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Introduction The number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer. Methods Data from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008–2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity. Results The mean age was 58.7 (range: 18–87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7). Conclusions This retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.

Background CH5126766 (also known as VS-6766, and previously named R05126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. Methods We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or inetastatic solid tumours. For the basket doseexpansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4.0 mg or 3.2 mg CH5126766 three times per week; (2) 4.0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4.0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. Findings Between June 5,2013, and Jan 10,2019,58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2.3 months (IQR 1.6-3.5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4.0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3.2 mg CH5126766 three times per week. 4.0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%1), hypoalbuminaemia (six [11%]), and fatigue (four [7%1). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11.6-47.8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. Interpretation To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Purpose: Drug-induced interstitial lung disease (DILD) is a rare, but potentially fatal toxicity. Clinical and radiological features of DILD in the early experimental setting are poorly described. Patients and Methods: A total of 2,499 consecutive patients with advanced cancer on phase I clinical trials were included. DILD was identified by a dedicated radiologist and investigators, categorized per internationally recognized radiological patterns, and graded per Common Terminology Criteria for Adverse Events (CTCAE) and the Royal Marsden Hospital (RMH) DILD score. Clinical and radiological features of DILD were analyzed. Results: Sixty patients overall (2.4%) developed DILD. Median time to onset of DILD was 63 days (range, 14–336 days). A total of 45% of patients who developed DILD were clinically asymptomatic. Incidence was highest in patients receiving drug conjugates (7.4%), followed by inhibitors of the PI3K/AKT/mTOR pathway (3.9%). The most common pattern seen was hypersensitivity pneumonitis (33.3%), followed by nonspecific interstitial pneumonia (30%), and cryptogenic organizing pneumonia (26.7%). A higher DILD score [OR, 1.47, 95% confidence interval (CI), 1.19–1.81; P < 0.001] and the pattern of DILD (OR, 5.83 for acute interstitial pneumonia; 95% CI, 0.38–90.26; P = 0.002) were significantly associated with a higher CTCAE grading. The only predictive factor for an improvement in DILD was an interruption of treatment (OR, 0.05; 95% CI, 0.01–0.35; P = 0.01). Conclusions: DILD in early-phase clinical trials is a toxicity of variable onset, with diverse clinical and radiological findings. Radiological findings precede clinical symptoms. The extent of the affected lung parenchyma, scored by the RMH DILD score, correlates with clinical presentation. Most events are low grade, and improve with treatment interruption, which should be considered early.

Background and purpose Limited information is available on incidence and outcomes of COVID‐19 in patients with multiple sclerosis (MS). This study investigated the risks of SARS‐CoV‐2 infection and COVID‐19‐related outcomes in patients with MS, and compared these with the general population. Methods A regional registry was created to collect data on incidence, hospitalization rates, intensive care unit admission, and death in patients with MS and COVID‐19. National government outcomes and seroprevalence data were used for comparison. The study was conducted at 14 specialist MS treatment centers in Madrid, Spain, between February and May 2020. Results Two‐hundred nineteen patients were included in the registry, 51 of whom were hospitalized with COVID‐19. The mean age ± standard deviation was 45.3 ± 12.4 years, and the mean duration of MS was 11.9 ± 8.9 years. The infection incidence rate was lower in patients with MS than the general population (adjusted incidence rate ratio = 0.78, 95% confidence interval [CI] = 0.70–0.80), but hospitalization rates were higher (relative risk = 5.03, 95% CI = 3.76–6.62). Disease severity was generally low, with only one admission to an intensive care unit and five deaths. Males with MS had higher incidence rates and risk of hospitalization than females. No association was found between the use of any disease‐modifying treatment and hospitalization risk. Conclusions Patients with MS do not appear to have greater risks of SARS‐CoV‐2 infection or severe COVID‐19 outcomes compared with the general population. The decision to start or continue disease‐modifying treatment should be based on a careful risk–benefit assessment., In this multicenter registry‐based cohort study, patients with multiple sclerosis did not have an increased risk of becoming infected with COVID‐19 compared with the general population, and were not more likely to have a severe outcome of COVID‐19 (i.e., admission to an intensive care unit or death). No relationship was found between the use of any disease‐modifying treatment and the development of severe COVID‐19 disease.

BackgroundGrowth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. Recent research has though indicated a prominant role in modulation of the tumor microenvironment and the immune synapse, too1 2 indicating that GDF-15 may be a major tumor-derived immunosuppressant. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [Front Immunol 2020 May 19;11:951]. To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15.MethodsThis is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments, including prior anti-PD1/-PD-L1 treatment, and present with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for ”GDF-15 Antibody-mediaTed Effector cell Relocation”.Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect)In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a ”mono-followed-by-combination”-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination.The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 4 is ongoing at time of submission (07/2021) and so far no DLT has occurred. Updated safety, biomarker and response assessments will be reported at the meeting. The ClinicalTrials.gov Identifier is NCT04725474. For more information please contact info@catalym.com.Trial RegistrationNCT04725474ReferencesWischhusen J, Wistuba-Hamprecht K, Harter PN, Cheng P, Martens A, Gogolla F, Nonomura Y, Romer P, Koch SD, Haake M, Schuberth-Wagner C, Rudiger M, Leo E, Mittelbronn M, Levesque MP, Hackl H, Dummer R, Weide B. Identifying GDF-15 as potential novel immunotherapeutic target linked to immune cell exclusion in tumors and resistance to anti-PD-1 treatment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27–28 and Jun 22–24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl): Abstract nr 2161.Hurt E, Thomas S, Mulgrew K, Blackmore S, Moynihan J, Cusdin F, Dodd R, Cariuk P, Sigurdardottir A, Brannigan E, Dobson C, Kumar R, Cobbold M. AZD8853: A novel antibody targeting GDF15 for immunotherapy refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10–15 and May 17–21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl): Abstract nr 1828.Ethics ApprovalAll participants gave informed consent prior to participation. EC approval by Gobierno de Navarra, Departamento de Salud, EC_2020/30, Dated: Oct 13, 2020 in Pamplona, Spain. Respective additional national lead EC approvals for Germany (Ethikkommission der Universität Würzburg, 203–20ff of Oct 26, 2020) and Switzerland (Kantonale Ethikkommission Zürich, 2020–02308 of Nov 24, 2020).

Key Points Question Do patients receiving abiraterone acetate with prednisone as first-line therapy for the treatment of metastatic castration-resistant prostate cancer with bone metastases benefit from the addition of bone resorption inhibitors? Findings In this cohort study of 745 patients receiving first-line abiraterone acetate with prednisone for the treatment of metastatic castration-resistant prostate cancer with bone metastases, the use of concomitant bone resorption inhibitors was associated with improvements in overall survival, particularly among those with a high volume of disease. Meaning These findings suggest that the addition of bone resorption inhibitors to abiraterone acetate with prednisone as first-line therapy could be beneficial for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases., Importance Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. Objective To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. Design, Setting, and Participants This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Exposures Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. Main Outcomes and Measures The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Results Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P, This cohort study examines whether the addition of bone resorption inhibitors is associated with improvements in overall survival and skeletal-related events among patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate with prednisone as first-line therapy.

Introduction: Phase I trials aim to determine the maximum-tolerated dose of a particular drug while minimizing the number of patients exposed to either sub-therapeutic doses or severe toxicity. Thus, patient selection for phase I trials is a key component of any clinical trial design. Though several studies have been made to address this issue, patient selection still represents a major clinical challenge that needs further investigation. Methods: Twenty-nine baseline clinical and analytical characteristics of 773 consecutive patients treated in phase I trials between 2008 and 2016 in START Madrid-CIOCC were analysed and correlated to objective response (OR), progression-free survival, median overall survival, toxicity, and treatment type. The ones associated to OR in the univariate analysis were included in the stepwise logistic regression multivariate and Cox analysis. The statistically significant ones were included in a predictive score (named here as the Madrid score) of antitumour activity. Results: Body mass index (BMI) >25 (p = 0.027), two or less previous lines of treatment (p = 0.007), and normal levels of alkaline phosphatase (ALP) (p = 0.007) were found to positively correlate to radiological response. A Madrid score was generated using these three factors as predictive parameters: compared to a score of 2–3 (where 2 or 3 of these variables are altered), a score of 0–1 is associated with longer survival time (11.6 vs. 8.6 months; p = 0.005) and overall response (17 vs. 7.6%; p = 0.003). Conclusion: The predictive Madrid score, based on the BMI, number of prior lines of treatment, and ALP levels, might be helpful to accurately select patients who would benefit from oncology phase I clinical trials.

Background: SARS-CoV-2 is a novel coronavirus that has been responsible for the largest pandemic in the last century: COVID-19 Some patients (pts) develop a severe pneumonia with higher mortality rate Oncological population could be at higher risk Methods: We evaluated the association between COVID-19 severe pneumonia and clinical/laboratory/radiological parameters in cancer pts admitted to our institution from March to April 2020 We considered a severe pneumonia if the patient required more than 5L supplemental oxygen Past medical history and COVID-19-related parameters (such as symptoms, laboratory/x-ray findings and specific treatments for the COVID-19) were retrospectively collected Univariate and multivariate analysis have been done using logistic regression Results: Forty-three cancer pts were hospitalized with COVID-19 diagnosis;27 pts (62 8%) were male Median age was 68 8 ± 7 8 years Most part of the pts had gastrointestinal (13;30 2%), thoracic (12;27 9%) and breast (6;14%) cancer 33 pts (83 7%) presented pneumonia, which was bilateral in 24 pts (55 8%) Median basal saturation of oxygen (O2) was 92% (87-94 5) Severe pneumonia was observed in 23 pts (53 5%) In these patients, the most common symptoms were dyspnea (16;69 6%), cough (14;60 9%) and fever (11;47 8%) Hydroxychloroquine was administered in 20 pts (87%), antiretrovirals in 14 pts (60 9%), steroids in 13 pts (56 5%) and tocilizumab in 9 pts (39%) Mortality rate due to COVID-19 was 84 6% in pts with severe pneumonia versus 15 4% in the rest of patients (p=0 03) Thoracic cancer and diabetes were associated with severe pneumonia development in univariate analysis Thoracic cancer [OR: 12 0 (1 8 – 246 5)] was also associated in multivariate analysis Conclusions: Severe pneumonia was frequent in cancer patients with COVID-19 admitted to our institution and was associated with a high mortality rate Thoracic tumours were found to be a risk factor for developing severe pneumonia Further investigations with larger number of pts are needed Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

Lay Summary Currently, the complexity of clinical trial development in oncology is being further complicated by the coronavirus disease 2019 (COVID‐19) pandemic, which is reducing the resources needed to comply with protocol‐specific procedures while putting patients in units, who are already vulnerable, at increased general risk not only for COVID‐19 infection but also with respect to their baseline disease.Individualizing the management of patients while ensuring their safety and adherence to the study protocol, establishing specific staff contingency plans, and maintaining sponsor and contract research organization (CRO) alignment are some of the key issues for maintaining the continuity of cancer patients’ investigational treatment and minimizing their infection risk as well as the risk to staff members of the unit, sponsors, and CROs while maintaining the integrity of data quality and compliance with good clinical practice., This commentary describes the potentially deep, specific, and rapid impact of the coronavirus disease 2019 pandemic on clinical research units in oncology, and it establishes different processes and action plans in order to allow the performance of clinical research activities during this challenging period.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. MS is more prevalent in women and is estimated to affect some 2.3 million people across the world. There is unequivocal genetic susceptibility in MS. The most consistent genetic determinant identified is the major histocompatibility complex (MHC). The haplotypes more strongly related to susceptibility and protection for MS are HLA-DR2 and HLA-DR11, respectively. Some genes outside the MHC, such as IL2RA, IL7R and TNFRSF1A, have also been related to MS. There is a latitudinal gradient of MS prevalence, probably due to environmental factors on the genetic susceptibility. The most important MS risk factors are seropositivity against Epstein–Barr virus, infectious mononucleosis, and smoking. Other factors such as vitamin D or parasitic infections require further investigation. The clinical manifestations of relapsing forms of MS in initial stages are related to demyelination of the susceptible structures such as the optic nerves or spinal cord. In established MS, the clinical symptoms are related to the multisystemic affectation and neurodegeneration such as cognitive impairment or sphincter disorders. An unmet need exists for highly effective medications with low risk for deep immunosuppression and for the symptomatic relief of MS.

[Background] Studies evaluating leptin levels in patients with first-episode psychoses (FEP) have been inconclusive, and apparently, the high levels of leptin reported in patients with schizophrenia may be associated with weight gain. The aim of this study was to evaluate leptin levels at the early stages of the disease and the relationship between leptin and lifestyle habits, stress-related variables and metabolic parameters., [Methods] In total, 14 at-risk mental state (ARMS) patients, 39 FEP patients, 32 psychotic patients in the critical period (CP) and 21 healthy controls (HCs) were assessed. Anthropometric and biochemical parameters, as well as dietary intake, physical activity, stress-related variables and symptomatology, were collected., [Results] Leptin levels were higher in the ARMS, FEP and CP patients than in the HCs. After controlling for age, sex, BMI, physical exercise, tobacco use and dietary intake, the highest differences in leptin levels were observed between the ARMS patients and HCs (p = 0.025). In the whole sample, leptin levels were positively correlated with BMI (p < 0.001), waist circumference (p < 0.001), insulin levels (p = 0.020), levels of the inflammatory marker IL-6 (p = 0.007) and energy intake (p = 0.043) and negatively correlated with HDL cholesterol (p = 0.018). Interestingly, energy intake and food craving scores were positively correlated with levels of leptin only in females (p = 0.022 and p = 0.036, respectively)., [Discussion] The present study detected increased leptin levels in the early stages of psychosis and significant correlations between leptin levels and anthropometric, lipid, hormone, and cytokine parameters. We found higher leptin levels in women, and we identified dietary intake habits associated with leptin exclusively in females that advocate considering sex in future studies., Funding for this study was provided by Fundació la Marató de TV3 (grants numbers 092230, 092231) and from the Instituto de Salud Carlos III (grant number PI10/01607). GM was the recipient of a BP-DGR scholarship from the Generalitat de Catalunya. LO and JL have received a personal grant to support their research activity (SLT002/16/0125 and SLT006/17/00012, respectively). The Health Department of the Generalitat de Catalunya also supported this study.

Background Surgical site infection (SSI) is one of the most frequent complications in colorectal surgery. It is diagnosed in 10%–20% of colorectal procedures. Negative Pressure Wound Therapy (NPWT) has shown efficacy in the treatment of chronic and traumatic wounds, wound dehiscence, flaps and grafts. The main objective of this study is to assess NPWT in the prevention of SSI in colorectal surgery. Hospital stay reduction and SSI risk factors are secondary objectives. Methods We present a prospective case–control study including 80 patients after a colorectal diagnosis and surgical procedure (elective and non-elective) in 2017. Forty patients were treated with prevention NPWT for one week. Forty patients were treated according to the standard postoperative surgical wound care protocol. Results No significant differences were found in demographic variables, comorbidities, surgical approach, elective or non-elective surgery, mechanical bowel preparation and surgical procedure. Three patients has SSI in the NPWT group (8%) (95%CI 0–17.5). Ten patients presented SSI in the control group (25%) (95%CI 12.5–37.5) (P=.034); OR 0.7 (95%CI 0.006–0.964). Hospital stay in the NPWT group was 8 days versus 12 days in the non-NPWT group (P=.22). In the multivariate analysis, mechanical bowel preparation was found to be the only risk factor for SSI (P=.047; OR: 0.8, CI 0.45–0.93). Conclusions NPWT is a useful SSI prevention treatment in colorectal surgery.

Resumen Introducción. La obesidad infantil se ha asociado con la ingesta de alimentos densamente energéticos, con el sedentarismo y con indicadores de salud mental como la ansiedad manifiesta y la percepción de la imagen corporal. En México no se ha reportado la relación entre dichas variables en población infantil. Objetivo. Evaluar la auto-percepción corporal y el riesgo de ansiedad, de acuerdo con la presencia de sobrepeso u obesidad, controlando las variables dietéticas y los hábitos de salud en niños en edad escolar. Método. Clasificados por su Índice de Masa Corporal (IMC) se compararon 259 niños y niñas sin sobrepeso/obesidad vs. 326 quienes presentaron dicha condición, en tres escuelas públicas del Estado de México. El IMC se obtuvo por medición directa del peso y la estatura. Se exploró la relación del consumo de alimentos (dieta) y el estilo de vida con la presencia de ansiedad (cuestionario CMAS-R), auto-percepción y satisfacción corporal (test–SC). Resultados. El 43% de los escolares presentan riesgo cardiovascular y 7.7% riesgo de síndrome metabólico. Los participantes sin sobrepeso/obesidad presentaron mayor satisfacción con su imagen corporal (68.3%). No se encontraron diferencias entre el IMC y la ansiedad total, ni con cada una de sus dimensiones. Discusión y conclusión. No se reportaron diferencias en la ansiedad de acuerdo con el IMC. La auto-percepción de la imagen corporal fue menos favorable, en zonas específicas del cuerpo en niñas y niños con sobrepeso u obesidad.

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

KRAS mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the BRAF gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of KRAS and BRAF mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. KRAS mutations and BRAF V600E mutations exhibited a poor outcome (p = 0.021 and p &lt, 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595, 95% CI: 1.086&ndash, 2.343, p = 0.017), KRAS mutation (HR = 1.643, 95% CI: 1.110&ndash, 2.431, p = 0.013) and BRAF V600E mutation (HR = 5.861, 95% CI: 2.531&ndash, 13.570, p &lt, 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with KRAS mutations were associated with a poor response to first line standard chemotherapy (p = 0.008). In contrast, the BRAF V600E mutation did not have any impact on the first line standard chemotherapy response (p = 0.540). Therefore, in the present study, we provide new insight on the role of KRAS and BRAF, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.

Background: Fingolimod is a functional sphingosine-1-phosphate antagonist approved for the treatment of multiple sclerosis (MS). Fingolimod affects lymphocyte subpopulations and regulates gene expression in the lymphocyte transcriptome. Translational studies are necessary to identify cellular and molecular biomarkers that might be used to predict the clinical response to the drug. In MS patients, we aimed to clarify the differential effects of fingolimod on T, B, and natural killer (NK) cell subsets and to identify differentially expressed genes in responders and non-responders (NRs) to treatment. Materials and methods: Samples were obtained from relapsing-remitting multiple sclerosis patients before and 6 months after starting fingolimod. Forty-eight lymphocyte subpopulations were measured by flow cytometry based on surface and intracellular marker analysis. Transcriptome sequencing by next-generation technologies was used to define the gene expression profiling in lymphocytes at the same time points. NEDA-3 (no evidence of disease activity) and NEDA-4 scores were measured for all patients at 1 and 2 years after beginning fingolimod treatment to investigate an association with cellular and molecular characteristics. Results: Fingolimod affects practically all lymphocyte subpopulations and exerts a strong effect on genetic transcription switching toward an anti-inflammatory and antioxidant response. Fingolimod induces a differential effect in lymphocyte subpopulations after 6 months of treatment in responder and NR patients. Patients who achieved a good response to the drug compared to NR patients exhibited higher percentages of NK bright cells and plasmablasts, higher levels of FOXP3, glucose phosphate isomerase, lower levels of FCRL1, and lower Expanded Disability Status Scale at baseline. The combination of these possible markers enabled us to build a probabilistic linear model to predict the clinical response to fingolimod. Conclusion: MS patients responsive to fingolimod exhibit a recognizable distribution of lymphocyte subpopulations and a different pretreatment gene expression signature that might be useful as a biomarker. This work was mostly supported by grants from Novartis (PI110/13 JGM-INM2014-01) and Fondo de Investigación Sanitaria FIS PI12/02672 and PI15/02099 integrated in the Plan Nacional de I+D+I (2008–2011 and 2013–2016, respectively), supported by the ISCIII—subdirección General de Evaluación and co-financed by the Fondo Europeo de Desarrollo Regional (FEDER). The funding sources had no involvement in the study design, data collection, analysis, interpretation, preparation of the manuscript, and the decision to submit the article for publication. Sí

The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond and suffer unnecessary toxicities and surgery delays, there are no biomarkers to guide preoperative CRT outcome. MicroRNA-21 has been related to acquisition of 5-fluorouracil resistance; however, its potential predictive value of response to preoperative chemoradiotherapy in locally advanced rectal cancer remains unknown. Nighty-two patients diagnosed with locally advanced rectal cancer who were preoperatively treated with chemoradiotherapy were selected for this study. Moreover, microRNA-21 expression was quantified in formalin-fixed paraffin-embedded biopsies from this cohort, and the results obtained were correlated with clinical and molecular characteristics, pathological response, and outcome. MicroRNA-21 was found overexpressed in 77.6 % cases, and significantly correlated with tumor grade after preoperative chemoradiotherapy (P = 0.013) and with pathological response (P = 0.013). The odds ratio of having miR-21 overexpression and not getting a respond to chemoradiotherapy resulted in 9.75 CI 2.24 to 42. Sensitivity, specificity, negative predictive values, and positive predictive value were 86.6, 60, 42.8, and 92 %, respectively. Multivariate analysis confirmed the clinical significance of miR-21 determining preoperative chemoradiotherapy response. MicroRNA-21 expression efficiently predicts preoperative chemoradiotherapy pathological response in locally advanced rectal cancer.

Cannabidiol (CBD) is one of the most important compounds in Cannabis sativa, lacks psychotropic effects, and possesses a high number of therapeutic properties including the amelioration of experimental autoimmune encephalomyelitis (EAE). The aim of this study was to analyse the relative efficacy of CBD in adoptively transferred EAE (at-EAE), a model that allows better delineation of the effector phase of EAE. Splenocytes and lymph nodes from mice with actively induced EAE were cultured in the presence of MOG35-55 and IL-12 and inoculated intraperitoneally in recipient female C57BL/6J mice. The effects of CBD were evaluated using clinical scores and magnetic resonance imaging (MRI). In the central nervous system, the extent of cell infiltration, axonal damage, demyelination, microglial activation and cannabinoid receptors expression was assessed by immunohistochemistry. Lymph cell viability, apoptosis, oxidative stress and IL-6 production were measured in vitro. Preventive intraperitoneal treatment with CBD ameliorated the clinical signs of at-EAE, and this improvement was accompanied by a reduction of the apparent diffusion coefficient in the subiculum area of the brain. Inflammatory infiltration, axonal damage, and demyelination were reduced, and cannabinoid receptor expression was modulated. Incubation with CBD decreased encephalitogenic cell viability, increasing early apoptosis and reactive oxygen species (ROS) and decreasing IL-6 production. The reduction in viability was not mediated by CB1, CB2 or GPR55 receptors. CBD markedly improved the clinical signs of at-EAE and reduced infiltration, demyelination and axonal damage. The CBD-mediated decrease in the viability of encephalitogenic cells involves ROS generation, apoptosis and a decrease in IL-6 production and may contribute to the therapeutic effect of this compound.

Prostate Cancer (PC) is the second most frequent type of cancer in men worldwide. The therapeutic strategy for advanced PC continues to be based on androgen deprivation therapy usually in combination with chemotherapy or androgen receptor-targeting therapy. However, new therapies such as targeted therapies or immune-based therapy have emerged as an option for the treatment of this disease. Immunotherapy approaches have been encouraged since the approval of sipuleucel-T by the FDA in 2010. In addition, these new agents have stimulated the search for predictors of response and resistance and have improved the understanding of the biological mechanisms how they. This chapter discusses the rationale for using immunotherapy in PC and the recent clinical developments of immune-based therapies for this disease. Alongside reviewing the approved immune-based therapies, we present an overview of the experimental promising agents, such as PROSTVAC-VF Tricom vaccine or new approaches using the checkpoints inhibitors.

Refractory spasticity, central neuropathic pain and bladder dysfunction are common clinical problems in patients with multiple sclerosis (MS). None of the currently available oral medications has proven to be reliably effective and can be limited by toxicity. Cannabinoids have shown therapeutic effects on those MS-associated symptoms. Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) Sativex (nabiximols) is an oromucosal spray formulation that contains THC and CBD in an approximate 1:1 ratio and is described as an endocannabinoid system modulator. The efficacy of THC/CBD on MS-associated spasticity, pain and bladder dysfunction has been studied in clinical trials as well as in clinical practice studies. Adverse effects are usually mild or moderate and the low rate of drug discontinuation provides good evidence of long-term tolerability. This article focuses on the pharmacological properties, clinical efficacy and tolerability of THC/CBD in MS patients.

e16508 Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. > 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]

Background Mutations of RAF/RAS genes are one of the most common oncogenic events in multiple myeloma. Therapeutic targeting of RAF/RAS/MAPK signalling using small molecule inhibitors has led to significant responses in solid cancers. Recently, combined inhibition of key pathway kinases has demonstrated increased efficacy and decrease toxicity, leading to development of second-generation small molecules with dual inhibitory function. RO5126766 is a potent dual RAF-MEK inhibitor that has demonstrated significant clinical activity with minor toxicities in various solid cancers carrying RAS mutations in a currently ongoing phase I basket study (Trial number NCT204007509; Chenard-Poirier et al. ASCO 2017). Based on the drug's promising efficacy, the trial has been expanded to include myeloma patients with RAF/RAS tumour mutations to provide information on safety and preliminary efficacy in this patient population. We report updated results for RAF/RAS-mutant relapsed and refractory MM patients treated with RO5126766. Methods MM patients with relapsed or relapsed and refractory myeloma whose disease had progressed after at least 3 prior therapies were recruited to the study. All patients had been treated with an IMiD and a proteasome inhibitor and their tumours were confirmed to carry a RAS mutation by sequencing. Patients were treated with RO5126766 4mg twice weekly for 3 out of 4 weeks, in 28 day cycles, with the addition of optional weekly dexamethasone as per investigator's discretion. Response assessment was completed using IMWG criteria and toxicities were reported according to CTCAE version 4.0. Whole body diffusion-weighted MRI every 3 cycles was used for functional imaging disease assessment. Results At the time of analysis, a total of five patients were recruited; one was still receiving cycle 1 of therapy, with the four remaining patients being evaluable at the point of abstract submission. The median age of evaluable patients at initiation of treatment was 74 years (range 70-76). Patients had received median 4 (range 3-5) lines of prior therapy, including autologous stem cell transplant (75%). Three tumours had a KRAS mutation whilst in one tumour, synchronous KRAS and NRAS mutations were found. Three patients received RO5126766 alone, while 1 patient also received weekly concomitant dexamethasone. One patient (KRAS and NRAS mutations) achieved a partial response after 1 cycle of therapy but progressed after 7 months. A second patient achieved stable disease (confirmed biochemically and by functional MRI imaging) with single agent RO5126766 treatment and currently continues on trial having completed 8 cycles of therapy. The two remaining patients progressed after 2 and 1.5 cycles, with the latter patient receiving dexamethasone in combination with RO5126766. The two patients who received 7 and 8 cycles of RO5126766 experienced no clinically significant adverse events (AE), with commonly reported toxicities including grade 1 rash (2/2), grade 1 diarrhoea and grade 1 thrombocytopenia. This is in line with tolerability profile observed in the solid tumour cohorts (n=28 solid tumour patients recruited to date) of this basket trial. One patient developed worsening kidney impairment attributable to disease progression with rising serum free light chains and came off study. Interestingly, ocular toxicities, commonly associated with RAF-MEK inhibitors, were not observed in this patient cohort, which may be related to their dosing schedule. Conclusion In this basket study across RAS mutated tumours, the novel, dual RAF-MEK inhibitor RO5126766 as monotherapy in myeloma patients has shown promising single agent activity. In line with observations in the in parallel recruiting solid tumour cohorts, the dual RAF-MEK inhibitor RO5126766 is generally well tolerated and can be administered as an ongoing therapy. This has been observed in a solid tumour patient who has been receiving RO5126766 for 3.5 years with little and manageable toxicities. Longitudinal patient bone marrow trephine material has been collected and analysis of phospho-protein markers of RAS/MAPK pathway activation for PD biomarker evaluation will be performed. Recruitment to this study continues and data will be updated prior to the conference. Potential single-agent activity of RO5126766 with manageable toxicity grants further evaluation of its use as a molecularly targeted therapy in myeloma. Disclosures Sriskandarajah: Celgene: Other: Travel, Accommodation expenses, Speakers Bureau. Boyd:Celgene: Consultancy, Honoraria, Other: Advisory role; Janssen: Honoraria, Other: Travel and Accommodation expenses; Novartis: Consultancy, Honoraria. Shah:Sanofi: Other: Travel and Accommodation expenses; Celgene: Other: Travel, Accommodation expenses. Hall:Sanofi (Inst): Research Funding; Cambridge Major Laboratories (Inst): Research Funding; Accuray (Inst): Research Funding; Kyowa Hakko Karin (Inst): Research Funding; Astrazeneca (Inst): Research Funding; Bayer (Inst): Research Funding. Tunariu:Janssen: Speakers Bureau; Sanofi: Speakers Bureau. de Bono:Sanofi (Inst): Research Funding; AstraZeneca (Inst): Research Funding; GlaxoSmithKline: Other: Travel, Accomodation expenses; AstraZeneca: Consultancy, Honoraria, Other; Astellas Pharma: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Sanofi: Consultancy, Honoraria, Other: Travel, Accommodation expenses; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Orion Pharma GmBH: Other: Travel, Accommodation expenses; Qiagen: Other: Travel, Accommodation expenses; Taiho Pharmaceutical: Other: Travel, Accommodation expenses; Vertex: Other: Travel, Accommodation expenses; Genentech (Inst): Research Funding; Abiraterone Rewards to Investors (Inst): Patents & Royalties: Abiraterone; PARP inhibitors and DNA repair defects (Inst): Patents & Royalties: PARP inhibitors; Genmab: Other: Travel, Accommodation expenses. Banerji:Institute of Cancer research: Employment; Novartis: Consultancy; Onyx (Inst): Research Funding; Chugai Pharma (Inst): Research Funding; AstraZenca (Inst): Research Funding; Astex Pharmaceuticals: Consultancy. Kaiser:Janssen: Consultancy, Honoraria; Takeda: Consultancy, Other: Travel Support; Bristol-Myers Squibb: Consultancy, Other: Travel support; Chugai: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

The therapeutic utility of the anti-CD20 monoclonal antibodies (mAbs) is currently being evaluated in multiple sclerosis (MS) in line with the better understanding of the role of B lymphocytes in MS pathogenesis. Area covered: We conducted a literature search using Medline/Pub Med database of basic research and available controlled trials about anti-CD20 mAbs in MS. Additionally, ongoing studies were identified in the ClinicalTrials.gov database. B cells exert multiple inflammatory and regulatory functions playing an important role in MS pathogenesis as is demonstrated by the production of autoantibodies, infiltration of B cells in MS lesions and the formation of ectopic B cell follicle-like structures in meninges, among others. B-cell depletion by anti-CD20 mAbs has been shown to have an impact on these pathogenic mechanisms. The efficacy of three of them, rituximab, ocrelizumab and ofatumumab in MS has been confirmed by placebo-controlled clinical trials demonstrating a significant reduction of the annualized relapsing rate (ARR), new gadolinium-enhancing (GdE) and T2 lesions. There have been no significant safety problems so far but the overall benefit to risk profile is still to be determined. Expert commentary: After recent good results of these agents in MS therapy, questions related to maintenance therapy, markers of response and control of B cells values remain unanswered.

Background Models of attention-deficit/hyperactivity disorder (ADHD) classically emphasize the relevance of executive processes and, recently, reward circuits. The neural bases of reward processes have barely been explored in relation to this disorder, in contrast to extensive neuroimaging studies that examine executive functions in patients with ADHD. To our knowledge, no previous studies have analyzed the volume of the ventral striatum, a key region for reward processes in ADHD children. Methods We used a manual region-of-interest approach to examine whether there were volumetric differences in the ventral striatum of ADHD children. Forty-two children/adolescents with ADHD (ages 6–18), and 42 healthy control subjects matched on age, gender, and handedness were selected for the study. Results The ADHD children presented significant reductions in both right and left ventro-striatal volumes ( t = 3.290, p = .001; and t = 3.486, p = .001, respectively). In addition, we found that the volume of the right ventral striatum negatively correlated with maternal ratings of hyperactivity/impulsivity ( r = −.503, p = .003). Conclusions Our study provides neuroanatomical evidence of alterations in the ventral striatum of ADHD children. These findings coincide with previous explicative models as well as with recent reports in behavioral and functional neuroimaging studies. Furthermore, the negative correlations we observed strongly uphold the relation between the ventral striatum and symptoms of hyperactivity/impulsivity.

Childhood trauma, a risk factor of psychosis, is associated the clinical expression of the illness (greater severity of psychotic symptoms; poorer cognitive performance). We aimed to explore whether there are sex differences in this relationship. We studied 79 individuals with a psychotic disorder (PD) with < 3 years of illness and 59 healthy subjects (HS). All participants were administered the MATRICS Cognitive Consensus Cognitive Battery (MCCB) to assess cognition. Depressive, positive and negative psychotic symptoms, and global functioning were also assessed. History of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Patients reported a greater history of childhood trauma on all CTQ domains (emotional, physical and sexual abuse, and physical and emotional neglect). A poorer cognitive performance was also observed in PD when compared to HS. No sex differences were found in the CTQ scores. In the relationship between childhood trauma and psychopathological symptoms, significant correlations were found between CTQ scores and positive and negative psychotic symptoms, depressive symptoms and poorer functionality, but only in women. Childhood trauma was associated with poorer social cognition in both men and women. Of all CTQ dimensions, emotional neglect and physical neglect were more clearly associated with a more severe psychopathological and cognitive profile. Our results suggest that childhood trauma, particularly emotional and physical neglect, is associated with the clinical expression of psychosis and that there are sex differences in this relationship.

Infliximab (IFX) is widely used in ulcerative colitis and in Crohn’s disease treatment. Both diseases are characterised by increased oxidative stress, which may affect albumin oxidation. In order to test this hypothesis, the effect of IFX on colitis induced by dextran sulphate sodium (DSS) in rats was evaluated by measuring the Disease Activity Index, biochemical parameters, serum albumin oxidation and colonic mucosa oxidation. Rats with colitis showed an increase in oxidised serum albumin levels and in the oxidation of colon mucous cells. Both decreased after IFX treatment. This suggests that oxidised albumin could be a useful biomarker for monitoring inflammatory bowel disease.

e12007 Background: Breast cancer prognosis is influenced by several factors including Ki67 expression which may have a predictive role in luminal breast cancer patients. The aim of this study was to assess the value of Ki67 in breast cancers with positive hormonal receptors and HER2 overexpressed and to evaluate its impact on survival. Methods: Seventy eight consecutive patients diagnosed with locally advanced HER2 positive breast cancer who were treated with adjuvant therapy based on HER2 treatment were selected for this study (2004-2014). The adjuvant chemotherapy schemes were 44% TCH, 16% FEC, 11% AC/T and 29% other therapies. The median of followup was 68 months. Tumor proliferation was assessed immunohistochemically by Ki67 expression and calculated as percentage of stained tumor cells from this cohort previous to adjuvant chemotherapy administration and the results obtained were correlated with disease status and outcome. Results: High proliferation defined as a percentage > 15 of tumor cells was observed in 69% of the breast cancer patients cases. High proliferation significantly predicted longer overall survival (OS) (Log rank 0,012). At 10 years of follow-up, 93% of the patients with KI67 high expression were alive versus 43% of patients without overexpression. Multivariate analysis confirmed the clinical significance of Ki67 predicting OS for luminal HER2 breast cancer patients (p 0,04 y HR 9,6). Conclusions: High proliferation identifies a setting of luminal-B HER2+ subtype breast cancer patients with a significantly longer overall survival.

353 Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.

790 Background: The role of adjuvant chemotherapy (AC) after chemoradiotherapy and surgery in stage II and III of rectal cancer is not well defined. Neither the regimen nor the duration is clear. Besides, guidelines from different expert groups are conflicting. Methods: 224 patients diagnosed from January 2003 to December 2013 with rectal adenocarcinoma T3/T4 and/or positive node staged by ultrasound or magnetic resonance imaging was collected retrospectively from the Pathology Department data base. Results: Of the 224 patients 61.6% were male, median of age at diagnosis 68.6 years (range 31.3-85.4). All of them received 50.4 Gy with different concomitant regimens (capecitabine, continuous infusion of fluoracil or bolus of fluoracil-leucovorin). 13.4% of patients achieved a pathological complete response. 76.8% of the cohort received adjuvant chemotherapy. The main reasons for not receiving chemotherapy were ECOG ≥ 2, surgery complications and a decision of the patient. 51.2% of patients received an oxaliplatin based regimen and the median time of chemotherapy duration was 4 months (range 1-6 months). Local relapse was diagnosed in 6.3% of patients while a systemic relapse was found in 22.3%. Patients without AC had a mean overall survival (OS) of 85.5 months (CI 95% 70.7-100.4) versus 119.8 monts (CI 95% 110.8-128.8) in the AC cohort (p 0.002) without reaching the median after 58 months (range 8-153.9) median follow-up. Disease free survival (DFS) was also better in the AC cohort with a mean DFS of 104 months (CI 95% 94.3-113.6) versus 71.4 months (CI 95% 55.4-87.4), p = 0.01. Conclusions: AC after chemoradiotherapy and surgery in stage II and III rectal cancer as a standard does not exist. In our cohort, AC showed a significant improve in OS and DFS, but the limitations of a retrospective study should be considered, as well as the impact of surgery on metastasis and salvage chemotherapies. Randomized studies are clearly needed.

10.1016/j.jpsychires.2014.10.011 Stress and inflammation are thought to play a role in the risk of developing a psychotic disorder. We aimed to identify stress-related biomarkers for psychosis transition in help-seeking individuals with an at-risk mental state (ARMS). We studied 39 ARMS subjects who were attending an Early Intervention Service. We included a control group of 44 healthy subjects (HS) matched by sex and age. Stressful life events and perceived stress were assessed. Stress-related biomarkers were determined in serum (cortisol, prolactin, C-reactive protein and albumin), plasma (fibrinogen) or saliva (morning cortisol, cortisol awakening response). All ARMS were followed-up at our Unit for at least one year. We divided the ARMS group into two subgroups based on the development of a psychotic disorder (ARMS-P, N=10) or not (ARMS-NP, N=29). ARMS-P reported more stressful life events and perceived stress than HS and ARMS-NP groups. In relation to baseline stress biomarkers, ARMS-P subjects had increased prolactin and lower albumin levels in serum, when compared to ARMS-NP and HS groups. These results did not change when repeated in a subsample of antipsychotic-naïve ARMS subjects. We also found significant differences between groups in the cortisol secretion after awakening. In a multinomial logistic regression adjusting for age, sex and life stress, prolactin was a predictor of psychosis transition whereas albumin levels had a protective effect. Our study underscores the role of stress and stress-related biomarkers (cortisol awakening response, prolactin and albumin) in the pathogenesis of psychosis.

e17088Background: Nearly 75 % of ovarian cancer cases are diagnosed in advanced stages. The standard treatment for metastatic ovarian cancer is based on sensitivity to platinum-based chemotherapy. ...

According to the most recent data on nutritional evaluation in Mexican population, one of every four children between 5 and 11 years of age (26%) presents overweight or obesity, dramatically surpassing the estimate calculated for 2010 for childhood obesity at the worldwide level of 6.7% (Olaiz-Fernandez G, 2006). This problem acquires great relevance not only because of the prevalence of obesity, but also due to the consequences associated with this condition, such as high risk of adult-age obesity and chronic diseases such as diabetes mellitus, high blood pressure, dyslipidemias, obstructive apnea sleep disorder syndrome, and non-alcoholic steatosis (Pimenta AM, 2010; Elizondo-Montemayor L, 2010). Conclusive evidence has been established that physical activity is a promoter of healthy lifestyle promoter and a preventer of excessive weight gain (Summerbell CD, 2005) and other diseases. In particular, habitual physical activity at early ages increases the probability of exerting an impact on the mortality and longevity of persons, as well as improving some cardiovascular risk indicators (Hills AP, 2007; Balas-Nakaxh M, 2010). Generality in existing consensuses for the prevention and treatment of childhood obesity cites the promotion of physical activity as an imperative strategy. The different guidelines that exist on physical activity in children recommend 60 min of physical activity daily of at least moderate intensity, including vigorous aerobic activity at least 3 days a week (Jasen I, 2010; O’Donovan G, 2010). Unfortunately, in Mexico, the reality concerning the time devoted to physical activity in children lies very far from these recommendations. An observational study conducted in Mexico quantified the physical activity engaged in within the school environment, identifying that children have few opportunities to participate in moderateand vigorous-intensity physical activity, scarcely achieving one half of the time recommended by international guidelines for this age group (Jennings-Aburto N ,2009). A large proportion of the reports on studies examining the promotion of physical activity in this age group are hardly encouraging in terms of the results obtained regarding body weight modification, eating habits, and a sedentary lifestyle at the

e14625 Background: The treatment of choice for locally advanced rectal cancer is preoperative chemoradiotherapy. Despite half of patients do not respond, suffer unnecessary toxicities and surgery d...

Corrigendum to “Stress biomarkers as predictors of transition to psychosis in at-risk mental states: Roles for cortisol, prolactin and albumin” [J. Psychiatr. Res. 60 (2015) 163e169] Javier Labad a, , Alexander Stojanovic-P erez , Itziar Montalvo , Montse Sol e , Angel Cabezas , Laura Ortega , Irene Moreno , Elisabet Vilella , Lourdes Martorell , Rebecca M. Reynolds , Alfonso Guti errez-Zotes a a Early Intervention Service and Research Department, Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, CIBERSAM, Reus, Spain b Department of Psychiatry, Corporaci o Sanit aria i Universit aria Parc Tauli, Sabadell, Barcelona, Spain c Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

We retrospectively analyze our experience in conservative treatment for infiltrating advanced breast cancer before implementation of selective sentinel node biopsy, specially focusing on characteristics, incidence, treatment and evolution of local-regional recurrences, disease-free survival time, overall survival and patient's satisfaction.From January 1984 to 31st December 1998, 739 female patients were operated in our institution, diagnosed as having infiltrating breast cancer. One hundred and eighty-eight patients (25.43%) received conservative treatment and they were followed up until December 2003.Average age when diagnosed was 50.42 years old (24-87 years). 53.19% of the patients were premenopausal. After a median follow-up of 129 months (60-198 months), 13 women (6.91%) presented local -regional recurrence and the disease-free time was 48.4 months (8-108 months). Global survival rate was 83.5% and disease free survival rate was 80.85%.The management of choice for early stage (I and II) infiltrating breast cancer is nowadays conservative, with a low local-regional recurrence rate and survival rate that are comparable to radical mastectomy, according to the literature. It's a safe and efficient method that let us preserve the breast with a good esthetical result. In selected cases, when a regional recurrence occurs, a second conservative management is possible with a good control of the disease, although the most widely accepted treatment in these cases is total mastectomy.

e19109 Background: Bevacizumab is a recombinant monoclonal humanized antibody to vascular endothelial growth factor (VEGF) that improves Time to Progression (TTP) in patients with advanced non-squamous NSCLC in combination with a doublet of platins, but currently no proven predictive markers exist. The VEGF-A 165 splice variant has been described as the most abundant and active isoform in cancer. Exon 8 splice modifications of VEGF 165 generates the VEGF-A 165a family of isoforms, which has a pro-angiogenic effect, and VEGF-A 165b family, with an anti-angiogenic activity. This study is aimed to explore the role of VEGF165a and VEGF165b expression in tumors as predictive biomarkers of efficacy in patients with NSCLC treated with platins plus bevacizumab. Methods: 22 patients were included (20 adenocarcinomas and 2 large cell carcinomas): 5 received carboplatin-taxol-bevacizumab, 14 carboplatin-taxotere-bevacizumab and 3 cisplatin-gemcitabine-bevacizumab. Total RNA was isolated by RNeasy FFPE procedure. VEGF165a and VEGF165b expression was analyzed by RT-qPCR using appropriate specific primers and probes. Individual VEGF165a and VEGF165b family of isoforms expression was calibrated to normal tissue and the ratio between both isoforms was calculated. Results: VEGF165a overexpression was detected in 14 (63.6%) cases and VEGF165b overexpression in 15 (68.2%). Individual overexpression for each family of isoforms was not predictive of benefit to bevacizumab therapy (p=0.933 and 0.166). However, the ratio between VEGF165a and VEGF165b was associated with TTP, correlating a predominant expression of pro-angiogenic VEGF165a with a significant benefit compared with cases with predominant VEGF165b expression (median TTP, 15 vs. 8 months respectively, p=0.005). The expression of both isoforms did not impact on OS (p=0.477). Conclusions: The overexpression of VEGF165a and low expression of VEGF165b family of isoforms correlated with benefit to anti-angiogenic therapy in NSCLC patients, supporting a potential use as predictive biomarkers for bevacizumab treatment in stage IV non-squamous NSCLC.

10525 Background: Mature microRNAs (miRNA) are small RNA molecules that act as negative regulators of gene expression, either inhibiting mRNA by blocking its translation into protein or destroying it by RNA interference. Many miRNAs participate in essential processes, including normal embryonic development and carcinogenesis. Methods: We have assessed 156 mature miRNAs in colon tissue from eleven 7–12-week human embryos and 44 colorectal human samples. Data were analyzed using TIGR Multiexperiment viewer. Two multivariate permutation test were performed. Potential target genes of differentially expressed miRNAs are evaluated by western blot. Results: 28 miRNAs were expressed in stage I tumor tissue but not in the corresponding normal tissue, and 13 of these 28 miRNAs (46%) were also expressed in embryonic tissue. Sixty-four miRNAs were differentially expressed in stage II tumor tissue, and 29 of these 64 miRNAs (45%) were also expressed in embryonic tissue. Some miRNAs that are active during embryogenesis, such as mir-17–92, miR-181a, miR-181b and miR-181c (linked to HOXA11), and miR-10a (linked to HOXB8)23, are also expressed during tumor growth. The analysis of 156 miRNAs by K-means support revealed two well-differentiated groups: the embryos of 7–8 weeks and those of 9–12 weeks. Lower miRNA expression was also observed in tumor tissue from stage I in comparison with stage II disease (P=0.014). Analysis of potential target genes revealed that cluster mir-17–92 is differentially expressed in colon cancer and embryonic tissue and may contribute to carcinogenesis through E2F1 expression. Conclusions: Our findings indicate that miRNAs expressed during the embryonic development of the human colon are also expressed in colon tumor tissue. During colon organogenesis, miRNA expression is at first high, while cells are still undifferentiated, but expression levels decrease as cells become more differentiated. In contrast, during the development of colorectal cancer, this process is reversed. No significant financial relationships to disclose.

Background DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer. Methods Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment. Results The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan-induced apoptosis. In addition, low DEK expression level predicted irinotecan-based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type. Conclusions These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status.