Lymphocytic infiltration in stage II microsatellite stable colorectal tumors: A retrospective prognosis biomarker analysis.

BACKGROUND: Identifying stage II patients with colorectal cancer (CRC) at higher risk of progression is a clinical priority in order to optimize the advantages of adjuvant chemotherapy while avoiding unnecessary toxicity. Recently, the intensity and the quality of the host immune response in the tumor microenvironment have been reported to have an important role in tumorigenesis and an inverse association with tumor progression. This association is well established in microsatellite instable CRC. In this work, we aim to assess the usefulness of measures of T-cell infiltration as prognostic biomarkers in 640 stage II, CRC tumors, 582 of them confirmed microsatellite stable. METHODS AND FINDINGS: We measured both the quantity and clonality index of T cells by means of T-cell receptor (TCR) immunosequencing in a discovery dataset (95 patients with colon cancer diagnosed at stage II and microsatellite stable, median age 67, 30% women) and replicated the results in 3 additional series of stage II patients from 2 countries. Series 1 and 2 were recruited in Barcelona, Spain and included 112 fresh frozen (FF, median age 69, 44% women) and 163 formalin-fixed paraffin-embedded (FFPE, median age 67, 39% women) samples, respectively. Series 3 included 270 FFPE samples from patients recruited in Haifa, Northern Israel, as part of a large case-control study of CRC (median age 73, 46% women). Median follow-up time was 81.1 months. Cox regression models were fitted to evaluate the prognostic value of T-cell abundance and Simpson clonality of TCR variants adjusting by sex, age, tumor location, and stage (IIA and IIB). In the discovery dataset, higher TCR abundance was associated with better prognosis (hazard ratio [HR] for ≥Q1 = 0.25, 95% CI 0.10-0.63, P = 0.003). A functional analysis of gene expression on these tumors revealed enrichment in pathways related to immune response. Higher values of clonality index (lower diversity) were not associated with worse disease-free survival, though the HR for ≥Q3 was 2.32 (95% CI 0.90-5.97, P = 0.08). These results were replicated in an independent FF dataset (TCR abundance: HR = 0.30, 95% CI 0.12-0.72, P = 0.007; clonality: HR = 3.32, 95% CI 1.38-7.94, P = 0.007). Also, the association with prognosis was tested in 2 independent FFPE datasets. The same association was observed with TCR abundance (HR = 0.41, 95% CI 0.18-0.93, P = 0.03 and HR = 0.56, 95% CI 0.31-1, P = 0.042, respectively, for each FFPE dataset). However, the clonality index was associated with prognosis only in the FFPE dataset from Israel (HR = 2.45, 95% CI 1.39-4.32, P = 0.002). Finally, a combined analysis combining all microsatellite stable (MSS) samples demonstrated a clear prognosis value both for TCR abundance (HR = 0.39, 95% CI 0.26-0.57, P = 1.3e-06) and the clonality index (HR = 2.13, 95% CI 1.44-3.15, P = 0.0002). These associations were also observed when variables were considered continuous in the models (HR per log2 of TCR abundance = 0.85, 95% CI 0.78-0.93, P = 0.0002; HR per log2 or clonality index = 1.16, 95% CI 1.03-1.31, P = 0.016). LIMITATIONS: This is a retrospective study, and samples had been preserved with different methods. Validation series lack complete information about microsatellite instability (MSI) status and pathology assessment. The Molecular Epidemiology of Colorectal Cancer (MECC) study had information about overall survival instead of progression-free survival. CONCLUSION: Results from this study demonstrate that tumor lymphocytes, assessed by TCR repertoire quantification based on a sequencing method, are an independent prognostic factor in microsatellite stable stage II CRC.

Asociación entre la incidencia de leishmaniosis cutánea y el índice de desarrollo humano y sus componentes en cuatro estados endémicos de Venezuela / Association between cutaneous leishmaniasis incidence and the human development index and its components in four endemic states of Venezuela

Objetivos. Evaluar las posibles asociaciones entre el índice de desarrollo humano (IDH) y sus componentes, y la incidencia de Leishmaniosis cutánea (LC) en cuatro estados endémicos de Venezuela (Mérida, Trujillo, Lara y Sucre) en el período 1994 al 2003. Materiales y métodos. La data socioeconómica (clasificada de acuerdo al Banco Mundial) se obtuvo del Instituto Nacional de Estadística y la epidemiológica del Ministerio de Salud, ambos de Venezuela. Para este estudio ecológico se evaluó la variación anual de las variables y se realizó modelos de regresión. Resultados. El IDH varió en el período, de 0,6746 en 1994 a 0,8144 en 2003 (p=0,90), asimismo, se observó un aumento de la incidencia acumulada de Leishmaniosis, en especial del año 1998 (7,3 casos/100 000 hab) a 1999 (11,3 casos/100 000 hab). Al analizar con los modelos de regresión lineal, se observó que la relación entre las variables epidemiológicas y sociales era diferente a nivel de los Estados evaluados. Para Mérida y Trujillo se observó un descenso significativo de la incidencia de LC con relación al aumento del porcentaje de alfabetización (p menor que 0,05), de estudiantes matriculados (p menor que 0,05), la esperanza de vida (p menor que 0,05), su ingreso en USD per cápita por año (p menor que 0,05) e IDH (p minor that 0,05). Conclusión. Esta información refleja la influencia significativa de los indicadores socioeconómicos sobre la incidencia de la LC en los Estados Trujillo y Mérida, siendo inversa entre ambos tipos de variables; con el incremento o mejoría de los indicadores socioeconómicos, la incidencia acumulada de la enfermedad disminuyó.

Objectives. Assess potential relationships between the Human Development Index (HDI) and its components and the incidence of cutaneous leishmaniasis (CL) in four endemic States of Venezuela (Mérida, Trujillo, Lara and Sucre) in the period 1994-2003. Material and methods. Socioeconomical data (classified according the World Bank) wasobtained from the National Institute of Statistics, and the epidemiological data from the Ministry of Health, both fromVenezuela. For this ecological study the annual variation of the variables was assessed and also regression modelswere done. Results. The HDI varied in the period from 0.6746 in 1994 to 0.8144 in 2003 (p=0.90). During this time an increase in the cumulative incidence of Leishmaniasis was observed, particularly from 1998 (7.3 cases/100,000 pop) to 1999 (11.3 cases/100,000 pop). Analyzing the linear regression models, it was observed that the relationship betweenepidemiological and social variables was different at States levels. For Mérida and Trujillo it was observed a significantdecrease in the CL regard to the increase of literacy (p minor that 0.05), of the gross combined enrollment (p minor that 0.05), life expectancy (p minor that 0.05), money income (p minor that 0.05) and the HDI (p minor that 0.05). Conclusion. This information reflects the significant influence of socioeconomical indicators on the CL incidence at Trujillo and Merida, being an inverse relationship between both types of variables; with an increase or improvement in the socioeconomical indicators, the disease incidence rate decreased.

Aspectos sociales de la malaria importada en Latinoamérica / Social Aspects related to imported malaria in Latin America

La malaria continúa siendo un grave problema de salud pública mundial, ya no sólo en países endémicos, sino comenzando a representar un dilema médico en países distantes por la llegada de casos importados. Ahora bien, aun cuando en términos de las disciplinas médicas convencionales se ha publicado muchos estudios clínico-epidemiológicos y reportes de caso, los aspectos sociales, que parecerían obvios en el contexto de la malaria importada por supeditarse a la migración de la población, no han sido exhaustivamente explorados en relación con este fenómeno. Por estas razones, en esta revisión se analiza los aspectos sociales relacionados con el fenómeno de lamalaria importada con énfasis al contexto epidemiológico de América Latina.

Malaria continues to be a world public health problem, not only in those endemic countries but also now beginning to be a medical dilemmain distant countries for the arrival of imported cases. Now, even when in terms of the conventional medical disciplines many clinical andepidemiological studies, as well case reports, have been published, the social aspects, apparently obvious given the fact imported malaria is related to human population migration, have been not furtherly studied in regard to this phenomena. For these reasons in the current review, the social aspects related with the imported malaria phenomena with emphasis in the epidemiological context of Latin Americaare analyzed.