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Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged ≥80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged ≥80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged ≥80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged ≥80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged ≥80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged ≥80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. The phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. Here we investigate the relationships between CHIP and associated pathologies in people aged >80 years. Methods: We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies (“Health_&_Anemia” and “Monzino_80+”). Findings: Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival and increased risk of cancers. Mutations in JAK2 and splicing genes (SF3B1, SRSF2, U2AF1, ZRSR2), multiple mutations (DNMT3A, TET2, ASXL1) combined with additional genetic lesions) and variant allele frequency ≥0.14 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia (most including anemia) was a common finding in oldest-old population (>20%), the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with a myeloid neoplasms-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. Interpretation: Specific mutational patterns define different risk of developing cancers vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms. Trial Registration: (ClinicalTrials.gov number:NCT03907553) Funding: Supported by European Union; Cariplo Foundation, Italy; Italian Association for Cancer Research; Italian Ministry of Health and Research. Declaration of Interests: The Authors declare no competing interests. Ethics Approval Statement: Study procedures were in accordance with the Declaration of Helsinki. Ethics Committees of Humanitas Research Hospital and Mario Negri Pharmacological Institute, Milan Italy approved the study. Written informed consent was obtained prior to blood sampling.

Aim In this study, the relationship between kidney function, cognitive performance, functional abilities and mood was investigated in a community-dwelling Italian oldest-old population. Methods Serum creatinine was used to calculate estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula, for 415 oldest-old without dementia participating in the 'Health and Anemia' study, a prospective, observational cohort study. The cross-sectional associations of kidney function with cognitive performance on several neuropsychological tests, basic and instrumental functional abilities and mood were analyzed using univariate and multivariable linear regression models. Results Cognitive performance and functional ability significantly worsened with decreasing kidney function. After adjusting for age, sex, education, comorbidity index of the Cumulative Illness Rating Scale (CIRS), body mass index, bone fracture and serum ferritin levels the associations of eGFR categories with basic and instrumental functional abilities continued to be statistically significant whereas that with global cognitive functions did not. No significant independent association was found between renal function and mood. Conclusions Oldest-old with reduced kidney function showed greater basic and instrumental functional disabilities, while cognitive function, although decreased with decreasing eGFR, was no longer significantly associated with eGFR categories after adjusting for confounders.

In the preoperative setting of breast cancer, fine-needle aspiration biopsy (FNAB) guided by ultrasonography can be used to detect axillary lymph node metastases. The aim of the current study was to determine whether measurement in needle washouts of CYFRA 21-1, a soluble fragment of cytokeratin 19 (CK19), can improve the diagnosis of lymph node tumor deposits.Our prospective study included 329 breast cancer patients eligible for a sentinel node procedure. Eighty-two patients had a ultrasonography-guided FNAB of an abnormal or suspicious axillary node and were included in the current analysis. Samples were processed with smears and cell-block histology; afterwards, needles were washed with saline solution, and the CYFRA 21-1 content in the washouts was measured. The cutoff value for positive samples that expressed CK19, as shown by their immunohistochemistry, was determined by a receiver operating characteristic curve. On the basis of this value, the specificity and the sensitivity, as well as the positive and negative predictive values, were then calculated using cytology results as a reference standard.Of the 82 axillary lymph nodes sampled, 61 were positive on cytology and were metastatic for breast cancer, as confirmed by surgery. The median CYFRA 21-1 concentration of positive samples was 88.94 ng/mL, whereas in the 21 negative nodes, its median concentration was 1.02 ng/mL (P0.0001). A CYFRA 21-1 cutoff value of 1.98 ng/mL, obtained by the receiver operating characteristic curve, was able to clearly separate negative from positive samples and gave the test a sensitivity of 0.98 and a specificity of 1.00. Positive and negative predictive values were 1.00 and 0.95, respectively.The measurement of CYFRA 21-1 levels in needle washouts after axillary lymph node FNABs represents an accurate, sensitive, and highly predictive procedure in detecting metastatic deposits of breast cancer and is fit to complement cytology and CK19 immunohistochemistry as a diagnostic tool.

ABstRA ct : Vascular access recirculation rate (AR) monitoring is fundamental to guarantee treatment adequacy and to detect access failure early. We have evaluated the GIt2 test to measure AR unaffected by cardio-pulmonary recirculation (cPR), based on a short glucose infusion in place of the bolus and on a two-operator sampling, differently from the classical glucose infusion test (GIt). t he GIt2 test is based on four steps: 1) basal (B) glucose arterial sample; 2) 10% glucose infusion for 1 min, by infusion pump at 600 ml/hr; (or 20% at 300 ml/hr); 3) simultaneous sampling at arterial (A) and venous (V) ports, after 35-40 sec from starting the infusion, taking care to avoid blood pump stop during the test; 4) AR=100*((A-B)/(V-B)). In vitro tests by dialysis on a 40 l tank containing a urea solution, with AR volumetrically simulated at 0, 5, 10, 20%, and in vivo comparison of GIt , GIt2 with stop-flow (sF) urea method. our results have shown in vitro an almost perfect correspondence of sF urea method and a better reliability of GIt2 than GIt . t he methylene-blue test has shown that a single color bolus in V reaches the A port after variable time, depending on blood flow and AR, while the continuous infusion determines a steady gradient after about 30”. In vivo tests (n=24) show good correspondence between GIt2 (4.37 ± 3.36) and sF (4.51 ± 3.62), while GIt data (1.01 ± 0.51) are significantly underestimated. In conclusion, our preliminary results have evidenced a good reliability of the new test, the continuous infusion causing a steady gradient in V and A that more precisely reflects the AR rate. (J Vasc Access 2010; 11: 38-40)