We describe an unusual presentation of primary effusion lymphoma in CSF of a 45‐year‐old HIV‐positive man, with no evidence of involvement of pleural, peritoneal or pericardial cavities. Cytologic ...examination and flow cytometric analysis suggested the diagnosis, eventually made in an excised deep cervical lymph node, in which the neoplastic cells involved selectively the sinuses. This case represents the fifth reported example of CSF involvement by this type of lymphoma, and supports the alleged connection between CSF and cervical lymph nodes via lymphatic vessels. Interestingly, review of an adenoidectomy specimen obtained 9 months before presentation for nonspecific complaints showed rare clusters of neoplastic cells involving surface epithelium and chorium, a finding that might represent a homing mechanism and implies an asymptomatic, occult phase of lymphoma development.
Anaplastic large cell lymphoma (ALCL) with leukaemic presentation (either ab initio or along the course of the disease) has been rarely reported. Irrespective of ALK expression in the neoplastic ...cells, it features a dismal prognosis. We report a rare case of leukaemic, small cell variant ALK-positive ALCL with 9-year survival in a young woman who was treated upfront with corticosteroids and standard chemotherapy, and review thoroughly the previously published cases. Such an unexpected, good outcome hints at the existence of different clinical subgroups in the leukaemic variant of ALK-positive ALCL.
Within the pathogenesis of the chronic obstructive pulmonary disease (COPD) there are interactions between different inflammatory mediators that are enhanced during an exacerbation. Arginase is ...present in bronchial epithelial cells, endothelial, fibroblasts and alveolar macrophages, which make it a probable key enzyme in the regulation of inflammation and remodelling. We aimed to find a potential relationship between arginase activity, inflammatory mediators in COPD patients in stable phase and during exacerbations.
We performed a prospective, observational study of cases and controls, with 4 study groups (healthy controls, stable COPD, COPD during an exacerbation and COPD 3 months after exacerbation). We measured arginase, inflammation markers (IL-6, IL-8, TNF-∝, IFN-γ and C reactive protein), and mediators of immunity: neutrophils, monocytes, total TCD3 + lymphocytes (CD3ζ), CD4 + T cells, CD8 + T cells, NK cells.
A total of 49 subjects were recruited, average age of 69.73 years (59.18% male). Arginase activity is elevated during an exacerbation of COPD, and this rise is related to an increase in IL-6 production. The levels of IL-6 and IL-8 remained elevated in patients with COPD at 3 months after hospital exacerbation. We did not find a clear relationship between arginase activity, immunity or with the degree of obstruction in COPD patients.
Arginase activity is elevated during an exacerbation of COPD, and it could be related to an increase in the production of IL-6. Levels of IL-6, IL-8, and arginase activity remain elevated in patients with COPD at 3 months after hospital exacerbation. Arginase activity could contribute to the development of COPD.
The majority of patients with acute promyelocytic leukemia (APL) manifest a specific chromosomal translocation t(15;17)(q22;q21), characterized by the fusion of RARA and PML genes. However, a ...proportion of APL cases are due to variant translocations, being t(11;17) (q23;q21) the most common amongst them. With the major exception of ZBTB16-RARA t(11;17) APL, these variant APL cases present similar morphological features as classic APL and are characterized by a lack of differentiation response to retinoids.
We describe the case of variant APL with the ZBTB16-RARA fusion gene, showing a distinct morphology of classical APL, characterized by crystalline intracytoplasmic inclusions in both peripheral blood (PB) and bone marrow (BM) patients' blasts. Our patient was treated with two courses of intensive chemotherapy, initiating maintenance treatment with all-trans retinoic acid (ATRA) on day twenty-eight of the second course. Our patient achieved complete remission (CR) once the intensive chemotherapy was combined with ATRA.
This is the second case described of APL with t(11;17) that showed crystalline intracytoplasmic inclusions. The finding of these morphological features may suggest the presence of a variant translocation with RARA, being that both cases described are related to the presence of t(11;17). Despite induction treatment with intensive chemotherapy that included a seven-day continuous treatment with cytarabine (200 mg/m
), plus daily idarubicin (12 mg/m
) during the first three days, our patient did not achieve complete remission (CR) until scheduled 3 + 7 regimen combined with ATRA treatment was established. This observation suggests that ATRA may be partially effective in some ZBTB16-RARA APLs.
Metoprolol in Critically Ill Patients With COVID-19 Clemente-Moragón, Agustín; Martínez-Milla, Juan; Oliver, Eduardo ...
Journal of the American College of Cardiology,
09/2021, Letnik:
78, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Severe coronavirus disease-2019 (COVID-19) can progress to an acute respiratory distress syndrome (ARDS), which involves alveolar infiltration by activated neutrophils. The beta-blocker metoprolol ...has been shown to ameliorate exacerbated inflammation in the myocardial infarction setting.
The purpose of this study was to evaluate the effects of metoprolol on alveolar inflammation and on respiratory function in patients with COVID-19–associated ARDS.
A total of 20 COVID-19 patients with ARDS on invasive mechanical ventilation were randomized to metoprolol (15 mg daily for 3 days) or control (no treatment). All patients underwent bronchoalveolar lavage (BAL) before and after metoprolol/control. The safety of metoprolol administration was evaluated by invasive hemodynamic and electrocardiogram monitoring and echocardiography.
Metoprolol administration was without side effects. At baseline, neutrophil content in BAL did not differ between groups. Conversely, patients randomized to metoprolol had significantly fewer neutrophils in BAL on day 4 (median: 14.3 neutrophils/µl Q1, Q3: 4.63, 265 neutrophils/µl vs median: 397 neutrophils/µl Q1, Q3: 222, 1,346 neutrophils/µl in the metoprolol and control groups, respectively; P = 0.016). Metoprolol also reduced neutrophil extracellular traps content and other markers of lung inflammation. Oxygenation (PaO2:FiO2) significantly improved after 3 days of metoprolol treatment (median: 130 Q1, Q3: 110, 162 vs median: 267 Q1, Q3: 199, 298 at baseline and day 4, respectively; P = 0.003), whereas it remained unchanged in control subjects. Metoprolol-treated patients spent fewer days on invasive mechanical ventilation than those in the control group (15.5 ± 7.6 vs 21.9 ± 12.6 days; P = 0.17).
In this pilot trial, intravenous metoprolol administration to patients with COVID-19–associated ARDS was safe, reduced exacerbated lung inflammation, and improved oxygenation. Repurposing metoprolol for COVID-19–associated ARDS appears to be a safe and inexpensive strategy that can alleviate the burden of the COVID-19 pandemic.
Display omitted
ObjectivesThis study aimed to evaluate the effectiveness, safety and costs of FreeStyle Libre (FSL) glucose monitoring system for children and adolescents with type 1 diabetes mellitus (T1DM) in ...Spain.DesignProspective, multicentre pre-post study.SettingThirteen Spanish public hospitals recruited patients from January 2019 to March 2020, with a 12-month follow-up.Participants156 patients were included.Primary and secondary outcome measuresPrimary: glycated haemoglobin (HbA1c) change. Secondary: severe hypoglycaemic events (self-reported and clinical records), quality of life, diabetes treatment knowledge, treatment satisfaction, adverse events, adherence, sensor usage time and scans. Healthcare resource utilisation was assessed for cost analysis from the National Health System perspective, incorporating direct healthcare costs. Data analysis used mixed regression models with repeated measures. The intervention’s total cost was estimated by multiplying health resource usage with unit costs.ResultsIn the whole sample, HbA1c increased significantly (0.32%; 95% CI 0.10% to 0.55%). In the subgroup with baseline HbA1c≥7.5% (n=88), there was a significant reduction at 3 months (−0.46%; 95% CI −0.69% to −0.23%), 6 months (−0.49%; 95% CI −0.73% to −0.25%) and 12 months (−0.43%; 95% CI −0.68% to –0.19%). Well-controlled patients had a significant 12-month worsening (0.32%; 95% CI 0.18% to 0.47%). Self-reported severe hypoglycaemia significantly decreased compared with the previous year for the whole sample (−0.37; 95% CI −0.62 to –0.11). Quality of life and diabetes treatment knowledge showed no significant differences, but satisfaction increased. Adolescents had lower sensor usage time and scans than children. Reduction in HbA1c was significantly associated with device adherence. No serious adverse effects were observed. Data suggest that use of FSL could reduce healthcare resource use (strips and lancets) and costs related to productivity loss.ConclusionsThe use of FSL in young patients with T1DM was associated with a significant reduction in severe hypoglycaemia, and improved HbA1c levels were seen in patients with poor baseline control. Findings suggest cost savings and productivity gains for caregivers. Causal evidence is limited due to the study design. Further research is needed to confirm results and assess risks, especially for patients with lower baseline HbA1c.
Cutaneous lesions in the setting of myeloproliferative neoplasms and myelodysplastic syndromes are poorly understood. We report 6 patients with pruritic papular eruptions composed of mature ...T-lymphocytes with large clusters of CD123-positive cells. Double immunohistochemical studies demonstrated a lack of myeloid cell nuclear differentiation antigen in the CD123-positive cells, which expressed SPIB, confirming that they were mature plasmacytoid dendritic cells. Four patients were diagnosed with chronic myelomonocytic leukemia and 2 with myelodysplastic syndromes (AREB-I and myelodysplastic syndromes with 5q deletion, respectively). All patients had a long history of hematological alterations, mainly thrombocytopenia, preceding the cutaneous disorder. Nevertheless, the skin lesions developed in all cases coincidentally with either progression or full-establishment of their hematological disease. Most cutaneous lesions disappeared spontaneously or after corticosteroid treatment. Molecular studies performed in both bone marrow and cutaneous lesions in 2 patients demonstrated the same mutational profile, confirming the specific, neoplastic nature of these mature plasmacytoid dendritic cells-composed cutaneous lesions.
Systemic lupus erythematosus is a chronic autoimmune disease characterized by loss of tolerance against nuclear and cytoplasmic self-antigens, induction of immunity and tissue inflammation. Lupus ...nephritis (LN), the most important predictor of morbidity in SLE, develops in almost 30% of SLE patients at disease onset and in up to 50-60% within the first 10 years. Firstly, in this review, we put the pathogenic mechanisms of the disease into a conceptual frame, giving emphasis to the role of the innate immune system in this loss of self-tolerance and the induction of the adaptive immune response. In this aspect, many mechanisms have been described such as dysregulation and acceleration of cell-death pathways, an aberrant clearance and overload of immunogenic acid-nucleic-containing debris and IC, and the involvement of antigen-presenting cells and other innate immune cells in the induction of this adaptive immune response. This result in a clonal expansion of autoreactive lymphocytes with generation of effector T-cells, memory B-cells and plasma cells that produce autoantibodies that will cause kidney damage. Secondly, we review the immunological pathways of damage in the kidney parenchyma, initiated by autoantibody binding and immune complex deposition, and followed by complement-mediated microvascular injury, activation of kidney stromal cells and the recruitment of leukocytes. Finally, we summarize the rationale for the treatment of LN, from conventional to new targeted therapies, focusing on their systemic immunologic effects and the minimization of podocytary damage.
Introduction
Acute myeloid leukemia (AML) is a clonal disease with a reduced life expectancy due to a high relapse rate. One explanation is that leukemic stem cells (LSC) evade the action of ...conventional chemotherapy due to their quiescent state. Several mechanisms have been proposed that regulate their quiescence, however, by analogy with normal hematopoietic stem cells, a key role may be carried out by the signaling pathways Notch and Hedgehog (Hh). The objectives of this study are to analyze the role of Notch and Hh pathways in the quiescence of LSC and to verify if the pharmacological inhibition of the Notch and Hh pathways decreases the percentage of quiescent LSC. In this way, LSCs would be sensitized to chemotherapy treatments and the high relapse rate of AML could be reduced.
Methods
Expression of GLI1, a transcription factor of the Hh signaling pathway and NOTCH Internal Cleaved Domain (NICD) were analyzed in the hematopoietic stem and progenitor cells of four patients diagnosed with AML. The selection of quiescent fraction was performed by flow cytometry using anti-CD34-FITC, anti-CD117-PerCP, anti-CD45PE-Cy7, anti-CD38-APC-Cy7 and anti-KI67-BV510 antibodies. KI67 negative cells were considered quiescent. The activation of NOTCH and Hh pathways was studied using rabbit anti-GLI, anti-NICD primary antibodies and anti-rabbit BV421 secondary antibodies. Results were expressed in median (range) or mean ± standard deviation.
Dose-response curves of inhibitors of the Notch pathway (BMS-906024, inhibitor of γ-secretase), Hh pathway (BMS-833923, SMO inhibitor and GANT61, GLI inhibitor), and cytarabine (AraC) were made to study drug potency in the OCI-AML3 cell line. We also analyzed its synergistic behavior in combination with Arac by calculating the combination index (CI) of each of them. These experiments were conducted in triplicate and values were expressed as the mean ± standard deviation.
Finally, the effect of BMS-833923 and BMS-906024 on the quiescence of the CD34+CD38- cells of two patients diagnosed with AML was studied by flow cytometry.
The paired samples t-test was used in the statistical analysis of GLI and NICD expression between G0 and proliferating cells and in the statistical analysis of the decrease of quiescent cells due to Notch and Hh inhibitors.
Results
First of all, hematopoietic and progenitor cells were quantified in four AML patients: the median of the percentage of CD34+CD38- cells with respect to total cells in the bone marrow of the AML patient studied was 1.1% (range: 0.12%-9.05%), within which 71.50% (range: 64.30%-88.43%) are quiescent. Interestingly, we found a trend for a higher expression of NOTCH signaling pathway in the proliferating CD34+CD38- cells (relative median fluorescent intensity (MFI) = 1.91 (range: 1.51-3.34)) compared to the quiescent fraction (relative MFI=1.55 (range: 1.18-1.94); p=0.105). But no differences were found in expression of GLI1.
Before studying the effect on cellular quiescence of Notch and Hh inhibitors in monotherapy and in combination with AraC, we evaluated their effect on cell viability. The most potent drug studied was AraC (IC50 = 4.055 μM), followed by inhibitors of the Hh pathway (IC50 BMS-833923 = 5.041 μM; IC50 GANT61 = 7.042 μM) on the OCI-AML3 cell line. In contrast, the γ-secretase inhibitor (BMS-906024) showed no effect. Moreover, it was found that the combination 0.8 μM AraC plus 8 μM BMS-833923 was the most synergistic (CI = 0.53, 15% viability with respect to DMSO control).
Subsequently, the effect of the SMO inhibitor on the quiescent CD34+CD38- cells of two patients diagnosed with CD34+ AML was analyzed: BMS-833923 decreased the percentage of quiescent CD34+CD38- cells by 88.5±16.3% in monotherapy (p=0.083) and in presence of AraC by 85.8 ± 21.2% (p=0.113) (figure 1).
Conclusion
The use of SMO inhibitors for the treatment of AML is promising because it increases the sensitivity of leukemic cells to chemotherapy and facilitates their action by reducing the percentage of quiescent LSC. This could mean a decrease in the probability of relapse in patients with AML treated with Hh inhibitors. These results were derived from an ongoing project and more patients are being studied in order to confirm the explained results.
This work is partially funded by the Madrid Association of Hematology and Hemotherapy.
Display omitted
No relevant conflicts of interest to declare.
PDF
