Cytoreductive treatment in patients with CALR-mutated essential thrombocythaemia: a study comparing indications and efficacy among genotypes from the Spanish Registry of Essential Thrombocythaemia.

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.

SARS-CoV-2: what it is, how it acts, and how it manifests in imaging studies. / SARS-CoV-2: cómo es, cómo actúa y cómo se expresa en la imagen.

COVID-19 is a disease with many clinical, biochemical, and radiological signs that has a predilection for the lungs, probably because of the high number of ACE-2 receptors in this organ. The infection of cells activates proinflammatory substances, causing diffuse alveolar damage, which is the histopathological basis of ARDS. The exudative phase would manifest as ground-glass opacities and consolidation, and the proliferative phase would manifest as a tendency toward a more linear morphology. Both CT and PET/CT findings support the inflammatory character of the lung lesions in the initial phase of the disease and in patients with mild-moderate disease. Severe cases have pulmonary hypoperfusion that is likely due to abnormal alveolar ventilation and perfusion. On the other hand, a prothrombotic state increases the risk of thromboembolic disease through the activation of coagulation and platelet pathways with the production of fibrin degradation products (D-dimer) and consumption of platelets.

How societal responses to COVID-19 could contribute to child neglect.

BACKGROUND: The ecosystemic approach to children's needs demands a cohesive response from societies, communities, and families. During the COVID-19 pandemic, the choices societies made to protect their community members from the virus could have created contexts of child neglect. With the closure of services and institutions, societies were no longer available to help meet the needs of children. OBJECTIVE: The purpose of this study is to examine parents' reports on the response their children received to their needs during the COVID-19 crisis. METHODS: During the period of the spring 2020 lockdown, 414 parents in the province of Quebec, Canada, completed an online questionnaire about the impact of the crisis on the response their children received to their needs. RESULTS: Compared to parents of younger children, parents of older children reported less fulfillment of their child's needs in three measured domains, namely cognitive and affective, security, and basic care needs. CONCLUSION: These results are discussed in light of the policies and the resources societies have put in place during the crisis to help families meet the needs of their children. Societies must learn from this crisis to put children at the top of their priorities in the face of a societal crisis. Thoughtful discussions and energy must be given to ensure that, while facing a crisis, the developmental trajectories of children are not sacrificed.

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.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Fungal endophytes from arid areas of Andalusia: high potential sources for antifungal and antitumoral agents.

Native plant communities from arid areas present distinctive characteristics to survive in extreme conditions. The large number of poorly studied endemic plants represents a unique potential source for the discovery of novel fungal symbionts as well as host-specific endophytes not yet described. The addition of adsorptive polymeric resins in fungal fermentations has been seen to promote the production of new secondary metabolites and is a tool used consistently to generate new compounds with potential biological activities. A total of 349 fungal strains isolated from 63 selected plant species from arid ecosystems located in the southeast of the Iberian Peninsula, were characterized morphologically as well as based on their ITS/28S ribosomal gene sequences. The fungal community isolated was distributed among 19 orders including Basidiomycetes and Ascomycetes, being Pleosporales the most abundant order. In total, 107 different genera were identified being Neocamarosporium the genus most frequently isolated from these plants, followed by Preussia and Alternaria. Strains were grown in four different media in presence and absence of selected resins to promote chemical diversity generation of new secondary metabolites. Fermentation extracts were evaluated, looking for new antifungal activities against plant and human fungal pathogens, as well as, cytotoxic activities against the human liver cancer cell line HepG2. From the 349 isolates tested, 126 (36%) exhibited significant bioactivities including 58 strains with exclusive antifungal properties and 33 strains with exclusive activity against the HepG2 hepatocellular carcinoma cell line. After LCMS analysis, 68 known bioactive secondary metabolites could be identified as produced by 96 strains, and 12 likely unknown compounds were found in a subset of 14 fungal endophytes. The chemical profiles of the differential expression of induced activities were compared. As proof of concept, ten active secondary metabolites only produced in the presence of resins were purified and identified. The structures of three of these compounds were new and herein are elucidated.

Successful lichen translocation on disturbed gypsum areas: A test with adhesives to promote the recovery of biological soil crusts.

The loss of biological soil crusts represents a challenge for the restoration of disturbed environments, specifically in particular substrates hosting unique lichen communities. However, the recovery of lichen species affected by mining is rarely addressed in restoration projects. Here, we evaluate the translocation of Diploschistes diacapsis, a representative species of gypsum lichen communities affected by quarrying. We tested how a selection of adhesives could improve thallus attachment to the substrate and affect lichen vitality (as CO2 exchange and fluorescence) in rainfall-simulation and field experiments. Treatments included: white glue, water, hydroseeding stabiliser, gum arabic, synthetic resin, and a control with no adhesive. Attachment differed only in the field, where white glue and water performed best. Adhesives altered CO2 exchange and fluorescence yield. Notably, wet spoils allowed thalli to bind to the substrate after drying, revealing as the most suitable option for translocation. The satisfactory results applying water on gypsum spoils are encouraging to test this methodology with other lichen species. Implementing these measures in restoration projects would be relatively easy and cost-effective. It would help not only to recover lichen species in the disturbed areas but also to take advantage of an extremely valuable biological material that otherwise would be lost.

Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study.

The single-arm, phase 2 ENESTfreedom trial assessed the potential for treatment-free remission (TFR; i.e., the ability to maintain a molecular response after stopping therapy) following frontline nilotinib treatment. Patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase with MR4.5 (BCR-ABL1⩽0.0032% on the International Scale (BCR-ABL1IS)) and ⩾2 years of frontline nilotinib therapy were enrolled. Patients with sustained deep molecular response during the 1-year nilotinib consolidation phase were eligible to stop treatment and enter the TFR phase. Patients with loss of major molecular response (MMR; BCR-ABL1IS⩽0.1%) during the TFR phase reinitiated nilotinib. In total, 215 patients entered the consolidation phase, of whom 190 entered the TFR phase. The median duration of nilotinib before stopping treatment was 43.5 months. At 48 weeks after stopping nilotinib, 98 patients (51.6%; 95% confidence interval, 44.2-58.9%) remained in MMR or better (primary end point). Of the 86 patients who restarted nilotinib in the treatment reinitiation phase after loss of MMR, 98.8% and 88.4%, respectively, regained MMR and MR4.5 by the data cutoff date. Consistent with prior reports of imatinib-treated patients, musculoskeletal pain-related events were reported in 24.7% of patients in the TFR phase (consolidation phase, 16.3%).

[Cardiovascular management of patients with chronic myeloid leukemia from a multidisciplinary perspective, and proposing action protocol by consensus meeting]. / Gestión cardiovascular de los pacientes con leucemia mieloide crónica desde una perspectiva multidisciplinar, y propuesta de protocolo de actuación por reunión de consenso.

INTRODUCTION AND OBJECTIVES: The second generation tyrosine kinase inhibitors (TKI, dasatinib and nilotinib) used in chronic myeloid leukemia (CML) treatment have shown a benefit compared to imatinib in responses achieved and disease progression. However, both have been related to some cardiovascular toxicity, being more frequent in patients with cardiovascular risk factors (CVRFs). Nowadays, due to the lack of recommendations for CML patients, CVRF management is carried out heterogeneously. The aim of this work is to develop recommendations on the prevention and monitoring of cardiovascular events (CVD) in patients with CML treated with TKIs. MATERIAL AND METHODS: Experts from the Spanish Group of Chronic Myeloid Leukemia together with experts in cardiovascular risk have elaborated, after a consensus meeting, recommendations for the prevention and follow-up of CVE in patients with CML treated with TKI. RESULTS: Recommendations regarding the necessary information to be collected on clinical history, treatment decisions, as well as treatment and monitoring of CVRFs are shown in this document. CONCLUSIONS: TKI treatment requires comprehensive patient management from a multidisciplinary approach, in which both the prevention and management of CVRFs are essential.

Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera.

The clinical significance of resistance/intolerance to hydroxycarbamide (HC) was assessed in a series of 890 patients with polycythaemia vera (PV). Resistance/intolerance to HC was recorded in 137 patients (15·4%), consisting of: need for phlebotomies (3·3%), uncontrolled myeloproliferation (1·6%), failure to reduce massive splenomegaly (0·8%), development of cytopenia at the lowest dose of HC to achieve a response (1·7%) and extra-haematological toxicity (9%). With a median follow-up of 4·6 years, 99 patients died, resulting in a median survival of 19 years. Fulfilling any of the resistance/intolerance criteria had no impact on survival but when the different criteria were individually assessed, an increased risk of death was observed in patients developing cytopenia [Hazard ratio (HR): 3·5, 95% confidence interval (CI): 1·5-8·3, P = 0·003]. Resistance/intolerance had no impact in the rate of thrombosis or bleeding. Risk of myelofibrotic transformation was significantly higher in those patients developing cytopenia (HR: 5·1, 95% CI: 1·9-13·7, P = 0·001) and massive splenomegaly (HR: 9·1, 95% CI: 2·3-35·9, P = 0·002). Cytopenia at the lowest dose required to achieve a response was also an independent risk factor for transformation to acute leukaemia (HR: 20·3, 95% CI: 5·4-76·5, P < 0·001). In conclusion, the unified definition of resistance/intolerance to HC delineates a heterogeneous group of PV patients, with those developing cytopenia being associated with an adverse outcome.

High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.

Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2.

Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea.

Therapeutic options for patients with polycythemia vera (PV) and essential thrombocythemia (ET) resistant or intolerant to hydroxyurea are limited. Busulfan is effective as first-line therapy, but there is scarce information on this drug as second-line treatment. The efficacy of busulfan in patients with advanced PV or ET refractory or intolerant to hydroxyurea was assessed in 36 patients (PV n = 15, ET n = 21) treated for a median of 256 days. Complete hematological response (CHR) was achieved in 83 % of patients, after a median time of 203 days (range 92-313). The probability of sustained CHR at 1 and 2 years was 87 and 62 %, respectively. Time to CHR was shorter in patients treated with ≥14 mg of busulfan per week than with lower doses (141 versus 336 days, p = 0.01). Partial molecular response was achieved in three out of nine (33 %) patients. Busulfan was stopped in 27 patients (75 %) due to CHR achievement in 18 cases (67 %), hematological toxicity in 8 cases (30 %), and disease transformation in 1 case. With a median follow-up of 721 days, six patients have died, with the probability of survival at 2 years being 85 %. The probability of thrombosis at 2 years was 11 %. Transformation into acute leukemia or myelodysplastic syndrome was observed in three cases, all of them in a JAK2V617F-negative clone carrying additional mutations. Busulfan, at a dose of 2 mg/day, is an effective option for elderly patients with PV or ET who fail to hydroxyurea, but a significant rate of transformation was observed.

[Left ventricular systolic function: how to understand it and analyze it]. / Función sistólica del ventrículo izquierdo: cómo comprenderla y analizarla.

In cardiac magnetic resonance imaging studies, left ventricular systolic function is usually calculated automatically. To understand and interpret parameters of left ventricular systolic function correctly, it is fundamental to understand how each parameter is obtained and why values obtained with different techniques, for example, ultrasonography and magnetic resonance imaging, can differ. This article provides details about the usual analysis of systolic function from the quantitative and qualitative points of view; it also explains other methods that do not require specific software. Moreover, we provide a file that we designed for use with Microsoft Excel(®) to enable simple, intuitive analysis of systolic function. Readers can use this file freely.

[Influence of age on the clinical manifestations of invasive pneumococcal disease and antibiotic resistance rates]. / Influencia de la edad en la enfermedad neumocócica invasiva y en la resistencia a antimicrobianos.

BACKGROUND AND OBJECTIVE: Invasive pneumococcal disease (IPD) shows different epidemiological characteristics depending on age and pneumococcus serotype. The aims of the work were to analyze the clinical manifestations and mortality associated with IPD, the serotype isolated and the antibiotic resistance rates in different age groups. PATIENTS AND METHOD: Retrospectively, 141 patients with IPD diagnosed between 2002 and 2008 were studied. Patients were classified in 4 age groups: ≤ 2 year-old, 3-14 year-old, 15-64 year-old and ≥ 65 year-old. RESULTS: Pneumonia was the most common manifestation in all age groups (71%). Pneumococcal meningitis was more prevalent in patients ≤ 2 year-old (28 vs. 9%, P=.054) and empyema was more frequent in those between 3-14 year-old (31 vs. 5%, P<.001). Mortality was associated with age ≥ 65 year-old (odds ratio [OR] 7, 95% confidence interval [95% CI] 1.9-28.9), primary bacteremia (OR 7, 95% CI 1.9-28.9) and orotracheal intubation (OR 9, 95% CI 1.9-41.1). The more prevalent serotypes among patients ≤ 2 year-old were 14, 19A and 19F. The serotype 1 was most common in patients between 3-14 year-old and serotype 3 in those ≥ 65 year-old. A higher rate of non-susceptible penicillin strains was observed in pediatric population (42 vs. 19%, P=.007). CONCLUSIONS: Age was related to the clinical manifestations, mortality and antibiotic resistance rates. Primary bacteremia was one of the risk factors of mortality.

Analysis of the 'Educational Climate' in Spanish Public Schools of Dentistry using the Dundee Ready Education Environment Measure: a multicenter study.

AIM: To analyse the 'Educational Climate' (EC) of dental students in Spain. METHODS: The study group consisted of 1391 students from nine Spanish Public Schools of Dentistry, who responded to the questionnaire based on 'Dundee Ready Education Environment Measure' (DREEM). This questionnaire has 50 items that are grouped into five domains: Learning, Teachers, Academic, Atmosphere and Social. RESULTS: The global score on the EC was 123.1 (interpretation: 'EC more positive than negative'). The scores obtained in the different domains were: 28.0 in Learning (interpretation: 'a generally positive perception of learning'), 26.8 in Teachers (interpretation: 'teachers are going in the right direction'), 20.8 in Academic (interpretation: 'feeling more on the positive side'), 29.7 in Atmosphere (interpretation: 'a generally positive atmosphere') and 17.7 in Social (interpretation: 'social perception acceptable'). In seven items (14%), an average of <2 was detected, showing that there are some educational problem areas. Regarding the EC in the different Schools of Dentistry, an average of >100 was achieved in all of them, although there were two centres that showed significantly higher values of EC. CONCLUSIONS: Spanish dental students felt that their EC was more positive than negative and considered that the different domains were positive and acceptable. However, they pointed out the existence of several educational problem areas associated with the development of a traditional curriculum. Accordingly, and in parallel with the implementation of an innovative curriculum in all Spanish Dental Schools in the coming years, immediate educational goals must address the problem areas identified, thereby further promoting a more positive perception of EC.

Cranioplasty with bandaging. New forms of limitation of life support and organ donation.

Most of transplanted organs are obtained from brain death (BD) donors. In neurocritical patients with catastrophic injuries and decompressive craniectomy (DC), which show a dreadful development in spite of this treatment, DC could be a futile tool to avoid natural progress to BD. We propose if cranial compressive bandage (cranioplasty with bandage) could be an ethically correct practice, similar to other life-sustaining treatment limitation (LSTL) common methods. Based on a clinical case, we contacted with the Assistance Ethics Committee and some bioethics professionals asking them two questions: 1) Is ethically correct to perform a cranioplasty with bandage in those patients with LSTL indication? 2) Thinking in organ donation possibility, is this option preferable? Conclusions 1) Cranioplasty with bandage could be considered an ethically acceptable LSTL practice, similar to other procedures. 2) It facilitates organ donation for transplant, which provides value-added because of its own social good. 3) In these cases, it is necessary to know previous patient's will or, in absentia, to obtain family consent after a detailed procedure report.

MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.).

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and dasatinib. In the CML-derived K562 cell line, low concentrations of imatinib induce proliferative arrest and erythroid differentiation. We found that imatinib upregulated the cell cycle inhibitor p27(KIP1) (p27) in a time- and -concentration dependent manner, and that the extent of imatinib-mediated differentiation was severely decreased in cells with depleted p27. MYC (c-Myc) is a transcription factor frequently deregulated in human cancer. MYC is overexpressed in untreated CML and is associated to poor response to imatinib. Using K562 sublines with conditional MYC expression (induced by Zn(2+) or activated by 4-hydroxy-tamoxifen) we show that MYC prevented the erythroid differentiation induced by imatinib and dasatinib. The differentiation inhibition is not due to increased proliferation of MYC-expressing clones or enhanced apoptosis of differentiated cells. As p27 overexpression is reported to induce erythroid differentiation in K562, we explored the effect of MYC on imatinib-dependent induction of p27. We show that MYC abrogated the imatinib-induced upregulation of p27 concomitantly with the differentiation inhibition, suggesting that MYC inhibits differentiation by antagonizing the imatinib-mediated upregulation of p27. This effect occurs mainly by p27 protein destabilization. This was in part due to MYC-dependent induction of SKP2, a component of the ubiquitin ligase complex that targets p27 for degradation. The results suggest that, although MYC deregulation does not directly confer resistance to imatinib, it might be a factor that contributes to progression of CML through the inhibition of differentiation.