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OBJECTIVE: The paper proposes a non-invasive original methodology to directly and automatically identify the spine line from the external position of vertebral apophyses, which are key anatomical landmarks. METHODS: Apophyses are detected directly on discrete high-density geometric models of human backs acquired by a 3D scanner. The methodology is inspired by the posturologist's approach that detects the spine line through the identification, by manual palpation, of the spinal apophyses. For this purpose, an appropriate shape index is used to identify vertebral positions. The shape index estimates the local differential geometric properties of the back surface. This index is very discriminating in locating both pronounced and blurred apophyses. To validate the method, the research involved the analysis of 21 healthy human backs acquired in both standing and asymmetric postures. For each of them, a skilled operator detected the spinal apophyses by tactile investigation and located them through cutaneous marking. Markers have been used as the reference for spinal apophyses' positions. RESULTS: A comparison of the proposed approach with state-of-the-art methods has been conducted. This study evidences the high accuracy of the methodology proposed here and the capability to recognize also blurred apophyses. CONCLUSION: The method automatically performs the spine line identification and accurately locates apophyses along both vertical and coronal directions. SIGNIFICANCE: The proposed inexpensive and easy-to-use approach significantly advances over other non-invasive methods. Its ability to detect the apophyses' location potentially offers new capabilities in detecting, diagnosing, and monitoring spinal disorders.
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Previous studies showed an association between single nucleotide gene variants (SNVs) of PD-1 and cancer susceptibility. We analyzed PD1.5 C > T and PD1.7 T > C SNVs to investigate their association with the risk of developing metastatic melanoma (MM). Utilizing a cohort of 125 MM patients treated with anti-PD-1 agents and 84 healthy controls, we examined genotype/allele frequencies through a modified Poisson regression model, adjusted for age and sex. Our findings indicate that the PD1.5 T allele is associated with a reduced risk of MM, showing a significantly lower risk in both codominant (RR = 0.56, 95%CL: 0.37-0.87) and dominant (RR = 0.73 95%CL: 0.59-0.90) models. Conversely, the PD1.7 C allele is linked to an increased risk of MM, with the C/C genotype exhibiting a higher risk in the codominant (RR = 1.65, 95%CL: 1.32-2.05) and allelic (RR = 1.23, 95%CL: 1.06-1.43) models. These results are consistent with previous meta-analyses on other cancer types, mainly highlighting the PD1.5 SNV's potential role in promoting anti-tumor immunity through increased PD1-positive circulating effector T cell activity.
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Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Melanoma , Polimorfismo de Nucleótido Simple , Receptor de Muerte Celular Programada 1 , Neoplasias Cutáneas , Humanos , Melanoma/genética , Receptor de Muerte Celular Programada 1/genética , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Anciano , Estudios de Casos y Controles , Adulto , Genotipo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , AlelosRESUMEN
Uveal melanoma (UM) is the most common primary intraocular malignancy with a limited five-year survival for metastatic patients. Limited therapeutic treatments are currently available for metastatic disease, even if the genomics of this tumor has been deeply studied using next-generation sequencing (NGS) and functional experiments. The profound knowledge of the molecular features that characterize this tumor has not led to the development of efficacious therapies, and the survival of metastatic patients has not changed for decades. Several bioinformatics methods have been applied to mine NGS tumor data in order to unveil tumor biology and detect possible molecular targets for new therapies. Each application can be single domain based while others are more focused on data integration from multiple genomics domains (as gene expression and methylation data). Examples of single domain approaches include differentially expressed gene (DEG) analysis on gene expression data with statistical methods such as SAM (significance analysis of microarray) or gene prioritization with complex algorithms such as deep learning. Data fusion or integration methods merge multiple domains of information to define new clusters of patients or to detect relevant genes, according to multiple NGS data. In this work, we compare different strategies to detect relevant genes for metastatic disease prediction in the TCGA uveal melanoma (UVM) dataset. Detected targets are validated with multi-gene score analysis on a larger UM microarray dataset.
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Melanoma , Neoplasias de la Úvea , Humanos , Melanoma/patología , Neoplasias de la Úvea/patología , Análisis por MicromatricesRESUMEN
From archaeological excavations, huge quantities of material are recovered, usually in the form of fragments. Their correct interpretation and classification are laborious and time-consuming and requires measurement, analysis and comparison of several items. Basing these activities on quantitative methods that process 3D digital data from experimental measurements allows optimizing the entire restoration process, making it faster, more accurate and cheaper. The 3D point clouds, captured by the scanning process, are raw data that must be properly processed to be used in automatic systems for the analysis of archeological finds. This paper focuses on the integration of a shape feature recognizer, able to support the semantic decomposition of the ancient artifact into archaeological features, with a structured database, able to query the large amount of information extracted. Through the automatic measurement of the dimensional attributes of the various features, it is possible to facilitate the comparative analyses between archaeological artifacts and the inferences of the archaeologist and to reduce the routine work. Here, a dedicated database has been proposed, able to store the information extracted from huge quantities of archaeological material using a specific shape feature recognizer. This information is useful for making comparisons but also to improve the archaeological knowledge. The database has been implemented and used for the identification of pottery fragments and the reconstruction of archaeological vessels. Reconstruction, in particular, often requires the solution of complex problems, especially when it involves types of potsherds that cannot be treated with traditional methods.
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PURPOSE: Programmed death-ligand 1 (PD-L1) protein plays a central role in the antitumor immune response, and appears to be a predictor of prognosis and efficacy for PD-L1 and programmed death 1 (PD-1) blockade therapy. The immunoregulatory role and prognostic impact of PD-L1 soluble form (sPD-L1) have been investigated in biological fluids of patients with different tumors. In malignant pleural mesothelioma (MPM), circulating sPD-L1 has been recently reported in patients' sera, but no data are available in pleural effusions (PE). In our study, we evaluated the baseline expression levels of sPD-L1 in PE from 84 MPM patients and correlated them with PD-L1-status in matched tumors and patients' overall survival (OS). METHODS: sPD-L1 in PE was determined by ELISA and tumor PD-L1 by immunohistochemistry. Association of sPD-L1 with OS was estimated using the Cox regression model. RESULTS: We observed that sPD-L1 was variably expressed in all the PE and tended to be higher (by 30%) in patients with PD-L1-positive tumors (cut-off ≥ 1% stained cells) as compared to patients with PD-L1-negative tumors (geometric mean ratio = 1.28, P value = 0.288). sPD-L1 levels were significantly higher than those of sPD-1 (P value = 0.001) regardless of the MPM histotypes and they were positively correlated (r = 0.50, P value < 0.001). Moreover, high PE sPD-L1 concentrations were associated with a trend towards increased OS (hazard ratio 0.79, 95% CL 0.62-1.01, P value = 0.062). CONCLUSIONS: Our study documents the presence of sPD-L1 in PE of MPM patients, and suggests its possible biological and prognostic role in MPM.
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Antígeno B7-H1/fisiología , Mesotelioma Maligno/inmunología , Derrame Pleural/metabolismo , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Mesotelioma Maligno/mortalidad , Persona de Mediana Edad , Pronóstico , Receptor de Muerte Celular Programada 1/análisis , Modelos de Riesgos ProporcionalesRESUMEN
The expression of the immune checkpoint molecule CTLA-4 has been almost exclusively studied in the T cell lineage, but increasing evidence has shown its expression on tumors with implications for immunotherapy. To date, the degree of expression of CTLA-4 on tumor cells as a predictive biomarker of response to immune checkpoint inhibitors has not been studied. In this report, we analyzed this issue in melanoma patients treated with CTLA-4 inhibitor Ipilimumab (IPI). We show that the level of CTLA-4 expression on melanoma cells is higher than that on tumor infiltrating lymphocytes (TIL) and it is associated with clinical response to IPI therapy supporting the idea of its possible role as a predictive biomarker.
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Antineoplásicos Inmunológicos/uso terapéutico , Antígeno CTLA-4/metabolismo , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana EdadRESUMEN
Immune checkpoint inhibitors, including ipilimumab (IPI), achieve a clinical benefit in a small proportion of melanoma patients highlighting the need to investigate predictive biomarkers. In this study, we characterized tumor infiltrating lymphocytes (TILs), focusing on the CTLA-4+ subset, and evaluated their possible predictive significance. We characterized TIL density, cell type, and localization in 40 melanoma lesions from 17 patients treated with IPI. Associations of TILs with IPI timing, tissue localization, and response to IPI were estimated using a linear mixed-effects modelling approach. We found that most of TIL subsets increased in situ upon IPI therapy, with particular reference to FoxP3+ cells. TILs and TIL subsets, such as CD3+, CD45RO+, CTLA-4+, CD4+, CD8+ T cells, CD20+ B cells, and NKp46+ NK cells, showed significantly different spatial distributions in the tumor microenvironment being higher at the invasive margin (IM) as compared to the tumor center (TC) (P value < 0.001 for TIL score and P value < 0.05 for all subsets). Remarkably, high TIL score and density of CD3+, CD8+ T cells, and CTLA-4+ immune cells were significantly associated with a better response to IPI (P values = 0.002, 0.023, 0.007, and 0.001, respectively, for responders vs non-responders). In conclusion, we provide a detailed analysis of CTLA-4+ TIL distribution in melanoma tissues taking into account localization, relationship with CD3+/CD8+ TILs, and changes in response to IPI treatment. We identified that CTLA-4+ TILs may represent a marker of IPI response, alone or with CD3+/CD8+ subsets, although this requires confirmation in larger studies.
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Antígeno CTLA-4/antagonistas & inhibidores , Ipilimumab/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Melanoma/tratamiento farmacológico , Microambiente Tumoral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígeno CTLA-4/inmunología , Antígeno CTLA-4/metabolismo , Femenino , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Melanoma/inmunología , Melanoma/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Microambiente Tumoral/inmunologíaAsunto(s)
Antígeno B7-H1/metabolismo , Membrana Celular/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Interferón gamma/farmacología , Regulación hacia Arriba/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Humanos , Mesotelioma/inmunología , SolubilidadRESUMEN
The construction of the artificial emissary of Fucino Lake is one of the most ambitious engineering buildings of antiquity. It was the longest tunnel ever made until the 19th century and, due to the depth of the adduction inlet, it required a monumental and complex incile, which, for functionality, cannot be compared to other ancient emissaries. The Roman emissary and its "incile" (Latin name of the inlet structure) were almost completely destroyed in the 19th century, when Fucino Lake was finally dried. Today, only few auxiliary structures such as wells, tunnels, and winzes remain of this ancient work. As evidence of the ancient incile remains a description made by those who also destroyed it and some drawings made by travelers who, on various occasions, visited the site. This paper presents a virtual reconstruction of the Roman incile, obtained both through the philological study of the known documentation, interpreting iconographic sources that represent the last evidence of this structure, and through the survey on the territory. The main purpose is to understand its technical functionalities, the original structures, and its evolution during the time, taking into account the evolution of the Fucino Lake water levels, technological issues, and finally offering its visual reconstruction.
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The design of bone scaffolds for tissue regeneration is a topic of great interest, which involves different issues related to geometry of architectures, mechanical behavior, and biological requirements, whose optimal combination determines the success of an implant. Additive manufacturing (AM) has widened the capability to produce structures with complex geometries, which should potentially satisfy the different requirements. These architectures can be obtained by means of refined methods and have to be assessed in terms of geometrical and mechanical properties. In this paper a triply periodic minimal surface (TPMS), the Schwarz's Primitive surface (P-surface), has been considered as scaffold unit cell and conveniently parameterized in order to investigate the effect of modulation of analytical parameters on the P-cell geometry and on its properties. Several are the cell properties, which can affect the scaffold performance. Due to the important biofunctional role that the surface curvature plays in mechanisms of cellular proliferation and differentiation, in this paper, in addition to properties considering the cell geometry in its whole (such as volume fraction or pore size), new properties were proposed. These properties involve, particularly, the evaluation of local geometrical-differential properties of the P-surface. The results of this P-cell comprehensive characterization are very useful for the design of customized bone scaffolds able to satisfy both biological and mechanical requirements. A numerical structural evaluation, by means of finite element method (FEM), was performed in order to assess the stiffness of solid P-cells as a function of the changes of the analytical parameters of outer surface and the thickness of cell. Finally, the relationship between stiffness and porosity has been analyzed, given the relevance that this property has for bone scaffolds design.
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Células Artificiales , Regeneración Ósea , Huesos/química , Ingeniería de Tejidos , Andamios del Tejido/química , Algoritmos , Células Artificiales/química , Sustitutos de Huesos/química , Modelos Estructurales , Porosidad , Propiedades de Superficie , Ingeniería de Tejidos/métodosRESUMEN
CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
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Biomarcadores de Tumor/metabolismo , Antígeno CTLA-4/metabolismo , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/sangre , Antígeno CTLA-4/sangre , Femenino , Humanos , Italia , Estimación de Kaplan-Meier , Masculino , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Solubilidad , Adulto JovenRESUMEN
Targeting the Immune Checkpoint molecules (ICs; CTLA-4, PD-1, PD-L1/2, and others) which provide inhibitory signals to T cells, dramatically improves survival in hard-to-treat tumors. The establishment of an immunosuppressive environment prevents endogenous immune response in glioblastoma; therefore, manipulating the host immune system seems a reasonable strategy also for this tumor. In glioma patients the accumulation of CD4+/CD8+ T cells and Treg expressing high levels of CTLA-4 and PD-1, or the high expression of PD-L1 in glioma cells correlates with WHO high grade and short survival. Few clinical studies with IC inhibitors (ICis) were completed so far. Notably, the first large-scale randomized trial (NCT 02017717) that compared PD-1 blockade and anti-VEGF, did not show an OS increase in the patients treated with anti-PD-1. Several factors could have contributed to the failure of this trial and must be considered to design further clinical studies. In particular the possibility of targeting at the same time different ICs was pre-clinically tested in an animal model were inhibitors against IDO, CTLA-4 and PD-L1 were combined and showed persistent and significant antitumor effects in glioma-bearing mice. It is reasonable to hypothesize that the immunological characterization of the tumor in terms of type and level of expressed IC molecules on the tumor and TIL may be useful to design the optimal ICi combination for a given subset of tumor to overcome the immunosuppressive milieu of glioblastoma and to efficiently target a tumor with such high cellular complexity.
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Biomarcadores de Tumor/genética , Antígeno CTLA-4/genética , Enfermedades del Sistema Endocrino/diagnóstico , Ipilimumab/efectos adversos , Melanoma/tratamiento farmacológico , Polimorfismo Genético , Neoplasias Cutáneas/tratamiento farmacológico , Enfermedades del Sistema Endocrino/inducido químicamente , Enfermedades del Sistema Endocrino/genética , Humanos , Melanoma/patología , Pronóstico , Neoplasias Cutáneas/secundarioRESUMEN
[This corrects the article on p. 386 in vol. 8, PMID: 28446908.].
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Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA), that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode. MicroRNAs (miRNA) are a class of ncRNA of about 22 bp that regulate gene expression by binding to complementary sequences in the mRNA and silence its translation into proteins. MicroRNAs reversibly regulate transcription through nonmutational mechanisms; accordingly, they can be considered as epigenetic effectors. In this review, we will discuss the role of miRNA in glioma focusing on their role in drug resistance and on their potential applications in the therapy of this tumor.
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Ipilimumab (IPI) blocks CTLA-4 immune checkpoint resulting in T cell activation and enhanced antitumor immunity. IPI improves overall survival (OS) in 22% of patients with metastatic melanoma (MM). We investigated the association of CTLA-4 single nucleotide variants (SNVs) with best overall response (BOR) to IPI and OS in a cohort of 173 MM patients. Patients were genotyped for six CTLA-4 SNVs (-1661A>G, -1577G>A, -658C>T, -319C>T, +49A>G, and CT60G>A). We assessed the association between SNVs and BOR through multinomial logistic regression (MLR) and the prognostic effect of SNVs on OS through Kaplan-Meier method. Both -1577G>A and CT60G>A SNVs were found significantly associated with BOR. In particular, the proportion of responders was higher in G/G genotype while that of stable patients was higher in A/A genotype. The frequency of patients experiencing progression was similar in all genotypes. MLR evidenced a strong downward trend in the probability of responsiveness/progression, in comparison to disease stability, as a function of the allele A "dose" (0, 1, or 2) in both SNVs with reductions of about 70% (G/A vs G/G) and about 95% (A/A vs G/G). Moreover, -1577G/G and CT60G/G genotypes were associated with long-term OS, the surviving patients being at 3 years 29.8 and 30.8%, respectively, as compared to 12.9 and 14.4% of surviving patients carrying -1577G/A and CT60G/A, respectively. MM patients carrying -1577G/G or CT60G/G genotypes may benefit from IPI treatment in terms of BOR and long-term OS. These CTLA-4 SNVs may serve as potential biomarkers predictive of favorable outcome in this subset of patients.
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BACKGROUND: In the literature, there exist conflicting data on the value of fibulin-3 (FBLN3) for the diagnosis of pleural effusion (PE) in malignant pleural mesothelioma (MPM). Therefore we compared the diagnostic performance of FBLN3 against that of soluble mesothelin-related peptide (SMRP) in a cohort of Italian patients. MATERIALS AND METHODS: FBLN3 and SMRP were detected in PE from 33 patients with MPM, 64 with pleural benign lesions and 23 with non-MPM pleural metastases using a commercial enzyme-linked-immunosorbent(ELISA)-assay kit according to manufacturers' instructions. RESULTS: Levels of FBLN3 were similar in PE from MPM and PE from other pathologies (geometric mean=68.1 vs. 66.2 ng/ml; p=0.872) in contrast to SMRP levels, which were significantly higher in PE from MPM (geometric mean=14.6 vs. 3.2 nM; p<0.001). Receiver operating characteristic analysis confirmed that SMRP showed a good performance (area under the curve=0.79, p<0.001), whereas FBLN3 was not able to discriminate MPM from other pathologies (area under the curve=0.44, p=0.838). CONCLUSION: FBLN3 detection in PE, in contrast to SMRP detection, is not useful as a biomarker for the diagnosis of PE from MPM.
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Proteínas de la Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/metabolismo , Mesotelioma/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Derrame Pleural Maligno/metabolismo , Neoplasias Pleurales/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Estudios de Cohortes , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Italia , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/patología , Mesotelioma Maligno , Persona de Mediana Edad , Derrame Pleural Maligno/patología , Neoplasias Pleurales/patología , Curva ROCRESUMEN
IMPORTANCE: Chromosome 6p amplification is associated with more benign behavior for uveal melanomas (UMs) with an otherwise high risk of metastasis conferred by chromosome 3 monosomy. Chromosome 6p contains several members of the B7 family of immune regulator genes, including butyrophilin-like 2 (BTNL2; OMIM, 606000), which is associated with prostate cancer risk and autoimmune diseases. OBJECTIVE: To investigate the expression and variant allele frequencies of BTNL2, a candidate gene for chromosome 6 amplification, in patients with UM. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, we analyzed the expression of BTNL2 in UM cell lines and human macrophages in patients with UM. Variants of BTNL2 were analyzed using probes for polymerase chain reaction and high-resolution melting. The association of missense variants rs28362679 and rs41441651 with tumor risk was analyzed in 209 patients with UM and 116 matched control patients as well as 12 UM and 64 other tumor cell lines. Genes that were differentially expressed in M1- and M2-polarized macrophages were identified by microarray analysis of 111 patients with UM, and the association of the expression of these genes with disease-free survival was analyzed by Cox regression analysis. Data were collected from September 2013 to November 2015. MAIN OUTCOMES AND MEASURES: Butyrophilin-like 2 single-nucleotide variants were associated with UM risk; M1 and M2 macrophage-specific gene expression was associated with disease-free survival. RESULTS: We genotyped a total of 325 patients. Of the 209 patients with UM, 124 (59.3%) were male, 114 (54.5%) were Italian, and 95 (45.5%) were German; the mean (range) age was 65 (27-94) years. Of the 116 Italian control patients, 67 (57.8%) were female, and the mean (range) age was 39 (21-88) years. Butyrophilin-like 2 is expressed in patients with UM and macrophages. The frequency of the rs28362679 variant was higher in patients with UM (16 of 209 [7.7%]; 95% CI, 4.7-12.2) than frequencies from European Variation Archive and Exome Aggregation Consortium data (2134 of 118â¯564 [1.8%]; 95% CI, 1.7-1.9) and Exome Sequencing Project data (100 of 4540 [2.2%]; 95% CI, 1.8-2.7) but were not higher compared with Italian control patients (10 of 116 [8.6%]; 95% CI, 4.6-15.4). The rs41441651 variant was present in 5 patients with UM (2.4%; 95% CI, 0.9-5.7), 2 Italian control patients (1.7%; 95% CI, 0.1-6.5), 2846 patients from European Variation Archive and Exome Aggregation Consortium data (2.4%; 95% CI, 2.3-2.5), and 23 patients from Exome Sequencing Project data (0.5%; 95% CI, 0.3-0.8). Human UM cells express M1 and M2 macrophage-specific genes, whose expression is associated with disease-free survival. CONCLUSIONS AND RELEVANCE: Butyrophilin-like 2, expressed at various levels by UM cells and macrophages, might interfere with the immune control of the tumor. Butyrophilin-like 2 variants showed highly variable frequencies among ethnically related cohorts. There was no enrichment of BTNL2 variants in patients with UM compared with control patients.
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Butirofilinas/genética , ADN de Neoplasias/genética , Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Úvea/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Butirofilinas/biosíntesis , Línea Celular Tumoral , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Melanoma/diagnóstico , Melanoma/metabolismo , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Estudios Retrospectivos , Neoplasias de la Úvea/diagnóstico , Neoplasias de la Úvea/metabolismoRESUMEN
CTLA-4 function as a negative regulator of T cell-mediated immune response is well established, whereas much less is known about the immunoregulatory role of its soluble isoform (sCTLA-4). No data are available on CTLA-4 expression and prognostic impact in malignant pleural mesothelioma (MPM). We investigated, by immunohistochemistry, CTLA-4 expression in tumor tissues and, by ELISA, sCTLA-4 levels in sera and matched pleural effusions from 45 MPM patients. Prognostic effect of CTLA-4 expression on overall survival (OS) was assessed through Cox regression and prognostic significance expressed as death rate ratio (HR). We found that 56.0 % of MPM tissues expressed CTLA-4 with variable intensity and percentage of positive cells estimated by the immunoreactive score. sCTLA-4 levels were significantly higher in sera (S-sCTLA-4) than in pleural effusions (PE-sCTLA-4) (geometric mean ratio = 2.70, P value = 0.020). CTLA-4 expression at the tissue level was higher in the epithelioid histological subtype than in the sarcomatoid, whereas at the serum level, it was higher in the sarcomatoid subtype. A homogeneous favorable prognostic effect was found for CTLA-4 overexpression in tissue, serum and pleural effusion. Interestingly, only the PE-sCTLA-4 was found to be a statistically significant positive prognostic factor (HR = 0.37, 95 % CI = 0.18-0.77, P value = 0.007). Indeed, PE-sCTLA-4 correlated with CTLA-4 expression in tissues, whereas this latter expression showed a weak association with OS. To confirm our findings, further experimental evidences obtained from a larger cohort of MPM patients are required. However, our results would indicate a positive correlation of PE-sCTLA-4 levels and OS in MPM patients.