Analysis of redox and apoptotic effects of anthracyclines to delineate a cardioprotective strategy.

PURPOSE: Cardiotoxic side effects of anthracyclines limit their use as effective chemotherapeutics. One mechanistic model of anthracycline-induced cardiotoxicity is attributed to the generation of intracellular reactive oxygen species (ROS). However, this theory has been questioned because several cardioprotective strategies have included the use of antioxidants without significant clinical benefit. We sought to determine whether measurement of intracellular reactive oxygen species after anthracycline exposure in vivo and in vitro could provide a means for designing more effective antioxidant-based cardioprotective schemes. METHODS: Intracellular levels of ROS were assessed in peripheral blood mononuclear cells from leukemia bearing mice exposed to anthracyclines and in patients receiving anthracyclines. Comparison of cell death induction and ROS levels were also conducted in vitro in cardiomyocyte and leukemia lines. ROS blockade using antioxidants was conducted, and effects on cell death were assessed. RESULTS: Elevated ROS in blood of mice and representative patient samples correlated with cardiomyocyte necrosis and decreased ejection fraction. In vitro, comparison of the cytotoxic effects of anthracyclines in acute leukemia cells and in cardiomyocytes revealed distinct kinetics of cell death induction and dependence upon oxidative stress. Although apoptotic cell death was observed in both acute leukemia cells and cardiomyocytes, the antioxidant N-acetylcysteine protected cardiomyocytes but not acute leukemia cells from anthracycline cytotoxicity. CONCLUSIONS: Our findings point toward revisiting the use of NAC as a cardioprotective agent since it does not appear to interfere with the cytotoxic action of anthracyclines. NAC has been evaluated clinically for cardioprotective activity but future trials must ensure that adequate dose, scheduling and incorporation of markers of oxidative stress are included.

Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis.

The survival of patients with advanced osteosarcoma is poor with limited therapeutic options. There is an urgent need for new targeted therapies based on biomarkers. Recently, theranostic molecular profiling services for cancer patients by CLIA-certified commercial companies as well as in-house profiling in academic medical centers have expanded exponentially. We evaluated molecular profiles of patients with advanced osteosarcoma whose tumor tissue had been analyzed by one of the following methods: 1. 182-gene next-generation exome sequencing (Foundation Medicine, Boston, MA), 2. Immunohistochemistry (IHC)/PCR-based panel (CARIS Target Now, Irving, Tx), 3.Comparative genome hybridization (Oncopath, San Antonio, TX). 4. Single-gene PCR assays, PTEN IHC (MDACC CLIA), 5. UT Houston morphoproteomics (Houston, TX). The most common actionable aberrations occur in the PI3K/PTEN/mTOR pathway. No patterns in genomic alterations beyond the above are readily identifiable, and suggest both high molecular diversity in osteosarcoma and the need for more analyses to define distinct subgroups of osteosarcoma defined by genomic alterations. Based on our preliminary observations we hypothesize that the biology of aggressive and the metastatic phenotype osteosarcoma at the molecular level is similar to human fingerprints, in that no two tumors are identical. Further large scale analyses of osteosarcoma samples are warranted to test this hypothesis.

Rhabdomyosarcoma in adolescent and young adult patients: current perspectives.

Rhabdomyosarcoma (RMS), a malignant tumor of mesenchymal origin, is the third most common extracranial malignant solid tumor in children and adolescents. However, in adults, RMS represents <1% of all solid tumor malignancies. The embryonal and alveolar histologic variants are more commonly seen in pediatric patients, while the pleomorphic variant is rare in children and seen more often in adults. Advances in the research of the embryonal and alveolar variants have improved our understanding of certain genes and biologic pathways that are involved in RMS, but much less is known for the other variants. Multimodality therapy that includes surgery and chemotherapy with or without radiation therapy is the mainstay of treatment for RMS. Improvements in the risk stratification of the pediatric patients based on presurgical (primary tumor site, tumor size, regional lymph node involvement, presence of metastasis) and postsurgical parameters (completeness of resection or presence of residual disease or metastasis) has allowed for the treatment assignment of patients in different studies and therapeutic trials, leading to increases in 5-year survival from 25%-70% over the past 40 years. However, for adult patients, in great part due to rarity of the disease and the lack of consensus on optimal treatment, clinical outcome is still poor. Many factors have been implicated for the differing outcomes between pediatric RMS versus adult RMS, such as the lack of standardized treatment protocols for adult RMS patients and the increased prevalence of advanced presentations. Now that there are increased numbers of survivors, we can appreciate the sequelae from therapy in these patients, such as bone growth abnormalities, endocrinopathies, and infertility. Improvements in risk stratification have led to clinical trials using lower doses of chemotherapy or radiation therapy with the intention of decreasing the incidence of side effects without compromising survival outcome.

Cerebral sinovenous thrombosis associated with iron deficiency anemia secondary to severe menorrhagia: a case report.

Cerebral sinovenous thrombosis is a rare condition presenting with a wide spectrum of nonspecific symptoms that can make early diagnosis difficult. Cerebral sinovenous thrombosis has been associated with various etiologies. Iron deficiency anemia associated with cerebral sinovenous thrombosis in teenagers is rare. We present a teenage patient with complete thrombosis of the vein of Galen, straight sinus, and left internal cerebral vein associated with iron deficiency anemia due to severe menorrhagia. Mechanisms that can explain the association between iron deficiency anemia and thrombosis are discussed.

Clinical characteristics and outcomes of pediatric oncology patients with aggressive biology enrolled in phase I clinical trials designed for adults: the university of Texas MD anderson cancer center experience.

BACKGROUND: Children (patients ≤ 18 years of age) are not usually included on pharmaceutical industry sponsored Phase I trials. METHODS: We reviewed the medical records of 40 patients ≤ 18 years treated in ≥ 1 phase I trial at MD Anderson. RESULTS: The median OS was 8.5 months (95% CI, 5.5-13.2 months). In the multivariate analysis, age ≥15 only predicted increased OS (P = 0.0065), and >3 prior therapies (P = 0.053) predicted decreased OS. The median PFS was 2.8 months (95% CI, 2.3-4.1 months). In the multivariate analysis, independent factors that predicted increased PFS were age ≥15 years (P < 0.001) and prior radiation therapy (P = 0.049); performance status >1 (P < 0.001) and >3 prior therapies (P = 0.002) predicted decreased PFS. RMH score ≥ 2 and MDACC score ≥ 3 were associated with decreased median OS (P = 0.029 and P = 0.031 respectively). CONCLUSIONS: It is feasible to conduct phase I studies in pediatric patients based on adult protocols. In the era of targeted therapy more trials should allow pediatric patients earlier in the drug development especially if deemed safe in adults in early phase trials. TRANSLATIONAL RELEVANCE: Most pharmaceutical industry sponsored trials exclude patients less than 18 years in phase I clinical trials. Even in the era of targeted therapy pediatric patients usually have to wait for most phases of trials to be completed in adults before being allowed to enroll in clinical trials of new therapies, even in the advanced metastatic and relapsed setting. Some investigator initiated phase 1 trials of combinations of US FDA approved agents allow patients less than 18 years. We report the preliminary analyses of the outcomes of pediatric patients enrolled in phase I studies initially designed for adults, but allowing for enrollment of patients under 18.

Anemia fanconi: evidencia de un caso / Fanconi’s anemia: case evidence

La anemia de Fanconi es una enfermedad heredada con carácter autosómico recesivo, caracterizada por el desarrollo gradual de pancitopenia en la niñez1. Se asocia con frecuencia a diversas anomalías congénitas que incluyen principalmente anormalidades del esqueleto, corazón y riñones, malformaciones del sistema nervioso central con retraso mental y pigmentación anormal de la piel2,3. Fue descrita por Fanconi en 1927 y en 1931 Naegeli sugirió que el término "Anemia de Fanconi" se utilice para los pacientes con anemia aplásica familiar y malformaciones congénitas.

Fanconi’s Anemia is a hereditary disease with autosomal recessive character, that causes a gradual development of pancytopenia in infancy. Frequently it is associated to several congenital abnormalities, mainly in the skeleton, heart and kidneys, malformations of the central nervous system, with mental retardation and abnormal skin pigmentation. It was described by Fanconi in 1927 and in 1931 Naegeli suggested that the term “Fanconi’s anemia be used for patients with familial aplastic anemia and congenital malformations.

Analysis of CFTR gene mutations and cystic fibrosis incidence in the Ecuadorian population.

Ecuador is one of the Latin American countries where cystic fibrosis has not been thoroughly studied. The goal of this study was to establish the incidence of this specific pathology and the incidence of the 29 most common European CF mutations in Ecuador's population. We performed a prospective-descriptive study with the intention of including patients registered at the Ecuadorian Cystic Fibrosis Foundation as well as the main pediatric hospitals in Ecuador. The inclusion criteria were clinical manifestations of cystic fibrosis plus two positive pilocarpine iontophoresis sweat tests (CI >60 mEq/L). We tested F508del mutation by heteroduplex method and then, we confirmed these results and searched for other 28 frequent European-mutations aside from F508del by a reverse dot blot technique (INNO-LiPA CFTR 29 + Tn). Sixty two unrelated patients were included. Both heteroduplex and reverse dot blot methods identified 53.22% of all mutations. The estimated Ecuadorian cystic fibrosis incidence was 1:11,252. The mutations found and their incidence were F508del (37.1%), G85E (8.9%), G542X (2.4%), N1303K (2.4%), G551D (1.6%) and R334W (0.8%). The incidence of cystic fibrosis in Ecuador is closely similar to other Latin American countries where there is a large "mestizo" population. We are reporting one of the highest incidences of G85E in the world.

Analysis of CFTR gene mutations and cystic fibrosis incidence in the ecuatorian population

Ecuador es uno de los países latinoamericanos donde la fibrosis quística no ha sido profundamente estudiada. El objetivo de este estudio fue establecer la incidencia de esta patología identificar las 29 mutaciones europeas mas frecuentes que afectan a los pacientes fibroquísticos ecuatorianos. Se realizó un estudio descriptivo-prospectivo que incluyó pacientes provenientes de las Fundación Fibrosis Quística y de los principales hospitales pediátricos del Ecuador. Los criterios de inclusión fueron la presencia de manifestaciones clínicas clásicas de fibrosis quística más dos pruebas del sudor por iontoforesis de pilocarpina positivas CI > 60 mEq/L. Se utilizó heteroduplex para identificar la mutación F508del y posteriormente se confirmó dichos resultados e identificó otras 28 mutaciones frecuentes de la población europea utilizando un test de hibridación reversa in situ (INNO-LiPA CFTR 29 + Tn). Sesenta y dos pacientes fueron incluidos y se logró identificar el 53,22 por ciento de todos los alelos mutados. Las mutaciones encontradas fueron F508del (37,1 por ciento), G85E (8,9 por ciento), G542X (2,4 por ciento), N1303K (2,4 por ciento), G551D (1,6 por ciento) y R334W (0,8 por ciento). La incidencia estimada de la fibrosis quística en el Ecuador (1:11.252) es muy similar a la de otros países latinoamericanos que poseen un gran porcentaje de población mestiza. Reportamos una de las frecuencias más altas de la mutación G85E en el mundo.

Determinación de resistencia a la insulina en pacientes con diabetes tipo 2 / Determine if type 2 diabetes mellitus patients are insulin resistant

Estudio realizado en la consulta externa de Endocrinología del hospital “Luis Vernaza”, Guayaquil, en un grupo de pacientes con diabetes mellitus tipo 2, sobrepeso u obesidad durante los meses de junio a septiembre 2003 y que respondían a los criterios de inclusión. Tipo de estudio: Descriptivo analítico y transversal. Objetivo general: Determinar la frecuencia de insulinorresistencia (IR) y los factores; (en otras palabras, aún no se ha determinado si la IR es causa o efecto) en pacientes con diabetes tipo 2 y/o sobrepeso u obesidad que acuden a la consulta externa del servicio de Endocrinología del hospital “Luis Vernaza”. Específicos: Determinar la frecuencia de insulinorresistencia en pacientes con diabetes mellitus tipo 2 y/o sobrepeso u obesidad en este estudio. Determinar sexo, edad, procedencia, hábitos y factores constitucionales de los pacientes diabéticos y/o con sobrepeso u obesidad e IR. Identificar los factores de riesgo para síndrome metabólico presentes en el grupo de pacientes con diabetes mellitus tipo 2 y/o con sobrepeso u obesidad que acuden a la consulta externa del hospital “Luis Vernaza”. Valorar glicemia e insulinemia obtenidos en los pacientes con IR. Resultados: Durante el período de estudio 58 pacientes cumplieron criterios de inclusión; de los cuales 25 presentaron sobrepeso u obesidad y 33 diabetes mellitus tipo 2. Del total de pacientes estudiados 24 presentaron insulinorresistencia, lo que corresponde a un 41.4.

Study was done at department of endocrinology of “Luis Vernaza” hospital in Guayaquil, in a group of patients with type 2 diabetes mellitus, who are overweight or obese during the months of June thru September 2003 and that had criteria of inclusion. Type of study: Descriptive, analytic and transversal. Objectives: General: Determine the frequency of insulin resistance in patients that have type 2 diabetes mellitus and are overweight or have obese. Specific: Determine the frequency of insulin resistance in patients with type 2 diabetes mellitus and who are overweight or obese; Identify patients who are overweight or have obesity. Results: During the study 58 patients had criteria of inclusion: 25 patients were obese or overweight and 33 had type 2 diabetes mellitus. A total of 24 patients were insulin resistant which is 41.4. In group A (obesity or overweight) 24 were insulin resistant and in group B (type 2 diabetic) 54.5 were insulin resistant. Conclusions: We found that 41.4 of the patients with diabetes and/or obese or overweight were insulin resistant. A larger percent of patients with type 2 diabetes mellitus were insulin resistant (54.5) compared to 24 of patients who are obese or overweight Compared to findings from other authors (10), it is considered that 85 of patients that have type 2 diabetes and 40 to 80 of that patients have obesity are insulin resistant, even though it is not the same percentage both groups studied have high percentages. Insulin resistance is frequent between the ages of 50 and 60 years.

Detección molecular y genotipificación del virus del papiloma humano en el Instituto Oncológico Nacional ION-SOLCA del Ecuador / Molecular detection and genotype classification of human papillomavirus in the National Oncology Institute NOI-SOLCA of Ecuador

Pocos son los datos que existen en la población ecuatoriana referentes a la infección por virus del papiloma humano (VPH), entidad íntimamente relacionada con el cáncer de cérvix, patología que según estadísticas del ION-SOLCA, representa el 51% de las neoplasias malignas detectadas en mujeres. Realizamos un estudio transversal junto con el personal del servicio de colposcopía del ION SOLCA. Tomamos muestras citológicas cervicales a 15 pacientes altamente sospechosas de estar infectadas con VPH. Se extrajo el ADN de dichas muestras y se identificó y genotipificó el virus por medio de PCR en tiempo real y PCR-dot blot reverso (INNO-LiPA HPV Genotyping v2) respectivamente. Todas las pacientes fueron positivas para VPH. Los genotipos encontrados fueron: 6, 11, 31, 40, 51, 52, 53, 59 y 68. El 80% de los pacientes mostró infección con más de un genotipo del VPH. No se encontró ningún paciente con genotipo 16 y/o 18.

There are not much information in the Ecuadorian population about human papillomavirus infection (HPV), is associated with cervix cancer, pathology that represent 51% of malignant neoplasm detected in women according to the NOI-SOLCA statistics. It took cervical cytology samples to 15 patients with high risk of be infected by HPV. It got DNA of these samples and it realized a identification a genotype classification of virus by a PCR in real time and reverse PCR-dot blot (INNO-LiPA HPV Genotyping v2). All the patients were positive for HPV. The genotypes founded were: 6, 11,31,40,51,52,53,59 and 68. The 80% of all patients showed infection with more one genotype of HPV. It was not found any patient with genotype 16 and/or 18.

Insulinorresistencia / Insulin resistance

La resistencia insulínica o insulinorresistencia (IR) es una disminución en la función biológica de esta hormona caracterizada por un alto nivel de la insulina plasmática que es requerido para mantener la homeostasis metabólica.Se ha estimado que aproximadamente un 25% de individuos tienen IR. Su estudio ha cobrado gran importancia en los últimos años en el ámbito médico, pues se ha demostrado que la IR conduce al desarrollo de un “síndrome de insulinorresistencia” (SIR), que comprende un conjunto de alteraciones metabólicas (hiperinsulinismo, obesidad visceral, hipertensión arterial sistólica y diastólica y dislipidemia). Todas estas alteraciones son factores de riesgo conocidos de enfermedad cardiovascular, siendo ésta una de las principales causas de morbilidad y mortalidad a nivel mundial. Fue Reaven quien en 1988 sugirió que la diabetes mellitus, la hipertensión arterial y la dislipemia eran factores que tendían a ocurrir en un mismo individuo en la forma de un síndrome, al que denominó “X”, en el que la IR constituía el mecanismo fisiopatológico básico.El incremento en la incidencia de enfermedades como la diabetes tipo 2, enfermedad cardiovascular y obesidad, es producido en muchos casos, por el aumento en la prevalencia de IR en la población, lo que podría atribuirse, en parte, a los cambios en el estilo de vida que ha experimentado la sociedad occidental a lo largo de las últimas décadas.

Insulin resistance (IR) is a decrease of the biological function of this hormone characterized by a high level of plasmic insulin which is required for the metabolic homeostasis.It is estimated that approximately 25% of people have IR. Its’ study has acquired great importance in the last years, because it has been demonstrated to lead to an insulin resistance syndrome (IRS), which includes various metabolic disorders: hiperinsulinesm, visceral obesity, systolic and diastolic hypertension, dislipidemia. All these alterations are well known to be risk factors for coronary heart disease, constituting one of the main causes of morbimortality worldwide.It was reaven who suggested in 1988, that diabetes mellitus, arterial hypertension and dislipidemia are factors which tended to occur in this the same individual as a syndrome, which he demonstrated “X”, where the IR constituted the basic fisiopathological mechanism.The increase in the incidence of diseases such as DM2, cardiovascular disease, and obesity is due mainly, to the increase in the prevalence of IR among the population, which could be attributed to the life style changes experimented by the occidental society during the last decades.