Causes of erythrocytosis and its impact as a risk factor for thrombosis according to etiology: experience in a referral center in Mexico City.

BACKGROUND: Thrombotic events are well documented in primary erythrocytosis, but it is uncertain if secondary etiologies increase the risk of thrombosis. This study aimed to determine the causes of erythrocytosis and to identify its impact as a risk factor for thrombosis. METHODS: Data were obtained from patients with erythrocytosis between 2000 and 2017 at a referral hospital in Mexico City. Erythrocytosis was defined according to the 2016 WHO classification. Time to thrombosis, major bleeding, or death were compared among groups of patients defined by the etiology of erythrocytosis using a Cox regression model, adjusting for cardiovascular risk factors. RESULTS: In total, 330 patients with erythrocytosis were studied. The main etiologies of erythrocytosis were obstructive sleep apnea (OSA) in 29%, polycythemia vera (PV) in 18%, and chronic lung disease (CLD) in 9.4% of the patients. The incidence rate of thrombosis was significantly higher in patients with PV and CLD than that in patients with OSA (incidence rates of 4.51 and 6.24 vs. 1.46 cases per 100 person-years, P=0.009), as well as the mortality rate (mortality rates of 2.72 and 2.43 vs. 0.17 cases per 100 person-years, P =0.003). CONCLUSION: The risk of thrombosis in CLD with erythrocytosis was comparable to that in patients with PV. Further larger-scale studies are needed to confirm these findings and evaluate the benefits of preventive management of COPD with erythrocytosis similar to PV.

Importance of CD117 in the Assignation of a Myeloid Lineage in Acute Leukemias.

The correct classification of acute leukemias (AL) is an essential part in the evaluation of any patient with this disease. Historically, CD117 has been an important asset in the diagnosis of patients with mixed-phenotype acute leukemia (MPAL). In an attempt to simplify the diagnosis of MPAL with fewer and more lineage specific markers, the World Health Organization (WHO) proposed in 2008 a new criteria for the diagnosis of this type of AL, which excluded CD117 from the myeloid markers that are utilized to diagnose MPAL. In order to assess whether CD117 is necessary in the diagnosis of MPAL, we evaluated the sensitivity and specificity of CD117 for acute myeloid leukemia (AML) in 331 patients with AL. The calculated sensitivity of CD117 for AML was 85.88% (103/120), while the specificity was 83.9% (177/211). Besides myeloperoxidase (MPO), which was used as the gold standard in differentiating AML from other type of ALs, the most specific markers for AML in our study were CD14 and CD64 (99.5 and 95.6%). Although the specificity of CD117 in this study is not as high as CD14 and CD64, markers concomitantly used in this this study and in the WHO classification, based on the results of other researches (i.e. the specificity of CD117 for AML was 100% in one study) and due to the fact that its specificity for AML in this study is relatively high, we recommend the use CD117 in assigning a myeloid lineage in MPAL.

Global methylation and promoter-specific methylation of the P16, SOCS-1, E-cadherin, P73 and SHP-1 genes and their expression in patients with multiple myeloma during active disease and remission.

Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of P16, suppressor of cytokine signaling 1 (SOCS-1), P73, E-cadherin and Src homology region 2 domain-containing phosphatase 1 (SHP-1), as well as global methylation in patients with MM during active disease and remission. Bone marrow samples were obtained from 43 patients at the Multiple Myeloma Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (Mexico City, Mexico) during active disease and remission. Methylation-specific polymerase chain reaction and ELISA were performed on bisulfite-treated or untreated DNA to determine promoter-specific or genomic methylation, respectively. Gene expression was measured using reverse-transcription polymerase chain reaction. The results indicated that SOCS-1 methylation occurred more frequently during active disease than remission [29 vs. 3.2% (P=0.021)] and was associated with more advanced forms of the disease [international staging system (ISS) 3, 16.67% vs. ISS 1, 8.3% (P=0.037)]. SHP-1 methylation during active disease was associated with a lower probability of survival at 39-month follow up (median), 52.5 vs. 87.5% (P=0.025). The percentage of methylation was associated with active disease at remission, but this was not significant. Global hypomethylation at remission was a negative predictor factor for overall survival (OS). The results indicated that methylated P16, SOCS-1 and SHP-1 were associated with clinical variables of poor prognosis in MM, likewise the persistence of global hypomethylation at remission. The negative impact on OS of global hypomethylation at remission must be confirmed in a larger sample. Future studies are necessary to investigate whether patients with global hypermethylation at remission should receive more aggressive treatments to improve their OS.

Expression of HER2/Neu in B-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: The expression of HER2/neu in B-cell acute lymphoblastic leukemia has been reported in previous studies. OBJECTIVE: The objective of this research was to study the expression of HER2/neu on the blasts of patients with acute leukemia from the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. METHODS: From June 2015 to February 2016, a HER2/neu monoclonal antibody was added to the panel of antibodies that we routinely use in patients with acute leukemia. An expression of ≥ 30% was considered positive. RESULTS: We studied 33 patients: 19 had de novo leukemia (57.6%), three (9.1%) were in relapse, and in 11 (33.3%) their status could not be specified. Seventeen patients (51.5%) were classified as B-cell acute lymphoblastic leukemia with a median expression of HER2/neu of 0.3% (range 0-90.2). Three patients with B-cell acute lymphoblastic leukemia were positive for HER2/neu: 89.4%, 90.9%, and 62.4%. The first and third patient had de novo B-cell acute lymphoblastic leukemia. The second patient was in second relapse after allogeneic stem cell transplant. All three patients were categorized as high-risk at the time of diagnosis. CONCLUSIONS: In the studied Mexican population, we found a positive expression of HER2/neu in 17% of the B-cell acute lymphoblastic leukemia patients, similar to previous studies in which the expression was found in 15-50%.

Primary thrombophilia in Mexico: a single tertiary referral hospital experience.

Thrombophilia is a complex hypercoagulable state that increases the risk of thrombosis. Most reports in medical literature of the Mexican population with this disease lack statistical validity. Therefore, the aim of this study is to describe the prevalence of primary thrombophilia in a tertiary referral hospital in Mexico. This is a study of patients referred to our hospital because of a hypercoagulable state and who later on were diagnosed with primary thrombophilia. The thrombophilia workup included methylenetetrahydrofolate reductase (MTHFR) C677T, antiphospholipid antibodies, protein C, protein S, antithrombin, factor VIII, factor V Leiden, prothrombin mutation G20210A, activated protein C resistance, JAK2 V617F and homocysteine. Ninety-five individuals were tested. The MTHFR C677T polymorphism was the most frequent anomaly in 84.1% of the tested individuals. There was a relatively low prevalence of factor V Leiden (5.2%) and anticoagulant protein deficiency (8.3%). The MTHFR C677T polymorphism has a very high prevalence compared with the low prevalence of anticoagulant protein deficiency and factor V Leiden mutation in Mexicans.

Mixed-phenotype acute leukemia: suboptimal treatment when the 2008/2016 WHO classification is used.

BACKGROUND: Different criteria have been used to diagnose mixed-phenotype acute leukemia (MPAL), which has impacted the number of individuals diagnosed with this pathology. Better outcomes have been reported when using acute lymphoblastic leukemia (ALL)-type chemotherapy in the treatment of MPAL. METHODS: We compared the outcome of 4 groups of patients with MPAL. Group 1 included patients diagnosed using the 2008/2016 World Health Organization (WHO) classification; group 2 included patients diagnosed using the European Group for the Immunological Characterization of Leukemias (EGIL) criteria; group 3 included patients diagnosed using either the EGIL or the 2008/2016 WHO criteria; and group 4 was comprised of patients diagnosed with MPAL using the EGIL classification only. RESULTS: We found a significantly worse disease-free survival (groups 1-4) and overall survival (OS) (groups 2 and 3) when comparing MPAL patients to other acute leukemia (AL) patients. A significantly better OS was obtained in patients (groups 2-4) treated with ALL-type chemotherapy compared to acute myeloid leukemia (AML)-type regimens. CONCLUSION: In light of these results, and because a trend (P=0.06) was found with regard to a better OS in group 4 when compared to other AL patients, an argument can be made that the 2008/2016 WHO classification is underpowered to diagnose all MPAL cases, potentially resulting in the suboptimal treatment of some individuals with AL.

Impact of Aberrant Antigens in the Outcome of Patients with Acute Leukemia at a Referral Institution in Mexico City.

BACKGROUND: Patients with acute leukemia can express aberrant markers, defined as antigens that are normally restricted to a different lineage. The reported significance and frequency of these markers is inconclusive. We assessed the frequency and impact of aberrant markers in patients with acute leukemia in a referral institution in Mexico City. METHODS: We included 433 patients, diagnosed and treated between 2005 and 2015 in our institution. RESULTS: Aberrant markers were expressed in 128 patients (29.6%); CD13 and CD33 were the most frequent aberrant markers in patients with acute lymphoblastic leukemia, while CD7 and CD19 were the most frequent in patients with acute myeloid leukemia. In the univariate analysis, the group with aberrant markers had a lower disease-free survival when compared with the aberrant-free group (8 vs. 13 months) (p = 0.03). Aberrant expression of CD10, CD20, and CD33 correlated with a worse outcome in a statistically significant manner. In the multivariate analysis, male gender, lymphoid lineage, secondary leukemia, high risk at diagnosis, and the presence of aberrant markers had a significantly negative impact on disease-free survival. CONCLUSION: The use of more aggressive treatment strategies could be considered in patients with acute leukemia and an aberrant expression of CD10, CD20, and CD33.

Plasma total homocysteine in Mexican rural and urban women fed typical model diets.

OBJECTIVE: The purpose of the present work was to determine the fasting plasma total homocysteine (tHcy) levels and the time-course response of tHcy concentrations after the consumption of urban and rural Mexican model diets in two groups of Mexican women from urban and rural areas. METHODS: Thirty-three adult women (age range = 18-49 y) were studied. Fifteen women were from a rural community in the state of Mexico. The other 18 were from cities and consumed diets that regularly included an important amount of animal foods. The study was designed as a two-period crossover study in which subjects consumed the model urban or rural diet in a 2-wk interval. Seven milliliters of venous blood was drawn before ingestion of experimental diets (basal) to measure total cholesterol, high-density lipoprotein cholesterol, triacylglycerol, tHcy, folate, vitamin B12, and methionine. Blood samples were then obtained 30, 60, 90, 180, and 240 min after the beginning of meal consumption. RESULTS: The rural and urban groups showed similar concentrations of tHcy 4 h after meal consumption and after fasting. However, the urban and rural groups had higher methionine plasma concentrations after the urban diet than after the rural diet. In contrast, there was no significant difference in methionine plasma levels between the rural and urban groups with each diet. Those women with low tHcy concentrations maintained those values over the study period, and those with high tHcy concentrations maintained those values. There was no significant difference in tHcy concentrations due to consumption of the two diets (P = 0.31) or the interaction between population and diet (P = 0.84). However, there was a significant difference in the concentration of tHcy between the rural (8.73 +/- 0.17 microM/L) and the urban (9.27 +/- 0.13 microM/L) populations (P = 0.01). In both groups, average tHcy concentration was in the normal range. In both populations, the nutrition status for folate and vitamin B12 was adequate, although plasma folate concentration was significantly lower in the rural population than in the urban population (P < 0.01). Plasma vitamin B12 concentrations were similar in both groups. No subject had low plasma vitamin B12. CONCLUSIONS: Plasma tHcy concentrations in rural and urban Mexican women were within the range considered adequate; however, urban women showed significant higher concentrations than did rural women independently of the consumed diet and the plasma methionine concentration. These results indicated that there is no short-term variation in plasma tHcy due to the consumption of rural or urban diets.

Effect of azacytidine in the release of leukemia inhibitory factor, oncostatin m, interleukin (IL)-6, and IL-11 by mononuclear cells of patients with refractory anemia.

5-azacytidine (AZA) yields hematologic improvement in patients with myelodysplastic syndromes (MDS). Ineffective hemopoiesis in MDS produce the paradox of high intramedullary cellularity with peripheral cytopenias. Leukemia inhibitory factor (LIF), oncostatin M (OSM), interleukin (IL)-6, and IL-11 regulate hemopoiesis and LIF, OSM, and IL-6 also inhibit the proliferation of myeloid leukemic cell lines through the signal-transducing subunit gp130. These IL-6-type cytokines were measured by enzyme-linked immunosorbent assay in cell culture supernatants (SN) obtained from peripheral blood mononuclear cells (MNC) and monocyte-depleted MNC of patients with refractory anemia (RA; n=12) and healthy individuals (n=10). AZA down-regulated OSM, IL-6, and IL-11 release by MNC of patients but not by MNC from healthy individuals. Patient's SN had significantly lower concentrations of LIF, OSM, and IL-11 than SN of normal subjects. When monocyte-depleted MNC of patients were stimulated with phytohemagglutinin a significant increment in OSM levels was observed. In contrast, monocyte depletion in healthy subjects did not cause any significant change in OSM values. We conclude that: (a) AZA inhibits the release of OSM, IL-6, and IL-11 exclusively in RA-diseased MNC, (b) Patient's MNC release subnormal amounts of LIF, OSM, and IL-11, and (c) RA-derived monocytes probably down-regulate OSM release by phytohemagglutinin-activated MNC.

Clasificación de las leucemias agudas de acuerdo con el consenso de la primera conferencia latinoamericana en la tipificación inmunológica de las leucemias / Classification of acute leukemias according to the first Latinoamerican consensus conference for the immunophenotyping of leukemia

Objetivo. Evaluar las recomendaciones del consenso de la primera conferencia latinoamericana en la tipificación inmunológica de las leucemias agudas (LA) en pacientes con LA de novo, sin tratamiento previo y clasificados inmunológicamente empleando citometría de flujo y un panel extenso de anticuerpos monoclonales. Material y métodos. En la conferencia mencionada se decidió el empleo de los siguientes anticuerpos: CD79ac (c = citoplásmico) y CD19 para definir a la LA de linaje linfoide B (LAL-B); CD3c y CD7 para la LAL de estirpe T (LAL-T) y CD13, CD33 y mieloperoxidasa (MPOc) para la LA mieloide (LAM). Se analizó la expresión de estos antígenos celulares en 91 pacientes, no consecutivos, clasificados con el panel extenso como: LAL-B 28 casos; LAL-T 7; LAL-B-T 2; LAM 47 y LA de linaje mixto 7 casos. Resultados. Los 28 pacientes con LAL-B mostraron positividad con cada uno de los dos anticuerpos recomendados (CD79ac y CD19), mientras que, en 24 casos con LAM (en 23 casos no se estudió la expresión del CD79ac) y en 7 con LAL-T ambos antígenos estuvieron ausentes. Los antígenos CD3c y CD7 se identificaron en el 71 por ciento y 100 por ciento de los casos con LAL-T, respectivamente. El CD7 no se expresó en ninguno de los 28 casos de LAL-B pero si en 6 de los 47 casos de LAM, mientras que, el CD3c fue negativo en los 75 casos estudiados con LAL-B y LAM. El 49 por ciento de las LAM expresaron los tres marcadores recomendados (MPOc, CD13 y CD33), y el 51 por ciento de los casos resultaron positivos a uno o dos de estos tres anticuerpos. Seis de las 28 LAL-B tuvieron expresión aberrante de antígenos mieloides (3 casos del CD33 y 3 del CD13). Conclusiones. No hubo diferencia en la definición de linaje de las LA entre emplear el panel extenso de anticuerpos y el mínimo recomendado por el consenso latinoamericano.