The efficacy and toxicity of immune checkpoint inhibitors in a real-world older patient population

ImportanceImmunotherapy has emerged as an effective treatment option for the management of advanced cancers. The effects of these immune checkpoint inhibitors in the older patient population has not been adequately assessed.ObjectiveTo understand the impact of aging on CTLA-4 and PDL-1 inhibitors efficacy and immune-related adverse events (irAE) in the context of real-world management of advanced solid cancers.Design, Setting, and ParticipantsThis retrospective study involved all non-study patients with histologically-confirmed metastatic or inoperable solid cancers receiving immunotherapy at Kingston Health Sciences Centre. We defined ‘older patient’ as age ≥ 75. All statistical analyses were conducted under SPSS IBM for Windows version 24.0.Main Outcomes and MeasuresStudy outcomes included immunotherapy treatment response, survival, as well as number, type, and severity of irAEs.ResultsOur study (N = 78) had 29 (37%) patients age <65, 26 (33%) patients age 65–74, and 23 (30%) patients age ≥75. Melanoma, non-small cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the study population, respectively. Distributions of ipilimumab (32%), nivolumab (33%), and pembrolizumab (35%) were similar in the study. The response rates were 28%, 27%, and 39% in the age <65, age 64–74, age ≥75 groups, respectively (P = 0.585). Kaplan-Meier curve showed a median survival of 28 months (12.28–43.9, 95% CI) and 17 months (0–36.9, 95% CI) in the age <65 and age 64–74 groups, respectively; the estimated survival probability did not reach 50% in the age ≥75 group (P = 0.319). There were no statistically significant differences found in terms of irAEs, multiple irAEs, severity of grade 3 or higher, types of irAEs, and irAEs resolution status when comparing between different age groups.Conclusion and RelevanceOur results suggest that patients age ≥75 are able to gain as much benefit from immunotherapy as younger patients, without excess toxicity. Our findings suggest that single agent immunotherapy is generally well-tolerated across different age groups with no significant difference in the type, frequency or severity of irAEs. Future studies evaluating aging and combination immunotherapy are warranted.     

Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Diet and nutrition against inflammatory bowel disease: Trick or treat(ment)?

Even if the relationships between nutrition and inflammatory bowel disease (IBD) remain underexplored, the current literature is providing, day by day, much more evidence on the effects of various diets in both prevention and treatment of such illnesses. Wrong dietary habits, together with other environmental factors such as pollution, breastfeeding, smoke, and/or antibiotics, are among the theoretical pathogenetic causes of IBD, whose multifactorial aetiology has been already confirmed. While some of these risk factors are potentially reversible, some others cannot be avoided, and efficient treatments become necessary to prevent IBD spread or recurrence. Furthermore, the drugs currently available for treatment of such disease provide low-to-no effect against the symptoms, making the illnesses still strongly disabling. Whether nutrition and specific diets will prove to effectively interrupt the course of IBD has still to be clarified and, in this sense, further research concerning the applications of such dietary interventions is still needed.     

Factors influencing choice of medical vs. surgical treatment of pediatric appendicitis

PurposeTo examine what proportion of caregivers, if given a choice, would choose medical versus surgical treatment of appendicitis and what factors would be important in their decision.MethodsA survey was devised and given to the caregivers of children presenting to the pediatrician for a routine visit in community and academic pediatric clinics. The survey presented a summary of outcomes after medical (non-operative) and surgical treatment of uncomplicated appendicitis. Participants were then asked to choose medical versus surgical treatment if their child were to develop appendicitis. They were also asked to rate the importance of certain factors in their decision ? 1 being “not important” and 5 being “very important”.ResultsFour hundred surveys were distributed with an 86.2% (345/400) response rate. Six percent (21/342) of respondents reported a history of appendicitis and 49.4% (168/340) reported having known someone who had appendicitis. The majority of respondents, 85.3% (284/333), were mothers. A minority of respondents, 41.7% (95% CI: 36.7, 47.0), chose medical treatment over surgery for appendicitis. There was no statistical difference in the proportion of mothers (41.6%) versus fathers who chose medical treatment (41.3%). Caregivers who chose medical treatment were more likely to rate time in hospital (p = .008) and time out of school (p = 05) as important in decision making when compared with those who chose surgery. Those who chose surgical treatment were more likely to rate risk of recurrent appendicitis (p < .001) as important to decision making. In the multivariate analysis, those who rated time in hospital as very important had more than twice the odds of choosing medical therapy (OR 2.20, p = 0.02) when compared with those who rated it as less important. Not knowing someone who has had appendicitis was significantly associated with choosing medical therapy when compared with those who do know someone who has had appendicitis, OR 2.3, p = .002. Rating pain as very important was also significantly associated with choosing medical therapy, when compared to those rating pain 1–3, OR 3.38, p = .03.ConclusionsIn this survey of caregivers of children presenting for routine care, 41.7% would choose medical, or non-operative, therapy for their children with acute appendicitis. The risk of recurrence, time in hospital, and time out of school, pain, and knowing someone who has had appendicitis were all important factors that families may consider when making a decision. These data may be useful for surgeons counseling patients on which treatment to pursue.