Thyroid dysfunction after immune checkpoint inhibitors in a single-centre UK pan-cancer cohort: A retrospective study.

PURPOSE: This study investigated thyroid dysfunction with immune checkpoint inhibitors (ICIs) in terms of proportions affected, risk factors, thyroid sequelae, and overall survival (OS). METHODS: Among patients with normal baseline free T4 (fT4) and thyroid stimulating hormone (TSH) receiving ICIs at a large cancer centre, proportions of hyperthyroidism/hypothyroidism were determined (any, subclinical [normal fT4, abnormal TSH], overt [abnormal fT4, abnormal TSH], isolated hyperthyroxinaemia/hypothyroxinaemia and secondary) with onset times and subsequent thyroid statuses. Associations of overt dysfunction with OS were estimated using Cox regression and methods robust to immortal time bias (time-dependent Cox regression and 3- and 6-month landmark analyses). Associations of baseline variables with overt hyperthyroidism and hypothyroidism were estimated using Fine and Gray regression. RESULTS: Of 1349 patients, 34.2% developed hyperthyroidism (10.3% overt), including 54.9% receiving combination ICIs, while 28.2% developed hypothyroidism (overt 9.3%, secondary 0.5%). A third of overt hypothyroidism cases occurred without preceding hyperthyroidism. Subclinical thyroid dysfunction returned directly to normal in up to half. Overt hyperthyroidism progressed to overt hypothyroidism in 55.4% (median 1.6 months). Melanoma treatment in the adjuvant vs. advanced setting caused more overt hyperthyroidism (12.1% vs. 7.5%) and overt hypothyroidism (14.5% vs. 9.7%). Baseline eGFR < 60 mL/min/1.73 m2 (HR=1.68, 1.07-2.63) was associated with overt hyperthyroidism and sex (HR=0.60, 0.42-0.87) and TSH (4th vs. 1st quartile HR=1.87, 1.10-3.19) with overt hypothyroidism. Overt dysfunction was associated with OS in the Cox analysis (HR=0.65, 0.50-0.85, median follow-up 22.2 months) but not in the time-dependent Cox (HR=0.79, 0.60-1.03) or landmark analyses (3-month HR=0.74, 0.51-1.07; 6-month HR=0.91, 0.66-1.24). CONCLUSION: Thyroid dysfunction affects up to half of patients receiving ICIs. The association with OS is unclear after considering immortal time bias. The clinical courses include recovery, thyrotoxicosis and de novo overt hypothyroidism. Adjuvant treatment for melanoma, where longer-term harms are of concern, causes more frequent/aggressive dysfunction.

Predictive value and interrater reliability of mental status and mobility assessment in the emergency department.

AIM: To investigate the predictive value of both mental status, assessed with the AVPUC (Alert, responds to Voice, responds to Pain, Unresponsive, and new Confusion) scale, and mobility assessments, and their interrater reliability (IRR) between triage clinicians and a research team. METHOD: Prospective study of consecutive patients who presented to an ED. Mental status and mobility were assessed by triage clinicians and by a dedicated research team. RESULTS: 4,191 patients were included. After adjustment for age and sex, patients with altered mental status have an odds ratio of 6.55 [4.09-10.24] to be admitted in the ICU and an odds ratio of 21.16 [12.06-37.01] to die within 30 days; patients with impaired mobility have an odds ratio of 7.08 [4.60-11.12] to be admitted in the ICU and an odds ratio of 12.87 [5.93-32.30] to die within 30 days. The kappa coefficient between triage clinicians and the research team for mental status assessment was 0.75, and 0.80 for mobility. CONCLUSION: Assessment of mental status by the AVPUC scale, and mobility by a simple dichotomous scale are suitable for ED triage. Both altered mental status and impaired mobility are associated with adverse outcomes. Mental status and mobility assessment have good interrater reliability.

Provision of acute oncology services in the UK: data from the Society for Acute Medicine Benchmarking Audit 2022 (SAMBA22).

Acute oncology services (AOS) manage acute cancer-related presentations alongside acute medical teams. This study assessed AOS provision against national peer review measures and the burden of acute cancer-related admissions. The 2022 Society for Acute Medicine Benchmarking Audit surveyed UK hospitals, collecting hospital-level and patient-level data for all medical admissions over a 24-h period. Logistic regression models were constructed to identify differences in patient outcomes for cancer-related admissions. Most hospitals (n=120 or 91.6%) reported having an AOS. There was heterogeneity in AOS provision, with many failing to meet peer-review measures. Of the 7,116 patients, 542 (7.6%) were cancer-related admissions. Cancer-related admissions had greater clinical acuity (p<0.05), length of stay (p<0.001) and 14-day mortality (adjusted odds ratio (OR)=3.54, 95% confidence interval (CI): 2.41-5.22, p<0.001) compared with other medical admissions. Increasing availability of AOS with integration of ambulatory pathways are vital next steps to improving care for acute cancer-related admissions.

A prospective, real-world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN: a MASCC Neutropenia, Infection, and Myelosuppression Study Group initiative.

PURPOSE: Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10-20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice. METHODS: This prospective, real-world, observational, multinational, multicenter study (December 2016-October 2019) recruited patients with solid tumors or Hodgkin's/non-Hodgkin's lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration). RESULTS: In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2-3, and 1% in cycles 4-6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia. CONCLUSIONS: Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician's judgement.

The need for ambulatory emergency oncology: exemplified by the management of immune checkpoint inhibitor toxicity.

Cancer patients seeking emergency care can be vulnerable in increasingly overcrowded Emergency Departments and timely delivery of care is often aspirational rather than reality in many acute care systems. Ambulatory emergency care and its various international models are recognized as contributing to the safety and sustainability of emergency care services. This schema can logically be extended to the emergency oncology setting. The recent proliferation of immune checkpoint inhibitors (ICIs) has led to another opportunity for the management of oncologic complications in the ambulatory emergency care setting. More nuanced risk stratification of currently perceived high-risk toxicities may also afford the opportunity to personalize acute management. Virtual wards, which predominantly provide virtual monitoring only, and hospital at home services, which provide more comprehensive in-person assessment and interventions, may be well suited to supporting care for ICI toxicity alongside hospital-based assessment. Emergency management guidelines for immune-mediated toxicities will increasingly need to be both pragmatic and deliverable, especially as larger numbers of patients will present outside cancer centers. Identifying and modelling those suitable for emergency ambulatory care is integral to achieving this.

Improved outcomes with early immunosuppression in patients with immune-checkpoint inhibitor induced myasthenia gravis, myocarditis and myositis: a case series.

PURPOSE: Myasthenia gravis (MG) is a rare but life-threatening complication of immune-checkpoint inhibitor (ICI) therapy and often co-presents with myositis and myocarditis. Previous case series of ICI-related MG have reported high mortality rates. We present a series of ten patients from a tertiary oncology centre outlining outcomes of an early multi-modal immunosuppression strategy. METHODS: We reviewed The Christie Hospital database of immunotherapy-related toxicity from 2017 to 2020. Symptom severity was assessed using the Myasthenia Gravis Foundation of America (MGFA) classification. RESULTS: Ten patients with ICI-related MG were identified. All patients presented following 1 (n = 4) or 2 (n = 6) cycles of ICI. Symptom progression was rapid with a median of 3 days from onset of symptoms to admission. Concomitant myositis and myocarditis were observed in nine patients. AChR or MuSK autoantibodies were positive in six patients. All patients received urgent treatment with intravenous methylprednisolone (IVMP) and eight received intravenous immunoglobulin (IVIG). A single patient died from myasthenia-related symptoms; the remaining 9 patients were successfully discharged. CONCLUSION: In our cohort, we demonstrate good outcomes associated with early intensive immunosuppressive treatment with IVIG and IVMP. An agreed national treatment protocol or clinical discussion forum would be beneficial.

Performance of admission pathways within acute medicine services: Analysis from the Society for Acute Medicine Benchmarking Audit 2022 and comparison with performance 2019 - 2021.

Urgent and emergency care services face increasing pressure, impacting patient care. We evaluated the performance of acute medicine services, assessing clinical quality indicators for unplanned medical admissions to acute hospital services. 152 acute UK hospital services accepting unplanned admissions to acute and general internal medicine completed a day-of-care survey incorporating organisational structure questionnaire and patient-level data over a pre-defined 24-hour period in June 2022. Clinical quality indicators were: Early Warning Score (EWS) measurement within 30 min of hospital arrival; clinician assessment within 4 h; assessment by consultant physician within 6 h (daytime) or 14 h (night-time). Results were compared with 2019, 2020, 2021. 7293 sequential patients were included (and compared with 19,817 patients across 2019-2021). In 2022, 69% of patients (95%CI 67.7-69.9%) had an EWS documented within 30 min. 79% of patients (95%CI 77.8-79.7%) were reviewed by a clinical decision maker within 4 h of hospital arrival. Patients assessed in Same Day Emergency Care services were more likely to meet this target than those assessed in Acute Medical Units or Emergency Departments (OR 2.4, 95%CI 2.02-2.87, p<0.001). Overall, 50% of patients received consultant physician review within the target time (3065/6161, 95%CI 48.5-51.0%); performance varied with time of arrival and location of initial assessment. Performance against all three clinical quality indicators was lower than 2019, 2020 and 2021 (p<0.001 for all). Performance against all quality indicators within acute medicine services is deteriorating. However, performance in Same Day Emergency Care Units is greater than in Acute Medical Units or Emergency Departments.

National Early Warning Scores Following Emergency Hospital Transfer: Implications for Care Home Residents.

OBJECTIVE: Care home residents have high rates of hospital admission. The UK National Early Warning Score (NEWS2) standardizes the secondary care response to acute illness. However, the ability of NEWS2 to predict adverse health outcomes specifically for care home residents is unknown. This study explored the relationship between NEWS2 on admission to hospital and resident outcome 7 days later. DESIGN: Repeated cross-sectional study. SETTING AND PARTICIPANTS: Data on UK care home residents admitted to 160 hospitals in two 24-hour periods (2019 and 2020). METHOD: Chi-squared and Kruskal-Wallis tests, and multinomial regression were used to explore the association between low (score ≤2), intermediate (3-4), high (5-6), and critically high (≥7) NEWS2 on admission and each of the following: discharge on day of admission, admission and discharge within 7 days, prolonged hospital admission (>7 days), and death. RESULTS: From 665 resident admissions across 160 hospital sites, NEWS2 was low for 54%, intermediate for 18%, high for 13%, and critically high for 16%. The 7-day outcome was 10% same-day discharge, 47% admitted and subsequently discharged, 34% remained inpatients, and 8% died. There is a significant association between NEWS2 and these outcomes (P < .001). Compared with those with low NEWS2, residents with high and critically high NEWS2 had 3.6 and 9.5 times increased risk of prolonged hospitalization [relative risk ratio (RRR) 3.56; 95% CI 1.02-12.37; RRR 9.47; CI 2.20-40.67], respectively. The risk of death was approximately 14 times higher for residents with high NEWS2 (RRR 13.62; CI 3.17-58.49) and 54 times higher (RRR 53.50; CI 11.03-259.54) for critically high NEWS2. CONCLUSION AND IMPLICATIONS: Higher NEWS2 measurements on admission are associated with an increased risk of hospitalization up to 7 days duration, prolonged admission, and mortality for care home residents. NEWS2 may have a role as an adjunct to acute care decision making for hospitalized residents.

Immune checkpoint inhibitor-mediated hypophysitis: no place like home.

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium <125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.

Intensive care unit requirements in patients treated with immune checkpoint inhibitors.

OBJECTIVE: To determine the proportion of emergency patients treated with immune checkpoint inhibitors (ICIs) that require critical care admission and their requirements. DESIGN: Prospective case series. METHODS: Analysis of acutely unwell patients treated with ICIs attending a tertiary UK cancer hospital between May 2018 and May 2022. The primary outcome measure was the percentage of patients treated with ICI therapy requiring ICU admission. The secondary outcome measure was whether this need was driven by an immune-mediated toxicity. RESULTS: Eighteen (1.2%) patients of the 1561 acutely admitted patients treated with ICI therapy required an admission to ICU. Ten (55.5%) patients were admitted due to an immune-mediated toxicity; four due to pneumonitis and four due to myasthenia gravis. Seven of 10 survived their ICU admission with 6 surviving at least 6-month post-ICU discharge. CONCLUSIONS: Only a small minority of emergency admissions in patients treated with ICIs require admission to ICU. This series adds further evidence that patients with organ failure due to immune-mediated toxicity may achieve good outcomes from ICU admission.

The impact of frailty and geriatric syndromes on metrics of acute care performance: results of a national day of care survey.

Background: Frailty is associated with a range of adverse clinical outcomes in the acute hospital setting. We sought to determine whether frailty and related factors affected clinical processes such as time to assessment during emergency hospital admission within the National Health Service (NHS) in the UK. Methods: The Society for Acute Medicine Benchmarking Audit (SAMBA) is an annual cross-sectional day of care survey. SAMBA 2022 was conducted on Thursday 23rd June 2022. We assessed whether the Clinical Frailty Scale (CFS) and presence of a geriatric syndrome affected performance against nationally recognised clinical quality indicators based on time to initial assessment and time to consultant review. CFS was graded into robust (CFS1-3), mild (CFS 4-5), moderate (CFS 6), severe (CFS7-8) and terminal illness (CFS 9). Plausible values were created for missing variables using multi-level multiple imputation. The association was described using mixed effect generalised linear models adjusting for initial National Early Warning Score 2 (NEWS2) and time of arrival. Findings: A total of 152 hospitals provided patient level data relating to 7248 emergency medical admissions. Patients with mild, moderate and severe frailty were less likely to be assessed within 4 h of arrival (adjusted OR, mild 0.79, 95% CI 0.68-0.96, moderate 0.67 95% CI 0.53-0.84, severe, 0.75 95% CI 0.58-0.96, terminally ill 0.59 95% CI 0.23-1.43) and less likely to be achieve the clinical quality indicator for consultant review (adjusted OR, mild 0.69 95% CI 0.58-0.83, moderate 0.55 95% CI 0.44-0.70, severe 0.54 95% CI 0.41-0.69, terminally ill 0.76 95% CI 0.42-1.5). Patients with geriatric syndromes were also less likely to be assessed within 4 h of arrival (adjusted OR 0.66 95% CI 0.56-0.76) or by a consultant within the recommended time frame (adjusted OR 0.45 95% CI 0.39-0.51). The difference was partially explained by differential use of SDEC pathways. Sub-group analysis of 5148 patients assessed outside of SDEC areas demonstrated patients with geriatric syndromes (adjusted OR 0.71, 95% CI 0.60-0.83), but not frailty defined by CFS were less likely to be assessed within 4 h of arrival. Moderate and severe frailty and the presence of a geriatric syndrome were associated with a decreased likelihood of achieving the consultant review standard (moderate, adjusted OR 0.75, 95% CI 0.59-0.94, severe adjusted OR 0.75 95% CI 0.58-0.96, geriatric syndrome adjusted OR 0.59, 95% CI 0.50-0.69). Interpretation: Frailty is associated with delayed clinical assessment. This association may suggest a systemic issue with clinical prioritisation, with important implications for acute care policy. Funding: The database for SAMBA is funded by the Society for Acute Medicine.

Immune checkpoint inhibitor-mediated hypophysitis: no place like home.

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium <125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.

Guest Editorial - Curry clubs, uncertain times, and social media.

COVID-19, the eternal hospital winter, heatwaves, global warming, energy costs, inflation, and an unnecessary war. We truly do live in uncertain times. That said, we would wager our grandparents said the same thing. What gets us through is family, friends and out shared communities, including acute medicine. Which brings us to this edition of the journal, where many excellent articles will hopefully distract our reader from all the doom and gloom, and instead light up your grey cells.