BK Virus-Associated Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation in the Pediatric Population.

OBJECTIVE: To study the incidence, risk factors, and treatment of hemorrhagic cystitis secondary to BK-virus reactivation (HC-BKV) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the pediatric population. METHODS: Case-control study in which all pediatric patients (0-18 years) who underwent allo-HSCT from September 2009 to January 2014 were followed. RESULTS: Twenty-nine patients underwent an allo-HSCT. The median age was 9 years (range = 6 months to 15 years), 61% male. The primary diagnosis was acute lymphoblastic leukemia (72.4%). Six (20.7%) developed HC-BKV. In a multivariate analysis of risk factors, it was observed that the reactivation of BK virus was associated with age more than 10 years ( P = .098) and those with positive serology for Epstein-Barr virus ( P = .06). Five of the 6 patients with HC-BKV received cidofovir (CDV) at doses of 3 to 5 mg/kg/week. The treatment lasted a median of 3 cycles (range = 2-5). One of the patients (20%) developed nephrotoxicity. Of the 5 patients treated with CDV, 3 (60%) had a complete response, 1 (20%) partial response, and 1 (20%) no response. CONCLUSION: We conclude that HC-BKV is a frequent complication after allo-HSCT. CDV therapy can be effective but controlled clinical trials are needed.

[Applying dose banding to the production of antineoplastic drugs: a narrative review of the literature]. / Dose banding aplicado a la elaboración de antineoplásicos: una revisión narrativa de la literatura.

The dosage of antineoplastic drugs has historically been based on individualized prescription and preparation according to body surface area or patient´s weight. Lack of resources and increased assistance workload in the areas where chemotherapy is made, are leading to the development of new systems to optimize the processing without reducing safety. One of the strategies that has been proposed is the elaboration by dose banding. This new approach standardizes the antineoplastic agents doses by making ranges or bands accepting a percentage of maximum variation. It aims to reduce processing time with the consequent reduction in waiting time for patients; to reduce errors in the manufacturing process and to promote the rational drug use. In conclusion, dose banding is a suitable method for optimizing the development of anticancer drugs, obtaining reductions in oncologic patients waiting time but without actually causing a favorable impact on direct or indirect costs.

La dosificación de los fármacos antineoplásicos se ha basado históricamente en la prescripción y elaboración individualizada según la superficie corporal o peso del paciente. La falta de recursos y el aumento de la carga asistencial en las áreas de elaboración de quimioterapia están propiciando que se desarrollen nuevos sistemas que optimicen la elaboración sin reducir la seguridad. Una de las estrategias que se ha propuesto es la elaboración mediante dose banding. Este nuevo enfoque estandariza las dosis de antineoplásicos en rangos o bandas aceptando un porcentaje de variación máxima. Pretende reducir los tiempos de elaboración con la consiguiente reducción de los tiempos de espera de los pacientes, disminuir los errores en la elaboración y fomentar el uso racional de los fármacos. En definitiva, el dose banding es un método adecuado para la optimización de la elaboración de antineoplásicos, obteniendo reducciones del tiempo de espera de los pacientes oncológicos, aunque sin llegar a causar un impacto favorable sobre los costes directos o indirectos.

Dose banding aplicado a la elaboración de antineoplásicos: una revisión narrativa de la literatura / Applying dose banding to the production of antineoplastic drugs: a narrative review of the literature

La dosificación de los fármacos antineoplásicos se ha basado históricamente en la prescripción y elaboración individualizada según la superficie corporal o peso del paciente. La falta de recursos y el aumento de la carga asistencial en las áreas de elaboración de quimioterapia están propiciando que se desarrollen nuevos sistemas que optimicen la elaboración sin reducir la seguridad. Una de las estrategias que se ha propuesto es la elaboración mediante dose banding. Este nuevo enfoque estandariza las dosis de antineoplásicos en rangos o bandas aceptando un porcentaje de variación máxima. Pretende reducir los tiempos de elaboración con la consiguiente reducción de los tiempos de espera de los pacientes, disminuir los errores en la elaboración y fomentar el uso racional de los fármacos. En definitiva, el dose banding es un método adecuado para la optimización de la elaboración de antineoplásicos, obteniendo reducciones del tiempo de espera de los pacientes oncológicos, aunque sin llegar a causar un impacto favorable sobre los costes directos o indirectos (AU)

The dosage of antineoplastic drugs has historically been based on individualized prescription and preparation according to body surface area or patient ́s weight. Lack of resources and increased assistance workload in the areas where chemotherapy is made, are leading to the development of new systems to optimize the processing without reducing safety. One of the strategies that has been proposed is the elaboration by dose banding. This new approach standardizes the antineoplastic agents doses by making ranges or bands accepting a percentage of maximum variation. It aims to reduce processing time with the consequent reduction in waiting time for patients; to reduce errors in the manufacturing process and to promote the rational drug use. In conclusion, dose banding is a suitable method for optimizing the development of anticancer drugs, obtaining reductions in oncologic patients waiting time but without actually causing a favorable impact on direct or indirect costs (AU)

[Quality and legibility of written informed consent form in pharmacogenetic research]. / Calidad y Legibilidad de la Hoja de Información al Paciente en Estudios con Análisis Farmacogenético.

BACKGROUND AND OBJECTIVE: Pharmacogenetic studies have become in recent years a common practice in the development of new drugs, with the need to evaluate the information and readability of Informed Consent Forms(ICFs) to ensure compliance with the recommendations set by current legislation and expert groups. MATERIALS AND METHODS: Retrospective observational study that analyzes the content of ICFs received by participants of pharmacogenetic studies approved in a tertiary hospital. To evaluate the quality of the ICFs, a questionnaire of 42 questions was prepared (Table 1) with the elements that must contain the information given to subjects, while readability was assessed using different readability indices. RESULTS: The 31.5% of the 92 ICFs analyzed showed more than 75% of sections considered in the questionnaire. Sections with lower compliance were relative to risks and benefits (41.7%) and compensation for study participation (56.1%). None of the ICFs fulfilled with less than 50% of overall sections. Regarding legibility, about 90%, have a suitable degree for the most of population based on indexes used. CONCLUSIONS: Deficiencies were found in some parts of the information contained in ICFs, while the degree of legibility was high, being necessary for future studies to establish the degree of real understanding of patients.

Calidad y legibilidad de la hoja de información al paciente en estudios con análisis farmacogenético / Quality and legibility of written informed consent form in pahrmacogenetic research

Fundamento y objetivo: Los estudios de farmacogenética se han convertido en una práctica habitual en el desarrollo de nuevos medicamentos, surgiendo la necesidad de evaluar las Hojas de Información al Paciente (HIP). Los objetivos de este estudio son evaluar el grado de adecuación a las recomendaciones establecidas por la legislación y grupos de expertos de la información contenida en las HIP de estudios que incluyan análisis del material genético y analizar su legibilidad. Material y métodos: Se analizó el contenido de las HIP que recibieron los participantes en los estudios farmacogenéticos presentados al Comité Ético entre abril de 2011 y abril de 2013 en un hospital de tercer nivel. Para evaluar la calidad de la HIP se elaboró un cuestionario con 42 preguntas con los elementos que debe contener la información que reciben los sujetos. La facilidad de lectura fue evaluada aplicando distintos índices de legibilidad. Resultados: El 31,5% de las 92 HIP presentaron más del 75% de los apartados considerados en el cuestionario. Las secciones con menor grado de cumplimiento fueron las relativas a los riesgos y beneficios (41,7%) y a las compensaciones derivadas del estudio (56,1%). Ninguna de las HIP cumplió con menos del 50% del global del cuestionario. El 90% de las HIP mostraron un grado adecuado de legibilidad. Conclusiones: Se han encontrado deficiencias en algunos puntos de la información contenida en las HIP evaluadas. El grado de legibilidad es elevado, siendo necesario futuros estudios para establecer el grado de entendimiento real de los pacientes

Background and objective: Pharmacogenetic studies have become in recent years a common practice in the development of new drugs, with the need to evaluate the information and readability of Informed Consent Forms (ICFs) to ensure compliance with the recommendations set by current legislation and expert groups. Materials and methods: Retrospective observational study that analyzes the content of ICFs received by participants of pharmacogenetic studies approved in a tertiary hospital. To evaluate the quality of the ICFs, a questionnaire of 42 questions was prepared (Table 1) with the elements that must contain the information given to subjects, while readability was assessed using different readability indices. Results: The 31.5% of the 92 ICFs analyzed showed more than 75% of sections considered in the questionnaire. Sections with lower compliance were relative to risks and benefits (41.7%) and compensation for study participation (56.1%). None of the ICFs fulfilled with less than 50% of overall sections. Regarding legibility, about 90%, have a suitable degree for the most of population based on indexes used. Conclusions: Deficiencies were found in some parts of the information contained in ICFs, while the degree of legibility was high, being necessary for future studies to establish the degree of real understanding of patients

Active colitis exacerbates immune response to internalized food antigens in mice.

BACKGROUND: Previous studies have indicated that colitis increases intestinal permeability to food antigens. This condition also generates an immunoreactive milieu in the gut, which may exacerbate or counteract allergy reactions. This, along with the fact that both colitis and allergy are being codiagnosed more frequently, means the scientific interest on the immune relation between these pathologies is increasing. We evaluated the immune response to an internalized food antigen that was initiated during a concomitant active intestinal inflammatory response. METHODS: An ovalbumin (OVA)-induced immune response was analyzed in healthy mice and in mice suffering from colitis induced by the administration of dinitrofluorobenzene/dinitrosulfonic acid (DNFB/DNS) at the moment of OVA challenge. The OVA-induced clinical score and allergy response both in plasma and in splenocyte cultures from these animals were compared. RESULTS: Although no differences were observed in the allergy clinical score, the concomitant active colitis led to an increase in the immune response to OVA antigen, as shown by increased spleen size and OVA-induced splenocyte proliferation, exacerbated expression of total and OVA-specific IgG1 levels, increased colonic IL-4 expression and OVA-induced IL-4 and IL-5 cytokine expression in spleen cells. CONCLUSIONS: Our results indicate that animals with active colitis undergo an exacerbated immune response to an internalized antigen. This finding could be relevant for the allergy management of patients presenting simultaneously with chronic colitis.

A shorter and more specific oral sensitization-based experimental model of food allergy in mice.

Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research.

DNFB-DNS hapten-induced colitis in mice should not be considered a model of inflammatory bowel disease.

BACKGROUND: The dinitrofluorobenzene/dinitrosulfonic acid (DNFB/DNS) model was originally described as an experimental model of intestinal inflammation resembling human ulcerative colitis (UC). Due to the absence of acceptable UC experimental models for pharmacological preclinical assays, here we examine the immune response induced in this model. METHODS: Balb/c mice were sensitized by skin application of DNFB on day 1, followed by an intrarectal challenge with DNS on day 5. We further expanded this model by administering a second DNS challenge on day 15. The features of colonic inflammation and immune response were evaluated. RESULTS: The changes observed in colonic tissue corresponded, in comparison to the trinitrobenzene sulfonic acid (TNBS) colitis model, to a mild mucosal effect in the colon, which spontaneously resolved in less than 5 days. Furthermore, the second hapten challenge did not exacerbate the inflammatory response. In contrast to other studies, we did not observe any clear involvement of tumor necrosis factor alpha (TNF-α) or other Th1 cytokines during the initial inflammatory response; however, we found that a more Th2-humoral response appeared to mediate the first contact with the hapten. An increased humoral response was detected during the second challenge, although an increased Th1/Th17-cytokine expression profile was also simultaneously observed. CONCLUSIONS: On the basis of these results, although the DNFB/DNS model can display some features found in human UC, it should be considered as a model for the study of the intestinal hypersensitivity seen, for example, during food allergy or irritable bowel syndrome but not intestinal inflammation per se.

The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties.

Some antibiotics, including minocycline, have recently been reported to display immunomodulatory properties in addition to their antimicrobial activity. The use of a compound with both immunomodulatory and antibacterial properties could be very interesting in the treatment of inflammatory bowel disease (IBD), so the aim of our study was to evaluate the anti-inflammatory effect of minocycline in several experimental models of IBD. Firstly, the immunomodulatory activity of the antibiotic was tested in vitro using Caco-2 intestinal epithelial cells and RAW 264.7 macrophages; minocycline was able to inhibit IL-8 and nitrite production, respectively. In vivo studies were performed in trinitrobenzenesulfonic acid (TNBS)-induced rat colitis and dextran sodium sulfate (DSS)-induced mouse colitis. The results revealed that minocycline exerted an intestinal anti-inflammatory effect when administered as a curative treatment in the TNBS model, modulating both immune and microbiological parameters, being confirmed in the DSS model; whereas none of the other antibiotics tested (tetracycline and metronidazole) showed anti-inflammatory effect. However, minocycline administration before the colitis induction was not able to prevent the development of the intestinal inflammation, thus showing that only its antimicrobial activity is not enough for the anti-inflammatory effect. In conclusion, minocycline displays an anti-inflammatory effect on different models of rodent colitis which could be attributed to the association of its antibacterial and immunomodulatory properties.

The combination of fructooligosaccharides and resistant starch shows prebiotic additive effects in rats.

Different types of dietary fiber can be distinguished considering their rate of fermentability, thus determining the location of the large intestine where they exert their beneficial effect. Their combination could be interesting to obtain health-promoting effects throughout the entire colon. The aim of the present study was to evaluate the synergistic effect of two dietary fibers with different fermentation patterns, fructooligosaccharides (FOS) (Beneo(®)-95) and resistant starch (Fibersol(®)-2), after their administration to healthy rats or in trinitrobenzenesulphonic acid-(TNBS) colitic rats, with an altered colonic immune response. In healthy rats, the administration of the combination of FOS and resistant starch induced changes in the intestinal microbiota, by increasing lactobacilli and bifidobacteria in caecum and colonic contents. Furthermore, its administration up-regulated the expression of the trefoil factor-3 and MUC-2 in comparison with untreated rats, thus improving the intestinal barrier function. The beneficial effects observed with this combination were confirmed in the TBNS model of rat colitis, since it was able to exert intestinal anti-inflammatory effect, associated with an increase of protective bacteria and up-regulation of epithelial defense mechanisms. In conclusion, the combination of two different dietary fibers may result in a synergistic prebiotic effect, and may confer greater health benefits to the host.

Butyrate in vitro immune-modulatory effects might be mediated through a proliferation-related induction of apoptosis.

Survival and proliferation signals are two processes closely interrelated and finely controlled in most cell types, whose deregulation may lead to carcinogenesis. In the last decade, different studies have suggested that both cellular functions are also intimately associated with other cellular activities such as differentiation and cellular activation, especially in immune cells. The aim of this study was to evaluate the effects of the short-chain fatty acid (SCFA) butyrate on the proliferation and activation state of different cell types involved in inflammatory bowel disease. We focused on intestinal epithelial cells, macrophages and T-lymphocytes, using both primary non-transformed cultures and established cell lines. The results showed that low concentrations of butyrate inhibited the proliferation of all the immune cell types tested in this work, whereas it only induced apoptosis in activated T-lymphocytes, non-differentiated epithelial cells and macrophage cell lines, but not in differentiated epithelial cells or primary macrophages. Butyrate apoptosis induction was mediated by caspase-3/7 activation. This SCFA was only able to modify cell activation, measured as expression of inflammatory cytokines, in those cell types in which apoptosis was induced. In conclusion, our results suggest a cell type-specificity of the immune-modulatory effects of butyrate based on the proliferation/activation characteristic physiology of these processes in different cells types.