Concentración preoperatoria de fibrinógeno plasmático como predictor de sangrado en artroplastía total de cadera / Preoperative concentration of plasma fibrinogen as a predictor of bleeding in total hip arthroplasty

Resumen: Introducción: La artroplastía total de cadera tiene popularidad debido al éxito en el tratamiento de coxartrosis; son procedimientos asociados a la pérdida de sangre. Un sangrado importante provoca complicaciones como aumento en días de estancia intrahospitalaria, mayor costo de la enfermedad, exponiendo al paciente a complicaciones asociadas a transfusión sanguínea. El objetivo del estudio es investigar asociación entre concentración de fibrinógeno plasmático preoperatorio con sagrado transquirúrgico y determinar el nivel de corte de fibrinógeno para presentar mayor sangrado transquirúrgico. Material y métodos: Estudio retrospectivo, observacional, analítico, de Junio a Diciembre de 2020, incluyendo 227 pacientes con coxartrosis IV de la escala de Kellgren y Lawrence sometidos a artroplastía total primaria de cadera, derechohabientes, mayores de 18 años, en ausencia de enfermedades hepáticas o hematológicas y antecedente de sangrado quirúrgico importante. Resultados: El valor promedio de hemoglobina preoperatoria fue 14.6 ± 1.3 g/dl, posterior a cirugía (48 horas) 10.5 ± 1.4 g/dl; observando descenso de 4.1 ± 1.2 g/dl (p ≤ 0.0001). Valor promedio del hematocrito prequirúrgico 43% [41-45], posterior al procedimiento 32% [29-35]; se observó descenso de 11% [8-14] (p ≤ 0.0001); 98 pacientes presentaron sangrado transquirúrgico ≥ 300 ml; 129 tuvieron sangrado ≤ 300 ml; 61.2% de pacientes con sangrado mayor de 300 ml mostraron valores de fibrinógeno debajo del punto de corte (388 mg/dl). Conclusión: En pacientes postoperados los niveles preoperatorios de fibrinógeno ≤ 388 mg/dl y edad ≥ 58 años se asociaron al aumento en el riesgo del OR = 0.18 (IC 95% 0.10-0.32) de presentar sangrado transquirúrgico ≥ 300 ml, con descenso de la Hb de 4.1 ± 1.2 g/dl (p = 0.0001) y Hto de 11% [8-14] (p = 0.0001) entre el preoperatorio y el postoperatorio en 48 horas.

Abstract: Introduction: Total hip arthroplasty is popular for its success in treating coxarthrosis, its associated with substantial blood loss. Significant bleeding causes complications such as increase in hospitalization days, higher costs, exposing the patient to complications associated with blood transfusion. The aim of the study is to investigate the association between preoperative plasma fibrinogen concentration and trans-surgical bleeding and determine fibrinogen level cut-off to present greater trans-surgical bleeding. Material and methods: Retrospective, observational, analytical study, from June to December 2020, including 227 patients with Kellgren and Lawrence scale IV coxarthrosis undergoing primary total hip arthroplasty, beneficiaries, older than 18 years, without liver or hematological diseases, and history of significant surgical bleeding. Results: Mean preoperative hemoglobin value was 14.6 ± 1.3 g/dl, after surgery (48 hours) 10.5 ± 1.4 g/dl; decrease of 4.1 ± 1.2 g/dl (p ≤ 0.0001). Mean preoperative hematocrit value 43% [41-45], after the procedure; 32% [29-35]; decrease of 11% [8-14] (p ≤ 0.0001). 98 patients had intraoperative bleeding ≥ 300 ml, 129 had ≤ 300 ml; 61.2% of patients with bleeding greater than 300 ml had fibrinogen values below the cut-off point (388 mg/dl). Conclusion: In postoperative patients, preoperative fibrinogen levels ≤ 388 mg/dl and age ≥ 58 years were associated with an increased risk of OR = 0.18 (95% CI 0.10-0.32) of presenting trans-surgical bleeding ≥ 300 ml, with a decrease in Hb of 4.1 ± 1.2 g/dl (p = 0.0001) and Hto of 11% [8-14] (p = 0.0001) between the pre and postoperative period in 48 hours.

Incidence and risk factors for acute kidney injury: a prospective, randomized, single-blind clinical trial comparing total knee arthroplasty with and without tourniquet.

PURPOSE: Identify the incidence and risk factors for acute kidney injury (AKI) following total knee arthroplasty (TKA) with and without tourniquet. MATERIAL AND METHODS: 100 patients were randomized into two groups. Postoperative AKI was defined as the postoperative creatinine level 0.3 mg/dl compared with baseline. Potential variables associated with AKI were analyzed by multivariate logistic regression model to identify the AKI risk factors in TKA patients with and without tourniquet. RESULTS: AKI rate was 22%, tourniquet use (OR = 2.66, p = 0.014), blood loss > 500 cm3 (OR = 3.99, p = 0.001), postoperative Hb < 10 g/dl (OR = 2.68, p = 0.008), blood transfusions (OR = 2.86, p = 0.012) and diabetes (OR = 2.80, p = 0.006) were associated with increased risk of postoperative AKI. CONCLUSIONS: The use of tourniquet should be indicated with caution and should not be used routinely in patients with other risk factors for the development of acute kidney dysfunction, other measures to achieve trans-surgical hemostasis should be implemented in our environment to reduce the incidence of acute kidney dysfunction related to the use of the tourniquet.

PROPÓSITO: Identificar la incidencia y factores de riesgo para lesión renal aguda (LRA) después de la artroplastia total de rodilla (ATR) con y sin uso de torniquete. MATERIAL Y MÉTODOS: Se dividieron 100 pacientes en dos grupos. Se definió la LRA como una elevación postoperatoria de la creatinina 0.3 mg/dl comparada con el nivel basal preoperatorio. Las potenciales variables asociadas con la DRA fueron analizadas con un modelo de regresión logística multivariada para identificar los factores de riesgo de DRA en pacientes sometidos a ATR con y sin torniquete. RESULTADOS: La incidencia de LRA fue de 22%. El uso de torniquete (OR = 2.66, p = 0.014), pérdida sanguínea > 500 cm3 (OR = 3.99, p = 0.001), Hb postoperatoria < 10 g/dl (OR = 2.68, p = 0.008), transfusión sanguínea (OR = 2.86, p = 0.012) y la diabetes (OR = 2.80, p = 0.006) fueron asociados a un mayor riesgo postoperatorio de LRA. CONCLUSIONES: El uso de torniquete debe estar indicado con precaución y no debe utilizarse de forma rutinaria en pacientes con otros factores de riesgo para el desarrollo de disfunción renal aguda, otras medidas para lograr la hemostasia transquirúrgica deben implementarse en nuestro entorno para reducir la incidencia de disfunción renal aguda relacionada con el uso del torniquete.

Incidence and risk factors for acute kidney injury: a prospective, randomized, single-blind clinical trial comparing total knee arthroplasty with and without tourniquet / Incidencia y factores de riesgo para lesión renal aguda: Un ensayo clínico ciego, prospectivo y aleatorizado comparando la artroplastía total de rodilla con y sin torniquete

Abstract: Purpose: Identify the incidence and risk factors for acute kidney injury (AKI) following total knee arthroplasty (TKA) with and without tourniquet. Material and methods: 100 patients were randomized into two groups. Postoperative AKI was defined as the postoperative creatinine level ≥ 0.3 mg/dl compared with baseline. Potential variables associated with AKI were analyzed by multivariate logistic regression model to identify the AKI risk factors in TKA patients with and without tourniquet. Results: AKI rate was 22%, tourniquet use (OR = 2.66, p = 0.014), blood loss > 500 cm3 (OR = 3.99, p = 0.001), postoperative Hb < 10 g/dl (OR = 2.68, p = 0.008), blood transfusions (OR = 2.86, p = 0.012) and diabetes (OR = 2.80, p = 0.006) were associated with increased risk of postoperative AKI. Conclusions: The use of tourniquet should be indicated with caution and should not be used routinely in patients with other risk factors for the development of acute kidney dysfunction, other measures to achieve trans-surgical hemostasis should be implemented in our environment to reduce the incidence of acute kidney dysfunction related to the use of the tourniquet.

Resumen: Propósito: Identificar la incidencia y factores de riesgo para lesión renal aguda (LRA) después de la artroplastia total de rodilla (ATR) con y sin uso de torniquete. Material y métodos: Se dividieron 100 pacientes en dos grupos. Se definió la LRA como una elevación postoperatoria de la creatinina ≥ 0.3 mg/dl comparada con el nivel basal preoperatorio. Las potenciales variables asociadas con la DRA fueron analizadas con un modelo de regresión logística multivariada para identificar los factores de riesgo de DRA en pacientes sometidos a ATR con y sin torniquete. Resultados: La incidencia de LRA fue de 22%. El uso de torniquete (OR = 2.66, p = 0.014), pérdida sanguínea > 500 cm3 (OR = 3.99, p = 0.001), Hb postoperatoria < 10 g/dl (OR = 2.68, p = 0.008), transfusión sanguínea (OR = 2.86, p = 0.012) y la diabetes (OR = 2.80, p = 0.006) fueron asociados a un mayor riesgo postoperatorio de LRA. Conclusiones: El uso de torniquete debe estar indicado con precaución y no debe utilizarse de forma rutinaria en pacientes con otros factores de riesgo para el desarrollo de disfunción renal aguda, otras medidas para lograr la hemostasia transquirúrgica deben implementarse en nuestro entorno para reducir la incidencia de disfunción renal aguda relacionada con el uso del torniquete.

[Preoperative concentration of plasma fibrinogen as a predictor of bleeding in total hip arthroplasty]. / Concentración preoperatoria de fibrinógeno plasmático como predictor de sangrado en artroplastía total de cadera.

INTRODUCTION: Total hip arthroplasty is popular for its success in treating coxarthrosis, its associated with substantial blood loss. Significant bleeding causes complications such as increase in hospitalization days, higher costs, exposing the patient to complications associated with blood transfusion. The aim of the study is to investigate the association between preoperative plasma fibrinogen concentration and trans-surgical bleeding and determine fibrinogen level cut-off to present greater trans-surgical bleeding. MATERIAL AND METHODS: Retrospective, observational, analytical study, from June to December 2020, including 227 patients with Kellgren and Lawrence scale IV coxarthrosis undergoing primary total hip arthroplasty, beneficiaries, older than 18 years, without liver or hematological diseases, and history of significant surgical bleeding. RESULTS: Mean preoperative hemoglobin value was 14.6 ± 1.3 g/dl, after surgery (48 hours) 10.5 ± 1.4 g/dl; decrease of 4.1 ± 1.2 g/dl (p 0.0001). Mean preoperative hematocrit value 43% [41-45], after the procedure; 32% [29-35]; decrease of 11% [8-14] (p 0.0001). 98 patients had intraoperative bleeding 300 ml, 129 had 300 ml; 61.2% of patients with bleeding greater than 300 ml had fibrinogen values below the cut-off point (388 mg/dl). CONCLUSION: In postoperative patients, preoperative fibrinogen levels 388 mg/dl and age 58 years were associated with an increased risk of OR = 0.18 (95% CI 0.10-0.32) of presenting trans-surgical bleeding 300 ml, with a decrease in Hb of 4.1 ± 1.2 g/dl (p = 0.0001) and Hto of 11% [8-14] (p = 0.0001) between the pre and postoperative period in 48 hours.

INTRODUCCIÓN: La artroplastía total de cadera tiene popularidad debido al éxito en el tratamiento de coxartrosis; son procedimientos asociados a la pérdida de sangre. Un sangrado importante provoca complicaciones como aumento en días de estancia intrahospitalaria, mayor costo de la enfermedad, exponiendo al paciente a complicaciones asociadas a transfusión sanguínea. El objetivo del estudio es investigar asociación entre concentración de fibrinógeno plasmático preoperatorio con sagrado transquirúrgico y determinar el nivel de corte de fibrinógeno para presentar mayor sangrado transquirúrgico. MATERIAL Y MÉTODOS: Estudio retrospectivo, observacional, analítico, de Junio a Diciembre de 2020, incluyendo 227 pacientes con coxartrosis IV de la escala de Kellgren y Lawrence sometidos a artroplastía total primaria de cadera, derechohabientes, mayores de 18 años, en ausencia de enfermedades hepáticas o hematológicas y antecedente de sangrado quirúrgico importante. RESULTADOS: El valor promedio de hemoglobina preoperatoria fue 14.6 ± 1.3 g/dl, posterior a cirugía (48 horas) 10.5 ± 1.4 g/dl; observando descenso de 4.1 ± 1.2 g/dl (p 0.0001). Valor promedio del hematocrito prequirúrgico 43% [41-45], posterior al procedimiento 32% [29-35]; se observó descenso de 11% [8-14] (p 0.0001); 98 pacientes presentaron sangrado transquirúrgico 300 ml; 129 tuvieron sangrado 300 ml; 61.2% de pacientes con sangrado mayor de 300 ml mostraron valores de fibrinógeno debajo del punto de corte (388 mg/dl). CONCLUSIÓN: En pacientes postoperados los niveles preoperatorios de fibrinógeno 388 mg/dl y edad 58 años se asociaron al aumento en el riesgo del OR = 0.18 (IC 95% 0.10-0.32) de presentar sangrado transquirúrgico 300 ml, con descenso de la Hb de 4.1 ± 1.2 g/dl (p = 0.0001) y Hto de 11% [8-14] (p = 0.0001) entre el preoperatorio y el postoperatorio en 48 horas.

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Psicoestimulantes menores consumidos por estudiantes de la Universidad San Francisco Xavier de Chuquisaca, 2019 / Minor psychostimulants consumed by students of San Francisco Xavier de Chuquisaca University, 2019

El objetivo del estudio fue determinar el consumo de psicoestimulantes en estudiante de la Universidad San Francisco Xavier de Chuquisaca. Se recolectaron los datos mediante encuestas aplicadas a 331 estudiantes. El estudio reveló el psicoestimulante de mayor consumo con 31,88% el café y la coca cola con 26,65%, en su mayoría fueron consumidos con fines académicos. En los efectos secundarios, la sed se estableció como el más frecuente en estudiantes con 30,74%, seguido por cefalea con 27,56% y el cansancio en 14,84%. Se concluye que el café se determina como psicoestimulante menor más consumido en épocas de actividad académica y la sed como el efecto secundario más frecuente.

The objective of the study was to determine the consumption of psychostimulants in a student at the San Francisco Xavier de Chuquisaca University. The data were collected through surveys applied to 331 students. The study revealed the psychostimulant with the highest consumption with 31.88%, coffee and coca cola with 26.65%, most of which were consumed for academic purposes. Regarding side effects, thirst was established as the most frequent in students with 30.74%, followed by headache with 27.56% and fatigue in 14.84%. It is concluded that coffee is determined as the minor psychostimulant most consumed in times of academic activity and thirst as the most frequent side effect.

Improved reductive transformation of iopromide by magnetite containing reduced graphene oxide nanosacks as electron shuttles.

The novel application of magnetite containing reduced graphene oxide nanosacks (MrGO-N) as electron shuttles to improve the reductive degradation of pharmaceutical pollutant, iopromide (IOP), was evaluated. The MrGO-N were synthesized by ultrasonicated nebulization process, and their physicochemical characterization was performed by potentiometric titrations, zeta potential, high resolution transmission electron microscopy (HR-TEM), X-ray diffraction, as well as by Raman and Fourier transform infrared spectroscopies. Results demonstrated the thermal reduction of precursor graphene oxide sheets, the removal of different oxygenated groups, and the successful assembly of magnetite nanoparticles (MNP) in the graphene sacks. Also, reduction experiments revealed 72 % of IOP removal efficiency and up to 2.5-fold faster degradation of this pollutant performed with MrGO-N as redox catalysts in batch assays and with sulfide as electron donor. Chemical transformation pathway of IOP provides evidence of complete dehalogenation and further transformation of aromatic ring substituents. Greater redox-mediating ability of MrGO-N was observed, which was reflected in the catalytic activity of these nanomaterials during the reductive degradation of IOP. Transformation byproducts with simpler chemical structure were identified, which could lead to complete degradation by conventional methodologies in a complementary treatment process. Redox-mediating activity of MrGO-N could potentially be applied in wastewater treatment systems in order to facilitate the biodegradation of priority contaminants.

Novel application of magnetic nano-carbon composite as redox mediator in the reductive biodegradation of iopromide in anaerobic continuous systems.

The redox-mediating capacity of magnetic reduced graphene oxide nanosacks (MNS) to promote the reductive biodegradation of the halogenated pollutant, iopromide (IOP), was tested. Experiments were performed using glucose as electron donor in an upflow anaerobic sludge blanket (UASB) reactor under methanogenic conditions. Higher removal efficiency of IOP in the UASB reactor supplied with MNS as redox mediator was observed as compared with the control reactor lacking MNS. Results showed 82% of IOP removal efficiency under steady state conditions in the UASB reactor enriched with MNS, while the reactor control showed IOP removal efficiency of 51%. The precise microbial transformation pathway of IOP was elucidated by high-performance liquid chromatography coupled to mass spectroscopy (HPLC-MS) analysis. Biotransformation by-products with lower molecular weight than IOP molecule were identified in the reactor supplied with MNS, which were not detected in the reactor control, indicating the contribution of these magnetic nano-carbon composites in the redox conversion of this halogenated pollutant. Reductive reactions of IOP favored by MNS led to complete dehalogenation of the benzene ring and partial rupture of side chains of this pollutant, which is the first step towards its complete biodegradation. Possible reductive mechanisms that took place in the biodegradation of IOP were stated. Finally, the novel and successful application of magnetic graphene composites in a continuous bioreactor to enhance the microbial transformation of IOP was demonstrated.

A rural environment does not protect against asthma or other allergic diseases amongst Mexican children.

INTRODUCTION: The commonly held notion that a rural environment decreases the frequency of allergic diseases has proven to be inconsistent amongst children. OBJECTIVE: Our objective was to contrast the prevalence of bronchial asthma (BA), allergic rhinitis (AR), and atopic dermatitis (AD) between children that live in a rural environment and those that live in urban areas. METHODS: We carried out a cross-sectional study amongst children aged six to seven; they were selected through probabilistic, stratified and conglomerated sampling. The prevalence of BA, AR, and AD was identified with the use of the questionnaire provided by The International Study of Asthma and Allergies in Childhood, additionally, we inquired about each child's family history of atopy, their exposure to farm animals, the intake of unpasteurised cow's milk, and the number of siblings related to every child. We used logistic regression and multivariate analysis to determine the correlation between asthma, allergic diseases, and rural environment. RESULTS: We included 189/1003 (18.8%) children from a rural environment, and 814/1003 (81.2%) from an urban area. BA and AR were associated to a family history of atopy (OR=2.15, p=0.001; OR=2.58, p=0.002, respectively). BA was more prevalent in males (OR=1.92, p=0.007). Notably, a higher number of siblings seems to protect against AR (OR=0.45, p=0.008). A paternal history of allergies was associated to AD. CONCLUSIONS: In our study, we were unable to find protective factors in a rural environment that might decrease the prevalence of asthma or allergic diseases.

A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms with variable risk of evolution into post-PV and post-ET myelofibrosis, from now on referred to as secondary myelofibrosis (SMF). No specific tools have been defined for risk stratification in SMF. To develop a prognostic model for predicting survival, we studied 685 JAK2, CALR, and MPL annotated patients with SMF. Median survival of the whole cohort was 9.3 years (95% CI: 8-not reached-NR-). Through penalized Cox regressions we identified negative predictors of survival and according to beta risk coefficients we assigned 2 points to hemoglobin level <11 g/dl, to circulating blasts ⩾3%, and to CALR-unmutated genotype, 1 point to platelet count <150 × 109/l and to constitutional symptoms, and 0.15 points to any year of age. Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) allocated SMF patients into four risk categories with different survival (P<0.0001): low (median survival NR; 133 patients), intermediate-1 (9.3 years, 95% CI: 8.1-NR; 245 patients), intermediate-2 (4.4 years, 95% CI: 3.2-7.9; 126 patients), and high risk (2 years, 95% CI: 1.7-3.9; 75 patients). Finally, we found that the MYSEC-PM represents the most appropriate tool for SMF decision-making to be used in clinical and trial settings.

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis.

Ruxolitinib is a Janus kinase (JAK) (JAK1/JAK2) inhibitor that has demonstrated superiority over placebo and best available therapy (BAT) in the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) studies. COMFORT-II was a randomized (2:1), open-label phase 3 study in patients with myelofibrosis; patients randomized to BAT could crossover to ruxolitinib upon protocol-defined disease progression or after the primary end point, confounding long-term comparisons. At week 48, 28% (41/146) of patients randomized to ruxolitinib achieved ⩾35% decrease in spleen volume (primary end point) compared with no patients on BAT (P<0.001). Among the 78 patients (53.4%) in the ruxolitinib arm who achieved ⩾35% reductions in spleen volume at any time, the probability of maintaining response was 0.48 (95% confidence interval (CI), 0.35-0.60) at 5 years (median, 3.2 years). Median overall survival was not reached in the ruxolitinib arm and was 4.1 years in the BAT arm. There was a 33% reduction in risk of death with ruxolitinib compared with BAT by intent-to-treat analysis (hazard ratio (HR)=0.67; 95% CI, 0.44-1.02; P=0.06); the crossover-corrected HR was 0.44 (95% CI, 0.18-1.04; P=0.06). There was no unexpected increased incidence of adverse events with longer exposure. This final analysis showed that spleen volume reductions with ruxolitinib were maintained with continued therapy and may be associated with survival benefits.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Myeloproliferative neoplasms and inflammation: whether to target the malignant clone or the inflammatory process or both.

The Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal disorders involving hematopoietic stem and progenitor cells and are associated with myeloproliferation, splenomegaly and constitutional symptoms. Similar signs and symptoms can also be found in patients with chronic inflammatory diseases, and inflammatory processes have been found to play an important role in the pathogenesis and progression of MPNs. Signal transduction pathways involving JAK1, JAK2, STAT3 and STAT5 are causally involved in driving both the malignant cells and the inflammatory process. Moreover, anti-inflammatory and immune-modulating drugs have been used successfully in the treatment of MPNs. However, to date, many unresoved issues remain. These include the role of somatic mutations that are present in addition to JAK2V617F, CALR and MPL W515 mutations, the interdependency of malignant and nonmalignant cells and the means to eradicate MPN-initiating and -maintaining cells. It is imperative for successful therapeutic approaches to define whether the malignant clone or the inflammatory cells or both should be targeted. The present review will cover three aspects of the role of inflammation in MPNs: inflammatory states as important differential diagnoses in cases of suspected MPN (that is, in the absence of a clonal marker), the role of inflammation in MPN pathogenesis and progression and the use of anti-inflammatory drugs for MPNs. The findings emphasize the need to separate the inflammatory processes from the malignancy in order to improve our understanding of the pathogenesis, diagnosis and treatment of patients with Philadelphia-negative MPNs.

Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia.

In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.