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Resumen El tratamiento para la osteoporosis suele ser largo en el tiempo, por lo que es necesario en muchas ocasiones recurrir a una estrategia secuencial de tratamiento. El clínico debe saber no solo seleccionar la mejor terapia disponible en cada situación clínica, sino también cómo discontinuar o cambiar de tratamiento en un momento determinado de la evolución de la enfermedad. En este documento presentamos de forma resumida una revisión de los mecanismos de acción y las consecuencias de la discontinuación de cada uno de los fármacos para la osteoporosis, así como qué ocurre en las diferentes secuencias de tratamiento. La discontinuación de denosumab tiene consecuencias claramente negativas para el hueso, y solo los bisfosfonatos, por tener un efecto antirresortivo residual, podrían discontinuarse durante un tiempo limitado (vacaciones terapéuticas). El cambio de un antirresortivo por otro antirresortivo con diferente mecanismo de acción es una opción que puede ser favorable en el manejo de algunos pacientes con osteoporosis. Cambiar un antirresortivo por un osteoformador puede asociarse a una pérdida inicial de densidad mineral ósea que no parece tener consecuencias negativas en la eficacia antifractura. Empezar con un tratamiento osteoformador (teriparatida o romosozumab) y cambiar posteriormente a un antirresortivo constituye la mejor secuencia de tratamiento, por lo que podría ser la opción preferente en pacientes con muy alto riesgo de fractura.

The notion of ‘ranking dynamics’ was stablished in a previous work (García-Zorita et al. Rankings: competitiveness versus stability, STI International conference. Paris, 2017) where we include the study of rankings with ties, entrants and leavers. In this contribution, we generalize our method by taking the absolute difference in position between consecutive rankings into account. We introduced the concept of Relative Ranking Volatility (RRV) to normalizing the absolute volatility of a ranking using a factor who is defined in section 5. Finally, we show a real-example taken from the Web of Science / Journal Impact Factor for each IF-quartile distribution in the Information Sciences & Library Sciences category.

Altres ajuts: The project received financial support from Amgen S.A. to conduct the study. LC and MB work at Amgen S.A. and hold stock in Amgen. LL works at a Life Science Boutique that received funding from Amgen S.A. to coordinate and conduct the study and to write up the manuscript. MMT has received research grants from UCB and MSD; is a consultant for Amgen, Lilly, and UCB; and speakers' bureau member for Amgen and Lilly. EJ has received research grants from Amgen, Lilly, and MSD and consulting fees from Amgen, UCB, and Lilly. XN has received research grants from Lilly and Amgen; is a consultant for Lilly and Amgen; and speakers' bureau member for Lilly, Amgen, and MSD. JMN is a consultant for Abbvie, Amgen, BMS, Gebro, Lilly, MSD, Roche, Sandoz, and UCB and speakers' bureau member for Abbvie, Amgen, BMS, Gebro, Lilly, MSD, Roche, and UCB. JMQ has received research grants from Amgen, Lilly, FIS Carlos III, RETICEF, and Intensification of Investigation Junta de Andalucía; is a consultant for Amgen, MSD, Italfarmaco, and FAES; and speakers' bureau member for Amgen, MSD, Italfarmaco, and FAES. EC has participated in the speakers' bureau for Amgen, Lilly, MSD, FAES, and Rubió. All authors declare that all the results presented in the manuscript are the true expression of findings and there has been no interference in respondents' free communication and dissemination. To reach a Spanish expert consensus on a treat-to-target strategy in osteoporosis, a Delphi Consensus Study has been developed. Most of the experts (59.8%) were rheumatologist with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items. Therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been defined. The paper aims to achieve a Spanish expert consensus on a treat-to-target (T2T) strategy in osteoporosis. A scientific committee led the project and was involved in expert panel identification and Delphi questionnaire development. Two Delphi rounds were completed. The first-round questionnaire included 24 items and assessed, using a seven-point Likert scale, the experts' wish (W) and prognosis (P) in 5 years for each topic (applicability, therapeutic objectives, patient follow-up, and possible treatment to be prescribed). Items for which there was no consensus in the first round were included in the second round. Consensus was defined as ≥75% agreement (somewhat/mostly/entirely agree) or disagreement (somewhat/mostly/entirely disagree) responses. Of the experts, 112 and 106 completed the first and second rounds, respectively. 59.8% were rheumatologists with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items, and was established regarding the utility of a T2T strategy to define therapeutic objectives, optimal follow-up, and therapeutic algorithm. Participants agreed on the utility of the bone mineral density (BMD) value (T-score >−2.5 SD for spine and >−2.5/−2.0 SD for femoral neck), lack of fractures, and fracture risk (FRAX) as therapeutic objectives. For measuring BMD changes, consensus was achieved on the suitability of hip and femoral neck locations. Experts agreed to consider treatment failure as when a significant BMD gain could not be achieved, or when a new fracture occurs within 2-3 years. There was consensus that all proposed therapies should achieve a therapeutic target through T2T strategy (treatments with the highest consensus scores were denosumab and teriparatide). The therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been established by a panel of experts. Some aspects nevertheless still require further analysis.

Pig slurry was treated in a pilot wastewater treatment plant composed of a rotobioreactor based on rotating microalgae-biofilm discs, and a helophyte floating filter. Slurry in this work included cleaning water and its main characteristics were: 8,400-5,500 mg O2·L-1 COD, 1,575-800 mg O2·L-1 BOD5 and 2,275-1,799 mg·L-1 total nitrogen. Prior to the experiment, the rotobioreactor was conditioned adding pig slurry for 15 days in order to adapt the microorganisms biofilm to that substrate; at the end of the conditioning period, COD was 3,200 mg O2·L-1. The experiment was carried out for 10 days, adding 200 L pig slurry·day-1 to the rotobioreactor. The mixture in the reactor (diluted pig slurry) flowed by plug-flow to the helophytes floating filter to continue the depuration process. After 10-day treatment, the daily average reduction achieved was 88.3% COD, 97.6% BOD5, 78.5% phosphorous and 85.6% total nitrogen. From the results, it was estimated that a load of 1 m3·day-1 pig slurry would require about 1,008 m2 discs area in the reactor and 54 m2 of helophytes floating filter.

Purpose: To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors. Methods and Materials: This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT . Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy. Results: A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy-three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT. Conclusions: According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted. (C) 2016 Elsevier Inc. All rights reserved.

Aim. Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers.Design and methods. The study included 68 proteinuric (>500 mg/day) patients (age 63,1±12,9 years, 69,1 % males and 30,9 % females). All patients were receiving ACE inhibitors (51,4 %) or angiotensin II receptor blockers (48,6 %) therapy but had higher blood pressure (BP) than recommended for proteinuric patients (Results. BP significantly decreased from 152±15/86±11 mm Hg to 135±12/77±10 mm Hg at six months of follow-up (ppp=0,022). Basal proteinuria was 1,63±1,34 g/day; it was significantly (pConclusion. Lercanidipine at 20 mg dose, associated with renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.

Objective To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if =2, low disease activity if >2 and =5), moderate if >5 and

La asignatura Prevención y Salud Pública de contenidos teórico-prácticos se imparte en el primer curso de los estudios de Grado en Odontología que se implantaron en el curso 2009-10 en la UCM. Consideramos que Campus Virtual podría ser una herramienta de utilidad para la asignatura y especialmente beneficioso para alumnos de primer curso que carecen de una visión general de la carrera posibilitándoles un aprendizaje más individualizado tanto por el acceso las veces y el tiempo que lo necesitan a los contenidos de la materia disponibles en Campus Virtual, como por la posibilidad de realizar tutorizaciones en línea que, de hecho, han utilizado con más frecuencia que las presenciales. Además permite al profesorado realizar un seguimiento tanto individual como de grupo e intervenir y reforzar en un momento determinado. Por ello, a lo largo de estos cursos hemos ido incorporando de forma paulatina actividades al espacio de la asignatura en Campus Virtual contando durante el curso 2010-11 con el apoyo de un Proyecto de Innovación Educativa de la UCM.

Objetivo: La nefropatía hipertensiva es la segunda causa más común de entrada en tratamiento renal sustitutivo en España, con una incidencia que parece estable desde 1997. Los datos sobre incidencia de nuevos diagnósticos de nefropatía hipertensiva en consulta son escasos al no existir registros similares a los usados en el tratamiento renal sustitutivo. Diseño y métodos: Se ha revisado retrospectivamente la incidencia de este diagnóstico en la base de datos de la Consulta de Nefrología del Hospital Infanta Cristina de Badajoz entre el 1 de enero de 1991 y el 31 de diciembre de 2007. El diagnóstico se hizo en la mayor parte de los casos por criterios clínicos. En 60 casos se realizó biopsia renal por proteinuria superior a 1 g/24 h. Resultados: Durante ese tiempo fueron atendidos en consulta 5.071 pacientes, de los cuales 479 fueron diagnosticados de nefropatía hipertensiva. La incidencia media de nefroangioesclerosis ha sido 44,0 casos pmp, con una edad media de 66,6 ± 12,1 años, siendo el 43,0% mujeres. Se aprecia una tendencia progresiva desde 16,7 pmp en 1991 hasta 89,5 pmp en 2007. Las tasas medias fueron 31,8 pmp en el período 1991-1995; 32,1 pmp entre 1996 y 2000, y 54,4 en el período 2001-2006. La edad media de los pacientes incidentes a lo largo del período estudiado ha seguido una curva en "J"; 53 pacientes (11,6%) han iniciado tratamiento renal sustitutivo durante estos años. La supervivencia estimada antes de llegada a tratamiento renal sustitutivo fue el 96,0% al año, el 85,9% a los 5 años de seguimiento y el 81,6% a los 7 años de seguimiento. Conclusiones: La incidencia de nefropatía hipertensiva parece tender a crecer significativamente en los últimos años a pesar del perfeccionamiento de los tratamientos preventivos utilizados. La mayor permisividad en la edad para la derivación podría influir en estos resultados.

En la provincia de Córdoba se está consolidando la implantación de Agendas 21 tanto en lo que respecta a las Agendas 21 Locales como a la Agenda 21 Provincial. Una vez superadas las etapas iniciales, en la cuales se sientan las bases del proceso y se desarrolla la planificación estrategia hacia la sostenibilidad, resulta necesario plantear la puesta en valor de los logros alcanzados, sobre todo considerando la explotación de los indicadores de sostenibilidad ya determinados In the Cordoba province is consolidating the implenentation of Agenda 21 as in regard to Local Agenda 21 as to the Provincial. Once you get past the initial stages, in which the foundations of the process and develop the planning strategy towards sustainability, it is necessary to consider the enhancement of the achievements, above all considering the use of sustainability indicators already certain

The aim of this paper is to determine if the scientific papers published in high impact journals are not only of sufficient "a priori" quality to be accepted by such journals, but acquire further impact because they are cited by journals with at least a similar impact. A normalized impact factor (NIF) is proposed as a measure to compare the visibility of research conducted by different university departments working in different disciplines. This analysis is supplemented by a study of the distribution by quartiles of the journals involved. In addition, the quality of the journals citing the papers in the sample selected for the study is evaluated to determine research prestige. The feasibility of using citation journal impact in the evaluation as an incentive for research quality is posed in this work. This paper will be of interest to those institutions interested in quality research evaluation as well as those involved in science policy.

Either inflammation or hyperuricemia has been related with increased cardiovascular risk and mortality. A hypothetical relationship between serum uric acid levels (SUA) and inflammatory markers has never been tested in chronic kidney disease (CKD) patients. The purpose of this study was to determine the prevalence of increased C-reactive protein (CRP) levels in CKD patients, and to test the hypothesis of a relationship between SUA and CRP levels. The study group consisted of 337 patients (174 males, mean age 63 +/- 16 years) with advanced chronic renal failure not yet on dialysis. None of them had overt inflammatory or infectious diseases. High sensitivity CRP levels were analyzed as a binary (above or below median value), or continuous variable (log-transformed CRP), by multiple logistic or linear regression analysis, respectively. Demographics, clinical, and biochemical characteristics, including SUA levels, were the variables tested in these analysis. In a subset of 169 patients without diabetes, the same analysis were carried out, with the inclusion of fasting insulin levels and HOMA-IR as independent variables. Median CRP level was 3.25 mg/L, and mean SUA level was 7.59 +/- 1.94 mg/dl. Patients with CRP levels above the median had significantly higher mean SUA level than that of the rest of study patients (7.93 +/- 1.79 vs 7.24 +/- 2.03 mg/dl, p = 0.001). SUA levels correlated significantly with log-transformed CRP levels (r = 0. 16, p = 0.0022). The relationship between SUA and CRP levels remained statistically significant after adjustment for age, sex, comorbid index, obesity, residual renal function, diuretic and allopurinol treatment, in the multivariate logistic and linear regression models (OR: 1.296, p = 0.0003; and beta: 0.204, p = 0.0002). The significant association between SUA and CRP levels did not change when HOMA-IR and fasting insulin levels were included as independent variables in the subset of 169 patients without diabetes. In conclusion, SUA levels are related with CRP levels in CKD patients.

A protective effect of obesity on the mortality of end-stage renal failure patients has been observed in several studies. Most of these studies have been based on prevalent dialysis population. The aim of the present study was to evaluate if obesity has beneficial effects on the survival of advanced chronic renal failure patients. The study group consisted of 376 patients (mean age 63 +/- 15 years) with advanced chronic renal failure not yet on dialysis. Obesity was defined as a body mass index (BMI)or = 30 kg/m2. Grade of comorbidity was quantified by the method devised by Davies. Survival was analyzed as time from the referral to the predialysis outpatient clinic to patient death, censoring from contributing additional survival data to the analysis following transplantation. Kaplan-Meier analysis was used to test survival differences according to quartiles of BMI, and between obese and nonobese patients. Further analysis were performed, stratifying survival curves by comorbid scores, lean body mass, age, and sex. Cox proportional hazard regression models were used to investigate the best determinants of mortality, and the role of obesity adjusted for other covariates. Median survival time was 1,453 days. During the follow-up time, 158 patients (42%) died. Survival differences among quartiles of BMI were statistically significant (Breslow = 10.7, p = 0.017). Patients within the lowest and the highest quartiles of BMI had higher mortality than the rest of patients. Survival curves between obese and non-obese patients did not differ significantly. However, when patients without comorbidity were studied apart, those with obesity showed worse survival than the rest of patients (log-rank = 7.42, p = 0.0064). Since the effect of obesity on mortality did not follow a proportional hazard pattern throughout the study period, multivariable analysis for mortality was stratified by 18 months intervals. The variables which fitted the best model were: age (Hazard Ratio: 1.04), comorbid score (HR: 2.17), serum albumin (HR: 0.62), GFR at the study entry (HR: 0.91), male gender (HR: 1.48), and obesity (HR: 1.51). In conclusion, obesity had no survival benefit in patients with advanced chronic renal failure. Obesity had a noteworthy impact on early mortality of advanced chronic kidney disease patients without comorbidities.

The rate of decline of renal function (RDRF) in the pre-end stage renal disease setting (pre-ESRD) is highly variable. Several factors have been involved as potential modifiers of renal failure progression. This retrospective study attempts to establish which were the main determinants of the RDRF in pre-ESRD patients followed in the predialysis consult. The study group consisted of 230 patients with pre-ESRD not yet on dialysis who were referred to the predialysis consult from January 1998 to July 2002. The mean follow-up time per patient was 356 days. RDRF was assessed as delta of the average of creatinine and urea clearances (CrCl-UCl). Data obtained at time of referral to the predialysis consult were analyzed as potential predictors of the subsequent RDRF. These independent variables included: demographics, comorbid conditions, main hematological and biochemical data, antihypertensive and statin treatment, mean blood pressure, and CrCl-UCl at time of referral. The predictors of delta CrCl-UCl were determined by multiple linear regression analysis. The determinants of the survival without dialysis were established by the Cox regression hazard model, adjusted to renal function at time of referral. Mean CrCl-UCl at time of referral was 10.98 +/- 2.58 ml/min/1.73 m2, and mean delta CrCl-UCl was -0.37 +/- 0.46 ml/min/1.73 m2/month. Patients with diabetic nephropathy and chronic glomerulonephritis had the fastest RDRF, while patients with ischemic nephropathy and chronic interstitial nephritis had the slowest RDRF. Seventy-five patients (46%) required EPO therapy. The best determinants of delta CrCl-UCl were: the 24-hour proteinuria (p0.0001), and the hematocrit at time of referral (p = 0.0024). The best determinants of the survival rate without dialysis during the study period were: the proteinuria (in g/24 hours) (R 1, 16; p0.0001), the hematocrit at time of referral (OR: 0.88; p0.0001), the treatment with EPO (OR: 0.59; p = 0.02), and the diagnosis of diabetes mellitus (OR: 1.59; p = 0.01). In conclusion, apart from the rate of proteinuria, which could represent the best marker of the RDRF in chronic renal diseases, the development of anemia was associated with faster decline in renal function.

Desde la promulgación de la LOGSE se han producido cambios que afectan al concepto de evaluación y al proceso de aprendizaje. Todas las disposiciones legales sobre evaluación remiten al proyecto curricular la responsabilidad final de fijar el procedimiento específico dentro del marco anterior, aquí se presenta una propuesta, fruto de la reflexión y experiencia desarrollada en el IES Damaso Alonso de Puertollano. Se detalla la justificación teórica de la experiencia, las directrices generales sobre los criterios de promoción y titulación y, por último, se presenta una ejemplificación con los criterios establecidos sobre la toma de decisiones de titulación de graduado en educación secundaria obligatoria de un alumno o alumna de cuarto de ESO. Cataluña ESP

In 2003 a reintroduction program of osprey started in the region of Andalusia, SW Spain, in order to recover the former breeding population in mainland Spain and to improve the situation of the species in the Mediterranean basin. From 2003 to 2009, 129 young ospreys were released by means of hacking. In 2009, the first breeding pair reared successfully three chicks in the Odiel Marshes for the first time in mainland Spain since 1981, when the species become extinct. The first breeding pair constitutes a significant indicator for the evaluation of the project and the beginning of a future population.

We studied a breeding population of Booted Eagles (Hieraaetusp ennatus)i n Doñana National Park (southwestern Spain) to develop a method of determining the sex of an individual based on the use of iscriminant functions. Because there are size differences between age classes and sexes of eagles, we developed two different discriminant functions for each age group. Our discriminant function method approached 100% accuracy in correctly aging individuals using forearm length and body massa s predictor variables.S ex of young eaglesw as also determined with 98.8% accuracyu sing forearm, tail, bill, and tarsus lengths

From the results of the Modification of Diet in Renal Disease (MDRD) study, a prediction equation for a more accurate estimate of glomerular filtration rate (GFR), was developed. The present study ais to compare the GFR estimated by MDRD formula and that calculated by the average of creatinine and urea clearances in unselected patients with advanced renal failure. The study group consisted of 320 (163 males) with advanced renal failure not yet on dialysis. Their mean age was 63 +/- 14 years. Diabetic nephropathy was the most common etiology of renal failure (25%). Significant comorbidity was observed in 115 patients. Serum creatinine (Cr), urea and albumin were determined in all patients. Creatinine (Ccr) and urea clearance (Cu) were calculated on a 24-hour urine collection. The GFR was estimated by summing Ccr and Cu, and dividing by two (Ccr-Cu). THe clearances were corrected for a body surface area of 1.73 m2. The MDRD formula for the estimation of GFR included the following parameters: serum Cr, BUN, age, gender and serum albumin. Linear regression analysis and Bland-Altmann plot were utilized to establish the degree of correlation and agreement between both estimations of GFR. The percent differences between the two estimations of GFR was especially analyzed in those subgroups of patients which were not included in the MDRD study (patients older than 70 years, diabetics and those with comorbid conditions). The mean GFR estimated by Ccr-Cu and by MDRD formula were 10.04 +/- 3.10 ml/min and 10.55 +/- 3.60 ml/min, respectively (p0.0001). The two parameters correlated significantly (R = 0.76, p0.0001). GFR by the MDRD formula tended to overestimate the highest values of Ccr-Cu. The mean percent difference between both methods was 6.5 +/- 23.6. MDRD predictive equation overestimated significantly Ccr-Cu in patients older than 70 years (mean overestimation of 15%), males (10%), diabetics (10%), and mainly in patients with comorbidity (17%). In conclusion, the GFR estimated by MDRD formula is very similar to Ccr-Cu in young uremic patients without comorbidity. However, major discrepancies between these two methods could be observed in older patients, and mainly in those with comorbidity.

Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d. Clin Cancer Res; 16(19); 4876–83. ©2010 AACR.

Purpose This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC). Patients and Methods The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m2 during week 1, then 250 mg/m2 weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1; leucovorin 200 mg/m2 on days 1 and 2, followed by fluorouracil 400 mg/m2 bolus then 600 mg/m2 intravenous infusion during 22 hours on days 1 and 2). Results The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated. Conclusion Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.

Esophageal cancer (EC) and gastric cancer (GC) constitute a major cause of cancer deaths worldwide. Recent improvements in both surgical techniques and adjuvant/neoadjuvant chemotherapy, radiotherapy or both have increased the survival of patients with loco-regional disease. However, most patients with GC or EC have advanced disease either at diagnosis or during the follow-up, and despite recent advances, these patients still do poorly. Understanding of the molecular pathways that characterize cell growth, cell cycle, apoptosis, angiogenesis and invasion has provided novel targets in cancer therapy. In this review we describe the current status of targeted therapies in the treatment of EC and GC, including EGFR inhibitors, antiangiogenic agents, cell cycle inhibitors, apoptosis promoters and matrix metalloproteinases inhibitors. The emerging data from the clinical development of these compounds has provided novel opportunities in the treatment of EC and GC that will probably translate into clinical benefit for patients with these common malignancies.