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Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy and overall prognosis remains poor, with a median survival of less than 24 months. Sequencing studies have revealed a high prevalence of genomic alterations in CCA, with multiple potential therapeutic targets. Next-generation sequencing (NGS) can identify actionable mutations such as FGFR, IDH, BRAF, ERBB2, ROS1, or microsatellite instability (MSI-H), among others.We conducted a retrospective multicenter study in Spain in 2019. Thirty consecutive patients from 15 centers were included. All patients were diagnosed with advanced CCA and underwent NGS (FoundationOne®) in 2019. Twenty-four patients underwent tissue-based NGS (FoundationOne® CDx), and 6 patients underwent blood-based NGS (FoundationOne®Liquid) with sequencing panels of 324 and 70 genes, respectively RESULTS: We identified 12 patients (40%) with an actionable genetic alteration in tissue: 2 FGFR2 fusions, 6 IDH1 mutations, 1 ERBB2 mutation, 1 ROS1 fusion, 1 PIK3CA mutation, and 1 MSI-H.Comprehensive genomic profiling (CGP) in cholangiocarcinoma can identify, in a high proportion of patients, clinically relevant genomic alterations that can lead to targeted therapies, expanding treatment options.

Background: Cytochrome p450 is the main drug metabolic pathway. CYP2D6 is a highly polymorphic gene that encodes a cytochrome p450 enzyme with three activity levels: null, reduced and normal. Apart from another type of mutations CYP2D6 can suffer duplications and deletions of the entire gene. This is the pathway to metabolize one of the Gaucher disease treatments, whose dose administration is regulated according to the metabolizer phenotype, this being one of the administration limitations. Objectives: The aim of this paper is to evaluate the allelic frequencies and the metabolizer status of Gaucher type 1 patients in the Spanish population and compare it with the general Spanish population and other Gaucher disease groups. Methods: In this study, 109 type 1 Gaucher disease patients were analyzed with the xTAG®CYP2D6 kit to identify the CYP2D6 gene alleles. Results: We observed that eighty-seven patients could be classified as extensive, 14 as intermediate, 6 as poor and 2 as ultra-rapid metabolizers. The allelic duplication frequency is 5.5% and deletion is 4.5%. The most common allele is wild-type and the second is the null *4 allele. Intermediate phenotype frequency is higher than expected (p < 0.05). Conclusions: Our Spanish GD series shows an unexpected distribution of some alleles and phenotypic metabolizer status, in contrast to that previously reported in the Spanish population.

We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p

La hipotesis inicial de este articulo es que, desde mediados de los anos noventa, la logica de marca se ha extendido al ambito de la cooperacion y de la ayuda humanitaria. Que en las ultimas decadas las grandes ONGD han devenido marcas postmodernas. A manera de ejemplo, hemos estudiado los logos aparecidos en los anuncios de television de cinco de estas organizaciones: Intermon Oxfam, Medicos Sin Fronteras, Anesvad, Ayuda en Accion y Africa Directo. Sin duda, el logo es el primer elemento a considerar para establecer un posicionamiento de marca porque en un logo, ademas de la identidad visual, se anticipan metonimicamente los relatos y los valores que sustenten la marca, bien sea una marca estrictamente comercial, bien sean las nuevas marcas de cuno solidario.

Resumen Fundamento y objetivo Describir una nueva variante molecular del Niemann-Pick tipo C (NPC) en una paciente de 27 anos con esplenomegalia y abolicion de reflejos osteotendinosos. Material y metodos NPC1 es el principal gen mutado en el NPC. Presentamos un caso con una nueva mutacion, p.N916S, no descrita previamente en pacientes con NPC. Resultados p.N916S fue descrita como causa de la enfermedad de NPC por los programas predictivos Mutation Master, PolyPhen2 y SIFT. Conclusiones p.N916S es una nueva mutacion detectada como causa de NPC en una paciente sin sintomas neurologicos graves.

Background and objective To describe a new molecular variant of Niemann–Pick disease type C (NPC) in a 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes. Material and methods NPC1 is the main gene with described mutation in NPC disease. Here we report a case with a new mutation, p.N916S, not described before in a patient diagnosed with NPC. Results p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master, PolyPhen2 and SIFT. Conclusions p.N916S is a new mutation detected as a cause of NPC disease in a patient without severe neurological symptoms.

Due to the ageing population and the increase of chronic diseases, new models of health care delivery are unavoidable. The rising cost of health care represents perhaps the most significant threat to long-term economic security. Ribera Salud has developed a Population Health Management (PHM) program that is based on: A population stratification model based on different tools such as ACG or CRG, to identify the level of risk of every citizen The creation and monitoring of personalized care plans, including prevention and health promotion. A complete assessment is done to every citizen and as a result a personalized care plan is created and all the interventions needed to accomplish the plan are scheduled. All this process is supported by a tool “TruCare”. The empowerment of the patients to self-manage their pathology by providing a variety of technologies (health portal to communicate directly with the doctor, to share health information, etc) and collaborative care models. An organizational transformation within the primary care centers to adopt this new manner of working. The measurements of outcomes. The main aim of this program is to improve clinical and financial outcomes. The whole population within the health departments managed by Ribera Salud (550.000 citizens) is the targeted population. All the professionals are PHM stakeholders. In 2012 Ribera Salud started working with a Chronic Plan focusing on high risk level patients. Since then, continual improvements have been developed and, in November 2016 we started a pilot phase with the implementation of the PHM program and the software “TruCare” with the aim of covering the whole population. Highlights: A reduction in hospital admissions and emergencies An improvement in the citizens` satisfaction Awareness of the importance of a healthy lifestyle PHM has been identified as a critical tactic for developing sustainable healthcare models as, through it, health organizations can improve the health status of their population by providing each person with the care they need in a proactive manner. This program can be transferred to any organization, mostly to those with integrated care between primary care and hospitals. It can also be transferred to those that just manage primary care but which have a good coordination with other levels of care. Conclusions: PHM is an effective model to improve population health. Engagement of patients and health professionals is essential in this model. Technology provides tools to make things different, more accessible and effective, BUT we must use it in the right way and never forget about the humanism in the relationship between patients and doctors and nurses. Although PHM was identified many years ago as a critical tactic for developing sustainable healthcare models, very few healthcare organizations have successfully implemented an effective program to manage patient populations. The barriers must be overcome. Lessons learned: Leadership is critical. Population must be correctly stratified to obtain good results. Care must always be patient centered. Empowerment of the patient from the beginning, actively participating in the development of their care plan Providing continual feedback to professionals Community participation

Background: The enzymatic replacement therapy (ERT) availability for Gaucher disease (GD) has changed the landscape of the disease, several countries have screening programs. These actions have promoted the early diagnosis and avoided many complications in pediatric patients. In Spain ERT has been available since 1993 and 386 patients have been included in the Spanish Registry of Gaucher Disease (SpRGD). The aim of this study is to analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. Aim: To analyze the impact of ERT on the characteristics at time of diagnosis and initial complications in pediatric Gaucher disease patients. Methods: A review of data in SpRGD from patients' diagnosed before 18 years old was performed. The cohort was split according the year of diagnosis (= 1995, cohort B). Results: A total of 98 pediatric patients were included, GD1: 80, GD3: 18; mean age: 7.2 (0.17-16.5) years, 58 (59.2%) males and 40 (40.8%) females. Forty-five were diagnosed = 1995. Genotype: N370S/N370S: 2 (2.0%), N370S/L444P: 27 (27.5%), N370S/other: 47 (48%), L444P/L444P: 7 (7.1%), L444P/D409H: 2 (2.0%), L444P/other: 3 (6.2%), other/other: 10 (10.2%). The mean age at diagnosis was earlier in patients diagnosed after 1995 (p < 0.001) and different between the subtypes, GD1: 8.2 (0.2-16.5) years and GD3: 2.8 (0.17-10.2) years (p < 0.001). There were more severe patients in the group diagnosed before 1994 (p = 0.045) carrying L444P (2), D409H (2), G377S (1), G195W (1) or the recombinant mutation. The patients' diagnosed = 1994 showed worse cytopenias, higher chance of bone vascular complications at diagnosis and previous spleen removal. The patients started ERT at a median time after diagnosis of 5.2 years [cohort A] and 1.6 years [cohort B] (p < 0.001). Conclusions: The early diagnosis of Gaucher disease in the era of ERT availability has permitted to reduce the incidence of severe and irreversible initial complication in pediatric patients, and this has permitted better development of these patients. This is the largest pediatric cohort from a national registry.

Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

682 Background: Prognostic and predictive factors are becoming more important in mCRC patients, and may have an impact in overall survival and in the number of lines of chemotherapy that a patient can receive. Methods: We conducted a retrospective analysis of 334 patients with mCRC. We analyzed the clinical characteristics of 113 (33.8%) mCRC patients who received ≥3 lines of chemotherapy. We apply the statistical test Chi square in order to identify significant association. Results: Several characteristics were significantly associated with receiving ≥ 3 lines of chemotherapy (n = 113): age < 80 years (n = 93, OR = 3.07, p = 0.001), ECOG 0-1 (n = 98, OR = 3.21, p = 0.055), primary tumor resection (n = 62, OR = 2.36, p = 0.000) and resection of metastases (n = 56, OR = 2.07, p = 0.002). Partial or complete response rate in the first line of chemotherapy was also significantly associated with receiving ≥ 3 lines of treatment (n = 65, p = 0.011). Tumor mutational status was analyzed in 333 patients: KRAS mutation was detected in 163 over 333 patients genotyped (48.9%), NRAS in 25/206 (12.1%), BRAF in 15/217 (6.9%) and PI3K in 31/213 (14.5%). In the group of patients receiving ≥ 3 lines of chemotherapy (n = 113): KRAS mutation was found in 60/113 patients (53.1%), NRAS in 5/77 (6.5 %), BRAF in 5/84 (5.9%) and PI3K in 8/80 (11.1%). Tumor mutations were not significantly associated with ≥ 3 lines of chemotherapy. No significant association was found between sex, tumor location (right [n = 33, 29.2%] or left [n = 76, 73%]), liver or lung isolated metastases and 3 or later lines of chemotherapy. We also performed in our database a survival analysis in the 334 patients: those who received ≥3 lines of chemotherapy had significantly higher survival rates (median OS 18 m in the group of < 3 lines of treatment vs. 37.2 m in the group of ≥ 3 lines of chemotherapy, HR = 1,6; CI 95% 1,2-2.1; p < 0,001). Conclusions: This retrospective analysis showed that mCRC patients with < 80 years, ECOG 0-1, primary tumor and or metastases resected and those with complete or partial response in the first line of treatment have a higher probability of receiving ≥ 3 lines of chemotherapy. [Table: see text]

Realizar una evaluacion economica de XELOX vs FOLFOX-4 en el tratamiento en primera linea de cancer colorrectal metastatico (CCRm) en Espana. De acuerdo con los resultados del ensayo clinico NO16966, se considero que los tratamientos XELOX y FOLFOX-4 tienen perfiles de eficacia similares, por lo que se llevo a cabo un modelo de minimizacion de costes con el objetivo de estimar el coste medio por paciente de XELOX y FOLFOX-4. Se incluyeron costes farmacologicos, de administracion y acceso venoso central, de manejo de efectos adversos y costes indirectos. Los costes se expresaron en €2012 y se conto con un panel de expertos clinicos para la validacion y determinacion del uso de recursos en Espana. El coste asociado a la administracion, al acceso venoso central y manejo de efectos adversos fue menor con XELOX que con FOLFOX-4 (473 € vs 1.175 €, 125 € vs 824 € y 599 € vs 623 €, respectivamente), mientras que el coste farmacologico fue menor con FOLFOX-4 (2.855 € vs 4.020 €). De esta forma, el coste por paciente desde la perspectiva del Sistema Nacional de Salud fue 261 € inferior con XELOX que con FOLFOX-4. Desde la perspectiva de la sociedad, XELOX tambien presento un menor coste, siendo la diferencia de 1.215 €. El coste por paciente estimado del tratamiento en primera linea de CCRm con XELOX fue significativamente menor que con FOLFOX-4, pudiendo generar ahorros tanto para el Sistema Nacional de Salud como para la sociedad.

Metastatic pancreatic cancer (PC) has been associated with a considerably poor prognosis. Due to its toxicity, first-line combination chemotherapy is limited to patients with a good performance status (PS). Previously nab-paclitaxel plus gemcitabine has been demonstrated to improve the overall survival rate in patients with advanced pancreatic cancer with a good PS. The present study reports a case of a patient with metastatic PC with a poor PS (Eastern Cooperative Oncology Group 2) and a complex set of comorbidities treated with nab-paclitaxel plus gemcitabine as a first-line palliative therapy. Adjusted doses of nab-paclitaxel plus gemcitabine reached a favourable clinical, radiological and biochemical response in the present patient, which increased the quality of life for the patient. Eventually, the patient succumbed to acute cholangitis. Based on the results of the present study, nab-paclitaxel plus gemcitabine appears to be a favourable treatment as first-line palliative chemotherapy for patients with metastatic PC, comorbidities and poor PS.

The membrane lipid glucosylceramide (GlcCer) is continuously formed and degraded. Cells express two GlcCer-degrading β-glucosidases, glucocerebrosidase (GBA) and GBA2, located in and outside the lysosome, respectively. Here we demonstrate that through transglucosylation both GBA and GBA2 are able to catalyze in vitro the transfer of glucosyl-moieties from GlcCer to cholesterol, and vice versa. Furthermore, the natural occurrence of 1-O-cholesteryl-β-D-glucopyranoside (GlcChol) in mouse tissues and human plasma is demonstrated using LC-MS/MS and (13)C6-labeled GlcChol as internal standard. In cells, the inhibition of GBA increases GlcChol, whereas inhibition of GBA2 decreases glucosylated sterol. Similarly, in GBA2-deficient mice, GlcChol is reduced. Depletion of GlcCer by inhibition of GlcCer synthase decreases GlcChol in cells and likewise in plasma of inhibitor-treated Gaucher disease patients. In tissues of mice with Niemann-Pick type C disease, a condition characterized by intralysosomal accumulation of cholesterol, marked elevations in GlcChol occur as well. When lysosomal accumulation of cholesterol is induced in cultured cells, GlcChol is formed via lysosomal GBA. This illustrates that reversible transglucosylation reactions are highly dependent on local availability of suitable acceptors. In conclusion, mammalian tissues contain GlcChol formed by transglucosylation through β-glucosidases using GlcCer as donor. Our findings reveal a novel metabolic function for GlcCer., This study was made possible by the ERC AdG CHEMBIOSPHIN. The authors declare no financial conflicts of interest relevant to this study.

In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC–MS/MS, we comparatively investigated the occurrence of abnormal lyso-glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal α-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso-glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in α-galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase-deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed.

Gaucher disease (GD) is a disorder of glycosphingolipid metabolism caused by deficiency of lysosomal glucocerebrosidase (GlcCerase) activity, due to conformationally or functionally defective variants, resulting in progressive deposition of glycosylceramide in macrophages. The glucose analogue, N-butyldeoxynojirimycin (NB-DNJ, miglustat), is an inhibitor of the ceramide-specific glycosyltransferase, which catalyzes the first step of glycosphingolipid biosynthesis and is currently approved for the oral treatment of type 1 GD. In a previous work, we found a GlcCerase activity increase in cell cultures in the presence of NB-DNJ, which could imply that this compound is not only a substrate reducer but also a pharmacological chaperone or inhibitor for GlcCerase degradation. In this work we compare imiglucerase (the enzyme currently used for replacement therapy) and velaglucerase alfa (a novel therapeutic enzyme form) in terms of conformational stability and enzymatic activity, as well as the effect of NB-DNJ on them. The interaction between these enzymes and NB-DNJ was studied by isothermal titration calorimetry. Our results reveal that, although velaglucerase alfa and imiglucerase exhibit very similar activity profiles, velaglucerase alfa shows higher in vitro thermal stability and is less prone to aggregation/precipitation, which could be advantageous for storage and clinical administration. In addition, we show that at neutral pH NB-DNJ binds to and enhances the stability of both enzymes, while at mildly acidic lysosomal conditions it does not bind to them. These results support the potential role of NB-DNJ as a pharmacological chaperone, susceptible of being part of pharmaceutical formulation or combination therapy for GD in the future.

Gaucher disease (GD) is an autosomal recessive disorder characterized by defective function of glucocerebrosidase. GD presents a wide spectrum of manifestations, and patients and their relatives may develop neurological abnormalities more frequently than the general population. This study aims to determine the presence of neurological symptoms (NS) and Parkinson's disease (PD) in Spanish GD patients and their relatives. We surveyed 87 GD Spanish families and validated the information obtained on the neurological involvement through their physicians, as well as the historical data included in the Spanish Gaucher Disease Registry. Neurological abnormalities were correlated with the genetic characteristics. Statistical analyses included descriptive parameters, ANOVA, t-test, correlation study and Pearson coefficient. Information was obtained from 118 patients and 324 relatives. Out of 110 patients with type 1 GD, 32 (29.1%) reported NS and 7 (6.4%) had PD. In relatives, a total of 39 (13.1%) subjects had NS, including 16 with PD (5.3%). The prevalence of NS in genetic carriers (15.9%) was greater than that in non-carriers (5.9%; p 0.01). Patients with PD carried the following GBA mutations: S364R, D409H, L444P, R257Q, IVS4-2A G, c.500insT, and L336P. Relatives with PD exhibited a wide spectrum of mutations: L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT. We observed a high incidence of PD in type 1 GD and relative's carriers. PD was more frequent in carriers of L444P and other rare GBA mutations. Therefore, it is important to perform a systematic neurological exam in patients with type 1 GD and carriers with high risk mutations.

Background Gaucher disease (GD) is a rare autosomal recessive disorder caused mainly by mutations in the glucocerebrosidase (GBA) gene. Great phenotypic variability has been observed among patients with the same genotype, suggesting other factors, such as polymorphic variants, might influence GD phenotypes. We previously reported the c.(-203)A>G (g.1256A>G) variant in exon 1 of the GBA gene in Spanish GD patients. Methods We analyzed the frequency and transcriptional activity of the promoter carrying the G-allele using restriction isotyping, electrophoretic mobility shift assay, cell culture, transfection, and luciferase assays. Results We found the variant is present at a similar frequency to the control group. In our patients, the G-allele was always found in combination with another mutation in the same allele, and patients carrying the c.(-203)A>G variant showed a more severe GD phenotype. The promoter containing the G-allele showed a 35% reduction in promoter activity when transfected into HepG2 cells. Conclusion The c.(-203)A>G variant seems to be a polymorphism resulting in a decrease in activity of the GBA promoter. The change, per se, is not enough to elicit a GD phenotype, but it may produce a more severe phenotype in GD patients when combined with an already defective GBA protein.

Recently, an acute restriction of imiglucerase has occurred as a result of viral contamination and manufacturing problems. A position statement from the European Working Group for Gaucher Disease and European Gaucher Alliance established a set of key recommendations for identifying and monitoring at-risk patients. In Spain, a profile of the shortage situation was obtained through follow-up of patients with Gaucher disease (GD) and compliance with the therapy recommendations. Here we describe a group of patients, with modified doses of imiglucerase, during the shortage. Fifty adult GD1 patients (25 males/25 females), previously on ERT, were analysed before and after the 6-month shortage. The mean age was 45.3 ± 15.3 years (range: 18-84). The mean Severity Score Index at diagnosis was 8.7 ± 3.8 (range: 3-19); 20% of patients were splenectomized; and 78% had bone disease. During the shortage, 23 patients (46%) discontinued therapy; as complications in this group only one patient suffered a bone crisis and another anaemia (Hb

Colorectal cancer is the first cause of cancer diagnosis in Spain. Over half of the patients are diagnosed with or will eventually develop distant metastasis. The current manuscript aims to provide synthetic practical guidelines for the therapeutic approaches in advanced disease. Available systemic therapeutic options, and integration and sequencing of chemotherapy with surgical procedures are discussed. Extent of disease, treatment objective, tumor kras mutation status, as well as patient's functional and comorbid conditions shall be considered to properly design the most adequate therapeutic strategy.

Background JAK1 LoF mutations were reported as a mechanism of resistance to anti-PD-1 therapy in patients with metastatic melanoma (n = 2) or mCRC (n = 1).1,2 Here, we report an exploratory analysis of CheckMate-142 (NCT02060188) investigating whether JAK1 LoF mutations were present in patients with dMMR/MSI-H mCRC who achieved clinical benefit with nivolumab + ipilimumab treatment. Methods Patients received nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W × 4 doses and then nivolumab 3 mg/kg Q2W. Whole-exome sequencing was performed on pretreatment biopsies preserved in RNAlater and germline DNA from peripheral blood mononuclear cells. Single nucleotide variants and insertions/deletions were called by 2 variant callers in paired normal and tumor samples, and the union of mutations was included in the downstream analysis as previously described.3 Best overall response was assessed by investigators (RECIST v1.1). Results JAK1 LoF mutations were identified in 4 of 40 patients evaluated in this analysis. Of these 4 patients, 1 had an ongoing partial response of 9.7 months at data cutoff, and 3 had stable disease (Table); 2 patients with stable disease were still on treatment (12 and 17 months) at data cutoff, and 1 discontinued treatment after 2.9 months due to an unrelated adverse event and had not progressed after 10 months off treatment. Conclusions Clinical benefit was achieved with nivolumab + ipilimumab in patients with dMMR/MSI-H mCRC who harbored a JAK1 LoF mutation. Additional analyses are needed to assess the effect of concurrent JAK1 loss of heterozygosity and other genetic alterations in patients with dMMR/MSI-H mCRC. 1. Zaretsky JM et al. N Engl J Med. 2016;375:819-829. 2. Shin D et al. Cancer Discov. 2017;7:188-201. 3. Carbone DP et al. N Engl J Med. 2017;376:2415-2426. Table. Best overall response in patients with dMMR/MSI-H mCRC identified as having wild-type JAK1 or a JAK1 LoF mutationJAK1 LoF mutant n = 4JAK1 wild type n = 36Best overall response, nComplete response01Partial response1a18Stable disease3b11Progressive disease04Not evaluable02fs, frameshift. a JAK1 mutation: I975*. b JAK1 mutations: D899Gfs*10, K860Nfs*16, and K142Rfs*26. Citation Format: Scott Kopetz, Theirry Andre, Michael J. Overman, Vittorina Zagonel, Sara Lonardi, Massimo Aglietta, Fabio Gelsomino, Ray McDermott, Ka Yeung Mark Wong, Alain Hendlisz, Pilar Garcia Alfonso, Heinz-Josef Lenz, Alice Walsh, Rebecca A. Moss, Danielle Greenawalt, Z. Alexander Cao. Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab + ipilimumab in CheckMate-142 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2603.

3566Background: More than 80% of squamous cell carcinoma of the anal canal (SCCAC) express epidermal growth factor receptor protein (EGFR). VITAL was a phase II, multicentre, single arm study, whic...

e15602Background: Tumor biopsies are widely used in clinical practice to assess RAS mutation status in mCRC patients. However, new techniques of genotyping based on circulating tumor (ct) DNA prese...

3536Background: FOLFOXIRI plus bevacizumab has demonstrated a survival benefit compared with FOLFIRI plus bevacizumab (TRIBE Lancet Oncol 2015) in first-line mCRC. This schedule is not routinely re...

690 Background: In recent years, prognostic and predictive factors in mCRC are becoming more important, outstanding the tumor and metastasic location, the primary tumor and/or metastasis resections as well as molecular biomarkers (KRAS, NRAS, BRAF and PIK3CA). Methods: We conducted a retrospective study of 334 patients with mCRC diagnosticated between January 2010 and June 2015 in the Oncology Service from HGUGM. The objective of our study was to evaluate the overall survival (OS) relating to each of these settings. We also evaluated OS considering the biological treatment received in first line. Multivariant analysis was performed with independence of tumor and metastasic location, metastasectomies, no primary tumor resection, biological treatment used in first line, age, sex and moleculars biomarkers. Results: Median OS was 24,34m. The advantageous prognostic factors which statistically significant impact on the median OS have been triple (RAS and BRAF) (n = 86) and quadruple (RAS, BRAF and PIK3CA) (n = 76) wild-type (wt 36,6m vs mut 23m, p = 0,02; wt 37,6m vs mut 23,38m, p = 0.02, respectively), left tumor location with rectum (left 25,55m vs right 19,44m, p = 0,001) and isolated hepatic and pulmonary metastasic location (30,32 vs 23 m, p = 0,03; 45,32m vs 23,38 m, p = 0,004, respectively). The main disadvantageous prognostic factor has been the no primary tumor resection (13,75m vs 31,61m, p = 0,00001) with independence of synchronous presentation of the disease as well as biomarkers mutational status. Median OS in first line was 30.13 m with bevacizumab (n = 54) vs 16,18m with antiEGFR (n = 28) (p = 0.02) in extended RAS wild-type patients (n = 101). Considering the multivariate analysis, the independent prognostic factors have been the isolated pulmonary metastasis (HR = 0,46; CI 95% 0,30-0,73;p = 0,001), quadruple wild-type (HR = 0,69;CI 95% 0,49-0,97; p = 0,031), metastasectomies (HR = 0,29; CI 95% 0,21-0,4; p = 0,000), right location (HR = 1,43; CI 95% 1,08-1,9;p = 0,014) and no primary tumor resection (HR = 2,06; CI 95% 1,49-2,86; p = 0,000). Conclusions: Isolated pulmonary metastasis, quadruple wild-type, metastasectomies, left location and primary tumor resection have independent positive prognostic value, according to our retrospective study.

622 Background: The RAISE trial (NCT01183780) demonstrated that ramucirumab (RAM) plus leucovorin, fluorouracil, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo (PBO) plus FOLFIRI as second-line mCRC treatment. RAS/RAF mutations are associated with resistance to anti-EGFR therapies and poor prognosis, particularly BRAF mutations. The extensive RAISE biomarker program assessed the association of multiple candidate markers with efficacy outcomes. Here we present the results for RAS/ RAF mutations. Methods: Plasma and tumor tissue collection were mandatory. KRAS mutation status was determined locally before randomization. Further RAS and RAF mutations were assessed centrally by multiplex qPCR using the Modaplex system (Qiagen) only in samples that were initially reported as KRAS wild type. Thus, patients were classified into one of the 3 categories in the table. OS and PFS by RAS and RAF subgroups were evaluated by Kaplan-Meier and Cox proportional hazards analyses. Results: As with previously reported KRAS analyses, the favorable RAM treatment effect was similar between patients with expanded RAS mutations compared with patients with RAS/ RAF wild-type tumors. However, in the 41 patients with BRAF mutated tumors, the RAM benefit was even more notable for both OS (hazard ratio [HR] 0.54; 95% CI 0.25–1.13) and PFS (HR 0.55; 95% CI 0.28–1.08). Conclusions: RAISE demonstrated that the addition of RAM to FOLFIRI improved patient outcomes regardless of RAS mutation status. The noteworthy signal for patients with BRAF mutant tumors is encouraging due to their poor prognosis but requires further validation in other clinical trials. Clinical trial information: NCT01183780. [Table: see text]

Resumen Fundamento y objetivo Fulvestrant es un antiestrogeno puro que ha demostrado eficacia en cancer de mama avanzado como tratamiento de segunda linea tras progresion a tamoxifeno. El objetivo del trabajo fue describir la experiencia clinica con fulvestrant y evaluar su eficacia y tolerabilidad. Material y metodo 36 mujeres posmenopausicas con cancer de mama avanzado recibieron tratamiento con fulvestrant. El 62,8% de las pacientes recibio fulvestrant al menos en tercera linea. Resultados El 91,4% habia recibido tratamiento hormonal previo en la enfermedad avanzada y mas del 50%, quimioterapia. La enfermedad metastasica fue visceral en un 5,7%, no visceral en un 54,3% y en ambas localizaciones en un 40%. Se obtuvo un 11,4% de respuestas parciales (RP), un 22,9% presento estabilidad de la enfermedad (EE), alcanzando beneficio clinico (BC) el 31,4% de las pacientes. La mediana de tiempo a la progresion (TTP) fue de 4,18 meses (intervalo de confianza del 95% [IC] del 95%, 2,6–5,7 meses), mientras que la mediana de supervivencia global (SG) no se ha alcanzado, con una mediana de seguimiento de 8,9 meses. Se produjeron eventos adversos de grado I–II en un 22,9% de las pacientes. Conclusiones Fulvestrant es un farmaco bien tolerado, que representa una eficaz opcion de tratamiento hormonal en el cancer de mama avanzado intensamente tratado con hormonoterapia y quimioterapia.

There are few published data from real-world clinical experience with miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease. We report data from a prospective, open-label investigational study that evaluated substrate reduction therapy with miglustat 100 mg t.i.d. as a maintenance therapy in patients with Type 1 Gaucher disease who had been switched from previous enzyme replacement therapy. Long-term data on changes in organ size, blood counts, disease severity bio-markers, bone marrow infiltration, overall clinical status and safety/tolerability were analyzed from 28 patients with Type 1 Gaucher disease who were attending routine clinic visits. Assessments were performed at six, 12, 24, 36 and 48 months of therapy. Disease severity biomarkers improved up to 48 months after initiation of miglustat, while other disease parameters remained stable. Miglustat showed an acceptable profile of safety and tolerability throughout treatment. In conclusion, miglustat is an effective therapy for the long-term maintenance of patients with Type 1 Gaucher disease previously stabilized with enzyme replacement therapy.

Pathologic complete response (pCR) after preoperative systemic chemotherapy (PSCh) is associated with better outcome in locally advanced breast cancer (LABC).PSCh included: doxorubicin (A) 50 mg/m(2) i.v. on day 1; docetaxel (T) 30 mg/m(2) i.v. on days 1, 8 and 15; and capecitabine (X) 1,500 mg/m(2)/day p.o. on days 1-14, in a 4-week course repeated for up to four cycles (ATX), followed by surgery. The primary end point of this study was to evaluate the pCR rate. Secondary endpoints included clinical response rate, disease-free survival (DFS), overall survival (OS), and the toxicity profile.A total of 60 patients were included in the analysis. Median age was 49 years, and 63.3% of patients were hormone receptor positive. The median number of cycles of PSCh was four (95% CI: 3-4). Five patients (8.3%) achieved pCR in both breast and nodes, and 16.7% reached pCR only in nodes. The clinical response rate was 77% (27% complete response), but only 18% of the patients underwent conservative surgery. With a median follow-up of 20 months, 3-year DFS and OS were 76 and 90%, respectively. Grade III/IV toxicity included neutropenia (74%), febrile neutropenia (9%), mucositis (12%), and diarrhea (12%).ATX every 28 days for four cycles is associated with a modest activity (low pCR rate) in the neoadjuvant setting of LABC.

Fundamento y objetivo La enfermedad de Gaucher (EG) se caracteriza por su heterogeneidad clinica. Estudios previos indican que los familiares pueden presentar anomalias neurologicas con mayor frecuencia que la poblacion general. El objetivo de este trabajo ha sido conocer la presencia de manifestaciones neurologicas (MN) en pacientes con EG y sus familiares. Pacientes y metodo Entre enero y diciembre de 2006 se remitio una encuesta a 42 medicos y 92 familias con afectados de EG para obtener informacion sobre MN y correlacionarla con las caracteristicas geneticas. Se realizo un analisis estadistico descriptivo, con analisis de ANOVA, prueba de la t de Student y estudio de correlacion (coeficiente de Pearson). Resultados Se obtuvo informacion de 72 familias (un 78,3% de respuestas): 99 pacientes y 266 familiares. De los pacientes con EG tipo 1, 30 (32,6%) presentaban MN: temblor en 8 casos (8,7%), movimientos incoordinados en 9 (9,8%), falta de concentracion en 11 (11,9%), estrabismo en 7 (7,6%), hipoacusia en 8 (8,7%), enfermedad de Parkinson (EP) en 7 (7,6%) y neuropatia periferica en 10 (10,9%). En cuanto a los familiares (primer/segundo grado), 36 (13,5%) presentaron alguna MN: EP en 14 casos (4,9%), epilepsia en 8 (3,0%), temblor en 7 (2,6%), hipoacusia en 2 (0,7%) y otros en 5 (1,9%). La frecuencia de MN en portadores de mutacion en el gen de la enzima betaglucosidasa acida (GBA) fue del 17,3%, frente al 5,7% en los no portadores (p = 0,0096). Los pacientes con EG que presentaban EP tenian las mutaciones S364R, D409H, L444P [IVS4-2a → g; c.(–203)A → G], c.500insT y L336P. Los familiares con EP presentaban diversas mutaciones: L444P, N370S, V398I, G202R, c.1439-1445del7 [E326K; N188S] y c.953delT. En otras MN, las predominantes fueron D409H, G195W, R120W, R147X, L336P y G377S. Conclusiones La EP y otras MN tuvieron en pacientes con EG tipo 1 y sus familiares una incidencia superior a la esperada y aparecieron mas frecuentemente en portadores de L444P o mutaciones raras. Se recomienda realizar un examen neurologico sistematico a los pacientes con EG tipo 1 y a portadores de mutaciones de riesgo.

Type 1 Gaucher disease (GD1) is characterised by lack of central nervous system involvement; however, there are several reports of associated neurological manifestations. The aim of this study was to systematically evaluate neurological manifestations in 31 patients with GD1 (12 males and 19 females; mean age 39.4 (range 5-77) years). Participants underwent a complete neurological examination and cognitive tests. Investigation of symptoms and medication intake, and motor and sensory electroneurograms were obtained. 30.7% of adult patients had neurological deficits, including psychomotor delay, parkinsonism, dementia, impaired saccadic ocular movements and peripheral nerve dysfunction. Three patients were redefined as type 3 GD. Electrodiagnosis was performed on 15 patients; 26.7% had reduced amplitude and/or abnormal waveforms in at least three nerves, 33.3% had a mild reduction in amplitude of two nerves and 40% had amplitude reduction in one nerve. Patients with three or more affected nerves had additional neurological symptoms. Our results demonstrate that neurological alterations occur in patients diagnosed with GD1, and subclinical peripheral neuropathy is a frequent finding.

To describe a new molecular variant of Niemann-Pick disease type C (NPC) in a 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes.NPC1 is the main gene with described mutation in NPC disease. Here we report a case with a new mutation, p.N916S, not described before in a patient diagnosed with NPC.p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master, PolyPhen2 and SIFT.p.N916S is a new mutation detected as a cause of NPC disease in a patient without severe neurological symptoms.

La hipótesis inicial de este artículo es que, desde mediados de los años noventa, la lógica de marca se ha extendido al ámbito de la cooperación y de la ayuda humanitaria. Que en las últimas décadas las grandes ONGD han devenido marcas postmodernas. A manera de ejemplo, hemos estudiado los logos aparecidos en los anuncios de televisión de cinco de estas organizaciones: Intermón Oxfam, Médicos Sin Fronteras, Anesvad, Ayuda en Acción y África Directo. Sin duda, el logo es el primer elemento a considerar para establecer un posicionamiento de marca porque en un logo, además de la identidad visual, se anticipan metonímicamente los relatos y los valores que sustenten la marca, bien sea una marca estrictamente comercial, bien sean las nuevas marcas de cuño solidario. The initial hypothesis of this article states that from the middle nineties, branding has extended to the field of cooperation and human aid, and that in the last decades, the big NGDOs have become postmodern brands. The logos of five of these NGDOs (Intermón Oxfam, Médicos Sin Fronteras, Anesvad, Ayuda en Acción and África Directo) shown on TV advertisements have been analysed. Logos are the first elements to be considered in order to establish brand placing. Besides visual identity, logos bring metonymically forward stories and values that support brands, both tradicional trade brands and new charity brands.

Background : Gaucher disease (GD) is a heterogeneous disease characterized by an impaired activity of the lysosomal glucocerebrosidase. This heterogeneity is attributed in part to the existence of a large number of mutations in the corresponding gene. Subjects and methods : To establish genotype–phenotype relationships, we analyzed the residual enzyme activities of six naturally occurring mutations found in Spanish population in the glucocerebrosidase gene [c.160G > A (V15M), c.485T>C (M123T), c.914C>T (P266L), c.1124T>C (L336P), c.1207A>C (S364R) and c.1510–1512delTCT (S465del)]. The mutated genes were subcloned into the mammalian expression vector pCR® 3.1 and expressed by transient transfection in COS cells. The enzymatic activity of the expressed protein were measured and compared with the wild-type human glucocerebrosidase cDNA. Also, two previously alleles, c.1226A>G (N370S) and c.1448T>C (L444P), were used for comparative purposes. Results : The residual activity of the expressed proteins using the synthetic substrate (4-methylumbelliferyl-β- d -glucopyranoside, 4MU-Glu) ranged from 5.5% (for the 3-bp deletion) to 42.7% (for S364R mutation) of the activity of the wild-type enzyme. Conclusion : The present analyses may help to better understand the molecular basis and the pathogenesis of Gaucher disease. However, results of expression of mutated enzymes are necessary but not sufficient to explain the ultimate clinical outcome of Gaucher disease.

Fundamento y objetivo: La enfermedad de Gaucher (EG) es una enfermedad lisosomal producida por el defecto de la enzima s-glucocerebrosidasa, que origina el deposito de material lipidico en los macrofagos. Los sujetos con EG tienen concentraciones plasmaticas disminuidas de colesterol total (CT), colesterol unido a lipoproteinas de baja densidad (cLDL) y de alta densidad (cHDL), apolipoproteinas (apo) A-I y B, y concentraciones elevadas de apo E y de la enzima quitotriosidasa (QT), una quitinasa producida por los macrofagos activados. El tratamiento enzimatico sustitutivo (TES) es un procedimiento eficaz y seguro que permite revertir las manifestaciones clinicas en pacientes sintomaticos. El proposito de este trabajo ha sido evaluar el efecto del TES sobre el perfil lipidico en pacientes con EG. Pacientes y metodo: Se incluyo a 70 pacientes procedentes del Registro Espanol de Enfermedad de Gaucher (REEG), que fueron distribuidos en dos grupos: 54 sometidos a TES, siguiendo los criterios establecidos, y 16 que no habian recibido TES. Se midieron las concentraciones de apolipoproteinas, lipoproteinas, lipidos plasmaticos y la actividad de la QT en ambos grupos. Para el analisis estadistico de las diferencias observadas se utilizo la prueba no parametrica de comparacion de medias (U de Mann Whitney) entre los dos grupos. Resultados: El grupo con TES presento un incremento significativo en las concentraciones de cHDL (+38%) y apo A-I (+18%), mientras que las de cLDL y apo B no se modificaron. Por el contrario, se observo una reduccion drastica de la actividad de la QT (­58%) y en los valores plasmaticos de apo E (­32%) y de apo E en HDL (­26%) despues del TES. En el grupo que no habia recibido TES, no se observaron modificaciones significativas. Conclusiones: El tratamiento enzimatico sustitutivo en pacientes con enfermedad de Gaucher tiene efectos significativos sobre la concentracion de lipoproteinas plasmaticas, originando un perfil lipidico menos aterogenico y una reduccion de macrofagos activados.

3539 Background: VEGF-A and ANG-2 have complementary roles in regulation of tumor angiogenesis. Targeting VEGF-A with BEV in combination chemotherapy (CT) in mCRC has proven to increase PFS and OS. ANG-2 is overexpressed and associated with poor outcome of mCRC pts receiving BEVcontaining treatment. Hence, dual blockade of VEGF-A and ANG-2 by the bispecific mAb VAN with standard CT may improve clinical activity in mCRC. Methods: All pts received mFOLFOX-6 and were randomized 1:1 to also receive intravenous VAN 2000 mg every other week (Q2W) (Arm A) or BEV 5 mg/kg Q2W (Arm B). The primary end point was investigator assessed progression-free survival (PFS). Key eligibility criteria included pts with non-resectable mCRC, no prior therapy for advanced disease, PS 0-1, adequate organ functions, and no history of GI fistula/perforation or intraabdominal abscess within the last 6 months. Results: 192 pts were randomized (Arms A/B, n = 95/97) by 39 sites in 7 countries, between Oct 2014 and May 2016. Median follow-up was 17.6 months (range 2.8 – 20.7). In the ITT population (n = 189; Arms A/B, n = 94/95), median PFS in Arms A and B was 11.3 and 11.0 months (stratified hazard ratio (HR) 1.00 (95%CI 0.64-1.58; p = 0.985)), respectively. Objective response rate was 52.1% vs 57.9%. Relevant prognostic factors incl. RAS/BRAF status and tumor sidedness were balanced between arms and did not significantly influence outcome. Baseline plasma ANG-2 levels were prognostic in both arms but not predictive for response to VAN. The overall incidence of adverse events (AEs) grade ≥ 3 was similar (Arms A/B, 83.9%/82.1%); AEs grade ≥ 3 attributed to the mode of action of VAN/BEV included hypertension (37.6%/18.9%), hemorrhage (2.2%/1.1%), thromboembolic events (venous 6.5%/2.1%; arterial 1.1%/3.2%) and GI perforations incl. GI fistula & abdominal abscess (10.6%/8.4%). Conclusions: The combination of VAN and FOLFOX did not improve PFS and was associated with a marked increase in hypertension compared with BEV plus FOLFOX. Our results strongly suggest that ANG-2 is not a relevant therapeutic target in the setting of first line mCRC. Clinical trial information: NCT02141295.

668 Background: Ramucirumab is a human IgG1 monoclonal antibody antagonist of VEGFR-2. Overall survival (OS) and progression-free survival (PFS) in 2nd line FOLFIRI based treatment for metastatic colorectal cancer (mCRC) were improved with RAM therapy versus PBO in the RAISE trial. Recent work suggests mCRC primary tumor location is both prognostic and predictive; with improved OS and therapy-specific sensitivity observed in left (L)- vs right (R)-sided tumors. Given these findings, the RAISE trial data was subjected to post-hoc analysis to determine if sidedness influenced RAM efficacy. Methods: Primary tumor site was obtained. L-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum, while R-CRC included transverse, ascending colon and cecum. OS/PFS in L and R subgroups were analyzed via Kaplan-Meier method and unstratified log-rank test (treatments within subgroup), unstratified Cox proportional hazards model (estimate hazard ratio [HR] and 95% CI), and Wald test (treatment-by-subgroup interaction). Results: Tumor location was available for 1012/1072 (94%) patients, 699 L- and 313 R-CRC. Baseline characteristics were balanced between arms. RAM treatment enhanced L-CRC median OS by 2.5 mo (median 14.5 vs 12.0 mo) with a HR (95% CI) = 0.807 (0.675, 0.965), P = 0.019; compared to a 1.1 mo increase in median OS in R-CRC vs PBO (12.7 vs 11.6) with a HR (95% CI) = 0.971 (0.750, 1.258), P = 0.823; and, RAM enhanced L-CRC median PFS by 1.6 mo (6.0 vs 4.4 mo) and HR (95% CI) = 0.776 (0.664, 0.906), P = 0.001 compared to a 1.1 mo increase in median PFS R-CRC vs PBO (5.6 vs 4.5) with a HR (95% CI) = 0.855 (0.674, 1.084), P = 0.197. The treatment-by-subgroup interaction for both OS and PFS was not significant ( P = 0.276, 0.578, respectively). Conclusions: Despite L-CRC patients having longer OS/PFS and a seemingly stronger RAM treatment effect than R-CRC, the non-significant interaction test cannot verify sidedness as being predictive of RAM efficacy. The current study confirms ramucirumab benefits mCRC patients regardless primary tumor location. Clinical trial information: NCT01183780.

663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]