Interleukin-6 blockade for prophylaxis and management of immune-related adverse events in cancer immunotherapy

Background Immune checkpoint inhibitors (ICIs) have activity across many tumor types, but activation of the immune system may also lead to significant, often steroid-refractory immune-related adverse events (irAEs). We sought to determine the activity of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in treatment or prevention of auto-immune irAE in ICI-treated patients. Methods Institutional databases from 2 melanoma centers were reviewed for patients treated with ICIs and tocilizumab. Longitudinal assessment of C-reactive protein (CRP) and assessment of clinical improvement or prevention of flare of pre-existing auto-immune conditions were utilised to evaluate the benefit of tocilizumab. Results Twenty-two patients were identified. Two were treated prophylactically. Twenty were treated for management of irAEs. Median time to irAE onset from ICI start was 48 days (range 8–786) and from irAE onset to tocilizumab 32 days (range 1–192). Median time to irAE resolution from tocilizumab was 6.5 days (range 1–93). Clinical improvement/benefit was demonstrated in 21/22 patients. Median CRP prior to ICI administration was 32 mg/l (range 0.3–99), at the onset of irAE 49.5 mg/L (range 0.3–251, P = 0.047) and after tocilizumab 18 mg/L (range 0.3–18, P = 0.0011). Tocilizumab was well tolerated with self-limiting and transient toxicities in 11 (50%) patients. From start of ICI, median progression-free survival was 6 months (range 3.9–18.8) and median overall survival was not reached. Conclusions Tocilizumab was a well-tolerated and effective steroid-sparing treatment for both management of irAEs, as well as prevention of flare of pre-existing auto-immune disorders. Prospective trials to evaluate its efficacy and impact on cancer outcomes compared with standard strategies are required

A baseline method for benchmarking mortality losses in Atlantic salmon (Salmo salar) production

On-farm databases provide a large diversity of information regarding fish health and stock performance. Mortality records held in on-farm database are indicators of fish health status and of great interest for studying fish health, such as patterns of diseases. Mortality records from a Scottish Atlantic salmon production database of one company were used to develop a method of benchmarking production losses due to mortality. The records used concerned mortality loss numbers of Atlantic salmon in the seawater phase. The median, 10th and 90th percentiles of mortality were calculated for each week of production from 88 production recorded cycles. These values were used to delimit the range of a standard mortality curve through the production cycle. The effects of the different mortality losses from each cycle on production in terms of costs and time consumed were also described. Likewise, substantial interannual variation in mortality time series is described as well as the mortality variation associated with three diseases (Pancreas Disease, Cardiomyopathy Syndrome and Infectious Pancreatic Necrosis)

Detection of BRAF splicing variants in plasma-derived cell-free nucleic acids and extracellular vesicles of melanoma patients failing targeted therapy therapies

The analysis of plasma circulating tumour nucleic acids provides a non-invasive approach to assess disease burden and the genetic evolution of tumours in response to therapy. BRAF splicing variants are known to confer melanoma resistance to BRAF inhibitors. We developed a test to screen cell-free RNA (cfRNA) for the presence of BRAF splicing variants. Custom droplet digital PCR assays were designed for the detection of BRAF splicing variants p61, p55, p48 and p41 and then validated using RNA from cell lines carrying these variants. Evaluation of plasma from patients with reported objective response to BRAF/MEK inhibition followed by disease progression was revealed by increased circulating tumour DNA (ctDNA) in 24 of 38 cases at the time of relapse. Circulating BRAF splicing variants were detected in cfRNA from 3 of these 38 patients; two patients carried the BRAF p61 variant and one the p55 variant. In all three cases the presence of the splicing variant was apparent only at the time of progressive disease. BRAF p61 was also detectable in plasma of one of four patients with confirmed BRAF splicing variants in their progressing tumours. Isolation and analysis of RNA from extracellular vesicles (EV) from resistant cell lines and patient plasma demonstrated that BRAF splicing variants are associated with EVs. These findings indicate that in addition to plasma ctDNA, RNA carried by EVs can provide important tumour specific information

Adjuvant immunotherapy recommendations for stage III melanoma: physician and nurse interviews

Background Adjuvant immunotherapy is revolutionising care for patients with resected stage III and IV melanoma. However, immunotherapy may be associated with toxicity, making treatment decisions complicated. This study aimed to identify factors physicians and nurses considered regarding adjuvant immunotherapy for melanoma. Methods In-depth interviews were conducted with physicians (medical oncologists, surgeons and dermatologists) and nurses managing patients with resected stage III melanoma at three Australian tertiary melanoma centres between July 2019 and March 2020. Factors considered regarding adjuvant immunotherapy were explored. Recruitment continued until data saturation and thematic analysis was undertaken. Results Twenty-five physicians and nurses, aged 28–68 years, 60% females, including eleven (44%) medical oncologists, eight (32%) surgeons, five (20%) nurses, and one (4%) dermatologist were interviewed. Over half the sample managed five or more new resected stage III patients per month who could be eligible for adjuvant immunotherapy. Three themes about adjuvant immunotherapy recommendations emerged: [1] clinical and patient factors, [2] treatment information provision, and [3] individual physician/nurse factors. Melanoma sub-stage and an individual patient’s therapy risk/benefit profile were primary considerations. Secondary factors included uncertainty about adjuvant immunotherapy’s effectiveness and their views about treatment burden patients might consider acceptable. Conclusions Patients’ disease sub-stage and their treatment risk versus benefit drove the melanoma health care professionals’ adjuvant immunotherapy endorsement. Findings clarify clinician preferences and values, aiding clinical communication with patients and facilitating clinical decision-making about management options for resected stage III melanoma

A tailored approach to horizon scanning for cancer medicines

BACKGROUND: Horizon scanning (HS) is the systematic identification of emerging therapies to inform policy and decision-makers. We developed an agile and tailored HS methodology that combined multi-criteria decision analysis weighting and Delphi rounds. As secondary objectives, we aimed to identify new medicines in melanoma, non-small cell lung cancer and colorectal cancer most likely to impact the Australian government's pharmaceutical budget by 2025 and to compare clinician and consumer priorities in cancer medicine reimbursement.METHOD: Three cancer-specific clinician panels (total n = 27) and a consumer panel (n = 7) were formed. Six prioritisation criteria were developed with consumer input. Criteria weightings were elicited using the Analytic Hierarchy Process (AHP). Candidate medicines were identified and filtered from a primary database and validated against secondary and tertiary sources. Clinician panels participated in a three-round Delphi survey to identify and score the top five medicines in each cancer type.RESULTS: The AHP and Delphi process was completed in eight weeks. Prioritisation criteria focused on toxicity, quality of life (QoL), cost savings, strength of evidence, survival, and unmet need. In both curative and non-curative settings, consumers prioritised toxicity and QoL over survival gains, whereas clinicians prioritised survival. HS results project the ongoing prevalence of high-cost medicines. Since completion in October 2021, the HS has identified 70 % of relevant medicines submitted for Pharmaceutical Benefit Advisory Committee assessment and 60% of the medicines that received a positive recommendation.CONCLUSION: Tested in the Australian context, our method appears to be an efficient and flexible approach to HS that can be tailored to address specific disease types by using elicited weights to prioritise according to incremental value from both a consumer and clinical perspective.POLICY SUMMARY: Since HS is of global interest, our example provides a reproducible blueprint for adaptation to other healthcare settings that integrates consumer input and priorities.</p

The role of diabetes in metastatic melanoma patients treated with nivolumab plus relatlimab

Background The combination of nivolumab + relatlimab is superior to nivolumab alone in the treatment of naive patients and has activity in PD-1 refractory melanoma. We had previously observed a reduced expression of LAG3 in melanoma tissue from patients with type 2 diabetes. Method To evaluate the impact of diabetes on oncological outcomes of patients with advanced melanoma treated with nivolumab plus the LAG3 inhibitor relatlimab we performed a retrospective multicenter study. Results Overall, 129 patients were included: 88 without diabetes before the treatment, 37 who were diagnosed with type 2 diabetes before the start of treatment, and 4 without diabetes before treatment who developed immune checkpoint inhibitor-induced diabetes (ICI-DM). PFS was 21.71 months (95% CI: 15.61–27.81) in patients without diabetes, 10.23 months (95% CI: 5.81–14.66) in patients with type 2 diabetes, and 50.85 months (95% CI: 23.04–78.65) in patients who developed ICI-DM. OS was 37.94 months (95% CI: 31.02–44.85) in patients without diabetes, 22.12 months (95% CI: 14.41–29.85) in those with type 2 diabetes and 57.64 months (95% CI: 42.29–72.99) in those who developed ICI-DM. Multivariate analysis showed that the presence of diabetes and LDH was correlated with OS and PFS. The mean OS was 64.63 months in subjects with low levels of glucose ( 1.5) had a worse prognosis than those whose glucose level had not increased. This result was observed also in subgroups treated either in first line or further lines. Patients who developed ICI-DM during the study period had better outcomes than the overall population and patients without diabetes. Conclusions LAG3 inhibition for treating metastatic or unresectable melanoma has a reduced efficacy in patients with type 2 diabetes, possibly due to a low expression of LAG3 in tumor tissue. Higher level evidence should be obtained

Cost-Effectiveness of PET/CT Surveillance Schedules to Detect Distant Recurrence of Resected Stage III Melanoma

Objective: To estimate the cost-effectiveness of three surveillance imaging strategies using whole-body positron emission tomography (PET) with computed tomography (CT) (PET/CT) in a follow-up program for adults with resected stage III melanoma. Methods: An analytic decision model was constructed to estimate the costs and benefits of PET/CT surveillance imaging performed 3-monthly, 6-monthly, or 12-monthly compared with no surveillance imaging. Results: At 5 years, 3-monthly PET/CT surveillance imaging incurred a total cost of AUD 88,387 per patient, versus AUD 77,998 for 6-monthly, AUD 52,560 for 12-monthly imaging, and AUD 51,149 for no surveillance imaging. When compared with no surveillance imaging, 12-monthly PET/CT imaging was associated with a 4% increase in correctly diagnosed and treated distant disease; a 0.5% increase with 6-monthly imaging and 1% increase with 3-monthly imaging. The incremental cost-effectiveness ratio (ICER) of 12-monthly PET/CT surveillance imaging was AUD 34,362 for each additional distant recurrence correctly diagnosed and treated, compared with no surveillance imaging. For the outcome of cost per diagnostic error avoided, the no surveillance imaging strategy was the least costly and most effective. Conclusion: With the ICER for this strategy less than AUD 50,000 per unit of health benefit, the 12-monthly surveillance imaging strategy is considered good value for money

The Impact of Surveillance Imaging Frequency on the Detection of Distant Disease for Patients with Resected Stage III Melanoma

Background It is not known whether there is a survival benefit associated with more frequent surveillance imaging in patients with resected American Joint Committee on Cancer stage III melanoma. Objective The aim of this study was to investigate distant disease-free survival (DDFS), melanoma-specific survival (MSS), post distant recurrence MSS (dMSS), and overall survival for patients with resected stage III melanoma undergoing regular computed tomography (CT) or positron emission tomography (PET)/CT surveillance imaging at different intervals. Patients and Methods A closely followed longitudinal cohort of patients with resected stage IIIA–D disease treated at a tertiary referral center underwent 3- to 4-monthly, 6-monthly, or 12-monthly surveillance imaging between 2000 and 2017. Survival outcomes were estimated using the Kaplan–Meier method, and log-rank tests assessed the significance of survival differences between imaging frequency groups. Results Of 473 patients (IIIA, 19%; IIIB, 31%; IIIC, 49%; IIID, 1%) 30% underwent 3- to 4-monthly imaging, 10% underwent 6-monthly imaging, and 60% underwent 12-monthly imaging. After a median follow-up of 6.2 years, distant recurrence was recorded in 252 patients (53%), with 40% detected by surveillance CT or PET/CT, 43% detected clinically, and 17% with another imaging modality. Median DDFS was 5.1 years (95% confidence interval 3.9–6.6). Among 139 IIIC patients who developed distant disease, the median dMSS was 4.4 months shorter in those who underwent 3- to 4-monthly imaging than those who underwent 12-monthly imaging. Conclusion Selecting patients at higher risk of distant recurrence for more frequent surveillance imaging yields a higher proportion of imaging-detected distant recurrences but is not associated with improved survival. A randomized comparison of low versus high frequency imaging is needed

Institutional creativity and pathologies of potential space: The modern university

This paper proposes the applicability of object relations psychoanalytic conceptions of dialogue (Ogden, 1986, 1993) to thinking about relationships and relational structures and their governance in universities. It proposes that: the qualities of dialogic relations in creative institutions are the proper index of creative productivity; that is of, as examples, ’thinking’ (Evans, 2004), ’emotional learning’ (Salzberger-Wittenburg et al., 1983) or ’criticality’ (Barnett, 1997); contemporary institutions’ explicit preoccupation in assuring, monitoring and managing creative ’dialogue’ can, in practice, pervert creative processes and thoughtful symbolic productivity, thus inhibiting students’ development and the quality of ’thinking space’ for teaching and research. In this context the paper examines uncanny and perverse connections between Paulo Freire’s (1972) account of educational empowerment and dialogics (from his Pedagogy of the oppressed) to the consumerist (see, for example, Clarke & Vidler, 2005) rhetoric of student empowerment, as mediated by some strands of managerialism in contemporary higher education. The paper grounds its critique of current models of dialogue, feedback loops, audit and other mechanisms of accountability (Power, 1997; Strathern, 2000), in a close analysis of how creative thinking emerges. The paper discusses the failure to maintain a dialogic space in humanities and social science areas in particular, exploring psychoanalytic conceptions from Donald Winnicott (1971), Milner (1979), Thomas Ogden (1986) and Csikszentmihalyi (1997). Coleridge’s ideas about imagination as the movement of thought between subjective and objective modes are discussed in terms of both intra- and inter-subjective relational modes of ’dialogue’, which are seen as subject to pathology in the pathologically structured psychosocial environment. Current patterns of institutional governance, by micromanaging dialogic spaces, curtail the ’natural’ rhythms and temporalities of imagination by giving an over-emphasis to the moment of outcome, at the expense of holding the necessary vagaries of process in the institutional ’mind’. On the contrary, as this paper argues, creative thinking lies in sporadic emergences at the conjunction of object/(ive) outcome and through (thought) processes