Immune Checkpoint Inhibitors and Cardiotoxicity: A Comparative Meta-Analysis of Observational Studies and Randomized Controlled Trials.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have uncommon associations with cardiotoxicity, yet these cardiotoxic effects are associated with high mortality. An accurate assessment of risk for cardiotoxicity is essential for clinical decision-making, but data from randomized controlled trials often differ from real-world observational studies. METHODS AND RESULTS: A systematic search of PubMed, Embase, Cochrane Library, and Scopus was performed, including phase II and III randomized controlled trials (RCTs) and observational studies (OSs) reporting myocarditis or pericardial disease, myocardial infarction, or stroke with an immunotherapy. Odds ratios (ORs) were used to pool results between ICIs and other cancer therapy in RCTs and OSs. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline was followed. In total, 54 RCTs (N=38 264) and 24 OSs (N=12 561 455) were included. In RCTs, ICI use resulted in higher risk of myocarditis (OR, 3.55 [95% CI, 2.10-5.98]), pericardial disease (OR, 2.73 [95% CI, 1.57-4.77]), and myocardial infarction (OR, 1.83 [95% CI, 1.03-3.25]), compared with non-ICI (placebo or chemotherapy). In OSs, ICI use was not associated with myocarditis, pericardial disease, or myocardial infarction compared with controls; however, combination ICIs demonstrated higher risk of myocarditis compared with single ICI use (OR, 3.07 [95% CI, 1.28-7.39]). Stroke risk was not increased with use of ICIs in RCTs. CONCLUSIONS: We demonstrated increased risk of ICI myocarditis, pericardial disease, and myocardial infarction in RCTs but not OSs. Results of this study suggest there are differences between ICI cardiotoxicity risk, possibly suggesting differences in diagnoses and management, in clinical trials versus the OSs.

Eosinophilic granulomatosis with polyangiitis and its association with montelukast: a case-based review.

The association between the use of certain medications (including sulfonamides, hydralazine, and procainamide) and the occurrence of drug-induced lupus or hepatitis is well established. More recently, cases of immune-related adverse events ranging from inflammatory polyarthritis to necrotizing myositis in patients taking checkpoint inhibitors have been reported. However, data linking drugs to systemic vasculitis are scarce and at times debatable. Propylthiouracil, hydralazine, and minocycline have been associated with rare cases of ANCA-associated syndromes, including life-threatening pulmonary-renal syndromes and systemic polyarteritis nodosa-like diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has been reported in patients taking leukotriene inhibitors. Since the link between the use of leukotriene inhibitors and occurrence of EGPA remains highly controversial, we performed a literature review for cases of EGPA in patients taking montelukast without prior history of oral corticosteroid use. We found 24 cases, along with our own two cases described, making 26 cases in total. The mean age was 43 and a majority (18/26) were female. In majority of cases EGPA-like disease never relapsed after they were taken off leukotriene inhibitors suggesting a clear causal relationship between the use of these drugs and occurrence of eosinophil-rich systemic EGPA.

Cardiac pseudoaneurysms: a clinical case series.

Background: Cardiac pseudoaneurysms are a potentially life-threatening pathology with a variety of non-specific clinical manifestations. This case series uniquely shares a collection of rare pathologies with differing preceding risk factors and presentations, with an emphasis on the utility of multi-modality imaging in diagnosis and management. Case summary: We present three cases of cardiac pseudoaneurysms. Case 1 is a 27-year-old woman with delayed presentation of a traumatic left ventricular pseudoaneurysm (LVP). Case 2 is a 73-year-old man with post-myocardial infarction LVP. Case 3 is a 38-year-old man with left ventricular outflow tract pseudoaneurysm after aortic valve replacement. Discussion: Cardiac pseudoaneurysms are rare and important to diagnose in a timely manner. Advances in non-invasive imaging modalities have improved our ability to distinguish pseudoaneurysms from other pathologies, leading to more timely management.

Better Late Than Never.

Symptomatic bradycardia may be iatrogenic or from a conduction system abnormality. Here we show an interesting case of iatrogenic symptomatic bradycardia that may be confused with a conduction system abnormality. (Level of Difficulty: Advanced.).

Ultrafast non-radiative decay of gas-phase nucleosides.

The ultrafast photo-physical properties of DNA are crucial in providing a stable basis for life. Although the DNA bases efficiently absorb ultraviolet (UV) radiation, this energy can be dissipated to the surrounding environment by the rapid conversion of electronic energy to vibrational energy within about a picosecond. The intrinsic nature of this internal conversion process has previously been demonstrated through gas phase experiments on the bases, supported by theoretical calculations. De-excitation rates appear to be accelerated when individual bases are hydrogen bonded to solvent molecules or their complementary Watson-Crick pair. In this paper, the first gas-phase measurements of electronic relaxation in DNA nucleosides following UV excitation are reported. Using a pump-probe ionization scheme, the lifetimes for internal conversion to the ground state following excitation at 267 nm are found to be reduced by around a factor of two for adenosine, cytidine and thymidine compared with the isolated bases. These results are discussed in terms of a recent proposition that a charge transfer state provides an additional internal conversion pathway mediated by proton transfer through a sugar to base hydrogen bond.

Detection limits of organic compounds achievable with intense, short-pulse lasers.

Many organic molecules have strong absorption bands which can be accessed by ultraviolet short pulse lasers to produce efficient ionization. This resonant multiphoton ionization scheme has already been exploited as an ionization source in time-of-flight mass spectrometers used for environmental trace analysis. In the present work we quantify the ultimate potential of this technique by measuring absolute ion yields produced from the interaction of 267 nm femtosecond laser pulses with the organic molecules indole and toluene, and gases Xe, N2 and O2. Using multiphoton ionization cross sections extracted from these results, we show that the laser pulse parameters required for real-time detection of aromatic molecules at concentrations of one part per trillion in air and a limit of detection of a few attomoles are achievable with presently available commercial laser systems. The potential applications for the analysis of human breath, blood and tissue samples are discussed.

A novel experimental approach to investigate radiolysis processes in liquid samples using collimated radiation sources.

Here is detailed a novel and low-cost experimental method for high-throughput automated fluid sample irradiation. The sample is delivered via syringe pump to a nozzle, where it is expressed in the form of a hanging droplet into the path of a beam of ionising radiation. The dose delivery is controlled by an upstream lead shutter, which allows the beam to reach the droplet for a user defined period of time. The droplet is then further expressed after irradiation until it falls into one well of a standard microplate. The entire system is automated and can be operated remotely using software designed in-house, allowing for use in environments deemed unsafe for the user (synchrotron beamlines, for example). Depending on the number of wells in the microplate, several droplets can be irradiated before any human interaction is necessary, and the user may choose up to 10 samples per microplate using an array of identical syringe pumps, the design of which is described here. The nozzles consistently produce droplets of 25.1 ± 0.5 µl.