Management of immune-related adverse events resulting from immune checkpoint blockade

Introduction: Immune checkpoint inhibitors (ICI) are now a standard of care in the treatment of many cancers leading to durable responses in patients with metastatic disease. These agents are generally well tolerated but may lead to the occurrence of immune-related adverse events (irAEs). As any organ may be affected, clinicians should be aware of the broad range of clinical manifestations and symptoms and keep in mind that toxicities may occur late, at any point along a patient’s treatment course. Although the most common irAEs are rarely severe, some of them may be associated with great morbidity and even become life-threatening. The rate of occurrence, type and severity of irAEs may vary with the type of ICI; thus, grade 3 and 4 irAEs are reported in more than 55% of patients treated with the combination of ipilimumab 3 mg/kg and nivolumab 1 mg/kg.

Area covered: This review presents the management of irAEs resulting from checkpoint blockade, with a focus on rare irAEs.

Expert commentary: With the development of immuno-oncology and the expanding role of ICI, physicians have learnt to diagnose and treat most of the irAEs that can occur. This review provides an overview of current guidelines, previously published studies and our multidisciplinary team based practices.     

C.B‐17 SCID mice develop epicardial calcinosis with unaltered cardiac function

Inbred mouse strains are the most widely used mammalian model organism in biomedical research owing to ease of genetic manipulation and short lifespan; however, each inbred strain possesses a unique repertoire of deleterious homozygous alleles that can make a specific strain more susceptible to a particular disease. In the current study, we report dystrophic cardiac calcinosis (DCC) in C.B‐17 SCID male mice at 10 weeks of age with no significant change in cardiac function. Acquisition of DCC was characterized by myocardial injury, fibrosis, calcification, and necrosis of the tissue. At 10 weeks of age, 38% of the C.B‐17 SCID mice from two different commercial colonies exhibited significant calcinosis on the ventricular epicardium, predominantly on the right ventricle. The frequency of calcinosis was more than 50% for mice obtained from Taconic's Cambridge City colony and 25% for mice obtained from Taconic's German Town colony. Interestingly, the DCC phenotype did not affect cardiac function at 10 weeks of age. No differences in echocardiography or electrocardiography were observed between the calcinotic and non‐calcinotic mice from either colony. Our findings suggest that C.B‐17 SCID mice exhibit DCC as early as 10 weeks of age with no significant impact on cardiac function. This strain of mice should be cautiously considered for the study of cardiac physiology.     

Demonstration of a modelling-based multi-criteria decision analysis procedure for prioritisation of occupational risks from manufactured nanomaterials

Several tools to facilitate the risk assessment and management of manufactured nanomaterials (MN) have been developed. Most of them require input data on physicochemical properties, toxicity and scenario-specific exposure information. However, such data are yet not readily available, and tools that can handle data gaps in a structured way to ensure transparent risk analysis for industrial and regulatory decision making are needed. This paper proposes such a quantitative risk prioritisation tool, based on a multi-criteria decision analysis algorithm, which combines advanced exposure and dose-response modelling to calculate margins of exposure (MoE) for a number of MN in order to rank their occupational risks. We demonstrated the tool in a number of workplace exposure scenarios (ES) involving the production and handling of nanoscale titanium dioxide, zinc oxide (ZnO), silver and multi-walled carbon nanotubes. The results of this application demonstrated that bag/bin filling, manual un/loading and dumping of large amounts of dry powders led to high emissions, which resulted in high risk associated with these ES. The ZnO MN revealed considerable hazard potential in vivo, which significantly influenced the risk prioritisation results. In order to study how variations in the input data affect our results, we performed probabilistic Monte Carlo sensitivity/uncertainty analysis, which demonstrated that the performance of the proposed model is stable against changes in the exposure and hazard input variables.     

Predicting Renal Function Outcomes After Partial and Radical Nephrectomy

Background

Partial nephrectomy (PN) is generally favored for cT1 tumors over radical nephrectomy (RN) when technically feasible. However, it can be unclear whether the additional risks of PN are worth the magnitude of renal function benefit.

A Novel Nomogram to Identify Candidates for Extended Pelvic Lymph Node Dissection Among Patients with Clinically Localized Prostate Cancer Diagnosed with Magnetic Resonance Imaging-targeted and Systematic Biopsies

Background

Available models for predicting lymph node invasion (LNI) in prostate cancer (PCa) patients undergoing radical prostatectomy (RP) might not be applicable to men diagnosed via magnetic resonance imaging (MRI)-targeted biopsies.

Accuracy evaluation of image registration and segmentation tools used in conformal treatment planning of prostate cancer.

Segmentation and registration tools are commonly used in radiotherapy for target and at risk organs localisation. In this work the performances of three different segmentation tools and of a surface matching registration technique, used on computed tomography (CT) and magnetic resonance (MR) images for the treatment planning of conformal prostate carcinoma, are studied. The accuracy of the segmentation and registration tools was evaluated by phantom experiment and on patient data, respectively. A preliminary estimate of MR image distortion was also performed.     

Chronic treatment with scopolamine and physostigmine changes nerve growth factor (NGF) receptor density and NGF content in rat brain

Nerve growth factor (NGF) and NGF receptors were measured in cortex and hippocampus of rats treated with drugs affecting cholinergic neurotransmission. High (K_d= 0.045nM) and low (K_d= 21nM) affinity¹²⁵I-NGF binding sites were present in both cortical and hippocampal membranes with hippocampus containing higher numbers of both sites than cortex. Chronic treatment of rats with the muscarinic receptor antagonist scopolamine (5 mg/kg, twice daily) decreased the density of high- and low-affinity sites by 50–90% in cortical and hippocampal membranes. These changes were seen after 7 days, but not 3 days, of scopolamine treatment. Chronic infusion of physostigmine (1 mg/kg/day) using minipumps increased the number of high- and low-affinity sites in cortex 3- and 6-fold, respectively. The changes in receptor-binding parameters induced by physostigmine were transient as they were evident after 3 days of treatment, but returned to control levels after 7 days. NGF content in cortex and hippocampus was reduced by about 50% following 7, but not 3, days of chronic physostigmine infusion. In contrast, scopolamine treatment failed to change NGF levels in the cholinergic neuronal target regions but it decreased NGF content in the septal area. The content of NGF mRNA in the cortex measured by Northern blot analysis failed to change following either scopolamine or physostigmine treatment. The results suggest that levels of NGF and NGF receptors in the target regions of cholinergic neurons are regulated by the extent of cholinergic neurotransmitter activity.