11C-Methionine PET/CT in Assessment of Multiple Myeloma Patients: Comparison to 18F-FDG PET/CT and Prognostic Value.

Multiple myeloma (MM) is the second most common haematological malignancy and remains incurable despite therapeutic advances. 18F-FDG (FDG) PET/CT is a relevant tool MM for staging and it is the reference imaging technique for treatment evaluation. However, it has limitations, and investigation of other PET tracers is required. Preliminary results with L-methyl-[11C]- methionine (MET), suggest higher sensitivity than 18F-FDG. This study aimed to compare the diagnostic accuracy and prognostic value of 1FDG and MET in MM patients. We prospectively compared FDG and MET PET/CT for assessment of bone disease and extramedullary disease (EMD) in a series of 52 consecutive patients (8 smoldering MM, 18 newly diagnosed MM and 26 relapsed MM patients). Bone marrow (BM) uptake patterns and the detection of focal lesions (FLs) and EMD were compared. Furthermore, FDG PET parameters with known MM prognostic value were explored for both tracers, as well as total lesion MET uptake (TLMU). Median patient age was 61 years (range, 37-83 years), 54% were male, 13% of them were in stage ISS (International Staging System) III, and 31% had high-risk cytogenetics. FDG PET/CT did not detect active disease in 6 patients, while they were shown to be positive by MET PET/CT. Additionally, MET PET/CT identified a higher number of FLs than FDG in more than half of the patients (63%). For prognostication we focussed on the relapsed cohort, due to the low number of progressions in the two other cohorts. Upon using FDG PET/CT in relapsed patients, the presence of more than 3 FLs (HR 4.61, p = 0.056), more than 10 FLs (HR 5.65, p = 0.013), total metabolic tumor volume (TMTV) p50 (HR 4.91, p = 0.049) or TMTV p75 (HR 5.32, p = 0.016) were associated with adverse prognosis. In MET PET/CT analysis, TMTV p50 (HR 4.71, p = 0.056), TMTV p75 (HR 6.27, p = 0.007), TLMU p50 (HR 8.8, p = 0.04) and TLMU p75 (HR 6.3, p = 0.007) adversely affected PFS. This study confirmed the diagnostic and prognostic value of FDG in MM. In addition, it highlights that MET has higher sensitivity than FDG PET/CT for detection of myeloma lesions, including FLs. Moreover, we show, for the first time, the prognostic value of TMTV and TLMU MET PET/CT in the imaging evaluation of MM patients.

Immunothrombosis: Molecular Aspects and New Therapeutic Perspectives.

Thromboinflammation or immunothrombosis is a concept that explains the existing link between coagulation and inflammatory response present in many situations, such as sepsis, venous thromboembolism, or COVID-19 associated coagulopathy. The purpose of this review is to provide an overview of the current data regarding the mechanisms involved in immunothrombosis in order to understand the new therapeutic strategies focused in reducing thrombotic risk by controlling the inflammation.

Analysis of common biomarkers in capillary blood in routine clinical laboratory. Preanalytical and analytical comparison with venous blood.

OBJECTIVES: Remote self-collected capillary blood samples have been proposed as alternative to venous blood samples as an aid in telemedicine. The aim of this work is to compare the preanalytical and analytical performance of these two types of samples and to study the stability of common measurands in capillary blood. METHODS: Capillary and venous blood samples were collected in parallel from 296 patients in serum tubes to analyze 22 common biochemistry magnitudes after centrifugation and in EDTA tubes to analyze 15 hematologic magnitudes. Quality of the preanalytical process was assessed applying the model of quality indicator. 24 h stability at room temperature was studied by obtaining paired capillary samples. A questionnaire of assessment was conducted. RESULTS: Mean hemolysis index was higher in capillary samples compared to venous blood samples (p<0.001). Regression analysis and difference analysis showed no bias for all studied biochemistry parameters and hematologic parameters, except mean corpuscular volume (MCV), between capillary and venous blood samples. Regarding sample stability, percentage deviation was higher than the corresponding minimum analytical performance specification for ferritin, vitamin D, hematocrit, MCV, mean corpuscular hemoglobin concentration, platelets distribution wide, mean platelet volume and basophils. Finger pricking was perceived as less painful (p<0.05) than venipuncture in participants who undergo more than one blood test per year. CONCLUSIONS: Capillary blood can be used as an alternative to venous blood for the studied parameters in automated common clinical analyzers. Cautious should be taken if samples are not analyzed within 24 h from the collection.

Therapeutic versus Prophylactic Bemiparin in Hospitalized Patients with Nonsevere COVID-19 Pneumonia (BEMICOP Study): An Open-Label, Multicenter, Randomized, Controlled Trial.

Thromboprophylaxis with low molecular weight heparin in hospitalized patients with COVID-19 is mandatory, unless contraindicated. Given the links between inflammation and thrombosis, the use of higher doses of anticoagulants could improve outcomes. We conducted an open-label, multicenter, randomized, controlled trial in adult patients hospitalized with nonsevere COVID-19 pneumonia and elevated D-dimer. Patients were randomized to therapeutic-dose bemiparin (115 IU/kg daily) versus standard prophylaxis (bemiparin 3,500 IU daily), for 10 days. The primary efficacy outcome was a composite of death, intensive care unit admission, need of mechanical ventilation support, development of moderate/severe acute respiratory distress, and venous or arterial thrombosis within 10 days of enrollment. The primary safety outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). A prespecified interim analysis was performed when 40% of the planned study population was reached. From October 2020 to May 2021, 70 patients were randomized at 5 sites and 65 were included in the primary analysis; 32 patients allocated to therapeutic dose and 33 to standard prophylactic dose. The primary efficacy outcome occurred in 7 patients (22%) in the therapeutic-dose group and 6 patients (18%) in the prophylactic-dose (absolute risk difference 3.6% [95% confidence interval [CI], -16% -24%]; odds ratio 1.26 [95% CI, 0.37-4.26]; p = 0.95). Discharge in the first 10 days was possible in 66 and 79% of patients, respectively. No major bleeding event was registered. Therefore, in patients with COVID-19 hospitalized with nonsevere pneumonia but elevated D-dimer, the use of a short course of therapeutic-dose bemiparin does not appear to improve clinical outcomes compared with standard prophylactic doses. Trial Registration: ClinicalTrials.gov NCT04604327.

Post-Transplantation Cyclophosphamide After HLA Identical Compared to Haploidentical Donor Transplant in Acute Myeloid Leukemia: A Study on Behalf of GETH-TC.

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival. © 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Association of SDF1 and MMP12 with Atherosclerosis and Inflammation: Clinical and Experimental Study.

BACKGROUND: Atherosclerosis is the main etiology of cardiovascular diseases (CVD), associated to systemic inflammation. Matrix metalloproteinases (MMPs) are related to atherosclerosis progression through the SDF1/CXCR4 axis promoting macrophages recruitment within the vascular wall. The goal was to assess new circulatory inflammatory markers in relation to atherosclerosis. METHODS: Measurement of SDF1, MMP12 and CRP in blood samples of 298 prospective patients with cardiovascular risk. To explore atherosclerosis progression, CXCR4/SDF1 axis and MMP12 expression were determined by RT-qPCR and by immunohistochemistry in the aorta of accelerated and delayed atherosclerosis mice models (Apoe-/- and Apoe-/-Mmp10-/-). RESULTS: SDF1, MMP12 and CRP were elevated in patients with clinical atherosclerosis, but after controlling by confounding factors, only SDF1 and CRP remained increased. Having high levels of both biomarkers showed 2.8-fold increased risk of presenting clinical atherosclerosis (p = 0.022). Patients with elevated SDF1, MMP12 and CRP showed increased risk of death in follow-up (HR = 3.2, 95%CI: 1.5-7.0, p = 0.004). Gene and protein expression of CXCR4 and MMP12 were increased in aortas from Apoe-/- mice. CONCLUSIONS: The combination of high circulating SDF1, MMP12 and CRP identified patients with particular inflammatory cardiovascular risk and increased mortality. SDF1/CXCR4 axis and MMP12 involvement in atherosclerosis development suggests that they could be possible atherosclerotic targets.

18F-FDG and 11C-Methionine PET/CT in Newly Diagnosed Multiple Myeloma Patients: Comparison of Volume-Based PET Biomarkers.

11C-methionine (11C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than 18F-fluorodeoxyglucose (18F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of 11C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to 18F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone 11C-MET and 18F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion 11C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), 11C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in 11C-MET than in 18F-FDG (p < 0.05, respectively). 11C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that 11C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than 18F-FDG. Its implications for prognosis evaluation need further investigation.

Analysis of monocitary subpopulations in relation to cardiovascular risk factors. / Análisis de subpoblaciones monocitarias en relación con los factores de riesgo cardiovascular.

INTRODUCTION: Monocytes play an important role in atherosclerotic progression having both pro and anti-inflammatory effects depending on different circulating monocyte subpopulations. The objective of this study is to characterize these subpopulations and their association with cardiovascular risk factors. METHODS: Transversal study including 102 selected patients, mean age: 65 years-old (range 41-86), 69% males. A set of specific antibodies against classical monocytes (Mon1, CD14+CD16- CD300e+HLADR+), intermediate (Mon2, CD14+CD16+CD300e+HLADR+) and non-classical (Mon3, CD14-CD16+CD300e+HLADR+) was assayed. Three groups of patients were included: 17 asymptomatic with more than one cardiovascular risk factor (group 1), 56 subjects asymptomatic but with vascular pathology assessed by ultrasound or microalbuminuria (group 2) and 19 patients with a previous atherothrombotic event (group 3). The cardiovascular risk was determined by Framingham and REGICOR scores. RESULTS: An association between study groups and the percentage of Mon1 and Mon2 was observed (ANOVA, p<.05), being independent of age and sex for Mon2. Likewise Mon1 and Mon2 subpopulations were associated with cardiovascular adverse events (ß=0.86, p=.02 y ß=0.1 p=.002, respectively), independently of age and sex in the case of Mon2. Moreover the percentage of Mon3 was associated with the presence of several cardiovascular risk factors (ß=0.21, p=.04) in the univariate analysis. In addition, there was a correlation between the levels of Mon1 and Mon2 and leukocytes (r=0.7, p<.001 and r=0.26, p=.01, respectively). CONCLUSIONS: The analysis of monocyte subpopulations may be clinically useful to stratify the inflammatory profile related to the different cardiovascular risk groups.

Análisis de subpoblaciones monocitarias en relación con los factores de riesgo cardiovascular / Analysis of monocitary subpopulations in relation to cardiovascular risk factors

Introducción: La participación monocitaria en la progresión aterosclerótica y sus efectos pro- o antiinflamatorios dependen de las subpoblaciones circulantes. El objetivo de este estudio es la caracterización de dichas subpoblaciones y su asociación con los factores de riesgo cardiovascular. Métodos: Estudio transversal que incluye 102 pacientes seleccionados; edad media: 65 años (rango 41-86 años), 69% varones. Se utilizó un panel de anticuerpos específicos frente a monocitos clásicos (Mon1, CD14+CD16− CD300e+HLADR+), intermedios (Mon2, CD14+CD16+CD300e+HLADR+) y no clásicos (Mon3, CD14-k-CD16+CD300e+HLADR+). Se establecieron tres grupos de estudio; grupo 1: sujetos asintomáticos con más de un factor de riesgo cardiovascular (n = 17); grupo 2: sujetos asintomáticos, pero con patología vascular por ecografía o microalbuminuria (n = 56); y grupo 3: pacientes con algún evento vascular aterotrombótico previo (n = 19). Asimismo, se calculó el riesgo cardiovascular mediante las escalas Framingham y REGICOR. Resultados: Se observó una asociación entre las subpoblaciones Mon1 y Mon2 y los grupos del estudio (ANOVA, p < 0,05), independiente de la edad y el sexo para los Mon2. Asimismo, las subpoblaciones Mon1 y Mon 2 se asociaron con eventos vasculares adversos (ß = 0,86, p = 0,02 y ß = 0,1 p = 0,002, respectivamente), siendo la asociación de Mon2 independiente de la edad y el sexo. Además, el porcentaje de Mon3 se asoció con la presencia de más de 2 factores de riesgo cardiovascular (ß=0,21, p=0,04) en el análisis univariante. Finalmente, se halló una correlación entre los niveles de Mon1 y Mon2 con el número de leucocitos (r = 0,7, p < 0,001 y r = 0,26 p < 0,01, respectivamente). Conclusiones: El análisis de subpoblaciones monocitarias es de gran interés clínico, ya que permite establecer un diferente perfil inflamatorio según los grupos de riesgo cardiovascular establecidos

Introduction: Monocytes play an important role in atherosclerotic progression having both pro and anti-inflammatory effects depending on different circulating monocyte subpopulations. The objective of this study is to characterize these subpopulations and their association with cardiovascular risk factors. Methods: Transversal study including 102 selected patients, mean age: 65 years-old (range 41-86), 69% males. A set of specific antibodies against classical monocytes (Mon1, CD14+CD16- CD300e+HLADR+), intermediate (Mon2, CD14+CD16+CD300e+HLADR+) and non-classical (Mon3, CD14-CD16+CD300e+HLADR+) was assayed. Three groups of patients were included: 17 asymptomatic with more than one cardiovascular risk factor (group 1), 56 subjects asymptomatic but with vascular pathology assessed by ultrasound or microalbuminuria (group 2) and 19 patients with a previous atherothrombotic event (group 3). The cardiovascular risk was determined by Framingham and REGICOR scores. Results: An association between study groups and the percentage of Mon1 and Mon2 was observed (ANOVA, p < .05), being independent of age and sex for Mon2. Likewise Mon1 and Mon2 subpopulations were associated with cardiovascular adverse events (ß = 0.86, p =.02 y ß = 0.1 p =.002, respectively), independently of age and sex in the case of Mon2. Moreover the percentage of Mon3 was associated with the presence of several cardiovascular risk factors (ß = 0.21, p = .04) in the univariate analysis. In addition, there was a correlation between the levels of Mon1 and Mon2 and leukocytes (r = 0.7, p < .001 and r = 0.26, p = .01, respectively). Conclusions: The analysis of monocyte subpopulations may be clinically useful to stratify the inflammatory profile related to the different cardiovascular risk groups