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Background Standard oncology tools are inadequate to distinguish which older patients are at higher risk of developing chemotherapy-related complications. Materials and Methods Patients over 70 years of age starting new chemotherapy regimens were prospectively included in a multicenter study. A prechemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and the development of grade 3–5 toxicity was examined by using logistic regression. Results A total of 551 patients were accrued. Chemotherapy doses (odds ratio [OR] 1.834; 95% confidence interval [CI] 1.237–2.719) and creatinine clearance (OR 0.989; 95% CI 0.981–0.997) were the only factors independently associated with toxicity. Only 19% of patients who received reduced doses of chemotherapy and had a creatinine clearance ≥40 mL/minute had grade 3–4 toxicity, compared with 38% of those who received standard doses or had a creatinine clearance Conclusion Chemotherapy doses and renal function were identified as the major risk factors for developing severe toxicity in the older patient. These factors should be considered when planning to initiate a new chemotherapy regimen and should also lead to a closer follow-up in these patients.

Introduction Triple negative breast cancer (TNBC) accounts for 15-20% of the breast cancer and is characterized by an aggressive phenotype and worst prognosis. TNBC does not benefit from any targeted therapy, so further characterization would be needed to define subgroups with potential therapeutic value. Material and methods 125 TNBC paraffin samples were analyzed using high-throughput proteomics based on SWATH-MS. Survival analyses and a prognostic predictor were done using BRB Array Tools. Proteins related with disease-free survival were established and, then, a prognostic signature was built based on their p-values. Results and discussion Using SWATH-MS, 1,206 proteins were identified in a cohort of 125 TNBC tumors. Of these 1,206 proteins, 29 proteins were related with disease-free survival. In addition, a prognostic signature based on the expression of two proteins, RMB3 and NIPSNAP1, was defined. The predictor split our population into a low-risk and a high-risk group (p=0.0002, HR= 6.519). Multivariate analysis showed that the prognostic signature based on the expression of these two proteins supplied significant information to the clinical parameters. Conclusion SWATH-MS proteomics demonstrates its utility in the analysis of TNBC paraffin samples. Moreover, this proteomics data allows us to build a prognostic signature based on the expression of two proteins (RBM3 and NIPSNAP1). This prognostic signature could be used in the future to identify a population with a high-risk of relapse that may be directed to a clinical trial. Citation Format: Pilar Zamora Auñon, Silvia García Adrián, Lucia Trilla-Fuertes, Angelo Gámez-Pozo, Guillermo Prado-Vázquez, Andrea Zapater-Moros, Mariana Díaz- Almirón, Rocío López Vacas, Cristina Chiva, Cristina Chiva, Eduard Sabidó, Enrique Espinosa Arranz, Juan Ángel Fresno Vara. Disease-free survival prognostic signature in triple-negative breast cancer based on high-throughput proteomics data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-42.

Biological therapies, such as TNF inhibitors (TNFi), are increasing remission (REM) rates in rheumatoid arthritis (RA) patients, although these are still limited. The aim of our study was to analyze changes in the profile of peripheral blood mononuclear cells (PBMC) in patients with RA treated with TNFi in relation to the clinical response. This is a prospective and observational study including 78 RA patients starting the first TNFi. PBMC were analyzed by flow cytometry both at baseline and at 6 months. Disease activity at the same time points was assessed by DAS28, establishing DAS28 ≤ 2.6 as the criteria for REM. Logistic regression models were employed to analyze the association between the changes in PBMC and REM. After 6 months of TNFi treatment, 37% patients achieved REM by DAS28. Patients who achieved REM showed a reduction in the percentage of naive B cells, but only when patients had received concomitant methotrexate (MTX) (OR: 0.59; 95% CI: 0.39–0.91). However, no association was found for patients who did not receive concomitant MTX (OR: 0.85; 95% CI: 0.63–1.16). In conclusion, PBMC, mainly the B-cell subsets, are modified in RA patients with TNFi who achieve clinical REM. A significant decrease in naive B-cell percentage is associated with achieving REM after 6 months of TNFi treatment in patients who received concomitant therapy with MTX.

Background: Estimation of life expectancy in older patients is relevant to select the best treatment strategy. We aimed to develop and validate a score to predict early mortality in older patients with cancer. Patients and Methods: A total of 749 patients over 70 years starting new chemotherapy regimens were prospectively included. A prechemotherapy assessment that included sociodemographic variables, tumor/treatment variables, and geriatric assessment variables was performed. Association between these factors and early death was examined using multivariable logistic regression. Score points were assigned to each risk factor. External validation was performed on an independent cohort. Results: In the training cohort, the independent predictors of 6-month mortality were metastatic stage (OR 4.8, 95% CI [2.4–9.6]), ECOG-PS 2 (OR 2.3, 95% CI [1.1–5.2]), ADL≤5 (OR 1.7, 95% CI [1.1–3.5]), serum albumin levels ≤ 3.5 g/dL (OR 3.4, 95% CI [1.7–6.6]), BMI &lt, 23 kg/m2 (OR 2.5, 95% CI [1.3–4.9]), and hemoglobin levels &lt, 11 g/dL (OR 2.4, 95% CI (1.2–4.7)). With these results, we built a prognostic score. The area under the ROC curve was 0.78 (95% CI, 0.73 to 0.84), and in the validation set, it was 0.73 (95% CI: 0.67–0.79). Conclusions: This simple and highly accurate tool can help physicians making decisions in elderly patients with cancer who are planned to initiate chemotherapy treatment.

[Objective]: Describe the GETH haploidentical stem cell transplantation (haplo‐HSCT) activity in non‐malignant disease (NMDs)., [Methods]: We retrospectively analyzed data from children with NMDs who underwent haplo‐HSCT., [Results]: From January 2001 to December 2016, 26 pediatric patients underwent 31 haplo‐HSCT through ex vivo T cell‐depleted (TCD) graft platforms or post‐transplantation cyclophosphamide (PT‐Cy) at 7 Spanish centers. Five cases employed unmanipulated PT‐Cy haplo‐HSCT, 16 employed highly purified CD34+ cells, and 10 employed ex vivo TCD grafts manipulated either with CD3+CD19+ depletion, TCRαβ+CD19+ selection or naive CD45RA+ T‐cell depletion. Peripheral blood stem cells were the sole source for patients following TCD haplo‐HSCT, and bone marrow was the source for one PT‐Cy haplo‐HSCT. The most common indications for transplantation were primary immunodeficiency disorders (PIDs), severe aplastic anemia, osteopetrosis, and thalassemia. The 1‐year cumulative incidence of graft failure was 27.4%. The 1‐year III‐IV acute graft‐versus‐host disease (GvHD) and 1‐year chronic GvHD rates were 34.6% and 16.7%, respectively. The 2‐year overall survival was 44.9% for PIDs, and the 2‐year graft‐versus‐host disease‐free and relapse‐free survival rate was 37.6% for the other NMDs. The transplantation‐related mortality at day 100 was 30.8%., [Conclusion]: Although these results are discouraging, improvements will come if procedures are centralized in centers of expertise., This work was supported in part by the National Health Service of Spain, Carlos III Health Institute (ISCIII), FONDOS FEDER grant (FIS) PI18/01301, the CRIS Cancer Foundation (http://criscancer.org), and the Association Pablo Ugarte (http://www.asociacionpablougarte.es/).

BACKGROUND Patients with asthma exacerbations and frequent relapses that require admission to the emergency department (ED) often have more severe disease, worse quality of life, and higher use of health care resources. OBJECTIVE The aim of this study was to identify potential predictors of relapse after patients are treated in an ED for an asthma exacerbation. METHODS A retrospective, noninterventional cohort study was conducted in adult patients who attended the ED of a tertiary hospital in 2014 for an asthma exacerbation. We analyzed the subpopulation who experienced at least one relapse (returned to the ED < 15 days after the previous event). RESULTS Fifty-two of 831 patients experienced 66 relapses after going to the ED (mean ± standard deviation [SD] age, 58.5 ± 23.4 years). The average ± SD probability of a relapse was 6 ± 0.8%. The frequency of episodes was higher in May and November. Twenty-four patients had ≥260 blood eosinophils/μL, including 17 who had ≥400 eosinophils/μL. Only 15% of the patients were referred to an asthma specialist at discharge. Factors related to a higher probability of relapse were the following: having multiple visits to the ED in 1 year, uncontrolled asthma, wheezing in the pulmonary auscultation, peripheral eosinophilia with ≥400 eosinophils/ μL, and being discharged in the first visit to the ED (p < 0.01 for all). CONCLUSION In this population, patients who had multiple ED visits in 1 year, those with uncontrolled asthma, wheezing, ≥400 blood eosinophils/μL, or who had been discharged at the first ED visit are at higher risk of relapse.

Breast cancer is the most frequent tumor in women and its incidence is increasing. Neoadjuvant chemotherapy has become standard of care as a complement to surgery in locally advanced or poor-prognosis early stage disease. The achievement of a complete response to neoadjuvant chemotherapy correlates with prognosis but it is not possible to predict who will obtain an excellent response. The molecular analysis of the tumor offers a unique opportunity to unveil predictive factors. In this work, gene expression profiling in 279 tumor samples from patients receiving neoadjuvant chemotherapy was performed and probabilistic graphical models were used. This approach enables addressing biological and clinical questions from a Systems Biology perspective, allowing to deal with large gene expression data and their interactions. Tumors presenting complete response to neoadjuvant chemotherapy had a higher activity of immune related functions compared to resistant tumors. Similarly, samples from complete responders presented higher expression of lymphocyte cell lineage markers, immune-activating and immune-suppressive markers, which may correlate with tumor infiltration by lymphocytes (TILs). These results suggest that the patient’s immune system plays a key role in tumor response to neoadjuvant treatment. However, future studies with larger cohorts are necessary to validate these hypotheses.

Abiraterone and enzalutamide are two oral novel androgen receptor axis-targeted agents approved for the treatment of castration-resistant prostate cancer (mCRPC). Despite the availability of multiple treatments, there is a need to improve the knowledge and management of these drugs in the real-world setting, especially in patient groups under-represented in clinical trials. Our aim was to review the outcome of patients with chemotherapy-naïve mCRPC treated with abiraterone or enzalutamide in routine clinical practice in order to identify factors that are predictive for response.This observational retrospective study was performed in a Spanish tertiary hospital and included men with chemotherapy-naïve mCPRC who started treatment with abiraterone or enzalutamide between September 2012 and November 2018. The study end date was 30 October 2020.Ninety patients with mCRPC were included, 57 with abiraterone and 33 with enzalutamide. Median overall survival (OS) was 26.87 months (95% CI 19.68 to 34.05), with no difference found between the two treatment groups. Nine variables were related to increased OS in the univariate analysis: Eastern Cooperative Oncology Group (ECOG) performance status (0-1 vs 2), pain (need of opioids for cancer pain), visceral disease, ≥3 bone lesions, exclusively lymph node metastases, baseline prostate specific antigen (PSA) (50 vs ≥50 ng/dL and20 vs ≥20 ng/dL), haemoglobin (12 vs ≥12 g/dL) and alkaline phosphatase (≤116 vs116 IU/L). A PSA response50% was observed in 65 patients (76.5%). In the multivariate analysis, ECOG performance status, pain, visceral disease and alkaline phosphatase provided independent prognostic information. Median OS by Kaplan-Meier analysis was significantly longer for patients with a PSA response (32.1 vs 17.9 months; HR 0.46, 95% CI 0.27 to 0.78; p=0.003).This study assessed the efficacy of abiraterone and enzalutamide in a real-world setting, including patients under-represented in pivotal studies. Some clinical factors were correlated with improved OS in chemotherapy-naïve men with mCPRC treated with these drugs.

Introduction: Abdominal fat and its increment over time in particular has become a cardiovascular risk factor in uraemic patients. Objectives: To analyse changes in abdominal fat in haemodialysis patients over one year and study their possible correlation with the variation in adipocytokine serum levels. As a secondary objective, we tried to validate the data obtained by bioelectrical impedance analysis (BIA) with data obtained by dual X-ray absorptiometry (DXA). Material and methods: A prospective one-year study was performed in 18 patients on haemodialysis (HD). In each patient, body composition by BIA and DXA was estimated at baseline and after one year. Several adipocytokine and biochemical parameters were determined. Results: A significant increase in phase angle [4.8° (4.1–5.6) vs. 5.2° (4.4–5.8), p

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which had a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 96 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as mitochondrial function or extracellular matrix between breast cancer subtypes, including our new defined subtype TN-like. In addition, one of the components, mainly related with extracellular matrix processes, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context., PLoS ONE, 15 (6), ISSN:1932-6203

Aims:Differences in metabolism among breast cancer subtypes suggest that metabolism plays an important role in this disease. Flux Balance Analysis is used to explore these differences as well as drug response.Materials & Methods:Proteomics data from breast tumors were obtained by mass-spectrometry. Flux Balance Analysis was performed to study metabolic networks. Flux activities from metabolic pathways were calculated and used to build prognostic models.Results:Flux activities of vitamin A, tetrahydrobiopterin and beta-alanine metabolism pathways split our population into low- and high-risk patients. Additionally, flux activities of glycolysis and glutamate metabolism split triple negative tumors into low- and high-risk groups.Conclusions:Flux activities summarize Flux Balance Analysis data and can be associated with prognosis in cancer.

Triple-negative breast cancer is a heterogeneous disease characterized by a lack of hormonal receptors and HER2 overexpression. It is the only breast cancer subgroup that does not benefit from targeted therapies, and its prognosis is poor. Several studies have developed specific molecular classifications for triple-negative breast cancer. However, these molecular subtypes have had little impact in the clinical setting. Gene expression data and clinical information from 494 triple-negative breast tumors were obtained from public databases. First, a probabilistic graphical model approach to associate gene expression profiles was performed. Then, sparse k-means was used to establish a new molecular classification. Results were then verified in a second database including 153 triple-negative breast tumors treated with neoadjuvant chemotherapy. Clinical and gene expression data from 494 triple-negative breast tumors were analyzed. Tumors in the dataset were divided into four subgroups (luminal-androgen receptor expressing, basal, claudin-low and claudin-high), using the cancer stem cell hypothesis as reference. These four subgroups were defined and characterized through hierarchical clustering and probabilistic graphical models and compared with previously defined classifications. In addition, two subgroups related to immune activity were defined. This immune activity showed prognostic value in the whole cohort and in the luminal subgroup. The claudin-high subgroup showed poor response to neoadjuvant chemotherapy. Through a novel analytical approach we proved that there are at least two independent sources of biological information: cellular and immune. Thus, we developed two different and overlapping triple-negative breast cancer classifications and showed that the luminal immune-positive subgroup had better prognoses than the luminal immune-negative. Finally, this work paves the way for using the defined classifications as predictive features in the neoadjuvant scenario.

12030 Background: Determining life expectancy in older patients is needed to select the best treatment strategy. We aimed to develop and validate a score to predict early death risk ( < 6 months) in elderly patients with cancer that are planned to initiate chemotherapy treatment. Methods: Patients over 70 years starting new chemotherapy regimens were prospectively included in a multicenter study. A pre-chemotherapy assessment that included sociodemographics, tumor/treatment variables, and geriatric assessment variables, was performed. Association between these factors and early death was examined by using multivariate logistic regression. Score points were assigned to each risk factor based on their b coefficient. We validated the risk score with an external validation cohort of 206 patients. Results: Three hundred forty two patients were included in the training cohort. The independent predictors for early death were metastasic cancers (odds ratio [OR] 4.8, 95% confidence interval [CI], [2.4-9.6]), ECOG performance status (OR 2.3, 95% CI:1.084-5.232), ADL (OR 1.7, 95% CI:1.08-3.5), serum albumin levels (3.3, 95% CI: 1.6-6.6), BMI (OR 2.4, 95% CI:1,2-4.8), serum GGT levels (OR 1.5, 95% CI:1.05-1.8) and hemoglobin levels (OR 2.3, 95% CI:1.2-4.6). With these results, a score was to stratify patients regarding their risk of early death: low (0 to 2 points; 5%), intermediate (3 to 5 points; 19%) or high (6 to 14 points; 50%) (p < 0.001). The area under the curve of the receiver-operating characteristic (ROC) curve was 0.79 for the training cohort (95% CI, 0.74 to 0.85), and 0.70 (95% CI: 0.60-0.80) for the validation cohort (difference between cohorts not statistically different). Conclusions: We developed a highly accurate tool that uses basic clinical and analytical information to predict the probability of early death in elderly patients with cancer that are planned to initiate chemotherapy treatment. This tool can help physicians in decision making for this population of patients.

Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which has a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 106 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as metastasis or proliferation between breast cancer subtypes, including our new subtype TN-like. In addition, one of the components, mainly related with metastasis, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.Author SummaryBreast cancer classification in the clinical practice is defined by three biomarkers (estrogen receptor, progesterone receptor and HER2) into hormone receptor positive, HER2+ and triple negative breast cancer (TNBC). Our group recently described a new ER+ subtype with molecular characteristics and prognosis similar to TNBC. In this study we propose a mathematical method, the Bayesian networks, as a useful tool to study protein interactions and differential biological processes in breast cancer subtypes, characterizing differences in relevant processes such as proliferation or metastasis and associated them with patient prognosis.

BACKGROUND Surgery for the primary tumor in metastatic breast cancer is usually not recommended, assuming that local therapy provides no advantage. Recent reports suggest a survival improvement after locoregional treatment, but this is still controversial. We aimed to evaluate the effectiveness of locoregional treatment in primary metastatic breast cancer and to determine associated factors. METHODS A retrospective analysis of 39 women with de-novo metastatic breast cancer at La Paz University Hospital, from January 2012 to June 2016, grouped by locoregional treatment (n=23) or not (n=16). Multivariate assessment of prognostic factors was performed using Cox regression analysis. RESULTS Mean tumor size was 6 cm. Eighteen patients (46.2%) had multifocal tumors, 29 (74.4%) multicentric and 10 (25.7%) bilateral breast cancer. Eighteen patients (46.2%) had an oligometastatic disease and 21 (53.8%) multiorgan metastatic disease. The average time from diagnosis to surgery was 7.7 months, without delay in the start of systemic treatment compared to the no-surgery group. The main surgical procedure was mastectomy in 18 (78.3%) patients. Half of the patients survived 48 months (95% CI: 39-57). In the multivariate analysis, we have not detailed differences in survival by age, chemotherapy, neoadjuvancy, number of systemic treatment lines, radiotherapy, and tumor histology or grade. However, surgery (HR=0.2; 95% CI: 0.07-0.57) and high tumor burden (HR=2.96, 95% CI: 1.23-7.13) have acted as a protective and a risk factor respectively. CONCLUSIONS Our cohort supports that locoregional treatment in selected patients with de-novo MBC significantly improved survival, so it might be considered in combination with systemic therapy.

Background The molecular analysis of melanoma has improved our understanding of the disease. The Cancer Genome Atlas (TCGA) Network proposed the molecular classification of melanoma in three subtypes: keratin-high, immune-high and membrane-low. However, this classification has not translated into therapeutic advances so far. Immunotherapy has contributed to improve survival, yet the mechanisms explaining differences in efficacy have not been elucidated. The aim of this study is to characterize the immune status of melanoma tumors through gene expression, and to analyze if these differences have an impact in the response to immunotherapy. Methods A probabilistic graphical model, followed by successive sparse k-means and consensus cluster analyses, was used to classify melanoma tumor samples from the TCGA cohort. Findings were translated into a cohort of patients treated with anti-PD1 antibodies (GSE78220, Hugo W et al) as a validation dataset. Results A probabilistic graphical model, including the 2,971 more variable genes from 472 melanoma samples from the TCGA dataset was built, and the resulting graph was processed to seek functional structures. Sparse k-means selected 119 genes. Gene ontology analysis showed that these genes were mainly related with immune processes. Immune genes split the population into two groups with different immune status. The so-called immune-high group included 232 patients (49%) and the immune-low group groups 238 patients (51%). The validation dataset GSE78220 provided mRNA expression in melanomas being treated with anti-PD-1 antibodies (28 biopsies belonging to 27 patients). The immune layer was translated to the new cohort by centroid method: 9 patients had immune-low tumors, whereas the remaining 18 had immune-high tumors. Kaplan Meier analysis using the clinical data from the GSE78220 cohort found a favorable response in patients with immune-low tumors (90% long-term survival). Conclusions We found a gene signature related to the tumor immune status that split the TCGA cohort in two groups. When applied to a cohort of patients treated with anti-PD1 antibodies, the group with immune-low tumors had 90% of long-term survival. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Breast cancer is a heterogeneous disease comprising a variety of entities with various genetic backgrounds. Estrogen receptor-positive, human epidermal growth factor receptor 2-negative tumors typically have a favorable outcome; however, some patients eventually relapse, which suggests some heterogeneity within this category. In the present study, we used proteomics and miRNA profiling techniques to characterize a set of 102 either estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) or triple-negative formalin-fixed, paraffin-embedded breast tumors. Protein expression-based probabilistic graphical models and flux balance analyses revealed that some ER+/PR+ samples had a protein expression profile similar to that of triple-negative samples and had a clinical outcome similar to those with triple-negative disease. This probabilistic graphical model-based classification had prognostic value in patients with luminal A breast cancer. This prognostic information was independent of that provided by standard genomic tests for breast cancer, such as MammaPrint, OncoType Dx and the 8-gene Score, The authors would like to acknowledge funding from grants PI12/00444, PI12/01016 and PI15/01310 from the Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry, Spain, and co-funded by the FEDER program, “Una forma de hacer Europa”. This study has also been supported by the PRIME-XS project, grant agreement number 262067, funded by the EU’s Seventh Framework Program for Research. AG-P and RL-V are supported by Instituto de Salud Carlos III, and the Spanish Economy and Competitiveness Ministry grants, CA12/00258 and CA12/00264, respectively. . We want to particularly acknowledge the patients in this study for their participation and to the IdiPAZ, I+12 and O+EHUN Biobanks for the generous gifts of clinical samples used in this study. LT-F is supported by the Spanish Economy and Competitiveness Ministry (DI-15-07614). IdiPAZ, I+12 and O+EHUN Biobanks are supported by Instituto de Salud Carlos III, Spanish Economy and Competitiveness Ministry (RD09/0076/00073, RD09/0076/00118 and RD09/0076/00140, respectively) and FarmaIndustria, through the Cooperation Program in Clinical and Translational Research of the Community of Madrid and Basque Autonomous Community

BACKGROUND Risk factors for asthma exacerbations are not fully understood. The aim of this study was to determine the epidemiological and clinical characteristics of patients with an asthma exacerbation, potential triggers, and possible predictors of hospitalization. METHODS A retrospective, non-interventional cohort study was conducted in adult patients who attended the Emergency Department of a tertiary hospital with an asthma exacerbation during 2014. RESULTS 831 patients (888 events) were included. The highest number of episodes occurred in January and May. Respiratory infection was considered the trigger in 523 events. 34.21% had ≥260 eosinophils/mm3 (20.7%≥400 eosinophils/mm3), significantly associated with allergic asthma (p

Introduction Breast cancer is one of the most prevalent cancers in the world. Traditionally, early breast cancer treatment is based on surgery and, after surgery, hormone treatment or chemotherapy. However, the neoadjuvant treatment is increasingly used. Metabolomics is the most recent ‘omics’ which allows quantify metabolites into blood patient samples. Coupled with computational analyses it could be possible to study differential metabolomics patterns and associate them with neoadjuvant response. Material and methods Blood plasma samples from patients with breast cancer treated with neoadjuvant chemotherapy were used to perform metabolomics experiments. One sample before the treatment (basal) and one sample after the chemotherapy (post-treatment) were analysed and clinical data regarding response (complete response or partial response) was also collected. Metabolomics experiments were performed using liquid chromatography coupled with mass-spectrometry.). Bayesian network and class comparison analyses were used to establish differential metabolic patterns between conditions. Additionally, a response prediction model based on logistic regression was build using metabolomics data from basal samples. Results and discussions A network showing the relationships between metabolites was build. Comparing metabolite measurements between complete response and partial response tumours in basal samples, 19 metabolites showed a differential quantification between both types of responses. Moreover, one of these metabolites is linoleic acid, previously described as a biomarker of complete response in neoadjuvant treatment in breast cancer. Using these 19 differential metabolites, a response predictive model was build. According to this model, it is possible to predict response to neoadjuvant treatment based on the amount of one metabolite, still only identified by its mass and charge. On the other hand, comparing basal and post-treatment samples, the network showed differential metabolomics patterns. These differential metabolites could be used as predictive biomarkers of response. Conclusion This study is a proof of concept that using a new ‘omics’ technique such as metabolomics in blood samples, coupled with computational analyses, it is possible to identify differential metabolomics patterns between complete and partial response or basal and post-treatment samples and design predictive models of response These results could facilitate in the future the implementation of blood-based tests into the clinical routine.

Introduction Breast cancer is one of the most prevalent cancers in the world. In previous works we observed differences in glucose metabolism between breast cancer subtypes, suggesting that metabolism plays an important role in this disease. Flux Balance Analysis (FBA) is widely used to study metabolic networks, allowing predicting growth rates or the rate of production of a given metabolite. Material and methods Proteomics data from 96 breast cancer tumours were obtained applying a high-throughput proteomics approach to routinely archive formalin-fixed, paraffin-embedded tumour tissue. Proteomics tumour data were analysed using the human metabolic reconstruction Recon2 and FBA. The tumour growth rate for each tumour was calculated. In order to analyse fluxes from the different metabolic pathways, flux activities were calculated as the sum of the fluxes of each reaction in each pathway defined in the Recon2. Then, flux activities were used to build prognostic models. Results and discussions Using the results obtained from FBA in the proteomics dataset, flux activities were calculated for each pathway. Employing these flux activities, a prognostic signature was built. Flux activities of vitamin A, tetrahydrobiopterin metabolism, and beta-alanine metabolism pathways split our population into a low and a high-risk group (p=0.044). Conclusion Vitamine A, beta-alanine and tetrahydrobiopterin metabolism flux activities could be used to predict relapse risk. Flux activities is a method proposed in a previous work to study response against drugs that now also demonstrated its utility in summarising FBA data and is associated with prognosis.

Objective To evaluate the efficacy of 1% topical cidofovir cream for the treatment of anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals. Design Single-arm, open-label, pilot clinical trial. Methods The study medication was applied intraanally three times per week for 4 weeks. Lesions were assessed with high-resolution anoscopy and biopsy at weeks 12 and 24. The primary endpoint was complete remission (CR) at week 12, defined as clinical and histological remission. We also evaluated partial remission defined as regression to low-grade squamous intraepithelial lesion. Results We included 17 HIV-infected patients with intraanal HSIL. Median (interquartile range) age was 36 years (28-41), median (interquartile range) CD4 cell count was 545 cells/μl (358-630), and viral load was less than 50 copies/ml in 93.7%. Two patients were lost to follow-up, one of them did not apply treatment. At 12 weeks, in the intention-to-treat population, 10 out of 16 patients [62.5%; 95% confidence interval (CI), 38.2-85.7%] had achieved CR. At 24 weeks, seven of the 10 patients (70%; 95% CI, 47-93%) remained in CR, but two out of 10 patients (20%; 95% CI, 0-40%) presented HSIL. One patient did not attend the visit at 24 weeks. Three patients with persistent HSIL at 12 weeks improved at 24 weeks (partial response in one and CR in two). The mean number of human papillomavirus genotypes decreased from 5.2 to 2.7 at 12 weeks (P = 0.002). Local adverse effects were frequent (81%), although there were no discontinuations because of adverse events. Conclusion One percent topical cidofovir could be an appropriate alternative therapy in HIV-infected patients with anal HSIL. Clinical trial gov unique identifier: NCT01946009.

Background Human fibroblast growth factor 21 (FGF-21) is an endocrine liver hormone that stimulates adipocyte glucose uptake independently of insulin, suppresses hepatic glucose production and is involved in the regulation of body fat. Peritoneal dialysis (PD) patients suffer potential interference with FGF-21 status with as yet unknown repercussions. Objectives The aim of this study was to define the natural history of FGF-21 in PD patients, to analyze its relationship with glucose homeostasis parameters and to study the influence of residual renal function and peritoneal functional parameters on FGF-21 levels and their variation over time. Methods We studied 48 patients with uremia undergoing PD. Plasma samples were routinely obtained from each patient at baseline and at 1, 2 and 3 years after starting PD therapy. Results Plasma FGF-21 levels substantially increased over the first year and were maintained at high levels during the remainder of the study period (253 pg/ml (59; 685) at baseline; 582 pg/ml (60.5–949) at first year and 647 pg/ml (120.5–1116.6) at third year) (p

Advanced oxidation protein products (AOPPs) are considered as markers and even mediators of the proinflammatory effect of oxidative stress in uremia. We hypothesized that an increase of oxidative stress associated with peritoneal dialysis (PD), estimated by the variation of plasma AOPPs over time, might be associated with cardiovascular (CV) risk and overall prognosis. In 48 PD patients, blood samples were collected on two occasions: the first one in the first six months after starting PD therapy and the second one, one year after. The plasma AOPPs level variation over the first year on PD was significantly associated with CV antecedents and also with CV prognosis. In those patients in whom the AOPPs levels increased more than 50% above the baseline value, a significant association with past and future CV disease was confirmed. These patients had 4.7 times greater risk of suffering later CV disease than those with a smaller increase, even after adjusting for previous CV history. Our data suggest that the increase of AOPPs plasma level over the first year on PD is conditioned by CV antecedents but also independently predicts CV prognosis. AOPPs plasma levels seem to represent the CV status of PD patients with sufficient sensitivity to identify those with a clearly sustained higher CV risk.

Objetivo: Relacionar los niveles de hormonas esteroideas foliculares con el ciclo de estimulación ovárica y sus resultados globales. Métodos: Se incluyeron pacientes ≤ 38 años, con esterilidad de causa masculina, tubárica o desconocida, que recibieron un protocolo largo con agonistas de GnRH y rFSH. Se recogieron las muestras de la primera y segunda aspiración folicular de cada ovario y se realizó un quimioinmunoanálisis de estradiol, progesterona, testosterona y DHEAS. Resultados: Se obtuvieron cifras menores de DHEAS folicular en las pacientes con más días de frenado con agonistas de GnRH (p=0,0003). Cuantos más días de rFSH administrados, mayores fueron los niveles de testosterona y DHEAS folicular (p=0,03; p=0,03). En los resultados globales del ciclo, se obtuvo una correlación negativa entre las cifras de testosterona folicular y el número de complejos puncionados (r= -0,360; p=0,002) y entre la testosterona folicular y el número de embriones de calidad D (r= -0,233; p=0,047). El número de ovocitos maduros fue menor en pacientes con mayores niveles de testosterona folicular (p=0,008). La progesterona folicular fue superior en ovocitos de buena calidad frente a los de calidad no destacable (p=0,006) y muy mala calidad (p=0,04). Conclusiones: Las cifras altas de testosterona folicular se correlacionaron con menor número de complejos puncionados, ovocitos maduros y embriones de calidad D. La buena calidad ovocitaria se asoció a niveles de progesterona folicular superiores. Objective: To relate the levels of follicular steroid hormones with the ovarian stimulation cycle and its overall results. Method: It was included patients ≤ 38 years old with sterility of male, tubaric or unknown origin who underwent a long protocol with GnRH agonists and rFSH. Samples were obtained from the first and second follicular aspiration of each ovary. A chemiluminescent immunoassay of estradiol, progesterone, testosterone and DHEAS was performed. Results: Figures of follicular DHEAS decreased as the days of treatment with GnRH agonists increased (p=0.0003) and levels of follicular testosterone and DHEAS increased along with the days of treatment with rFSH (p=0.03, p=0.03). In regard to the outcomes of the overall cycle it was found a negative correlation between follicular testosterone levels and the number of punctured complexes (r= -0.360; p=0.002) and between follicular testosterone and the number of D quality embryos (r= -0.233; p=0.047). The number of mature oocytes was lower in patients with higher levels of follicular testosterone (p=0.008). Follicular progesterone was higher in good quality oocytes as compared to those of no remarkable quality (p=0.006) and very poor quality (p=0.04). Conclusions: High levels of follicular testosterone were correlated with a fewer number of punctured complexes, mature oocytes and D quality embryos. Good oocyte quality was associated with higher follicular progesterone levels.