Cardiotoxicidad inducida por tratamientos oncológicos: fundamentos para la implementación de equipos de Cardio-Oncología / Cardiotoxicity of anticancer therapies: towards the implementation of cardio-oncology units

Recently, we have witnessed major improvements in cancer treatment. Early diagnosis and development of new therapies have reduced cancer-related mortality. However, these new therapies, along with greater patient survival, are associated with an increase in untoward effects, particularly in the cardiovascular system. Although cardiotoxicity induced by oncologic treatments affects predominantly the myocardium, it can also involve other structures of the cardiovascular system, becoming one of the main causes of morbidity and mortality in those who survive cancer. The main objective of cardio-oncology is to achieve the maximum benefits of oncologic treatments while minimizing their deleterious cardiovascular effects. It harbors the stratification of patients at risk of cardiotoxicity, the implementation of diagnostic tools (imaging techniques and biomarkers) for early diagnosis, preventive strategies and early treatment options for the complications. Herein, we discuss the basic knowledge for the implementation of cardio-oncology units and their role in the management of cancer patients, the diagnostic tools available to detect cardiotoxicity and the present therapeutic options.

Infecciones y alteraciones epigenéticas en cáncer / Infections and epigenetic changes in cancer

La participación de mecanismos epigenéticos, junto con infecciones en etapas tempranas de la vida, moldean lesiones premalignas del cáncer, en particular el cáncer gástrico, uno de los tumores más frecuentes en Chile, Latinoamérica y el mundo. El principal objetivo de este artículo, como parte de la serie de revisiones en torno a mecanismos epigenéticos en el desarrollo de enfermedades crónicas, es actualizar el rol de alteraciones epigenéticas (i.e. metilación del ADN) en el contexto de la infección crónica por H. pylori en las etapas precursoras del cáncer gástrico. Las investigaciones desarrolladas en esta área permiten delinear desafíos e interrogantes, en los cuales la pediatría tiene un papel preponderante en el desarrollo de estrategias de prevención y detección temprana de esta enfermedad.

The role of epigenetics and infectious diseases at early stages of life influence pre-malignant lesions of cancer, in particular, gastric cancer, one of the most frequent tumours in Chile, Latin America, and worldwide. This article examines the role of H.pylori and epigenetic alterations (i.e. DNA methylation) at early stages of gastric cancer and proposes, from the paediatric point of view, strategies for prevention and early detection.

Reprimo as a modulator of cell migration and invasion in the MDA-MB-231 breast cancer cell line

BACKGROUND: Reprimo (RPRM), a highly glycosylated protein, is a new downstream effector of p53-induced cell cycle arrest at the G2/M checkpoint, and a putative tumor suppressor gene frequently silenced via methylation of its promoter region in several malignances. The aim of this study was to characterize the epigenetic inactivation and its biological function in BC cell lines. METHODS: The correlation between RPRM methylation and loss of mRNA expression was assessed in six breast cancer cell lines by methylation specific PCR (MSP), 5'-Aza-2'-deoxycytidine treatment and RT-PCR assays. MDA-MB-231 cells were chosen to investigate the phenotypic effect of RPRM in cell proliferation, cell cycle, cell death, cell migration and invasion. RESULTS: In the cancer methylome system (CMS) (web-based system for visualizing and analyzing genome-wide methylation data of human cancers), the CpG island region of RPRM (1.1 kb) was hypermethylated in breast cancer compared to normal breast tissue; more interesting still was that ERa(+) tumors showed higher methylation intensity than ERa(-). Downregulation of RPRM mRNA by methylation was confirmed in MDA-MB-231 and BT-20 cell lines. In addition, overexpression of RPRM in MDA-MB-231 cells resulted in decreased rates of cell migration, wound healing and invasion in vitro. However, RPRM overexpression did not alter cell viability, phosphatidylserine (PS) translocation or G2/M cell cycle transition. CONCLUSION: Taken together, these data suggest that RPRM is involved in decreased cell migration and invasion in vitro, acting as a potential tumor suppressor gene in the MDA-MB-231 cell line.

A snapshot of cancer in Chile: analytical frameworks for developing a cancer policy

INTRODUCTION: The South American country Chile now boasts a life expectancy of over 80 years. As a consequence, Chile now faces the increasing social and economic burden of cancer and must implement political policy to deliver equitable cancer care. Hindering the development of a national cancer policy is the lack of comprehensive analysis of cancer infrastructure and economic impact. OBJECTIVES: Evaluate existing cancer policy, the extent of national investigation and the socio-economic impact of cancer to deliver guidelines for the framing of an equitable national cancer policy. METHODS: Burden, research and care-policy systems were assessed by triangulating objective system metrics -epidemiological, economic, etc. - with political and policy analysis. Analysis of the literature and governmental databases was performed. The oncology community was interviewed and surveyed. RESULTS: Chile utilizes 1% of its gross domestic product on cancer care and treatment. We estimate that the economic impact as measured in Disability Adjusted Life Years to be US$ 3.5 billion. Persistent inequalities still occur in cancer distribution and treatment. A high quality cancer research community is expanding, however, insufficient funding is directed towards disproportionally prevalent stomach, lung and gallbladder cancers. CONCLUSIONS: Chile has a rapidly ageing population wherein 40% smoke, 67% are overweight and 18% abuse alcohol, and thus the corresponding burden of cancer will have a negative impact on an affordable health care system. We conclude that the Chilean government must develop a national cancer strategy, which the authors outline herein and believe is essential to permit equitable cancer care for the country.

Síndrome de Lynch: selección de pacientes para el estudio genético mediante análisis de inestabilidad microsatelital e inmunohistoquímica / Lynch syndrome: selection of families by microsatellite instability and immunohistochemistry

Background: Selection of patients with Lynch Syndrome (LS) for a genetic study involves the application of clinical criteria. To increase the rate of identification of mutations, the use of molecular studies as Microsatellite Instability (MSI) and Im-munohistochemistry (IHC) in the tumor has been proposed. Aim: To demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. Material and Methods: From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. Results: A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. Conclusions: MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes.

Expresión diferencial de genes asociados a carcinoma de próstata / Differential expression of genes associated with prostate carcinoma

Objetivo: La introducción del Antígeno Prostático Específico (APE) como herramienta de uso masivo en la detección precoz de cáncer prostático (CaP), parece ser al menos parcialmente responsable de la disminución en la mortalidad observada en el último tiempo. Sin embargo, el APE tiene una baja especificidad como marcador de cáncer, especialmente en el rango de 4 a 10 ng/ml donde existe una alta sobreposición con otras patologías de mayor prevalencia como por ejemplo, Hiperplasia Prostática Benigna (HPB). Es por esto, que existe una búsqueda constante de nuevos marcadores. Nuestro objetivo fue caracterizar el perfil de expresión génica del CaP utilizando microarray. Material y métodos: Doce casos de CaP con PSA <10 ng/ml y 4 casos con PSA >10 ng/ml fueron seleccionados prospectivamente para análisis de microarray para 96 genes característicos de tejido prostático. Los análisis se efectuaron por el método de Hierarchical Clustering y se realizó Transcripción Reversa y Reacción de Polimerasa en Cadena para confirmar la información obtenida mediante microarray. Además, se evaluó la presencia en sangre periférica de los genes sobre-expresados en tejido y que pudieran ser marcadores sistémicos de CaP. Resultados: Se definieron 13 genes basándose en su alta expresión, los cuales se agruparon en NCOA4/NDRG1, LDHA/LIM/GSTP1 y KLK2/KLK4 y estos con CALR y CSTB. Los genes SPARCL1, KLK3(PSA), ARSDR1 y ACPP se ordenaron en ramas independientes. El gen ACPP (fosfatasa ácida prostática) fue el más independientemente sobreexpresado. Realizamos RT-PCR para ACPP en 15 tumores primarios y sangre periférica observando señal positiva en 10 (71 por ciento) de 14 casos analizados. Conclusiones: Nuestros resultados indican que el gen ACPP se encuentra sobreexpresado a nivel molecular en tumor primario y sangre periférica, convirtiéndolo en un potencial marcador de CaP con niveles de PSA <10 ng/ml.

Objective: The introduction of prostate specific antigen (PSA) as a screening tool for early detection of prostate cancer (CaP), seems to take a role in being responsible for the decreasing of mortality observed in the last time. Nevertheless, the APE has a low specificity like cancer marker, especially in the rank from 4 to 10 ng/ml where a high superposition with other pathologies of greater prevalence like Benign Prostate Hiperplasia (HPB) exists. This is why there is a constant research for new markers. Our objective was to characterize the gene expression profile of prostate using microarray. Material and Methods: Twelve cases of CaP with PSA <10 ng/ml and 4 cases with PSA >10 ng/ml were prospectively selected for microarray analysis for 96 genes characteristic of prostate tissue. The analysis was performed by the method of Hierarchical Clustering and performed reverse transcription polymerase chain reaction to confirm the information obtained by microarray. We assessed the presence in peripheral blood of over-expressed genes in tissue that could become in systemic markers of PC. Results: We identified 13 genes based on their high expression, which were grouped into NCOA4/NDRG1, LDHA/LIM/GSTP1 and KLK2/KLK4 and those with CALR and CSTB. Genes SPARCL1, KLK3 (PSA) and ACPP ARSDR1 were ordered in separate branches. The ACPP gene (prostatic acid phosphatase) was overexpressed more independently. We RT-PCR for ACPP in 15 primary tumors and peripheral blood positive signal observed in 10 (71per cent) of 14 cases analyzed. Conclusions: Our results indicate that the ACPP gene is overexpressed in a molecular level in primary tumor and peripheral blood, making it a potential marker for prostate cancer with PSA levels <10 ng/ml.

Factores de riesgo de alteraciones citológicas del cuello uterino en mujeres chilenas: Un estudio de casos y controles / Risk factors associated with abnormal cervical cytology among Chilean women: A case control study

Background: Cervical cancer is the third cause of cancer death among Chilean women, affecting mainly women from low socioeconomic status. Aim: To determine main risk factors (RF) including human papilomavirus (HPV) types associated with abnormal cervical cytology (Atypical Squamous Cells of Undetermined Significance or ASCUS) among Chilean women from low socioeconomic status in Santiago, Chile. Material and Methods: A random population based sample of616 women from La Pintana (a low-income district in Santiago) participated in 2001 in a HPV prevalence study and were re-evaluated in 2006 through a risk factors questionnaire, Papanicolaou test and DNA detection for HPV. The Papanicolaou test was analyzed in Santiago and HPV analysis (PCR_GP5+/GP6+) was conducted in Vrije University, Amsterdam. Cases included 42 women with cervical lesions and controls included 574 women with normal cytology during the period 2001-2006. Logistic regression with uni and multivariate analysis was performed to identify RF for cervical lesions. Results: During the study period, there was a significant increase in the proportion of single women, from 8.3 to 14.8 percent (p < 0.05), of women with 3 or more sexual partners from 8.9 to 13.3 and of women high risk HPV, from 9.1 to 14.3 percent. The proportion of abnormal Papanicolaou tests remained stable (3.08 and 3.9 percent > ASCUS). High risk HPV was the most significant factor associated with cervical lesions (odds ratio (OR) = 9.695 percent> confidence intervals (CI) = 4.4-21.1) followed by oral contraceptive use (OR = 2.58 95 percent> CI= 1.2-5.7). Among women infected by high risk HPV, the use of oral contraceptives was a risk factor while compliance with screening was protective for cervical lesions. Conclusions: From 2001 to 2006, there was an increase in the proportion of women with high-risk HPV infections.

DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis

Diffuse type gastric carcinoma is the most aggressive type of gastric cancer. This type of tumor is not preceded by precancerous changes and is associated with early-onset and hereditary syndromes. To test the hypothesis that DNA methylation profile would be useful for molecular classification of the diffuse type gastric carcinoma, DNA methylation patterns of the CpG Island of 17 genes were studied in 104 cases and 47 normal adjacent gastric mucosa by Methylation-specific PCR, Immunohistochemistry and Hierarchicalclustering analysis. The most frequent methylated genes were FHIT, E-cadherin, BRCA1 and APC (>50%),followed by p14, p16, p15, p73, MGMT and SEMA3B (20-49%). Hierarchical clustering analysis reveals four groups with different clinical features. The first was characterized by hypermethylation of BRCA1 and younger age (<45 years old), and the second by hypermethylation of p14 and p16 genes, male predominance and Epstein-Barr virus infection. The third group was characterized by hypermethylation of FHIT and antrum located tumors and the fourth was not associated with any clinical variables. In normal adjacent mucosa only the p73 gene was significantly less methylated in comparison to tumor mucosa. DNA methylation identified subgroups of diffuse type gastric cancer. Hypermethylation of BRCA1 associated with young age suggests a role in early-onset gastric carcinoma.

Perfiles de expresión génica en decisiones terapéuticas en cáncer de mama / Gene expression profiles for therapeutic decisions in breast cancer

In the early stages of breast cancer, surgery and radiotherapy arrest the local and regional disease. However 30 percent of patients will die as a consequence of tumor dissemination. Parameters with a relative predictive value are used to assess candidates to adjuvant therapy. Genomic analysis methods (cDNA microarray) identified a gene expression profile of greater aggressiveness in breast cancer. This knowledge generated the project "Translating Molecular Knowledge Into Early Breast Cancer Management" of the Breast International Group (BIG). This is a consortium of 32 research groups in which Chile participates through the Chilean Cooperative Oncological Research Group (GOCCHI). The project consists in three protocols. In the first, denomimated MINDACT (Microarray for Node Negative Disease may Avoid Chemotherapy), 8000 women will be evaluated by gene expression profile and clinical pathological criteria to decide adjuvant therapy. Since a group of patients will not receive therapy, solely based on gene expression profile, GOCCHI is preparing a follow up protocol based on the expression of 22 genes. MINDACT is the first prospective effort to evaluate gene expression profiles in clinical practice. Our participation in this protocol, installs us in the first line of worlwide oncological investigation.

High frequency of p 16 promoter methylation in non-small cell lung carcinomas from Chile

The inactivation of tumour suppressor genes by aberrant methylation of promoter regions has been described as a frequent event in neoplasia development, including lung cancer. The p16 gene is a tumour suppressor gene involved in the regulation of cell cycle progression that has been reported to be inactivated by promoter methylation in lung carcinomas at variable frequencies around the world in a smoking habit dependent manner. The purpose of this study was to investigate the methylation status of the promoter region of the p16 gene in 74 non-small cell lung carcinomas from Chile. The frequency of p16 gene inactivation by promoter methylation was determined as 79.7 percent (59/74). When we considered histological type, we observed that p16 promoter methylation was significantly higher in squamous cell carcinomas (30/33, 91 percent) compared with adenocarcinomas (21/30, 70 percent) (p=0.029). In addition, no association between p16 promoter methylation and gender, age or smoking habit was found (p=0.202, 0.202 and 0.147 respectively). Our results suggest that p16 promoter hypermethylation is a very frequent event in non-small cell lung carcinomas from Chile and could be smoking habit-independent.

Helicobacter pylori: análisis de cagA y genotipificación de vacA en Chile: detección de una cepa s2/m1 / Helicobacter pylori: cagA status and vacA genotyping in Chile, detection of a s2/m1 strain

Background: The genes cagA and vacA encode H pylori virulence factors. Aim: To genotype these genes in H pylori strains isolated from patients with upper gastrointestinal symptoms. Material and methods: We studied 50 patients who underwent an upper gastrointestinal endoscopy, with positive culture for H pylori. Detection of cagA and vacA gerotyping was done using polymerase chain reactions. Results: The gene cagA was detected in 19 samples (38 per cent). Signal sequences s1 and s2 of vacA gene were detected in 16 samples each (32 per cent). There was simultaneous amplification of s1 and s2 in 6 samples and they were not detected in 9 samples. The middle region of vacA was m1 in 9 samples, m2 in 29 samples and there was simultaneous amplification of m1 and m2 in 12 samples. In 16 samples (32 per cent), more than one type of signal sequence or medial region was detected. Of those patients in whom vacA was the only genotype detected, 15 were s2/m2, 7 were s1/m1, 4 were s1/m2 and 1 was s2/m1. Conclusions: In these patients, the infection with cagA- H pylori strains, predominates, the prevalence of infection with s1 or s2 strains is similar and the predominant medial region is m2

Neoplasias ováricas: análisis factorial Hospital Paula Jaraquemada, período 1975-1984 / Ovaric neoplasms: factorial analysis at the Hospital Paula Jaraquemada, 1975-1984

Se revisan los datos clínicos e histopatológicos de 10.558 pacientes hospitalizadas e intervenidas en la división de Ginecología Servicio de Obstetricia, Ginecología y Neonatología Hospital Paula Jaraquemada en el período 1975-1984; de ellas se estudian 510 pacientes en las cuales el diagnóstico histopatológico correspondió a una tumoración ovárica. Se exponen los conceptos básicos para decidir conducta ante un tumor ovárico. En el grupo de estudio se analizan: histología de los distintos tumores, frecuencia relativa de cada variedad histopatológica y edad de la paciente