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Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7·5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16–37) in the bevacizumab group and 25 months (17–37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0·97, 95% CI 0·78–1·22; p=0·76); this finding persisted after adjustment for stratification variables (HR 1·03; 95% CI 0·81–1·29; p=0·83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21–52) and dose intensity was 86% (41–96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0·83, 95% CI 0·70–0·98, p=0·03), but no significant difference between groups for distant-metastasis-free interval (HR 0·88, 95% CI 0·73–1·06, p=0·18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years. Cancer Research UK.

Somatic mutations in PIK3CA (encoding a class I phosphoinositide 3 kinase (PI3K) subunit) modulate PI3K signalling to influence tumour behaviour and occur in up to 40% of breast cancers. Inhibitors of PI3K signalling are entering clinical trials, but the impact of PIKC3A mutation on tumour response has yet to be clarified. This study investigated the potential utility of circulating free DNA (cfDNA) as a source for PIK3CA mutation detection in patients with breast cancer. cfDNA extracted (QIAamp Virus spin kit) from blood and matched archival tumour from 46 patients with metastatic breast cancer and 30 patients with localised, operable breast cancer was assessed for hotspot PIK3CA mutations using Amplification Refractory Mutation System (ARMS™) allele-specific PCR and Scorpion probes. PIK3CA mutations were detected in 13/46 (28%) plasma-derived and 10/46 (21%) serum-derived cfDNA samples from metastatic breast cancer patients. In 41 cases with matched tumour and plasma-derived cfDNA data, concordance (same mutation status in plasma and tumour) was 95%. Where a PIK3CA mutation was present in tumour, the ‘pick up' in plasma-derived cfDNA was 80%. PIK3CA mutations were present in tumours from 14/30 (47%) localised breast cancers, but no PIK3CA mutations were detected in matched cfDNA. These data demonstrate feasibility and potential utility of cfDNA for PIK3CA mutation detection in patients with metastatic breast cancer. Studies are underway to qualify PIK3CA mutation in cfDNA as a predictive biomarker allowing patient stratification in clinical trials of mechanism-based therapeutics that target PI3K signalling pathways.

Background Health care staff should be given the opportunity to participate in research, but recruiting clinicians via their employing organisation is not always straightforward or quick in the UK. Unlike many countries outside the UK, very low-risk survey, interview or focus group studies can be subject to some of the same governance approval procedures as interventional studies. An exemplar study carried out by the NIHR funded Palliative Care Research Partnership North West Coast is used to highlight the challenges still faced by researchers and health care organisations when setting up a low-risk staff study across multiple NHS and non-NHS sites. Methods A study database was created and information was collected on the first point of contact with the clinical site, Health Research Authority (HRA) and local organisational approval times, time from trust or hospice agreement to the first survey participant recruited and overall site survey recruitment numbers. Descriptive statistics (median, range) were used to analyse these data. Results Across participating NHS trusts, it took a median of 147.5 days (range 99–195) from initial contact with the local collaborator to recruitment of the first survey participant and hospice sites mirrored these lengthy timescales (median 142 days, range 110–202). The lengthiest delays in the HRA approval process were the period between asking NHS trusts to assess whether they had capacity and capability to support the research and them granting local agreement. Local approval times varied between trusts and settings which may indicate organisations are applying national complex guidance differently. Conclusions There is the potential for HRA processes to use more NHS resources than the research study itself when recruiting to a low-risk staff study across multiple organisations. There is a need to reduce unnecessary administrative burden and bureaucracy to give clinicians and research staff more opportunities to participate in research, and to free up NHS R&D departments, research nurses and clinicians to focus on more demanding and patient focused research studies. Hospices need standardised guidance on how to assess the risk of being involved in low-risk research without adopting the unnecessarily complex systems that are currently used within the NHS.

We aimed to characterize the safety profile of pembrolizumab in advanced melanoma patients at our center to better reflect 'real-world' data on anti-PD-1 inhibitors. At our institution, 58 ipilimumab-naive and 30 ipilimumab-treated patients with advanced melanoma who have received pembrolizumab between June 2014 and June 2017 were included for analysis. Incidence of any-grade and grade 3/4 toxicities were 81.8% (n = 72) and 12.5% (n = 11), respectively. The most common side effects were skin-related (61.4%, n = 54) and gastrointestinal-related (51.1%, n = 45) events. In total, 25% of patients required oral steroids to manage immune-related adverse events with a median cumulative prednisolone dose of 683 mg (range: 40-3745 mg). Pembrolizumab is well tolerated in 'real-world' patients and severe toxicities can be effectively managed with systemic steroids.

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.

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

There have been impressive improvements in the diagnosis and treatment of cancer in recent decades. In economically advantaged countries with well-developed healthcare systems over 50% of all cancer patients achieve long term survival and are probably cured. Not only has survival improved radically for cancer patients but also there has been an increasing focus on the quality of patient's lives, on improving the patient experience of care and on developing effective support for the very many cancer survivors. Despite the progress in cancer treatment, unfortunately a substantial number of cancer patients will still ultimately die of their disease. For many this will follow periods of successful treatment which results in good remissions and good quality of life. Helping patients to make the right choices about their care towards the end of their lives is one of the greatest and most challenging responsibilities of all healthcare professionals. Legal change on the provision of assisted dying by healthcare professionals has occurred in a substantial number of jurisdictions. This work brings together contributions on end of life choices from experienced professionals from oncology disciplines, palliative care, law, nurses and professions allied to medicine. The goals are: * To better inform cancer care professionals and the wider community about developments in choices in end of life care for cancer patients internationally. * To better answer questions from patients and respond to requests from patients, including questions about and requests for assisted dying in countries where it is legal to do so. * To have a balanced and well informed dialogue about choices available to patients without developing a formal policy position on change in law. * To provide a basis of information for future educational activities.

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.

Immune checkpoint inhibitors have transformed the treatment of various cancers including metastatic melanoma. Immune checkpoints are regulatory mechanisms which modulate the immune system and prevent overwhelming autoimmune attack. This may be exploited by certain tumour types, leading to attenuation of T cell activation and thus expansion and growth of tumour cells. Blockade of pathways including CTLA-4, PD-1 and PDL-1 has emerged as an approach to remove this inhibitory immune checkpoint mechanism and allow host to mount immune responses against tumour cells.1 2 Immune related adverse events (irAEs) are important, as high grade toxicities may require corticosteroids and discontinuation of treatment. The incidence of high grade irAEs is greater with CTLA-4 inhibitors (ipilimumab) than PD-1 inhibitors (nivolumab), and risk is increased further in combination (Ipi/Nivo). Ipi/Nivo induced hepatitis is an important irAE occurring in 17.6% patients (any grade) with 8.3% experiencing grade 3/4 hepatitis, based on previous trial data.3–6 Continued analysis of real-world data is important to better establish the natural history of immunotherapy related hepatitis. Lancashire Teaching Hospitals is the tertiary cancer centre for Lancashire and South Cumbria. Electronic records, biochemistry results and oncology prescribing databases were retrospectively analysed for 68 patients treated with Ipi/Nivo between August 2016 and October 2020.36 (52.9%) patients experienced hepatotoxicity (any grade) with n= 11 (16.2%) patients developing grade 3 or 4 hepatitis. The median time of onset of hepatotoxicity from the first dose (all grades) was 40 days (range 8–322).Amongst patients who experienced hepatotoxicity, the proportion treated with intravenous, oral or nil corticosteroids was 47.2%, 38.9% and 13.9% respectively. 4 patients required escalation to MMF and 1 patient needed tacrolimus as a third agent. Of patients who developed hepatotoxicity, n=29 had combination treatment discontinued prior to completion of 4 cycles. 15 patients were re-challenged with single agent nivolumab. Of the patients re-challenged, n=9 (60%) did not experience any further hepatotoxicity.This data demonstrated Ipi/nivo induced hepatitis occurring at a higher rate than in reported studies. This highlights the importance in monitoring real world data with novel anti-cancer therapies however, larger collaborative datasets are required. In addition, further comparative effectiveness research regarding treatment with oral vs intravenous corticosteroids will be important. The latter usually requires hospital admission, which has cost, service and patient experience implications. Finally, further analysis of phenotypic and biochemical variables associated with hepatotoxicity may identify important trends to allow better prediction and thus appropriate counselling and informed discussion when planning treatment.Abstract P017 Figure 1Treatment with corticosteroids amongst patients with any grade of hepatotoxicityIn addition, 4 patients (11.1% of all patients with any grade hepatotoxicity) required addition of mycophenolate mofetil (MMF) due to suboptimal response to steroids. One patient also required addition of tacrolimus. Other agents used for different iRAEs included infliximab and sulfasalazine.Abstract P017 Figure 2Abstract P017 Figure 3Summary of overall incidence of immunotherapy related hepatotoxicity according to grade and pattern of liver injuryAbstract P017 Table 1Summary of patient characteristics, onset and resolution of hepatotoxicity Male n (%) Female n (%) Mean and (median) age Median number of cycles prior to onset of toxicity n Median time from first dose to onset of hepatotoxicity Median time for resolution of hepatotoxicity* Hepatotoxicity (Any grade) 21 (48.9%) 15 (60%) 53.5 years (55) 2 40 days (range 8–322) n/a Hepatotoxicity (Grade 3 or 4) 5 (11.6%) 6 (24%) 53.6 (57) 1 27 days 27.5 days (range 5–154) No Hepatotoxicity 17 (39.5%) 4 (16%) 57.2 years (58) n/a n/a n/a *Defined as the point at which ALT < 3 times upper limit of normalReferencesWei S, et al. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8(9):1069–1086.Marin-Acevedo JA, et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J Haematol Oncol 2018:11:39.Zhou X, et al. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? A systematic review and meta-analysis. BMC Med 2020;18:87.Larkin J, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Eng J Med 2015;373:23–34.Hodi F, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med 2010;363:711–723.Wolchok J, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 2010;11(2):155–64.U.S Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. November 2017.Haanen J, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28(suppl 4):119–142.Cheung V, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterology 2019;10:364–371.Eun Y, et al. Risk factors for immune-related adverse events associated with anti-PD-1 pembrolizumab. Sci Rep 2019;9:14039.Owen D, et al. Incidence, risk factors, and effect on survival of immune-related adverse events in patients with non-small-cell lung cancer. Clin Lung Cancer 2018;19(6):893–900.Parmanande A, et al. Risk factors for immune related adverse events: a retrospective study. Ann Oncol 2019;30(suppl11).Barata M, et al. Predictors of immunotherapy induced immune-related adverse events. Eur Respir J 2019:54(suppl63).Aimono Y, et al. Evaluation of risk factors for immune-related adverse events associated with treatment with immune checkpoint inhibitors. Gan To Kagaku Ryoho 2021;48(1):57–61.Angum F, et al. The prevalence of autoimmune disorders in women: a narrative review. 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Background: Mutations in the PIK3CA gene (phosphoinositide-3-kinase, catalytic, alpha polypeptide) have recently been described in a number of cancers, and their detection is currently limited because of the low sensitivity of conventional sequencing techniques. Methods: We combined Amplification Refractory Mutation System (ARMS™; AstraZeneca) allele-specific PCR and Scorpions™ (DxS) to develop assays for tumor-borne PIK3CA mutations and used real-time PCR to develop high-throughput multiplexed assays for the most commonly reported PIK3CA mutants (H1047L, H1047R, E542K, E545K). Results: These assays were more sensitive than sequencing and could detect 5 copies of mutant DNA in proportions as low as 0.1% of the total DNA. We assayed DNA extracted from human tumors and detected PIK3CA mutation frequencies of 10.2% in colorectal cancer, 38.7% in breast cancer, 1.9% in lung cancer, and 2.9% in melanoma. In contrast, sequencing detected only 53% of the mutations detected by our assay. Conclusions: Multiplexed assays, which can easily be applied to clinical samples, have been developed for the detection of PIK3CA mutations.