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Las pérdidas económicas que anualmente sufre la industria avícola mundial por concepto de mala calidad del cascarón son elevadas. Cox (1967) estimó qué 6.7% del total de huevos producidos en los Estados Unidos de Norteamérica se pierde por fragilidad del cascarón.

Se realizaron 4 experimentos, con objeto de determinar el efecto del reemplazo de soya con pasta de semilla de calabaza (PSC). En el primero, se estudió el efecto de varios niveles (0, 5. 10 y 15%) de PSC en dietas sorgo + soya para pollos de engorda. Los datos a la semana 9 indicaron (P

Para estudiar el valor alimenticio de la espirulina (Spirulina geitleri) en dietas para pollos de engorda se llevaron a cabo tres experimentos. En el primero se incluyó O, 5, 10 y 15% de espirulina en las dieta durante todo el ciclo o únicamente en la fase de engorda (1 a 9 semanas o 5 a 9 semanas de edad). Los datos obtenidos a la 9' semana de edad indicaron que la ganancia de peso se reduce (P 0.05) para las dietas con los dos lotes de espirulina y ambas dietas respondían significativamente a la adición del aceite.

Fueron realizados dos experimentos con gallinas de una línea comercial Legborn, para estudiar el efecto de la adición de espirulina en niveles de 0, 2.5, 5.0, 7 .5, 10.0% y 0, 1, 2, 3, 4, 5% en dietas con igual contenido de proteína. Cada tratamiento se ofreció por triplicado a grupos de 10 aves cada uno. Los resultados obtenidos en 70 días y 126 días respectivamente indicaron que no existen diferencias estadísticas en consumo de alimento, producción de huevo, peso del huevo y conversión alimenticia. Al valorar Visualmente la pigmentación de la yema de los huevos con el abanico colorimétrico de Roche, se encontraron diferencias altamente significativas (P

Can objeto de determinar el valor de la gallinaza calcinada COJIIO fuente de Ca y P en dietas para pollos, se realizaron dos experimentos. La muestra de la gallinaza calcinada tenía un contenido de 23.98% de Ca-y 11.03% de P. En el primero, una dieta sorgo+ soya, fue suplementada con diferentes niveles de gallinaza calcinada (0.835, 1.570, 2.505 y 3.340%). Cada tratamiento se ofreció por triplicado a grupos de 9 Pollo de 7 a 35 días de edad. Los resultados obtenido en ganancia de peso, consumo y conversión indicaron un efecto cuadrático (P

Se realizaron tres experimentos para estudiar el valor de la gallinaza para pollas de reemplazo y gallinas en postura. Los diseños experimentales empleados fueron completamente al azar. Las dietas experimentales se ofrecieron por triplicado o cuadruplicado a grupos de 10 aves de una línea comercial Légborn blanca. En el primer experimento se estudió en pollas de 8-22 semanas, el efecto de 0. 5, 10 y 15% de gallinaza (11.83% de proteína verdadera) en dietas isoproteicas sorgo + soya con 16%. Los resultados mostraron que no había diferencia estadística entre tratamientos en consumo de alimento y edad al primer huevo. La ganancia de peso y la conversión alimenticia se redujeron (P

El uso de drogas en la nutrición de las aves, tanto en profilaxis como en el control de algunas enfermedades, se ha generalizado y ha sido uno de los factores que han contribuido al desarrollo y progreso de la industria avícola (Morrison, Tremer y Standish, 1974).

Se realizaron dos experimentos con objeto de estudiar el efecto que ejerce sobre las aves la melaza tratada con diferentes inhibidores de la fermentación alcohólica. En el primer experimento, se alimentaron pollos de engorda sin sexar de 7-35 días de edad con dietas conteniendo dos niveles de melaza (0 y 10%) con y sin inhibidores de la fermentación alcohólica. Los resultados obtenidos indicaron que no hubo diferencia significativa en ganancia de peso y conversión alimenticia. Sin embargo, el consumo de alimento se incrementó significativamente en las dietas con melaza. En el segundo experimento, se alimentaron gallinas de una línea comercial Leghorn con dietas conteniendo dos niveles de melaza (0 y 10%) con y sin inhibidores de la fermentación alcohólica. Datos de 56 días no indicaron diferencia significativa entre tratamientos para porcentaje de postura, peso del huevo y conversión alimenticia; el consumo de alimento se incrementó (P < 0.05) con las dietas de melaza

Se realizaron cuatro experimentos, con objeto de evaluar el frijol texturizado como fuente de proteína en dietas para pollos y gallinas.

Para estudiar el efecto de la adición de gallinaza en dietas para pollos de engorda, se llevaron a cabo tres experimentos. En el primer trabajo se remplazó 0.5, 10 y 15% de sorgo por gallinaza, en dietas para pollos de engorda en etapa de iniciación. Los datos en 28 días indicaron que no había diferencia entre tratamientos en el crecimiento y consumo de alimento; la conversión alimenticia disminuyó en forma significativa (P < 0.05) a medida que fue incrementándose el nivel de gallinaza en las dietas. En el segundo experimento, la adición de gallinaza (0, 25, 5.0, 7.5 y 10% suplementando con aceite) fue estudiada en dietas para pollos en etapa de iniciación. Se observó que la ganancia de peso se redujo linealmente (P

Objectives: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7-12 years later., Design: Prospective cohort study., Settings and Participants: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals., Measurements: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7-12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores., Results: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: -0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: -0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time., Conclusions: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT., Methods: This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels., Results: From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy., Conclusions: Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy., Clinical Trial Registry: ClinicalTrials.gov Identifier: NCT01733628., (© 2024. The Author(s).)

Background: In the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer (ABC)., Objective: We assessed health-related quality of life (QoL) using patient-reported outcomes (PROs)., Design and Methods: In this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively., Results: Of the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p  = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p  = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales., Conclusions: Although TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2- ABC., Trial Registration Number: Sponsor Study Code: GEICAM/2014-12EudraCT Number: 2015-002437-21ClinTrials.gov reference: NCT02690480., Competing Interests: Dr. Tibau has received speaker fees from Novartis and Eisai. Dr. Ramos has received speaker’s bureau from Novartis, Pfizer and Roche Farma. Dr. de La Cruz-Merino has received advisory board fees from MSD-Merk, Roche Farma, Bristol-Myers-Squibb, Pierre-Fabré, Amgen and Novartis; research funding from MSD-Merck, Roche Farma, Celgene; speaking fees from MSD-Merck, Roche Farma, Bristol-Myers-Squibb and Amgen; grant support from Bristol-Myers-Squibb and Roche Farma. Dr. Santaballa has received consulting or advisory role fees from GSK, Clovis, MSD, AstraZeneca, Roche and Pfizer; speakers’ honoraria from GSK, Clovis, Roche, MSD, AstraZeneca and Pfizer; and grant support by Pfizer, GSK and MSD. Dr. Martínez-Jañez has received advisory board fees from Roche Farma, Astra Zeneca, Pfizer, Novartis, Lilly, Daiichi Sankyo, Agendia and Eisai. Dr. Moreno has received advisory board fees from Roche/Genentech, Novartis, Pfizer, AstraZeneca, MSD-Merck and Daiichi Sankyo/AstraZeneca; speaker’s bureau fees from Pfizer; travel accommodations expenses from Roche/Genentech, Pfizer, Novartis, Daiichi Sankyo/Astra Zeneca. Dr. Fernández has received consultant or advisory fees from MSD-Astra Zeneca; speaker’s bureau fees from Pfizer, AstraZeneca, Roche, MSD, Clovis and GSK. Dr. Alarcón: has received honoraria from GSC, Clovis, Roche and AstraZeneca; consulting or advisory board honoraria from GSK and Clovis; speaker and expert testimony fees from GSK, Clovis and Roche; and travel and accommodation support from GSK. Dr. de La Haba-Rodríguez has received speaker’s honoraria from AstraZeneca, Pfizer, Novartis and Lilly. Dr. Sánchez-Rovira has received honoraria from Novartis, Lilly, Pfizer, Roche and Seagen. Dr. Bueno Muiño has received speaker fees from Novartis, Lilly, AstraZeneca, BMS, Pfizer and GSK. Dr. Albanell has received consulting or advisory role fees from Roche, Pfizer, Amgen, MSD, Lilly and Daiichi-Sankyo; research funding or grant support trials by Roche, Pfizer, Amgen, MSD, Lilly, Daiichi-Sankyo; and travel and accommodation support from Roche, Pfizer, Amgen, MSD, Lilly and Daiichi-Sankyo. All remaining authors have declared no conflicts of interest. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre and Takeda. A complete list of the FLIPPER trial collaborators is provided in the Supplemental Appendix., (© The Author(s), 2023.)

Breast cancer (BC) survivors are advised to follow the WCRF/AICR cancer prevention recommendations, given their high risk of developing a second tumour. We aimed to explore compliance with these recommendations in BC survivors and to identify potentially associated clinical and sociodemographic factors. A total of 420 BC survivors, aged 31-80, was recruited from 16 Spanish hospitals. Epidemiological, dietary and physical activity information was collected through questionnaires. A 7-item score to measure compliance with the recommendations was built according to the 2018 WCRF/AICR scoring criteria. Standardized prevalences and standardized prevalence ratios of moderate and high compliance across participant characteristics were estimated using multinomial and binary logistic regression models. The mean score was 3.9 (SD: 1.0) out of 7 points. Recommendations with the worst adherence were those of limiting consumption of red/processed meats (12% of compliance, 95% CI: 8.2-15.0) and high fibre intake (22% of compliance, 95% CI: 17.6-27.0), while the best compliance was observed for the consumption of fruits and vegetables (73% of compliance, 95% CI: 69.2-77.7). Overall, adherence was worse in women with university education and in those with first-degree relatives with BC. This information may be of interest to design and implement personalized preventive measures adapted to the characteristics of these patients.

The Epi-GEICAM study comprises 1017 invasive BC cases matched with controls of similar age (49 ± 9 years) and residence. Diet and OO consumption were collected through a validated food frequency questionnaire. 75% of women referred OO, common (refined) or virgin, as the main fat source. Using conditional logistic regression models, we compared different scenarios of type and frequency of OO consumption, using as reference those women not always using OO for the three culinary practices (seasoning, cooking, and frying) and adding <2 tablespoons (tbsps.) per day during the meal to bread, salad, or dishes. A substantial inverse association was observed in those women always using VOO for the three culinary practices and consuming ≥2 tbsps. of OO per day during meals (adjusted OR, 0.72; 95% CI: 0.51, 1.03; P = 0.07). Potential benefits from OO consumption, at least as regards the protection provided for BC, could be mostly conferred with VOO, and when its consumption is high., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The aim of this study was to evaluate the capacity to return to competition of a 28-yr-old female 400-m hurdle elite athlete after a diagnosis of breast cancer. The study lasted 14 mo after diagnosis. She was tested four times (T1-T4) to measure body mass (BM), body mass index (BMI), percentage of total fat mass (TFM%), total fat-free mass (TFFM%), bone mineral density (BMD), one-repetition maximum (1RM), and maximal power (MP) in bench press and half squat, maximum oxygen uptake, and 400-m dash and hurdles. T0 (baseline time) was established with values before diagnosis. BM and BMI increased from T0 to T1 (5.3% and 5.2%) and remained stable. BMD experienced no change. TFM% values decreased from T1 to T4 (3.5%). TFFM% values increased from T1 to T3 (0.9%). During T1-T2, the athlete presented a global decline from T0 in 1RM Squat , 1RM Bench , MP Squat , and MP Bench (32.6%, 27.2%, 37.5%, and 27.6%, respectively). Results during T3-T4 were also lower for these parameters from T0 (23.3%, 20.6%, 23.4%, and 11%). During T1-T2, the V̇o 2max declined compared with T0 (1.8% and 6.4%), showing a small increase at T3 (+1%) and reaching the lowest level at T4 (9%). During T1-T2, the time record of 400-m dash (8.3%) and hurdles (7.4%) increased. However, a slight improvement was found at T3 (1.3% and 0.6%, respectively). The results of this case study reflect that exercise training improved body composition, maintained BMD and TFFM, but could not completely reverse the worsening of the cardiorespiratory, muscle strength and power, and running performance levels. NEW & NOTEWORTHY This case study follows an elite athlete and measures her performance during cancer treatment. It improves the knowledge on applied physiology showing the details of her training program and demonstrating the strong ability of the athlete to continue training and competing at a high level during antineoplastic treatment. Exercise training improved body composition but failed to restore previous cardiorespiratory, muscle strength and power, and running performance levels.

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon's design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2-37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Background: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive., Objective: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC)., Methods: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime., Results: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood., Conclusions: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk., (© 2021. The Author(s).)

This study evaluates the impact of breast cancer (BC) in health related quality of life (HRQL) and in psychological distress (PD) during the initial phases of the disease and looks for contributing factors. A multicentric case-control study, EpiGEICAM, was carried out. Incident BC cases and age- and residence- matched controls were included. Clinical, epidemiological, HRQL (SF-36) and PD information (GHQ-28) was collected. We used multivariable logistic regression models to estimate OR of low HRQL and of PD in cases compared to controls, and to identify factors associated with low HRQL and with PD. Among 896 BC cases and 890 control women, cases had poorer scores than both, the reference population and the control group, in all SF-36 scales. BC women with lower education, younger, active workers, never smokers, those with comorbidities, in stage IV and with surgical treatment had lower physical HRQL; factors associated with low mental HRQL were dissatisfaction with social support, being current smoker and having children. Cases had a fivefold increased odds of PD compared to controls. Managing comorbidities and trying to promote social support, especially in younger and less educated women, could improve well-being of BC patients.

This study analyzes the association of excessive energy intake and caloric restriction with breast cancer (BC) risk taking into account the individual energy needs of Spanish women. We conducted a multicenter matched case-control study where 973 pairs completed lifestyle and food frequency questionnaires. Expected caloric intake was predicted from a linear regression model in controls, including calories consumed as dependent variable, basal metabolic rate as an offset and physical activity as explanatory. Overeating and caloric restriction were defined taking into account the 99% confidence interval of the predicted value. The association with BC risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. While premenopausal women that consumed few calories (>20% below predicted) had lower BC risk (OR = 0.36; 95% CI = 0.21-0.63), postmenopausal women with an excessive intake (≥40% above predicted) showed an increased risk (OR = 2.81; 95% CI = 1.65-4.79). For every 20% increase in relative (observed/predicted) caloric intake the risk of hormone receptor positive (p-trend < 0.001) and HER2+ (p-trend = 0.015) tumours increased 13%, being this figure 7% for triple negative tumours. While high energy intake increases BC risk, caloric restriction could be protective. Moderate caloric restriction, in combination with regular physical activity, could be a good strategy for BC prevention.

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m 2 ) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard "3 + 3" design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m 2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29-155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376.

The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC.

The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m 2 ) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A "3+3" design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established as the recommended RP2D. The median number of administered cycles was 12 (range, 1 to 18). Grade 3 treatment-related AEs at DL1 were diarrhea ( n = 2), hyponatremia ( n = 1), fatigue ( n = 1), and AST/ALT elevation ( n = 1). A significant reduction in p-SRC expression on epidermal keratinocytes on sequential skin biopsies was observed. In conclusion, we describe the feasibility of the combination of dasatinib, trastuzumab and paclitaxel, and its effect on proteins involved in trastuzumab resistance. The phase II part of this study is currently evaluating efficacy., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest with the content of this study.

Pemetrexed disodium (ALIMTa, [pemetrexed], LY231514; Eli Lilly and Company; Indianapolis, IN), a novel antifolate antimetabolite with multiple enzyme targets involved in both pyrimidine and purine synthesis, has entered clinical trials due to its favorable pleclinical profile. Many studies utilizing the drug, as a single or combination agent, are currently ongoing, including Phase III trials in mesothelioma, nonsmall cell lung carcinoma (NSCLC) and pancreatic cancer. Promising feasibility and activity data have been obtained with pemetrexed in combination with platinum compounds and gemcitabine. The supplementation with daily oral folate could reduce the incidence of hematologic toxicities while preserving the antitumor activity of pemetrexed., (Copyright 2003 American Cancer Society)