Value of combining biological age with assessment of individual frailty to optimize management of cancer treated with targeted therapies: model of chronic myeloid leukemia treated with tyrosine kinase inhibitors (BIO-TIMER trial).

BACKGROUND: In the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient. METHODS: The BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023. DISCUSSION: The assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making. TRIAL REGISTRATION: ClinicalTrials.gov , ID NCT06130787; registered on November 14, 2023.

Transfemoral versus trans-subclavian access in transcatheter aortic valve implantation using self-expandable valve: A propensity-matched comparison.

BACKGROUND: Transcatheter aortic valve implantation is unfeasible for 10-15% of patients using the conventional transfemoral approach. Other alternative approaches, such as the subclavian approach, have emerged, with no clear recommendation indicating the superiority of one technique over another. AIM: To compare the 1-month mortality and postprocedural outcomes of patients undergoing transcatheter aortic valve implantation using a self-expandable valve via transfemoral and subclavian access. METHODS: This was a retrospective single-centre study including 1496 patients who underwent transcatheter aortic valve implantation between January 2016 and December 2020 at Clermont-Ferrand University Hospital, France. Propensity score matching was used to compare transfemoral and subclavian access. RESULTS: After building two propensity score-matched groups of 221 patients each with either access route (total n=442), baseline characteristics were similar. The procedure duration was significantly longer in the subclavian access group (53 [45-64] versus 60 [51-72] minutes; P<0.001), but with a lower amount of contrast agent (138 [118-165] versus 123 [105-150] mL; P<0.001), fluoroscopy time (11.2 [9-14] versus 9.9 [7-12] minutes; P<0.001) and radiation dose (397 [264-620] versus 321 [217-485] mGy; P<0.001). No significant difference was observed concerning 1-month mortality (odds ratio 1.62, 95% confidence interval 0.52-5.03; P=0.39) or periprocedural complications. Follow-up at 1 year confirmed no difference in longer-term mortality (hazard ratio 0.78, 95% confidence interval 0.52-5.03; P=0.43). CONCLUSIONS: The subclavian approach provides similar results to the transfemoral approach in terms of mortality, efficacy and safety; it is a reasonable and effective alternative when the reference transfemoral approach is impossible or seems complex.

Minerals and Antioxidant Micronutrients Levels and Clinical Outcome in Older Patients Hospitalized for COVID-19 during the First Wave of the Pandemic.

Excessive inflammatory response has been implicated in severe respiratory forms of coronavirus disease 2019 (COVID-19). Trace elements such as zinc, selenium, and copper are known to modulate inflammation and immunity. This study aimed to assess the relationships between antioxidant vitamins and mineral trace elements levels as well as COVID-19 severity in older adults hospitalized. In this observational retrospective cohort study, the levels of zinc, selenium, copper, vitamin A, ß-carotene, and vitamin E were measured in 94 patients within the first 15 days of hospitalization. The outcomes were in-hospital mortality secondary to COVID-19 or severe COVID-19. A logistic regression analysis was conducted to test whether the levels of vitamins and minerals were independently associated with severity. In this cohort (average age of 78 years), severe forms (46%) were associated with lower zinc (p = 0.012) and ß-carotene (p < 0.001) concentrations, and in-hospital mortality (15%) was associated with lower zinc (p = 0.009), selenium (p = 0.014), vitamin A (p = 0.001), and ß-carotene (p = 0.002) concentrations. In regression analysis, severe forms remained independently associated with lower zinc (aOR 2.13, p = 0.018) concentrations, and death was associated with lower vitamin A (aOR = 0.165, p = 0.021) concentrations. Low plasma concentrations of zinc and vitamin A were associated with poor prognosis in older people hospitalized with COVID-19.

Does iron overload in metabolic syndrome affect macrophage profile? A case control study.

AIMS: Dysmetabolic iron overload syndrome (DIOS) is common but the clinical relevance of iron overload is not understood. Macrophages are central cells in iron homeostasis and inflammation. We hypothesized that iron overload in DIOS could affect the phenotype of monocytes and impair macrophage gene expression. METHODS: This study compared 20 subjects with DIOS to 20 subjects with metabolic syndrome (MetS) without iron overload, and 20 healthy controls. Monocytes were phenotyped by Fluorescence-Activated Cell Sorting (FACS) and differentiated into anti-inflammatory M2 macrophages in the presence of IL-4. The expression of 38 genes related to inflammation, iron metabolism and M2 phenotype was assessed by real-time PCR. RESULTS: FACS showed no difference between monocytes across the three groups. The macrophagic response to IL-4-driven differentiation was altered in four of the five genes of M2 phenotype (MRC1, F13A1, ABCA1, TGM2 but not FABP4), in DIOS vs Mets and controls demonstrating an impaired M2 polarization. The expression profile of inflammatory genes was not different in DIOS vs MetS. Several genes of iron metabolism presented a higher expression in DIOS vs MetS: SCL11A2 (a free iron transporter, +76 %, p = 0.04), SOD1 (an antioxidant enzyme, +27 %, p = 0.02), and TFRC (the receptor 1 of transferrin, +59 %, p = 0.003). CONCLUSIONS: In DIOS, macrophage polarization toward the M2 alternative phenotype is impaired but not associated with a pro-inflammatory profile. The up regulation of transferrin receptor 1 (TFRC) in DIOS macrophages suggests an adaptive role that may limit iron toxicity in DIOS.

A curable pseudo-dementia related to an atypical presentation of giant cell arteritis.

A 70-year-old patient was admitted with rapidly progressive cognitive decline associated with limitations in activities of daily living, weight loss and cerebellar ataxia. The diagnosis of giant cell arteritis (GCA) with vascular involvement was made, based on the presence of a metabolically active vasculitis of the brachiocephalic trunk on 18FDG-PET imaging. Temporal artery biopsy also revealed pan-arteritis. A progressive regression of cognitive disorders occurred under corticosteroid treatment and immunosuppressive therapy. Previously published case reports concerning this atypical presentation of GCA are scarce. They suggest that numerous cognitive symptoms, such as impairment of short-term memory, disorientation, delirium, impaired attention or visual hallucinations might be related to GCA. Thus, this diagnosis should be considered as a curable cause of unexplained cognitive impairment associated with weight loss and systemic inflammation.

Management of inflammatory rheumatic conditions in the elderly.

The number of elderly people with chronic inflammatory rheumatic diseases is increasing. This heterogeneous and comorbid population is at particular risk of cardiovascular, neoplastic, infectious and iatrogenic complications. The development of biotherapies has paved the way for innovative therapeutic strategies, which are associated with toxicities. In this review, we have focused on the scientific and therapeutic changes impacting the management of elderly patients affected by RA, SpA or PsA. A multidimensional health assessment resulting in an integrated therapeutic strategy was identified as a major research direction for improving the management of elderly patients.

Overview of biologic treatments in the elderly.

As life expectancies rise, the number of elderly people with inflammatory rheumatic diseases will continue to grow. Treatment of this frail population, whose clinical features differ from those of younger subjects, poses new challenges to healthcare systems. However, this issue is rarely addressed in the current literature. Thanks to their targeted mechanism of action, biologics represent one of the major therapeutic advances of the last 15 years, but their use in the elderly has been slow in developing. Published data, derived mainly from cohorts, focus on the use of TNF inhibitors in rheumatoid arthritis and show that these treatments are effective and generally well tolerated. Nevertheless, the risk of infection and cancer, particularly skin and lymphoid malignancies, must not be neglected. The use of these biologics as second-line treatment improves patient outcomes and comfort, while reducing consumption of the widely used and more deleterious drugs such as glucocorticoids and non-steroidal anti-inflammatory drugs. Additional studies on biologics, focusing on the longer term and in indications apart from anti-TNF therapies in rheumatoid arthritis should help overcome some of the reluctance and promote the rational use of these drugs in the elderly.

Immune-mediated myopathy related to anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies as an emerging cause of necrotizing myopathy induced by statins.

Immune-mediated necrotizing myopathy (IMNM) associated with statin use and anti 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibody is a new and emerging entity that supports a link between statin use and IMNM and raises the questions of distinct clinical phenotypes and treatment strategy. We describe the clinical and histopathological characteristics of a patient and discuss the spectrum of IMNM and statin-induced myopathies. A 65-year-old man was suffering from proximal muscle weakness and elevated CK levels, following exposure to statin therapy. The symptoms worsened despite discontinuation of the drug. At that point, no myositis-specific or -associated antibodies were detected. Malignancy screening did not reveal abnormalities. Muscle biopsy demonstrated a predominantly necrotizing myopathy with minimal lymphocytic infiltrates, MHC class I expression in necrotic muscle fibers, and complement deposition on scattered non-necrotic muscle fibers. Muscle protein analysis by western blot was normal. The patient did not improve with steroid and methotrexate and required monthly intravenous immunoglobulin (IVIG) therapy. Muscle strength gradually improved, CK levels normalized and IVIG were stopped 1 year later. Screening for anti-HMGCR antibodies, not available at the time of presentation, was highly positive. Identification of anti-HMGCR antibodies in statin-exposed patients with myopathy appears to be helpful both for differential diagnosis and for treatment strategy. In patients who did not improve after discontinuation of the statin treatment, a muscle biopsy should be performed as well as screening for anti-HMGCR antibodies. Patients with this disorder require aggressive immunosuppressive treatment.