppm was calculated, with the means being 72.6 % and 5.4 % respectively. Minimum fan speed was associated with only a marginally higher mean CO 2 value than maximum fan speed., Discussion: The use of surgical helmet systems for elective orthopaedic surgery, can result in CO 2 levels regularly rising to a point which may affect cognitive function., Conclusion: Further research is needed to corroborate these findings however, we recommend that future designs of SHS include active management of exhaust gases, possibly returning to Charnley's original design principles of the body exhaust system., (Crown Copyright © 2024 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

A large public nursing data set was used to determine whether orientation and/or preceptor programs impact job satisfaction among registered nurses in Maine and Massachusetts. There was no association between orientation and preceptor programs and satisfaction, nor evidence that new nurse status modified the relationship. There is a need for evaluation of orientation and preceptor programs' structure and effectiveness, and innovation is needed in promoting job satisfaction, thereby increasing nurse retention., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy., (© 2024. The Author(s).)

Background: Maine (ME) and Massachusetts (MA) nursing programs aim to develop collaborative training programs, but need to identify which nurses have interest in such programs., Purpose: We sought to determine sociodemographics of nurses seeking advanced nursing degrees nationally, and in ME and MA using the 2018 publicly available, National Sample Survey of Registered Nurses (NSSRN)., Methods: Weighted multivariable logistic regression for advanced degree-seeking, adjusted for sociodemographics., Results: Of the n = 47,274 nurses (weighted n [Wn] = 3,608,633), 90.7 % were female, 74.1 % were white, and 15.8 % sought an advanced nursing degree on average 12.7 (SD 0.2) years after their first. Females vs. males had lower odds (OR 0.63, 95%CI [0.44-0.90]) and Black vs. White race had higher odds (OR 1.30, 95%CI [1.05-1.60]) of seeking doctorates. In Maine (Wn = 20,389), age 24-29 had higher odds (OR 2.98 (95%CI [1.06-3.74]), but in Massachusetts (Wn = 101,984), age 30+ had lower odds (OR 0.32, 95%CI [0.13-0.78]) of degree-seeking vs. <24 years. Initial nursing degrees earned between 1980 and 1989 had higher odds (OR 1.99, 95%CI [1.06-3.74]) in Maine, but between 2010 and 2014 had lower odds (OR 0.32, 95%CI [0.14-0.72]) in Massachusetts of degree-seeking, vs. before 1980., Conclusions: Targets for advanced nursing training programs may vary by state and sociodemographic profile., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: BRAF+MEK inhibitors extend life expectancy of patients with BRAF V600 mutant advanced melanoma. Acquired resistance limits duration of benefit, but preclinical and case studies suggest intermittent dosing could overcome this limitation. INTERIM was a phase 2 trial evaluating an intermittent dosing regimen., Methods: Patients with BRAF V600 mutant advanced melanoma due to start dabrafenib+trametinib were randomised to receive either continuous (CONT), or intermittent (INT; dabrafenib d1-21, trametinib d1-14 every 28 days) dosing. A composite primary endpoint included progression-free survival (PFS) and quality of life (QoL). Secondary endpoints included response rate (ORR), overall survival (OS) and adverse events (AEs). Mutant BRAF V600E ctDNA was measured by droplet digital PCR (ddPCR), using mutant allele frequency of > 1 % as the detection threshold., Results: 79 patients (39 INT, 40 CONT) were recruited; median age 67 years, 65 % AJCC (7th ed) stage IV M1c, 29 % had brain metastases. With 19 months median follow-up, INT was inferior in all efficacy measures: median PFS 8.5 vs 10.7mo (HR 1.39, 95 %CI 0.79-2.45, p = 0.255); median OS 18.1mo vs not reached (HR 1.69, 95 %CI 0.87-3.28, p = 0.121), ORR 57 % vs 77 %. INT patients experienced fewer treatment-related AEs (76 % vs 88 %), but more grade > 3 AEs (53 % vs 42 %). QoL favoured CONT. Detection of BRAF V600E ctDNA prior to treatment correlated with worse OS (HR 2.55, 95 %CI 1.25-5.21, p = 0.01) in both arms. A change to undetected during treatment did not significantly predict better OS., Conclusion: INTERIM findings are consistent with other recent clinical trials reporting that intermittent dosing does not improve efficacy of BRAF+MEK inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Background: Pembrolizumab is approved for the treatment of advanced and resected melanoma and was originally licensed as a three-weekly infusion (Q3W). In April 2019, a six-weekly infusion schedule (Q6W) was also approved. We retrospectively reviewed pembrolizumab prescribing for patients with melanoma across multiple United Kingdom (UK) centres to compare the safety and efficacy of Q6W with Q3W in real-world clinical practice., Methods: Case notes for melanoma patients treated with pembrolizumab between April 2019 and August 2020 at eight UK centres were reviewed. Prespecified baseline characteristics of the Q3W and Q6W cohorts were compared, as well as toxicity and efficacy outcomes. Prescribers were surveyed about their prescribing practice., Results: Two hundred seventy-seven patients were included: 116 commenced Q3W and 161 commenced Q6W pembrolizumab. The proportion of Q6W prescriptions varied by the centre (range 32-88%). Patient factors associated with an increased likelihood of receiving Q3W over Q6W were preexisting autoimmune comorbidity (odds ratio [OR] 0.33; 95% confidence interval [CI] 0.12-0.82) and treatment for advanced (versus resected) disease (OR 0.54; 95%CI 0.33-0.90). Toxicity outcomes were broadly similar for Q6W and Q3W: 14.9% versus 15.5% ≥ grade 3 Common Terminology Criteria for Adverse Events. Estimated 12-month recurrence-free survival for adjuvantly treated patients was 78.9% for Q6W and 74.2% for Q3W (hazard ratio [HR] 0.93; 95%CI 0.50-1.73). Estimated 12-month progression-free survival for advanced patients was 41.8% for Q6W and 55.9% for Q3W (HR 1.21, 95%CI 0.67-2.18)., Conclusions: Q6W is an appropriate option for administering pembrolizumab, given the opportunity to reduce the health service resource burden., Competing Interests: Declaration of Competing Interest Dr. Corrie has received advisory board and speaker fees from MSD. Dr. Oladipo has received advisory board fees from MSD. All other authors have no potential conflicts of interest to disclose., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Background: Providing detailed skin cancer statistics, including incidence and survival, by tumour type and patient characteristics is important for up-to-date epidemiological information., Objectives: To create a new clinically relevant consensus-based classification for registered skin tumours using tumour type and patient characteristics and to describe its application to all registered tumours in England between 2013 and 2019., Methods: Tumours with skin topographical codes (ICD-10) and morphology and behaviour (ICD-O3) were grouped together in an iterative process creating a hierarchical tree structure. The primary-level grouping partitioned skin tumours into skin cancer, melanoma in situ, extramammary Paget disease (EMPD) and tumours of uncertain malignant potential. Second-level groups split skin cancer into keratinocyte cancer (KC), melanoma and rare cancers. The third-level group split KC into basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC). Further groups were split into genital or non-genital, first or subsequent tumour, age, gender, stage, or National Health Service (NHS) region. Incidence counts, Kaplan-Meier and net survival estimates and referral routes [two-week wait (TWW), general practitioner (GP), outpatient] categorisations were calculated for each grouping across all years., Results: A total of 1 445 377 skin cancers and 49 123 precancerous lesions and undefined entities were registered in England between 2013 and 2019. Skin tumours and skin cancer incidence rates are increasing for most tumour types. The most common type of skin cancer was BCC with an incidence rate of 282.36 per 100 000 person-years (PYs) [n = 158 934, 95% confidence interval (CI) 280.98-283.76] in 2019, followed by cSCC with an incidence rate of 85.24 per 100 000 PYs (n = 47 977, 95% CI 84.48-86.00) and melanoma with 27.24 (n = 15 332, 95% CI 26.81-27.67) per 100 000 PYs. Each year approximately 1800 rare skin cancers, 1500 genital cSCCs and 100 cases of EMPD are registered. Of 15 000 melanoma cases, 120 cases of melanoma occur in individuals aged < 25 years annually. One-year and five-year overall net survival varies by tumour type. cSCC 5-year net survival (89.8%, 95% CI 88.8-90.9) was comparable to the net survival of all melanomas (89.6%, 95% CI 88.7-90.6). BCC had excellent survival (overall net survival > 100%). Patients with late-stage melanoma, Merkel cell carcinoma and genital cSCC have a 5-year net survival < 60%. Older patients received fewer TWW referrals than their younger counterparts with the same tumour type at the same location. Patients with acral lentiginous melanoma had fewer TWW referrals and more standard GP referrals than patients with common melanomas., Conclusions: 'Get Data Out' Skin provides detailed and up-to-date statistics on all registrable skin tumours in England, including for the first time precancerous lesions and rare subtypes of common cancers. These data can be used by clinicians, researchers and commissioners to better understand skin cancer and improve resource allocation., Competing Interests: Conflicts of interest B.v.B. is an employee of the British Association of Dermatologists. N.J.L. is a trustee of the British Association of Dermatologists. N.R. is a Deputy Editor at the BJD., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Importance: Immune checkpoint blockade (ICB) has improved the survival of patients with advanced melanoma. Durable responses are observed for 40% to 60% of patients, depending on treatment regimens. However, there is still large variability in the response to treatment with ICB, and patients experience a range of immune-related adverse events of differing severity. Nutrition, through its association with the immune system and gut microbiome, is a poorly explored but appealing target with potential to improve the efficacy and tolerability of ICB., Objective: To investigate the association between habitual diet and response to treatment with ICB., Design, Setting, and Participants: This multicenter cohort study (the PRIMM study) was conducted in cancer centers in the Netherlands and UK and included 91 ICB-naive patients with advanced melanoma who were receiving ICB between 2018 and 2021., Exposures: Patients were treated with anti-programmed cell death 1 and anti-cytotoxic T lymphocyte-associated antigen 4 monotherapy or combination therapy. Dietary intake was assessed through food frequency questionnaires before treatment., Main Outcomes and Measures: Clinical end points were defined as overall response rate (ORR), progression-free survival at 12 months (PFS-12), and immune-related adverse events that were grade 2 or higher., Results: There were a total of 44 Dutch participants (mean [SD] age, 59.43 [12.74] years; 22 women [50%]) and 47 British participants (mean [SD] age, 66.21 [16.63] years; 15 women [32%]). Dietary and clinical data were prospectively collected from 91 patients receiving ICB between 2018 and 2021 for advanced melanoma in the UK and the Netherlands. Logistic generalized additive models revealed positive linear associations between a Mediterranean dietary pattern that was high in whole grains, fish, nuts, fruit, and vegetables and the probability of ORR and PFS-12 (probability of 0.77 for ORR; P = .02; false discovery rate, 0.032; effective degrees of freedom, 0.83; probability of 0.74 for PFS-12; P = .01; false discovery rate, 0.021; effective degrees of freedom, 1.54)., Conclusions and Relevance: This cohort study found a positive association between a Mediterranean diet, a widely recommended model of healthy eating, and response to treatment with ICB. Large prospective studies from different geographies are needed to confirm the findings and further elucidate the role of diet in the context of ICB.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response., Methods: We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment., Results: We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone., Conclusion: While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response., (© 2023. The Author(s).)

Background: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma., Methods: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival., Findings: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10 -4 , 2.29 × 10 -4 , and 1.02 × 10 -3 , respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10 -2 ), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10 -3 ). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response., Interpretation: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy., Funding: This work was supported by the Seerave Foundation and Dutch Cancer Society., Competing Interests: Declaration of interests RKW acted as a consultant for Takeda, received unrestricted research grants from Takeda, Johnson & Johnson, Tramedico, and Ferring, and received speaker fees from MSD, Abbvie and Janssen Pharmaceuticals. TDS is a co-founder of Zoe Global. EGEdV reports an advisory role at Daiichi Sankyo, NSABP and Sanofi (paid to University Medical Center Groningen), and research funding from Amgen, AstraZeneca, Bayer, Crescendo, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier and Synthon (paid to University Medical Center Groningen). SP received speaker fees from Almirall, BMS, ISDIN, La Roche Posay, Leo Pharma, Regeneron, Roche, Sanofi, and acted as an advisory board for Almirall, ISDIN, La Roche Posay, Pfizer, Roche, Regeneron, Sanofi, Sunpharma and research funding from Abbie, AMGEN, ISDIN, La Roche Posay, Leo Pharma, Novartis. SP is also an employee of Enara Bio. RB has received honoraria from, and sits on advisory boards of, Novartis, BMS and MSD. PN has received honoraria in the last 2 years for advisory board membership for AztraZeneca, Esai, BMS, Immunocore, Ipsen, Merck, MSD, Novartis, Pfizer, 4SC. HS has received honoraria for consulting/advisory board membership and speaker's bureau from Novartis, BMS, Sanofi and MSD, along with honoraria for consulting/advisory board membership from Immunocore, Idera, Iovance, Genmab, Genzyme/Regeneron, Macrogenics and Roche. JS received a grant to his institution to fund investigator led research from Immunocore, along with personal fees and institution fees for advisory roles and presentations at meetings from Immunocore. JS also declares a grant for an investigator sponsored trial, personal fees for advisory board attendance and support in attending conferences along with institutional support to run BMS sponsored trials from BMS. JS has received a grant to fund investigator sponsored trials from AstraZeneca, funding from Replimune to his institution to fund Replimune sponsored research and honoraria from Pierre-Fabre. JS has received fees from MSD for advisory board/conference attendance as well as his institution receiving funding to run MSD clinical trials. PL has received personal fees from BMS, Merck, Novartis, GSK, Amgen, Chugai, Pierre-Fabre, NeraCare, Roche and Oncology Education Canada. LT reports research funding from a Sanofi iAward. GH received a research grant from BMS, along with consultancy/advisory relationships with Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi and Pierre Fabre., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Poor nutrition is one of the leading risk factors for preventable chronic diseases in the United States. Nutrition counseling has been shown to improve clinical outcomes in the adult primary care setting. Nurse practitioners (NPs) can help fill the critical need for nutrition counseling, yet little is known about their role providing nutrition counseling., Purpose: To describe the primary care NP's experience in providing nutrition counseling to adult patients in primary care practice., Methods: Qualitative descriptive study design. Data were collected through virtual semi-structured interviews with 18 board-certified primary care NPs. Interviews were audio-recorded, de-identified, transcribed verbatim, and analyzed. Data collection and analysis took place concurrently and continued until data saturation was achieved., Results: Five themes emerged from NPs' descriptions of their experiences in providing nutrition counseling to adult patients in primary care practice: (1) role of nutrition counseling in NP primary care practice; (2) developing NP self-efficacy in nutrition counseling; (3) nutrition counseling is more than the provision of information; (4) emotional aspect of nutrition; and (5) barriers to behavior change., Conclusions: Findings suggest that although NPs understand the importance of nutrition counseling in primary care practice and provide it in some capacity, its continuance is limited by multiple barriers. Future research should evaluate ways to enhance NPs' preparedness to provide nutrition counseling, assess specific resources and tools to aid in nutrition counseling, and determine best practices for communication when delivering nutrition counseling., Implications for Practice: Future interventions have the potential to positively affect patients' dietary practices and improve clinical outcomes., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2022 American Association of Nurse Practitioners.)

Aims: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres., Materials and Methods: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored., Results: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88)., Conclusions: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients., (Copyright © 2021 The Royal College of Radiologists. All rights reserved.)

The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course., (© 2022. The Author(s).)

Individuals with cancer are at increased risk of developing new-onset diabetes mellitus and hyperglycaemia, and an estimated 20% of people with cancer already have an underlying diagnosis of diabetes mellitus. People with both cancer and diabetes may have an increased risk of toxicities, hospital admissions and morbidity, with hyperglycaemia potentially attenuating the efficacy of chemotherapy often secondary to dose reductions and early cessation. Numerous studies have demonstrated that hyperglycaemia is prognostic of worse overall survival and risk of cancer recurrence. These guidelines aim to provide the oncology/haemato-oncology and diabetes multidisciplinary teams with the tools to manage people with diabetes commencing anti-cancer/glucocorticoid therapy, as well as identifying individuals without a known diagnosis of diabetes who are at risk of developing hyperglycaemia and new-onset diabetes., (© 2021 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: Ipilimumab has shown long-term overall survival (OS) in patients with advanced melanoma in clinical trials, but robust real-world evidence is lacking. We present long-term outcomes from the IMAGE study (NCT01511913) in patients receiving ipilimumab and/or non-ipilimumab (any approved treatment other than ipilimumab) systemic therapies., Methods: IMAGE was a multinational, prospective, observational study assessing adult patients with advanced melanoma treated with ipilimumab or non-ipilimumab systemic therapies between June 2012 and March 2015 with ≥3 years of follow-up. Adjusted OS curves based on multivariate Cox regression models included covariate effects. Safety and patient-reported outcomes were assessed., Results: Among 1356 patients, 1094 (81%) received ipilimumab and 262 (19%) received non-ipilimumab index therapy (systemic therapy [chemotherapy, anti-programmed death 1 antibodies, or BRAF ± MEK inhibitors], radiotherapy, and radiosurgery). In the overall population, median age was 64 years, 60% were male, 78% were from Europe, and 78% had received previous treatment for advanced melanoma. In the ipilimumab-treated cohort, 780 (71%) patients did not receive subsequent therapy (IPI-noOther) and 314 (29%) received subsequent non-ipilimumab therapy (IPI-Other) on study. In the non-ipilimumab-treated cohort, 205 (78%) patients remained on or received other subsequent non-ipilimumab therapy (Other-Other) and 57 (22%) received subsequent ipilimumab therapy (Other-IPI) on study. Among 1151 patients who received ipilimumab at any time during the study (IPI-noOther, IPI-Other, and Other-IPI), 296 (26%) reported CTCAE grade ≥ 3 treatment-related adverse events, most occurring in year 1. Ipilimumab-treated and non-ipilimumab-treated patients who switched therapy (IPI-Other and Other-IPI) had longer OS than those who did not switch (IPI-noOther and Other-Other). Patients with prior therapy who did not switch therapy (IPI-noOther and Other-Other) showed similar OS. In treatment-naive patients, those in the IPI-noOther group tended to have longer OS than those in the Other-Other group. Patient-reported outcomes were similar between treatment cohorts., Conclusions: With long-term follow-up (≥ 3 years), safety and OS in this real-world population of patients treated with ipilimumab 3 mg/kg were consistent with those reported in clinical trials. Patient-reported quality of life was maintained over the study period. OS analysis across both pretreated and treatment-naive patients suggested a beneficial role of ipilimumab early in treatment., Trial Registration: ClinicalTrials.gov , NCT01511913. Registered January 19, 2012 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01511913.

Purpose: The admission of a critically ill child to the Pediatric Intensive Care Unit (PICU) is well known to be a stressful experience for parents. The overall aim of this study was to explore whether the use of journal writing would be acceptable and feasible to PICU parents as a stress-reducing intervention., Design and Methods: A longitudinal, quasi-experimental two-group study design was conducted with a convenience sample of 28 parents. Experimental group parents were given instructions on how to journal write each day their child was hospitalized, while control group parents received usual care. Data were collected at three evaluation time points., Results: The response rates at the final time point (6-8 weeks after discharge) were 93% for the control group and 71% for the experimental group. Outcome measure trends were similar for parents in both groups, with most perceiving mild-to-moderate stress from the PICU environment. A significant correlation was found between the perceived stress from the PICU environment and parental traumatic stress symptoms 6-8 weeks postdischarge for the experimental group (Time 1 r = .919, p = .00; Time 2 r = .969, p = .00). The majority of the experimental group parents wrote in their journals daily and found the intervention helpful., Practice Implications: Although further research is warranted, journal writing is a simple-to-do intervention that should be considered for use with future PICU parents., (© 2021 Wiley Periodicals LLC.)

Immune checkpoint inhibitors (CPIs) have radically changed outcomes for patients diagnosed with metastatic melanoma globally in the last 10 years, based on evidence of overall survival (OS) benefits generated from international randomised controlled trials (RCTs). Since RCTs do not always reflect real-world prescribing, we interrogated established national databases to track prescribing of CPIs approved for first line treatment of metastatic melanoma patients in England since 2014 and determined patient outcomes associated with OS, as well as treatment-related toxicity. Between April 2014 and March 2018, 5465 melanoma patients were diagnosed and treated with systemic anticancer therapy (SACT), 2322 of which received first-line CPIs. There was good 3-year OS concordance with RCT outcomes for ipilimumab (32%), ipinivo (56%) and nivolumab (51%), but OS was lower than expected for pembrolizumab (40%). Comparing patients prescribed ipinivo with those prescribed pembrolizumab, ipinivo-treated patients were younger (88% vs 49% patients <70 years, P < .001) and fitter (60% vs 38% patients with Eastern Cooperative Oncology Group [ECOG] performance status 0, P < .0001). Emergency hospital admission rates from the earliest and last treatment dates were higher for patients prescribed ipinivo (37% and 55%) compared to those prescribed pembrolizumab (17% and 29%). The 30-day mortality rates favoured ipinivo patients (3.8% ipinivo, 9.1% pembrolizumab, P < .0001) and likely reflected marked differences in median treatment durations: 63 (range 7-440) days for ipinivo and 192 (range 5-943) days for pembrolizumab. The dominant treatment-related condition linked to hospital admission was colitis, recorded for 25% of patients prescribed ipinivo compared to 4% of patients prescribed pembrolizumab. Our population data has demonstrated that RCT outcomes can be achieved in routine care settings with careful patient selection., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Age-related hearing loss is a very common sensory disability, affecting one in three older adults. Establishing a link between anatomical, physiological, and behavioral markers of presbycusis in a mouse model can improve the understanding of this disorder in humans. We measured age-related hearing loss for a variety of acoustic signals in quiet and noisy environments using an operant conditioning procedure and investigated the status of peripheral structures in CBA/CaJ mice. Mice showed the greatest degree of hearing loss in the last third of their lifespan, with higher thresholds in noisy than in quiet conditions. Changes in auditory brainstem response thresholds and waveform morphology preceded behavioral hearing loss onset. Loss of hair cells, auditory nerve fibers, and signs of stria vascularis degeneration were observed in old mice. The present work underscores the difficulty in ascribing the primary cause of age-related hearing loss to any particular type of cellular degeneration. Revealing these complex structure-function relationships is critical for establishing successful intervention strategies to restore hearing or prevent presbycusis., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In recent years, the diagnosis of brain tumors has been investigated with attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy on dried human serum samples to eliminate spectral interferences of the water component, with promising results. This research evaluates ATR-FTIR on both liquid and air-dried samples to investigate "digital drying" as an alternative approach for the analysis of spectra obtained from liquid samples. Digital drying approaches, consisting of water subtraction and least-squares method, have demonstrated a greater random forest (RF) classification performance than the air-dried spectra approach when discriminating cancer vs control samples, reaching sensitivity values higher than 93.0% and specificity values higher than 83.0%. Moreover, quantum cascade laser infrared (QCL-IR) based spectroscopic imaging is utilized on liquid samples to assess the implications of a deep-penetration light source on disease classification. The RF classification of QCL-IR data has provided sensitivity and specificity amounting to 85.1% and 75.3% respectively., (© 2020 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Introduction: Anorectal melanoma (ARM) is a rare disease with a poor prognosis. There is no consensus as to the optimal primary surgical treatment for ARM, with advocates for both radical (abdominoperineal resection [APR]) and conservative strategies (wide local excision [WLE]). Here, we report a systematic review of studies comparing outcomes between these strategies., Methods: Studies comparing APR with WLE in patients with ARM were included, and a systematic review using the Grading of Recommendations, Assessment, Development and Evaluation methodology was performed. Outcomes deemed critical included overall survival, disease-free survival, local recurrence and quality of life., Results: Forty studies were identified, of which 27 were suitable for inclusion. Twenty-three studies compared overall survival between WLE and APR, with no difference in outcomes noted (risk ratio [RR]: 0.80, 95% confidence interval [CI]: 0.60-1.07, p = 0.13). Seven studies compared disease-free survival, with no difference in outcomes noted (RR: 1.08, 95% CI: 0.61-1.91, p = 0.79). A total of 19 studies compared local recurrence rates, with again no significant difference in outcomes noted (RR: 0.71, 95% CI: 0.44-1.14, p = 0.16). None of the studies identified reported quality of life-related outcomes., Conclusion: There is no evidence to suggest that a radical primary surgical strategy improves outcomes in ARM. Therefore, given the well-documented morbidity associated with APR, WLE with regular surveillance for local recurrence should be the primary strategy in most patients., Competing Interests: Conflict of interest statement None to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To determine the potential costs and health benefits of a serum-based spectroscopic triage tool for brain tumours, which could be developed to reduce diagnostic delays in the current clinical pathway., Design: A model-based health pre-trial economic assessment. Decision tree models were constructed based on simplified diagnostic pathways. Models were populated with parameters identified from rapid reviews of the literature and clinical expert opinion., Setting: Explored as a test in both primary and secondary care (neuroimaging) in the UK health service, as well as application to the USA., Participants: Calculations based on an initial cohort of 10 000 patients. In primary care, it is estimated that the volume of tests would approach 75 000 per annum. The volume of tests in secondary care is estimated at 53 000 per annum., Main Outcome Measures: The primary outcome measure was quality-adjusted life-years (QALY), which were employed to derive incremental cost-effectiveness ratios (ICER) in a cost-effectiveness analysis., Results: Results indicate that using a blood-based spectroscopic test in both scenarios has the potential to be highly cost-effective in a health technology assessment agency decision-making process, as ICERs were well below standard threshold values of £20 000-£30 000 per QALY. This test may be cost-effective in both scenarios with test sensitivities and specificities as low as 80%; however, the price of the test would need to be lower (less than approximately £40)., Conclusion: Use of this test as triage tool in primary care has the potential to be both more effective and cost saving for the health service. In secondary care, this test would also be deemed more effective than the current diagnostic pathway., Competing Interests: Competing interests: MJB, MGH, HJB and DSP are all involved in ClinSpec Diagnostics, a prospective spin-out company from the University of Strathclyde focusing on the translation of serum spectroscopic diagnostics (Company No SC535447)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Agreement on the utility of imaging follow-up in patients with high-risk melanoma is lacking. A UK consensus statement recommends a surveillance schedule of CT or positron-emission tomography-CT and MRI brain (every 6 months for 3 years, then annually in years 4 and 5) as well as clinical examination for high-risk resected Stages II and III cutaneous melanoma. Our aim was to assess patterns of relapse and whether imaging surveillance could be of clinical benefit., Patients and Methods: A retrospective study of patients enrolled between July 2013 and June 2015 from three UK tertiary cancer centres followed-up according to this protocol was undertaken. We evaluated time-to-recurrence (TTR), recurrence-free survival (RFS), method of detection and characteristics of recurrence, treatment received and overall survival (OS)., Results: A total of 173 patients were included. Most (79%) had treated Stages IIIB and IIIC disease. With a median follow-up of 23.3 months, 82 patients (47%) had relapsed. Median TTR was 10.1 months and median RFS was 21.2 months. The majority of recurrences (66%) were asymptomatic and detected by scheduled surveillance scan. Fifty-six (68%) patients recurred with Stage IV disease, with a median OS of 25.3 months; 26 (31.7%) patients had a locoregional recurrence, median OS not reached (P=0.016). Patients who underwent surgery at recurrence for either Stage III (27%) or IV (18%) disease did not reach their median OS. The median OS for the 33 patients (40%) who received systemic therapy was 12.9 months., Conclusion: Imaging appears to reliably detect subclinical disease and identify patients suitable for surgery, conferring favourable outcomes. The short median TTR provides rationale to intensify imaging schedule in the first year of surveillance. The poor OS of patients treated with systemic therapy probably reflects the relatively inferior treatment options during this time and requires further evaluation in the current era., Competing Interests: Competing interests: JL is supported by the NIHR Royal Marsden/Institute of Cancer Research BRC for Cancer.

Background: Infants born with long-gap esophageal atresia (LGEA) pose unique physiologic risks in the newborn period. Anatomic and physiologic anomalies require an extended hospitalization with procedural analgesia and sedation that impact the mother's experience of birth, maternal response, and nurturing of her infant., Purpose: The aim of this study was to understand the meaning of experiences that mothers of infants born with LGEA encounter in the neonatal intensive care unit while their infant undergoes esophageal repair., Methods: A hermeneutical phenomenological design was used to guide this inquiry. Three mothers were interviewed on 3 separate occasions. The conversations were audio-recorded and transcribed verbatim. The findings were analyzed using fundamental existential lifeworld themes., Results: The essence that conceptualized the study was "making connections: day-by-day." Themes that emerged are (a) the many phases; (b) the long and winding road; (c) a new me, my purpose; and (d) our new community., Implications for Practice: Nurses' knowledge and understanding of maternal experiences of having an infant with LGEA will enable for increased physical closeness, optimizing time spent together to learn their infant's unique personality. Creating partnerships with mothers can enhance our understanding of their perspectives, concerns, needs, and guide interventions., Implications for Research: Further exploration of family dynamics including fathers, siblings, and contextual factors may illuminate interventions to enhance relationships and communication that may influence developmental outcomes for families of infants with LGEA.

Introduction: Spectroscopic and spectrometric analysis of biological samples is regarded as quick, cost effective, easy to operate, and spectroscopic sample preparation involves minimal sample preparation., Results: Techniques like infrared (IR) spectroscopy, surface-enhanced laser desorption/ionization (SELDI)-mass spectroscopy (MS), and matrix-assisted laser desorption/ionization (MALDI) -MS could enable early diagnosis of cancer, disease monitoring, and assessment of treatment responses allowing refinement, if required., Discussion: Carrying out analytical testing within outpatient clinics would dramatically cut the time spent by patients attending different appointments, at different locations, save hospital time and resources but importantly would theoretically enable a reduction in mortality and morbidity. While the advantages of such a prospect seem obvious, this review aims to evaluate the use of human serum spectroscopic and spectrometric analysis as a diagnostic tool for brain cancers, creating a platform for the future of cancer diagnostics.

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.

The purpose of the study was to evaluate serum concentration of antibiotics drawn from a peripherally inserted central catheter (PICC) compared with a peripheral venipuncture. This prospective comparative study included patients with ages 1month to 21years admitted with a respiratory infection requiring IV vancomycin or IV tobramycin via a newly placed PICC. The difference between the antibiotic levels from the venipuncture and PICC samples was statistically significant for both the peak and trough levels. However, the difference in values was not enough to impact antibiotic dosing and therefore was not clinically significant., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0-1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.