Epigenetic quantification of circulating immune cells in peripheral blood of triple-negative breast cancer patients.

BACKGROUND: A shift in the proportions of blood immune cells is a hallmark of cancer development. Here, we investigated whether methylation-derived immune cell type ratios and methylation-derived neutrophil-to-lymphocyte ratios (mdNLRs) are associated with triple-negative breast cancer (TNBC). METHODS: Leukocyte subtype-specific unmethylated/methylated CpG sites were selected, and methylation levels at these sites were used as proxies for immune cell type proportions and mdNLR estimation in 231 TNBC cases and 231 age-matched controls. Data were validated using the Houseman deconvolution method. Additionally, the natural killer (NK) cell ratio was measured in a prospective sample set of 146 TNBC cases and 146 age-matched controls. RESULTS: The mdNLRs were higher in TNBC cases compared with controls and associated with TNBC (odds ratio (OR) range (2.66-4.29), all Padj. < 1e-04). A higher neutrophil ratio and lower ratios of NK cells, CD4 + T cells, CD8 + T cells, monocytes, and B cells were associated with TNBC. The strongest association was observed with decreased NK cell ratio (OR range (1.28-1.42), all Padj. < 1e-04). The NK cell ratio was also significantly lower in pre-diagnostic samples of TNBC cases compared with controls (P = 0.019). CONCLUSION: This immunomethylomic study shows that a shift in the ratios/proportions of leukocyte subtypes is associated with TNBC, with decreased NK cell showing the strongest association. These findings improve our knowledge of the role of the immune system in TNBC and point to the possibility of using NK cell level as a non-invasive molecular marker for TNBC risk assessment, early detection, and prevention.

White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?

BACKGROUND: White cell count (WCC) is a clinical marker of inflammation. Data are limited regarding the association of total and differential WCC with risk of mortality, and its role related with smoking and body mass index (BMI). METHODS: A total of 14 433 participants (4150 men; 10 283 women; average age 47.3±11.8 years) from the Dutch European Prospective Investigation into Cancer and Nutrition-Netherlands cohort were included. The associations between prediagnostic total WCC and its subtypes and risk of all-cause, cancer and cardiovascular disease (CVD) mortality were assessed. The role of WCC related with smoking and BMI on mortality was further explored. Multivariate Cox regression models were performed to estimate the HR and 95% CI. RESULTS: After an average follow-up of 15.8 years, a total of 936 death cases were identified (466 cancer; 179 CVD; 291 other causes). Statistically significant graded associations between total WCC, and counts of lymphocytes, monocytes, neutrophils and eosinophils and risk of total mortality were observed. These associations were more apparent in current smokers. Strong associations for all-cause mortality or cancer mortality were observed in subjects with BMI ≥25 kg/m2, ever smoking and elevated WCC (HR 3.92, 95% CI 2.76 to 5.57; HR 3.93, 95% CI 2.30 to 6.72). WCC partly mediated the associations between smoking or BMI and all-cause mortality. CONCLUSIONS: Prediagnostic WCC and its subtypes are associated with all-cause, cancer and CVD mortality risk. It may play a partially mediate role on the association between smoking or obesity and mortality.

Outpatient management of children at low risk for bacterial meningitis.

OBJECTIVE: To determine the outcome of children aged 2-14 years with cerebrospinal fluid (CSF) pleocytosis and at very low risk for bacterial meningitis managed as outpatients without antibiotics. METHODS: Multicentre, prospective, observational study conducted at nine Spanish paediatric EDs. Patients were diagnosed with meningitis based on clinical suspicion of meningitis and CSF pleocytosis when evaluated in the ED. Children between 2 and 14 years of age with pleocytosis and very low-risk criteria for bacterial meningitis (well appearing, Bacterial Meningitis Score (BMS)=0, procalcitonin (PCT)<0.5 ng/mL and observation without deterioration for less than 24 hours in the ED) were treated as outpatients without antibiotics pending CSF cultures. The primary composite outcome was a final diagnosis of bacterial meningitis or return to the ED for clinical deterioration. RESULTS: Of 182 children between 2 and 14 years old diagnosed with meningitis, 56 met the very low-risk criteria and 45 were managed as outpatients. None was diagnosed with bacterial meningitis or returned due to clinical deterioration. Another 31 patients with BMS=1 (due to a peripheral absolute neutrophil count (ANC)>10 000/mm3) and PCT <0.5 ng/mL were managed as outpatients, diagnosed with aseptic meningitis and did well. BMS using PCT had the same sensitivity but greater specificity than classic BMS. CONCLUSIONS: This set of low-risk criteria appears safe for the outpatient management without antibiotics of children with CSF pleocytosis. Larger studies are needed to evaluate the predictive values of replacing peripheral ANC with PCT in the BMS.

Asthma phenotypes: consistency of classification using induced sputum.

BACKGROUND AND OBJECTIVE: Asthma can be classified as eosinophilic or non-eosinophilic based on the cell profile of induced sputum. This classification can help determine whether corticosteroid treatment is indicated. We assessed the stability of these phenotypes over time and with different treatment regimens. METHODS: Clinically stable, non-smoking, asthmatic adults were enrolled in one of two studies. In study one, induced sputum cell counts from 28 subjects were analysed after 4 weeks without corticosteroid treatment and after 6 week treatments with placebo, regular inhaled beta-agonist, inhaled corticosteroid, and combined beta-agonist and corticosteroid. In study two, sputum from 26 subjects with non-eosinophilic asthma was analysed after 12 weeks of placebo and after four 2-week corticosteroid washouts. Sputum with <2% eosinophils was classified as non-eosinophilic. RESULTS: Sputum classification changed frequently in both studies. In study one, only one of eight participants with non-eosinophilic sputum after placebo treatment remained non-eosinophilic throughout. In study two, all of participants had at least one eosinophilic sputum sample, despite the fact that all had been non-eosinophilic at recruitment. Neutrophilic asthma was uncommon in both studies and was also inconsistent. CONCLUSIONS: The phenotypic classification of asthma changes frequently. A diagnosis of non-eosinophilic asthma should not be based on a single sputum sample.

Reactive peripheral blood plasmacytosis in a patient with acute hepatitis A.

Reactive plasmacytosis is a transient expansion of plasma cell progenitors and precursors. This rare condition has been reported to occur mainly in infections and tumors. We describe a case of acute hepatitis A presenting with marked peripheral blood plasmacytosis. Plasma cells made up 27.5% of the mononuclear cells and had the immunophenotype CD10-CD19+CD20-CD21-CD23-CD34-CD38++HLA-DR+. Although the level of interleukin 6 was not increased, the presence of activated T-cells with an inverted CD4/CD8 ratio and high levels of soluble interleukin 2 receptor and neopterin indicated a marked immune response to acute hepatitis A. The patient's plasma cells had almost disappeared from the blood by hospital day 16. This report may represent the first described case of reactive peripheral blood plasmacytosis in acute hepatitis A.

Contribution of monocytes to viral replication in macaques during acute infection with simian immunodeficiency virus.

Monocytes are known as an alternative target for HIV/SIV infection, but the contribution of monocytes to viral spread in a host is unclear. In this study, CD14 monocytes were monitored in 6 macaques until six weeks postinfection (wpi) with SIVmac239 to evaluate their contribution to viral load. The monocyte count in blood significantly increased with peak viremia at 2 wpi and the expression level of CD14 on monocytes significantly decreased at 1-2 wpi, though the number of CD4(+) T cells was stable in these macaques. The number of CD14 monocytes and the expression level of CD14 on monocytes at 2 wpi were also significantly related to the extent of viremia in plasma. An increased number of monocytes at 2 wpi was associated with a lower postacute viral load, suggesting that monocytes have a role in suppressing the virus. The lower expression level of CD14 in monocytes at 2 wpi was associated with a higher viral load and greater degree of infection of monocytes. This correlation suggests that monocytes with a low level of CD14 may be more susceptible to SIV and may enhance viral replication. The analysis of monocytes in persistently infected macaques revealed that the expression level of CD14 was also significantly low during persistent infection compared with naïve macaques, though the monocyte count was within the normal range. Monocytes may suppress viruses, perhaps by their immune function, during acute infection. However, infection of monocytes may increase the viral load and spread viruses in a host.

[Diagnostic utility of pleural fluid eosinophilia]. / Diagnostyczne znaczenie kwasochlonnego wysieku w jamie oplucnej.

Diagnostic utility of eosinophilic pleural effusion (EPE) is still the matter of controversy. Some earlier studies have showed that pleural fluid eosinophilia considerably reduces the probability of malignancy, while some later analyses were not able to confirm such an observation. To evaluate the diagnostic significance of EPE the retrospective study of all patients with pleural effusion (PE) managed in our hospital between 1995 and 2001 has been undertaken. We analyzed 915 patients with PE and 1086 pleural effusions subjected to a biochemical, cytological and bacteriological examinations. We identified 72 (7,9%) patients with EPE and 82 EPEs liquid (7,5%) among them. The group of patients with EPE consisted of 41 (57%) males and 31 (43%) females; average age 62.2 year (range 21.0-94.0). Etiologic distribution showed the largest subgroup were patients with malignant EPE (n=28, 38.9%) followed by idiopathic EPE (n=12, 16.7%) and parapneumonic EPE (n=11, 15.3%). Looking for predictors of malignancy in EPE we found some differences between malignant and nonmalignant EPE: patients with malignant EPE were older (67.9+/-13.6) then patients with nonmalignant EPE (58.7+/-15.6; p<0.015), and have higher percentage of lymphocytes in PE (47.9+/-16.9 vs. 37.9+/-18.9; p<0.03). Similarly we noticed some differences between two largest groups (malignant and idiopathic PE). Patients with malignant PE were older (67.9+/-13.6 vs. 53.9+/-13.6 yrs; p=0.005), had lower pleural fluid eosinophilia (25.2+/-15.3% vs. 41.4+/-21.0%; p=0.01) and higher percentage of lymphocyte in PE (47.9+/-16.9 vs. 29.6+/-19.1%; p=0.004). We conclude that pleural fluid eosinophilia cannot be considered as predictor of nonmalignant etiology. The older age and the higher number of lymphocytes in EPE might suggest malignant etiology of pleural effusion.

Leukogram and white blood cells count in native people of Chukotka.

A representative sample of male and female Chukotka natives aged 25-6 years (362 persons) has been surveyed using the cross-sectional epidemiological method. The results have been compared with the data obtained when surveying a representative sample of the non-organised population of the same age in Novosibirsk (n = 2071 persons). The mean age was 43 years. The total count of white blood cells (WBC) in peripheral blood of Chukotka natives was lower than the corresponding values of that index in the inhabitants of Novosibirsk, the 10-90% range of white blood counts being 3.0-7.0 10(9)/l in natives and 4.0-9.0 10(9)/l in residents of Novosibirsk. A significant incidence of leukopenias (<4.0 10(9)/l) has been detected, being 30% in the population of Chukotka, 24% in men and 35% in women. Modification in White Blood Cells differentials (leukogram) has been found in native Chukotka people, particularly relative and absolute lymphocytopenia.