Search

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.

Resumen Objetivos Conocer la prevalencia de enfermedad renal cronica (ERC) y determinar los factores asociados al deterioro de la funcion renal en poblacion asistida en atencion primaria. Pacientes y metodo Estudio transversal y multicentrico realizado en los pacientes basales del estudio IBERICAN (identificacion de la poblacion espanola de riesgo cardiovascular y renal). Se considero ERC a un filtrado glomerular estimado (FGe) Resultados Se incluyeron 7.895 pacientes (edad media 57,9 ± 14,8 anos; 54,5% mujeres). El 14,4% (IC 95%: 13,6-15,1) presentaba ERC; en hombres un 16,1% (IC 95%: 14,9-17,3) y en mujeres un 12,9% (IC 95%: 11,9-14,0). Se observo un aumento continuo de la prevalencia con la edad (24,8% ≥ 65 anos) y con la agregacion de FRCV. Las variables que mas se asociaron a la probabilidad de padecer ERC fueron hipertrofia ventricular izquierda (OR: 1,95; p Conclusiones Catorce de cada 100 pacientes incluidos en el estudio IBERICAN presenta ERC. La prevalencia de ERC afecta a la cuarta parte de pacientes ≥ 65 anos y aumenta exponencialmente con la agregacion de FRCV.

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.

Dimethyl fumarate (DMF) tolerability and safety in multiple sclerosis (MS) has been analyzed in randomized clinical trials. Real-life studies are needed to assess possible harms of this therapy in a wider MS population. To evaluate DMF tolerability, safety and persistence in MS in a real-world setting. We conducted a multicenter prospective study of patients who started DMF, attended in 16 public hospitals of Spain. A specific database was elaborated to collect data on most frequent adverse events (AE). Regression models were used to analyze the effect of demographic and clinical characteristics on risk of AEs and DMF discontinuation. We collected data of 886 patients (2681 patients/years-exposition) with median 39.5 (IQR 23, 51.5) months on DMF exposure; 25.3% were treatment naive and 74.7% switched to DMF from other disease-modifying therapies. DMF was discontinued in 29.9% of patients, in 13.2% due to AEs and in 13.5% to inefficacy. AEs were experienced by 71.2%, being flushing the most frequent (44.1%), 5.4% developed grade III lymphopenia, without cases of grade IV. Females showed a higher risk of flushing and gastroenteric symptoms (OR 1.49, p = 0.011; OR 1.69, p = 0.001, respectively); lymphopenia was associated with older age (OR 1.04, p

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.

Resumen Introduccion La infeccion del sitio quirurgico (SSI) es una de las principales complicaciones quirurgicas, con una incidencia del 10-20% en cirugia colorrectal. Las terapias basadas en presion negativa (NPWT) han mostrado su eficacia en el tratamiento de heridas cronicas, traumaticas, en las dehiscencias de piel, en el uso de colgajos o injertos. El objetivo principal del estudio es valorar la eficacia de NPWT en la prevencion de SSI en cirugia colorrectal. Los objetivos secundarios son valorar la reduccion del ingreso hospitalario y analizar los factores de riesgo de SSI. Metodos Estudio casos y controles prospectivo. Ochenta pacientes intervenidos tras diagnostico de enfermedad colorrectal, de forma programada o urgente durante el ano 2017. Cuarenta pacientes fueron tratados con NPWT preventivo durante una semana. Cuarenta pacientes fueron tratados segun protocolo habitual postoperatorio de cuidado de herida quirurgica. Resultados No se encontraron diferencias entre NPWT y grupo control en variables demograficas, comorbilidades, abordaje quirurgico, indicacion urgente o programada, preparacion colonica o procedimiento quirurgico. Se objetivo SSI con el empleo de NPWT en 3 (8%) pacientes (IC del 95%, 0-17,5). SSI en 10 (25%) pacientes (IC del 95%, 12,5-37,5) (p = 0,034); OR 0,7 (IC del 95% 0,006-0,964). La estancia hospitalaria en el grupo NPWT fue de 8 dias vs. 12 dias en el grupo control (p = 0,22). En el analisis multivariante se encontro como unico factor relacionado con SSI la preparacion colonica (p = 0,047; OR: 0,8, IC 0,45-0,93). Conclusiones El uso de dispositivos NPWT para la cobertura de incisiones cerradas tras cirugia colorrectal puede disminuir la incidencia de SSI.

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.

Aim This report presents phenotypic and genetic data on the prevalence and characteristics of extended-spectrum β-lactamases (ESBLs) and representative carbapenemases-producing Gram-negative species in Mexico. Material and methods A total of 52 centers participated, 43 hospital-based laboratories and 9 external laboratories. The distribution of antimicrobial resistance data for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, Acinetobacter baumannii complex, and Pseudomonas aeruginosa in selected clinical specimens from January 1 to March 31, 2020 was analyzed using the WHONET 5.6 platform. The following clinical isolates recovered from selected specimens were included: carbapenem-resistant Enterobacteriaceae, ESBL or carbapenem-resistant E. coli, and K. pneumoniae, carbapenem-resistant A. baumannii complex, and P. aeruginosa. Strains were genotyped to detect ESBL and/or carbapenemase-encoding genes. Results Among blood isolates, A. baumannii complex showed more than 68% resistance for all antibiotics tested, and among Enterobacteria, E. cloacae complex showed higher resistance to carbapenems. A. baumannii complex showed a higher resistance pattern for respiratory specimens, with only amikacin having a resistance lower than 70%. Among K. pneumoniae isolates, blaTEM, blaSHV, and blaCTX were detected in 68.79%, 72.3%, and 91.9% of isolates, respectively. Among E. coli isolates, blaTEM, blaSHV, and blaCTX were detected in 20.8%, 4.53%, and 85.7% isolates, respectively. For both species, the most frequent genotype was blaCTX-M-15. Among Enterobacteriaceae, the most frequently detected carbapenemase-encoding gene was blaNDM-1 (81.5%), followed by blaOXA-232 (14.8%) and blaoxa-181(7.4%), in A. baumannii was blaOXA-24 (76%) and in P. aeruginosa, was blaIMP (25.3%), followed by blaGES and blaVIM (13.1% each). Conclusion Our study reports that NDM-1 is the most frequent carbapenemase-encoding gene in Mexico in Enterobacteriaceae with the circulation of the oxacillinase genes 181 and 232. KPC, in contrast to other countries in Latin America and the USA, is a rare occurrence. Additionally, a high circulation of ESBL blaCTX-M-15 exists in both E. coli and K. pneumoniae.

Background RO7122290 (RO) is a bispecific antibody-like fusion protein that simultaneously targets FAP, abundantly expressed by cancer-associated fibroblasts in most solid tumors, and 4-1BB, transiently expressed on activated T cells. Pre-clinical experiments revealed strong intra-tumoral CD8+ T cells infiltration in FAP-positive tumors, cytokines induction and significant anti-tumor activity mediated by RO (signal 2 of T cell activation), upon TCR/CD3 engagement (signal 1) or in combination with atezolizumab (ATZ). In this first-in-human study, the pharmacodynamic (PD) effects of RO were assessed, both as single agent (SA) (Part A) and in combination with ATZ (Part B). Methods Pts with advanced and/or metastatic solid tumors were eligible for this ongoing Phase 1/1b trial (EUDRACT 2017-003961-83). RO was administered intravenously, weekly (QW) at escalating dose levels (DLs). In Part A, 62 pts were treated at 13 DLs of RO, dose range 5–2000 mg. In Part B, 39 pts were treated at 8 DLs of RO, dose range 45–2000 mg, with ATZ 1200 mg Q3W. Secondary biomarker objective was characterization of PD effects in tumor tissue and blood. The endpoints were change from baseline in intra-tumoral density (cell/mm2) and proliferation (Ki67) of CD8+ T cells measured by immunohistochemistry (IHC), and change in activation (4-1BB) and proliferation (Ki67) of peripheral CD8+ T cells measured by flow cytometry. Exploratory objectives were characterization of PD effects in plasma/serum and measurement of intra-tumoral immune activation. The endpoints were change in peripheral cytokines (TNF-alfa, IFN-gamma, IL-6) and soluble(s) factors (sCD25, s4-1BB) concentration measured by ELISA, and intra-tumoral changes in gene expression measured by RNAseq. Results In the periphery, we observed transient expression of 4-1BB on CD4+ and CD8+ T cells, along with secretion of s4-1BB and inflammatory cytokines, suggesting 4-1BB targeting and potent T cell activation. The concomitant induction of proliferating T cells indicated the potential association to priming and formation of tumor-reactive T cells. In the tumor, we detected increased CD8+ T cells infiltration and proliferation, in both Parts. Proliferating CD8+ T cells increased in both tumor nests and surrounding stroma, with a preferential accumulation in the latter. RNAseq analysis revealed induction of 4-1BB, PD-1 and IFN-gamma, indicating intra-tumoral T cells activation in Part B. Conclusions PD activity was consistent with the postulated MoA, confirming RO to be a potent tumor-targeted 4-1BB agonist in the clinical setting. Our observations suggest that RO can synergize with endogenous T cell receptor stimulation, both as SA and in combination with ATZ.

Background: SARS-CoV-2 is a novel coronavirus that has been responsible for the largest pandemic in the last century: COVID-19 This disease has widely affected Spain with a high lethality in ancient patients (pts) and with comorbidities Oncological pts were not an exception Methods: We evaluated the association between COVID-19 mortality and clinical/laboratory/radiological parameters in cancer pts from March to April 2020 at our institution Past medical history and COVID-19-related parameters (symptoms, laboratory/x-ray findings and treatments) were retrospectively collected Univariate analysis (UA) has been done using Fisher exact and U-Mann-Withney test for qualitative and quantitative variables, respectively Multivariant analysis (MA) has been done using logistic regression Results: Forty three hospitalized pts were diagnosed with COVID-19;30 pts (69 8%) were symptomatic on admission and 13 pts (30 2%) were hospital-acquired cases Median age was 68 8 ± 7 8 years Most part of the pts had gastrointestinal (GI) (13;30 2%), thoracic (Tx) (12;27 9%) and breast (6;14%) cancer A higher prevalence of Tx tumours compared to our new pts prevalence is observed (9%) Fever was the most common symptom (27;62 8%) and bilateral pneumonia was observed in 24 pts (55 8%) SARS-Co-V-2 PCR was positive in 34 pts (79 1%) Hydroxychloroquine was administered in 35 pts (81 4%), steroids and antiretrovirals in 19 pts (44 1%) and tocilizumab in 12 pts (27 9%) Mortality rate due to COVID-19 was 30 23% (13 pts) and 8 pts could resume oncological treatment Hypertension (HTA) and previous daily steroids given during last month before admission;as well as performance status, fever, Curb-65, SOFA score and D-Dimer (DD) at admission were associated with COVID-19 mortality in UA Similarly, high flow oxygen requirements during hospitalization and DD at 72 hours are predictors of mortality HTA [OR: 8 3 (1-5-70 1)], steroids [OR: 10 7 (1 3 – 143 8)] and fever [OR: 0 09 (0 01 – 0 55)]were also associated in MA Conclusions: COVID-19 showed a relative higher incidence in pts with Tx and GI tumours Some clinical and laboratory parameters were found to be predictive factors for mortality as previously reported in non-cancer pts Further investigations with larger number of pts are needed Legal entity responsible for the study: HM Hospitales Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

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.

BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods. RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion. CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.

Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors.Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model.The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non-responders.hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy.

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.

e15229 Background: HPD is a new pattern of response consisting of accelerated tumor growth due to immunotherapy (5%-20% of pts on IO drugs). The tumor growth rate (TGR, Champiat et al.) estimates the differential increase in tumor volume over time, pre- and on IO drugs, to assess for HPD, but it is not easily calculated in practice. A comparison of the different methods to identify HPD is missing. Methods: Retrospective study of 182 consecutive pts treated in Phase 1 studies of IO drugs at START Madrid-CIOCC in 2017-8, comparing 3 HPD measurement criteria (Champiat, Matos -which does not use pre-baseline CT scans-, and Saâda-Bouzid). Cohen’s Kappa index was calculated as a measure of the agreement between the 3 methods, being those values closer to 1 the more concordant ones. Overall survival (OS) rates were calculated by Kaplan-Meier (p < 0.05 to be significant). Results: 99 (54%) of 182 pts had progressive disease at cycle 1 of treatment and in 62 (34%) pre-baseline CT scans were available to calculate TGR. The Champiat method identified 18 (9.9%) pts with HPD. Of 61 cases validated to comparison, the Matos criteria labeled 27 pts (14.8% of 182) with HPD, of whom only 10 pts coincided with those identified by Champiat with a low agreement (Kappa: 0.140, p:0.251). No significant differences in OS between pts with non-HPD vs HPD by Matos criteria were seen (p = 0.16). With Saâda-Bouzid method, of 59 cases validated to comparison, 17 pts (9.3% of 182) were labeled with HPD and 13 of them coincided with those identified by Champiat method with a high agreement (Kappa:0.706, p:0.000). Differences in OS between non-HPD vs HPD pts were statistically significant (p = 0.038). Conclusions: HPD might have a detrimental effect to 10% of pts on IO drugs, also in our series. Every effort should be done to obtain pre-baseline CT scans to identify HPD response to IO drugs, based on differential TGR. The use of Saâda-Bouzid method is preferred due to its practical application and its correlation with survival. [Table: see text]

Forty-four pure Iberian pigs (14 months age, ~96.5 kg live weight) were randomly assigned to four different rearing systems: i. Free range conditions along with an acorn and pasture feed (AGFR), ii. Free range conditions with grass availability and fed on concentrate (CGFR), iii. Intensive system fed on concentrate supplemented with 100 ppm of α-tocopheryl acetate (α-TAc) (CI) and iv. Intensive system fed on concentrate supplemented with 200 ppm of α-TAc (CEI). Blood samples were taken every 30 days during 90 days (t0: 0d, t1: 30d, t2: 60d and t3: 90d -slaughter-) and tocopherols isomers contents, 2,2′-azino-bis (3-ethylbezothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) activities were measured in plasma as determinants of antioxidant status. At slaughter time (t3), TBA-RS and protein carbonyls were measured as biomarkers of lipid and protein oxidative damage. Acorn, grass and concentrate feeds were analysed and classified according to the content of tocopherols and antioxidant potential. 200 ppm of α-TAC supplementation increased α-tocopherol contents in feed. Acorns and pasture had high γ- and α-tocopherol contents, respectively, and both were found to show the highest antioxidant activities. Plasma from AGFR pigs contained significant (P 0.05). Plasma from pigs fed on 200 ppm α-TAC enriched diets (CEI) or grass (CGFR) had intermediate antioxidant activities and TBA-RS. These results indicate that free range rearing system increased blood plasma antioxidant status while reduced lipid oxidative biomarker.

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.

Introduccion. La pandemia actual por el SARS-CoV-2 esta obligando a los neurologos a una serie de adaptaciones en el manejo de la esclerosis multiple. Los neurologos deben sopesar la necesidad de iniciar o continuar los tratamientos modificadores de la enfermedad en funcion del riesgo de infeccion, del riesgo de complicaciones de la infeccion y del riesgo de actividad de la esclerosis multiple. Dado que esta es una situacion sin precedentes, la mayoria de las decisiones se estan tomando sobre la base de un abordaje teorico y del criterio de cada neurologo. Objetivos. Se pretende, a traves de una busqueda bibliografica, recopilar la evidencia disponible sobre la relacion entre tratamientos modificadores de la enfermedad en la esclerosis multiple y la infeccion por el SARS-CoV-2. Esta evidencia, junto con la experiencia de los autores en el manejo de pacientes con esclerosis multiple durante la pandemia, permitira brindar algunas propuestas de tratamiento y seguimiento de los pacientes en este contexto epidemiologico. Desarrollo. Despues de la busqueda bibliografica y de nuestra experiencia en el manejo de pacientes, se establecen unas propuestas de tratamiento sobre cada farmaco que necesariamente han de individualizarse para cada paciente, ya que, en esta circunstancia excepcional, sus peculiaridades pueden marcar el pronostico. Conclusiones. El neurologo debe tener conocimiento de la evidencia actual para valorar el riesgo-beneficio de iniciar, mantener y suspender los tratamientos modificadores de la enfermedad en la esclerosis multiple durante la pandemia.

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

TPS2610Background: Membrane type I matrix metalloproteinase (MT1-MMP) is a member of the matrix metalloproteinase (MMP) family which are involved in tissue remodelling through proteolysis of extrac...

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.

3088 Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p < 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.

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]

Aim We aimed to assess the resistance rates of antimicrobial-resistant, in bacterial pathogens of epidemiological importance in 47 Mexican centers. Material and methods In this retrospective study, we included a stratified sample of 47 centers, covering 20 Mexican states. Selected isolates considered as potential causatives of disease collected over a 6-month period were included. Laboratories employed their usual methods to perform microbiological studies. The results were deposited into a database and analyzed with the WHONET 5.6 software. Results In this 6-month study, a total of 22,943 strains were included. Regarding Gram-negatives, carbapenem resistance was detected in ≤ 3% in Escherichia coli, 12.5% in Klebsiella sp. and Enterobacter sp., and up to 40% in Pseudomonas aeruginosa; in the latter, the resistance rate for piperacillin-tazobactam (TZP) was as high as 19.1%. In Acinetobacter sp., resistance rates for cefepime, ciprofloxacin, meropenem, and TZP were higher than 50%. Regarding Gram-positives, methicillin resistance in Staphylococcus aureus (MRSA) was as high as 21.4%, and vancomycin (VAN) resistance reached up to 21% in Enterococcus faecium. Acinetobacter sp. presented the highest multidrug resistance (53%) followed by Klebsiella sp. (22.6%) and E. coli (19.4%). Conclusion The multidrug resistance of Acinetobacter sp., Klebsiella sp. and E. coli and the carbapenem resistance in specific groups of enterobacteria deserve special attention in Mexico. Vancomycin-resistant enterococci (VRE) and MRSA are common in our hospitals. Our results present valuable information for the implementation of measures to control drug resistance.

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.