Objectives
In patients with essential thrombocythemia (ET), after the JAK2V617F driver mutation, mutations in CALR are common (classified as type 1, 52‐bp deletion or type 2, 5‐bp insertion). CALR ...mutations have generally been associated with a lower risk of thrombosis. This study aimed to confirm the impact of CALR mutation type on thrombotic risk.
Methods
We retrospectively investigated 983 ET patients diagnosed in Spanish and Polish hospitals.
Results
With 7.5 years of median follow‐up from diagnosis, 155 patients (15.8%) had one or more thrombotic event. The 5‐year thrombosis‐free survival (TFS) rate was 83.8%, 91.6% and 93.9% for the JAK2V617F, CALR‐type 1 and CALR‐type 2 groups, respectively (P = .002). Comparing CALR‐type 1 and CALR‐type 2 groups, TFS for venous thrombosis was lower in CALR‐type 1 (P = .046), with no difference in TFS for arterial thrombosis observed. The cumulative incidence of thrombosis was significantly different comparing JAK2V617F vs CALR‐type 2 groups but not JAK2V617F vs CALR‐type 1 groups. Moreover, CALR‐type 2 mutation was a statistically significant protective factor for thrombosis with respect to JAK2V617F in multivariate logistic regression (OR: 0.45, P = .04) adjusted by age.
Conclusions
Our results suggest that CALR mutation type has prognostic value for the stratification of thrombotic risk in ET patients.
Since enzyme replacement therapy for Gaucher disease (MIM#230800) has become available, both awareness of and the natural history of the disease have changed. However, there remain unmet needs such ...as the identification of patients at risk of developing bone crisis during therapy and late complications such as cancer or parkinsonism. The Spanish Gaucher Disease Registry has worked since 1993 to compile demographic, clinical, genetic, analytical, imaging and follow-up data from more than 400 patients. The aims of this study were to discover correlations between patients' characteristics at diagnosis and to identify risk features for the development of late complications; for this a machine learning approach involving correlation networks and decision trees analyses was applied.
A total of 358 patients, 340 type 1 Gaucher disease and 18 type 3 cases were selected. 18% were splenectomyzed and 39% had advanced bone disease. 81% of cases carried heterozygous genotype. 47% of them were diagnosed before the year 2000. Mean age at diagnosis and therapy were 28 and 31.5 years old (y.o.) respectively. 4% developed monoclonal gammopathy undetermined significance or Parkinson Disease, 6% cancer, and 10% died before this study. Previous splenectomy correlates with the development of skeletal complications and severe bone disease (p = 0.005); serum levels of IgA, delayed age at start therapy (> 9.5 y.o. since diagnosis) also correlates with severe bone disease at diagnosis and with the incidence of bone crisis during therapy. High IgG (> 1750 mg/dL) levels and age over 60 y.o. at diagnosis were found to be related with the development of cancer. When modelling the decision tree, patients with a delayed diagnosis and therapy were the most severe and with higher risk of complications.
Our work confirms previous observations, highlights the importance of early diagnosis and therapy and identifies new risk features such as high IgA and IgG levels for long-term complications.
Soybean rust in Brazil is currently controlled with several commercial fungicide premixes composed of demethylation inhibitors (EPOXiconazole, CYPRoconazole, PROThioconazole, TEBUconazole), ...quinone‐outside inhibitors (AZOXystrobin, TriFLoXystrobin, PYRAclostrobin, PICOxystrobin), and succinate demethylation inhibitors (BENZovindiflupyr, BIXaFen, FLUXapyroxad). Here, we summarize the performance of eight premixes evaluated in 177 cooperative trials conducted in 46 locations across 10 states from 2015 to 2020. All fungicide treatments were sprayed three times starting at R1/R2. Percentage control (C¯, %), from back‐transforming meta‐analytic estimates of the log of the ratio, ranged from 56.2% (PICO + CYPR) to 76.8% (BIXF + TFLX + PROT). Estimates of mean yield difference (D¯, kg/ha) between fungicide‐treated and untreated plots were greatest for BIXF + TFLX + PROT (1,080) followed by PICO + BENZ (1,010), PYRA + EPOX + FLUX (981.5), AZOX + BENZ (910), TFLX + PROT (891), PICO +TEBU (682), TFLX + CYPR (646), and PICO + CYPR (600). Significant declines in both C¯ and D¯ in as little as 4 years were detected for AZOX + BENZ (35.3%; 550 kg/ha) and PICO + BENZ (15.5%; 359.8 kg/ha). Variance in D¯ was reduced by the inclusion of baseline severity as covariate. In trials where baseline disease was ≥70%, yield was 250 kg/ha greater compared to areas with low baseline disease. Disease control and yield response were generally greater in the south‐east, where the frequency of profitable scenarios was 30% higher on average than in the north‐west. Results of this meta‐analysis are critical for supporting decisions during planning of fungicide programmes.
A meta‐analytic approach was used to summarize the performance of eight commercial premixes of fungicides evaluated in cooperative research trials in 46 locations in Brazil in 2015 to 2020 to aid decision‐making for spray programmes.
Pediatric deep vein thrombosis (DVT) is an emerging problem in tertiary care hospitals, recent reviews shows a rate of 40.2/10,000 admissions. Experts affirm that enoxaparin has become in the drug of ...choice for DVT therapy. Despite this, there is a little information regarding the optimal dose schedule for enoxaparin therapy in children and the therapeutic guidelines for enoxaparin use in children are extrapolated from adult guidelines. Monitoring by antifactor Xa (anti-Xa) measurement and target concentrations between 0.5-1 U/ml at 4-6 h postdose are recommended. This study was designed to analyse our experience in paediatric-specific dosage requirements for enoxaparin therapy. A retrospective study was performed with patients less than 16 years old, who were treated with enoxaparin for DVT and monitored by anti-Xa concentration, between January 2005 and March 2012. Demographic and clinical characteristics and outcomes were obtained. Fourteen patients were analyzed: boy/girl ratio, 8/4; median age, 3.5 months. Cerebral venous sinus thrombosis was the most common indication for therapy. All patients presented thrombosis risks factors. Dose increases were necessary only in patients less than 6 years old. Target anti-Xa concentrations were achieved in 12 (85%) patients. Children younger than 1 year required a higher dose of enoxaparin/kg (1.5-2.7 mg/kg per 12 h). Complete resolutions of DVT were registered in all cases. The mean number of dose increases was three and a median of 11 days to achieve target anti-Xa concentration. This study indicates that an initial higher enoxaparin dose may be necessary in neonates and infants, but other factors must be considered to improve management.
The mean age of patients included in clinical trials does not reflect the current clinical practice for patients with B-cell non-Hodgkin lymphoma (B-NHL). We compared our outcomes for patients with ...B-NHL aged < 65 and > 65 years who were treated with 90-yttrium-ibritumomab tiuxetan therapy ((90)Y-IT).
A total of 108 patients who had received (90)Y-IT according to the hospital protocol (ISCRTN36210045) were eligible. A quality of life (QoL) assessment using the Medical Outcomes Study short form 36-item survey was performed for patients aged > 65 years.
Of the 108 patients, 43 were aged > 65 years (mean age, 73.4 years; men 46.15%); 37 had follicular NHL (86.0%). Also, 27 patients had previously undergone < 2 therapy regimens (62.8%). The mean follow-up period was 45.2 months. The mean progression-free survival (PFS) period was 71.3 months, and the mean overall survival was 78.2 months. The median values were not reached. The overall response rate was 90.5%, and a complete response was observed in 36 of the 43 patients aged > 65 years (85.7%). Neutropenia (43.3%) and thrombocytopenia (45.2%) were the most frequent grade 3 and 4 toxicities. Five patients required a red blood cell transfusion and 11, a platelet transfusion. Five patients aged > 65 years (11.6%) developed a second tumor. These outcomes were similar to those for the younger patients. The QoL assessment showed scores similar to those of general population for general health and social functioning.
This is the largest cohort of NHL treated with RIT in a single institution in Spain. We observed a high response rate and prolonged PFS in patients with B-NHL, independent of patient age. Thus, consolidation RIT offers better outcomes with manageable toxicity.
Introduction
Type 1 Gaucher disease (GD)(OMIM # 230800), has a pan-ethnic distribution, in Spain its prevalence is about 1/100,000. Since more than twenty years the impact of therapies in the ...awareness of the disease is changing the characteristics and expectations of patients. The Spanish Gaucher disease Registry (SGDR) is working since 1993 and compiled demographic, clinical, genetic, analytical and imaging data about 360 type 1 GD Spanish patients. The application of new high computing capacity and powerful network analysis to analyze the registered data could provide a visualization tool and allows to extract knowledge from complex and very numerous relationships. The objective of this analysis is to discover useful ideas and new correlations to predict the risk of developing late complications and to extract knowledge of complex and very numerous relationships.
Patients & Methods
From 416 patients included in the SGDR we have selected 358 with more than 70% of data and follow-up. GD type 2 patients have been excluded. The variables included in the database at diagnosis: demographic data and the clinical, analytical and imaging information at diagnostic and during the treatment follow-up as well as comorbidities. With Kampal Data Solutions, a spin-off company of the University of Zaragoza dedicated to the development of computer applications and advanced data analytics, this company has experience in the homogenization of information and in the elaboration of classic and advanced statistics projects, as well as in the visualization of said information complex network techniques and the relationship between variables and model designs.Variables:Birthdate, age at diagnosis, gender, death date, severity category of disease (mild, moderate, severe), concomitant diseases, Parkinson disease in relatives, liver volume, spleen volume, spleen removal, bone disease, S-MRI, DEXA, chitotriosidase, CCL18/PARC, lyso Gb1, B12 vitamin level, iron concentration, ferritin, cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, AST, ALT, GGT, acid phosphatase, bilirubin, hemoglobin concentration, Hsc, WBC count, platelets count, serum gammaglobulin fraction, IgG, IgA, IgM, GBA activity, GBAgenotype, CHIT1genotype, age to start therapy, type of therapy (ERT, SRT), new bone crisis or joint replacement, development of malignancies or Parkinson disease.
Results: The 358 subjects were mostly GD1 (340 vs 18 GD3), 18% were splenectomized and 39% have advanced bone disease and bone complications. Most of the patients have a complex heterozygous genotype (81% vs 19% homozygous). 47% of patients were diagnosed before 2,000 and 10% die before this study. Most of them are receiving ERT (54%). About comorbidities, 4% of patients developed MGUS or Parkinson disease and 6% malignant neoplasias. The main results have founded a significant correlation between skeletal complications and impaired and spleen removal (p=0.0005); this fact confirm previous reports. In this study a low IgA serum level shows a significant correlation with severe bone disease(p=0.0000), and with the incidence of new bone crisis during long term ERT. A IgG increase was related to the development of neoplasia. There were two more important factors that we have found; the age at diagnosis and the age to start therapy.
Comments:
Registries are key resources to help increasing timely and accurate diagnosis, improving patient's management, tailoring treatments, facilitating clinical trials, supporting healthcare planning and speeding up research. This is the very first attempt to establish a correlation network among different biomarkers and clinical characteristics in a national base cohort. As has been hypothesized seems that the impairment of immune system has a strong impact in long term complications, in our study the humoral immunity dysfunction pops up as an important factor. Despite of our short cohort, the quality of data is accurate and can reflect the own Spanish Gaucher disease characteristics. Currently we are working in the design of algorithms to help to predict patient outcomes.
No relevant conflicts of interest to declare.
Background:The isolation of cell-free DNA (cfDNA) evolved the concept of liquid biopsy. Several works have analyzed the presence of cfDNA in lymphomas, especially in diffuse large B-cell lymphoma ...(DLBCL) and Hodgkin lymphoma (HL), however there is limited information regarding the detection of cfDNA in other types of lymphomas or the role of cfDNA detection to monitor disease outcome.
Objectives:1.- To analyze the presence of cfDNA at diagnosis of patients with lymphoproliferative malignancies. 2.- To evaluate the change in concentration of cfDNA (cfDNA) after treatment in DLBCL patients.
Material and Methods:A retrospective study in a single center was performed including 221 adult patients since January 2015 to February 2019 with: DLBCL, HL, marginal zone lymphoma (MZL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL) and peripheral T-cell lymphomas (TCL). All patients had plasma samples collected at diagnosis that were stored in the institutional biobank (MarBiobank). The cfDNA were obtained from 1 mL of -80°C frozen stored plasma using the MagMax Cell Free DNA isolation kit (Thermo Fisher Scientific). The cfDNA quantification was performed using the Qubit system with the dsDNA high sensitivitykit (Thermo Fisher) and is expressed as ng/mL of plasma. In addition, patients with DLBCL who were treated with rituximab-CHOP/CHOP-like regimens were evaluated for cfDNA analysis, pre and post-treatment, and results were compared with PET-CT scan findings.
Results: Stored plasma samples at diagnosis were available in 221 patients: DLBCL 82, HL 22, CLL/LPL 13, FL 36, MZL 37, MCL: 11, TCL 10 and others 10 (B-cell lymphoma unclassified, hairy cell leukemia, Burkitt lymphoma). Successful identification of cfDNA was obtained in 95.9% (212/221) of samples. DLBCL patients showed higher cfDNA globally and, DLBCL, HL and FL patients showed a higher concentration than MZL who exhibited the lower concentration of all groups (p=0.009; p=0.013 and p=0.002); see table 1.
50 DLBCL patients with a median follow-up since diagnosis of 25.5 (5-51) months were analyzed. Median age was 67 (19-79) years, males 56% (28). IPI distribution: low-risk 28% (14), low-intermediate 26% (13), high-intermediate 24% (12) and high risk 22% (11) cases. Detection of cfDNA was successful in 100% at diagnosis and in 98% (49) cases post-therapy. The mean cfDNA at diagnosis was 2.21 (standard deviation- SD: 1.60) ng/mL with a correlation with LDH concentration (p<0.001) and with high-risk IPI category (p=0.02). The mean cfDNA in the post-therapy sample was 4.39 (SD 16.46) ng/mL.
After therapy 86% (43) of patients achieved at least PR (41 complete response), and the mean cfDNA for these patients was 1.58 (SD 1.96); patients who showed no response or progressive disease after therapy exhibited higher cfDNA 21.25 ng/mL (SD 41.91)(p<0.001). In order to evaluate the clinical relevance of the changes of cfDNA after treatment, we considered a variation of +/-25% of cfDNA at diagnosis regarding cfDNA after therapy to classify the results. Therefore, 13 patients had an increase of cfDNA after therapy, 6 patients had no change, and 31 patients had a decrease. Patients with a decrease in cfDNA at the end of therapy were less likely to relapse (p<0.01) During follow-up, two patients relapsed after 24 and 8 months. The patient who relapsed after 24 months showed an increase in cfDNA, from 0.966 ng/mL to 20.80ng/mL three months before the histological confirmation of relapse.
Conclusions:Isolation of cfDNA was feasible in >95% of lymphoma patients independently of histology or disease stage. Patients with DLBCL exhibited the higher cfDNA concentration which were also correlated with LDH concentrations and high-risk IPI. Kinetics of cfDNA is related to response to therapy in DLBCL and also might detect relapse. Even though additional studies are necessary, monitoring of cfDNA may help in management of patients with DLBCL.
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Salar:Roche: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy. Sanchez-Gonzalez:Takeda: Consultancy, Speakers Bureau; Alexion: Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Gimeno:JANSSEN: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau. Bellosillo:Qiagen: Consultancy, Speakers Bureau; TermoFisher Scientific: Consultancy, Speakers Bureau.
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