Effector mechanisms of cd8+ hla-dr+ t cells in breast cancer patients who respond to neoadjuvant chemotherapy

Cytotoxic T lymphocyte (CTLs) activation is an independent predictor of response to neoadjuvant chemotherapy (NACT) in breast cancer (BC) patients. Here, we go deeper into the function of CD8+ HLA-DR+T cells from NACT treated HER2 negative BC patients. Flow cytometry analysis revealed that CD8+ HLA-DR+ T cell percentage was increased in NACT responder (R) compared to non-responder (NR) patients. R patients with ER-/PR- hormone receptors had the highest CD8+HLA-DR+T cell frequencies, while no differences were found when patients were classified according to cancer stage or menopause status. Interestingly, the cytotoxicity and production of anti-tumor cytokines were enhanced when CD8+ HLA-DR+ T cells from healthy donors were cultured with plasma from R, but not from NR patients. The induced anti-tumor profile of CD8+ HLA-DR+ T cells was associated with plasmatic IL-12 and IFN-γ levels, increased cytokines in R patients. IL-12 or IFN-γ neutralization decreased cytotoxic activity and TNF-α production by cultured CD8+ HLA-DR+ T cells in R plasma presence. All these data suggest that an effective response to NACT in BC patients is associated with increased IL-12 or IFN-γ levels involved in the induction of cytotoxic and pro-inflammatory mechanisms in CD8+ HLA-DR+ T cells

Case Report Fatal Strongyloides Hyperinfection Complicating a Gram-Negative Sepsis after Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature

Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T-lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed

Circulating microRNAs in Early Breast Cancer Patients and Its Association With Lymph Node Metastases

MicroRNAs have emerged as important regulators of the metastatic process. In addition, circulating miRNAs appear to be surprisingly stable in peripheral blood making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to investigate the expression profile of circulating miRNAs and their association with the metastatic lymph node status in early breast cancer patients. Sentinel lymph node status was detected by one-step nucleic acid (OSNA) analysis. We performed RNA-sequencing in 16 plasma samples and validated the results by qPCR. Gene Ontology term enrichment and KEGG pathway analyses were carried out using DAVID tools. We found16 differentially expressed miRNAs (q < 0.01) in patients with positive SLNs. Fourteen miRNAs were down-regulated (miR-339-5p, miR-133a-3p, miR-326, miR-331-3p, miR-369-3p, miR-328-3p, miR-26a-3p, miR-139-3p, miR-493-3p, miR-664a-5p, miR-146a-5p, miR-323b-3p, miR-1307-3p and miR-423-3p) and 2 were up-regulated (miR-101-3pand miR-144-3p). Hierarchical clustering using differentially expressed miRNAs clearly distinguished patients according to their lymph node status. Gene ontology analysis showed a significant enrichment of biological processes associated with the regulation of the epithelial mesenchymal transition, cell proliferation and transcriptional regulation. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further validation in a larger cohort of patients will be necessary to confirm our results

El microambiente tumoral : Su influencia pronóstica y predictiva en el cáncer de mama HER2- negativo

En el tractament del càncer de mama localment avançat o inflamatori es va imposar l'ús de citostàtics com a opció de tractament inicial, l'anomenada quimioteràpia neoadjuvant, de manera que molts dels tumors prèviament inoperables ara són susceptibles de ser tractats amb cirurgia. Disposem d'indicadors clínic-patològics associats al pronòstic de les pacients, entre els que s'inclouen la mida del tumor, el subtipus i grau histopatològic, la presència de metàstasi ganglionars i la invasió limfovascular. No obstant això, el seu poder predictiu en la selecció de l'enfocament terapèutic òptim és bastant limitat. Això és degut al fet que els resultats obtinguts de resposta i toxicitat al tractament no són uniformes tot i que les pacients pertanyin al mateixa subtipus histològic o presentin característiques immunohistoquímiques similars, que tradueix l'existència d'una heterogeineidad en el càncer de mama. Els mètodes d'alt rendiment permeten identificar grups de pacients amb una evolució diferent, però aquestes no reflecteixen tots els factors implicats en la resposta al tractament neoadjuvant. La resposta no només es deu a les característiques pròpies del tumor sinó també a un procés dinàmic basat en les interaccions de les cèl·lules tumorals amb el seu microambient. Arran del nostre primer treball publicat de variants farmacogenètiques pronòstiques del gen SPARC en càncer de pàncrees ens vam adonar que aquest podia tenir un paper en la resposta immunitària i que existien altres factors lligats a la mateixa que podien influir també en la resposta als tractaments en altres tumors com és el càncer de mama. Caracteritzar in vitro i in vivo el complex funcionament de l'microambient tumoral és de vital importància en la millora de l'ús de les pacients amb càncer. L'objectiu del nostre estudi ha estat identificar biomarcadors pronòstics i predictius al tractament així com valorar la resposta immunològica del microambient tumoral en el càncer de mama.En el tratamiento del cáncer de mama localmente avanzado o inflamatorio se impuso el uso de citostáticos como opción de tratamiento inicial, la denominada quimioterapia neoadyuvante, de manera que muchos de los tumores previamente inoperables ahora son susceptibles de ser tratados con cirugía. Disponemos de indicadores clínico-patológicos asociados al pronóstico de las pacientes, entre los que se incluyen el tamaño del tumor, el subtipo y grado histopatológico, la presencia de metástasis ganglionares y la invasión linfovascular. Sin embargo, su poder predictivo en la selección del enfoque terapéutico óptimo es bastante limitado. Ello es debido a que los resultados obtenidos de respuesta y toxicidad al tratamiento no son uniformes a pesar de que las pacientes pertenezcan al mismo subtipo histológico o presenten características immunohistoquímicas similares, que traduce la existencia de una heterogeineidad en el cáncer de mama. Los métodos de alto rendimiento permiten identificar grupos de pacientes con una evolución diferente, pero éstas no reflejan todos los factores implicados en la respuesta al tratamiento neoadyuvante. La respuesta no solo se debe a las características propias del tumor sino también a un proceso dinámico basado en las interacciones de las células tumorales con su microambiente. A raíz de nuestro primer trabajo publicado de variantes farmacogenéticas pronósticas del gen SPARC en cáncer de páncreas nos dimos cuenta que éste podía tener un papel en la respuesta inmunitaria y que existían otros factores ligados al mismo que podían influir también en la respuesta a los tratamientos en otros tumores como es el cáncer de mama. Caracterizar in vitro e in vivo el complejo funcionamiento del microambiente tumoral es de vital importancia en la mejora del manejo de las pacientes con cáncer. El objetivo de nuestro estudio ha sido identificar biomarcadores pronósticos y predictivos al tratamiento así como valorar la respuesta inmunológica del microambiente tumoral en el cáncer de mama.Treatment of locally advanced or inflammatory breast cancer, is usually based on neoadjuvant chemotherapy For instance many cases with previously inoperable tumors , could be treated with surgery at the end of primary treatment. Classic prognostic clinical-pathological variables for breast cancer patients include tumour size, subtype, histopathological grade, the presence of lymph node metastases and lymphovascular invasion. However, its predictive power in selecting the optimal therapeutic approach for neoadjuvant treatment is limited. Results obtained in response and toxicity to chemotherapy are not uniform, despite patients belonging to the same histological subtype or have similar immunohistochemical characteristics. Nowadays, genomic signatures are available as prognostic biomarkers. Nonetheless, these signatures do not reflect all the factors involved in the response to neoadjuvant treatment. The response to treatment is not only based on the characteristics of the tumour itself, but also depends on a dynamic process based on interactions of the tumour cells with their microenvironment. As a result of our first study evaluating pharmacogenetic variants of the SPARC gene in pancreatic cancer, we learned that SPARC and other factors could have a role in the immune response to treatments in other tumours such as breast cancer. The objective of our studywas to identify prognostic and predictive biomarkers for treatment, as well as to assess the immune response of the tumour microenvironment in breast cancer

Fatal Strongyloides Hyperinfection Complicating a Gram-Negative Sepsis after Allogeneic Stem Cell Transplantation: A Case Report and Review of the Literature

Strongyloides stercoralis is an intestinal nematode that causes strongyloidiasis, which affects 30 to 100 million people worldwide. Risk factors for hyperinfection and disseminated disease include immunosuppressive drug therapy, human T-lymphotropic virus-1 (HTLV-1) infection, solid organ and bone marrow transplantation, hematologic malignant diseases, hypogammaglobulinemia, and severe malnutrition and associated conditions. The diagnosis can be difficult because a single stool examination fails to detect larvae in up to 70% of the cases, and the symptoms are nonspecific. Although eosinophilia is a common finding in patients with chronic Strongyloides infection, it is an unreliable predictor of hyperinfection. Furthermore, the lack of eosinophilia while receiving immunosuppressive therapy cannot reliably exclude the underlying chronic Strongyloides infection. We report here a fatal Strongyloides hyperinfection in a patient receiving allogeneic stem cell transplantation; risk factors and outcome in this clinical setting are discussed

MicroRNA-1291 Is Associated With Locoregional Metastases in Patients With Early-Stage Breast Cancer

Evidence that microRNAs (miRNAs) regulate the various steps of metastasis is increasing. Several studies have looked at the miRNA expression profile in primary breast tumors but few have compared primary tumor and sentinel lymph node (SLN) metastasis. We correlated the expression of miRNAs with the SLN status and the outcome of axillary lymph node dissection (ALND) in 60 patients with early breast cancer. We profiled the expression of miRNAs in paired breast tumor samples and SLNs using the NextSeq500 Illumina platform and key findings were validated by qPCR. MultiMiR Bioconductor and Reactome pathways analysis were performed to identify target genes and signaling pathways affected by altered expressed miRNAs. Our results show that nine miRNAs were differentially expressed in tumor tissues (q ≤ 0.05). In tumor samples, a 13.5-fold up-regulation of miR-7641-2 (q < 0.001) and a 2.9-fold down-regulation of miR-1291 (q < 0.001) were associated with tumors with positive SLNs. However, only down-regulation of miR-1291 (q = 0.048) remained significant in paired SLNs samples. Interestingly, a 10.5 up-regulation of miR-1291 in SLNs samples was associated with additional axillary lymph node involvement (q < 0.001). The enrichment analyses showed that canonical and non-canonical WNT pathways and negative regulation of various receptor tyrosine kinases signaling pathways were targets of miR-1291 and supports the role of miR-1291 as a tumor suppressor gene (TSG). Further studies are warranted to investigate the use of miR-1291 as a surrogate biomarker of SLN node metastasis in patients with early-stage breast cancer