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Table S1.Summary of data for skin and gillssamples' processing and analysis Figure S1.Principal coordinate analysis (PCoA) of the bacterial communities was calculated from the weighted UniFrac distance matrix in gills (A) and skin (B) samples. Red, green and blue colours represent samples of S.aurata microbiota feed with control, Hydrolyzed and Raw diet respectly. Figure S2. Significantly different ASVs (DESeq2, p < 0.05) classified by genus and phylum in the mucus microbiota of the gills ((A) Hydrolyzed vs Control), (B) Raw vs Control) and skin ((C) Hydrolyzed vs Control, (D)Raw vs Control). Figure S3.Diet exclusive interactions in the gills (A) and in the skin (B).

This work addresses the evaluation in vitro of different marine (Dunaliella salina REC-0214B and Microchloropsis gaditana REC-0251B) and freshwater (Anabaena sp. BEA-0300B, Arthrospira platensis BEA-0007B, Chlorella vulgaris BEA-0753B, Spirogyra sp. BEA-0666B) microalgae and cyanobacteria as potential dietary ingredients in aquafeeds. For this purpose, total protein content, amino acid composition, and the presence of protease inhibitors were evaluated. In addition, protein bioaccessibility was estimated using a species-specific in vitro assay using Sparus aurata digestive enzymes. Overall, all the microalgae showed high protein content ranging from 25 to 61%, and a balanced essential to non-essential amino acid content (from 0.81 to 0.95). The inhibition assay confirmed the absence of protease inhibitors whatever the microalgae considered. Finally, the in vitro assays showed differences in the degree of protein hydrolysis with values for the coefficient of protein degradation ranging from 49.4% in Spirogyra sp. to 85.5% in D. salina. Similarly, the total amount of free amino acids released from the microalgal biomass (from 12.8 to 20.8 g L-leucine equivalents (100 g protein)−1), as well as their qualitative amino acids profile varied among the different species, although the profile can be considered as well balanced in all cases. In conclusion, the results obtained revealed that, even if significant differences were observed among species in terms of their susceptibility to be hydrolysed by S. aurata digestive enzymes, all the microalgae and cyanobacteria evaluated presented an adequate protein content and a balanced amino acid profile.

Aim: Darolutamide significantly prolonged metastasis-free survival (MFS) versus placebo in the Phase III ARAMIS study. We analyzed outcomes in Spanish participants in ARAMIS. Patients & methods: Patients with high-risk nonmetastatic castration-resistant prostate cancer were randomized 2:1 to darolutamide 600 mg twice daily or placebo, plus androgen-deprivation therapy. The primary end point was MFS. Descriptive statistics are reported for this post hoc analysis. Results: In Spanish participants, darolutamide (n = 75) prolonged MFS versus placebo (n = 42): hazard ratio 0.345, 95% confidence interval 0.175–0.681. The incidence and type of treatment-emergent adverse events were comparable between treatment arms. Conclusion: For Spanish participants in ARAMIS, efficacy outcomes favored darolutamide versus placebo, with a similar safety profile, consistent with the overall ARAMIS population. Clinical Trials Registration: NCT02200614 ( ClinicalTrials.gov )

We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy. Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients. A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7-49.2) and the control group (33.9%; 95% CI 19.5-48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3-5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%). Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice. NCT02036060 https://clinicaltrials.gov/ct2/show/NCT02036060.

OBJECTIVE To investigate the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus in first-line metastatic renal cell carcinoma (mRCC), as alternating blockade of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) pathways could potentially prevent the occurrence of resistance to anti-VEGFR therapy in mRCC. PATIENTS AND METHODS SUNRISES, a randomised open-label Phase II study, investigated the efficacy of alternating cycles of sunitinib and everolimus vs standard sequential treatment of sunitinib followed by everolimus upon progression. Treatment-naive patients with clear-cell mRCC were included. Alternating treatment consisted on 12 weeks of sunitinib, followed by 12 weeks of everolimus. The primary endpoint was the progression-free survival (PFS) rate at 1 year. The secondary endpoints included the median PFS, overall survival (OS), response rate, and safety. RESULTS Accrual was low due to the advent of new-generation therapies, and the study was stopped prematurely. Only 41 patients out of the planned 102 patients were accrued, and randomised in a 2:1 ratio (15 patients to the control arm, 26 to the experimental arm). In all, 60.9% of patients had performance status (PS) 0 and 39% PS 1; 63% had a favourable prognostic risk profile, while 36% were intermediate risk. The primary endpoint was not met. The 1-year PFS rate was 49.7% (experimental arm) vs 84.62% (control arm; P = 0.11). There was a trend towards fewer Grade ≥3 adverse events with the alternating approach (50% vs 73.3%; P = 0.14). The median OS was similar in both treatment arms. The other secondary endpoints favoured the control arm. CONCLUSIONS The study failed to show any benefit of alternating cycles of sunitinib and everolimus in patients with mRCC. The alternating approach using an mTOR inhibitor does not seem to prevent the occurrence of resistance to VEGFR blockade.

Introduction Autoimmune haemolytic anaemia (AIHA) is an infrequent and heterogeneous disease in its pathophysiology and clinical behaviour, therefore it is generally managed empirically. Patients and methods We conducted an observational, retrospective and multicentre study of 93 patients diagnosed with AHAI in 9 Spanish hospitals between 1987 and 2017, with a median follow-up of 28 months. Results Median age of 67 years; 85% AHAI for hot antibodies and 64% primary AHAI. The lowest haemoglobin values at diagnosis related to patients under 45 years of age and serological type IgG+C. Of the patients, 92% received first line treatment, 54% second line, and 27% third line. The warm AHAI were treated in first line with steroids, with overall responses of 83% and complete of 58%. Rituximab in monotherapy or in association with steroids was administered to 34 patients with overall responses close to 100% (complete responses 40–60%), relegating splenectomy to the third line. The immunosuppressive treatment was administered in patients with autoimmune diseases or in corticoid-dependent patients. Discussion We found high rates of response to steroids, with very prolonged treatments that cause side effects and corticoid dependence in a third of patients. The combination of steroids with rituximab in the first line, could be indicated in patients with low levels of haemoglobin and serological type IgG+C. The high relapse rates make necessary the development of randomised studies with new drugs or the combination with existing ones, which allow longer response times and with fewer side effects.

Resumen Introduccion Las anemias hemoliticas autoinmunes (AHAI) son enfermedades poco frecuentes y heterogeneas en su fisiopatologia y comportamiento clinico, siendo el manejo de las mismas fundamentalmente empirico. Pacientes y metodos Realizamos un estudio observacional, retrospectivo y multicentrico de 93 pacientes diagnosticados de AHAI en 9 hospitales espanoles entre 1987 y 2017, con una mediana de seguimiento de 28 meses. Resultados Mediana de edad de 67 anos; un 85% de AHAI por anticuerpos calientes y un 64% AHAI primarias. Los valores de hemoglobina mas bajos al diagnostico se relacionaron con edad Discusion Encontramos altas tasas de respuesta a esteroides, con tratamientos muy prolongados que provocan efectos secundarios y corticodependencia en un tercio de los pacientes. La asociacion de esteroides con rituximab en primera linea podria estar indicada en pacientes con bajos niveles de hemoglobina y tipo serologico IgG+C. Las altas tasas de recaida hacen necesario el desarrollo de estudios aleatorizados con nuevos farmacos o la asociacion con los ya existentes, que permitan mayor duracion de las respuestas y con menores efectos secundarios.

Abundant research is being carried out in the last years aimed at exploring microalgal biomass as nutrient source for different species of aquacultured fish. Some microalgae species, such as Nannochloropsis gaditana, have thick cell walls rich in cellulose, which might well reduce the bioavailability of intracellular active compounds. Among the alternatives aimed at overcoming this limitation, cellulase enzyme hydrolysis is proposed as a convenient and practical solution. In this regard, an in vitro assay was carried out, in which N. gaditana biomass was treated with cellulase (5% w/w basis) and the release of soluble compounds (reducing sugars, free amino acids and total phenolics) into the reaction medium was measured and compared to untreated raw biomass. The results confirmed increased yields of those compounds as a result of the enzyme pre-treatment. A 90-d feeding trial was also carried out in order to assess in vivo the influence of the inclusion of N. gaditana in feeds on juvenile gilthead seabream (Sparus aurata) growth, digestive physiology and body composition. Microalgal biomass was added at two inclusion levels (25 and 50 g kg􀀀 1 dry weight) in four experimental feeds, either crude or enzymatically pretreated. Animals (15.1 g initial body weight) were randomly assigned to five dietary treatments (two inclusion levels, 2.5 and 5%, and two microalgae formats, raw and enzymatically hydrolysed, plus a microalgae-free control), and distributed triplicate tanks per dietary treatment. Fish were withdrawn after 45 and 90 days, and proximate composition, muscle fatty acid and amino acid profiles, muscle and liver lipid oxidation, instrumental skin colour, digestive enzyme activities, as well as structural and ultrastructural changes in the intestinal mucosa were determined. No differences attributable to the dietary treatments were found with regard to fish growth or proximate composition at the end of the feeding trial. On the contrary, the inclusion of microalgal biomass, irrespectively of the cellulase pre-treatment, caused beneficial effects on some physiological parameters (namely digestive mucosa structure and functionality, oxidative status of muscle lipids, and instrumental colour). The only clear improvement found in fish attributable to the cellulase pre-treatment of the microalgal biomass was related to the prevention of muscle lipid oxidation. Overall, the results suggest that N. gaditana used as additive (at inclusion level below 5%) in feeds might represent a valuable nutritional strategy for S. aurata juveniles, even if growth was not affected., Evaluación de los efectos de las microalgas, incluidas en dietas de dorada, sobre el crecimiento, supervivencia y resistencia a infecciones., ALGAFISH, SI

Resumen Las micosis por Exophiala xenobiotica comprenden un amplio espectro clínico en pacientes inmunosuprimidos, desde infecciones localizadas, hasta diseminadas. Son incluidas como etiología de las feohifomicosis, actualmente consideradas como infecciones fúngicas emergentes en pacientes trasplantados de órgano sólido. Presentamos 2 casos de micosis por Eexophiala xenobiotica en paciente trasplantado renal, una micosis cutánea localizada y una infección sistémica con afectación del sistema nervioso central. Abstract Mycosis by exophiala xenobiotica comprise a broad clinical spectrum in immunosuppressed patients, from localized to disseminated infections. They are a recognized etiology of phaeohyphomycosis, currently considered as emerging fungal infections in transplanted solid organ recipients. We present 2 cases of mycosis by exophiala xenobiotica in kidney transplant recipients, a localized cutaneous mycosis and a systemic infection with central nervous system involvement.

In this paper, we explain the methodological shifts that have occurred over time in the study of company law. Our hypothesis is that comparative company law has developed and evolved as a bridge between two extremes. On the one hand, the doctrinal, black-letter law approach to company law, dominant in academic commentary at the domestic level. On the other hand, the instrumental, analytic approach of the law and economics view of company law. As we will see, the evolution of the comparative approach to company law has seen frequent rebranding, from comparative corporate law, to comparative corporate governance, to law and finance and to theory and empirics of comparative corporate law. These re-branding waves have taken place as new questions, in need of different levels of analysis and methodological approaches, arose. Interestingly, in a two-way road, the comparative perspective has also enriched the L&E view of company law.

In this paper we provide a simple and general framework that explains the nature of groups, their corporate governance problems and their ownership structures as the result of the double nature of the controlling shareholder in the group as both shareholder and stakeholder of the subsidiary. We use this framework to conduct an economic and empirical analysis that explores the limitations of regulation and shareholders’ agreements to deal with this dual nature of the parent. Our analysis is able to explain the extreme ownership structures prevalent across groups as solution of last resort to unresolved corporate governance problems when regulation is inefficient and transaction costs limit the use of contracts to provide shared control. We go on to test these ideas conducting an empirical study that explains groups ownership structures and allows us to derive important policy implications. First, it exposes the structural limitations that corporate law encounters to contain the corporate governance problems of groups. Second, it calls for an acknowledgement of the crucial role of shareholders agreements in corporate governance. Shareholder agreements offer the best alternative to protect parent and subsidiary from mutual opportunism, while preserving the incentives to cooperate. Guarantying the enforceability of these contracts offers jurisdictions the most efficient way forward to reduce expropriation in corporate groups.

Purpose: Docetaxel improves survival in patients with metastatic prostate cancer. This randomized phase 2 trial aimed to assess the activity of weekly docetaxel with radiation therapy (RT) plus androgen deprivation in patients with high-risk localized prostate cancer. The study examined the benefit of 9 weekly docetaxel administrations to RT plus 3 years of luteinizing hormone-releasing hormone analogues. Methods and Materials: A total of 132 patients were recruited for the study. Patients' characteristics included T3-T4 stage (81.1%), Gleason score >= 8 (77.3%), prostate-specific antigen level >20 ng/mL (28.9%), and pN+ (18.2%). All patients included in the trial received either the standard-of-care control arm with luteinizing hormone-releasing hormone analogues plus RT (arm A) or the experimental arm (RT + 9 weekly cycles of docetaxel + 3 years of androgen deprivation therapy, arm B). The primary objective was to achieve a high percentage of patients who were free of biochemical recurrence within 5 years of randomization. Secondary endpoints included biochemical recurrence-free survival (BRFS), progression-free survival (PFS), overall survival (OS), clinical response rate, biochemical response rate, and toxicity. Results: No difference between the arms of the study was found in biochemical recurrence (93.4% at 60 months for arm A vs 85.3% for arm B; P = .3297). PFS at 60 months was 93.4% and 83.7% in arms A and B, respectively (P = .2532). Five-year survival was 93.3% (95% confidence interval, 83.1-97.45) in arm A versus 93.6% (83.8-97.55) in arm B; median PFS and OS have not been reached. Prostate-specific antigen level

Background: Declines in prostate-specific antigen (PSA) levels at 12 wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4 wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study. Objective: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide. Design, setting, and participants: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12 wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline. Outcome measurements and statistical analysis: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results and limitations: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4 wk, and 948 at both 4 and 12 wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21–25) compared with no change (median: 17; 95% CI: 15–18) and progression (median: 13; 95% CI: 10–15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio = 0.57; 95% CI = 0.48–0.67; p < 0.001). PSA4w30 strongly correlated with PSA12w30 (ρ = 0.91; 95% CI = 0.90–0.92; p < 0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4 wk had a PSA12w30 (1% of the overall population). Conclusions: PSA changes in the first 4 wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions. Patient summary: Prostate-specific antigen changes at 4 wk after abiraterone/enzalutamide treatment are important to determine patients’ outcome and should be taken into consideration in clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

La introducción de las acciones de lealtad es una de las medidas que se incluyen en el anteproyecto de ley por el que se modifica la Ley de Sociedades de Capital para adaptar la normativa española a la Directiva (UE) 2017/828 del Parlamento y del Consejo de 17 de mayo de 2017 en lo que respecta al fomento de la implicación a largo plazo de los accionistas en las sociedades cotizadas. El propósito de este trabajo es estudiar, desde la perspectiva del análisis económico del derecho, su funcionalidad y regulación, The incorporation of loyalty shares is one of the measures included in the draft bill that amends the Stock Companies Law to adjust Spanish legislation to the Directive (EU) 2017/828 of the European Parliament and of the Council of 17 May 2017 as regards the encouragement of long-term shareholder engagement in listed companies. The aim of this paper is to study, using a Law and Economics perspective, its functionality and regulation

Early identification of germline BRCA1/2 mutations may be relevant for the management of patients with prostate cancer (PC) and to prevent future breast and ovarian cancers in their relatives. Several prediction tools have been developed to estimate the likelihood of a germline BRCA1/2 mutation and are widely used to optimize screening in breast and ovarian cancer patients. We aimed to elucidate the proportion of PC patients with known BRCA1/2 mutations who would have qualified for testing using two risk calculation models (BRCAPRO and the Manchester scoring system [MSS]). We analyzed 106 families with known BRCA1/BRCA2 mutations, including 23 with PC cases. Only 30% and 48% of PC patients who were known BRCA1/BRCA2 mutations carriers would have qualified for testing using BRCAPRO and MSS, respectively. A median of two breast and/or ovarian cancer cases per family had occurred between the first PC identified in a carrier and the cancer case leading to germline testing. Patient summary We tested two models developed to predict the probability of inherited BRCA1/BRCA2 mutations and found that these tools underperform in men with prostate cancer and should not be used to optimize testing in this population.

Aim: We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen. Patients & methods: Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients. Results: CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007–0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7–15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3–4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively). Conclusion: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

[Purpose] Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes., [Patients and Methods] Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored., [Results] We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (gBRCA2) carriers (17.4 v 33.2 months; P = .027), and gBRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio [HR], 2.11; P = .033). Significant interactions between gBRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in gBRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers., [Conclusion] gBRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of gBRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice., Supported by an unrestricted grant from Fundación Cris contra el cancer; three investigator awards from the Prostate Cancer Foundation (C.C.P. [2013], D.O. [2014], and E.C. [2017]); and three grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (No. PI13/01287 and PI16/01565 to D.O. and No. PI15/01471 to P.L.). During the conduct of this study, E.C., D.O., P.N., and L.M.-P. were supported by grants from Ministerio de Economía, Industria y Competitividad (No. JCI-2014-19129 [E.C.], No. RYC-2015-18625 [D.O.], No. SVP-2013-067937 [P.N.], No. SVP-2014-068895 [L.M.]); D.O. was also funded by a Return fellowship from Fundación Científica de la Asociación Española Contra el Cancer, 2012-2015; N.R.L. and R.L., by grants from Instituto de Salud Carlos III (No. CM14-00200 to N.R.L. and No. CM17-00221 [R.L.]); and Y.C., by a grant from Ministerio de Educación, Cultura y Deportes (No. FPU15/05126). C.C.P. was supported by a congressional-designated medical research program award (No. CMRP-PC131820).

Autoimmune haemolytic anaemia (AIHA) is an infrequent and heterogeneous disease in its pathophysiology and clinical behaviour, therefore it is generally managed empirically.We conducted an observational, retrospective and multicentre study of 93 patients diagnosed with AHAI in 9 Spanish hospitals between 1987 and 2017, with a median follow-up of 28 months.Median age of 67 years; 85% AHAI for hot antibodies and 64% primary AHAI. The lowest haemoglobin values at diagnosis related to patients under 45 years of age and serological type IgG+C. Of the patients, 92% received first line treatment, 54% second line, and 27% third line. The warm AHAI were treated in first line with steroids, with overall responses of 83% and complete of 58%. Rituximab in monotherapy or in association with steroids was administered to 34 patients with overall responses close to 100% (complete responses 40-60%), relegating splenectomy to the third line. The immunosuppressive treatment was administered in patients with autoimmune diseases or in corticoid-dependent patients.We found high rates of response to steroids, with very prolonged treatments that cause side effects and corticoid dependence in a third of patients. The combination of steroids with rituximab in the first line, could be indicated in patients with low levels of haemoglobin and serological type IgG+C. The high relapse rates make necessary the development of randomised studies with new drugs or the combination with existing ones, which allow longer response times and with fewer side effects.

Background Plasma androgen receptor (AR) copy number status has been identified as a potential biomarker of response in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR status in the context of cabazitaxel therapy is unknown. Patients and methods Between September 2011 and January 2018, pretherapy plasma samples were collected from 155 patients treated with second- or third-line cabazitaxel at standard or reduced dose in different biomarker protocols. Droplet digital polymerase chain reaction was used to identify plasma AR gain and normal samples. The primary objective was to evaluate associations of plasma AR status with treatment outcome. In an exploratory analysis, a comparison between plasma AR and treatment type was investigated by incorporating updated data from our prior study of 85 post-docetaxel patients receiving abiraterone or enzalutamide. Results We observed a shorter median overall survival (OS) and progression-free survival (PFS) in AR-gained compared to AR-normal patients (OS 10.5 versus 14.1 months, hazard ratio (HR) = 1.44, 95% confidence interval [CI] 0.98–2.13, P = 0.064 and PFS 4.0 versus 5.0 months, HR = 1.47, 95% CI 1.05–2.07, P = 0.024). In patients with mCRPC receiving second-line therapies, a significant treatment interaction was observed between plasma AR and cabazitaxel versus AR-directed therapies for OS (P = 0.041) but not PFS (P = 0.244). In an exploratory analysis, AR-gained patients treated with initial reduced dose of cabazitaxel had a significantly shorter median OS (7.3 versus 11.5 months, HR = 1.95, 95% CI 1.13–3.38, P = 0.016) and PFS (2.7 versus 5.0 months, HR = 2.27, 95% CI 1.39–3.71, P = 0.001). Conclusion Plasma AR status has a potential clinical utility in patients being considered for cabazitaxel. Validation of these findings in prospective trials is warranted.

Research Question/IssueWe study reward crowdfunding (RC), the most innovative segment of the crowdfunding market, where, instead of a debt or equity contract, fund providers are promised some good or service in the future in exchange for their contribution to the funding of the investment project under a contract that does not penalize the creator's failure to deliver. The existing economic and legal literature is puzzled by the platform's use of this seemingly inefficient contract where a standard pre-sale contract would appear to work better. Research Findings/InsightsCounterintuitively, we prove that the no-penalty contract is the optimal contract between creators of unknown talent and early adopters of their products when creators can benefit from being discovered as talented and from the goodwill generated by delivering on their promise to early adopters. Theoretical/Academic ImplicationsOur analysis contributes to understanding RC by showing that the no-penalty RC contract, far from being an inefficiency, is a contractual innovation specifically designed for talent discovery. We also contribute to the literature on relationship contracts, showing that even in a one-shot game, it is possible to sustain a contract in the desire to build a reputation that will be useful in a future contract with a third party. Practitioner/Policy ImplicationsOur analysis has important policy implications on how backers should be protected. Standard measures of consumer or investor protection may be counterproductive. María Gutiérrez‐Urtiaga gratefully acknowledges the financial support from Comunidad de Madrid and the EU's European Social Fund through grant S2015/HUM‐3353 EARLYFIN‐CM and from the European Regional Development Fund through grant FEDER UNC315‐EE‐3636.

203 Background: Plasma androgen receptor ( AR) copy number status has been identified as a potential biomarker of response in mCRPC patients receiving docetaxel or the AR-targeted therapies abiraterone or enzalutamide. However, the relevance of plasma AR status in the context of cabazitaxel therapy is unknown. Methods: Between September 2011 and January 2018, pre-therapy plasma samples were collected from 155 patients treated with second or third-line cabazitaxel at standard or reduced dose in different biomarker protocols. Droplet digital PCR was used to identify plasma AR gain and normal samples, with the primary objective to evaluate associations of plasma AR status with treatment outcome. In an exploratory analysis, a comparison between plasma AR status and treatment type was investigated by incorporating updated data from our prior study of 85 post-docetaxel patients receiving abiraterone or enzalutamide. Results: We observed a shorter median overall/progression-free survival (OS/PFS) in AR-gained compared to AR-normal patients (OS 10.5 versus 14.1 months, hazard ratio (HR) 1.44, 95% confidence interval (CI) 0.98-2.13, P = 0.064), and (PFS 4.0 versus 5.0 months, HR 1.47, 95%CI 1.05-2.07, P = 0.024). In mCRPC patients receiving second-line therapies, a significant treatment interaction was observed between plasma AR and cabazitaxel versus AR-directed therapies for OS (P = 0.041) but not PFS (P = 0.244). In an exploratory analysis, AR-gained patients treated with initial reduced-dose of cabazitaxel had a significantly shorter median OS (7.3 versus 11.5 months, HR 1.95, 95%CI 1.13-3.38, P = 0.016), and PFS (2.7 versus 5.0 months, HR 2.27, 95%CI 1.39-3.71, P = 0.001). Conclusions: Plasma AR status has a potential clinical utility in patients being considered for cabazitaxel. Validation of these findings in prospective trials are warranted.

Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management., Supported by Pfizer.

Summary Introduction The addition of cetuximab to weekly paclitaxel has demonstrated high efficacy in the first-line treatment of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidates for platinum-based CT. Material and methods We have retrospectively analyzed the efficacy and safety of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who present disease progression after platinum schedules or those who were not candidates for platinum-based CT. Patients received weekly paclitaxel 80 mg/m 2 and cetuximab 250 mg/m 2 (initial dose of 400 mg/m 2 ) until progression or unacceptable toxicity. Results Twenty-two patients were included. Median age was 58 (43–68), ECOG PS (0/1/2): 6/10/4, 19 patients had received prior platinum-based treatment (nine patients were platinum-sensitive and nine were platinum-refractory). With a median follow-up of 6.18 months (range 1.3–29.7), overall response rate (ORR) was 55% (95% CI 31–76%):1 (5%) complete response and 9 (50%) partial responses. Median duration of response was 10.23 months. Median progression free survival (PFS) and overall survival (OS) were 5.4 and 9.1 months, respectively. There were no differences in response rate according to platinum sensitivity (66% sensitive vs 44% refractory; P = 0.61). The main toxicity consisted of rash in 70% of patients (5% grade 3), with an association between rash severity and ORR (grade 0–1: 33% vs grade 2–3: 64%; P = 0.03) and a trend for better PFS and OS. Conclusion Weekly paclitaxel in combination with cetuximab is a well tolerated and highly active second-line treatment in patients with R/MSCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. Our results suggest that the efficacy of this combination is apparently superior than the published data on single agent cetuximab in this setting.

For drugs such as anticancer agents every effort should be made to minimize inter-patient variability in drug exposure in order to maximize the benefit while maintaining an acceptable risk level of serious adverse effects. Anticancer drugs generally have a preferential route of elimination, either in urine or in bile and feces. In consequence, dose individualization to renal and liver function permits excessive toxicity to be avoided and expected therapeutic benefit to be achieved. However, less is known about the most appropriate starting doses of antineoplastic agents in these individuals. In this review, we discuss trials that have specifically assessed new targeted agents dosing strategies (mainly monoclonal antibodies and tyrosine kinase inhibitors) in the setting of overt biochemical renal and liver dysfunction and we proportionate recommendations and practical guidelines for dose individualization.

5063Background: Declines in prostate specific antigen (PSA) levels at 12-weeks are currently used to evaluate treatments response in metastatic castration resistant prostate cancer (mCRPC). Early P...

Most listed firms have concentrated ownership structures. However this ownership type is problematic. A clinical analysis reveals that the corporate governance in these firms in terms of liability, voice and exit faces important design problems. Our analysis shows that the corporate governance of these firms is mainly aimed at checking the shareholders manager agency problem leaving the controlling shareholder-minority agency problem unresolved. Therefore it is crucial to provide growing companies with commitment tools that allow them to access capital markets and to raise funds from outside investors in better terms without having to give up the benefits of control. This leads us to a proposal that could improve the protection of outside investors while maintaining the informational benefits of concentrated ownership structures: a “Say-on-Dividend” policy. This proposal is centered in empowering independent directors and activist and institutional investors in the design of dividend policy as informed intermediaries that can represent the voice of the outside investors in the control of the funds that they invest in the firm.

Pharmacogenomics is the study of how variation in the genetic background affects an individual’s response to a specific drug and/or its metabolism. Using knowledge about the genes which produce the enzymes that metabolize a specific drug, a physician may decide to raise or lower the dose, or even change to a different drug. Targeted therapy with tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors has led to a substantial improvement in the standard of care for patients with advanced or metastatic renal cell carcinoma (RCC). Although few studies have identified biomarkers that predict the response of targeted drugs in the treatment of metastatic RCC, some associations have been found. Several studies have identified genetic polymorphisms with implications in the pharmacokinetics and/or pharmacodynamics of TKIs and mTOR inhibitors and which are associated with a prolonged progression-free survival and/or overall survival in patients with metastatic RCC. Among the genes of interest, we should consider IL8, FGFR2, VEGFA, FLT4, and NR1I2. In this review, we discuss single nucleotide polymorphisms (SNPs) associated with outcome and toxicity following targeted therapies and provide recommendations for future trials to facilitate the use of SNPs in personalized therapy for this disease.

The adverse effects associated to traditional chemotherapy are well known and broadly studied. In the recent years several tyrosine kinase inhibitors have been approved for cancer treatment and numerous are under investigation. These drugs target specific mutated/overexpressed tyrosin kinase receptors and frecuently their pharmacokinetic/pharmacodinamic behavior is not fully elucidated. These new drugs may interact with non-antineoplastic drugs leading to undesirable adverse effects. In this article, we will discuss different types of drug interactions and briefly review the pharmacokinetics and mechanisms of action of tyrosine kinase inhibitors in clinical use, with a particular emphasis on the risk of the occurrence of such interactions based on currently available scientific evidence.

Oncologists should carefully weigh up the risks and benefits of palliative chemotherapy in patients with advanced solid tumours (AST) and poor general status from the standpoint both of medical and ethical issues and of healthcare resources required. This study is intended to assess the impact on overall survival of palliative chemotherapy in patients with AST and admitted to hospital as a result of their poor ECOG status.We performed a retrospective analysis of 92 hospitalised patients with AST, ECOG 3-4, who were treated with palliative chemotherapy. Uni- and multivariate statistical analyses were conducted to determine the impact of clinical and disease variables (number of previous chemotherapy lines, presence of comorbidities, presentation of anorexia-cachexia syndrome, delirium, dyspnoea, ascitis, brain metastases, T-cell count, albumin, haemoglobin and LDH) on survival in this patient population.Mean age was 54 years (range 15-80). No chemotherapy had been given for advanced disease in 74%, 13% had received one line, 6% 2 lines and 7% ≥3 lines. Median survival, i.e., after initiation of chemotherapy to death, in these patients was 33 days (range 1-1390). The median of chemotherapy cycles was 1. In the multivariate analysis, no previous chemotherapy, and absence of anorexia-cachexia syndrome and of comorbidities was associated with significantly improved survival in patients. Forty-nine percent of patients died within 30 days of therapy, 28% died between days 30 and 90, and only 23% of patients lived longer than 90 days. Grade 3-4 toxicities mainly entailed blood disorders, namely anaemia 8%, neutropenia 13% and thrombocytopenia 8%. Six patients (5%) developed sepsis after therapy; of these, 3 died from this toxicity, 1 patient suffered cardiac toxicity, one patient leukoencephalopathy and 1 patient acute pulmonary thromboembolism.Palliative chemotherapy given to patients with AST and ECOG 3-4 with short life expectancy provided no benefit for survival. As a result, we may be over-treating these patients and contributing to poor-quality care.

4630 Background: Relevant biomarkers in RCC are needed to identify appropriate candidates for selected targeted therapies. Mutations in the von Hippel-Lindau (VHL) gene result in the accumulation of HIF and increased expression of proangiogenic factors, including VEGF. Methods: Metastatic clear RCC patients with available baseline tumor samples who received first-line oral VEGFR-TKI were included in this analysis. VHL mutation/hypermethylation status and HIF1α and HIF2α immunohistochemical staining were analyzed from paraffin-embedded tumors. Additionally, a panel of candidate VEGF and VEGFR2 genetic SNPs was determined from peripheral blood samples. HIF was scored as negative or positive based on staining intensity (0-10% and > 10%, respectively). Results were evaluated for associations with clinical outcome. Results: 80 patients were included: 71 evaluable for HIF expression, 63 for VHL status and 52 for SNPs. 73% received treatment with sunitinib and median follow-up was 21.5 months. Unlike VHL status, HIF1 and HIF2 positive expression showed a significant correlation with PFS and OS. HIF1α was also predictive for response rate (RR). On multivariate analysis adjusting for other prognostic factors, HIF1α and HIF2α remained the most significant independent predictive factors for survival (adjusted HR 0.09, 95% CI 0.03-0.28, p < 0.0001 and HR 0.13, 95% CI 0.04-0.37, p < 0.0001; respectively). We did not find any statistically significant differences based on the VEGF and VEGFR2 SNPs analyzed. Conclusions: HIF1α and HIF2α levels represent the most important independent predictive factors of outcome for VEGFR-TKI therapy in metastatic RCC. These findings may contribute to optimize treatment with targeted agents. [Table: see text]