Need for aligning the definition and reporting of cytokine release syndrome (CRS) in immuno-oncology clinical trials.

As cancer immunotherapies continue to expand across all areas of oncology, it is imperative to establish a standardized approach for defining and capturing clinically important toxicities, such as cytokine release syndrome (CRS). In this paper, we provide considerations for categorizing the variety of adverse events that may accompany CRS and for recognizing that presentations of CRS may differ among various immunotherapies (e.g., monoclonal antibodies, CAR T cell therapies and T cell engagers, which can include bispecific antibodies and other constructs). The goals of this paper are to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable more precise evaluation of the therapeutic risk-benefit profile and cross-study analyses; support evidence-based monitoring and management of important toxicities related to cancer immunotherapies; and improve patient care and outcomes. These efforts will become more important as the number and variety of molecular targets for immunotherapies broaden and as therapies with novel mechanisms continue to be developed.

Incidence of second primary malignancies in relapsed/refractory B-cell non-Hodgkin's lymphoma patients in England.

BACKGROUND: Treatments for relapsed/refractory (r/r) B-cell non-Hodgkin's lymphoma (NHL) may be associated with an increased risk of second primary malignancies (SPMs). Currently available SPM incidence benchmarks are unreliable due to small sample sizes. METHODS: The Cancer Analysis System (CAS), a population-level cancer database in England, was used to identify patients with incident B-cell NHL diagnosed during 2013-2018 with evidence of r/r disease. Incidence rates (IRs) of SPMs after r/r disease diagnosis were calculated per 1000 person-years (PYs) and stratified by age, sex, and SPM type. RESULTS: We identified 9444 patients with r/r B-cell NHL disease. Of those who were eligible for SPM analysis, nearly 6.0% (470/7807) developed at least one SPM after r/r disease diagnosis (IR: 44.7; 95% confidence interval [CI]: 40.9-48.9). Of note, 205 (2.6%) had a non-melanoma skin cancer (NMSC) SPM. IR of SPMs was the highest for patients with r/r chronic lymphocytic leukemia/small lymphocytic leukemia (80.0) and lowest for diffuse large B-cell lymphoma (DLBCL) (30.9). Patients with DLBCL had the shortest overall survival after r/r disease diagnosis. CONCLUSIONS: This real-world data study suggests that the IR of SPM among patients with r/r B-cell NHL is 44.7 per 1000 PY and that most SPMs diagnosed after r/r disease diagnosis are NMSCs, establishing a basis for the comparison of safety outcomes for new treatments being developed for r/r B-cell NHL.

Postmarketing hepatic adverse event experience with PEGylated/non-PEGylated drugs: a disproportionality analysis.

OBJECTIVE: To compare reporting frequencies of hepatic adverse events between PEGylated and non-PEGylated formulations of active medicinal compounds in spontaneous reporting systems using a data mining algorithm (DMA). METHODS: Statistical DMAs are being promoted as a means of identifying drug-event combinations that are disproportionately reported in large spontaneous reporting systems databases, a critical data source for pharmacovigilance. After a review of case reports of hepatotoxicity with PEGylated drugs possibly associated with the polyethylene glycol moiety, we carried out a retrospective disproportionality analysis of WHO's multinational drug safety database for events related to hepatic dysfunction comparing PEGylated versus non-PEGylated formulations of four active moieties. A threshold of posterior interval (PI) 95% lower limit >0 was used to define a signal of disproportionate reporting with a drug and an event and 90% PIs of the information component were compared to identify statistical differences between the two compounds. RESULTS: On the basis of a total of 18 477 cases containing at least one of the drug pairs, we found disproportionate reporting for hepatic-related events with both PEGylated and non-PEGylated formulations. Overlapping of 90% PIs of the information components, however, suggested that there was no statistically significant difference between the frequency of hepatic injury reported with PEGylated versus non-PEGylated drug formulations. CONCLUSION: We did not find significant indicators of differential reporting of hepatic injury between PEGylated and non-PEGylated drug formulations in this exploratory analysis using one DMA. The analysis also suggests that comparative disproportionality methodology although not in itself determinative, could be one useful component of a risk management plan for monitoring the postmarketing experience of drug delivery systems that uses multiple methods and data streams.

Hospital Accident and Emergency burden is unaffected by today's air pollution levels.

OBJECTIVES: Fifty years after the London smog incident, the Milan area (Italy) is still experiencing an air pollution emergency every winter, widely reported in the public media, complete with technical and political discussion, and well-studied short-term associations between air pollution and mortality and hospital admissions. The influence of air pollution on the daily activity of an Accident and Emergency Department have rarely been investigated, other than looking at hospital admissions. METHODS: To assess the possible effects of high air pollution levels we studied 9881 residents requiring care at the hospital Accident and Emergency triage of Vimercate, a city north of Milan with 25 600 inhabitants during one year. RESULTS: There was no correlation between the number of daily Accident and Emergency admissions and the daily mean of particulate matter less than 10 microm (PM), with a relative risk of 0.97 (95% confidence interval 0.67-1.41) for a 5th to 95th percentile variation of the PM, even after correcting for the day of the week, holidays and climate factors such as temperature and humidity. CONCLUSION: Air pollution, although still frequently high and relevant to the health of the population, is not easily recognizable on a small scale, such as a single hospital, and does not affect daily Accident and Emergency activities.

Age, a predictive factor for the reduction in the mean transmitral pressure gradient after percutaneous balloon mitral valvotomy.

BACKGROUND: The aim of this study was to evaluate the changes in mitral valve area and mean transmitral pressure gradient before and after percutaneous balloon mitral valvotomy and at 2 years of follow-up. We hypothesized that the patient's age would be an important determinant for the success of balloon valvotomy. METHODS: We studied 24 patients with mitral stenosis (6 men and 18 women with an average age of 58 years, range 39 to 80 years), who underwent percutaneous balloon mitral valvotomy. Two-dimensional and Doppler echocardiographic examinations were taken before, immediately after and at a mean follow-up of 24 months (range 12 to 73 months). The correlation between the changes in the mitral valve area or mean transmitral pressure gradient and age was assessed with rank correlation and with stepwise multiple linear regression analysis correcting for sex, days of follow-up, heart rate score, pulmonary hypertension, mitral regurgitation and Wilkins score at follow-up. RESULTS: Changes in the mitral valve area did not correlate with age. The reduction in mean transmitral pressure gradient at follow-up was associated with age with a 20.6% less reduction in mean transmitral pressure gradient (95% confidence interval 3.5-40.4%, p < 0.021) for every other year of the patients' age. When comparing changes in mean transmitral pressure gradient before and after percutaneous balloon mitral valvotomy, the strength and consistency of the association with age appeared similar (mean transmitral pressure gradient -0.9 +/- 3.0 vs -2.8 +/- 3.4 mmHg). CONCLUSIONS: Age is a predictive factor for the reduction in mean transmitral pressure gradient after percutaneous balloon mitral valvotomy. This suggests that a better outcome is to be expected in younger patients, independently of the list of factors taken into consideration in our study.

Patterns of respiratory drug use in the Lombardy region of Italy, 1995-1997.

OBJECTIVE: To examine the patterns of respiratory drugs use in the Lombardy region of Italy, and to quantify the period prevalence of different drug-dose combinations defined by reference to international guidelines for prescription in asthma and chronic obstructive pulmonary disease. DESIGN: Analysis of records from an anonymised population-based database of dispensed prescriptions. SETTING: Lombardy, 1995-1997. METHODS: Analyses were made of prescription records of patients who had at least one respiratory drug dispensed during the study period. Prescriptions for the same individual were linked using a unique identifier. MAIN OUTCOMES: Number of patients using respiratory drugs; number of visits to the pharmacy; defined daily doses. MAIN RESULTS: 1,387,004 or 15.5% of the resident Lombardy population had at least one dispensed prescription of a respiratory drug in the three years of study. The annual percentage increased from 6.6% in 1995 to 7.9% in 1997. 808,786 patients (58.3% of respiratory drug users) had only one visit to the pharmacy during this period, while the 25.1% of respiratory drug-user (3.9% of the resident population) who had three or more visits to the pharmacy in three years, accounted for 86.1% of all respiratory drug use in terms of defined daily doses. When combinations of prescribed drugs were examined in the light of published guidelines, we estimated that <2.8%> of the population had patterns of drug prescription appropriate for mild intermittent or persistent forms of asthma/chronic obstructive pulmonary disease, and <1.1%> had prescription patterns appropriate for moderate or severe disease. CONCLUSIONS: The definition of specific drug use patterns by individual can provide prevalence measures that are broad proxies for varying categories of respiratory disease. However, a very high proportion of people who receive respiratory drugs do so for one-off or very infrequent episodes of illness. Analysis of the infrequent and more regular users of respiratory drugs may be useful for comparative research.

Air pollution and respiratory drug use in the city of Como, Italy.

UNLABELLED: STUDY OBJECTIVE AND SETTING: Particulate air pollution has a known negative effect on human respiratory health, often studied with hospital admissions, emergency room access, or mortality as health indicators. We evaluate respiratory drug dispensing data as health indicators for the effects of total suspended particles (TSP) air pollution in the city of Como (84,713 inhabitants). DESIGN: Weekly count of individual patients with respiratory drug dispensed (Cases) and weekly dispensed daily defined doses (DDD) of drugs were modelled with weekly air mean concentrations of TSP using a Poisson regression model adjusted for long-term trends, seasonal variations, calendar variations due to holidays, and weather. MAIN RESULT: Relative risks (RR) were expressed for a variation from 10th to 90th percentile of TSP (29-92 microg/m3). Weekly aggregation was used in consideration of the complexity of drug dispensing data and potential biases of daily aggregation. For weekly mean concentrations of TSP, RR = 1.082 (95% Confidence level (CI) 1.002-1.169) for Cases and RR = 1.137 (95% CI 1.044-1.238) for DDD. CONCLUSION: Our study concludes that both Cases and DDD of dispensed respiratory drugs could be useful for epidemiological surveillance of air pollutant health effects. Further investigation may routinely allow health and economics considerations, producing a stimulating new tool for health policy makers.