Nitric oxide (NO) is an important signaling molecule for many physiological and pathological processes. Diseases associated with abnormal NO synthesis include cardiovascular diseases, insulin-dependent diabetes, or chronic kidney disease (CKD). The aim of the paper was to evaluate NO synthesis metabolites, i.e., asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), dimethylamine (DMA), arginine, citrulline in plasma of patients with different severity of CKD and to seek possible links between these parameters and the development of this disease. Forty-eight CKD children and thirty-three age-matched controls were examined. Patients were divided into groups depending on the CKD stages (Group II-stage II, Group III-stage III, Group IV-stage IV, and Group RRT children on dialysis). To determine the concentrations of the above-mentioned metabolites in plasma liquid chromatography-mass spectrometry was used. There were significant differences observed in levels of ADMA, SDMA, DMA, and citrulline between control vis CKD groups (p values ranging from <0.001 to 0.029). Plasma arginine concentration was also higher in CKD patients compared to the control group but statistically insignificant. ADMA levels in CKD children were statistically significantly higher in relation to particular stages of CKD (RRT vis II stage of CKD: p = 0.01; RRT vis III-IV stages of CKD: p < 0.046). Citrulline levels in CKD children were statistically significantly higher in RRT group vis control (p < 0.001). Children with CKD develop disturbances in most metabolites of NO synthesis. Dialysis children treated show the greatest disturbances of plasma ADMA and citrulline levels. ADMA seems to be a good indicator of the gradual progression of the CKD, which is proved by the negative correlation with eGFR.

The primary technique for detecting the presence and monitoring the development of carotid atherosclerotic plaque is ultrasound. The development of ultrasound techniques has made it possible to precisely visualise not only blood flow, but also vessel walls, including atherosclerotic plaque. Contrast-enhanced ultrasound examination enables one to make an objective observation of atherosclerotic plaque neovascularisation, clearly indicating active inflammation, which is an inherent feature of vulnerable (unstable) plaque. Depending on the examination method used, it is possible to precisely visualise different components of the plaque and its behaviour during blood flow through the vessel lumen or through the neovessels of the plaque, and, consequently, determine the possible presence of inflammation, which is a defining feature of plaque stability. The full utilisation of physical phenomena that underlie contrast-enhanced ultrasound will bring further enormous progress of diagnostic and probably also therapeutic methods for carotid atherosclerosis. The selection of the right examination method significantly accelerates diagnosis and adequate classification of plaque, and makes it possible to monitor the progression of atherosclerosis. However, one needs to bear in mind that ultrasound remains a very subjective method. The success of contrast-enhanced ultrasound also depends on the skills and experience of the examiner. Current attempts at increasing the objectivity of contrast-enhanced ultrasound examination using artificial intelligence will make it possible in the future to make a definitive evaluation of atherosclerotic plaque stability. This will allow one to assess the risk of ischaemic stroke adequately.

Introduction Imatinib, approved as first-line treatment for patients with newly diagnosed chronic myeloid leukemia (CML) by FDA approximately 20 years ago, revolutionized the treatment of this disease. The life expectancy of newly diagnosed patients with CML has been approaching that of the global population. Second generation TKI (2GTKI) administered as a frontline therapy can induce deeper and faster molecular responses in a higher percentage of patients, however, the overall survival is comparable to that achieved with imatinib. To investigate the outcomes of long-lasting therapy with imatinib administered as initial therapy, we analyzed patients with CML who received imatinib as initial therapy at our institution starting from 2001. Methods We retrospectively analyzed long term outcomes of 267 patients treated with imatinib 400 mg at the Department of Hematology, Jagiellonian University Medical College, Cracow, Poland from 2001. Data from medical records were collected and statistical analysis was performed using R software (R version 4.0.2). Results The median age was 53.5 (16 to 88 years), 129 of patients (pts) (48.31%) were female. At the time of this analysis, 99 pts (37.08 %) remained on imatinib with the median dose at last follow-up (FU) 400 mg. The mean initial dose of imatinib was 410.4 mg/d. Imatinib dose was increased in 53 pts (19.85%), up to 800mg and up to 600 mg in 3 pts (1.13%), and in 49 pts (18.35%) respectively. The mean maximal dose was 465.2 mg. At baseline 124 pts (46.44%) had comorbidities: 79 pts (29.59%) vascular/cardiac, 11 pts (4.12%) renal, and 101 pts (37.33%) other comorbidities. 15 patients (5.63%) had prior malignancies, newly diagnosed malignancies occurred among 11 (4.12%) pts on imatinib. The median follow-up time was 11.37 years (range from 2 months to 19.5 years). 168 pts (62.92%) discontinued imatinib permanently, the median time to imatinib discontinuation was 2.02 years. Among them, 123 pts (71.93 %) switched imatinib to 2GTKI- 79 pts (29.59%) to dasatinib, 68 pts (25.47%) to nilotinib, and 14 pts (5.24%) to bosutinib. During the following treatment 87 pts (32,58%) received one 2GTKI, 33 pts (12.36%) two, and 3 pts (1.12%) more than two 2GTKIs. The main reasons for imatinib therapy discontinuation were intolerance (87 pts, 32.58%) and disease progression (90 pts, 33.71%). The median time to the imatinib discontinuation due to its intolerance was 2 years. Adverse events (AEs) during imatinib therapy were as follows: cardiac/vascular AEs in 22 pts (8.24%), renal in 42 pts (15.73%), hematologic in 43 pts (16.10%), and other in 189 pts (70.79%). Overall, 28 patients died (10.5%), 7 pts (2.2%) transformed to blast phase, 9 pts (3.37%) underwent allo-HSCT. Estimated OS for patients that remained on imatinib for the whole observation period for 15 and 18 years was: 80.2%, and 64.1% respectively (Figure 1). Median follow-up time for patients who continued imatinib was 7.91 years. Intention to treat (ITT) analysis available for 99 pts (37.08%) revealed ITT responses at three months, one, five, ten and fifteen years: 50.52%, 77.4%, 86.25%, 90.28%, 100% for CCyR, 32.99%, 58.07%, 80%, 86.11%, 100% for MMR, 11.34%, 20.44%, 63.75%, 63.89%, 90% for MR4, 2.06%, 12.91%, 35%, 38.89%, 70% for MR4.5, 2.06%, 7.53%, 26.25%, 33.33%, 50% for CMR (undetectable transcripts with ≥100,000 copies ABL) (Table 1). The overall best response rates (at any time) for these 99 pts was 4.04% for MCyr, 5.05% for CCyR, 11.11% for MMR, 14.14% for MR4, 9.09% for MR4.5, 49.49% for CMR. Conclusion The analysis of long-term therapy with imatinib showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was associated with low rate of late toxic effects. Disclosures Sacha: Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau.

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