The Evaluation of 17 Gastrointestinal Tumor Markers Reveals Prognosis Value for MUC6, CK17, and CD10 in Gallbladder-Cancer Patients.

Gallbladder cancer (GBC) is an aggressive and highly lethal disease with relatively low global incidence, but one that constitutes a major health problem in Asian and Latin American countries, particularly in Chile. The identification of new tumor-associated markers with potential prognosis value is required for GBC clinical practice. Using immunohistochemistry/tumor tissue microarray, we evaluated the expression of 17 gastrointestinal tumor-associated protein markers (CK7, CK17, CK19, CK20, CKLMW, CKHMW, MUC1, MUC2, MUC5AC, MUC6, CA125, CD10, CEA, vimentin, villin, claudin-4, and CDX2) in primary gallbladder adenocarcinomas from 180 Chilean patients and analyzed potential associations with their pathological and clinical characteristics. Younger female patients with well- to moderately differentiated tumors had a better prognosis than that of older female or male patients with tumors with a similar tumor differentiation grade. Among all analyzed markers, MUC6 expression was associated with better prognosis in patients with well- to moderately differentiated tumors, whereas CK17 or CD10 was associated with worse prognosis in patients with poorly differentiated tumors. In addition, the MUC6+CK17- expression pattern was strongly associated with better prognosis in patients with well- to moderately differentiated tumors, whereas patients with poorly differentiated tumors and with the CK17+CD10+ expression pattern showed worse prognosis. Our results suggest that tumor MUC6, CK17, and CD10 can be considered as potential prognosis markers for GBC.

Decreased invariant natural killer T-cell-mediated antitumor immune response in patients with gastric cancer.

Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. Invariant natural killer T (iNKT) cells are innate-like cytotoxic T lymphocytes involved in tumor immune surveillance. They can be activated either through CD1d-presented glycolipid antigens recognized by their invariant T-cell receptor, cytokines or by sensing tumor-associated stress-induced ligands through the natural killer group 2, member D (NKG2D) receptor. Although the number and functionality of iNKT cells may be decreased in several types of cancer, here we show that GC patients presented a mild increase in iNKT cell frequencies and numbers in the blood compared with healthy donors. In GC patients, iNKT cells, expanded in vitro with α-galactosyl ceramide and stimulated with phorbol 12-myristate 13-acetate and ionomycin, produced higher levels of interleukin-2 and transforming growth factor-beta, while their capacity to degranulate remained preserved. Because tumor-derived epithelial cell adhesion molecule-positive epithelial cells did not display surface CD1d, and NKG2D ligands (NKG2DLs) were detected in the gastric tumor milieu, we envisioned a role for NKG2D in iNKT cell functions. Peripheral iNKT cells from GC patients and controls presented similar levels of NKG2D; nevertheless, the percentages of interferon-γ-producing and CD107a-positive iNKT cells from patients were reduced upon challenge with CD1d-negative, NKG2DL-positive K562 cells, suggesting a compromised response by iNKT cells in GC patients, which may not result from impaired NKG2D/NKG2DL signaling. The decreased response of iNKT cells may explain the fact that higher frequencies of circulating iNKT cells did not confer a survival benefit for GC patients. Therefore, functional impairment of iNKT cells in GC may contribute to tumor immune escape and favor disease progression.

High CD8+ and absence of Foxp3+ T lymphocytes infiltration in gallbladder tumors correlate with prolonged patients survival.

BACKGROUND: Gallbladder cancer (GBC), although infrequent in industrialized countries, has high incidence rates in certain world regions, being a leading cause of death among elderly Chilean women. Surgery is the only effective treatment, and a five-year survival rate of advanced-stage patients is less than 10%. Hence, exploring immunotherapy is relevant, although GBC immunogenicity is poorly understood. This study examined the relationship between the host immune response and GBC patient survival based on the presence of tumor-infiltrating lymphocytes at different disease stages. METHODS: Tumor tissues from 80 GBC patients were analyzed by immunohistochemistry for the presence of CD3+, CD4+, CD8+, and Foxp3+ T cell populations, and the results were associated with clinical stage and patient survival. RESULTS: The majority of tumor samples showed CD3+ T cell infiltration, which correlated with better prognosis, particularly in advanced disease stages. CD8+, but not CD4+, T cell infiltration correlated with improved survival, particularly in advanced disease stages. Interestingly, a < 1 CD4+/CD8+ T cell ratio was related with increased survival. Additionally, the presence of Foxp3+ T cells correlated with decreased patient survival, whereas a ≤ 1 Foxp3+/CD8+ T cell ratio was associated with improved patient survival. CONCLUSIONS: Depending on the disease stage, the presence of CD8+ and absence of Foxp3+ T cell populations in tumor tissues correlated with improved GBC patient survival, and thus represent potential markers for prognosis and management of advanced disease, and supports testing of immunotherapy.

Tumor lysate-based vaccines: on the road to immunotherapy for gallbladder cancer.

Immunotherapy based on checkpoint blockers has proven survival benefits in patients with melanoma and other malignancies. Nevertheless, a significant proportion of treated patients remains refractory, suggesting that in combination with active immunizations, such as cancer vaccines, they could be helpful to improve response rates. During the last decade, we have used dendritic cell (DC) based vaccines where DCs loaded with an allogeneic heat-conditioned melanoma cell lysate were tested in a series of clinical trials. In these studies, 60% of stage IV melanoma DC-treated patients showed immunological responses correlating with improved survival. Further studies showed that an essential part of the clinical efficacy was associated with the use of conditioned lysates. Gallbladder cancer (GBC) is a high-incidence malignancy in South America. Here, we evaluated the feasibility of producing effective DCs using heat-conditioned cell lysates derived from gallbladder cancer cell lines (GBCCL). By characterizing nine different GBCCLs and several fresh tumor tissues, we found that they expressed some tumor-associated antigens such as CEA, MUC-1, CA19-9, Erb2, Survivin, and several carcinoembryonic antigens. Moreover, heat-shock treatment of GBCCLs induced calreticulin translocation and release of HMGB1 and ATP, both known to act as danger signals. Monocytes stimulated with combinations of conditioned lysates exhibited a potent increase of DC-maturation markers. Furthermore, conditioned lysate-matured DCs were capable of strongly inducing CD4+ and CD8+ T cell activation, in both allogeneic and autologous cell co-cultures. Finally, in vitro stimulated CD8+ T cells recognize HLA-matched GBCCLs. In summary, GBC cell lysate-loaded DCs may be considered for future immunotherapy approaches.

Beneficio de la bursectomía en gastrectomía D2 para el cáncer gástrico: una revisión sistemática / Benefit of bursectomy in gastrectomy D2 for gastric cancer: a systematic review

Resumen Introducción: La resección quirúrgica ha demostrado ser la única opción curativa para el cáncer gástrico, al incluir linfadenectomía D2 como estándar de seguridad. Sin embargo, el beneficio de extender la resección a la bursa omentalis sigue siendo controvertido. La investigación publicada no ha arrojado evidencia categórica definiendo la eficacia. Realizamos una revisión sistemática de ensayos clínicos aleatorizados publicados (ECA), para evaluar el beneficio de la bursectomía en la sobrevida global (OS) y la sobrevida libre de enfermedad (SLE) de los pacientes. Como resultado secundario se consideró la seguridad del procedimiento. Métodos: Se realizó una búsqueda bibliográfica en las bases de datos de Pubmed, Cochrane, Scielo, Metabuscador PUC, Epistemonikos, Tripdatabase, Sciencedirect y Lilacs para ECA que compararan la bursectomía con la no bursectomía, publicados antes de marzo de 2016. Se establecieron y aplicaron criterios de inclusión y exclusión. Resultados: Se encontraron 3 ECA correspondientes a diferentes informes de la misma cohorte de pacientes. Se incluyeron 210 pacientes (104 en el grupo de bursectomía y 106 en el grupo de no bursectomía). La bursectomía no tuvo un efecto significativo ni en la OS a 5 años (HR: 1,4; IC del 95%: 0,87-2,25) ni en la SLE (HR: 1,25; IC del 95% 0,80-1,97). No se observó diferencia estadísticamente significativa en la tasa de complicaciones al comparar el grupo de bursectomía y el grupo de no bursectomía. Conclusión: La gastrectomía con bursectomía no es superior a la no bursectomía, ya sea en términos de OS a 5 años o de SLE.

Abstract Introduction: The surgical resection has proved to be the only curative option for Gastric Cancer, when including D2 linfadenectomy as security standard. The benefit of extending the resection to the bursa omentalis, however, is still controversial. The published research has not yielded categorical evidence on defining the efficacy of bursectomy. We conducted a systematic review of published randomized controlled trials (RCT), to evaluate the benefit of bursectomy in the overall survival (OS) and disease-free survival (DFS) of patients. As secondary outcome, was considered the safety of the procedure. Methods: A literature search was conducted in Pubmed, Cochrane library databases, Scielo, Metabuscador PUC, Epistemonikos, Tripdatabase, Sciencedirect, and Lilacs for randomized clinical trials comparing bursectomy with non-bursectomy, published before March 2016. Inclusion and exclusion criteria were established and applied. Results: We found three RCT corresponding to different reports of the same cohort of randomized patients. They included 210 patients (104 in the bursectomy group, and 106 in the non-bursectomy group). The bursectomy did not have a significant effect either on 5-years OS (HR: 1.4; 95%CI: 0,87-2,25), or on DFS (HR: 1.25; 95% CI: 0,80-1,97). No statistically significant difference was observed in the rate of complications, when comparing the bursectomy group and the non-bursectomy group. Conclusion: Gastrectomy with bursectomy is not superior to non-bursectomy either in terms of 5 years OS or on DFS.

Perfil epidemiológico de las embarazadas extranjeras atendidas en la maternidad del Hospital San Juan de Dios (2001) / Epidemiological profile of foreign pregnant patients seen at the maternity of the San Juan de Dios Hospital (2001)

El propósito del trabajo fue precisar el perfíl de un grupo de embarazadas extranjeras, cuyos partos fueron atendidos, durante el año 2001, en la Maternidad del Hospital San Juan de Dios. El objetivo de la revisión fue conocer las características de sus embarazos y partos a fin de identificar factores de riesgo que pudieran desmejorar los resultados obstétricos y perinatales.Del análisis de las fichas clínicas de 88 pacientes incluídas en el estudio se desprende que la muestra estuvo conformada por pacientes con edad promedio de 26 años (91 por ciento). Entre sus antecedentes obstétricos destacaron: la primiparidad (50 por ciento) y el bajo uso de métodos anticonceptivos (35 por ciento). Si bien un 70 por ciento inició control prenatal antes de las 20 semanas de gestación, sólo un 39 por ciento se controló en 9 o más oportunidades, requiriendo en un 52 por ciento derivación al departamento de Alto Riesgo Obstétrico (DARO), siendo los principales motivos de derivación el embarazo en vías de prolongación y la edad gestacional dudosa. En cuanto al resultado perinatal, un 19 por ciento de los partos fueron cesáreas. Sólo un recién nacido fue de pretérmino, mientras que otro presentó una asfixia neonatal. El peso de nacimiento fue adecuado para la edad gestacional en el 80 por ciento de los casos. El pequeño tamaño de la muestra no permite establecer conclusiones definitivas sino que tan sólo algunas tendencias, tales como:- empleo de métodos anticonceptivos predominantemente orales en 35 por ciento derivaciones al departanento de Alto Riesgo Obstétrico. - Partos operatorios (cesáreas) en 19 por ciento de la muestra. - Sobrepeso u obesidad en 38 por ciento de las embarazadas.- Necesidad de un mejor control de los embarazos; de educación en planificación familiar así como en conocimientos dietéticos dirigidos a evitar y por lo menos reducir el sobrepeso y la obesidad