Acute coronary syndromes (ACS) are one of the most dramatic manifestations of atherothrombosis and several efforts have been made in recent years to improve their prognosis. Morbidity and mortality ...of high-to-medium risk ACS have significantly reduced in the real world setting during the last few years, due to a very aggressive antithrombotic therapy, which always involves a combination of an anticoagulant and different antiplatelet agents, and an extensive indication to revascularization. However, it has become increasingly important for clinicians to identify the correct treatment between the several different combination of antithrombotic and antiplatelet agents. The selection and intensity of these combinations are based in the first instance on the ischemic risk profile of the patient and the treatment strategy (early invasive, delayed invasive or conservative) selected. However, the use of such an aggressive antithrombotic therapy coupled with coronary angioplasty exposes the patients to a significant risk of bleeding. Unfortunately, these bleeding complications have a negative prognostic significance and force clinicians to suspend (or decrease) the antithrombotic treatments to control bleeding.
Imaging of vulnerable plaque Guagliumi, Giulio; Musumeci, Giuseppe; Pierli, Carlo ...
Giornale italiano di cardiologia (2006)
11, Issue:
12 Suppl 3
Journal Article
Peer reviewed
Atherosclerosis is a dynamic degenerative disease, which can suddenly switch from a chronic condition to clinical instability, following a process of plaque rupture and thrombotic formation. Lesions ...at instability risk are described as "vulnerable plaque", i.e., lesions with a future high probability of becoming an acute event. Present diagnostic and screening methods are inadequate to identify these lesions. Recent ongoing research addresses two modalities: the development of non-invasive imaging techniques for a rapid diagnostic screening of middle-low risk coronary disease, and the implementation of invasive imaging microscopic techniques--involving the coronary wall--which are associated with coronarography. Some techniques (intravascular ultrasound-optical coherence tomography)--recently introduced in the clinical setting--allow in vivo monitoring of the sequence of changes in the plaque. For the first time we have now the possibility of measuring the thickness of the fibrous cap, the presence of neo-vessels and probably the density of macrophages, identifying high-risk plaques. The imaging techniques allow to track the evolution of the atherosclerotic disease (plaque volume, thickness of cap, number of thin cap plaques) assessing its progression and regression and the efficacy of treatments.
In the last 20 years clinical trials evaluating statins showed the importance of LDL-cholesterol lowering in decreasing the risk of cardiovascular disease. The efficacy of statin therapy has been ...well documented both in primary and secondary prevention, in patients with subclinical atherosclerosis and in those with average cholesterol levels. However, the so-called "residual risk" remains significant and new strategies are needed for reducing it, such as raising HDL-cholesterol levels. Recently, the JUPITER study demonstrated the efficacy of statins in reducing the risk in healthy subjects with elevated C-reactive protein levels, highlighting the potential protective mechanisms of these drugs. Different from the setting of primary and secondary prevention, the results of statin trials in patients with heart failure, end-stage renal disease and aortic stenosis have shown no benefit in terms of survival.
Background: Chronic heart failure (CHF) is a socially relevant condition carrying an adverse prognosis. Systematic analysis is needed of the relationship between quality of life (QoL) – what patients ...are most interested in – and objective parameters of CHF severity – which largely determines physicians’ care. Methods: We prospectively investigated QoL, as ascertained by the Minnesota Living with Heart Failure Questionnaire, alongside all the currently used objective clinical/instrumental (electrocardiographic, echocardiographic, hemodynamic and functional capacity) indicators of disease severity in 106 consecutive CHF patients. Results: Besides persistence of sinus rhythm (p = 0.007), the only objective parameters that correlated with QoL were NYHA class (p < 0.001) and distance covered during the six minutes walking test (p < 0.001) (two indications of patients’ ability to attend to their daily needs). Presence of left bundle branch block was associated with a worse QoL only in patients with CHF due to ischemic heart disease (p = 0.032). All the other clinical/instrumental parameters showed no relation with QoL (p > 0.150 in all cases). Conclusions: Objective indicators of disease severity, which largely determine physicians’ care, appear to have little bearing on QoL, suggesting that current treatment for CHF fails to satisfy patients’ perceived needs. The possibility of cost-effective nonpharmaceutical therapeutic protocols (e.g. psychological interventions) specifically designed to improve patients’ QoL deserves investigation as a much needed new approach to the management of CHF.
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BFBNIB, NMLJ, NUK, PNG, UL, UM, UPUK
The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with ...chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.
•Rituximab and lenalidomide combination is feasible and has moderate activity in frontline therapy of frail older patients with DLBCL.•The FIL_ReRi trial represents a benchmark for future studies ...devised for frail patients with DLBCL.
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Treatment of diffuse large B-cell lymphoma (DLBCL) in older patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a 2-stage single-arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2) in ≥70-year-old untreated frail patients with DLBCL. Frailty was prospectively defined using a simplified geriatric assessment tool. Patients were administered a maximum of 6 28-day cycles of 20 mg oral lenalidomide from days 2 to 22 and IV rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients with partial response or complete response (CR) at cycle 6 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary end point was the overall response rate (ORR) after cycle 6; the coprimary end point was the rate of grade 3 or 4 extrahematological toxicity. The ORR was 50.8%, with 27.7% CR. After a median follow-up of 24 months, the median progression-free survival was 14 months, and the 2-year duration of response was 64%. Thirty-four patients experienced extrahematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥3. The activity of the R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach in frail older patients with DLBCL. This trial was registered at EudraCT as #2015-003371-29 and clinicaltrials.gov as #NCT02955823.
Gini et al report on the results of a phase 2 study of rituximab and lenalidomide in 65 frail patients over 70 years of age with diffuse large B-cell lymphoma (DLBCL). Use of this chemotherapy-free combination yielded an overall response rate of 50.8% with 27.7% of patients achieving complete remission. Median progression-free survival was 14 months, and duration of response was 64% at 2 years. Toxicity of grade ≥ 3 occurred in 34 of 65 patients. This chemotherapy-free combination has significant activity and merits further study.
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
Minimal residual disease (MRD) analysis is a known predictive tool in mantle cell lymphoma (MCL). We describe MRD results from the Fondazione Italiana Linfomi phase 3 MCL0208 prospective clinical ...trial assessing lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) in the first prospective comprehensive analysis of different techniques, molecular markers, and tissues (peripheral blood PB and bone marrow BM), taken at well-defined time points. Among the 300 patients enrolled, a molecular marker was identified in 250 (83%), allowing us to analyze 234 patients and 4351 analytical findings from 10 time points. ASCT induced high rates of molecular remission (91% in PB and 83% in BM, by quantitative real-time polymerase chain reaction RQ-PCR). Nevertheless, the number of patients with persistent clinical and molecular remission decreased over time in both arms (up to 30% after 36 months). MRD predicted early progression and long-term outcome, particularly from 6 months after ASCT (6-month time to progression TTP hazard ratio HR, 3.83; P < .001). In single-timepoint analysis, BM outperformed PB, and RQ-PCR was more reliable, while nested PCR appeared applicable to a larger number of patients (234 vs 176). To improve MRD performance, we developed a time-varying kinetic model based on regularly updated MRD results and the MIPI (Mantle Cell Lymphoma International Prognostic Index), showing an area under the ROC (Receiver Operating Characteristic) curve (AUROC) of up to 0.87 using BM. Most notably, PB reached an AUROC of up to 0.81; with kinetic analysis, it was comparable to BM in performance. MRD is a powerful predictor over the entire natural history of MCL and is suitable for models with a continuous adaptation of patient risk. The study can be found in EudraCT N. 2009-012807-25 (https://eudract.ema.europa.eu/).
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IJS, IMTLJ, NUK, PNG, SAZU, UL, UM, UPUK, ZRSKP
Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B−/T cell acute lymphoblastic leukemia (ALL). Dox compromises ...topoisomerase II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair, and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B−/T cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes, and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses.
Graphical abstract
• Doxorubicin activates the G2/M cell cycle checkpoint in acute lymphoblastic leukemia (ALL) cells.
• ALL cells respond to doxorubicin-induced DNA damages by activating the ATR-CHK1 pathway.
• The inhibition of the ATR-CHK1 pathway synergizes with doxorubicin in the induction of cytotoxicity in ALL cells.
• The inhibition of ATR-CHK1 pathway induces aberrant chromosome segregation and mitotic spindle defects in doxorubicin-pretreated ALL cells.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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