Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Large-scale real-life analysis of survival and usage of therapies in multiple myeloma.

Survival in multiple myeloma has improved significantly in recent years, especially in young patients. We reviewed the evolution of the survival of patients with MM in three groups based on age at MM diagnosis over three time periods between 1999 and 2020 at our 12 de Octubre Hospital institution (H12O). Then, to confirm our results, we used data from TriNetx, a global health research platform that includes patients from Europe to US. Finally, we analysed differences in the patterns of treatment between networks across the world. Kaplan‒Meier analysis was used to estimate survival probabilities, and between-group differences were tested using the log-rank test and hazard ratio. For patients from H12O, the median OS was 35.61, 55.59 and 68.67 months for the 1999-2009, 2010-2014 and 2015-2020 cohorts, respectively (p = 0.0001). Among all patients included in the EMEA network, the median OS was 20.32 months versus 34.75 months from 1999-2009 versus 2010-2014. The median OS from the 2010-2014 versus 2015-2020 time cohorts was 34.75 months versus 54.43 months, respectively. In relation to the US cohort, the median OS from before 2010 versus 2010-2014 was not reached in either time cohort and neither when comparing the 2010-2014 versus 2015-2019 time cohorts. Bortezomib is the most commonly used drug in the EMEA cohort, while lenalidomide is the most commonly used drug in the US cohort. This large-scale study based on real-world data confirms the previous finding that MM patients have increased their survival in the last two decades.

Impact of COVID-19 in patients with multiple myeloma based on a global data network.

The COVID-19 pandemic has represented a major cause of morbidity/mortality worldwide, overstressing health systems. Multiple myeloma (MM) patients show an increased risk for infections and they are expected to be particularly vulnerable to SARS-CoV-2 infection. Here we have obtained a comprehensive picture of the impact of COVID-19 in MM patients on a local and a global scale using a federated data research network (TriNetX) that provided access to Electronic Medical Records (EMR) from Health Care Organizations (HCO) all over the world. Through propensity score matched analyses we found that the number of new diagnoses of MM was reduced in 2020 compared to 2019 (RR 0.86, 95%CI 0.76-0.96) and the survival of newly diagnosed MM cases decreased similarly (HR 0.61, 0.38-0.81). MM patients showed higher risk of SARS-CoV-2 infection (RR 2.09, 1.58-2.76) and a higher excess mortality in 2020 (difference in excess mortality 9%, 4.4-13.2) than non-MM patients. By interrogating large EMR datasets from HCO in Europe and globally, we confirmed that MM patients have been more severely impacted by COVID-19 pandemic than non-MM patients. This study highlights the necessity of extending preventive measures worlwide to protect vulnerable patients from SARS-CoV-2 infection by promoting social distancing and an intensive vaccination strategies.

miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk.

Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.

Chronic myeloid leukaemia in Spain: Its presentation characteristics have changed. Spanish section of the EUTOS population-based registry. / Leucemia mieloide crónica en España: sus características de presentación han cambiado. Sección española del registro poblacional EUTOS.

OBJECTIVES: To provide more reliable data on the epidemiology of chronic myeloid leukaemia (CML) in Spain than are currently available. MATERIAL AND METHODS: The EUTOS population-based project of European LeukemiaNet is a population registry of new CML cases in patients 18 years of age or older from 22 European areas. The Spanish section included the autonomous communities of Madrid, Castilla-La Mancha and Aragon, from 1-2-2010 to 31-12-2012. RESULTS: A total of 250 cases were recorded in 35 months. The overall incidence was 1.08 cases/10(5) inhabitants-year, with a predominance of men (58%) and clear differences among the communities. The incidence standardised by age was similar (overall, 1.04; men, 1.31; women, 0.81). The median age was 54 years. The incidence increased with age, reaching a peak at>65 years, although 31.7% of cases appeared between the ages of 20 and 44 years. Four percent of cases were diagnosed in advanced stages (2.4% in accelerated phase, 1.6% in blast crisis), 56% were asymptomatic, 38% had splenomegaly, and the Sokal score was high in 11% (lower than what was previously reflected in the literature). CONCLUSIONS: The current incidence of CML in Spain is higher than previously reported and similar to that of the European studies. Unlike the classical descriptions, CML presented mostly in asymptomatic form, with no splenomegaly, less leucocytosis and in stages with better prognosis.

Exome sequencing reveals novel and recurrent mutations with clinical impact in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P=0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.

Epigenomic profiling in polycythaemia vera and essential thrombocythaemia shows low levels of aberrant DNA methylation.

AIMS: The purpose of this study was to compare the DNA-methylation signature in classic chronic Philadelphia negative myeloproliferative neoplasms (MPN), polycythaemia vera (PV) and essential thrombocythaemia (ET), in order to obtain a global insight into DNA-methylation changes associated with these malignancies. METHODS: Thirty-five MPN samples from 11 ET JAK2 V617F, 12 ET JAK2 wild type (WT) and 12 PV JAK2 V617F patients as well as 12 from healthy donors were analysed. DNA samples extracted from whole peripheral blood were hybridised to the 'HumanMethylation27 DNA Analysis BeadChip.' RESULTS: All groups showed a very homogeneous methylation pattern. Only the ZNF577 gene showed a differential methylation profile between PV JAK2 V617F positive and controls. This aberrant methylation was correlated with a differential gene expression of ZNF577. No aberrant hypermethylation was found in the SOCS-1 and SOCS-3 genes. CONCLUSIONS: According to our results, an aberrant methylation pattern does not seem to play a crucial role in MPN pathogenesis; nor does it justify phenotypical differences between PV and ET.

The effect of nutritional supplementation on physical activity and exploratory behavior of Mexican infants aged 8-12 months.

BACKGROUND/OBJECTIVES: Physical activity and exploration in infancy affect physical and cognitive development. Nutritional supplementation improves activity in severely malnourished infants, but the evidence in mild-to-moderately malnourished and nutritionally at-risk infants is equivocal. We tested the effect of multiple-micronutrient supplementation on physical activity and exploration in Mexican infants. SUBJECTS/METHODS: Using a quasi experimental design, we analyzed data from a supplementation study that lacked a placebo-control group. We compared infants between 8 and 12 months measured at baseline who had received no supplementation (comparison group, n=78), with infants 8-12 months measured after 4 months of daily supplementation (treatment group, n=109). The treatment consisted of three supplement types: micronutrient powder, syrup (each containing only micronutrients) and a milk-based, fortified-food supplement (FFS; containing micronutrients and macronutrients). We formed the micronutrient-only group (MM) by combining the micronutrient powder and syrup groups. We measured activity and exploration by direct observation and used cluster analysis to form and characterize activity and exploration clusters. We performed logistic regression with activity or exploration cluster as the outcome variable and treatment versus comparison and MM or FFS versus comparison as the predictor variables. RESULTS: Treatment versus comparison increased the odds of being in the high activity (odds ratio (OR)=2.35, P<0.05) and high exploration (OR=1.87, P<0.05) cluster. MM increased the odds of being in the high activity (OR=2.64, P<0.05) cluster and FFS increased the odds (OR=3.16, P<0.05) of being in the high exploration cluster. CONCLUSIONS: Nutritional supplementation benefited activity and exploration in this sample of Mexican infants.

Real-time PCR quantification of haematopoietic chimerism after transplantation: a comparison between TaqMan and hybridization probes technologies.

This study aimed to compare the sensitivity and accuracy of two methods of quantitative real-time polymerase chain reaction (qrt-PCR), in order to determine haematopoietic chimerism (CH): single nucleotide polymorphisms using TaqMan (TM) probes and insertion/deletion polymorphisms using Hybridization (Hyb) probes. A total of 106 samples from 20 patients who underwent allogenic stem cell transplantation (n = 14) or live-donor liver transplantation (n = 6) were studied. The mean level of chimerism was 8.37% for the TM method and 7.73% in the Hyb method, which was not significantly different (P = 0.69). The Pearson correlation coefficient between the two methods was r = 0.91 (P < 0.001). The estimation of the regression line, using the Passing and Balbock method was Intercept A -0.0381 [95% confidence interval (CI) -0.1265 to 0.0296) and Slope B: 1.04609(95% CI 0.9349-1.161). Bland-Altman data showed that the standard deviations, which differed between the two methods (%Hyb-%TM), were 0.98 and -1.28. The accuracy and sensitivity of qrt-PCR chimerism is independent of the method used if the optimization is adequate and satisfies the criteria for adequate study. Real-time PCR, independent of the method adopted, is a very good tool for study levels of CH.

Living donor liver transplantation: usefulness of hemostatic and prothrombotic screening in potential donors.

Bleeding and thrombosis are serious complications of living donor liver transplantation (LDLT). The aim of this paper was to describe the results of a screening for coagulation disorders, including for thrombophilic factors, in potential living liver graft donors and to evaluate thrombotic and bleeding events in donors and recipients, during and after the procedure. From January 2001 to January 2007, 41 LDLTs were performed at our institution. We performed systematic screening for bleeding or prothrombotic states among 188 potential donors, 38 (20.2%) of whom showed at least one abnormality. We rejected potential donors with factor V Leiden, prothrombin mutation G20210A, and deficiencies in anticoagulant proteins (protein C, protein S, and antithrombin) or coagulation factors. Bleeding and thrombotic events in donors and recipients of the 41 LDLTs were evaluated during 7 days to 70 months follow-up. No major bleeding events were detected in the donors. Neither donor nor recipient experienced venous thrombosis or pulmonary embolism. Among all recipients, six suffered hepatic artery thrombosis including five in the first month probably related to surgery. Deep venous thrombosis and pulmonary embolism are well-known complications of hepatic surgery; Prothrombotic abnormalities in the donor can be transmitted to the recipient, leading to increased risk of serious postoperative events. Although the cost-effectiveness is not definitely established, we recommend systematic screening for hemostatic and prothrombotic disorders to prevent more morbidity of a procedure that already has high risks of bleeding and thrombosis.

A Validation and Reliability Study of the Physical Activity and Healthy Food Efficacy Scale for Children (PAHFE).

The purpose of this study was to obtain validity evidence for the Physical Activity and Healthy Food Efficacy Scale for Children (PAHFE). Construct validity evidence identifies four subscales: Goal-Setting for Physical Activity, Goal-Setting for Healthy Food Choices, Decision-Making for Physical Activity, and Decision-Making for Healthy Food Choices. The scores on each of these subscales show a moderate to high degree of internal consistency (0.59

Medición de los niveles de ruido ambiental en la ciudad de Santiago de Chile / Environmental noise levels measurement of the city of Santiago, Chile

Introducción. Un estudio realizado en Santiago en 1989, estimó que 1.300.000 personas estaban sometidas a niveles de ruido inaceptables por las normas internacionales. Considerando que no existen publicaciones sobre ruido ambiental realizadas por otorrinolaringólogos, y que el tema no ha sido revisado en los últimos 15 años, quisimos actualizar la información al respecto. Material y método. Se evaluó el ruido en lugares que afectan la rutina del ciudadano común, independiente de su profesión: Barrio residencial, parques, discotecas, bar-discoteque, calles principales, buses de transporte urbano habituales, buses de transporte urbano del proyecto transantiago y Metro. Las mediciones se realizaron con un sonómetro integrador, según lo establecido por la normas de la Comisión Nacional del Medio Ambiente (CONAMA), durante los meses de julio a septiembre del 2006. Resultados. Las discotecas son el lugar con mayor contaminación acústica. En relación a la Avda . Bernardo O'Higgins (Alameda), el nivel de ruido: 80.5 dB(A), se mantiene constante en diferentes puntos de medición. Entre el transporte público, el metro tiene los niveles de ruido más altos: 87 dB (A). No existen diferencias entre los buses antiguos o micros amarillas y los del proyecto transantiago. Conclusiones. Nuestros resultados ponen una nota de alerta mostrando que el nivel de ruido en Santiago, para la gran mayoría de los parámetros, son superiores a las normas establecidas.

Introduction. A study carried out in Santiago in 1989 estimated that 1,300,000 people were exposed to noise levels unacceptable by international standards. Considering that there are no reports of environmental noise evaluations performed by otorhinolaryngologists, and that the subject has not been reviewed in the past 15 years, in this paper we present up-to-date information on the topic. Materials and methods. Noise levels were evaluated in several places that are part of the common citizen life, disregarding their profession: Residential neighborhoods, parks, discos, pubs, main streets, city buses (old and new system), and subway. Measurements were taken using an integrating sound level meter, according to CONAMA standards, between the months of July and September, 2006. Results. The highest noise pollution was found in discos. With regard to the main avenue in Santiago, Libertador B. O'Higgins, noise levels (80 dB (A)) remained constant in different measured points. As of public transportation, the subway had the higher noise levels (87 dB (A)). There were no differences between the old and new public transit buses. Conclusions. Our results raise an environmental alert, showing that the noise level in Santiago, for most parameters, is above international standards.

Endocarditis infecciosa actinomicótica de la válvula mitral: caso de autopsia y revisión de la literatura / Actinomycotic infective endocarditis of the mitral valve: anatomoclinical case and review of literature

La infección actinomicótica del corazón es una enfermedad poco común, especialmente cuando el compromiso endocárdico valvular es primario. Sólo unos pocos casos han sido publicados. Comunicamos un caso de endocarditis primaria por Actinomyces sp de la válvula mitral, diagnosticada en la necropsia de un hombre de 34 años con antecedentes de valvulopatía reumática crónica, que falleció con una endocarditis infecciosa.

Actinomycotic infections of the heart is an uncommon disease, especially if the infection affects the valvular endocardium as primary focus. Just a few cases have been reported previously. We report a case of primary endocarditis of the mitral valve caused by Actinomyces sp diagnosed at necropsy in a 34 year-old man with history of chronic rheumatic disease presenting as a usual case of infective endocarditis.

Clostridium Perfringens: agente etiológico de queratitis infecciosa / Clostridium perfringens: etiologic agent of infectious keratitis

Clostridium perfringens es un raro agente causal de queratitis infecciosa, usualmente produce enfermedades necrotizantes severas. Presentación del caso: Agricultor de 32 años, procedente de General Artigas, Paraguay consultó en un servicio debido a un trauma con metal, cable en ojo derecho. Fue tratado con cicloplégico, AINES (antiinflamatorio no esteroideo) y aplicación de lente de contacto terapéutico. Después de 18 días sin mejoría acudió al Departamento de Oftalmología del Hospital de Clínicas de la Universidad Nacional de Asunción. El paciente presentó ausencia de percepción luminosa en el ojo afecto, quemosis, hipopion y ulcera central de cornea (5 mm). Se tomó muestra por raspado de cornea y el examen directo reveló bacilos Gram positivos. Se realizó cultivo en placas de agar sangre, agar chocolate y en caldo tioglicolato incubados a 37°C y en agar Sabouraud incubados a 28°C. Después del informe laboratorial se inició tratamiento con cefazolina 50 mg/ml y gentamicina 14 mg/ml cada hora. Del medio de enriquecimiento fue aislado Clostridium perfringens después de tres días. Desafortunadamente el paciente no asistió a su control.

Clostridium perfringens is a rare cause of infectious keratitis and usually produces severe necrotizing diseases. Case report: A 32 years old, male farmer from General Artigas, Paraguay consulted because of a history of trauma in the right eye, with a metal wire and was treated by cyclopegic NSAIDs (non­steroid anti­inflammatory) and therapeutic contact lenses for 18 days with no improvement He consulted to Ophthalmology Department of the National University of Asunción. The patient presented absence of light perception, chemosis, hypopyon and a deep central corneal defect (5 mm). Samples were collected by corneal scraping and Gram positive rods were revealed by direct examination. The culture was performed on sheep blood agar plate, chocolate agar plate and thioglycolate medium broth, incubated at 35°C. After laboratory results, the patient was treated with topic cefazolin (50 mg/ml) and gentamycin (14mg/ml) every hour. Clostridium perfringens grew in the thioglycolate medium broth after three days. Unfortunately, the patient did not return for control.

Conocimientos y hábitos de exposición solar de la población chilena / Sun exposure behaviors and knowledge among Chileans

Background: Ultraviolet light exposure has a pathogenic effect on the development of skin cancer, whose prevalence increases worldwide. In Chile and the rest of the world, preventive educational campaigns are carried out to change high risk sun exposure behaviors. Aim: To study the behavior of the Chilean population towards skin cancer prevention and to identify erroneous preventive practices and concepts. Material and methods: A survey containing 17 questions about sun exposure behaviors, photoprotective measures and knowledge about ultraviolet radiation and skin cancer was used. It was applied during January and February 2004, to 1,143 subjects (mean age 30 years, 409 males), taking vacations in beach resorts in Chile. Results: The hours of higher sun exposure ranged from 12 AM to 4 PM. Thirty seven percent of subjects were exposed more than 2 hours during this high risk lapse. Women and subjects aged less than 25 years were those with the riskiest behaviors. Fifty four percent used some type of photoprotection and 50% used ocular protection. Seventy percent used creams with sun screen and 74% used a sun protection factor higher than 15. Seventy percent applied the sun screen as recommended. Thirty eight percent had at least one sun burn in the last two years. More than 90% of subjects were aware of the relationship between sun exposure and skin cancer but 60% did not know the hours of higher ultraviolet radiation. The information about sun exposure was obtained from television in 57% of surveyed individuals. Conclusions: More educational campaigns about the risk of sun exposure are needed to reduce risky behaviors in the Chilean population.