Tendencia y distribución municipal de la incidencia de cáncer de vejiga en el área de salud de León (1996-2010) / Municipal distribution and trends in bladder cancer incidence in health area of León, Spain (1996-201

Objetivo: España presenta unas de las tasas más elevadas de incidencia y mortalidad por cáncer de vejiga del mundo. El presente estudio tiene por objeto conocer la incidencia, tendencia y distribución geográfica del cáncer de vejiga en el área de salud de León. Material y métodos: Fueron incluidos los casos nuevos de cáncer de vejiga (CIE-188) del registro hospitalario de tumores del Centro Asistencial Universitario de León, entre 1996-2010 con residencia en el ASL. Se calcularon las incidencias brutas trienales y ajustadas a población mundial y europea. Como denominador se utilizaron los datos del INE de población desagregada por sexo y grupos quinquenales de edad de residentes en municipios del ASL. Para el análisis de la distribución espacial se estimaron los riesgos relativos (RR) municipales suavizados mediante el ajuste del modelo de Besag, York y Mollié y sus probabilidades posteriores de que los RR fuesen > 1 (PP), utilizando métodos bayesianos. Resultados: Se incluyeron 1.573 casos. Las tasas estandarizadas a población europea ascendieron de 20,8 (1996-98) a 33,1 (2006-2008) casos nuevos por 100.000 hombres y de 1,9 a 5,9 en las mujeres. No se observaron diferencias de interés en la distribución municipal de las incidencias. Conclusiones: Las tasas de incidencia observadas son elevadas en el contexto europeo. Se observan tendencias ascendentes en hombres y especialmente relevantes en mujeres

Objective: Spain is a country where bladder cancer incidence and mortality rates are some of the highest in the world. The aim of this study is to know the incidence, trends and geographical distribution of bladder cancer in the health area of León. Material and methods: the new cases of bladder cancer (CIE-188) in patients residing in the health area of León and registered in the Hospital Tumor Registry of the Centro Asistencial Universitario in León (Spain) between 1996-2010 were included in this study. Triennial crude incidence and adjusted incidence rates to the worldwide and European population were calculated. Population data of the municipalities of Leon (Spain) were obtained from National Institute of Statistic of Spain (INE, Instituto Nacional de Estadística). Data were disaggregated by sex-groups and five-year age groups. Spatial distribution of smoothed municipal relative risks (RR) of bladder cancer was carried out using a Besag, York and Mollié model. Bayesian model were used to calculate the posterior probability (PP) of RR greater than one. Results: 1.573 cases were included. Incidence rates standardized to European population increased among men from 20,8/100.000 (1996-98) to 33,1/100.000 (2006-2008) and among women these rates increased from 1,9/100.000 to 5,9/100.000 for the same period of time. No relevant differences were found in the municipal distribution of the incidences. Conclusions: bladder cancer incidence rates are high in the European context. Rising trends in incidence in both sexs, particularly in women are observed

Municipal distribution and trends in bladder cancer incidence in health area of León, Spain (1996-2010).

OBJECTIVE: Spain is a country where bladder cancer incidence and mortality rates are some of the highest in the world. The aim of this study is to know the incidence, trends and geographical distribution of bladder cancer in the health area of León. MATERIAL AND METHODS: the new cases of bladder cancer (CIE-188) in patients residing in the health area of León and registered in the Hospital Tumor Registry of the Centro Asistencial Universitario in León (Spain) between 1996-2010 were included in this study. Triennial crude incidence and adjusted incidence rates to the worldwide and European population were calculated. Population data of the municipalities of Leon (Spain) were obtained from National Institute of Statistic of Spain (INE, Instituto Nacional de Estadística). Data were disaggregated by sex-groups and five-year age groups. Spatial distribution of smoothed municipal relative risks (RR) of bladder cancer was carried out using a Besag, York and Mollié model. Bayesian model were used to calculate the posterior probability (PP) of RR greater than one. RESULTS: 1.573 cases were included. Incidence rates standardized to European population increased among men from 20,8/100.000 (1996-98) to 33,1/100.000 (2006-2008) and among women these rates increased from 1,9/100.000 to 5,9/100.000 for the same period of time. No relevant differences were found in the municipal distribution of the incidences. CONCLUSIONS: bladder cancer incidence rates are high in the European context. Rising trends in incidence in both sexs, particularly in women are observed.

Distinct genomic aberration patterns are found in familial breast cancer associated with different immunohistochemical subtypes.

Five breast cancer subtypes have been described in sporadic breast cancer (SBC) using expression arrays: basal-like, ERBB2, normal breast-like, luminal A and B. These molecular subtypes show different genomic aberration patterns (GAPs). Recently, our group described these breast cancer subtypes in 50 non-BRCA1/2 familial tumors using immunohistochemistry assays. We extended this study to the other classes of familial breast cancer (FBC), including 62 tumors (18 BRCA1, 16 BRCA2 and 28 non-BRCA1/2), with the same panel of 25 immunohistochemical (IHC) markers and histological grade obtaining a similar classification. We combined these data with results generated by a 1 Mb BAC array-based CGH study to evaluate the genomic aberrations of each group. We found that BRCA1-related tumors are preferentially basal-like, whereas non-BRCA1/2 familial tumors are mainly luminal A subtype. We described distinct GAPs related to each IHC subtype. Basal tumors had a greater number of gains/losses, while luminal B tumors had more high-level DNA amplifications. Our data are similar to those obtained in SBC studies, highlighting the existence of distinct genetic pathways of tumor evolution, common to both SBC and FBC.

Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer.

Testosterone is essential for the growth and function of the luminal prostate cells, but it is also critical for the development of prostate cancer, which in the majority of the cases derives from luminal cells. Cytochrome P450 3A (CYP3A) enzymes hydroxylate testosterone and dehydroepiandrosterone to less active metabolites, which might be the basis for the association between CYP3A polymorphisms and prostate cancer. However, it is unknown whether the CYP3A enzymes are expressed at relevant levels in the prostate and which polymorphisms could affect this tissue-specific CYP3A activity. Thus, we measured CYP3A4, CYP3A5, CYP3A7, and CYP3A43 mRNA in 14 benign prostatic hyperplasias and ten matched non-tumoral/tumoral prostate samples. We found that CYP3A5 mRNA in non-tumoral prostate tissue was 10% of the average amount of liver samples, whereas the expression of the other CYP3A genes was much lower. Similarly to liver, CYP3A5*3 polymorphism decreased CYP3A5 mRNA content 13-fold. CYP3A5 protein was detected in non-tumoral prostate microsomes by western blot, and immunohistochemistry (IHC) localized CYP3A5 exclusively in the basolateral prostate cells. In contrast to the normal tissue, IHC and RT-PCR showed that tumoral tissue lacked CYP3A5 expression. In conclusion, prostate basolateral cells express high levels of CYP3A5 which dramatically decrease in tumoral tissue. This finding supports an endogenous function of CYP3A5 related to the metabolism of intra-prostatic androgens and cell growth, and that polymorphisms affecting CYP3A5 activity may result in altered prostate cancer risk and aggressiveness.

Classification of missense variants of unknown significance in BRCA1 based on clinical and tumor information.

Classification of rare missense variants in disease susceptibility genes as neutral or disease-causing is important for genetic counseling. Different criteria are used to help classify such variants in BRCA1 and BRCA2; however, the strongest evidence tends to come from segregation analysis and observed cooccurrence with known pathogenic mutations, which both require information that is not readily available in most circumstances. A likelihood-based model has been developed, integrating most of the data currently used to classify these variants. We have adapted the original model, including only that information that could be more easily obtained from a cancer genetics laboratory, such as loss of heterozygosity (LOH), grade, and immunohistochemical analysis to assess estrogen receptor (ER) status for the tumors of carriers of these variants. We also considered summary family history (personal or first-degree family history of bilateral breast or ovarian cancer), which was not incorporated into the original model. To test the ability of the modified model to classify missense variants in BRCA1, we analyzed 17 variants, of which 10 have previously been classified as pathogenic mutations or neutral polymorphisms. We also included a prior step consisting of the screening of the variants among 1,000 controls, with which we were able to classify five as neutral, based solely on their observed frequency. We found that combining this relatively easily collected information can be sufficient to classify variants as pathogenic or neutral if tumors from at least three carriers of the same variant can be collected and analyzed.

Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations.

Tumors arising in BRCA1 and BRCA2 mutation carriers appear to have specific pathological and gene expression profiles, which show a high level of concordance. BRCA1 tumors are high-grade, negative for hormone receptors, have a high proliferation rate, and are positive for some cell cycle promoter genes. BRCA2 tumors present a phenotype opposite to BRCA1 tumors but very similar to sporadic tumors, except that BRCA2 overexpress some DNA repair markers such as CHEK2, show high cytoplasmic expression of RAD51, and are negative for HER-2 amplification and expression. Some of these characteristics have also been found in cDNA expression studies, although more analysis are necessary in order to obtain new markers that can be associated with a germ line mutation in BRCA1 or BRCA2. In this way, some studies in normal tissues of BRCA1/2 carriers suggest that differences exist in the level of expression of some genes when compared with noncarriers. Finally, IHC studies in tumors carrying a mutation in CHEK2 are rare and show contradictory results, probably due to the low number of these cases. However, they represent an example showing how different mutations of the same gene may be associated with specific histological subtypes of cancer.

Differential expression of NF-kappaB pathway genes among peripheral T-cell lymphomas.

Nuclear factor kappa B (NF-kappaB) is one important pathway in T-cell proliferation and survival. In a previously reported microarray study, we found NF-kappaB pathway genes differentially expressed between peripheral (PTCL) and lymphoblastic lymphomas. Here, we investigated the expression of NF-kappaB pathway genes using cDNA microarrays in a group of 62 PTCL and in reactive lymph nodes. We found two different subgroups of PTCL based on the expression of NF-kappaB pathway genes. One-third of PTCL showed clearly reduced expression of NF-kappaB genes, while the other group was characterized by high expression of these genes. This distinction was found among all T-cell lymphoma categories analyzed (PTCL unspecified, angioimmunoblastic, cutaneous and natural killer/T lymphomas) with the exception of anaplastic lymphomas (ALCL), which were characterized by reduced NF-kappaB expression in anaplastic cells. Quantitative RT-PCR and immunohistochemical analysis of NF-kappaB-p65 protein confirmed these differences among PTCL subgroups. Importantly, we found that differentiation between NF-kappaB-positive and -negative PTCL could be of clinical interest. The expression profile associated to reduced expression of NF-kappaB genes was significantly associated with shorter survival of patients and seems to be an independent prognostic factor in a multivariate analysis.

TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma.

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.

Cost-effectiveness analysis of artesunate and quinine + tetracycline for the treatment of uncomplicated falciparum malaria in Chanthaburi, Thailand.

A randomized, controlled, malaria-clinic-based field trial was carried out to compare the cost-effectiveness of a 5-day 700-mg oral artesunate and a 7-day quinine + tetracycline regimen for the treatment of uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based on curative effectiveness. A total of 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days, 60 of them received quinine + tetracycline and 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine + tetracycline), using the intention-to-treat approach. Cost-effectiveness and sensitivity analyses were performed by varying the day 5/day 7 curative effectiveness and cost of artesunate. The cure rate with artesunate (100%) was significantly higher than with quinine + tetracycline (77.4%) (relative risk adjusted for sex (aRR) = 1.32, 95% confidence interval (CI) = 1.12-1.55; referent quinine + tetracycline). Artesunate was more cost-effective than quinine + tetracycline at the following costs: artesunate, < or = US$0.36 per 50-mg tablet; quinine, US$0.06 per 300-mg tablet; tetracycline, US$0.02 per 250-mg capsule; and services per case found, < or = US$11.49. Because of the higher cure rate and higher cost-effectiveness of the artesunate regimen compared with quinine + tetracycline, we recommend its use for the treatment of uncomplicated falciparum malaria in malaria clinics in Thailand.

PIP: Findings are presented from a randomized, controlled, malaria clinic-based field trial conducted to compare the cost-effectiveness of a 5-day 700 mg oral artesunate and a 7-day quinine and tetracycline regimen to treat uncomplicated falciparum malaria in Thailand. Cost-effectiveness was determined from the providers' perspective and based upon curative effectiveness. 137 patients, aged 15-60 years, attending a malaria clinic were followed for 28 days. 60 received quinine and tetracycline, while 77 received artesunate. Cure rates were assessed on day 5 (artesunate) and day 7 (quinine and tetracycline). The cure rate with artesunate was 100%, significantly higher than the 77.4% rate with quinine and tetracycline. Artesunate was more cost-effective than quinine and tetracycline, with artesunate costing a maximum of US$0.36 per 50 mg tablet, quinine at US$0.06 per 300 mg tablet, tetracycline at US$0.02 per 250 mg capsule, and services per case found no higher than US$11.49.

Compliance with artesunate and quinine + tetracycline treatment of uncomplicated falciparum malaria in Thailand.

A randomized, controlled, malaria-clinic-based field trial was conducted to compare compliance with a 7-day quinine + tetracycline regimen and a 5-day 700-mg artesunate regimen for the treatment of uncomplicated falciparum malaria in a community in Thailand. Of 137 patients, aged 15-60 years attending a malaria clinic, 77 received artesunate and 60 received quinine + tetracycline. Compliance and cure rates were evaluated on days 5 (artesunate) and 7 (quinine + tetracycline) using patient interview/residual pill counts and peripheral blood smear, respectively. Data were analysed using the intention-to-treat approach, and the reasons for compliance and noncompliance were investigated. Compliance was significantly higher (98.4%) with artesunate than with quinine + tetracycline (71.7%) (relative risk adjusted for sex (aRR) = 1.39 (95% C.I. = 1.15-1.68); referent: quinine + tetracycline). Cure rate (100%) was higher in those receiving artesunate than quinine + tetracycline (77.4%) (aRR = 1.32 (95% C.I. = 1.12-1.55)). Reasons for compliance included the desire to be cured and to follow the advice of malaria staff/employer, and the simple dosing regimen. Noncompliance was mostly due to adverse reactions and forgetting to take the drugs. These results can serve as a baseline for designing and evaluating new interventions to improve compliance, as well as for studying cost-effectiveness to help drug policy decision-making. We recommend a strategy which integrates a short-course, once-a-day regimen (with minimal adverse reactions), a better delivery system for antimalarial drugs and health education, and an enhanced advisory role of malaria staff. Considering the higher compliance rate and curative effectiveness of artesunate, we recommend its use instead of quinine + tetracycline for the treatment of uncomplicated malaria in clinics in Thailand.