Immunosenescence and Cancer: Cellular Aging Programs That Reshape Antitumor Immunity.

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

The ovarian immune system ages while coping with the two main challenges of the aging ovary before menopause, the inflammatory stimulations due to repeated cycles and the increasing need for clearance of accumulating atretic follicles.

Comparison of the Effect of Age (< 75 Versus ≥ 75) on the Efficacy and Safety of Dual Therapy (Dabigatran + Clopidogrel or Ticagrelor) Versus Triple Therapy (Warfarin + Aspirin + Clopidogrel or Ticagrelor) in Patients With Atrial Fibrillation After Percutaneous Coronary Intervention (from the RE-DUAL PCI Trial)

Comparative effectiveness of cardiac resynchronization therapy in older patients with heart failure: Systematic review and meta-analysis

The aim of this study was to identify the optimal anti-platelet therapy in older acute coronary syndrome (ACS) patients with a mean age ≥ 60 years by comparing the efficacy and safety of different anti-platelet therapies. The selection of antiplatelet therapy in older patients with ACS is a clinical challenge. Numerous evidences indicate that the de-escalation of dual anti-platelet therapy (DAPT) or P2Y12 inhibitor monotherapy may reduce bleeding risk without increasing thrombotic events. However, there is a lack of systematic reviews and optimal strategy analysis regarding older ACS patients. Randomized controlled trials (RCTs) of anti-platelet therapy in older ACS patients were identified. Major adverse cardiovascular events (MACE) were the primary outcome. Secondary outcomes included all death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and trial-defined major bleeding. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on posterior probability. Summary odds ratios (ORs) were estimated using Bayesian network meta-analysis. A total of 12 RCTs including 59,284 older ACS patients treated with five anti-platelet strategies were included. Ticagrelor monotherapy after 3 months DAPT was comparable to the other strategies (OR 0.73; 95% CI 0.32–1.6) in terms of MACE risk. Additionally, P score analysis and SUCRA Bayesian analysis showed that it was the most beneficial treatment for all deaths, cardiovascular death and revascularization. For safety, although there was no significant difference in direct comparisons, both SUCRA Bayesian (0.806) and P score (0.519) analysis suggested that ticagrelor monotherapy was the safest strategy. The current evidence demonstrated that ticagrelor monotherapy after 3 months DAPT may be a promising approach for achieving a more favorable balance between risk and benefit for older ACS patients, with a relatively low bleeding risk and without an increased risk of MACE events. Moreover, it remains the preferred option for clinical outcomes such as all death, CV death and revascularization. Further high-quality and long-term studies are required to validate anti-platelet therapies among older ACS patients.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal–Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3–4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

ABSTRACTThe risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated LDL‐cholesterol and non‐HDL‐cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co‐morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL‐cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid‐lowering with statins outweigh potential risks such as statin‐associated muscle symptoms and incident Type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin‐related cognitive effects. Shared decision‐making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non‐statin lipid‐lowering therapy in older patients are sparse. Deprescribing of lipid‐lowering agents may be appropriate for select patients older than 75 years with life‐limiting diseases. Finally, a patient‐centered approach should be taken when considering primary prevention strategies for older adults.

The risk of atherosclerotic cardiovascular disease increases with advancing age. Elevated low-density lipoprotein (LDL)-cholesterol and non-high-density lipoprotein (non-HDL)-cholesterol levels remain predictive of incident atherosclerotic cardiovascular events among individuals older than 75 years. Risk prediction among older individuals is less certain because most current risk calculators lack specificity in those older than 75 years and do not adjust for co-morbidities, functional status, frailty, and cognition which significantly impact prognosis in this age group. Data on the benefits and risks of lowering LDL-cholesterol with statins in older patients without atherosclerotic cardiovascular disease are also limited since most primary prevention trials have included mostly younger patients. Available data suggest that statin therapy in older primary prevention patients may reduce atherosclerotic cardiovascular events and that benefits from lipid-lowering with statins outweigh potential risks such as statin-associated muscle symptoms and incident type 2 diabetes mellitus. While some evidence suggests the possibility that statins may be associated with incident cognitive impairment in older adults, a preponderance of literature indicates neutral or even protective statin-related cognitive effects. Shared decision-making which is recommended for all patients when considering statin therapy is particularly important in older patients. Randomized clinical trial data evaluating the use of non-statin lipid-lowering therapy in older patients are sparse. Deprescribing of lipid-lowering agents may be appropriate for select patients older than 75 years with life-limiting diseases. Finally, a patient-centered approach should be taken when considering primary prevention strategies for older adults.

Dendritic Cell Infiltration In A Patient With Seminomatous Germ Cell Tumor Of The Testis: Is There A Relationship With Infertility And Tumor Stage?

Despite being prolific innate killers, NK cells are also key helper cells in antiviral defense, influencing adaptive immune responses via interactions with dendritic cells (DCs). In addition to causing NK cell dysfunction, HIV-1 infection contributes to the expansion of a rare population of NK cells deficient in FcRγ (FcRγ-), an intracellular adaptor protein that associates with CD16. The implications of this inflated NK cell subset in treated HIV-1 infection remain unclear. In this study, we explored the helper function of human NK cells in chronic HIV-1 infection, with a particular focus on characterizing FcRγ- NK cells. Exposure of NK cells to innate DC-derived costimulatory factors triggered their helper activity, defined by their ability to produce IFN-γ and to drive the maturation of high IL-12-producing DCs. In this setting, however, FcRγ- NK cells were defective at producing the dominant DC-polarizing agent IFN-γ. The reduced responsiveness of FcRγ- NK cells to IL-18 in particular, which was attributable to impaired inducible expression of IL-18Rα, extended beyond an inability to produce IFN-γ, as FcRγ- NK cells showed limited potential to differentiate into CD16-/CD25+/CD83+ helper cells. Notwithstanding their deficiencies in responsiveness to innate environmental cues, FcRγ- NK cells responded robustly to adaptive Ab-mediated signaling through CD16. The presence of an expanded population of FcRγ- NK cells with a diminished capacity to respond to IL-18 and to effectively modulate DC function may contribute to disturbances in proper immune homeostasis associated with HIV-1 infection and to defects in the initiation of optimal adaptive antiviral responses.

Tacrolimus: A new topical immunomodulatory therapy for atopic dermatitis

Macrophage- and Dendritic-Cell-Derived Interleukin-15 Receptor Alpha Supports Homeostasis of Distinct CD8+ T Cell Subsets

Older patients are becoming prevalent among people with heart failure (HF) as the overall population ages. However, older patients are largely under-represented, or even excluded, from randomised controlled trials on HF with reduced ejection fraction, limiting the generalisability of trial results in the real world and leading to weaker evidence supporting the use and titration of guideline-directed medical therapy (GDMT) in older patients with HF with reduced ejection fraction. This, in combination with other factors limiting the application of guideline recommendations, including a fear of poor tolerability or adverse effects, the heavy burden of comorbidities and the need for multiple therapies, classically leads to lower adherence to GDMT in older patients. Although there are no data supporting the under-use and under-dosing of HF medications in older patients, large registry-based studies have confirmed age as one of the major obstacles to treatment optimisation. In this review, the authors provide an overview of the contemporary state of implementation of GDMT in older groups and the reasons for the lower use of treatments, and discuss some measures that may help improve adherence to evidence-based recommendations in older age groups.

Protein tyrosine phosphatase nonreceptor type 2 (PTPN2) has emerged as a promising cancer immunotherapy target. Previously, we reported on the functional role of PTPN2 in the pathogenesis of colorectal carcinoma (CRC). We demonstrated increased PTPN2 phosphatase activity correlates with disease progression and decreased immune responses in tumor tissues, while loss of PTPN2 in T-cells or in dendritic cells (DCs) reduces tumor burden in several CRC models and potentiates anti-PD1 efficacy (Katkeviciute et al., 2021). Others reported that loss of PTPN2 in tumor cells sensitizes to immune-mediated tumor killing (Manguso et al., 2017; Goh et al., 2022). Thus, PTPN2 was proposed as a critical node to modulate anti-tumor immunity, and PTPN2 inhibition is expected to enhance anti-tumor immunity by sensitizing tumor cells and by activating immune cells. Recently, also the closely related phosphatase PTPN1 (PTP1B) was demonstrated to restrain T-cell mediated tumor killing (Wiede et al., 2022). Inhibition of Protein Tyrosine Phosphatases has historically been a demanding area for drug discovery. However, both allosteric PTP inhibitors (eg targeting SHP2/PTPN11) and catalytic-site inhibitors (targeting PTPN2/N1) have recently progressed to clinical studies. We now identified a chemical series of novel dual PTPN2/N1 inhibitors. These inhibitors bind to the catalytic site of PTPN2, as confirmed by crystallography. The best molecules of the series are low nM inhibitors of PTPN2 and PTPN1 enzymes with excellent selectivity across other phosphatases. As an immediate consequence of PTPN2/N1 inhibition, these compounds augment phosphorylation of STAT1 and/or STAT5 isoforms in myeloid and T-cell lines, and in primary T-cells, macrophages and DCs. This results in immune-cell activation as evidenced by increased production of effector cytokines (e.g. IFNγ), immune-activation, levels of cytotoxicity markers in T-cells (e.g. granzyme B) as well as upregulation of antigen presentation and co-stimulatory markers in macrophages and DCs. Furthermore, inhibition of PTPN2/N1 sensitizes murine and human cancer cell lines to IFNγ, and enhances immune-mediated tumor killing in co-culture assays in vitro. In vivo evaluation of selected examples is in progress and results will be presented at the conference. Our data indicate that inhibition of PTPN2/N1 phosphatase activity is a powerful pharmacologic strategy to promote anti-tumor immunity, with strong potential to be exploited for cancer immunotherapy both as a single agent treatment in anti-PD1 refractory cancers, and in combination with anti-PD1 therapy. Citation Format: Kalliopi Pervolaraki, Egle Katkeviciute, Dominique Lambin, Sandro Boland, Amuri Kilonda, Vincent Pericolle, Marnik Nijs, Wanda Haeck, Kristine Metzger, Hugo Klaassen, Arnaud Marchand, Patrick Chaltin, Matthias Versele, Marianne Spalinger, Michael Scharl. Discovery of potent and selective inhibitors of the protein tyrosine phosphatases PTPN2 and PTPN1 to trigger anti-tumor immunity through sensitization of tumor cells and activation of immune cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4038.

Older people with inflammatory bowel disease (IBD) appear to have a lower response to anti-tumour necrosis factor (TNF) therapy, with more frequent complications than younger patients. The objective of this study was to assess persistence on therapy and the safety of anti-TNF therapy in older patients (aged ≥60years). We retrospectively reviewed the database of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD), extracting data regarding IBD patients aged ≥ 60years and controls < 60years of age at their first course of anti-TNF treatment. Data concerning persistence on therapy over the first year of treatment (primary objective) together with data on reasons for treatment withdrawal, concomitant diseases and treatments were collected. We identified 114 anti-TNF-naϊve patients aged ≥ 60years (median age 64years, range 60-80years; 47 males) compared with 330 younger controls aged < 60years (median age 39years, range 18-59years; 57males). Older patients with Crohn's disease (n=73) showed a significantly lower persistence with every kind of anti-TNF therapy (whether analysed together [p<0.001] or separately for intravenous and subcutaneous [SC] therapy) than younger controls, whereas older patients with ulcerative colitis (n=41) showed a lower persistence when combining all kinds of anti-TNF treatment (p=0.004) and for SC therapy. Secondary failures, infections, and neoplasias, but not primary failure, occurred more frequently in older IBD patients than in younger controls. Despite a comparable number of primary failures, older IBD patients treated for the first time with anti-TNF agents showed lower treatment persistence due to higher rates of secondary failure, adverse events, infections, and tumours than younger patients in the first year of follow-up. The reasons for this difference still remain unclear.