The immune microenvironment: a major player in human cancers.

Cancer is a major public health issue and figures among the leading causes of death in the world. Cancer development is a long process, involving the mutation, amplification or deletion of genes and chromosomal rearrangements. The transformed cells change morphologically, enlarge, become invasive and finally detach from the primary tumor to metastasize in other organs through the blood and/or lymph. During this process, the tumor cells interact with their microenvironment, which is complex and composed of stromal and immune cells that penetrate the tumor site via blood vessels and lymphoid capillaries. All subsets of immune cells can be found in tumors, but their respective density, functionality and organization vary from one type of tumor to another. Whereas inflammatory cells play a protumoral role, there is a large body of evidence of effector memory T cells controlling tumor invasion and metastasis. Thus, high densities of memory Th1/CD8 cytotoxic T cells in the primary tumors correlate with good prognosis in most tumor types. Tertiary lymphoid structures, which contain mature dendritic cells (DC) in a T cell zone, proliferating B cells and follicular DC, are found in the tumor stroma and they correlate with intratumoral Th1/CD8 T cell and B cell infiltration. Eventually, tumors undergo genetic and epigenetic modifications that allow them to escape being controlled by the immune system. This comprehensive review describes the immune contexture of human primary and metastatic tumors, how it impacts on patient outcomes and how it could be used as a predictive biomarker and guide immunotherapies.

[Approach to establishing and evaluating clinical relevance of drug interactions in HIV patients: 2009 update]. / Aproximación para establecer y evaluar la relevancia clínica de las interacciones medicamentosas en pacientes infectados con virus de la inmunodeficiencia humana: actualización 2009.

OBJECTIVE: To update information on drug interactions in patients with HIV/AIDS. METHOD: PubMed was used to review English and Spanish articles published between 1 July 2007 and 30 April 2009 on antiretroviral drug interactions in humans. The search included a review of interactions between commonly-used medications in patients with HIV/AIDS and references from articles considered to be relevant. RESULTS: 52 new interactions were identified having to do with CYP3A4 metabolism and competition for intestinal absorption. New pharmacokinetic interactions were identified for medications that were already on the market, and we report interactions for drugs that were recently introduced: Tipranavir, Fosamprenavir, Darunavir, Raltegravir, Maraviroc and Etravirine. CONCLUSIONS: There is evidence of 52 new interactions between medications using metabolic routes in the CYP450 enzymatic system, and an explanation is given for others in the intestinal absorption process.

[Approach to evaluating the clinical relevance of drug interactions in HIV-infected patients]. / Interacciones medicamentosas en pacientes infectados con el VIH: aprocimación para establecer y evaluar su relevancia clínica.

OBJECTIVE: To systematize information about drug interactions in HIV/AIDS, and to test a proposal to identify and evaluate drug interactions considered clinically relevant highlight those associated to pharmacokinetic mechanism. METHOD: We performed a MEDLINE search of the literature published in English and Spanish from January 1995 to June 2007 on antiretroviral drug interactions in humans. Search terms were drug interactions and antiretroviral agents (or drugs) in title/abstract field. So, we searched for clinically relevant drug interactions of specific drugs commonly administered to patients with HIV, and we reviewed references cited in relevant articles. Finally, we followed a proposal to evaluate and use the clinical relevance complemented with a classification based on severity and probability of its occurrence. RESULTS: A total of 378 articles were achieved, among then we acquire the full text of 296. We presented the type and mechanism of drug interactions in HIV-infected patients. We evaluate and use the clinical relevance of drug interactions. Among pharmacokinetic interactions considered clinically relevant, approximately to 80% was related to changes in systemic clearance [due to induction or inhibition of systemic metabolic activity of cytochrome P450 3A4 (CYP3A4)]; and 15% with changes in bioavailability [(due to changes in gastrointestinal pH, presystemic metabolism or activity of the glicoprotein -P (Gp-P)]. CONCLUSIONS: Among patients with HIV/AIDS, most of the pharmacokinetic interactions of clinical relevance are attributed to inhibition or induction of hepatic systemic metabolic activity, mainly of CYP3A4.

Free software to analyse the clinical relevance of drug interactions with antiretroviral agents (SIMARV®) in patients with HIV/AIDS.

BACKGROUND: Highly active antiretroviral therapy has extended the expected lifespan of patients with HIV/AIDS. However, the therapeutic benefits of some drugs used simultaneously with highly active antiretroviral therapy may be adversely affected by drug interactions. OBJECTIVE: The goal was to design and develop a free software to facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS. METHODS: A comprehensive Medline/PubMed database search of drug interactions was performed. Articles that recognized any drug interactions in HIV disease were selected. The publications accessed were limited to human studies in English or Spanish, with full texts retrieved. Drug interactions were analyzed, assessed, and grouped into four levels of clinical relevance according to gravity and probability. Software to systematize the information regarding drug interactions and their clinical relevance was designed and developed. RESULTS: Overall, 952 different references were retrieved and 446 selected; in addition, 67 articles were selected from the citation lists of identified articles. A total of 2119 pairs of drug interactions were identified; of this group, 2006 (94.7%) were drug-drug interactions, 1982 (93.5%) had an identified pharmacokinetic mechanism, and 1409 (66.5%) were mediated by enzyme inhibition. In terms of clinical relevance, 1285 (60.6%) drug interactions were clinically significant in patients with HIV (levels 1 and 2). With this information, a software program that facilitates identification and assessment of the clinical relevance of antiretroviral drug interactions (SIMARV®) was developed. CONCLUSIONS: A free software package with information on 2119 pairs of antiretroviral drug interactions was designed and developed that could facilitate analysis, assessment, and clinical decision making according to the clinical relevance of drug interactions in patients with HIV/AIDS.

[Incidence of nutritional support complications in critical patients: multicenter study]. / Incidencia de complicaciones del soporte nutricional en pacientes críticos: estudio multicéntrico.

INTRODUCTION: Nutritional support (NS) leads complications that must be detected and prompt treated. OBJECTIVE: To estimate the incidence of some complications of nutritional support in critically ill patients. MATERIALS AND METHODS: A multicenter, descriptive, prospective study in patients with NS in intensive care units. Studied variables included medical diagnosis, nutritional status, length of NS, path, type of formula and ten complications. RESULTS: 419 patients evaluated, 380 received enteral nutrition (EN) and 39 parenteral nutrition (PN). The high gastric residue was the most incident complication in the ENS (24.2%), followed by diarrhea (14%) and withdrawal tube (6.6%). The high gastric residue and diarrhea were associated with the duration of the NS (p < 0.05). For the PNS the complication most incidents were hypophosphatemia (38.5%), followed by catheter sepsis (15.4%). The duration of the NS was associated with cholestasis, sepsis and hypophosphatemia (p < 0.05). CONCLUSIONS: complications of highest incidence were the high gastric residue for EN and hypophosphatemia for the PN; the withdrawal of the tube is a complication that claims further monitoring. The duration of the NS was the variable that showed greater association with the complications studied. Is a must to get consensus on complications definitions for comparisons establishment and best international standards target, furthermore propose protocols in order to decrease complications incidence of NS to fulfill the critical ill patient requirements.

Aproximación para establecer y evaluar la relevancia clínica de las interacciones medicamentosas en pacientes infectados con virus de la inmunodeficiencia humana: actualización 2009 / Approach to establishing and evaluating clinical relevance of drugs interactions in HIV patients: 2009 update

Objetivo Actualizar información sobre interacciones medicamentosas en pacientes con VIH/sida. Método Se realizó una revisión en PubMed de artículos publicados en inglés y español entre el 1 de julio de 2007 y el 30 de abril de 2009 sobre interacciones de antirretrovirales en humanos. La búsqueda fue complementada con la revisión de interacciones de medicamentos utilizados frecuentemente en pacientes con VIH/sida y de referencias de artículos considerados relevantes. Resultados Se encontraron 52 nuevas interacciones relacionadas con el metabolismo por el CYP3A4 y la competencia por la absorción intestinal, también se encontraron nuevas interacciones de tipo farmacocinético para medicamentos que ya estaban en el mercado, y se reportaron interacciones para medicamentos recientemente comercializados: tipranavir, fosamprenavir, darunavir, raltegravir, maraviroc y etravirina. Conclusiones Hay evidencia de 52 nuevas interacciones, encontrándose medicamentos que utilizan vías metabólicas en el sistema enzimático CYP450, y se aclaran otras del proceso de absorción intestinal (AU)

Objective To update information on drug interactions in patients with HIV/AIDS. Method PubMed was used to review English and Spanish articles published between 1 July 2007 and 30 April 2009 on antiretroviral drug interactions in humans. The search included a review of interactions between commonly-used medications in patients with HIV/AIDS and references from articles considered to be relevant.Results52 new interactions were identified having to do with CYP3A4 metabolism and competition for intestinal absorption. New pharmacokinetic interactions were identified for medications that were already on the market, and we report interactions for drugs that were recently introduced: Tipranavir, Fosamprenavir, Darunavir, Raltegravir, Maraviroc and Etravirine. Conclusions There is evidence of 52 new interactions between medications using metabolic routes in the CYP450 enzymatic system, and an explanation is given for others in the intestinal absorption process (AU)

Interacciones medicamentosas en pacientes infectados con el VIH: aproximación para establecer y evaluar su relevancia clínica / No disponible

Objetivo: Sistematizar información sobre interacciones medicamentosasen pacientes con VIH/sida, y verificar la funcionalidadde una propuesta para definir y evaluar la relevancia clínica delas interacciones, especialmente las farmacocinéticas.Método: Se realizó una revisión en PubMed de artículos publicadosen inglés o español, entre enero de 1995 y junio de 2007,sobre interacciones de antirretrovirales en humanos. La estrategiade búsqueda fue: drug interactions and anti-retroviral agents (ordrugs), en el título y resumen. La búsqueda fue complementadacon la revisión de interacciones de medicamentos utilizados frecuentementeen pacientes con VIH/sida y de referencias de artículosconsiderados relevantes. Finalmente, se siguió una propuestapara definir y evaluar la relevancia clínica, basada en laprobabilidad de ocurrencia y en la gravedad de la interacción.Resultados: Se identificaron 378 artículos, de los que sepudo acceder al texto completo de 296. Para pacientes conVIH/sida, se desarrolló el tipo y mecanismo de las interacciones;se evaluó y definió la relevancia clínica de las interacciones, conbase a una propuesta definida previamente. Entre las interaccionesfarmacocinéticas de relevancia clínica, cerca de un 80% estuvieronrelacionadas con cambios en el aclaramiento sistémico[debidos a la inhibición o a la inducción sistémica de la actividadmetabólica del citocromo P-450 3A4 (CYP3A4)]; mientras que un15% con cambios en la biodisponibilidad [variaciones en el pHgastrointestinal, en el aclamiento presitémico (mediado por laCYP3A4) o en la actividad de la glicoproteína-P (Gp-P)].Conclusiones: En los pacientes infectados con el VIH/sida,la mayoría de las interacciones farmacocinéticas de relevanciacínica se deben a la inhibición o inducción de la actividad metabólicasistémica del hígado

Objective: To systematize information about drug interactionsin HIV/AIDS, and to test a proposal to identify and evaluate druginteractions considered clinically relevant highlight those associatedto pharmacokinetic mechanism.Method: We performed a MEDLINE search of the literaturepublished in English and Spanish from January 1995 to June2007 on antiretroviral drug interactions in humans. Search termswere drug interactions and antiretroviral agents (or drugs) intitle/abstract field. So, we searched for clinically relevant druginteractions of specific drugs commonly administered to patientswith HIV, and we reviewed references cited in relevant articles.Finally, we followed a proposal to evaluate and use the clinical relevancecomplemented with a classification based on severity andprobability of its occurrence.Results: A total of 378 articles were achieved, among thenwe acquire the full text of 296. We presented the type and mechanismof drug interactions in HIV-infected patients. We evaluateand use the clinical relevance of drug interactions. Among pharmacokineticinteractions considered clinically relevant, approximatelyto 80% was related to changes in systemic clearance [dueto induction or inhibition of systemic metabolic activity ofcytochrome P450 3A4 (CYP3A4)]; and 15% with changes inbioavailability [(due to changes in gastrointestinal pH, presystemicmetabolism or activity of the glicoprotein –P (Gp-P)].Conclusions: Among patients with HIV/AIDS, most of thepharmcokinetic interactions of clinical relevance are attributed toinhibition or induction of hepatic systemic metabolic activity,mainly of CYP3A4