Lesiones detectadas en el programa de cribado de cáncer colorrectal en el País Vasco: primera ronda 2009-2011 / Lesions detected in a colorectal cancer screening program in the Basque Country: first round (2009-2011)

Resumen El cáncer colorrectal (CCR) es un problema importante de salud pública por su incidencia y mortalidad. La comunidad autónoma vasca aprobó en mayo de 2008 la puesta en marcha de un programa de cribado poblacional dirigido a las personas entre 50-69 años con test de sangre oculta en heces (SOH) inmunoquímica y colonoscopia con sedación en los casos positivos. Objetivo Describir los principales resultados del programa de cribado de CCR con SOH en cuanto a tasas de detección y valor predictivo positivo (VPP), primera ronda (2009-11).Metodología Estudio retrospectivo sobre invitaciones realizadas y hallazgos en colonoscopias con SOH positivo. Resultados Se incluyeron 230.505 personas invitadas, 148.249 muestras SOH procesadas. Participación media de 64,3% (IC 95%: 64,1-64,5), superior en mujeres que en hombres. Positividad media de 6,7% (IC 95%: 6,6-6,8) superior en hombres. Colonoscopia realizada al 93,1% de los casos positivos. Se observaron diferencias significativas entre mujeres y hombres en la tasa de de detección de Adenomas de Alto Riesgo (OR: 0,45 IC 95% 0,41-0,49) como en CCR (OR: 0,80 IC 95% 0,66-0,96), más frecuentes en hombres. El VPP para cualquier adenoma fue significativamente superior en hombres (72,4, IC 95% 71,2-73,5) que en mujeres (48,8%, IC 95% 47,2-50,5), con diferencias por grupo de edad y tipo de adenoma. Conclusiones Altas tasas de participación, detección de lesiones avanzadas y CCR por el programa. Necesidad de mejorar aspectos de participación en los hombres por su mayor riesgo de desarrollar CCR. Evaluar el impacto del programa a medio-largo plazo (AU)

Abstract Colorectal cancer (CRC) is a major public health problem due to its incidence and mortality. In May 2008, the Basque Country approved the implementation of a population-based colorectal cancer screening program, using the immunochemical fecal occult blood test (FOBT), in persons aged 50-69 years. Patients with a positive result were invited to undergo colonoscopy with sedation. Objective To describe the main results of the first round of the CRC screening program with FOBT (2009-2011) in terms of the detection rates and positive predictive value (PPV).Method Retrospective study of participation rates and colonoscopic findings in persons with a positive FOBT result. Results Invitations to attend screening were sent to 230.505 persons. A total of 148.249 FOBT tests were processed. The mean participation rate was 64.3% (95% CI: 64.1-64.5) and was higher in women than in men. The FOBT test was positive in 6.7% (95% CI: 6.6-6.8). Positive results were more frequent in men. Among persons with a positive result, colonoscopy was performed in 93.1%. There were significant differences between women and men in the detection rate of high-risk adenomas (OR: 0,45 95% CI 0,41-0,49), which, as with CRC (OR: 0,80 95% CI 0,66-0,96), were more frequent in men. The PPV for adenoma of any type was significantly higher in men (72.4 95% CI, 71.2-73.5) than in women (48.8% 95% CI 47.2-50.5), with differences by age group and type of adenoma. Conclusions Participation rates and detection of advanced lesions and CRC were high. Because men have a higher risk of developing CRC, efforts should be made to increase their participation. The impact of the CRC screening program should be evaluated in the medium to long term (AU)

[Lesions detected in a colorectal cancer screening program in the Basque Country: first round (2009-2011)]. / Lesiones detectadas en el programa de cribado de cáncer colorrectal en el País Vasco: primera ronda 2009-2011.

UNLABELLED: Colorectal cancer (CRC) is a major public health problem due to its incidence and mortality. In May 2008, the Basque Country approved the implementation of a population-based colorectal cancer screening program, using the immunochemical fecal occult blood test (FOBT), in persons aged 50-69 years. Patients with a positive result were invited to undergo colonoscopy with sedation. OBJECTIVE: To describe the main results of the first round of the CRC screening program with FOBT (2009-2011) in terms of the detection rates and positive predictive value (PPV). METHOD: Retrospective study of participation rates and colonoscopic findings in persons with a positive FOBT result. RESULTS: Invitations to attend screening were sent to 230.505 persons. A total of 148.249 FOBT tests were processed. The mean participation rate was 64.3% (95% CI: 64.1-64.5) and was higher in women than in men. The FOBT test was positive in 6.7% (95% CI: 6.6-6.8). Positive results were more frequent in men. Among persons with a positive result, colonoscopy was performed in 93.1%. There were significant differences between women and men in the detection rate of high-risk adenomas (OR: 0,45 95% CI 0,41-0,49), which, as with CRC (OR: 0,80 95% CI 0,66-0,96), were more frequent in men. The PPV for adenoma of any type was significantly higher in men (72.4 95% CI, 71.2-73.5) than in women (48.8% 95% CI 47.2-50.5), with differences by age group and type of adenoma. CONCLUSIONS: Participation rates and detection of advanced lesions and CRC were high. Because men have a higher risk of developing CRC, efforts should be made to increase their participation. The impact of the CRC screening program should be evaluated in the medium to long term.

MKP1 repression is required for the chemosensitizing effects of NF-kappaB and PI3K inhibitors to cisplatin in non-small cell lung cancer.

Treatment of non-small cell lung cancer (NSCLC) with cisplatin has a level of antitumor activity still modest. We have shown previously that MKP1/DUSP1 inhibits cisplatin-induced apoptosis in NSCLC cells and is overexpressed in tumors from most patients with stage I-II NSCLC. Here, using different NSCLC cell lines we found that MKP1 and NF-kappaB are differentially expressed. We studied whether targeting MKP1, NF-kappaB or both affects cisplatin-induced cell death. MKP1 is expressed in H460 and H727 cells. H727 and H1299 cells showed constitutive phosphorylation of Akt and increased NF-kappaB activity than did H460 cells. H460-MKP1-siRNA-expressing cells (but not H727-MKP1-siRNA or H1299-MKP1-siRNA cells) exhibit a marked increase in cisplatin response compared with parental cells. Treatment with the PI3K inhibitor LY294002 or the NF-kappaB inhibitor BAY11-7082 enhanced cisplatin antitumor activity in parental H1299 cells but only weakly affected responses of H727 and H460 cells. MKP1-siRNA expression enhanced the chemosensitization effect of LY294002 and BAY11-7082 on H727 and H460 cells. Additionally, NSCLC cell lines with higher NF-kappaB-constitutive activation were the most sensitive to PS-341 (Bortezomib), a non-specific NF-kappaB inhibitor. This finding suggests the proteasome as a suitable strategy in treating NSCLC tumors with high constitutive NF-kappaB activity. Altogether, these results showed that either an activated PI3K/Akt/NF-kappaB pathway and/or high MKP1 was linked to reduced sensitivity to cisplatin in NSCLC cells. Inhibition of NF-kappaB or PI3K potently enhanced cisplatin cytotoxicity in cells with endogenous or genetically induced low MKP1 levels. These findings support the potential improvement in cisplatin responses by co-targeting NF-kappaB or Akt and MKP1.

Inactivation of NF-kappaB by proteasome inhibition contributes to increased apoptosis induced by histone deacetylase inhibitors in human breast cancer cells.

Histone deacetylase inhibitors (HDACi) are a new class of anticancer agents that cause growth arrest, differentiation and/or apoptosis in many tumor cells. As acetylation regulates the activity of the anti-apoptotic transcription factor NF-kappaB, we investigated whether the proteasome inhibitor MG-132 would inhibit NF-kappaB activation and as a consequence potentiate HDACi-dependent apoptosis in breast cancer cells. We observed that the HDACi suberoylanilide hydroxamic acid (SAHA) or trichostatin A (TSA) induced cell death but also enhanced NF-kappaB-activity. This increase of NF-kappaB activity was strongly reduced by the addition of MG-132. Moreover, MG-132 potentiates the HDACi-induced cell death that was associated with caspase-3 activation, and PARP cleavage. Induction of the stress related kinases JNK and p38 and the up-regulation of p21 and p27 were also observed after co-treatment of cells with HDACi and MG-132. Disruption of the NF-kappaB pathway by BAY 11-7085 or IkappaB-SR mimicked the action of MG-132 in promoting HDACi-induced cell death. Thus, the combined treatment with HDACi and proteasome inhibitors potentiates apoptosis in breast cancer cells representing a novel strategy for breast cancer therapy.

Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity.

PURPOSE: To investigate whether nuclear factor kappaB (NF-kappaB)/interleukin 6 (IL-6) was linked to docetaxel response in human prostate cancer cell lines, and whether inhibition of NF-kappaB sensitized tumor cells to docetaxel. We also aimed to correlate IL-6 (as a surrogate marker of NF-kappaB) and docetaxel response in hormone-independent prostate cancer (HIPC) patients. EXPERIMENTAL DESIGN: Hormone-dependent (LNCaP) and hormone-independent (PC-3 and DU-145) prostate cancer cell lines were exposed to docetaxel alone or combined with the NF-kappaB inhibitor PS-1145 (an inhibitor of IkappaB kinase-2). Effects of dose, exposure time, and schedule dependence were assessed. Activation of NF-kappaB was assayed by electrophoresis mobility shift assay and luciferase reporter assay, IL-6 levels by ELISA, and cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle and apoptosis were assessed by fluorescence-activated cell sorting analysis. Apoptosis was also measured by detection of cleavage of poly(ADP-ribose) polymerase. In patients with metastatic HIPC receiving docetaxel-based chemotherapy, IL-6 serum levels were assayed before chemotherapy and every 3 to 4 weeks thereafter. RESULTS: PC-3 and DU-145 cells had higher NF-kappaB activity, secreted more IL-6, and were more resistant to docetaxel than LNCaP cells. NF-kappaB activity was induced by docetaxel. Cotreatment with docetaxel and PS-1145 prevented docetaxel-induced NF-kappaB activation, reduced IL-6 production, and increased docetaxel effects on cell viability in PC-3 and DU-145 cells but not in LNCaP. Synergism with docetaxel and PS-1145, as assayed by median-effect principle, was observed in DU-145 and PC-3. In HIPC patients, pretreatment IL-6 serum levels correlated to prostate-specific antigen (PSA) response: median IL-6 level was 10.8+/-9.5 pg/mL in PSA responders versus 36.7+/-20.8 pg/mL (P=0.006) in nonresponders. A PSA response was also linked to a decline in IL-6 levels during treatment. Median overall survival was 6.8 months in patients with high IL-6 versus 16.6 months in those with low IL-6 (P=0.0007). On multivariate analysis, pretreatment IL-6 (P=0.05) was an independent prognostic factor for time to disease progression and survival. CONCLUSIONS: Inhibition of NF-kappaB emerges as an attractive strategy to enhance docetaxel response in prostate cancer. The interest of this view is further supported by a significant association between high IL-6 in sera of HIPC patients and decreased response to docetaxel.