Controversies in the treatment of RAS wild-type metastatic colorectal cancer

Objective To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice. Methods Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement). Results Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus. Conclusions This document aims to describe the expert’s attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC (AU)

Biomarkers and intermediate-high risk non-muscle invasive bladder cancer: a multivariate analysis of three different cellular pathways with pronostic implications

Purpose To determine the presence of a group of mutations, and establish the prognostic value for recurrence and progression. Materials and methods Prospective observational study. Intermediate-to-high-risk non-muscle invasive bladder cancer (NMIBC) was evaluated. Data from genetic analyses were included in a database along with clinicopathological variables of interest. Results Seventy-four patients. Twenty-five (33.8%) recurred and 3 (4.1%) progressed. Median time to recurrence: 8 months (5.7–12.7). Median time to progression: 14 months (P75: 12). Mutation distribution: KRAS codon 12: one patient (1.4%), BAT25: five patients (6.8%), BAT-26: four patients (5.4%), and D2S123: 6 patients (8.1%). Arg72Pro polymorphism: 50 patients (67.6%) exhibited homozygous mutations, 23 (31.1%) were heterozygous, and 1 patient (1.4%) did not present the mutation. We found an association between presence of MSI at BAT26 and female sex (p < 0.05) and tumor stage and the TP53 Arg72Pro polymorphism. Recurrence-free survival (RFS) was significantly associated with presence of MSI at D2S123, with a HR of 5.44 for patients presenting the mutation (95% CI 1.83–16.16). On multivariate analysis, we found a statistically significant increase in risk of recurrence among patients with MSI at D2S123 (HR 5.15; p < 0.05) and more than 2 previous transurethral bladder resections (TURBs) (HR 5.07; p < 0.05) adjusted for tumor stage and grade. Harrell’s concordance index revealed an accuracy of 0.74 (p < 0.05). Conclusion An association was found between presence BAT26 MSI and female sex, Arg72Pro polymorphism with tumor stage and D2S123 and more than 2 TUR procedures were associated with RFS adjusted to tumor stage and grade (AU)

RIT1: un nuevo gen causal del síndrome de Noonan / RIT1: a novel gene associated with Noonan syndrome

Introducción. El síndrome de Noonan es el más frecuente del grupo de los síndromes malformativos congénitos originados por mutaciones germinales en genes de la vía RAS/MAPK, denominados genéricamente RAS-opatías, uno de los grupos más comunes de alteraciones genéticas congénitas en la práctica clínica. Recientemente se han descrito mutaciones en el gen RIT1 en pacientes con síndrome de Noonan. Caso clínico. Niña de 7 años con diagnóstico clínico de síndrome de Noonan, que entre sus manifestaciones clínicas incluye miocardiopatía hipertrófica, en la que se ha identificado una mutación de novo en heterocigosis, en RIT1, c.295T>C (p.Phe99Leu), no descrita previamente, probablemente causal. Conclusiones. RIT1 comparte homología con otras proteínas RAS y la expresión de alelos mutantes origina un efecto de ganancia de función que apoya su papel causal en el síndrome de Noonan. Podemos estimar actualmente que es responsable de un 3-5% de los casos del síndrome. Estos casos con síndrome de Noonan, respecto a los que presentan mutaciones en otros genes, se caracterizan por una mayor frecuencia de alteraciones prenatales, alta frecuencia de miocardiopatía hipertrófica y menor frecuencia de talla baja y deformidad torácica. Destaca la importancia de incorporar los nuevos genes identificados en los paneles diagnósticos (AU)

Introduction. Noonan syndrome is the most frequent of the congenital group of malformation syndromes caused by germline mutations that encode components of the RAS/MAPK pathway, termed RASopathies, one of the most frequent congenital genetic disorders in the clinical practice. Recently RIT1 mutations have been reported in patients with Noonan syndrome. Case report. A 7 years-old girl with a clinical diagnosis of Noonan syndrome, and with a hypertrophic cardiomyopathy included in her clinical manifestations, where a de novo heterozygous, probably pathogenic, novel mutation in RIT1, c.295T>C (p.Phe99Leu), has been identified. Conclusions. RIT1 shares homology with other RAS proteins and the expression of mutant alleles demonstrates a gain-offunction effect supporting a causative role in Noonan syndrome pathogenesis. Data suggest that the frequency of RIT1 mutations can be estimated as 3-5% in Noonan syndrome patients. These cases compared with Noonan patients harboring mutations in other genes are characterized by high frequency of prenatal abnormalities and hypertrophic cardiomyopathy, and lower frequencies of short stature and pectus abnormalities. We emphasize the importance of the novel identified genes in order to be included in the diagnostic panels (AU)

Prognostic importance of RASSF2 expression in patients with gastric cancer who had undergone radical gastrectomy

Background: Although Ras-association domain family of gene 2 (RASSF2) has been shown to undergo promoter methylation at high frequency in some cancer types and in brain metastases, its clinical utility as a useful prognostic molecular marker remains unclear in gastric cancer. Methods: Prognostic significance of RASSF2 expression was retrospectively analysed by immunohistochemically in 105 patients with gastric cancer who underwent curative gastrectomy. Results: Low RASSF2 expression was detected in 58 (55 %) patients, whereas 47 patients (45 %) had high RASSF2 expression. Lymph node involvement, pT stage, TNM stage, vascular invasion, perineural invasion and the presence of recurrence were found to be significantly related to RASSF2 expression levels. Low PRL-3 expression was closely correlated with lymph node metastasis (p = 0.001), advanced pT stage (p = 0.021), advanced TNM stage (p < 0.001), the presence of vascular invasion (p < 0.001), perineural invasion (p = 0.018) and high prevalence of recurrence (p = 0.003) compared with high RASSF2 expression. The median disease-free survival (DFS) time for patients with low RASSF2 expression was significantly worse than that of patients with high RASSF2 expression (10.2 vs. 50.6 months, p < 0.001). In addition, patients with high RASSF2 expression had the higher overall survival (OS) interval compared to patients with low RASSF2 expression (NR vs. 14.9 months, p < 0.001). In the multivariate analysis, the rate of RASSF2 expression levels was an independent prognostic factor, for DFS [p < 0.001, HR 0.12 (0.10-0.88)] and OS [p < 0.001, HR 0.10 (0.04-0.46)], as were pT stage and TNM stage, respectively. Conclusions: RASSF2 may be an important molecular marker for carcinogenesis, prognosis and progression in gastric cancer, but the potential value of RASSF2 expression as a useful molecular marker in gastric cancer progression should be evaluated, comprehensively. It would be possible to develop treatments targeting RASSF2 and advance new treatment strategies for gastric cancer

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RAS status in Korean patients with stage III and IV colorectal cancer

Background. KRAS mutations are common and clearly contribute to malignant progression. The frequency of NRAS mutations and their relationship to clinical, pathologic, and molecular features remains unclear. Methods. We evaluated 130 colorectal tumors for mutations in KRAS and NRAS gene. We tested for mutations in codons 61 and 146 of KRAS and codons 12, 13, 59, 61 and 146 of NRAS. Mutation status was determined by targeted dideoxy sequencing. Results. Among the analyzed primary tumors, 36.2 % had KRAS mutation. Of the 83 KRAS codon 12 and 13 wild-type patients, 7.2 % had KRAS codon 61, 146 or NRAS. 40.7 % harbored any RAS mutation. Conclusion. The frequency of other RAS (NRAS and KRAS exon 3, 4) activating mutations in colorectal cancers is relatively low in Korean colorectal cancer patients (AU)

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Exposición laboral a hidrocarburos clorados y cáncer de páncreas: revisión de la bibliografía reciente / Occupational exposure to chlorinated hydrocarbons and pancreatic cancer: review of recent literature

La proporción de cáncer de páncreas que puede atribuirse a exposiciones laborales es aproximadamente 12%, aunque representan un pequeño porcentaje, estos factores pueden ser prevenibles, siendo importante identificarlos. Algunas ocupaciones se han relacionado con el aumento de riesgo de cáncer de páncreas, y al parecer habría una asociación estadísticamente significativa para la exposición a hidrocarburos clorados u organoclorados. Objetivo: Revisar la literatura científica reciente, buscando evidencias sobre la relación entre la exposición laboral a organoclorados y cáncer de páncreas. Metodología: Se realizó una búsqueda en las principales bases de datos utilizando descriptores relacionados y aplicando criterios de pertinencia, inclusión y exclusión seleccionándose 10 artículos. Resultados: Se analizaron tres meta-análisis, tres estudios de cohortes y 4 estudios de casos y controles, encontrando una mayor producción bibliográfica entre los períodos 2000-2003 y 2007-2011. Conclusiones: Algunas exposiciones se han relacionado con el exceso de riesgo para el cáncer pancreático, sin embargo en la mayoría de estudios se encuentra un efecto débil o moderado a menudo relacionado con la limitada cantidad de participantes. Los estudios que investigan esta asociación por tipo de ocupación no suelen precisar los agentes específicos a los que se encuentra expuesto el trabajador, dificultando establecer asociaciones concretas. Es importante seguir estudiando las interacciones genético-ambientales relacionadas como la asociación con el gen K-ras en busca de resultados más concluyentes que permitan avanzar en el campo de la prevención de riesgos laborales

The proportion of pancreatic cancer that can be attributed to occupational exposures is about 12 %, although that is a small percentage, these factors can be prevented and it is important to identify them. Some occupations have been associated with an increased risk of pancreatic cancer, and these apparently have a statistically significant association for exposure to organochlorine or chlorinated hydrocarbons. Objective: To review the recent scientific literature looking for evidence on the relationship between occupational exposure to organochlorines and pancreatic cancer. Methods: A search was conducted in major databases using related descriptors and applying relevance, inclusion and exclusion criteria; finally we selected 10 articles. Results: Three meta- analysis, three cohort studies and four case-control studies were analyzed, finding more bibliographic production between the 2000-2003 and 2007-2011 periods. Conclusions: Some exposures have been associated with increased risk for pancreatic cancer, but in most studies the effect is weak or moderate, often associated with the limited number of participants. Studies that investigate the association by type of occupation do not usually determine specific agents to which the worker is exposed, making it difficult to establish specific associations. It is important to continue studying gene-environment interactions related to the association with K-ras gene in search of more conclusive results that advance the field of prevention of occupational hazards

Diacylglycerol kinase n modualtes oncogenic properties of lung cancer cells

PURPOSE: Lung cancer is a leading cause of cancer deaths and efforts are underway to identify novel therapies to treat these tumors. Diacylglycerol kinase η (DGKη), an enzyme that phosphorylates diacylglycerol to form phosphatidic acid, has been shown to modulate MAPK signaling downstream of EGFR, which is an oncogenic driver in some lung cancers. Since mutations in EGFR and K-Ras are common in lung cancer, we hypothesized that limiting the function of DGKη would attenuate oncogenic properties of lung cancer cells. METHODS: We determined the expression levels of DGKη in a mouse models of mutant EGFR and K-Ras lung cancer and in human lung cancer cell lines with activating mutations in either EGFR or K-Ras. We also tested the effects of shRNA-mediated depletion of DGKη in lung cancer cells and tested if DGKη depletion augmented the effects of afatinib, a new generation EGFR inhibitor. RESULTS: DGKη was expressed in malignant epithelium from mice with mutant EGFR or K-Ras lung cancer. It was also expressed in human lung cancer cell lines with EGFR or K-Ras mutations. Depleting DGKη in lung cancer cell lines, harboring mutant EGFR, reduced their growth on plastic and in soft agar and also augmented the effects of afatinib, an EGFR inhibitor. DGKη depletion also reduced growth of one of two lung cancer cell lines that harbored mutant K-Ras. CONCLUSIONS: Our data indicate that DGKη is a potential therapeutic target in lung cancers, especially those harboring EGFR mutations. Our findings warrant further studies to examine the effects of limiting its function in vivo (AU)

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Síndrome LEOPARD: una variante del síndrome de Noonan con fuerte asociación a miocardiopatía hipertrófica / LEOPARD syndrome: a variant of noonan syndrome strongly associated with hypertrophic cardiomyopathy

Introducción y objetivos. El síndrome LEOPARD es una enfermedad autosómica dominante relacionada con el síndrome de Noonan, aunque menos conocida. El objetivo del presente estudio es describir las características clínicas y moleculares de una serie amplia de pacientes con síndrome LEOPARD. Métodos. Se obtuvieron datos clínicos de 19 pacientes procedentes de 10 hospitales. Se estudiaron los genes PTPN11, RAF1 y BRAF mediante secuenciación bidireccional de los exones más recurrentes. Resultados. Tras las dismorfias faciales, la principal característica descrita es la cardiopatía congénita (88%). La más frecuente es la miocardiopatía hipertrófica (71%), por delante de la estenosis pulmonar (35%). Se describió lentiginosis múltiple o manchas café con leche en un 84% y sordera en 3 pacientes; 16 pacientes (84%) portaban mutación en PTPN11 (en 10 de ellos, la mutación recurrente en el síndrome LEOPARD, p.Thr468Met) (NP_002825.3). En otros 2 pacientes se identificó mutación en RAF1 y 1 solo en BRAF. En comparación con otros síndromes neurocardiofaciocutáneos, los pacientes con LEOPARD tienen mayor prevalencia de miocardiopatía hipertrófica y lesiones cutáneas y menor prevalencia de estenosis pulmonar y talla baja. Conclusiones. El síndrome LEOPARD presenta algunas características distintivas además de la lentiginosis múltiple, como son la mayor frecuencia de miocardiopatia hipertrófica y menor prevalencia de talla baja. Dadas las potenciales implicaciones clínicas de la miocardiopatía hipertrófica, se debe buscar activamente en los pacientes del espectro clínico del síndrome de Noonan, y muy especialmente en aquellos con síndrome LEOPARD (AU)

Introduction and objectives. LEOPARD syndrome is an autosomal dominant condition related to Noonan syndrome, although it occurs less frequently. The aim of this study was to characterize the clinical and molecular features of a large series of LEOPARD syndrome patients. Methods. We collected clinical data from 19 patients in 10 hospitals. Bidirectional sequencing analysis of PTPN11, RAF1, and BRAF focused on exons carrying recurrent mutations. Results. After facial dysmorphism, structural heart defects (88%) were the most common feature described. Hypertrophic cardiomyopathy (71%) was diagnosed more often than pulmonary valve stenosis (35%). Multiple lentigines or café au lait spots were found in 84% of the series, and deafness was diagnosed in 3 patients. Mutations in PTPN11 were identified in 16 (84%) patients (10 patients had the recurrent LEOPARD syndrome mutation, p.Thr468Met) (NP_002825.3T468M). Two other patients had a mutation in RAF, and 1 patient had a mutation in BRAF. When compared with other neurocardiofaciocutaneous syndromes, LEOPARD syndrome patients showed a higher prevalence of hypertrophic cardiomyopathy and cutaneous abnormalities, and a lower prevalence of pulmonary valve stenosis and short stature. Conclusions. LEOPARD syndrome patients display distinctive features apart from multiple lentigines, such as a higher prevalence of hypertrophic cardiomyopathy and lower prevalence of short stature. Given its clinical implications, active search for hypertrophic cardiomyopathy is warranted in Noonan syndrome spectrum patients, especially in LEOPARD syndrome patients (AU)

Metástasis orbitarias en carcinoma colorrectal: a propósito de un caso / Orbital metastases in colorectal cancer: a case report

Caso clínico: Varón, 32 años, con neoplasia de colon en estadio IV, resistente a tratamiento quimioterápico. Es referido a nuestro servicio por edema palpebral, quemosis conjuntival, exoftalmos severo no reductible y ptosis completa en el ojo izquierdo, así como limitación de la motilidad ocular en todas las posiciones de la mirada, de predominio en mirada lateral y supraversión. En RMN orbitaria observamos dos lesiones nodulares en la órbita izquierda, con afectación del complejo músculo recto superior-elevador del párpado y músculo recto externo, sugestivas de metástasis. Debido al mal estado general del paciente, que no permite radioterapia, se inician bolos de corticoides intravenosos, sin respuesta, falleciendo el paciente. Discusión: Las metástasis orbitarias suelen proceder de tumores de mama y pulmón, siendo las secundarias a carcinoma de colon muy infrecuentes. El tratamiento es paliativo, basado en corticoides intravenosos, y sobre todo, radioterapia, y, tan solo en casos de supervivencia más prolongada, cirugía(AU)

Clinical case: A 32-year-old male, with colon cancer stage IV, resistant to chemotherapy, was referred to our department due to palpebral oedema, conjunctival chemosis, severe exophthalmos, complete ptosis in left eye, and limitation in eye movements, mainly in abduction and supraversion. In the orbital MR scan we observed two nodular lesions in the left orbital, with involvement of the superior rectus-elevator muscle of upper eyelid complex and external rectus muscle, suggestive of metastases. Due to the patient generally feeling unwell, radiotherapy was not considered, and an intravenous bolus of corticoids was given, without response, resulting in the death of the patient. Discussion: Orbital metastases usually originate from breast and lung cancer, with those secondary to colon cancer being much less frequent. The treatment is palliative, based on intravenous corticoids, and, above all, radiotherapy, and, only in cases with a long-term survival, surgery(AU)

Rasopatías: trastornos del desarrollo con predisposición al cáncer y manifestaciones cutáneas / Rasopathies: Developmental Disorders That Predispose to Cancer and Skin Manifestations

Las proteínas de la vía RAS/MAPK (mitogen activated protein kinase pathway) desempeñan un papel fundamental en la proliferación, diferenciación, supervivencia y muerte celular. Desde hace más de 30 años se sabe que el 30% de los cánceres humanos presentan una mutación somática en alguno de los genes que codifican estas proteínas. En contraste con el elevado potencial de malignidad de las mutaciones somáticas, las mutaciones en la línea germinal provocan anomalías en el desarrollo del individuo que, si bien dependen específicamente del gen afectado, a menudo se superponen clínicamente. Así, todos los pacientes comparten un grado variable de retraso mental o dificultades de aprendizaje, trastornos cardiacos, dismorfismo facial, anomalías cutáneas y, en algunas instancias, predisposición al cáncer. Entre estos síndromes, conocidos como rasopatías, se incluyen el síndrome de Noonan, el síndrome de Costello, la neurofibromatosis 1, el síndrome LEOPARD, el síndrome cardio-facio-cutáneo y el síndrome de Legius. Es interesante conocer las manifestaciones cutáneas de las rasopatías, ya que estas pueden ayudar a esclarecer el diagnóstico de la enfermedad (AU)

Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes (AU)

Biomarkers in bronchopulmonary cancer

Non-small-cell lung cancer (NSCLC) ranks among the neoplasms with the worst prognoses and the highest mortality rates. Several factors, mainly clinical, are known that provide a predictive value on the course of the disease. In the era in which we live, the molecular basis of cancer is studied in depth and several molecular markers have been described that could play a prognostic role or that could predict the probability of responding to the different treatments used. Moreover, some mechanisms have been proposed that could explain primary or acquired resistance to treatment with chemotherapy and to targeted therapies. Knowing all these pathways is very important, as it allows the development of selective therapeutic strategies that minimise toxicity and optimise treatment effectiveness. However, the data obtained yield results that are at times contradictory, prospective studies with biomarkers thus being necessary so that their role can be established with the necessary evidence (AU)

Inhibiting PI3K as a therapeutic strategy against cancer

Class I PI3K is composed of heterodimeric lipid kinases regulating essential cellular functions including proliferation, apoptosis and metabolism. Class I PI3K isoforms are commonly amplified in different cancer types and the PI3Kalpha catalytic subunit, PIK3CA, has been found mutated in a variable proportion of tumours of different origin. Furthermore, PI3K has been shown to mediate oncogenic signalling induced by several oncogenes such as HER2 or Ras. These facts suggest that PI3K might be a good target for anticancer drug discovery. Today, the rise of PI3K inhibitors and their first in vivo results have cleared much of the path for the development of PI3K inhibitors for anticancer therapy. Here we will review the PI3K pathway and the pharmacological results of PI3K inhibition (AU)

EGFR and colon cancer: a clinical view

Signalling pathways that emerge from EGFR activation are critical in colon cancer (CC) biology. Its targeting with specific drugs has opened a new window in the treatment of this disease. In this regard, monoclonal antibodies (mAb) have evidenced a high degree of efficiency opposed to the uselessness of tyrosine-kinase inhibitors. Cetuximab is the mAb that has evidenced most activity in CC. After its initial approval as an irinotecan-resistance reversal agent, cetuximab has demonstrated its efficiency from the first line to heavily pretreated patients. In the first line, its addition may increase response rate to chemotherapy, improving liver metastases resection rate. Another promising approach has been suggested from combination schedules with bevacizumab. Panitumumab has been recently approved for CC. Although there is limited clinical experience, the latest data have confirmed its activity in heavily pretreated patients resulting in a clinical benefit vs. best support care. In spite of the clinical benefits, adverse events and the high sanitary cost derived from these drugs force the selection of patients with the highest probability of benefit. At the moment, when EGFR expression evidenced by immunohistochemistry has no value, skin toxicity and, fundamentally, K-Ras mutations may hint at critical information for confirmatory prospective studies (AU)

Los oligonucleótidos antisentido y el diseño racional de nuevos fármacos antitumorales / Antisense oligonucleotides and the rational design of new antitumor drugs

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Eficacia de la terapia génica antisentido utilizando oligonucleótidos anti K-ras y antitelomerasa en cáncer colorrectal / Antisesnse gene therapy using anti-k-ras and antitelomerase oligonucleotides in colorectal cancer

Objetivo: evaluar la eficacia de oligonucleótidos anti k-ras yantitelomerasa para detener el crecimiento tumoral en el cáncercolorrectal.Material y métodos: se ha empleado una línea celular establecidade cáncer colorrectal humano (SW 480, ATTC®). Los oligodesoxirribonucleótidos(ODN) utilizados en el presente trabajo presentanmodificación fosforotioato con el fin de mejorar su estabilidad enpresencia de fluidos biológicos. Hemos utilizado un ODN antitelomerasa(Telp5), y dos ODN anti k-ras (AS-KRAS e ISIS). AS-KRAS actúaen el exón 1 e ISIS actúa a nivel de la unidad terminal de transcripción5’ del oncogen k-ras. Telp5 se une a la subunidad hTR de latelomerasa. Se han aplicado en concentraciones 1, 5, 10 y 20 micromolar,midiendo la viabilidad celular a las 48 y 72 horas de tratamiento.El análisis estadístico y el diseño de los gráficos se han realizadomediante el programa “Analyzing Data with GraphPadPrism-1999”. GraphPad Sofware Inc., San Diego CA©. Para el tratamientoestadístico se ha utilizado el test t de Student.Resultados: la dosis mínima (1 µM) no fue efectiva ni a 48 nia 72 horas postratamiento. Con la dosis máxima (20 µM durante48 horas) y utilizando la combinación de AS-KRAS y Telp5 obtuvimosuna reducción de la viabilidad celular del 99,67%. El restode resultados fueron intermedios, dependiendo del tipo de oligonucleótidoempleado, la dosis y el tiempo de exposición.Conclusiones: los oligonucleótidos antisentido probados detienenel crecimiento celular en el cáncer colorrectal, siendo larespuesta más eficaz la combinación de ambos y aumentando dichaeficacia con mayor dosis y tiempo de exposición

Aim: to test the efficacy of anti-k-ras and antitelomeraseoligonucleotides for disabling colorectal cancer cell growth.Material and methods: an established human colorectalcancer cell line (SW 480, ATTC®) was used. Oligodeoxiribonucleotides(ODNs) have a phosphorotioate modification to ensureintracellular intake. We used an antitelomerase ODN (Telp5) andtwo anti-k-ras ODNs (AS-KRAS and ISIS). AS-KRAS is designedto join the k-ras oncogene’s exon 1. ISIS links to the terminaltranscription unit 5’ of k-ras. Telp5 joins the template region ofthe hTR telomerase subunit. ODNs have been tested in differentconcentrations (1, 5, 10, 20 micromolar). Cell viability has beentested at 48 and 72 hours. Statistical analysis and graphic designwere made with the statistical package “Analyzing Data withGraphPad Prism-1999”, GraphPad Sofware Inc., San DiegoCA©. We used the Student’s t test for statistical analysis.Results: the lowest dose (1 µM) was not effective. Using thehighest dose (20 µM for 48 hours) of combined AS-KRAS andTelp5 cell viability decreased to 99.67%. The rest of results varieddepending on ODN type, dose, and exposure time.Conclusions: tested antisense ODNs stop colorectal cancercell growth, and a combination of anti-telomerase and anti-k-ras isthe most useful treatment. Efficacy is best with a higher dose andlonger treatment period

Asociación de carcinoma renal y la exposición a radiaciones ionizantesdespués del accidente de Chernobyl / Association of renal cell carcinoma and radiation exposure after the Chernobyl accident

Después del accidente nuclear de Chernobyl, en la población de zonas contaminadas la incidencia de carcinoma renal se incrementó de 4,7 a 7,5 por 100.000 habitantes. La elevada concentración corporal de Cesium 137 (137Cs) así como su eliminación por vía renal los convierte en pacientes de alto riesgo. Presentamos un caso de una paciente, residente en la zona contaminada que acudió a nuestro hospital por dolor abdominal y sensación de masa en flanco izquierdo. Realizamos una revisión de la literatura y analizamos el manejo en este tipo de pacientes (AU)

After the nuclear accident of Chernobyl, in the population of zones contaminated the malignant renal tumors was increased from 4,7 to 7,5 per 100.000 of total population. Cesium 137 (137Cs) constitutes 80- 90% of the internal exposure of these people as well as eliminated through kidneys becomes an important risk factor. We present a case of a patient, residing in radiocontamined area, who consulted for abdominal pain and left flank mass. We review relevant literature and the management of these patients (AU)

Expresión de la proteína p21ras en el adenocarcinoma renal localmente confinado y sus implicaciones pronósticas / Expression of the p21ras protein in the locally confined renal cell carcinoma and prognostic significance

OBJETIVO: La proteína p21ras es codificada por los tres genes de la familia ras (H-, K- y N-ras), participando en la regulación del crecimiento y la diferenciación celular. El objetivo de este estudio es determinar la expresión de esta proteína en el adenocarcinoma renal localmente confinado, así como sus relaciones con diferentes variables histopatológicas y sus implicaciones pronósticas. MÉTODO: 58 adenocarcinomas renales, estadios pT1-T3a N0 M0 (TNM 1997), tratados mediante nefrectomía radical o parcial con intención curativa. Analizamos diferentes variables clínicas y anatomopatológicas, así como la expresión de p21ras en tejido parafinado, mediante técnicas de inmunohistoquímica. RESULTADOS: El porcentaje medio de núcleos teñidos fue de 6,1 per cent, con un rango comprendido entre 0 y 45 per cent. No obtuvimos asociación estadísticamente significativa de la expresión de p21ras y el tamaño tumoral (p=0,698), el grado nuclear (p=0,676) o el estadio histopatológico (p=0,095). El análisis de supervivencia tampoco demostró diferencias significativas cuando estratificamos a los pacientes utilizando como punto de referencia el valor medio de la muestra (p=0,134). CONCLUSIONES: La expresión de p21ras no ha demostrado relacionarse con ninguna de las variables histopatológicas analizadas; tamaño, grado y estadio, ni con la supervivencia, por lo que esta proteína no parece relacionarse con la evolución del adenocarcinoma renal (AU)

Nuevos compuestos de Trans-platino con aminas alifáticas asimétricas. Citotoxicidad, inducción de apoptosis e inhibición de la sobreexpresión de H-ras / New trasn-platinum compounds with asysmmetric aliphatic amines. Cytotoxicity, apoptosis induction, and inhinition of H-ras overexpresion

Hasta ahora el dogma central de la farmacología bioquímica de los complejos antitumorales de platino del tipo Pt(II)CI2X2 establecía que se necesitaba una configuración cis de los dos grupos salientes CI- para obtener compuestos biológicamente activos. Sin embargo, recientemente se han descubierto complejos de trans-platino que poseen actividad antitumoral tanto in vitro como in vivo. En este trabajo se presentan datos que muestran que ciertos compuestos de Trans-platino con aminas alifáticas asimétricas son activos no solo en células tumorales sensibles a cisplatino (Jurkat, Hela y Vero) sino también en células tumorales resistentes a dicho fármaco que sobreexpresan oncogenes ras (HL-60 y Pam 212-ras). Además, dichos compuestos de trans-platino inhiben la sobreexpresión de Hras e inducen apoptosis. Los resultados indican que los complejos de trans-platino con aminas alifáticas asimétricas pueden considerarse una nueva clase de derivados de platino con actividad citotóxica (AU)