Genomically matched therapy in refractory colorectal cancer according to ESMO Scale for Clinical Actionability of Molecular Targets: experience of a comprehensive cancer centre network.

Efficiency of expanded genomic profiling (EGP) programmes in terms of final inclusion of patients in genomically matched therapies is still unknown. Fit patients with advanced and refractory colorectal cancer (CRC) were selected for an EGP programme. Next-generation sequencing (NGS) analysis from formalin-fixed paraffin-embedded tumour samples was performed. The purpose was to describe the prevalence of genomic alterations defined by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), as well as the percentage of patients finally included in genomically guided clinical trials. In total, 187 patients were recruited. Mutational profile was obtained in 177 patients (10 patients were failure due to insufficient tumour sample), copy number alterations in 41 patients and fusions in 31 patients. ESCAT-defined alterations were detected in 28.8% of the intention-to-analyse population. BRAF V600E was clustered in ESCAT I, with a prevalence of 3.7%, KRAS G12C and ERBB2 amplification were clustered in ESCAT II, whose prevalence was 4.2% and 1.6%, respectively. Most alterations were classified in ESCAT III (mutations in ERBB2, PIK3CA or FGFR genes and MET amplification) and IV (mutations in BRAF non-V600E, ERBB3, FBXW7, NOTCH, RNF43), with a single prevalence under 5%, except for PIK3CA mutation (9%). The final rate of inclusion into genomically guided clinical trials was 2.7%, including therapies targeting BRAF V600E or RNF43 mutations in two patients each, and ERBB2 mutation in one patient. In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.

Chemotherapy and Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is one of the main causes of cancer death in the elderly. The older patients constitute a heterogeneous group in terms of functional status, comorbidities, and aging-related conditions. Therefore, therapeutic decisions need to be individualized. Additionally, a higher toxicity risk comes from the fact that pharmacokinetics and pharmacodynamics of the drugs as well as the tissue tolerance can be altered with aging. Although the chemotherapy efficacy in metastatic colorectal cancer (mCRC) is similar for older and young patients, more toxicity is presented in the elderly. While the mono-chemotherapy provides the same benefit for young and older patients, doublets front-line chemotherapy improves progression-free survival (PFS) but not overall survival (OS) in the elderly. Furthermore, the benefit of the addition of bevacizumab to chemotherapy in older patients has been shown in several clinical trials, while the clinical data for the benefit of anti-epidermal growth factor antibodies are scarcer. Immunocheckpoint inhibitors could be an appropriate option for patients with microsatellite instability (MSI) tumors. A prior geriatric assessment is required before deciding the type of treatment in order to offer the best therapeutic option.

Proyecto FIDUR: pacientes hiperfrecuentadores fidelizados en servicios de urgencias hospitalarios / Loyal frequent users of hospital emergency departments: the FIDUR Project

Objetivos: Describir las características del paciente hiperfrecuentador (HF) en servicios de urgencias hospitalarios (SUH) y analizar si existen diferencias en función de la distribución de revisitas durante el periodo de estudio. Método: Estudio de cohorte retrospectivo que seleccionó a pacientes mayores de 14 años que frecuentaron el SUH al menos en 10 ocasiones en 2013. Se reclutaron pacientes de 17 hospitales públicos de la Comunidad de Madrid (CM). Se recogieron variables relativas a la visita índice y visitas sucesivas. Se analizó la muestra en función del número de trimestres (TM) en el que se reparten las revisitas. Resultados: Se incluyeron 2.340 pacientes con una edad media de 54 (DE 21) años, 1.361 (58,2%) fueron mujeres, 1.160 (50,0%) no presentaban comorbilidad, 1.366 (58,2%) consumían tóxicos y 25 (1,1%) vivían en la calle. En la visita índice, 2.038 (87,1%) acudieron por un problema de salud reciente, 289 (12,4%) fueron hospitalizados, 60 (2,6%) concentraron sus revisitas en un solo TM, 335 (14,3%) en 2 TM, 914 (39,1%) las repartieron en 3 TM y 1.005 (42,9%) en 4 TM. En el grupo de pacientes cuyas revisitas se reparten en mayor número de TM observamos que aumenta la edad (> 65 años), la comorbilidad y la polifarmacia (p < 0,001), el deterioro cognitivo (p = 0,039) y la dependencia (p = 0,007), así como la hospitalización en la visita índice (p < 0,001). A medida que las revisitas se concentran en un menor número de TM, aumenta la proporción de mujeres (p = 0,012), determinados diagnósticos (p < 0,001) y la coincidencia entre el motivo de las revisitas y la visita índice (p = 0,012). Conclusiones: El paciente HF tiene unas características determinadas y acude a urgencias de una forma homogénea a lo largo del año (fidelizado). A medida que las revisitas se dispersan más, se objetivan pacientes con mayor complejidad y que consumen más recursos en la visita índice (AU)

Objectives: To describe the characteristics of frequent users of hospital emergency departments and analyze whether characteristics varied in relation to how revisits were distributed over the course of the year studied. Methods: Retrospective study of patients over the age of 14 years who were treated in a hospital emergency department at least 10 times in 2013. Patients were identified in 17 public hospitals in the Spanish autonomous community of Madrid. Data related to the first and successive visits were gathered and analyzed by quarter year. Results: We included 2340 patients with a mean (SD) age of 54 (21) years. A total of 1361 (58.%) were women, 1160 (50%) had no concomitant diseases, 1366 (58.2%) were substance abusers, and 25 (1.1%) were homeless. During the first visit, 2038 (87.1%) complained of a recent health problem, and 289 (12.4%) were admitted. Sixty (2.6%) patients concentrated their revisits in a single quarters 335 (14.3%) in 2 quarters, 914 (39.1%) in 3, and 1005 (42.9%) in 4. Patients whose revisits were distributed over more quarters were older (> 65 years), had more concomitant conditions, were on more medications (P < .001), showed cognitive impairment (P = .039), and were more functionally dependent (P = .007). They were also more likely to have been hospitalized on the first visit (P < .001). Patients whose revisits were concentrated in fewer quarters were more often women (P = .012) and more likely to have a specific diagnosis (P < .001) and revisit for a reason related to the initial visit (P = .012). Conclusions: Our study shows that the frequent user has specific characteristics and loyally comes to the same emergency department over the course of a year. Patients whose revisits are dispersed over a longer period have more complex problems and use more resources during their initial visit (AU)

[Loyal frequent users of hospital emergency departments: the FIDUR project]. / Proyecto FIDUR: pacientes hiperfrecuentadores fidelizados en servicios de urgencias hospitalarios.

OBJECTIVES: To describe the characteristics of frequent users of hospital emergency departments and analyze whether characteristics varied in relation to how revisits were distributed over the course of the year studied. MATERIAL AND METHODS: Retrospective study of patients over the age of 14 years who were treated in a hospital emergency department at least 10 times in 2013. Patients were identified in 17 public hospitals in the Spanish autonomous community of Madrid. Data related to the first and successive visits were gathered and analyzed by quarter year. RESULTS: We included 2340 patients with a mean (SD) age of 54 (21) years. A total of 1361 (58.%) were women, 1160 (50%) had no concomitant diseases, 1366 (58.2%) were substance abusers, and 25 (1.1%) were homeless. During the first visit, 2038 (87.1%) complained of a recent health problem, and 289 (12.4%) were admitted. Sixty (2.6%) patients concentrated their revisits in a single quarters 335 (14.3%) in 2 quarters, 914 (39.1%) in 3, and 1005 (42.9%) in 4. Patients whose revisits were distributed over more quarters were older (> 65 years), had more concomitant conditions, were on more medications (P < .001), showed cognitive impairment (P = .039), and were more functionally dependent (P = .007). They were also more likely to have been hospitalized on the first visit (P < .001). Patients whose revisits were concentrated in fewer quarters were more often women (P = .012) and more likely to have a specific diagnosis (P < .001) and revisit for a reason related to the initial visit (P = .012). CONCLUSION: Our study shows that the frequent user has specific characteristics and loyally comes to the same emergency department over the course of a year. Patients whose revisits are dispersed over a longer period have more complex problems and use more resources during their initial visit.

OBJETIVO: Describir las características del paciente hiperfrecuentador (HF) en servicios de urgencias hospitalarios (SUH) y analizar si existen diferencias en función de la distribución de revisitas durante el periodo de estudio. METODO: Estudio de cohorte retrospectivo que seleccionó a pacientes mayores de 14 años que frecuentaron el SUH al menos en 10 ocasiones en 2013. Se reclutaron pacientes de 17 hospitales públicos de la Comunidad de Madrid (CM). Se recogieron variables relativas a la visita índice y visitas sucesivas. Se analizó la muestra en función del número de trimestres (TM) en el que se reparten las revisitas. RESULTADOS: Se incluyeron 2.340 pacientes con una edad media de 54 (DE 21) años, 1.361 (58,2%) fueron mujeres, 1.160 (50,0%) no presentaban comorbilidad, 1.366 (58,2%) consumían tóxicos y 25 (1,1%) vivían en la calle. En la visita índice, 2.038 (87,1%) acudieron por un problema de salud reciente, 289 (12,4%) fueron hospitalizados, 60 (2,6%) concentraron sus revisitas en un solo TM, 335 (14,3%) en 2 TM, 914 (39,1%) las repartieron en 3 TM y 1.005 (42,9%) en 4 TM. En el grupo de pacientes cuyas revisitas se reparten en mayor número de TM observamos que aumenta la edad (> 65 años), la comorbilidad y la polifarmacia (p < 0,001), el deterioro cognitivo (p = 0,039) y la dependencia (p = 0,007), así como la hospitalización en la visita índice (p < 0,001). A medida que las revisitas se concentran en un menor número de TM, aumenta la proporción de mujeres (p = 0,012), determinados diagnósticos (p < 0,001) y la coincidencia entre el motivo de las revisitas y la visita índice (p = 0,012). CONCLUSIONES: El paciente HF tiene unas características determinadas y acude a urgencias de una forma homogénea a lo largo del año (fidelizado). A medida que las revisitas se dispersan más, se objetivan pacientes con mayor complejidad y que consumen más recursos en la visita índice.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation.

AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

RAC1b overexpression correlates with poor prognosis in KRAS/BRAF WT metastatic colorectal cancer patients treated with first-line FOLFOX/XELOX chemotherapy.

INTRODUCTION: Chemotherapy is the principal treatment in metastatic colorectal cancer (mCRC) patients. RAC1b, a RAC1 spliced variant, is over-expressed in colorectal cancer (CRC), and impairs apoptosis by activation of nuclear-factor-KB. Since RAC1b has been associated with the BRAF(V600E) mutation, associated with poor prognosis in CRC, we evaluated the role of RAC1b expression as a predictor of chemotherapy efficacy in mCRC. METHODS: We analysed KRAS and BRAF mutation, microsatellite instability and RAC1b expression in 157 mCRC patients treated with FOLFOX/XELOX in first-line therapy. RESULTS: KRAS mutations were detected in 46 patients (34%), 10 patients were BRAF mutant (7%) and 79 were WT for both, KRAS and BRAF (59%). RAC1b overexpression was found in 30 patients (19%). In the multivariate analysis, BRAF mutational status was a poor prognostic factor for overall survival (OS); hazard ratio (HR), 2.78 (95% confidence interval (CI), 1.35-5.72; p=0.0057). RAC1b overexpression was a poor survival factor for OS (HR, 2.35; 95% CI, 1.2-4.59; p=0.01) and progression-free survival (PFS) (HR, 2.4; 95% CI, 1.2-4.78; p=0.01) in KRAS/BRAF WT mCRC patients. CONCLUSIONS: RAC1b overexpression constitutes a marker of poor prognosis in KRAS/BRAF WT mCRC patients treated with first-line FOLFOX/XELOX therapy.

Soluble FAS in the prediction of benefit from cetuximab and irinotecan for patients with advanced colorectal cancer.

The FAS/FASL system, comprising membrane-bound (mFAS and mFASL) and soluble forms (sFAS and sFASL), has been related to apoptosis driven by chemotherapy administration. In vitro experiments show chemotherapy upregulating membrane-bound forms, leading to an increase of receptor availability (at 24-72 h) and favoring apoptosis. The regulatory effect of chemotherapy on sFAS in patients has never been explored prospectively in advanced colorectal cancer (ACRC). We performed a pharmacodynamic study to address sFAS/sFASL variation. A prospective phase II translational multicenter study was designed to evaluate progression-free rate (PFR) in patients with ACRC treated with irinotecan and cetuximab in third-line therapy. The effect of sFAS was studied in vitro in colorectal cancer cell lines. Our results showed that statistically significant changes were observed in sFAS at 24-72 h compared to baseline levels in the pharmacodynamic study. Of the 93 patients enrolled in the prospective study in third-line therapy with cetuximab-irinotecan, 85 were evaluated for sFAS/sFASL changes at 48 h. There was no difference in PFR at 4 months between patients with sFAS and sFASL changes. In vitro analysis showed that although LoVo cell lines were sensitive to oxaliplatin and fluorouracil due to modulation of sFAS and FAS, HT29 lines were not. In summary, chemotherapy regulates FAS soluble fractions in vitro and in vivo, but does not predict PFR in ACRC patients undergoing third-line therapy with the combination of cetuximab and irinotecan.

Lesiones graves y fatales en niños y adolescentes uruguayos secundarias a siniestros de tránsito por motos. Estudio epidemiológico / Serious and fatal injuries in Uruguayan children and adolescents secondary to traffic accidents by motorcycle. Epidemiological study

En países de ingresos medios, como Uruguay, los conductores de motos son parte importante de los lesionados o muertos en siniestros de tránsito. Objetivo: conocer la cantidad de niños y adolescentes que sufrieron siniestros con motos y que: a) fallecieron o, b) ingresaron a CTI/CI. De estos últimos describir las principales lesiones y características. Metodología: estudio descriptivo, retrospectivo, entre el 1 de junio y el 31 de diciembre de 2009. Fuentes de información: bases de datos del MSP, CTI/CI, certificados de defunción, partes policiales e historias clínicas. Resultados: en los 6 meses estudiados: a) fallecieron 20 menores de 19 años, 54% de los fallecidos por accidentes de tránsito del rango etario. 70% varones, todos conductores o pasajeros. 16/20 en vía pública, el resto en CTI. Al menos 45% no usaban casco; b) ingresaron a CTI/CI 69 menores de 19 años (2.7% de las causas de ingreso /edad), 26% menores de 15 años, 71% varones, la mayoría conductores o pasajeros. 91% sufrieron TEC y 87% politraumatismos de 3 a 6 sectores. Presentaron lesiones de: miembros 65%, tórax 60%, facial 54%, abdomen 40%, pelvis 25%; coma 40%, shock 25%. No usaba casco 68%. Se encontró carencias de datos en los documentos analizados. Conclusiones: es necesario: 1) mejorar la calidad de la información relativa a los siniestros de tránsito. 2) legislar la pertinencia o no de los niños a bordo de moto y si corresponde, las condiciones de traslado 3) realizar campañas educativas permanentes de seguridad vial, además de fiscalización y penalización en caso de no cumplimiento de la ley...

[Guideline: type 2 diabetes mellitus therapy: metformin, a critical perspective]. / Norma terapêutica da diabetes mellitus tipo 2: metformina uma perspectiva crítica.

Clinical guidelines have the potential to increase health gains, but also to cause harm. In this opinion article we state some misgivings about the application of the Portuguese National Health Directorate's guideline type 2 diabetes therapy: metformin in primary care. We seek to highlight guideline wording that may allow for multiple interpretations (alternatives to monotherapy with metformin, hierarchy of drugs to be associated with metformin, and metformin contraindications). Furthermore, we argue that it seems that choosing a glycemic target of 6.5% in a normative document to be applied in the general population may have unforeseen consequences.

Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study.

BACKGROUND: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I. METHODS: A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses. RESULTS: Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis. CONCLUSIONS: Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.

Serum matrilysin correlates with poor survival independently of KRAS and BRAF status in refractory advanced colorectal cancer patients treated with irinotecan plus cetuximab.

The purpose of the study was to prospectively explore the role of serum MMP-7 as a predictive and prognostic marker of anti-epidermal growth factor receptor (EGFR) therapy and irinotecan efficacy in third-line advanced colorectal cancer therapy. One hundred patients were recruited prospectively from six Spanish hospitals. Patients were treated with biweekly irinotecan 180 mg/m(2) and cetuximab 400 mg/m(2) (loading dose) and weekly cetuximab 250 mg/m(2) until progressive disease or unacceptable toxicity. Baseline MMP-7 was determined using a quantitative solid-phase sandwich ELISA. KRAS and BRAF mutational status were also assessed. The clinical endpoints examined were overall survival (OS), progression-free survival (PFS), and response rate. No association between serum MMP-7 and neither KRAS nor BRAF mutational status was found. The multivariate analysis revealed that MMP-7 predicts PFS both in wild-type (WT) KRAS patients (HR 1.03, 95% CI 1.00-1.06; p = 0.046) and in mutant KRAS patients (HR 1.18, 95% CI 1.01-1.35; p = 0.036). The presence of mutant BRAF was associated with shorter PFS (HR 8.49, 95% CI 2.88-25.0; p < 0.001) and worse OS (HR 3.55, 95% CI 1.39-9.09; p = 0.008) in the subset of WT KRAS patients. Serum MMP-7 is associated with PFS in colorectal patients treated with anti-EGFR therapy as third-line treatment independently of KRAS status.

Serum matrilysin levels predict outcome in curatively resected colorectal cancer patients.

BACKGROUND: Matrix metalloproteinase 7 (MMP-7) is involved in invasion, metastasis, growth, and angiogenesis. The aim of this study is to assess the prognostic role of serum MMP-7 in curatively resected colorectal cancer (CRC). MATERIALS AND METHODS: Patients undergoing resection for CRC (n = 175) were recruited from July 2003 to December 2004. MMP-7 was determined using a quantitative solid phase sandwich ELISA. Cox analysis was used to assess the role of MMP-7 in predicting overall survival (OS) and disease-free survival (DFS). RESULTS: The median length of follow-up was 45 months (range 1 to 59). Levels of MMP-7 are predictors of DFS (hazard ratio [HR] 1.119, 95% confidence interval [95% CI] 1.038-1.207) and of OS (HR 1.113, 95% CI 1.025-1.209). Patients with MMP-7 higher than the median (4.3 ng/ml) are more likely to relapse (29.5% vs 18.4%, P = .084); median time to progression in relapsed patients is 8 months if MMP-7 is > or =4.3 ng/ml and 18 months if MMP-7 is <4.3 ng/ml. Node-negative patients with low MMP-7 have a predicted probability of relapse-free survival at 4 years of 88% (95% CI 83-92%); if the MMP-7 is higher than the median value; this probability is 77% (95% CI 73-81%). CONCLUSION: MMP-7 predicts recurrence in curatively resected CRC patients.

[Prediction of prognosis of patients with pancreatic adenocarcinoma with curative intent resection by means of histologic grade and pathologic N stage]. / Predicción del pronóstico de los pacientes con adenocarcinoma pancreático resecado con intención curativa mediante el grado histológico y el estadio N patológico.

BACKGROUND AND OBJECTIVE: Pancreatic cancer has the poorest prognosis of any common gastrointestinal malignancy, with a 5-year overall survival of less than 5%. A better knowledge of prognostic factors related to this neoplasia might help improve the survival of these patients. We evaluated the prognostic significance of different factors in both overall survival and tumor recurrence in patients with pancreatic adenocarcinoma who had undergone pancreatic resection with curative intent. PATIENTS AND METHOD: All patients with pancreatic adenocarcinoma submitted to surgical resection in our unit from January 1995 to February 2005 were evaluated. Twenty-three pre-surgical, therapeutic, and histopathologic variables were analyzed. Univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) analyses were performed to select independent prognostic factors. RESULTS: Ninety-four patients were evaluated. The median age of patients was 63 years and 53% were woman. The probability of overall survival was 63% at 1 year, 18% at 3 years, and 8% at 5 years, with a median survival of 18 months. Univariate analysis identified performance of adjuvant therapy, histologic grade, percentage of involved-resected lymph nodes, pathologic N stage, and pathologic TNM stage as variables associated with overall survival. On the other hand, the probability of tumor recurrence was 52% at 1 year, 83% at 3 years, and 91% at 5 years, with a median time to tumor recurrence of 12 months. Predictive variables of tumor recurrence in the univariate analysis were preoperative N stage, preoperative TNM stage, postoperative CA 19.9 serum concentration, histological grade, percentage of involved-resected lymph nodes, pathologic N stage and pathologic TNM stage. Multivariate analysis identified histological grade and pathologic N stage as independent predictive factors of both overall survival (histologic grade: HR=2.341 [CI 95%, 1.342-4.098; p=0.003]; pathologic N stage: HR=2.242 [1.213-4.149; p=0.01]) and tumor recurrence (histological grade: HR=1.742 [CI 95%, 1.121-3.086; p=0.05]; pathologic N stage: HR=2.096 [1.089-4.032; p=0.027]). CONCLUSIONS: The histological grade and pathologic N stage predict the prognosis of patients with pancreatic adenocarcinoma after surgical resection.

Predicción del pronóstico de los pacientes con adenocarcinoma pancreático resecado con intención curativa mediante el grado histológico y el estadio N patológico / Prediction of prognosis of patients with pancreatic adenocarcinoma with curative intent resection by means of histologic grade and pathologic N stage

Fundamento y objetivo: el cáncer de páncreas tiene el peor pronóstico de los tumores gastrointestinales, con una supervivencia media a los 5 años de menos del 5%. Un mejor conocimiento de los factores pronósticos de esta neoplasia podría ayudarnos a mejorar la supervivencia de estos pacientes. El objetivo de este estudio fue evaluar el significado pronóstico de diferentes factores en relación tanto con la supervivencia general como con la recurrencia tumoral en pacientes con adenocarcinoma pancreático intervenidos con intención curativa. Pacientes y método: se ha evaluado a todos los pacientes con adenocarcinoma pancreático intervenidos en nuestra unidad desde enero de 1995 a febrero de 2005. Se analizaron 23 variables prequirúrgicas, terapéuticas e histopatológicas. Para seleccionar los factores pronósticos independientes se realizó un análisis univariable (con curvas de Kaplan-Meier y prueba de rangos logarítmicos) y otro multivariable (regresión de Cox). Resultados: se evaluó a 94 pacientes. La mediana de edad de los pacientes fue 63 años y el 53% eran mujeres. La supervivencia general fue del 63% al año, del 18% a los 3 años y del 8% a los 5 años, con una mediana de supervivencia de 18 meses. El análisis univariable identificó como variables relacionadas con la supervivencia general el grado histológico, el porcentaje de ganglios afectados de los que fueron resecados, el estadio N patológico y el estadio TNM patológico. Por otro lado, la probabilidad de recurrencia tumoral fue del 52% al año, del 83% a los 3 años y del 91% a los 5 años, con una mediana para la recurrencia tumoral de 12 meses. Las variables predictivas de recurrencia tumoral en el análisis univariable fueron el estadio N preoperatorio, el estadio TNM preoperatorio, la concentración sérica postoperatoria de CA19.9, el grado histológico, el porcentaje de ganglios afectos de los que fueron resecados, el estadio N patológico y el estadio TNM patológico. El análisis multivariable identificó el grado histológico y el estadio N patológico como los factores predictivos independientes tanto de la supervivencia general (grado histológico: hazard ratio [HR]=2,341; intervalo de confianza[IC] del 95%, 1,342¿4,098; p=0,003; estadio N patológico: HR=2,242; IC del 95%, 1,213¿4,149; p=0,01) como de la recurrencia tumoral (grado histológico: HR=1,742; IC del 95%, 1,021¿3,086; p=0,05; estadio N patológico: HR=2,096; IC del 95%, 1,089¿4,032; p=0,027). Conclusiones: el grado histológico y el estadio N patológico predicen el pronóstico de los pacientes con adenocarcinoma pancreático después de la resección quirúrgica (AU)

Background and objective: Pancreatic cancer has the poorest prognosis of any common gastrointestinal malignancy, with a 5-year overall survival of less than 5%. A better knowledge of prognostic factors related to this neoplasia might help improve the survival of these patients. We evaluated the prognostic significance of different factors in both overall survival and tumor recurrence in patients with pancreatic adenocarcinoma who had undergone pancreatic resection with curative intent. Patients and method: All patients with pancreatic adenocarcinoma submitted to surgical resection in our unit from January 1995 to February 2005 were evaluated. Twenty-three pre-surgical, therapeutic, and histopathologic variables were analyzed. Univariate (Kaplan-Meier, log-rank test) and multivariate (Cox regression) analyses were performed to select independent prognostic factors. Results: Ninety-four patients were evaluated. The median age of patients was 63 years and 53% were woman. The probability of overall survival was 63% at 1 year, 18% at 3 years, and 8% at 5 years, with a median survival of 18 months. Univariate analysis identified performance of adjuvant therapy, histologic grade, percentage of involved-resected lymph nodes, pathologic N stage, and pathologic TNM stage as variables associated with overall survival. On the other hand, the probability of tumor recurrence was 52% at 1 year, 83% at 3 years, and 91% at 5 years, with a median time to tumor recurrence of 12 months. Predictive variables of tumor recurrence in the univariate analysis were preoperative N stage, preoperative TNM stage, postoperative CA 19.9 serum concentration, histological grade, percentage of involved-resected lymph nodes, pathologic N stage and pathologic TNM stage. Multivariate analysis identified histological grade and pathologic N stage as independent predictive factors of both overall survival (histologic grade: HR=2.341 [CI 95%, 1.342¿4.098; p=0.003]; pathologic N stage: HR=2.242 [1.213¿4.149; p=0.01]) and tumor recurrence (histological grade: HR=1.742 [CI 95%, 1.121¿3.086; p=0.05]; pathologic N stage: HR=2.096 [1.089¿4.032; p=0.027]). Conclusions: The histological grade and pathologic N stage predict the prognosis of patients with pancreatic adenocarcinoma after surgical resection (AU)

Serum IGF-I, IGFBP-3, and matrix metalloproteinase-7 levels and acquired chemo-resistance in advanced colorectal cancer.

Insulin-like growth factor-I (IGF-I) is thought to have antiapoptotic and mitogenic properties in colorectal cancer, whereas IGF-binding protein-3 (IGFBP-3) seems to exert a pro-apoptotic effect. Additionally, matrix metalloproteinase-7 (MMP-7), an enzyme with in vitro ability to degrade IGFBP-3, has been shown to be a prognostic factor in advanced colorectal cancer (ACRC). We studied whether chemotherapy treatment for ACRC modulates IGF-I, IGFBP-3, and MMP-7 serum levels. In 41 patients undergoing first-line therapy for ACRC, serum levels of IGF-I, IGFBP-3, and MMP-7 were measured with immunoassays at baseline and every 3 months until progressive disease, or a maximum of five determinations, during a chemotherapy regimen of either FOLFOX or FOLFIRI therapies. Associations were assessed for paired samples, using t-test or Wilcoxon ranks test depending on normality of the variable, verified with Shapiro-Wilk test. An average of four extractions (range 3-5) were done, for a total of 157 determinations. Mean pretreatment values of IGF-I, IGFBP-3, and MMP-7 were 83 (95% CI, 73-92) ng/ml, 2372 (95% CI, 2121-2623) ng/ml, and 10.6 (95% CI, 7.21-13.98) ng/ml respectively. No significant changes in IGF-I were found, but a significant increase in IGFBP-3 serum concentrations was observed during or after chemotherapy treatment without progressive disease, compared with basal levels (P<0.001). A significant decrease in IGFBP-3 to 1983 ng/ml (95% CI, 1675-2292) and a significant increase in MMP-7 levels to 14.6 (7.6-21.7) ng/ml were observed at progression of disease compared with baseline and treatment levels (P<0.001). This study shows that IGFBP-3 and MMP-7 serum levels change during chemotherapy treatment. The increased MMP-7 levels at disease progression support the hypothesis that this protease could play a role in acquired resistance by degrading IGFBP-3.

Phase I trial of neoadjuvant chemoradiotherapy (CRT) with capecitabine and weekly irinotecan followed by laparoscopic total mesorectal excision (LTME) in rectal cancer patients.

BACKGROUND: To analyze the feasibility of capecitabine with weekly irinotecan and concurrent radiotherapy followed by laparoscopic-total mesorectal excision (LTME) in rectal cancer patients. METHODS: Eligible criteria included adenocarcinoma of the rectum staged by endoscopic ultrasonography (u), spiral abdominal and pelvic CT and chest X-ray. Patients received weekly irinotecan 50 mg/m(2) (days 1, 8, 15, 22, 29) and capecitabine (days 1 through 5 for 5 weeks); dose level; (DL) I 250 mg/m(2)/bid; DL II 375 mg/m(2)/bid; DL III 500 mg/m(2)/bid, according to phase I methodology. External beam radiotherapy was delivered up to a total dose of 45 Gy in daily fractions of 1.8 Gy, 5 days a week. LTME was planned 5-7 weeks after CRT. RESULTS: From February 2003 to February 2006, 22 patients were included. Median age was 62 (range 48 to 78). Seven pts were uT3N0 and 15 pts uT3N1. Seven patients were treated at DL I, six at DL II and nine at DL III. Grade 3 adverse events were observed in all levels. The maximum tolerated dose was reached at 375 mg/m(2) (DL II). Conversion rate to open surgery was 5%. Median hospital stay was 6.6 days. One month post-surgical complications were noted in five patients (23%). Median excised nodes were 11 (range 4-21). Pathological complete response was observed in two patients (9%). CONCLUSIONS: LTME after preoperative CRT with CAPIRI is feasible but severe adverse events were found in all levels despite the use of lower dose of capecitabine than previously published.

Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms.

PURPOSE: A multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene. METHODS: Four dose levels with a fixed dose of cisplatin (60 mg/m(2)), day 1, and dose-escalation of CPT-11 (50-70 mg/m(2)) and docetaxel (25-30 mg/m(2)), days 1 and 8, every 3 weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood. RESULTS: Twenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60 mg/m(2) and docetaxel 25 mg/m(2) plus cisplatin 60 mg/m(2). Objective response was observed in 13 patients (50%). Median time to progression was 6.6 months, and median survival was 11.3 months. Median time to progression was 9.7 months for patients harboring the XRCC3 Met241Met genotype versus 8.4 months for patients with Thr241Met and 3.1 months for those with Thr241Thr (P = .04). CONCLUSIONS: CPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.