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Background: Most breastfeeding individuals take at least one prescription drug, yet limited data from lactation studies are available to inform the safety of these drugs during breastfeeding. As a result, healthcare providers (HCPs) rely on available information about safety of drugs used during pregnancy or on personal experiences to inform prescribing/counseling decisions for breastfeeding individuals. To improve risk communication regarding drugs used during lactation, the U.S. Food and Drug Administration published the Pregnancy and Lactation Labeling Rule (PLLR) in 2015, which added a narrative summary of available risk information to the lactation section of Prescribing Information (PI). Prior studies on labeling in PLLR format revealed that although HCPs found these details valuable, they regarded the narrative as too long to support decision-making during patient encounters., Objective: This qualitative study's objective was to assess the utility of adding a concise summary to the Lactation subsection of PI to complement the narrative and succinctly communicate to busy HCPs a drug's risks when used during lactation. The concise summary consisted of a bolded headline, bulleted descriptions of available study findings and potential adverse reactions, and recommendations for risk mitigation., Methods: Twenty-five online focus groups were conducted with five segments of HCPs to obtain their feedback on the concise summary and discuss their prescribing/counseling decisions for four fictitious prescription drugs including one vaccine., Results: HCPs utilized the concise summary to make initial prescribing/counseling decisions. Many also used the labeling narrative for a comprehensive benefit-risk assessment., Conclusion: The findings indicate a need to continue to improve communication about safety of drugs used during lactation, and that the concise summary may help facilitate this communication. The study also highlights the need to educate HCPs about PI limitations when clinical data are lacking and the need to encourage clinical studies to be conducted to support actionable recommendations about use of prescription drugs during lactation., (Published by Elsevier Inc.)

Introduction: Medication reconciliation (MC) is one of the main strategies to reduce medication errors in care transitions. In Spain, several guidelines have been published with recommendations for the implementation and development of MC aimed at the adult population, although paediatric patients are not included. In 2018, a study was carried out that led to the subsequent publication of a document with criteria for selecting paediatric patients in whom CM should be prioritised., Objectives: To describe the characteristics of paediatric patients most likely to suffer from errors of reconciliation (EC), to confirm whether the results of a previous study can be extrapolated., Methodology: Prospective, multicentre study of paediatric inpatients. We analysed the CE detected during the performance of the CM on admission. The best possible pharmacotherapeutic history of the patient was obtained using different sources of information and confirmed by an interview with the patient/caregiver., Results: 1043 discrepancies were detected, 544 were identified as CD, affecting 317 patients (43%). Omission of a drug was the most common error (51%). The majority of CD were associated with drugs in groups A (31%), N (23%) and R (11%) of the ATC classification. Polymedication and onco-haematological based disease were the risk factors associated with the presence of CD with statistical significance., Conclusions: The findings of this study allow prioritisation of CM in a specific group of paediatric patients, favouring the efficiency of the process. Onco-haematological patients and polymedication are confirmed as the main risk factors for the appearance of CD in the paediatric population., (Copyright © 2023 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: BRAF inhibitors are approved in BRAF V600 -mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAF V600 -mutated melanoma and NSCLC., Patients and Methods: Patients with advanced tumours other than BRAF V600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety., Results: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAF V600 mutations and 10 with BRAF nonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib., Conclusion: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Investigation of the disparities in the access to experimental treatment in early-phase clinical trials is lacking. The objective of the EGALICAN-2 study was to identify the factors underpinning such inequalities., Methods: A national prospective survey was conducted in 11 early-phase clinical trial centers (CLIP 2 ) certified by the French National Cancer Institute. Sociodemographic, socioeconomic and medical data were collected. Univariate logistic regression models were carried out to estimate odds ratios and 90% confidence intervals associated with the effect of each study variable. A multivariate logistic regression model was built to explore the independent factors associated with the administration of the experimental treatment (C1D1). A post hoc analysis was carried out excluding female cancer patients., Results: Between 2015 and 2016, 1355 patients referred from 11 CLIP 2 centers in France were included in the study. Eight hundred and forty-eight patients received C1D1 (73%) and 320 patients (27%) were screening failure. Median age was 58 years (range 17-97 years) and 667 patients (54%) were female. Most patients had a metastatic disease (n = 751, 87%). In the multivariate logistic regression analysis, the significant independent factors associated with C1D1 were male sex, initial care received in a hospital with an early-phase unit and living in wealthy metropolitan areas (P values <0.05). In the post hoc analysis, the sex factor was no longer significant [odds ratio = 1.21 (95% confidence interval 0.86-1.70), P value = 0.271]., Conclusions: This study investigated the factors producing social inequalities in the context of early-phase clinical trials in oncology. Our research highlights factors of sex, care pathway and geographic location. Gynecological cancer was found to impact C1D1 significantly, unlike breast cancer. The results of this study should contribute to improve patient access to early-phase clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate whether simplification of antiretroviral treatment to dual therapy (DT) negatively impacts immune recovery (IR), immune activation and inflammation (IA/I), and HIV reservoir., Methods: An open-label, single-centre, randomized controlled trial conducted in adult virologically suppressed HIV-infected patients on triple therapy (TT) with elvitegravir-cobicistat, emtricitabine and tenofovir alafenamide or dolutegravir (DTG), abacavir, and lamivudine (3TC). Participants were randomized to continue TT or switch to DTG, or darunavir/cobicistat (DRVc) plus 3TC. IR was assessed by CD4 + /CD8 + ratio at 48 and 96 weeks. Changes in immune activation, proliferation, exhaustion, senescence, and apoptosis in CD4 + and CD8 + T cells, plasma sCD14, hsCRP, D-dimers, β2-microglobulin, IL-6, TNF-α and IP-10 levels, cell-associated HIV-DNA (CA-DNA), and unspliced HIV-RNA (usRNA) were also analysed., Results: One hundred and fifty-one participants were enrolled. Fourteen patients did not complete the follow up. In the ITT and PP analysis, the IR was similar between the treatment arms. In the ITT analysis, the median increase in CD4 + /CD8 + ratio was 0.10, 0.04, and 0.07 at week 48, and 0.09, 0.05, and 0.08 at week 96 for TT, DTG/3TC, and DRVc/3TC, respectively. After adjusting for confounding factors, the slopes of changes in CD4 + /CD8 + ratio over time were independent of treatment (F = 1.699; p = 0.436) and related only to baseline values (F = 756.871; p = 0.000). There were no differences in IA/I, CA-DNA, or usRNA between treatment arms., Discussion: Both IR and IA/I, CA-DNA, and usRNA were similar in the three treatment groups, regardless of maintaining TT or simplifying to DTG/3TC or DRVc/3TC in virologically suppressed HIV-infected patients., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients., Patients and Methods: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute., Results: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045)., Conclusions: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To prove that 7-day courses of antibiotics for bloodstream infections caused by members of the Enterobacterales (eBSIs) allow a reduction in patients' exposure to antibiotics while achieving clinical outcomes similar to those of 14-day schemes., Methods: A randomized trial was performed. Adult patients developing eBSI with appropriate source control were assigned to 7 or 14 days of treatment, and followed 28 days after treatment cessation; treatments could be resumed whenever necessary. The primary endpoint was days of treatment at the end of follow-up. Clinical outcomes included clinical cure, relapse of eBSI and relapse of fever. A superiority margin of 3 days was set for the primary endpoint, and a non-inferiority margin of 10% was set for clinical outcomes. Efficacy and safety were assessed together with a DOOR/RADAR (desirability of outcome ranking and response adjusted for duration of antibiotic risk) analysis., Results: 248 patients were assigned to 7 (n = 119) or 14 (n = 129) days of treatment. In the intention-to-treat analysis, median days of treatment at the end of follow-up were 7 and 14 days (difference 7, 95%CI 7-7). The non-inferiority margin was also met for clinical outcomes, except for relapse of fever (-0.2%, 95%CI -10.4 to 10.1). The DOOR/RADAR showed that 7-day schemes had a 77.7% probability of achieving better results than 14-day treatments., Conclusions: 7-day schemes allowed a reduction in antibiotic exposure of patients with eBSI while achieving outcomes similar to those of 14-day schemes. The possibility of relapsing fever in a limited number of patients, without relevance to final outcomes, may not be excluded, but was overcome by the benefits of shortening treatments., (Copyright © 2021 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment., Methods: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment., Results: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data., Conclusion: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS., Competing Interests: Disclosure TA personal fees and travel grants from Bristol-Myers Squibb (BMS), personal fees, grants and travel grants from Novartis, personal fees from Pierre Fabre, grants from Neracare, Sanofi, and SkylineDx, personal fees from CeCaVa outside the submitted work; JBa reports grants, personal fees, and nonfinancial support from Ipsen; personal fees and nonfinancial support from Pfizer, Novartis; nonfinancial support from AAA, Nanostring, Roche; grants and personal fees from Servier; and personal fees from Nutricia outside the submitted work; JBo is a statistician on the SAG-O (scientific advice committee oncology) for EMA, and scientific director of EORTC Headquarters. EORTC carries out clinical trials with many (most) pharma and some biotechs either with financial or material support, or with the company as the sponsor (intent to register new indication); he is co-responsible for the management of EORTC. AC has received honoraria/consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Takeda, Novartis, Merck Sharp & Dohme (MSD), and BMS; GC scientific advisory board for BMS, Roche, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Daichii Sankyo, and Veracyte; UD Tumour Agnostic Evidence Generation Working Group Member, Roche; BG reports receiving consulting fees from Vivio Health. CG-R BMS (institutional research and travel grants, speaker’s honoraria), Roche/Genentech (institutional research and travel grants, speaker’s honoraria), Pierre Fabre (travel and educational grants, speaker’s honoraria); MSD (travel grants); Eisai (speaker’s honoraria); Foundation Medicine (research grant, speaker’s honoraria); BK Honoraria for lectures from Ipsen, Novartis and MSD; SO research grants from Celldex and Novartis to the institution; AP received honoraria for consulting, advisory role or lectures from AstraZeneca, Agilent/Dako, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche Genentech; GP received institutional financial support for advisory board/consultancy from Roche, Amgen, Merck, MSD, BMS, and institutional support for clinical trials or contracted research from Amgen, Roche, AstraZeneca, Pfizer, Merck, BMS, MSD, Novartis, Lilly; MP consulting or advisory role: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche, Genentech, Crescendo Biologics, Periphagen, Huya Bioscience, Debiopharm Group, Odante Therapeutics; Consulting or Advisory Role: G1 Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Oncolytics, Radius Health; Research Funding: AstraZeneca (Inst), Lilly (Inst), MSD (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Genentech (Inst), Radius Health (Inst), Synthon (Inst), Servier (Inst); Other Relationship: Radius Health; JT personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc., HalioDX SAS, Ikena Oncology, IQVIA, Imedex, Lilly, MSD, Menarini, Merck Serono, Mirati, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. Institutional financial interest in the form of financial support for clinical trials or contracted research for Amgen Inc., Array Biopharma Inc., AstraZeneca Pharmaceuticals LP, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Janssen-Cilag SA, MSD, Novartis Farmacéutica SA, Taiho Pharma USA Inc., Pharma Mar, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK; EGEdV declares: institutional financial support for advisory board/consultancy from Sanofi, Daiichi, Sankyo, NSABP, Pfizer and Merck, and institutional support for clinical trials or contracted research from Amgen, Genentech, Roche, AstraZeneca, Synthon, Nordic Nanovector, G1 Therapeutics, Bayer, Chugai Pharma, CytomX Therapeutics, Servier and Radius Health; CZ consultancies and speaker’s honoraria: Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, Athenex. Institution (Central European Cooperative Oncology Group): BMS, MSD, Pfizer, AstraZeneca, Servier, Eli Lilly; GZ received speaker’s honoraria from Amgen and Ipsen. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: There have been very few studies on the effect of assisted electronic prescription on paediatric patient safety. The objective of this study is to compare medication errors that occurred before and after its introduction in a tertiary hospital., Material and Methods: A quasi-experimental comparative study of medication errors detected before and after assisted electronic prescription introduction. All treatment lines were analysed in order to detect the point in the chain where the medication error occurred, as well as its type and cause. A Delphi study was conducted on the importance of each medication error involving doctors, nurses, and pharmacists., Results: The study included 166 patients (83 at each stage). At least one medication error was detected in 92% in the pre-introduction phase patients (2.8±2.1 errors/patient) and 7.2% of post-introduction phase patients (0.1±0.4 errors/patient). The assisted electronic prescription led to an absolute risk reduction of 40% (95% confidence interval=35.6-44.4%). The main cause of error was lapses and carelessness in both stages. Medication errors were considered serious in 9.5% of cases in the pre-introduction phase, while all of them were mild or moderate in the post-introduction phase., Conclusions: The assisted electronic prescription implementation with prescription, validation and medication administration assistance systems significantly reduces medication errors and eliminates serious errors., (Copyright © 2020 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Oral fosfomycin may constitute an alternative for the treatment of lower urinary tract infections (UTIs) in kidney transplant recipients (KTRs), particularly in view of recent safety concerns with fluroquinolones. Specific data on the efficacy and safety of fosfomycin in KTR are scarce. We performed a retrospective study in 14 Spanish hospitals including KTRs treated with oral fosfomycin (calcium and trometamol salts) for posttransplant cystitis between January 2005 and December 2017. A total of 133 KTRs developed 143 episodes of cystitis. Most episodes (131 [91.6%]) were produced by gram-negative bacilli (GNB), and 78 (54.5%) were categorized as multidrug resistant (including extended-spectrum β-lactamase-producing Enterobacteriaceae [14%] or carbapenem-resistant GNB [3.5%]). A median daily dose of 1.5 g of fosfomycin (interquartile range [IQR]: 1.5-2) was administered for a median of 7 days (IQR: 3-10). Clinical cure (remission of UTI-attributable symptoms at the end of therapy) was achieved in 83.9% (120/143) episodes. Among those episodes with follow-up urine culture, microbiological cure at month 1 was achieved in 70.2% (59/84) episodes. Percutaneous nephrostomy was associated with a lower probability of clinical cure (adjusted odds ratio: 10.50; 95% confidence interval: 0.98-112.29; P = 0.052). In conclusion, fosfomycin is an effective orally available alternative for treating cystitis among KTRs., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To evaluate the prevalence of non-approved prescriptions (off-label and unlicensed) in a Neonatal Intensive Care Unit (NICU), and to describe factors of the neonate associated with its use., Materials and Methods: Observational prospective study in a level III NICU during a 6-month period. Every prescription was analysed using the summary of product characteristics as a reference. A sequential algorithm was used to create a classification of prescriptions based on current status: approved, unlicensed, off-label (by age, route of administration, dosage, or indication)., Results: The study included 84 patients and 564 prescriptions. A total of 127 (22.5%) prescriptions were considered off-label, and 45 (8%) were considered unlicensed. More than half (59.5%) of the patients received at least one of these drugs, and this increases to 100% among very preterm neonates and surgical patients (P<.001). A positive linear correlation was found between duration of NICU stay and the number of off-label prescriptions (correlation coefficient 0.6; P<.001)., Conclusions: Non-licensed drugs are frequently prescribed in NICU, especially in the most vulnerable patients. Our results show the need to move forward on clinical research in order to homogenise the existing data about neonatology drugs, with the aim of making an efficient and safe prescription., (Copyright © 2019. Publicado por Elsevier España, S.L.U.)

Background: Emactuzumab is a monoclonal antibody against the colony-stimulating factor-1 receptor and targets tumor-associated macrophages (TAMs). This study assessed the safety, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of emactuzumab, as monotherapy and in combination with paclitaxel, in patients with advanced solid tumors., Patients and Methods: This open-label, phase Ia/b study comprised two parts (dose escalation and dose expansion), each containing two arms (emactuzumab, every 2 or 3 weeks, as monotherapy or in combination with paclitaxel 80 mg/m2 weekly). The dose-escalation part explored the maximum tolerated dose and optimal biological dose (OBD). The dose-expansion part extended the safety assessment and investigated the objective response rate. A PK/PD analysis of serial blood, skin and tumor biopsies was used to explore proof of mechanism and confirm the OBD., Results: No maximum tolerated dose was reached in either study arm, and the safety profile of emactuzumab alone and in combination does not appear to preclude its use. No patients receiving emactuzumab monotherapy showed an objective response; the objective response rate for emactuzumab in combination with paclitaxel was 7% across all doses. Skin macrophages rather than peripheral blood monocytes or circulating colony-stimulating factor-1 were identified as an optimal surrogate PD marker to select the OBD. Emactuzumab treatment alone and in combination with paclitaxel resulted in a plateau of immunosuppressive TAM reduction at the OBD of 1000 mg administered every 2 weeks., Conclusions: Emactuzumab showed specific reduction of immunosuppressive TAMs at the OBD in both treatment arms but did not result in clinically relevant antitumor activity alone or in combination with paclitaxel. (ClinicalTrials.gov Identifier: NCT01494688)., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Whereas immune checkpoint inhibitors of serine/threonine protein kinase B-raf therapy dramatically changed metastatic outcomes of patients with melanoma, they remain at high risk of brain extension. Additional local treatment can be offered in this situation such as surgery and or stereotactic radiotherapy. In this review article, we describe the different options with published data and their optimal timing., (Copyright © 2019 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.)

Introduction: The aim of this study was to collect retrospective data on the prescription of clopidogrel, describe the conditions of its use in the paediatric population of a tertiary referral hospital, and evaluate its use based on the current scientific evidence., Patients and Methods: We conducted a retrospective, observational and descriptive study between March 2010 and March 2017. We included all patients under the age of 18 who were discharged from our hospital for home treatment with clopidogrel within the study period. We collected data on the following: demographic data, diagnosis, indication for clopidogrel, start and end date of treatment, presence or absence of concomitant treatment with acetylsalicylic acid or other antiplatelet or anticoagulant drugs, concomitant treatment with proton pump inhibitors, effectiveness, and adverse effects., Results: The study included a total of 11 patients (45% male). The mean age was 3.1 years (range, 1 month-8 years). The prescribed dose of clopidogrel was 0.2mg/kg/day in all patients, and 10/11 patients received concomitant treatment with acetylsalicylic acid with the purpose of optimising antiplatelet therapy. None of the children received concomitant treatment with anticoagulants, and only one of them received treatment with a proton pump inhibitor. We did not find evidence of haemorrhagic complications or other adverse effects associated with clopidogrel., Conclusion: Based on our experience, a clopidogrel dose of 0.2mg/kg/day is a safe and effective treatment, regardless of the patient's age. The good tolerance observed in our study could be related to the adjustment of the optimal dose with the aim of achieving platelet aggregation without increasing the risk of adverse effects., (Copyright © 2017 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Because of our previous preclinical results, we conducted a phase I study associating the specific αvβ3/αvβ5 integrin inhibitor cilengitide, given as a continuous infusion, with exclusive chemoradiotherapy for patients with stage III non-small-cell lung cancer., Patients and Methods: A standard 3+3 dose escalation design was used. Cilengitide was given as a continuous infusion (dose levels of 12, 18, 27, and 40 mg/h), starting 2 weeks before and continuing for the whole course of chemoradiotherapy (66 Gy combined with platinum/vinorelbine), and then at a dose of 2000 mg twice weekly in association with chemotherapy. 2-Deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography (PET) and computed tomography scans were performed before and after the first 2 weeks of cilengitide administration and then every 3 months., Results: Of the 14 patients included, 11 were evaluable for evaluation of the dose-limiting toxicities (DLTs). One DLT, a tracheobronchial fistula, was reported with the 40 mg/h dose. No relevant adverse events related to cilengitide were observed overall. At the PET evaluation 2 months after chemoradiotherapy, 4 of 9 patients had a complete response and 4 had a partial response. The median progression-free and overall survival was 14.4 months (95% confidence interval [CI], 8.4 to not reached) and 29.4 months (95% CI, 11.73 to not reached), respectively., Conclusion: Cilengitide, given continuously with chemoradiotherapy, showed acceptable toxicity and gave encouraging clinical results., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The objective of the study was to assess the prognostic role of skeletal muscle index (SMI) in metastatic renal cell carcinoma (mRCC) patients treated with everolimus, and its effect of on everolimus-induced toxicity., Patients and Methods: Consecutive mRCC patients treated with everolimus between February 2007 and November 2014 underwent computed tomography scans at a single center performed by the same radiologist. SMI was assessed before everolimus treatment using the L3 cross-sectional area. Overall survival (OS) was analyzed according to SMI value. Results were adjusted using the International Metastatic Database Consortium (IMDC) prognostic group, body mass index (BMI), and/or number of previous tyrosine kinase inhibitor lines (NPL)., Results: One hundred twenty-four mRCC patients (mean age, 60.21 years) were treated with everolimus as second- or third-line (82.3%) or > third-line (17.7%) therapy. Most patients (87.9%) had clear cell carcinoma. IMDC prognostic group was "favorable" (32.3%), "intermediate" (50%), or "poor" (17.7%). Median SMI was 40.75. OS was longer in patients from the highest versus lowest SMI tercile: 21.9 versus 10 months (P = .002). Continuous SMI at baseline was not significantly associated with OS after adjustment for IMDC prognostic group, BMI, or NPL but the highest versus lowest SMI tercile was an independent prognostic factor in multivariate analysis (P = .025). There was no difference in everolimus toxicity between SMI tercile groups., Conclusion: SMI was an independent prognostic factor for mRCC patients treated with everolimus. Whether this provides additional prognostic value to IMDC criteria needs to be confirmed in a larger cohort. SMI does not seem to be predictive of everolimus-induced toxicity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Safety and efficacy of pembrolizumab, a humanized programmed death 1 monoclonal antibody, was assessed in KEYNOTE-028, a multicohort, phase Ib trial for patients with programmed death ligand 1 (PD-L1)-positive advanced solid tumors. We report results for the cohort of patients with advanced anal carcinoma., Patients and Methods: Patients with PD-L1-positive tumors (≥1%) received intravenous pembrolizumab 10 mg/kg once every 2 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter per Response Evaluation Criteria In Solid Tumors, version 1.1. Primary endpoints were safety and overall response rate per investigator review. Secondary endpoints included progression-free survival, overall survival, and response duration. Data cutoff date was 1 July 2015., Results: Of the 43 patients with advanced anal carcinoma evaluable for PD-L1 expression, 32 (74%) had PD-L1-positive tumors as assessed with the 22C3 prototype assay, of whom 25 were enrolled between April and September 2014. Sixteen patients (64%) experienced treatment-related adverse events; the most common ones were diarrhea and fatigue in four patients (16%) each and nausea in three patients (12%). There were no treatment-related deaths or discontinuations as of the data cutoff date. Among the 24 patients with squamous cell carcinoma histology, four had confirmed partial response, for an overall response rate of 17% [95% confidence interval (CI), 5%-37%) and 10 (42%) had confirmed stable disease, for a disease control rate of 58%. One additional patient with non-squamous histology had confirmed stable disease., Conclusion: In this population of patients with PD-L1-positive advanced squamous cell anal carcinoma, pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity. These data support further study of pembrolizumab for this patient population., Clinicaltrials.gov: NCT02054806., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Exopolysaccharides (EPS) are polymers excreted by some microorganisms with interesting properties and used in many industrial applications. A new Pseudoalteromonas sp. strain, MD12-642, was isolated from marine sediments and cultivated in bioreactor in saline culture medium containing glucose as carbon source. Its ability to produce EPS under saline conditions was demonstrated reaching an EPS production of 4.4g/L within 17hours of cultivation, corresponding to a volumetric productivity of 0.25g/Lh, the highest value so far obtained for Pseudoalteromonas sp. strains. The compositional analysis of the EPS revealed the presence of galacturonic acid (41-42mol%), glucuronic acid (25-26mol%), rhamnose (16-22mol%) and glucosamine (12-16mol%) sugar residues. The polymer presents a high molecular weight (above 1000kDa). These results encourage the biotechnological exploitation of strain MD12-642 for the production of valuable EPS with unique composition, using saline by-products/wastes as feedstocks., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Preventing influenza infection early after transplantation is essential, given the disease's high mortality. A multicentre prospective cohort study in adult solid organ transplant recipients (SOTR) receiving the influenza vaccine during four consecutive influenza seasons (2009-2013) was performed to assess the immunogenicity and safety of influenza vaccination in SOTR before and 6 months after transplantation. A total of 798 SOTR, 130 of them vaccinated within 6 months of transplantation and 668 of them vaccinated more than 6 months since transplantation. Seroprotection was similar in both groups: 73.1% vs. 76.5% for A/(H1N1)pdm (p 0.49), 67.5% vs. 74.1% for A/H3N2 (p 0.17) and 84.2% vs. 85.2% for influenza B (p 0.80), respectively. Geometric mean titres after vaccination did not differ among groups: 117.32 (95% confidence interval (CI) 81.52, 168.83) vs. 87.43 (95% CI 72.87, 104.91) for A/(H1N1)pdm, 120.45 (95% CI 82.17, 176.57) vs. 97.86 (95% CI 81.34, 117.44) for A/H3N2 and 143.32 (95% CI 103.46, 198.53) vs. 145.54 (95% CI 122.35, 174.24) for influenza B, respectively. After adjusting for confounding factors, time since transplantation was not associated with response to vaccination. No cases of rejection or severe adverse events were detected in patients vaccinated within the first 6 months after transplantation. In conclusion, influenza vaccination within the first 6 months after transplantation is as safe and immunogenic as vaccination thereafter. Thus, administration of the influenza vaccine can be recommended as soon as 1 month after transplantation., (Copyright © 2015 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Objective was to determine maximum tolerated dose (MTD), recommended dose (RD) and schedule, safety, pharmacokinetic (PK) profile, pharmacodynamic (PD) effects, and antitumor activity of Debio0932, a new second-generation oral heat shock protein (HSP) inhibitor., Patients and Methods: This was a multicenter, uncontrolled, open-label, nonrandomized, dose-escalation study in adults with treatment-resistant advanced cancer. Groups of three patients received oral Debio0932 either daily or every other day. The starting dose of 50 mg was escalated until the MTD was reached, i.e. dose-limiting toxicity (DLT) occurred in ≥2 patients. Further 9 patients and an extension cohort of 30 patients were treated at the next lower dose (=RD). Adverse events (AEs), tumor response, PK, and HSP70 levels in peripheral blood mononuclear cells were recorded over 30 days., Results: Fifty patients were treated with doses up to 1600 mg, at which level three DLT occurred (febrile neutropenia, diarrhea, asthenia). In total, 39 patients were then treated at the RD of 1000 mg daily. Most common drug-related AEs were asthenia and gastrointestinal events. No ocular toxicities were observed. Debio0932 was rapidly absorbed and metabolized. Plasma steady state was reached within 9 days. Volume of distribution was high and elimination half-life was 9-11 h. Food had no effect on PK. PD showed large interpatient variability, but no dose-effect relationship. Partial tumor response was observed in 2 patients (NSCLC and breast cancer), stable disease (SD) in 12 patients (5 of 8 NSCLC patients). In the extension cohort, 9 patients had SD, and 1 patient a partial metabolic tumor response., Conclusion: Debio0932 has limited clinical activity, together with manageable toxicity. Further development as adjunct treatment of NSCLC at daily doses of 1000 mg is warranted., Clinical Trial: NCT01168752., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although sarcomas account for only 1% of all solid tumours, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, we evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, we analysed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials., Patients and Methods: We used data from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007., Results: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line., Conclusion: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Glycerol, a highly abundant byproduct of the biodiesel industry, constitutes today a cheap feedstock for biobased succinic acid (SA) production. Actinobacillus succinogenes is one of the best SA producers. However, glycerol consumption by this biocatalyst is limited because of a redox imbalance during cell growth. The use of an external electron acceptor may improve the metabolism of SA synthesis by A. succinogenes in glycerol. In this study, the effect of dimethylsulfoxide (DMSO), an electron acceptor, on glycerol consumption and SA production by A. succinogenes under controlled fermentation conditions was investigated. Concentrations of DMSO between 1 and 4% (v/v) greatly promoted glycerol consumption and SA production by A. succinogenes. During fed-batch cultivation, SA concentration reached 49.62 g/L, with a product yield of 0.87 gSA/gGLR and a maximum production rate of 2.31 gSA/Lh, the highest values so far reported in the literature for A. succinogenes using glycerol as carbon source. These results show that using DMSO as external electron acceptor significantly promotes glycerol consumption and succinic acid production by A. succinogenes and may be used as a co-substrate, opening new perspectives for the use of glycerol by this biocatalyst., (Copyright © 2013 Elsevier B.V. All rights reserved.)

New sequencing technologies are one of the most important technical advances in biology in the last 10 years. These technologies allow sequencing millions of DNA fragments in parallel, covering billions of bases in a short period of time. These techniques allowed discovering millions of variants, which functional and clinical value rest yet to be confirmed. This technology allows us to search new constitutional and somatic mutations in various samples in a short time. The complexity of data interpretation and size of data as well as the important investment needed to implement make these technologies to be present only in big institutions. The objective of this article is to present the different techniques, their associated technologies and to discuss their current applications.

Background: Sequential tumour biopsies are of potential interest for the rational development of molecular targeted therapies., Patients and Methods: From June 2004 to July 2009, 186 patients participated in 14 phase I clinical trials in which sequential tumour biopsies (13 trials) and/or sequential normal skin biopsies (6 trials) were optional. All patients had to sign an independent informed consent for the biopsies., Results: Tumour biopsies were proposed to 155 patients and 130 (84%) signed the consent while normal skin biopsies were proposed to 70 patients and 57 (81%) signed the consent. Tumour biopsies could not be carried out in 41 (31%) of the 130 consenting patients. Tumour biopsies were collected at baseline in 33 patients, at baseline and under treatment in 56 patients. Tumour biopsies were obtained using an 18-gauge needle, under ultrasound or computed tomography guidance. Only nine minor complications were recorded. Most tumour biopsy samples collected were intended for ancillary molecular studies including protein or gene expression analysis, comparative genomic hybridization array or DNA sequencing. According to the results available, 70% of the biopsy samples met the quality criteria of each study and were suitable for ancillary studies., Conclusions: In our experience, the majority of the patients accepted skin biopsies as well as tumour biopsies. Sequential tumour and skin biopsies are feasible and safe during early-phase clinical trials, even when patients are exposed to anti-angiogenic agents. The real scientific value of such biopsies for dose selection in phase I trials has yet to be established.

Different types of dietary fiber can be distinguished considering their rate of fermentability, thus determining the location of the large intestine where they exert their beneficial effect. Their combination could be interesting to obtain health-promoting effects throughout the entire colon. The aim of the present study was to evaluate the synergistic effect of two dietary fibers with different fermentation patterns, fructooligosaccharides (FOS) (Beneo(®)-95) and resistant starch (Fibersol(®)-2), after their administration to healthy rats or in trinitrobenzenesulphonic acid-(TNBS) colitic rats, with an altered colonic immune response. In healthy rats, the administration of the combination of FOS and resistant starch induced changes in the intestinal microbiota, by increasing lactobacilli and bifidobacteria in caecum and colonic contents. Furthermore, its administration up-regulated the expression of the trefoil factor-3 and MUC-2 in comparison with untreated rats, thus improving the intestinal barrier function. The beneficial effects observed with this combination were confirmed in the TBNS model of rat colitis, since it was able to exert intestinal anti-inflammatory effect, associated with an increase of protective bacteria and up-regulation of epithelial defense mechanisms. In conclusion, the combination of two different dietary fibers may result in a synergistic prebiotic effect, and may confer greater health benefits to the host., (Copyright © 2010 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Irregular bleeding is often cited as the reason for discontinuation of depot-medroxyprogesterone acetate (DMPA) after the first injection. Estrogen supplementation during DMPA initiation may decrease bleeding and improve continuation., Study Design: This prospective, randomized, controlled trial evaluated estrogen supplementation during DMPA initiation. Women initiating DMPA were randomized to receive an estradiol vaginal ring for 3 months versus DMPA alone. Bleeding diaries and questionnaires at three and 6 months assessed bleeding, continuation and ring acceptability., Results: Seventy-one participants enrolled; 49 completed the first follow-up period. The median number of bleeding or spotting days was 16 in the estrogen ring group (n=26) versus 28 in the DMPA alone group (n=23) (p=.19). Seventy-seven percent of the intervention group received a second injection compared with 70% in the DMPA alone group (p=.56). For each additional day of bleeding and/or spotting reported, women were 3% less likely to receive a second injection (OR 0.97, 95% CI 0.94-0.99). Acceptability of the vaginal ring was high among those in the intervention group., Conclusions: Vaginal estrogen supplementation during DMPA initiation is acceptable to women and may decrease total bleeding., (Copyright 2010 Elsevier Inc. All rights reserved.)

Introduction: The use of biomarkers to evaluate the presence of a target or to select a specific therapy is increasingly advocated. The correlation of biomarker expression between the primary tumor and its corresponding metastasis has not yet been well documented and analyzed in patients with non-small cell lung cancer (NSCLC)., Methods: The expression of epidermal growth factor receptor (EGFR), excision repair cross-complementing (ERCC1), vascular-endothelial growth factor receptor, and Ki-67 was immunohistochemically analyzed in tumor samples of primary NSCLC and one corresponding metastasis in a population of 49 patients., Results: Sixteen cases (33%) displayed clear discordance in the EGFR status between the primary tumor and the metastasis, with a significant trend toward downregulation of EGFR in the metastasis (p = 0.01). The ERCC1 status was discordant in 20 cases (41%), with a trend toward overexpression in brain and adrenal metastases (p = 0.01 and p = 0.08, respectively). The vascular-endothelial growth factor receptor and Ki-67 statuses were discordant in 13 (27%) and 15 (31%) cases, respectively. No difference in expression was observed between synchronous and metachronous metastasis., Conclusion: Biomarker expression is discordant between the primary tumor and its corresponding metastasis in about one third of patients with NSCLC. These findings should be considered in the setting of clinical trials and further explored using frozen material and high-throughput techniques.

Pemetrexed is a structurally novel antifolate agent approved in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma who have unresectable disease and for the therapy of previously treated patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) as a single agent or in association with cisplatin as a first-line treatment in patients with nonsquamous histology. Herein, we report a case of pemetrexed-induced pneumonitis. Because pemetrexed is being prescribed with increasing frequency for NSCLC and mesothelioma, we believe that physicians should be aware of this rare but serious complication.

Background: Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women., Methods: We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleotide polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation., Results: Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences were seen in sliding-window analyses of two-, three-, and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype., Conclusions: These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant.

Objectives: We examined the efficacy of estrogen in the treatment of depression in perimenopausal women with and without hot flushes., Study Design: Women with perimenopause-related depression were randomized in a double-blind parallel design to receive either 17beta-estradiol or placebo for 3 weeks. Subsequently, women receiving estradiol during the first 3 weeks continued receiving estradiol for an additional 3 weeks, whereas women who had received placebo crossed over to estradiol for 3 weeks. Outcome measures included standardized mood rating scales and a visual analog scale self-report instrument., Results: Of 34 female subjects, 16 received estradiol first and 18 received placebo first. After 3 weeks of estradiol, standardized mood rating scale scores and visual analog scale symptom scores (eg, sadness, anhedonia, and social isolation) were significantly decreased compared with baseline scores (P <.01) and were significantly lower than scores in women receiving placebo (P <.01), who showed no significant improvement. Neither the presence of hot flushes nor the duration of treatment (3 weeks vs 6 weeks) influenced outcome. A full or partial therapeutic response was seen in 80% of subjects receiving estradiol and 22% of those receiving placebo., Conclusion: In this preliminary study estradiol replacement effectively treats perimenopausal depression independent of its salutary effects on vasomotor symptoms.

Background: Cerebrospinal fluid (CSF) somatostatin (SS) levels have been shown to be decreased in multiple sclerosis (MS) during relapse as well as in disorders characterized by depression or cognitive impairment. Since MS is often associated with depression and cognitive impairment, we examined both the effect of course of illness on CSF SS as well as the variance in SS attributable to associated features (e.g., depression or cognitive impairment)., Methods: Fifteen patients with chronic progressive MS participating in a 2-year cyclosporine trial underwent lumbar punctures for CSF SS at baseline and at 12 and 24 months. Additionally, patients were evaluated by neuropsychological testing, and physical disability and mood ratings. Baseline CSF SS levels were also obtained in a group of control subjects (n = 10)., Results: At baseline, CSF SS levels were lower in MS patients than control subjects (p < .001). Decreased CSF SS at 24 months was correlated with decreased cognitive performance on several measures and was best and significantly predicted by cognitive deterioration at 24 months., Conclusions: Our data support those from previous studies that found lower levels of CSF SS in MS during relapse and suggest that changes in CSF SS are related to the process responsible for diminished cognitive function in MS.

A burgeoning literature documents the convergence of reproductive endocrine and central serotonergic systems in the regulation of a variety of behaviors. This review will focus on one element of this interaction, the modulation of serotonergic function by estrogen. After describing the manifold neuroregulatory effects of gonadal steroids, we summarize the effects of estrogen on central serotonin systems in animals and humans as inferred from studies demonstrating the impact of gender, estrus (or menstrual) cycle, or hormone manipulation. Finally, we summarize the putative roles of estrogen and serotonin in two reproductive-endocrine-related mood disorders: premenstrual syndrome and perimenopausal depression.

A cross-sectional study was designed to determine whether plasma concentrations of glutathione and cysteine in HIV-infected hemophiliacs vary according to the progression of the disease and to compare them with those obtained in HIV negative hemophiliacs. Cysteine, total glutathione and glutathione disulphide were measured in plasma of HIV-infected hemophiliacs at different stages of HIV infection and in plasma of HIV-negative hemophiliacs. CD4 and CD8 T-cell counts, leukocyte and lymphocyte counts, beta 2-microglobulin and p24 antigen values were recorded for HIV positive hemophiliacs at the time of the study. The hemophiliac HIV-positive group showed a decrease in total glutathione levels (-18%) and an increase of glutathione disulphide (8.18 vs. 14.90%) compared to the HIV-negative group. The cysteine levels found in HIV-positive hemophiliacs were not different from those found in the HIV-negative group. There were no differences with statistical significance in total glutathione, glutathione disulphide and cysteine among HIV-infected hemophiliacs according to the different clinical stage of the disease (AIDS vs. non-AIDS). The interest of evaluating plasma concentrations of glutathione and cysteine in HIV-infected patients is limited from the point of view of considering them as markers of progression of the disease. Interest in a therapeutic strategy designed to replenish or normalize glutathione plasma levels is also limited.