Original Article
Soluble Human Leukocyte Antigen-G in the Bronchoalveolar Lavage of Lung Cancer Patients
Antígeno leucocitario humano-G soluble en el lavado broncoalveolar de pacientes con cáncer pulmonar
Dayana Montillaa, Mario Péreza, Lérida Borgesb, Guillermo Bianchic, José-Angel Covab,
Corresponding author
a Servicio de Neumonología y Cirugía de Tórax, Instituto Autónomo Hospital Universitario de los Andes, Mérida, Venezuela
b Instituto de Inmunología Clínica, Universidad de los Andes, Mérida, Venezuela
c Departamento de Mediciones y Evaluaciones, Facultad de Humanidades, Universidad de Los Andes, Mérida, Venezuela
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Clear points represent abnormally high and low values in each case.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Human leukocyte antigen G (HLA-G) is a molecule which belongs to the family of proteins forming the major histocompatibility complex class I (MHC-I). Its main function is to suppress the immune response (IR), which it does by interacting with receptors expressed on the membrane of the immune system effector cells: NK cells, T cells, dendritic cells, and B cells.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">1–3</span></a> HLA-G is expressed in placental tissue (extravillous cytotrophoblast), where it inhibits the IR to fetal antigens, helping the pregnancy to develop.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4,5</span></a> Tissues in which HLA-G has been described, either in a membrane-bound or soluble form, include the thymus, the anterior chamber of the eye, the umbilical cord, immature erythroid cells, the pancreas, and activated macrophages, among others.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> This molecule interacts with its ligands to transmit inhibitory signals to the interior of the cell which manifest as suppression of CD4+ T cell proliferation, inhibition of NK cell cytotoxicity and cytotoxic T cells, and diminished maturation of antigen-presenting dendritic cells.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">6–8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Lung cancer is one of the principal causes of death worldwide, originating up to 1.18 million deaths a year. Moreover, it is estimated that 900<span class="elsevierStyleHsp" style=""></span>000 new cases are detected every year among men and 300<span class="elsevierStyleHsp" style=""></span>000 among women, so it may be of diagnostic, therapeutic and prognostic interest to study the mechanisms leading to the development of this malignancy.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">MHC-I plays an essential role in the elimination of malignant cells by the immune system, since it helps the effector cells, NK cells and T cells to recognize the tumor cells and to infiltrate the tumor site to destroy them. However, tumor cells have developed strategies for avoiding detection and elimination by the immune system, thus promoting tumor growth; one of these strategies is the abnormal expression of immunoregulatory MHC proteins, such as HLA-G, in tumors, a response which may affect immunosurveillance.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">10</span></a> HLA-G expression has been detected in serum and tissue of tumors from different sources, including lung, colorectal, esophageal cancers, and B cell chronic lymphocytic leukemia, among others.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">11–14</span></a> Evidence shows that the HLA-G molecule, in its membrane-bound or soluble (sHLA-G) forms, determines to a large extent tumor growth and invasiveness, leading some authors to suggest its utility as a parameter in oncology.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">15,16</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The aim of this study was to determine sHLA-G levels in bronchoalveolar lavage (BAL) samples from patients with primary or metastastic lung cancer, and to correlate the results with the histological type and patient status, using the Karnofsky performance scale.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">17</span></a> Thus, the direct study of sHLA-G in the tumor compartment may better reflect levels of this molecule in this disease than those obtained by measuring concentrations in serum.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients</span><p id="par0025" class="elsevierStylePara elsevierViewall">After providing signed informed consent, 31 patients of both sexes, over 18 years of age, with primary or metastatic lung cancer, diagnosed on the basis of clinical criteria, imaging studies (chest radiograph or chest computed axial tomography), and microscopy of the lesion, attending the Instituto Autónomo «Hospital Universitario de Los Andes», in Mérida,Venezuela, were randomly selected. Patients with the following characteristics were excluded: respiratory infection at the time of admission, diffuse interstitial pulmonary disease, primary and secondary immunodeficiencies, pregnancy or recurrent abortions, contraindication for fiberoptic bronchoscopy (FB), treatment with immunosuppressive and anticancer drugs. Each patient was evaluated according to the Karnofsky performance scale. The study was approved by the local ethics committee.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Bronchoalveolar Lavage Collection and Lung Tissue Biopsy Using Fiberoptic Bronchoscopy</span><p id="par0030" class="elsevierStylePara elsevierViewall">After applying local anesthesia, a bronchoscope was used (Olympus BF, type P10) to instill 3 aliquots of 20<span class="elsevierStyleHsp" style=""></span>ml sterile saline solution at a temperature of 37<span class="elsevierStyleHsp" style=""></span>°C. The saline solution was then immediately aspirated at a negative pressure of 5–120<span class="elsevierStyleHsp" style=""></span>mmHg and transferred to a tube containing 1<span class="elsevierStyleHsp" style=""></span>ml ethylenediaminetetraacetic acid (EDTA) for subsequent analysis. The bronchoscope was advanced to the suspicious segment (located using imaging techniques) or to the most affected segment on direct visualization, and transbronchial biopsies were obtained (4 fragments) from the affected segments or lesions. If a definitive pathological diagnosis of the cancer type could not be obtained, sampling was repeated with ultrasound-guided fine needle aspiration and biopsy, or open-sky biopsy in the operating room was scheduled, to obtain a significant, adequate sample, according to the thoracic surgeon's criteria.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Determination of the Lung Tumor Histological Type</span><p id="par0035" class="elsevierStylePara elsevierViewall">Lung tumor samples were stored in a 10% formol solution until analysis. After being removed from this solution, the tissue was embedded in paraffin and 0.3–0.4<span class="elsevierStyleHsp" style=""></span>μm slices were prepared. The slices were placed on slides and stained with hematoxylin and eosin (H&E) following a protocol described elsewhere.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">18</span></a> The stained tissue was examined under an optical microscope (Nikon Labofhot 2, Germany) using 20× and 40× amplifications. Lesions were classified as benign or malignant, according to histological changes observed, and the cancer type was established (adenocarcinoma, epidermoid carcinoma, small cell or non-small cell cancer, and metastatic tumors).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Quantification of Levels of Soluble Human Leukocyte Antigen-G in Bronchoalveolar Lavage Using an Enzyme Immunoassay Technique</span><p id="par0040" class="elsevierStylePara elsevierViewall">Soluble HLA-G was quantified using a commercial assay (Human sHLA-G, elisa IBL, Germany), based on the ELISA sandwich or capture technique, following the manufacturer's specifications. Undiluted BAL samples were placed in wells in a polystyrene plate coated with a human anti-HLA-G monoclonal antibody; this antibody captures the HLA-G present in the BAL of the study subjects. A second anti-HLA-G conjugate antibody with biotin was then added and incubated for 2<span class="elsevierStyleHsp" style=""></span>h at room temperature. After this time, the plates were washed 3 times with washing solution and horseradish peroxidase (HRP)-conjugated streptavidin. After incubation and 3 washings, 3,3′, 5,5′-tetramethylbenzidine (TMB) substrate was added and incubated for 10<span class="elsevierStyleHsp" style=""></span>min in the dark. Finally, the stopping solution (H<span class="elsevierStyleInf">2</span>SO<span class="elsevierStyleInf">4</span> 2<span class="elsevierStyleHsp" style=""></span>N) was added and the developed colorimetric reaction was measured using a Sunrise spectrophotometer (Tecan, Austria) with a 450<span class="elsevierStyleHsp" style=""></span>nm wavelength. Values, expressed in optical densities, were transformed to ng/ml using a calibration curve and Magellan V 3.0 software.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical Analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">Results were grouped in double or triple entry tables, as appropriate. Means and standard deviations were calculated and the chi-squared and Duncan's post hoc tests were used to establish statistically significant differences between the variables. A <span class="elsevierStyleItalic">P</span>-value <.05 was considered statistically significant.</p><p id="par0050" class="elsevierStylePara elsevierViewall">A general or generalized linear model (GLM) using a fixed-effect design was constructed to compare and determine the significance of sHLA-G levels among patients with different types of lung cancer.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">19</span></a> The factors sex and smoking index were also added to the model as fixed effects, while the effect of age on sHLA-G values was estimated as a covariate. The same GLM model was used to estimate the correlation between the Karnofsky index and sHLA-G levels in BAL.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Soluble Human Leukocyte Antigen-G Levels in Bronchoalveolar Lavage of Lung Cancer Patients are not Associated with Age, Sex, or Symptoms of Disease</span><p id="par0055" class="elsevierStylePara elsevierViewall">The average age of the study population at the time of diagnosis was 59.2 years. A trend toward a higher rate of lung cancer among women than among men was observed (ratio men:women=1.22). Only 26% of the study patients reported that they were non-smokers. Finally, sHLA-G levels in BAL did not show statistically significant differences when compared with smoking index (mild, moderate or severe), age, sex and symptoms (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">The Most Common Lung Tumor was Adenocarcinoma</span><p id="par0060" class="elsevierStylePara elsevierViewall">Tumor tissue was obtained mainly by FB (87.1% of samples), followed by thoractomy or open-sky biopsy (6.4%) and ultrasound guided transthoracic biopsy (6.4%). A total of 38.7% of the tumors located in the lung were adenocarcinoma, followed by epidermoid carcinoma, metastatic tumors and small-cell cancer, respectively (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Human Leukocyte Antigen-G Occurs in Variable Concentrations in Bronchoalveolar Lavage from Lung Tumors</span><p id="par0065" class="elsevierStylePara elsevierViewall">Levels of sHLA-G in the lung compartment fluctuated widely, from a minimum concentration of 22<span class="elsevierStyleHsp" style=""></span>ng/ml to a maximum of 115<span class="elsevierStyleHsp" style=""></span>ng/ml, with a mean value for the overall group of 49.04<span class="elsevierStyleHsp" style=""></span>ng/ml (SD±27.4<span class="elsevierStyleHsp" style=""></span>ng/ml). The distribution of these levels was asymmetric and clearly bimodal. The first group (80% of patients) had sHLA-G values between 22 and 60<span class="elsevierStyleHsp" style=""></span>ng/ml, and the second group had levels between 80 and 115<span class="elsevierStyleHsp" style=""></span>ng/ml. All patients with metastatic tumors had sHLA-G levels of at least 90<span class="elsevierStyleHsp" style=""></span>ng/ml, with an average of 98.1<span class="elsevierStyleHsp" style=""></span>ng/ml (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">The GLM showed highly significant differences between sHLA-G levels and the tumor histological type (<span class="elsevierStyleItalic">P</span><.001). Firstly, significantly higher levels of sHLA-G were found in metastatic tumors compared to primary tumors of the lung. Secondly, mean levels of this molecule were distributed as follows: adenocarcinoma had the lowest sHLA-G levels determined in the study, with a mean of 26.49<span class="elsevierStyleHsp" style=""></span>ng/ml, followed by epidermoid carcinoma (mean 40.03<span class="elsevierStyleHsp" style=""></span>ng/ml) and small cell carcinoma (57.60<span class="elsevierStyleHsp" style=""></span>ng/ml), with metastatic lung tumors showing the highest arithmetic mean (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">A Correlation Between Soluble Human Leukocyte Antigen-G Levels and Patients’ Functional Status was Determined</span><p id="par0075" class="elsevierStylePara elsevierViewall">To study the correlation between sHLA-G levels in BAL and the Karnofsky performance index, sHLA-G values were grouped into 2 categories: moderately high sHLA-G ≤50<span class="elsevierStyleHsp" style=""></span>ng/ml, and very high >50<span class="elsevierStyleHsp" style=""></span>ng/ml. These 2 categories were compared with the Karnofsky index, and a significant, inverse relationship was identified between sHLA-G levels and the Karnofsky score (<span class="elsevierStyleItalic">P</span><.05). Patients with very high sHLA-G values had lower Karnofsky indices and vice versa (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Cancer is a major cause of morbidity and mortality throughout the world, and considerable effort is being made to identify additional diagnostic and prognostic markers which will be of benefit in the initial stages of the disease when anticancer treatment is the most effective. For this reason, some studies have indicated that serum/plasma concentrations of the molecule sHLA-G seem to be related with different tumor types, and may be a useful biomarker.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In this study, we quantified sHLA-G levels in patients with lung cancer using BAL instead of serum/plasma. We found that this molecule is present in differing concentrations in the tumor microenvironment, and that it also appears to be directly related with the tumor histology type, since the lowest mean values were recorded for adenocarcinoma, followed by epidermoid carcinoma and small cell lung cancer. The highest values corresponded to metastatic tumors. The tumor invasion phenomenon probably requires higher levels of immunosuppression, and for this reason, metastatic lung cancers produce greater amounts of sHLA-G. This molecule is known to inhibit the antitumoral immune response by binding with the ILT-2, ILT-4 and KIR2DL4 immunoreceptors expressed in the effector cells of the immune system.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">2</span></a> In the case of the soluble form of HLA-G, this inhibition occurs even before contact between the tumor cell and the lymphocyte, thus facilitating tumor invasion.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Measuring sHLA-G in serum/plasma has some disadvantages. Firstly, this molecule is detected in the blood of normal subjects, at levels ranging widely between 4.40 and 14<span class="elsevierStyleHsp" style=""></span>ng/ml, depending on the study.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">20,21</span></a> Secondly, some physiological situations, such as pregnancy and organ transplantation, cause sHLA-G levels to rise. Finally, a number of benign diseases (viral infection, asthma, and autoimmune diseases) also modify sHLA-G in serum.<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">4,22–27</span></a> These confounding variables, which may occur in patients with lung cancer, can make it difficult to quantify sHLA-G produced exclusively by the tumor, and to determine how it impacts on the lung cancer diagnosis and prognosis. Measuring sHLA-G directly in BAL could eliminate these factors and enhance the sensitivity and specificity of this molecule as a marker of malignant lung disease, a strategy that has also been explored in the context of malignant ascites in ovarian cancer.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">28</span></a> The disadvantage is that samples must be obtained by invasive methods, such as FB. However, this is routinely performed for precise biopsy of the tumor and for histopathological study in most patients with suspected lung cancer. Obtaining BAL in this group, then, would not be considered an additional procedure. Other methods are useful in locating HLA-G, such as mRNA detection in tumor cells or the identification of the membrane-bound isoform by immunohistochemistry techniques.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">11</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">The Karnofsky scale has been used to evaluate the performance status of cancer patients and its impact on survival and risk of mortality; the scale has also been used to evaluate quality of life in other areas, such as gerontology.<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">17,29</span></a> In this study we found a significant correlation between lower scores on the Karnofsky scale and higher levels of sHLA-G in BAL. The aforementioned immunosuppressive action of this molecule may affect the patient's general status, quality of life and survival prognosis by facilitating the appearance of pneumonia or the reactivation of underlying diseases. The sequence of events set in motion by locally elevated HLA-G levels and immunosuppression with pulmonary superinfection may be reflected in a reduction in Karnofsky score and a greater risk of death. Designing treatments which could correct HLA-G overproduction in the tumor microenvironment may interrupt this sequence and rescue the antitumor immune response. HLA-G is not a specific antigen against lung cancers, since it occurs in a range of tumors − breast, colorectal, esophageal, etc. − but used alongside the Karnofsky scale, it might be a prognostic marker and a determinant of the patient's clinical status.</p><p id="par0100" class="elsevierStylePara elsevierViewall">Although more studies are needed to confirm our findings, it is of interest to continue to evaluate the benefit of sHLA-G and other similar molecules, such as HLA-E and HLA-F, as prognostic markers in patients with malignant lung disease.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of Interest</span><p id="par0105" class="elsevierStylePara elsevierViewall">The authors state that they have no conflict of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres698488" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec708241" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres698487" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec708240" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patients" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Bronchoalveolar Lavage Collection and Lung Tissue Biopsy Using Fiberoptic Bronchoscopy" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Determination of the Lung Tumor Histological Type" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Quantification of Levels of Soluble Human Leukocyte Antigen-G in Bronchoalveolar Lavage Using an Enzyme Immunoassay Technique" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical Analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Soluble Human Leukocyte Antigen-G Levels in Bronchoalveolar Lavage of Lung Cancer Patients are not Associated with Age, Sex, or Symptoms of Disease" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "The Most Common Lung Tumor was Adenocarcinoma" ] 2 => array:2 [ "identificador" => "sec0055" "titulo" => "Human Leukocyte Antigen-G Occurs in Variable Concentrations in Bronchoalveolar Lavage from Lung Tumors" ] 3 => array:2 [ "identificador" => "sec0060" "titulo" => "A Correlation Between Soluble Human Leukocyte Antigen-G Levels and Patients’ Functional Status was Determined" ] ] ] 7 => array:2 [ "identificador" => "sec0065" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflicts of Interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-12-29" "fechaAceptado" => "2016-01-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec708241" "palabras" => array:4 [ 0 => "Human Leukocyte Antigen-G" 1 => "Bronchoalveolar lavage" 2 => "Lung cancer" 3 => "Karnofsky index" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec708240" "palabras" => array:4 [ 0 => "Antígeno leucocitario humano-G" 1 => "Lavado broncoalveolar" 2 => "Cáncer de pulmón" 3 => "Índice de Karnofsky" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The main function of the HLA-G molecule in its membrane-bound and soluble forms is to inhibit the immune response by acting on CD4+ T cells, cytotoxic T cells, NK cells and dendritic cells. Lung cancer is a leading cause of death worldwide, and annual incidence is high in both women and men. Some studies have reported an increase of HLA-G serum levels in lung cancer, probably generated by tumor cells escaping the antitumor immune response. In this study the concentration of soluble HLA-G in bronchoalveolar lavage (BAL) in patients with primary and metastatic lung cancer was measured to determine its relation with tumor histological type and overall patient status according to the Karnofsky scale.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Thirty-one lung cancer patients were included. A tumor biopsy was obtained by bronchoscopy and the tumor type was determined by hematoxylin and eosin staining. BAL samples were obtained to measure soluble HLA-G concentrations in an ELISA sandwich assay.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The average value of soluble HLA-G was 49.04<span class="elsevierStyleHsp" style=""></span>ng/ml. No correlation between soluble HLA-G levels and age, gender or smoking was observed. A highly significant difference was observed in the levels of soluble HLA-G in BAL from patients with different histological types of lung cancer, especially in metastatic tumors. The Karnofsky index showed a significant and inverse correlation with soluble HLA-G levels in BAL.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Soluble HLA-G protein is significantly associated with metastatic tumors and patients with lower Karnofsky index and may be useful as a prognostic marker in lung cancer.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La molécula antígeno leucocitario humano G (HLA-G), en sus formas unida a membrana y soluble, tiene como función principal inhibir la respuesta inmune actuando sobre los linfocitos T/CD4+, T/citotóxicos, células NK y células dendríticas. El cáncer de pulmón es una de las principales causas de muerte en el mundo, con una alta tasa de incidencia anual tanto en mujeres como en hombres. Algunos estudios han reportado un incremento de HLA-G sérica en el cáncer de pulmón, probablemente como un mecanismo de escape de la célula tumoral a la respuesta inmune antitumoral. En este estudio se midió la concentración de HLA-G soluble, en el lavado broncoalveolar (LBA), en pacientes con cáncer de pulmón primario y metastásico para determinar su relación con el tipo histológico tumoral y estado general del paciente usando la escala de Karnofsky.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 31 pacientes con diagnóstico de cáncer de pulmón y mediante fibrobroncoscopia se tomó biopsia de la neoplasia para determinar el tipo de tumor usando la coloración de hematoxilina y eosina, y líquido del lavado broncoalveolar para medir la concentración de la molécula HLA-G soluble mediante un ELISA tipo sándwich.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El valor medio de la HLA-G soluble fue de 49,04 ng/ml. No se observó ninguna correlación entre los niveles de HLA-G soluble y la edad, género o índice de tabaquismo. Se observó una diferencia altamente significativa en los niveles de HLA-G soluble en LBA de pacientes con diversos tipos histológicos de cáncer de pulmón, principalmente en tumores metastásicos. El índice de Karnofsky mostró una correlación significativa e inversa con el nivel de HLA-G soluble en LBA.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La proteína HLA-G soluble puede ser útil como marcador pronóstico del cáncer pulmonar al asociarse significativamente a los tumores metastásicos y a los pacientes con menor índice de Karnofsky.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Montilla D, Pérez M, Borges L, Bianchi G, Cova J-A. Antígeno leucocitario humano-G soluble en el lavado broncoalveolar de pacientes con cáncer pulmonar. Arch Bronconeumol. 2016;52:420–424.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1608 "Ancho" => 1418 "Tamanyo" => 53476 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Distribution of lung cancer by histological type, expressed in percentages. ADC, adenocarcinoma; epC, epidermoid cancer; Mt, metastasis; sCC, small cell cancer.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 828 "Ancho" => 1582 "Tamanyo" => 46131 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Soluble human leukocyte antigen (sHLA-G) levels in bronchoalveolar lavage (BAL) in patients with different histological types of lung cancer.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 881 "Ancho" => 1660 "Tamanyo" => 56187 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Soluble human leukocyte antigen (sHLA-G) levels in lung cancer, by histological type. Clear points represent abnormally high and low values in each case.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">F, female; M, male; NS, not significant; SD, standard deviation; sHLA-G, soluble human leukocyte antigen type G.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Variable \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Values \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">sHLA-G \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Age (years)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">59.2 (SD: ±11) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Sex (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>F \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">17 (54.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">14 (45.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Smoking index (%):</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Severe \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">58.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Moderate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">3.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mild \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Non-smoker (%)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">26 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Pack-years</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">29.6 (SD: ±36.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">sHLA-G in BAL (ng/ml)</span> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">49 (SD: ±27.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1144764.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">General Characteristics of Patients (<span class="elsevierStyleItalic">n</span>=31).</p>" ] ] 4 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">BAL, bronchoalveolar lavage; KI-H, Karnofsky index high; KI-L, Karnofsky index low; sHLA-G, soluble human leukocyte antigen-G.</p><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Percentages are expressed in brackets.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Karnofsky index \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="3" align="center" valign="top" scope="col" style="border-bottom: 2px solid black">sHLA-G in LBA</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">High (≤50<span class="elsevierStyleHsp" style=""></span>ng/ml) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Very High (>50<span class="elsevierStyleHsp" style=""></span>ng/ml) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">K \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 (10) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">L \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (23.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">K \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5 (23.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3 (30) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">I \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">70 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 (9.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">H \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">80 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 (42.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0 (0) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Total \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">31 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1144763.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Levels of Soluble Human Leukocyte Antigen-G in Lung Cancer and Correlation with Karnofsky Index.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:29 [ 0 => array:3 [ "identificador" => "bib0150" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Antígenos y su presentación a los linfocitos. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 0 | 3 |
| 2024 October | 48 | 41 | 89 |
| 2024 September | 64 | 27 | 91 |
| 2024 August | 64 | 42 | 106 |
| 2024 July | 53 | 22 | 75 |
| 2024 June | 69 | 40 | 109 |
| 2024 May | 89 | 28 | 117 |
| 2024 April | 39 | 28 | 67 |
| 2024 March | 34 | 22 | 56 |
| 2024 February | 34 | 18 | 52 |
| 2023 March | 10 | 5 | 15 |
| 2023 February | 32 | 21 | 53 |
| 2023 January | 27 | 38 | 65 |
| 2022 December | 71 | 39 | 110 |
| 2022 November | 83 | 43 | 126 |
| 2022 October | 100 | 44 | 144 |
| 2022 September | 54 | 31 | 85 |
| 2022 August | 33 | 63 | 96 |
| 2022 July | 43 | 59 | 102 |
| 2022 June | 31 | 42 | 73 |
| 2022 May | 55 | 45 | 100 |
| 2022 April | 41 | 34 | 75 |
| 2022 March | 61 | 64 | 125 |
| 2022 February | 62 | 41 | 103 |
| 2022 January | 50 | 42 | 92 |
| 2021 December | 57 | 41 | 98 |
| 2021 November | 51 | 45 | 96 |
| 2021 October | 83 | 54 | 137 |
| 2021 September | 49 | 53 | 102 |
| 2021 August | 47 | 31 | 78 |
| 2021 July | 27 | 29 | 56 |
| 2021 June | 56 | 44 | 100 |
| 2021 May | 53 | 57 | 110 |
| 2021 April | 98 | 103 | 201 |
| 2021 March | 52 | 37 | 89 |
| 2021 February | 41 | 27 | 68 |
| 2021 January | 42 | 18 | 60 |
| 2020 December | 35 | 24 | 59 |
| 2020 November | 37 | 22 | 59 |
| 2020 October | 34 | 23 | 57 |
| 2020 September | 29 | 18 | 47 |
| 2020 August | 36 | 22 | 58 |
| 2020 July | 27 | 28 | 55 |
| 2020 June | 29 | 13 | 42 |
| 2020 May | 53 | 20 | 73 |
| 2020 April | 59 | 28 | 87 |
| 2020 March | 43 | 20 | 63 |
| 2020 February | 34 | 24 | 58 |
| 2020 January | 32 | 20 | 52 |
| 2019 December | 40 | 15 | 55 |
| 2019 November | 34 | 19 | 53 |
| 2019 October | 28 | 11 | 39 |
| 2019 September | 32 | 14 | 46 |
| 2019 August | 30 | 12 | 42 |
| 2019 July | 39 | 25 | 64 |
| 2019 June | 23 | 13 | 36 |
| 2019 May | 29 | 17 | 46 |
| 2019 April | 27 | 14 | 41 |
| 2019 March | 36 | 23 | 59 |
| 2019 February | 37 | 19 | 56 |
| 2019 January | 27 | 13 | 40 |
| 2018 December | 34 | 17 | 51 |
| 2018 November | 47 | 17 | 64 |
| 2018 October | 37 | 16 | 53 |
| 2018 September | 15 | 18 | 33 |
| 2018 May | 13 | 4 | 17 |
| 2018 April | 37 | 16 | 53 |
| 2018 March | 17 | 3 | 20 |
| 2018 February | 21 | 10 | 31 |
| 2018 January | 26 | 6 | 32 |
| 2017 December | 31 | 11 | 42 |
| 2017 November | 17 | 9 | 26 |
| 2017 October | 22 | 16 | 38 |
| 2017 September | 30 | 3 | 33 |
| 2017 August | 19 | 8 | 27 |
| 2017 July | 24 | 4 | 28 |
| 2017 June | 39 | 10 | 49 |
| 2017 May | 51 | 14 | 65 |
| 2017 April | 28 | 10 | 38 |
| 2017 March | 25 | 8 | 33 |
| 2017 February | 22 | 7 | 29 |
| 2017 January | 12 | 8 | 20 |
| 2016 December | 32 | 19 | 51 |
| 2016 November | 55 | 34 | 89 |
| 2016 October | 2 | 2 | 4 |
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