Low-risk polycythemia vera treated with phlebotomies: clinical characteristics, hematologic control and complications in 453 patients from the Spanish Registry of Polycythemia Vera

Myelofibrosis; Phlebotomies; ThrombosisMielofibrosi; Flebotomies; TrombosiMielofibrosis; Flebotomías; TrombosisHematological control, incidence of complications, and need for cytoreduction were studied in 453 patients with low-risk polycythemia vera (PV) treated with phlebotomies alone. Median hematocrit value decreased from 54% at diagnosis to 45% at 12 months, and adequate hematocrit control over time ( 60 years, and microvascular symptoms constituted the main indications for starting cytoreduction. Median duration without initiating cytoreduction was significantly longer in patients younger than 50 years (< 0.0001). The incidence rate of thrombosis under phlebotomies alone was 0.8% per year and the estimated probability of thrombosis at 10 years was 8.5%. The probability of arterial thrombosis was significantly higher in patients with arterial hypertension whereas there was a trend to higher risk of venous thrombosis in cases with high JAK2V617F allele burden. Rates of major bleeding and second primary neoplasm were low. With a median follow-up of 9 years, survival probability at 10 years was 97%, whereas the probability of myelofibrosis at 10 and 20 years was 7% and 20%, respectively. Progression to acute myeloid leukemia was documented in 3 cases (1%). Current management of low-risk PV patients is associated with low rate of thrombosis and long survival. New treatment strategies are needed for improving hematological control and, in the long term, reducing progression to myelofibrosis.This work was supported by PI18/01472, PI18/00205, and PI21/00231 from the Instituto de Salud Carlos III (ISCIII), through the Plan Estatal de Investigación Científica y Técnica y de Innovación. GEMFIN received a grant from Novartis for the development of the Spanish Registry of Polycythemia Vera and for conducting the present project

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea

Hemorrhage; Polycythemia vera; RuxolitinibHemorràgia; Policitèmia vera; RuxolitinibHemorragia; Policitemia vera; RuxolitinibBackground Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. Methods A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. Results Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. Conclusions The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis.This work was supported by the Instituto de Salud Carlos III through a National Plan for Scientific and Technical Research and Innovation Innovación (PI18/01472, PI18/00205, and PI21/00231). The Spanish Group of Myeloproliferative Neoplasms (GEMFIN) received a grant from Novartis for developing the Spanish Registry of Polycythemia Vera and for conducting the current project

Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis

Comorbidities; Myelofibrosis; SurvivalComorbilidades; Mielofibrosis; SupervivenciaComorbiditats; Melofibrosi; SupervivènciaThe comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.This research was supported by an unrestricted grant from Novartis Pharmaceutical. The opinions expressed in this article are those of the authors and do not necessarily reflect those of Novartis

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification

Análisis genómico de dos cepas de K. pneumoniae ST11 resistentes a colistina portadoras de blaNDM-5 en una plataforma genética asociada a los integrones complejos de clase 1, con fenotipo de extrema resistencia a antibióticos

La metalo-β-lactamasa de Nueva Delhi (NDM) otorga resistencia a la mayoría de los antibióticos β-lactámicos, y generalmente se encuentra en aislamientos que poseen otros genes de resistencia (GRA) a otras familias de antibióticos. Estos aislamientos multidroga resistentes o con extrema resistencia, causan una variedad de infecciones asociadas con altas tasas de mortalidad en el ambiente hospitalario. Aunque el alelo NDM-1 es el más prevalente, otras variantes están aumentando su frecuencia en todo el mundo. En nuestro país se reportó recientemente el primer aislamiento clínico de Escherichia coli, Ec265, productora de NDM-5 y RmtB en América Latina. En nuestro estudio, se identificaron ambos genes blaNDM-5, y rmtB en dos cepas de Klebsiella pneumoniae aisladas de una mujer de 83 años en el año 2018. El primer aislamiento correspondió aun hisopado rectal que se tomó el primer día de ingreso al hospital dentro del programa de vigilancia. Se aisló la cepa H30pKpn productora de metalo-β-lactamasa y, en consecuencia, se instalaron las precauciones de contacto. Al cuarto día de hospitalización inició con fiebre, tos productiva y disnea. En este episodio se aisló de una muestra respiratoria la cepa HA31Kpn, también productora de metalo-β-lactamasa. HA30pKpn y HA31Kpn fueron resistentes a β-lactámicos (incluidos carbapenémicos y cefalosporinas de tercera y cuarta generación), gentamicina, amicacina, sulfametoxazol, trimetoprima, cloranfenicol, colistina (mutación R256G en gen pmrB) y ciprofloxacina. La paciente fue tratada con altas dosis de tigeciclina y fosfomicina. Evolucionó con descompensación aguda y coma hiperglucémico hiperosmolar y fallece a los 10 días de internación. Ambas cepas fueron secuenciadas por la tecnología MySeq Illumina. El ensamblado y posterior análisis por Bioinformática reveló que ambas cepas pertenecían al secuenciotipo (ST) 11. Además, al analizar los genomas por ResFinder y CARD, encontramos que ambas cepas compartían 17 genes de resistencia a antibióticos aac(6')-Ib-cr, aadA2, aph(3')-Ia, blaCTX-M-15, blaNDM-5, blaOXA-1, blaSHV-182, catB3, dfrA12, mph(A), oqxA, oqxB, qacE, qnrS1, rmtB, sul1, con 100% de identidad a GRA ya descriptos, y el gen fosA que correspondería a un nuevo alelo. La cepa HA30pKpn poseía además el GRA aph(3')-III. Considerando los resultados genotípicos y fenotipos, ambas cepas solo serían sensibles genéticamente a tigecilina, ya que el gen fosA, aunque presente en ambas cepas, no evidenció resistencia a nivel fenotípico. Ambas cepas poseían al replicón Col440I, y al igual que Ec265, compartían los replicones IncFIB y IncFII. También se realizaron ensayos de conjugación.La epidemiología mundial de K. pneumoniae productora de carbapenemasas muestra que diferentes linajes circulan en diferentes regiones geográficas, siendo el ST258 predominante en Europa y EE. UU., y el ST11 más frecuente en Asia oriental, y recientemente fue descripto también en Brasil y en nuestro pais. Aunque en general estos ST están asociados a la diseminación de la carbapenemasa blaKPC-2, nuestros resultados indican la emergencia del ST11 diseminando blaNDM-5, blaCTX-M-15, y rmtB en una misma cepa, con capacidad de colonizar y luego infectar a pacientes en nuestro país.Fil: Masso, Mariana Guillermina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: García Allende, Natalia. Hospital Alemán; ArgentinaFil: Alvarez, Verónica Elizabeth. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Campos, Josefina. Dirección Nacional de Instituto de Investigación.Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"; ArgentinaFil: Fox, Barbara. Hospital Aleman; ArgentinaFil: Carrera Paez, Laura Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Fernández Canigia, Liliana. Hospital Alemán; ArgentinaFil: Quiroga, María Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Centron, Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaXIX Jornadas Argentinas de MicrobiologíaArgentinaAsociacion Argentina de Microbiologi

A new assemblage of late Neanderthal remains from Cova Simanya (NE Iberia)

This study presents an exceptional collection of 54 Late Pleistocene human remains that correspond to at least three Neanderthal individuals from Simanya Gran, the main gallery of Cova Simanya, located in the northeastern Iberian Peninsula. The collection comprised 53 unpublished remains that were unearthed during the 1970s and an additional tooth discovered during 2021 excavations. The specimens represent an adult with a small stature, a periadolescent aged approximately 11.5 years, and an immature individual aged approximately 7.7 years, thus offering a more complete demographic perspective. The collection encompasses diverse anatomical parts including upper and lower dentition, mandible, vertebrae, and limb bones from both the upper and lower extremities. Attempts to extract aDNA were unsuccessful. Renewed archaeological investigations at Cova Simanya have facilitated the reevaluation of the original stratigraphic context of these remains, leading to the discovery of the additional tooth, aligning with the periadolescent individual. This assemblage is currently the most extensive Neanderthal collection from the northeastern Mediterranean Iberia, offering invaluable insights into the morphology and evolutionary trajectory of Late Pleistocene hominins. Hence, Simanya Neanderthals will enhance our understanding of Neanderthal demographics and evolution, paving the way for an in-depth examination of the morphological diversity and evolutionary context of Iberian Neanderthals.This research was funded by the Spanish Ministry of Science and Innovation through the projects PID2021-122356NB-I00 (MNCN-CSIC, AR), PID2020-113960GB-I00 (UB, JF), PID2021-124590NB-I00 (MCNB, CL-F), PID2019-103987GB-C31 (IPHES-CERCA), and PID2021-126004NB-100 (IBE-UPF-CSIC, TM-B); the AGAUR through the research groups 2021 SGR 01237 (IPHES-CERCA, EA), 2021 SGR 00337 (UB, JF), and 2021 SGR 00177 (IBE-UPF-CSIC, TM-B); the Culture Department of the Generalitat de Catalunya through the project ARQ001SOL-172-2022; and the Diputació de Barcelona and the Fundación Palarq. MS was funded by the UAM Tomás y Valiente Program, JR by the European Union-Next Generation EU, Ministry of Universities and UA (MARSALAS21-22), and DL by the Xunta de Galicia Grant ED481B-2022-048. ST and TM-B received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement no. 803147 RESOLUTION, https://site.unibo.it/resolution-erc/en (ST), and no. 864203 (TM-B)]. IPHES-CERCA received financial support from the Spanish Ministry of Science and Innovation through the “María de Maeztu” program for Units of Excellence (CEX 2019-000945-M)

COVID-19 and stem cell transplantation; results from an EBMT and GETH multicenter prospective survey

© The Author(s) 2021.This study reports on 382 COVID-19 patients having undergone allogeneic (n = 236) or autologous (n = 146) hematopoietic cell transplantation (HCT) reported to the European Society for Blood and Marrow Transplantation (EBMT) or to the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH). The median age was 54.1 years (1.0–80.3) for allogeneic, and 60.6 years (7.7–81.6) for autologous HCT patients. The median time from HCT to COVID-19 was 15.8 months (0.2–292.7) in allogeneic and 24.6 months (−0.9 to 350.3) in autologous recipients. 83.5% developed lower respiratory tract disease and 22.5% were admitted to an ICU. Overall survival at 6 weeks from diagnosis was 77.9% and 72.1% in allogeneic and autologous recipients, respectively. Children had a survival of 93.4%. In multivariate analysis, older age (p = 0.02), need for ICU (p < 0.0001) and moderate/high immunodeficiency index (p = 0.04) increased the risk while better performance status (p = 0.001) decreased the risk for mortality. Other factors such as underlying diagnosis, time from HCT, GVHD, or ongoing immunosuppression did not significantly impact overall survival. We conclude that HCT patients are at high risk of developing LRTD, require admission to ICU, and have increased mortality in COVID-19.JA acknowledges the support of the UK NIHR Imperial College Biomedical Research Centre

Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies

Recent studies have shown a suboptimal humoral response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines in patients diagnosed with hematologic malignancies; however, data about cellular immunogenicity are scarce. The aim of this study was to evaluate both the humoral and cellular immunogenicity 1 month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by using the Elecsys and LIAISON anti–SARS-CoV-2 S assays, and T-cell response was assessed by using interferon-γ release immunoassay technology. Overall, 76.3% (184 of 241) of patients developed humoral immunity, and the cellular response rate was 79% (184 of 233). Hypogammaglobulinemia, lymphopenia, active hematologic treatment, and anti-CD20 therapy during the previous 6 months were associated with an inferior humoral response. Conversely, age >65 years, active disease, lymphopenia, and immunosuppressive treatment of graft-versus-host disease (GVHD) were associated with an impaired cellular response. A significant dissociation between the humoral and cellular responses was observed in patients treated with anti-CD20 therapy (the humoral response was 17.5%, whereas the cellular response was 71.1%). In these patients, B-cell aplasia was confirmed while T-cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients undergoing immunosuppressive treatment of GVHD, whereas only 52.4% had a cellular response. The cellular and humoral responses to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematologic malignancies are highly influenced by the presence of treatments such as anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.The authors also thank the Cellex Foundation for providing research facilities and equipment and the CERCA Programme/Generalitat de Catalunya for institutional support

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Cancer health disparities in racial/ethnic minorities in the United States

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA—African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.Fil: Zavala, Valentina A.. University of California; Estados UnidosFil: Bracci, Paige M.. University of California; Estados UnidosFil: Carethers, John M.. University of Michigan; Estados UnidosFil: Carvajal Carmona, Luis. University of California at Davis; Estados UnidosFil: Coggins, Nicole B.. University of California at Davis; Estados UnidosFil: Cruz Correa, Marcia R.. Universidad de Puerto Rico; Puerto RicoFil: Davis, Melissa. No especifíca;Fil: de Smith, Adam J.. University of California; Estados UnidosFil: Dutil, Julie. Ponce Research Institute; Puerto RicoFil: Figueiredo, Jane C.. Cedars Sinai Medical Center; Estados UnidosFil: Fox, Rena. University of California; Estados UnidosFil: Graves, Kristi D.. University Of Georgetown; Estados UnidosFil: Gomez, Scarlett Lin. University of California; Estados UnidosFil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Neuhausen, Susan L.. No especifíca;Fil: Newman, Lisa. No especifíca;Fil: Nguyen, Tung. University of California; Estados UnidosFil: Palmer, Julie R.. National Institutes of Health; Estados UnidosFil: Palmer, Nynikka R.. University of California; Estados UnidosFil: Pérez Stable, Eliseo J.. National Institutes of Health; Estados UnidosFil: Piawah, Sorbarikor. University of California; Estados UnidosFil: Rodriquez, Erik J.. National Institutes of Health; Estados UnidosFil: Sanabria Salas, María Carolina. Instituto Nacional de Cancerología; ColombiaFil: Schmit, Stephanie L.. University of Southern California; Estados UnidosFil: Serrano Gomez, Silvia J.. Instituto Nacional de Cancerología; ColombiaFil: Stern, Mariana Carla. University of Southern California; Estados UnidosFil: Weitzel, Jeffrey. No especifíca;Fil: Yang, Jun J.. St. Jude Children’s Research Hospital; Estados UnidosFil: Zabaleta, Jovanny. No especifíca;Fil: Ziv, Elad. University of California; Estados UnidosFil: Fejerman, Laura. University of California; Estados Unido