Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, ...factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% 36.3-50.4 at 5 years, 40.9% 32.8-47.3 at 7 years and 34.5% 25.6- 43.3 at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).
Chemokine (C-X3-C motif) receptor 1 (CX3CR1) was identified as the most differentially expressed gene between survivors and non-survivors in two independent cohorts of septic shock patients and was ...proposed as a marker of sepsis-induced immunosuppression. Whether such a biomarker is associated with mortality in the heterogeneous group of critically ill patients is unknown. The primary objective of this study was to evaluate the association between CX3CR1 messenger RNA (mRNA) expression and mortality in intensive care unit (ICU) patients. The secondary objective was to evaluate similar endpoints in the subgroup of septic shock patients.
We performed a prospective, multicentre, non-interventional study in six ICUs of university hospitals in Lyon, France. Every consecutive adult patient with systemic inflammatory response syndrome and an expected length of stay in the ICU over 2 days was included. Whole-blood CX3CR1 mRNA expression was measured by quantitative real-time polymerase chain reaction at day 1 (D1) and D3 after inclusion.
In ICU patients (n = 725), decreased CX3CR1 mRNA expression at D1 was associated with high D7 mortality (AUC 0.70, adjusted OR aOR 2.03, 95 % CI 1.19-3.46), while decreased expression at D3 was associated with increased D28 mortality (AUC 0.64, aOR 2.34, 95 % CI 1.45-3.77). In septic shock patients (n = 279), similar associations were observed between decreased D1 CX3CR1 mRNA expression and D7 mortality (AUC 0.69, aOR 2.76, 95 % CI 1.32-5.75) as well as decreased D3 expression and D28 mortality (AUC 0.72, aOR 3.98, 95 % CI 1.72-9.23). These associations were independent of lactacidaemia, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment score and Charlson comorbidity index.
This study represents the largest evaluation of such an mRNA marker in a heterogeneous cohort of severely injured patients. Our results show that decreased CX3CR1 mRNA expression is associated with increased mortality in ICU patients. This suggests a link between injury-induced immunosuppression and mortality in critically ill patients. In this context, the monitoring of such a host response molecular biomarker could prove very helpful for the identification of patients at high risk of death in the ICU.
Despite the fact that animal posture is known to reflect emotional state, the presence of chronic postures associated with poor welfare has not been investigated with an objective tool for measuring, ...quantifying and comparing postures. The use of morphometric geometrics (GM) to describe horse posture (profile of the dorsum) has shown to be an effective method of distinguishing populations that are known to differ in terms of welfare states. Here we investigated photographs of 85 riding school horses differing in terms of welfare state, in order to determine if a specific posture (modelled by GM) is associated with altered welfare. The welfare state was estimated with the prevalence of stereotypic or abnormal repetitive behaviours, depressed-like posture and the ear positions. ANOVA results show that horses with stereotypic or abnormal behaviour, and to a lesser degree horses with depressed-like postures, tend to have a flatter, or even hollow, dorsal profile, especially at the neck and croup levels. These altered profiles could represent an additional indicator of poor welfare, easy to use in the field or by owners.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The BCR-ABL T315I mutation confers resistance to currently licensed tyrosine kinase inhibitors in chronic myelogenous leukemia. However, the impact of this mutation on survival in early stages of ...disease, in chronic phase, has never been detailed. Using matched pair analysis, a cohort of 64 patients with chronic phase chronic myelogenous leukemia harboring a T315I mutation and resistant to imatinib mesylate was compared to a similar cohort of 53 chronic phase patients resistant to imatinib, but with no detectable T315I mutation, in the pre-ponatinib era. These patients were matched according to age at diagnosis, interval between disease diagnosis and start of imatinib treatment, and duration of imatinib therapy. Kaplan-Meier survival analyses demonstrated the significant negative impact of the presence of the T315I mutation on overall survival (since imatinib-resistance: 48.4 months for T315I(+) patients versus not reached for T315I(-) ones; P=0.006) and failure-free survival (since imatinib-resistance: 34.7 months for T315I(+) patients versus not reached for T315I(-) patients; P=0.003). In addition, Cox proportional hazard models adjusted on overall survival demonstrated the negative influence of the T315I mutation (P=0.02, HR=2.54). These results confirm early assumptions concerning the poor prognosis of chronic phase chronic myelogenous leukemia patients with the T315I mutation who are not eligible for allogeneic transplantation, and demonstrate the need for more therapeutic options.
The study of animal behavior, especially regarding welfare, needs the development of tools to identify, quantify and compare animal postures with interobserver reliability. While most studies ...subjectively describe animal postures, or quantify only limited parts of the body, the usage of geometric morphometrics has allowed for the description of horses' and pigs' upper body outline and the comparison of postures from different populations thanks to robust statistical analysis. We have attempted here to optimize the geometric morphometrics (GM) method already used in horses by introducing the outline analysis with sliding semilandmarks (SSL), by eliminating the balance movement of the neck and by focusing only on parts of the upper line. For this purpose, photographs of 85 horses from 11 riding schools, known for differing in terms of housing and working conditions, were analyzed with previous and new GM methods and these results were compared with each other. Using SSL and eliminating the neck movement appeared to better discriminate the horse populations than the previous GM method. Study of parts of the dorsum proved efficient too. This new methodology should now be used to examine if posture could be an indicator of horse welfare state, and similar studies should be performed in other species in order to validate the same methodology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Objectives Human herpes virus 6 (HHV-6) can reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with significant clinical manifestations. ...Methods Case control study of HHV-6 infections after allo-HSCT. Chromosomal integration (ciHHV-6) for viral loads ≥ 5.5-log10 copies/mL was investigated. Viral co-infections, T-cell recovery, risk factors and outcome were compared in HHV-6- and non-HHV-6-infected patients. Antiviral treatment strategies were reviewed. Results Among 366 adult allo-HSCT recipients, 75 HHV-6 infections occurred. Three (4%) recipients were ciHHV-6. HHV-6 infections were associated with CMV ( p = 0.05; sdHR 1.73, CI 0.99–3.02) and/or BKV infections ( p < 0.0001; sdHR 4.63, CI 2.04–10.53) but not EBV reactivation ( p = 0.34). A slower CD8+ T-cells recovery was observed until 6 months after allo-HSCT in the HHV-6-infected group ( p < 0.001), independently of acute and/or chronic graft- versus -host disease. The overall probability of survival after allo-HSCT was diminished for active HHV-6-infected patients ( p = 0.0326). Cord blood unit recipients had a higher risk of developing HHV-6 infection compared to bone marrow recipients ( p = 0.0007; sdHR 3.82, CI 1.76–8.27). Anti-HHV-6 treatment achieved complete response in only 2/3 of the cases. Conclusions In this series of allo-HSCT recipients, 4% were ciHHV-6, active HHV-6 infection was likely associated with CMV and BKV co-reactivations, delayed CD8+ T-cell recovery and poorer outcome.
Allogeneic hematopoietic stem cell (HSC) transplantation is a curative treatment for many hematologic malignancies for which umbilical cord blood (UCB) represents an alternative source of HSCs. To ...overcome the low cellularity of one UCB unit, double UCB transplantation (dUCBT) has been developed in adults. We have analyzed the outcome of 136 patients who underwent dUCBT reported to the SFGM-TC registry between 2005 and 2007. Forty-six patients received myeloablative regimens, and 90 patients received reduced-intensity conditioning regimens. There were 84 cases of leukemia, 17 cases of non-Hodgkin lymphoma, 11 cases of myeloma, and 24 other hematologic malignancies. At transplantation, 40 (29%) patients were in complete remission. At day 60 after transplantation, the cumulative incidence of neutrophil recovery was 91%. We observed one UCB unit domination in 88% of cases. The cumulative incidence of day 100 acute graft-versus-host disease, chronic graft-versus-host disease, transplant-related mortality, and relapse at 2 years were 36%, 23%, 27%, and 28% respectively. After a median follow-up of 49.5 months, the 3-year probabilities of overall and progression-free survival were 41% and 35%, respectively, with a significant overall survival advantage when male cord engrafted male recipients. We obtained a long-term plateau among patients in complete remission, which makes dUCBT a promising treatment strategy for these patients.
Although the benefit of coronary revascularization in patients with stable coronary disease is debated, data assessing the potential interest of stress cardiovascular magnetic resonance (CMR) to ...guide coronary revascularization are limited. We aimed to assess the long-term prognostic value of stress CMR-related coronary revascularization in consecutive patients from a large registry.
Between 2008 and 2018, a retrospective cohort study with a median follow-up of 6.0 years (interquartile range, 5.0-8.0) included all consecutive patients referred for stress CMR. CMR-related coronary revascularization was defined by any coronary revascularization performed within 90 days after CMR. The primary outcome was all-cause death based on the National Death Registry.
Among the 31 762 consecutive patients (mean age 63.7±12.1 years and 65.7% males), 2679 (8.4%) died at 206 453 patient-years of follow-up. Inducible ischemia and late gadolinium enhancement by CMR were associated with death (both
<0.001). In multivariable Cox regression, inducible ischemia and late gadolinium enhancement were independent predictors of death (hazard ratio, 1.61 99.5% CI, 1.41-1.84; hazard ratio, 1.62 99.5% CI, 1.41-1.86, respectively;
<0.001). In the overall population, CMR-related coronary revascularization was an independent predictor of greater survival (hazard ratio, 0.58 99.5% CI, 0.46-0.74;
<0.001). In 1680, 1:1 matched patients using a limited number of variables (840 revascularized, 840 nonrevascularized), CMR-related revascularization was associated with a lower incidence of death in patients with severe inducible ischemia (≥6 segments,
<0.001) but showed no benefit in patients with mild or moderate ischemia (<6 segments,
=0.109). Using multivariable analysis in the propensity-matched population, CMR-related revascularization remained an independent predictor of a lower incidence of all-cause mortality (hazard ratio, 0.66 99.5% CI, 0.54-0.80,
<0.001).
In this large observational series of consecutive patients, stress perfusion CMR had important incremental long-term prognostic value to predict death over traditional risk factors. CMR-related revascularization was associated with a lower incidence of death in patients with severe ischemia.
Abstract
Aims
To determine whether fully automated artificial intelligence-based global circumferential strain (GCS) assessed during vasodilator stress cardiovascular (CV) magnetic resonance (CMR) ...can provide incremental prognostic value.
Methods and results
Between 2016 and 2018, a longitudinal study included all consecutive patients with abnormal stress CMR defined by the presence of inducible ischaemia and/or late gadolinium enhancement. Control subjects with normal stress CMR were selected using a propensity score-matching. Stress-GCS was assessed using a fully automatic machine-learning algorithm based on featured-tracking imaging from short-axis cine images. The primary outcome was the occurrence of major adverse clinical events (MACE) defined as CV mortality or nonfatal myocardial infarction. Cox regressions evaluated the association between stress-GCS and the primary outcome after adjustment for traditional prognosticators. In 2152 patients 66 ± 12 years, 77% men, 1:1 matched patients (1076 with normal and 1076 with abnormal CMR), stress-GCS was associated with MACE median follow-up 5.2 (4.8–5.5) years after adjustment for risk factors in the propensity-matched population adjusted hazard ratio (HR), 1.12 (95% CI, 1.06–1.18), and patients with normal CMR adjusted HR, 1.35 (95% CI, 1.19–1.53), both P < 0.001, but not in patients with abnormal CMR (P = 0.058). In patients with normal CMR, an increased stress-GCS showed the best improvement in model discrimination and reclassification above traditional and stress CMR findings (C-statistic improvement: 0.14; NRI = 0.430; IDI = 0.089, all P < 0.001; LR-test P < 0.001).
Conclusion
Stress-GCS is not a predictor of MACE in patients with ischaemia, but has an incremental prognostic value in those with a normal CMR although the absolute event rate remains low.
Graphical Abstract
Graphical Abstract
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