Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta.

We have shown previously that epimorphin (EPM), a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which EPM mediates luminal morphogenesis. Treatment of cells with EPM to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein (C/EBP)beta and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, since constitutive expression of LIP was sufficient to produce lumen formation, whereas constitutive expression of LAP blocked EPM-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which EPM expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPbeta, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for EPM in luminal morphogenesis through control of C/EBPbeta expression.

Caracterización epidemiológica de pacientes con Covid-19 en el Hospital Clínico Universidad de Chile / Epidemiological characterization of patients with Covid-19 in the Hospital Clínico Universidad de Chile

Purpose: Characterize Covid-19 patients diagnosed at the University of Chile Clinical Hospital (HCUCH) during the first 12 epidemiological weeks of the pandemia. Method: Retrospective, case series study of 1372 patients with Covid-19, from march 15 to may 23, 2020, with a follow-up of 3 months. The demographic and epidemiological characteristics were analyzed. Results: Of the 1372 patients, 19,9% were admitted to hospital and 25,18% of them were hospitalized in a critical unit. The median age was 40 years, there were more men than women and 68.5% was Chilean. 80,8% had FONASA as a health insurance. A lethality of 2% was observed. Half of the patients remained hospitalized in a critical unit on day 28. (AU)

Recomendaciones para el manejo de pacientes con enfermedad Inflamatoria Intestinal (EII) y COVID-19 / Recommendations for the management of patients with Inflammatory Bowel Disease (IBS) and COVID-19

The new Coronavirus (SARS-CoV-2) appeared in China in December 2019. Since then and until April 2020 it spread worldwide affecting more than three million people. Its exponential rise is still growing all over the world, taking thousands of lives. SARS-CoV-2 is very contagious, person to person, by droplets which can generate a respiratory infection known as COVID-19. Some patients are at higher risk: Older people, those with cardiovascular disease, diabetes and hypertension are the most prone to an unfavorable outcome. Our Inflammatory Bowel Disease (IBD) patients are a special cluster, with many of them taking immunosuppressive treatment for long periods, which could pose an important risk. Scientifics societies all over the world have joined efforts to generate data, share experiences and make recommendations for good clinical management. This is a review of the available evidence, expert opinion, and proposed ways of working during the pandemic

El nuevo coronavirus (SARS-CoV-2) apareció en China en diciembre de 2019. Desde su inicio hasta abril de 2020 se ha expandido por todo el mundo, afectando a más de tres millones de personas. Su ascenso exponencial sigue creciendo, generando miles de muertes. Su contagiosidad es persona a persona por gotitas, pudiendo llegar a generar un cuadro clínico de infección respiratoria conocido como COVID-19. Algunos pacientes tienen más riesgos de tener un curso desfavorable; adultos mayores, pacientes con enfermedad cardiovascular, hipertensos y diabéticos. Nuestros pacientes con enfermedad inflamatoria intestinal son un grupo de pacientes con características particulares, muchos de ellos reciben tratamiento inmunosupresor por largos períodos, lo que pudiese suponer un riesgo específico. Las sociedades científicas de Europa y Norteamérica han realizado un esfuerzo conjunto para generar datos, compartir experiencias y dictar recomendaciones de buen manejo clínico. Esta es una revisión de la evidencia disponible, opiniones de expertos y formas de trabajo propuestos durante la pandemia.

Involvement of EGF in medroxyprogesterone acetate (MPA)-induced mammary gland hyperplasia and its role in MPA-induced mammary tumors in BALB/c mice.

In previous papers we have demonstrated that sialoadenectomy inhibited MPA-induced mammary tumorigenesis in BALB/c mice. To further explore the role of EGF in this experimental model, we evaluated its effects on mammary glands of sialoadenectomized (sialox) MPA-treated female mice and on tumor growth. MPA-treated sialox mice were injected s.c. (n = 3) or not (n = 6) with 5 microg EGF every 36 h for 45 days; MPA-treated sham-operated mice were used as controls (n = 6). Mammary glands from sialox MPA-treated mice are considerably less developed as compared with sham-operated animals. The exogenous administration of EGF restores the usual MPA-induced growth pattern of the glands, thus confirming a role for EGF either in mediating or cooperating with MPA in inducing the mammary architectural changes observed in MPA-treated mice. On the other hand, primary cultures of progestin-dependent (PD) ductal mammary adenocarcinoma in vivo tumor lines and of lobular progestin-independent (PI) tumor lines were used to evaluate the effect of EGF on tumor growth. In vitro EGF was found to stimulate cell proliferation of lobular PI tumor cells and of fibroblastic cells from both types of tumors at concentrations higher than 0.1-0.5 ng/ml and in the presence of 1-5% of charcoal-stripped fetal calf serum. Conversely, no proliferative effects were observed in ductal PD cells under the same experimental conditions, regardless of the presence of 10 nM MPA. It can be concluded that although EGF plays an important role in MPA-induced mammary carcinogenesis, it is not necessary in PD tumor growth.

Regulation of cell growth of a progestin-dependent murine mammary carcinoma in vitro: progesterone receptor involvement in serum or growth factor-induced cell proliferation.

Primary cultures of the medroxyprogesterone acetate-induced mouse mammary tumor line C4-HD are stimulated by medroxyprogesterone acetate (MPA) or progesterone. Serum obtained from ovariectomized, MPA-treated animals (OVX-MPA) exerts a stimulatory effect that is significantly higher than that induced by serum obtained from OVX mice with the exogenous addition of MPA, suggesting the involvement of MPA-induced serum factors potentiating the proliferative effect of MPA. The object of this paper is to further explore the stimulatory effect of mouse serum and to investigate the role of aFGF and bFGF on cell proliferation. The role of PR as possible mediators was tested using two different antiprogestins and antisense oligodeoxynucleotides of PR A isoform. Serum was obtained from OVX untreated or MPA-treated mice and was charcoalized and/or heat-inactivated. The effect of MPA or mifepristone at 10 nM concentrations was tested. Charcoalization and heat inactivation exerted a stimulatory effect (P<0.01) when OVX-serum was used. This effect was potentiated by MPA. Charcoalized OVX-MPA serum induced a significant inhibition of cell proliferation that was restored by the exogenous addition of MPA or by heat inactivation. Mifepristone induced an inhibition of 3H-thymidine uptake when OVX-MPA serum was used. These results suggest that serum factors activated by different manipulations may replace the stimulatory effect of MPA. When charcoalized fetal calf serum (chFCS) was used, a higher proliferative activity was obtained using higher serum concentrations. Mifepristone and onapristone 10 nM also inhibited this effect. aFGF and bFGF 100 ng/ml were both able to stimulate 3H-thymidine uptake. MPA exerted an additive effect. Mifepristone 10 nM inhibited bFGF and MPA+bFGF induced cell proliferation. Antisense oligodeoxynucleotides of PR (ASPR) were used to further confirm the participation of PR in the proliferative pathway of these cells. They inhibited serum and bFGF-induced cell proliferation in a specific dose-dependent manner. Our results suggest that PR play a central role in proliferation and suggest the existence of a cross-talk between steroid and growth factor signaling pathways.

Involvement of insulin-like growth factors-I and -II and their receptors in medroxyprogesterone acetate-induced growth of mouse mammary adenocarcinomas.

The role of the insulin-like growth factors (IGFs) system was investigated in hormone-dependent (HD) and -independent (HI) in vivo lines of the medroxyprogesterone acetate (MPA)-induced mammary tumor model in Balb/c mice. IGF-II protein and message showed a three- to four-fold increase in HD lines growing in MPA-treated mice, as compared with HD tumors growing in untreated mice. Progression to a hormone-independent phenotype in all these lines was accompanied by a high constitutive expression of IGF-II. Similar IGF-I mRNA levels were detected in HD and HI lines. Both IGF-I and -II messages arose from the malignant epithelial cells, as shown by in situ hybridization studies. A significant decrease in Man-6P/type II IGF-R content was detected in HD tumors growing in MPA-treated mice as compared with HD lines growing in untreated mice. On the other hand, in HI tumors, notwithstanding high IGF-II synthesis, the levels of Man-6P/type II IGF-R remain high. Competitive inhibition and affinity labeling studies showed an almost exclusive binding of IGF-II to Man-6P/type II IGF-R on tumor membranes. The involvement of IGFs in the growth of epithelial primary cultures of the C4-HD line was evaluated. Exogenous IGF-I potentiated MPA stimulatory effect at concentrations of 50-100 ng/ml. Treatment of C4-HD cells with antisense oligodeoxynucleotides (ASODNs) to type I IGF-R and to IGF-II RNA resulted in a dose-dependent inhibition of MPA-mediated cell proliferation. The inhibition caused by IGF-II ASODNs could not be overcome by the addition of IGF-II up to 150 ng/ml. ASODNs to type I IGF-R at 40 microg/ml reduced by 75% the number of type I IGF-R; ASODNs to IGF-II at 1 microM decreased by 83% the levels of IGF-II protein. Our results provide support for the involvement of IGF-I and -II in MPA-induced mammary tumor growth by autocrine pathways.

[Progestin-induced mammary adenocarcinomas in BALB/c mice. Progression from hormone-dependent to autonomous tumors]. / Inducción de adenocarcinomas mamarios por progestagenos en ratones BALB/c. Progresión del tumor hormono-dependiente al autónomo.

We have developed an experimental model in which the administration of progestins induces mammary tumors in female virgin BALB/c mice. In this paper we review the morphological and biological features of progestin-induced tumors, such as estrogen receptor (ER) and progesterone receptor (PR) patterns of expression, hormone dependence and epidermal growth factor receptors (EGF-R) we also examine our data concerning the systemic effects of medroxyprogesterone acetate (MPA) as regards its stimulating EGF synthesis in salivary glands and its subsequent increase in serum. This growth factor seems to play an important role in the induction of mammary tumors. Direct MPA proliferative effects mediated by PR were demonstrated using primary cultures of progestin-dependent (PD) mammary tumors. Antiprogestins inhibited cell growth beyond control values, suggesting that PR are involved in cell proliferation even in the absence of the ligand. Progesterone-independent (PI) tumors expressing high levels of PR and ER are also inhibited by estrogen or antiprogestin treatment, suggesting that PR are involved in the control of autonomous tumor growth. Estrogen-resistant variants may be selected which may revert to an estrogen-sensitive phenotype after several transplants in untreated mice. The similarities between the tumors obtained with this model and human breast cancer as regards morphological features, evolution and the regulation of growth control converts this model into a useful tool to explore the mechanisms related with acquisition of hormone independence and autonomous tumor growth.

Terapia combinada en enfermedad inflamatoria intestinal: ¿una asociación necesaria? / Combination therapy in inflammatory bowel disease: a necessary association?

The management of inflammatory bowel disease (IBD) is constantly changing due to the arrival of new therapeutic agents. Combined therapy (biological associated with immunosuppressive therapy) has proven to be effective, reducing immunogenicity (antibody formation), optimizing the pharmacokinetics of biological therapy with anti-TNF. This therapeutic strategy has associated risks (neoplasia and intercurrent infections) that are not only explained by the use of drugs but also by the increase of cases in older ages. It is essential for the medical team to be familiar with the optimization and personalization of the therapy to achieve clear therapeutic objectives with the lowest possible risks.

El manejo de la enfermedad inflamatoria intestinal (EII) está en constante cambio, debido a la llegada de nuevos agentes terapéuticos. La terapia combinada (terapia biológica asociada a inmunosupresores) ha demostrado ser efectiva al disminuir la inmunogenicidad (formación de anticuerpos) permitiendo la optimización farmacocinética. Esta estrategia terapéutica tiene riesgos asociados (neoplasias e infecciones intercurrentes) que no sólo se explican por el uso de fármacos sino también por el aumento de casos en edades más avanzadas. Es fundamental que el equipo tratante este familiarizado con la optimización y personalización de la terapia para así lograr objetivos terapéuticos claros con los menores riesgos posibles.

Mortalidad en enfermedad inflamatoria intestinal / Mortality in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic disease of unknown cause. It has been attributed to an inflammation of the intestinal mucosa due to loss of immunotolerance to commensal intestinal flora in genetically predisposed individuals. It presents short- and long-term complications, impacting the quality of life and increasing patient mortality, although this risk is slightly increased with respect to the general population. Causes of mortality may be due to complications of the disease, secondary to drugs or surgical complications. Mortality associated with the disease, it occurs mainly in the first 5 years of diagnosis, due to the increased risk of acute complications such as severe ulcerative colitis, toxic megacolon and massive digestive hemorrhage. In addition, patients with IBD are at increased risk of digestive tract and extraintestinal neoplasias. Colorectal cancer occurs as a consequence of chronic inflammation of the colonic mucosa. Extraintestinal neoplasms include lung cancer, hematologic malignancies such as lymphoma, cholangiocarcinoma, cervical cancer, and skin cancer. They also present an increased risk of cardiovascular and thromboembolic diseases, associated with the prothrombotic state of these patients. This review aims to describe the main causes of mortality in IBD patients, in order to be able to prevent the disease and provide opportune diagnosis

La enfermedad inflamatoria intestinal (EII) es una enfermedad crónica de causa desconocida. Su etiología se ha atribuido a una inflamación de la mucosa intestinal debido a una pérdida de la inmunotolerancia a la flora intestinal comensal en individuos genéticamente predispuestos. La EII puede presentar complicaciones a corto y largo plazo, lo que puede afectar la calidad de vida y mortalidad de los pacientes, siendo este riesgo levemente mayor con respecto a la población general. Las causas de mortalidad pueden ser consecuencia de las complicaciones propias de la enfermedad, secundaria a fármacos o por complicaciones quirúrgicas. En cuanto a la mortalidad asociada a la enfermedad, se presenta principalmente en los primeros 5 años de diagnóstico, por mayor riesgo de complicaciones agudas como colitis ulcerosa grave, megacolon tóxico y hemorragia digestiva masiva. Además, los pacientes con EII presentan mayor riesgo de neoplasias tanto del tubo digestivo como extraintestinales. El cáncer colorrectal se presenta como consecuencia de la inflamación crónica de la mucosa colónica. Dentro de las neoplasias extraintestinales se encuentran el cáncer de pulmón, neoplasias hematológicas como el linfoma, colangiocarcinoma, cáncer cervicouterino y cáncer de piel. También presentan mayor riesgo de enfermedades cardiovasculares y tromboembólicas, asociadas al estado protrombótico de estos pacientes. Esta revisión tiene como objetivo describir las principales causas de mortalidad en los pacientes con EII, con el fin de poder prevenirlas y diagnosticarlas oportunamente.

Neoplasias extra-colónicas en pacientes con enfermedad inflamatoria intestinal / Extra-intestinal malignancies in patients with inflammatory bowel disease

Patients with inflammatory bowel disease (IBD) have shown to be at increased risk of developing extraintestinal malignancies. Immunomodulators (immunosuppressant and anti-tumor necrosis factor) diminish the mucosal inflammatory response changing the evolution of the disease, especially when these strategies are introduced earlier. However, therapies that alter the immune system may also promote carcinogenesis. Treatment of IBD in patients with prior malignancy is challenging and the final decision regarding therapeutic strategy should be made on a case-by-case basis. The purpose of this review is to show the characteristics of extra-colonic cancer in patients with IBD, including risks, pathogenesis and management of IBD after cancer diagnosis, the effect of neoplasm treatment on IBD, and the effect of IBD and its treatments on cancer outcomes.

Los pacientes con enfermedad inflamatoria intestinal (EII) presentan un mayor riesgo de desarrollar neoplasias extraintestinales. Los inmunomoduladores (inmunosupresores y terapia biológica anti-TNF) disminuyen la respuesta inflamatoria a nivel de la mucosa, modificando la evolución de la enfermedad, especialmente cuando son introducidos precozmente. Sin embargo, estas terapias pueden alterar el sistema inmune y promover la carcinogénesis. El tratamiento de la EII en pacientes con antecedentes de cáncer es un desafío y la decisión final sobre la estrategia terapéutica debe ser determinada caso a caso. Esta revisión tiene como objetivo mostrar las características de las neoplasias extra-intestinales en pacientes con EII, incluyendo los riesgos, patogénesis y manejo de la EII posterior al diagnóstico del cáncer, el efecto de la neoplasia sobre el tratamiento de la EII y el efecto de la EII y su tratamiento sobre el cáncer.

Educación al paciente con enfermedad inflamatoria intestinal: impacto de un equipo multidisciplinario / Education to IBD patients: impact of a multidisciplinary team

Inflammatory bowel disease (IBD) is a chronic, idiopathic disease characterized by inflammation of the gastrointestinal tract. It affects more than 5 million people worldwide and in Chile studies suggest that IBD incidence has increased in recent years. It is manifested by periods of remission and activity, requiring permanent pharmacological treatment. Both, the occurrence of a crisis episode and the need for lifetime medical treatment could affect the quality of life of IBD patients. Studies suggest that patients with IBD require education to develop self-management of their disease and adhere to treatment, thus reducing the risk of crisis episodes. The importance of this strategy or action is significant if we consider that studies have shown that the level of knowledge of IBD patients regarding their pathology is low. The purpose of this article is to review the effect of education on the management of IBD patients and the implications of a multidisciplinary team with an IBD specialist nurse.

La enfermedad inflamatoria Intestinal (EII) es una enfermedad crónica, idiopática, caracterizada por la inflamación del tracto gastrointestinal. Afecta a más de 5 millones de personas en el mundo y en Chile estudios sugieren que ha ido en aumento en los últimos años. Se manifiesta por períodos de remisión y actividad, siendo necesario un tratamiento farmacológico permanente. Tanto la presencia de crisis como la necesidad de un tratamiento médico de por vida, podrían afectar la calidad de vida de estos pacientes. Estudios sugieren que los pacientes con EII requieren de educación para poder desarrollar un buen autocuidado de su enfermedad, adherirse al tratamiento y disminuir así el riesgo de crisis. Esta estrategia o acción no deja de ser importante si consideramos que estudios han mostrado que el nivel de conocimiento de los pacientes con EII respecto a su patología es bajo. El propósito de este artículo es revisar el efecto de la educación en el manejo de los pacientes con EII, y las implicancias de un equipo multidisciplinario con una enfermera especialista en EII que realice el seguimiento de estos pacientes.

Obesidad y enfermedad inflamatoria intestinal / Obesity and inflammatory bowel disease

Incidence of obesity is rising worldwide, Chile is no exception with obese patients representing up to one third of general population. This parallels with increasing prevalence of inflammatory bowel disease (IBD). Contrary to conventional belief, comorbidity is high (15-40%), where both diseases present with chronic inflammation and dysbiosis which alters intestinal barrier. Causality between obesity and IBD is difficult to stablish and evidence is scarce to determine association. Obesity would be a risk factor for IBD, particularly in Crohn´s Disease (CD), females and obesity at young age. Other than body mass index (BMI), visceral adipose tissue (VAT) has been recently determined as the best indicator of metabolic and endocrine consequences of obesity. Increasing values of VAT have been related to complicated IBD and worst prognosis. On IBD-related therapy, increasing BMI has been related to suboptimal doses and in biologic therapy, obesity raises the probability of flares, loss of response and therapy optimization. Obese patients require IBD-related surgery before non-obese patients and present more postoperative complications. Similarly, VAT is an independent risk factor for postoperative recurrence in CD. Altogether this evidence suggests that obesity does have an influence on IBD, therefore, multidisciplinary healthcare providers should prevent, educate and intervene actively in obesity in order to improve results in intestinal disease

La obesidad ha ido aumentando progresivamente a nivel mundial. Chile no es la excepción, donde un tercio de la población es obesa. Así mismo, la incidencia y prevalencia de la enfermedad inflamatoria intestinal (EII) también ha ido en aumento. La comorbilidad entre obesidad y EII es alta (15-40%) donde ambas presentan inflamación crónica y dentro de su patogenia tienen en común la disbiosis, que altera la función de barrera intestinal. Establecer una asociación de causalidad es difícil y la evidencia es escasa en relación a su asociación. La obesidad puede ser considerada como factor de riesgo para EII, particularmente en pacientes con Enfermedad de Crohn (EC), mujeres y obesidad temprana. Además, se ha establecido que el tejido adiposo visceral (TAV) es mejor indicador de las consecuencias metabólicas de la obesidad en comparación al índice de masa corporal (IMC) y se ha asociado a EII más complicada y peor evolución natural. Con respecto a la terapia, los pacientes con mayor IMC tienen con mayor frecuencia, dosis subóptima de los fármacos, y en terapia biológica, la obesidad aumenta la probabilidad de crisis, pérdida de respuesta al fármaco u optimización de la terapia. Los pacientes obesos requieren cirugía relacionada a EII antes que los pacientes no obesos, presentan más complicaciones postoperatorias y el TAV es un factor de riesgo independiente para recurrencia postoperatoria en EC. Todos estos resultados sugieren que la obesidad influye en la EII, por lo que una intervención activa y multidisciplinaria pudiese mejorar también los resultados en la enfermedad intestinal.

Calidad del sueño en pacientes con enfermedad inflamatoria intestinal / Sleep quality in inflammatory bowel disease patients

Although inflammatory bowel disease (IBD) etiology is still unknown, genetic, environmental and immunological factors are implicated. Studies have considered quality of sleep as a risk factor in IBD course. Objective: To determine sleep quality in IBD patients, irritable bowel syndrome (IBS) patients and healthy controls (HC). Methods: Cross sectional study assessing sleep quality in adult patients with IBD, IBS and HC. All patients answered a validated Spanish version of the Pittsburgh Sleep Quality Index (PSQI) questionnaire in order to evaluate sleep quality. A PSQI global score > 5 is indicative of poor sleep quality. Demographic and clinical variables were assessed. Results: The study included 276 patients, 111 with IBD, 85 with IBS and 80 HC. A PSQI score > 5 was observed in 67 percent of IBD and IBS patients and 55 percent of HC. IBD and IBS patients exhibited poorer sleep quality than HC, although results did not reach statistical significance (p = 0.069 and p = 0.076, respectively). In IBD patients, an association between disease activity and sleep quality was observed (p = 0.025). However, when analyzing separately patients with ulcerative colitis (UC) and Crohn ́s Disease (CD), only in UC patients sleep quality was related with disease activity. The use of sleep medications was significantly higher in IBD and IBS patients compared with healthy controls (p = 0.021 and p = 0.009, respectively). Conclusion: Sleep disturbances are frequent in IBD, IBS patients and even healthy controls. Additionally, IBD patients with active disease, particularly those with UC, exhibit worse sleep quality.

Aunque la etiología de la enfermedad inflamatoria intestinal (EII) es aún desconocida, factores genéticos, ambientales e inmunológicos estarían implicados. Estudios han considerado la calidad del sueño como un factor de riesgo en la evolución de la EII. Objetivo: Determinar la calidad del sueño en pacientes con enfermedad inflamatoria intestinal (EII), síndrome intestino irritable (SII) y controles sanos (CS). Métodos:Estudio transversal en pacientes adultos con EII, SII y CS. Se evaluó la calidad del sueño mediante el Índice de Calidad del Sueño de Pittsburgh (ICSP), siendo una puntuación global > 5 indicativa de mala calidad del sueño. Variables demográficas y clínicas fueron evaluadas. Resultados:Se incluyeron 276 pacientes, 111 con EII, 85 SII y 80 CS. ICSP > 5 fue observado en 67 por ciento de los pacientes con EII y SII, y 55 por ciento de los CS. Los pacientes con EII y SII mostraron una peor calidad del sueño comparado con CS sin alcanzar significancia estadística (p: 0,069 y p: 0,076, respectivamente). En los pacientes con EII, se observó una asociación entre actividad de la enfermedad y calidad del sueño (p: 0,025). Sin embargo, al analizar por diagnóstico específico, sólo pacientes con colitis ulcerosa (CU) presentaron esta asociación. El uso de medicamentos para dormir fue significativamente mayor en los pacientes con EII y SII comparado con CS (p: 0,021 y p: 0,009, respectivamente). Conclusión:Los trastornos del sueño son frecuentes en pacientes con EII, SII e incluso CS. Pacientes con EII activa, en particular aquellos con CU, presentaron una peor calidad del sueño.

Role of MMPs in metastatic dissemination: implications for therapeutic advances.

Matrix metalloproteinases (MMPs) have been implicated in both normal and pathologic processes. In cancer in particular, in vitro and animal studies showed an involvement of MMPs in many stages of cancer progression. This led to the development of MMP inhibitors that in most cases failed in clinical trials. In this review we go over the role of MMPs in the different stages of cancer progression and try to understand why the early generation of MMP inhibitors failed. The analysis of the lessons from this first experience, plus the review of the current knowledge that shows that MMPs may be pro-or anti-tumorigenic may set the stage for a future success for this therapeutic strategy in cancer.

In vitro studies of cellular response to DNA damage induced by boron neutron capture therapy.

The aim of these studies was to evaluate the mechanisms of cellular response to DNA damage induced by BNCT. Thyroid carcinoma cells were incubated with (10)BPA or (10)BOPP and irradiated with thermal neutrons. The surviving fraction, the cell cycle distribution and the expression of p53 and Ku70 were analyzed. Different cellular responses were observed for each irradiated group. The decrease of Ku70 in the neutrons +BOPP group could play a role in the increase of sensitization to radiation.

Caracterización del infiltrado linfocitario (CD, CD4, CD8, CD45RO y FOXP3) e inestabilidad microsatelital en pacientes con cáncer colorrectal / Lymphocyte infiltration and microsatellite instability in colorectal cancer patients

Background: In colorectal cancer (CRC) patients, lymphocyte infiltration (LI) and microsatellite instability (MSI) have been associated with better prognosis. Aim: To analyze the association between components of LI (CD3/CD4/CD8/CD45R0/FoxP3) and MSI status with metastatic stages in CRC patients. Material and Methods: Prospective study of 109 patients diagnosed with CRC. The expression of CD3, CD4, CD8, CD45R0 and FoxP3 markers, was evaluated by immunohistochemical analysis, and tumors were classified into negative, low and intense expression. The MSI was assessed with seven markers amplified by PCR from normal and tumoral DNA. Tumors were grouped in MSS (stable)/MSI-low and MSI-high. Statistical analysis was performed with Fischer's exact test. Results: 29 percent, 28 percent, 12 percent and 86 percent of tumors exhibits intense expression of CD3+, CD4+, CD8+ and CD45RO+ lymphocytes, respectively. 84 percent of the tumors presented MSS/ MSI-low and 16 percent had MSI-high. Tumors that show a high density of T cells (CD3+, CD4+ y CD45R0+) are associated with early stage tumors (I and II) (p = 0.023; p = 0.030 and p = 0.003, respectively). Additionally, there was a significant association between the MSS/MSI-low tumors and a reduced ability to recruit CD8+ cytotoxic T lymphocytes (p = 0.037) and CD3+ (p = 0.064). Conclusion: There is an association between high densities of CD3+, CD4+ and CD45RO+ lymphocytes and non-metastatic tumors. In addition, MSS/ MSI-low tumors are associated with a lower recruitment of CD8+ and CD3+ lymphocytes.

Introducción: En el cáncer colorrectal (CCR), se sugiere que un mejor pronóstico podría asociarse a una respuesta inmune antitumoral (del huésped) y/o a la presencia de una alta inestabilidad microsatelital (MSI). Objetivo: Determinar si los niveles de expresión de los marcadores de linfocitos T (CD3/CD4/CD8/ CD45RO/FoxP3) y el estado de MSI se asocian a estadios metastásicos en pacientes con CCR. Material y Método: Estudio prospectivo de 109 pacientes con diagnóstico de CCR. El análisis de expresión de los marcadores CD3/CD4/CD8/CD45RO/FoxP3 fue realizado por inmunohistoquímica; los tumores fueron clasificados en negativo, débil e intenso. La MSI fue evaluada con siete marcadores amplificados desde ADN normal y tumoral; los tumores fueron agrupados en: MSS (estable)/MSI-baja y MSI-alta. El análisis estadístico fue realizado con el test exacto de Fischer. Resultados: Una intensa expresión de los marcadores CD3+, CD4+, CD8+ y CD45RO+, fue observada en el 29 por ciento, 28 por ciento, 12 por ciento y 86 por ciento de los tumores, respectivamente. El 16 por ciento de los tumores presentó MSI-alta. Los tumores que presentan una alta densidad de linfocitos T (CD3+, CD4+ y CD45RO+) se asocian a estadios tempranos I-II (p = 0,023; p = 0,030 y p = 0,003, respectivamente). Adicionalmente, se identificó una asociación estadística significativa entre los tumores con MSS/MSI-baja y una menor capacidad de reclutar linfocitos T citotóxicos CD8+ (p = 0,037) y totales CD3+ (p = 0,064). Conclusión: Existe una asociación entre altas densidades de linfocitos T CD3+, CD4+ y CD45RO+ y tumores con estadios no metastásicos. Además, tumores con MSS/MSI-baja se asocian a un menor reclutamiento de linfocitos T CD8+ y CD3+.

Prevención de la recurrencia post-quirúrgica de la enfermedad de Crohn: revisión de la literatura a partir de un caso clínico / Prevention of post-surgical recurrence in Crohn’s disease: review of the literature based on a clinical case

Crohn’s Disease (CD) is a chronic and progressive inflammatory bowel disease (IBD) which in some cases is characterized by bowel stenosis, fistulae and related abscesses. In the latter group of patients, surgery is an essential part of the treatment strategy. On the other hand, it is well known that surgery does not offer a definitive cure to these patients, and endoscopic and clinical recurrence at one year follow-up is observed in 72-93 percent and 20-30 percent of patients, respectively. Approximately half of the patients need another surgery within 10-20 years after their first intervention. Although colonoscopy remains being the gold-standard for the diagnosis of endoscopic post-operative recurrence, other non-invasive methods such as capsule endoscopy, imaging studies (abdominal ultrasound, CT- or MR-enterography) and biomarkers such as fecal calprotectin may be used to assess disease activity. Several strategies are being applied in order to prevent post-surgical recurrence, including mesalamine, antibiotics (metronidazol, ornidazol), immunomodulators (azathioprine/6-mercaptopurine and methotrexate) and biologic anti-TNF therapy (infliximab, adalimumab). Identifying risk factors for recurrence will allow a rational use of these treatment options according to their cost, benefits and availability. The purpose of this article is to provide by means of a clinical case, useful information for an adequate management of CD patients in the postoperative setting.

La Enfermedad de Crohn (EC) es una enfermedad inflamatoria intestinal (EII) crónica progresiva que puede manifestarse por estenosis, fístulas y abscesos. Es en este grupo de pacientes donde la cirugía juega un papel fundamental como estrategia terapéutica. Sin embargo, uno de los temas a considerar es que la resección de las lesiones no significa un tratamiento definitivo, y la recurrencia endoscópica y clínica puede ser observada en 72-93 por ciento y 20-30 por ciento, respectivamente, al año de la cirugía. Por otra parte, aproximadamente 50 por ciento de los pacientes necesitarán una nueva operación luego de 10-20 años de la primera cirugía. Aunque la colonoscopia sigue siendo el gold standard para evaluar la recurrencia endoscópica post-quirúrgica, otras técnicas no invasivas como la endoscopia por cápsula, estudios de imágenes [ecotomografía abdominal, enteroclisis por tomografía computada (TC) abdomen-pelvis, enteroclisis por resonancia magnética (RM) abdomen-pelvis] y biomarcadores como calprotectina fecal pueden ser utilizadas para evaluar a este grupo de pacientes. Para prevenir la recurrencia post-quirúrgica varias estrategias han sido sugeridas, tales como el uso de mesalazina, antibióticos nitroimidazólicos (metronidazol y ornidazol), inmunomoduladores (IMM; azatioprina/6-mercaptopurina y metotrexato) y terapia biológica (TB) anti-TNF (infliximab y adalimumab). El evaluar el riesgo de recurrencia según factores de riesgo permitirá un uso racional de estas estrategias terapéuticas, considerando su disponibilidad, costos y beneficios. El objetivo de este artículo es entregar, a través de un caso clínico, la información que permita un manejo adecuado de los pacientes con EC post-cirugía.

Tratamiento de la fístula perianal en la enfermedad de Crohn a partir de una experiencia local / Treatment of perianal fistulae in Crohn´s disease: a local experience

Background: Perianal fistula (PF) may be present in 40 percent of patients with Crohn´s Disease (CD). Due to its complexity, its management should be multidisciplinary. Purpose: To describe clinical treatment in patients with CD and PF in our institution. Materials and Methods: This is a descriptive retroprospective study, using a registry of CD patients. We selected patients with PF and further characterized those patients that received their treatment at Clínica las Condes (CLC). Results: From a total of 74 patients with CD in the registry, 23 (31 percent) had PF, 61 percent male, median of 7 years of disease and half with colonic extension. Twelve patients were treated in CLC, from these, seven had concomitant proctitis. Optimal diagnostic study (magnetic resonance imaging/endorectal ultrasound plus examination under anesthetic) was performed in eleven (92 percent) patients. Ten (83 percent) patients received an optimal treatment (drainage and installation of a loose seton + start or optimization of medical therapy). Complete clinical response was achieved in more than half of the patients under optimal treatment within the first 6 months. Six (50 percent) patients had one or more recurrences of PF with similar study and management in a median of 13 months. With a median follow-up of 29 months, eight out of 12 patients had complete clinical response. There was one patient with unfavorable course who required a proctectomy and terminal diversion. Conclusion: Treatment of PF in CD is complex and in our population, the first-line treatment includes the installation of a loose seton and medical therapy to achieve clinical response even though fistulous tracts may persist.

Introducción: La fístula perianal (FP) puede presentarse hasta en 40 por ciento de los pacientes con Enfermedad de Crohn (EC). Dada su complejidad el tratamiento debe ser multidisciplinario. Objetivo: Describir el tratamiento de los pacientes portadores de EC con FP. Métodos: Estudio descriptivo, utilizando un registro de pacientes con EC. Se seleccionaron los pacientes con FP y se caracterizaron aquellos que recibieron el tratamiento en Clínica Las Condes (CLC). Resultados: De un total de 74 pacientes con EC, 23 (31 por ciento) presentaban FP asociada, 61 por ciento de sexo masculino, mediana de duración de enfermedad 7 años y la mitad con extensión colónica. Doce pacientes fueron tratados en CLC, de ellos, siete presentaban proctitis al momento de la FP. En 11 (92 por ciento) pacientes se realizó un estudio diagnóstico óptimo (resonancia magnética/ endosonografía transrrectal y exploración bajo anestesia). Diez (83 por ciento) pacientes recibieron tratamiento óptimo biasociado (drenaje e instalación de sedal no cortante + inicio u optimización de terapia médica). Siete pacientes con tratamiento óptimo presentaron mejoría clínica completa dentro de los primeros 6 meses. Seis (50 por ciento) pacientes presentaron una o más recurrencia de FP con estudio y manejo similar en una mediana de 13 meses. Con una mediana de seguimiento de 29 meses, ocho de los 12 pacientes obtuvieron mejoría clínica completa. Una paciente evolucionó desfavorablemente, requiriendo proctectomía y ostomía terminal. Conclusión: El manejo del FP en EC es complejo, en nuestra población el tratamiento biasociado (sedal + fármacos) fue de elección para lograr una mejoría clínica aun cuando persistieron los trayectos fistulosos.

Escroto agudo en el niño / Acute scrotum syndrome in children

El síndrome de escroto agudo en el niño se caracteriza por dolor escrotal agudo, acompañado de signos inflamatorios. Las causas más frecuentes son torsión de apéndices testiculares, torsión de cordón espermático y epididimitis/orquitis. En esta revisión, se describe la clínica, métodos diagnósticos y tratamiento de estas patologías. Se destaca la importancia del diagnóstico diferencial precoz ya que el tratamiento oportuno de la torsión del cordón espermático disminuye la posibilidad de necrosis del testículo afectado.

Acute scrotum syndrome in children is characterized by acute scrotal pain, accompanied by inflammatory signs. The most common causes are torsion of testicular appendages, torsion of the spermatic chord and epididymitis/orchitis. In this review, we describe the clinical features, diagnostic methods and treatment of these pathologies. We also highlight the importance of early differential diagnosis because timely treatment of the spermatic chord torsion reduce the risk of necrosis in the affected testes.