Publications by authors named "David Lora"

64 Publications

Is Endometrial Scratching Beneficial for Patients Undergoing a Donor-Egg Cycle with or without Previous Implantation Failures? Results of a Post-Hoc Analysis of an RCT.

Diagnostics (Basel) 2021 Jun 26;11(7). Epub 2021 Jun 26.

Fetal Medicine Unit-Maternal and Child Health and Development Network (Red SAMIDRD12/0026/0016), Department of Obstetrics and Gynaecology, 12 de Octubre Research Institute (imas12), University Hospital 12 de Octubre, Complutense University of Madrid, Avda, Andalucia s/n, 28041 Madrid, Spain.

Endometrial scratching (ES) has been proposed as a useful technique to improve outcomes in in vitro fertilization (IVF) cycles, particularly in patients with previous implantation failures. Our objective was to determine if patients undergoing egg-donor IVF cycles had better live birth rates after ES, according to their previous implantation failures. Secondary outcomes were pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate, miscarriage rate, and multiple pregnancy rate. We analysed the results of 352 patients included in the Endoscratch Trial (NCT03108157). A total of 209 were patients with one or no previous implantation failures (105 with an ES done in the previous cycle, group A1, and 104 without ES, group B1), and 143 were patients with at least two previous failed implantations (71 patients with ES, group A2, and 72 without ES, group B2). We found an improvement in pregnancy rates (62.9% in group A1 vs. 55.8% in group B1 vs. 70.4% in group A2 vs. 76.4% in group B2, = 0.028) in patients with at least two previous implantation failures, but this difference was not statistically different when we compared clinical pregnancy rates (59.1% vs. 51.0% vs. 64.8% vs. 68.1% in groups A1, B1, A2 and B2, respectively, = 0.104) and live birth rates (52.4% vs. 43.3% vs. 57.8% vs. 55.6% in groups A1, B1, A2 and B2, respectively, = 0.218). According to these results, we conclude that there is no evidence to recommend ES in egg-donor IVF cycles, regardless of the number of previous failed cycles.
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http://dx.doi.org/10.3390/diagnostics11071167DOI Listing
June 2021

Plasma Gelsolin Reinforces the Diagnostic Value of FGF-21 and GDF-15 for Mitochondrial Disorders.

Int J Mol Sci 2021 Jun 15;22(12). Epub 2021 Jun 15.

Mitochondrial and Neuromuscular Disorders Research Group, Hospital 12 de Octubre Research Institute (imas12), 28041 Madrid, Spain.

Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers' plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15.
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http://dx.doi.org/10.3390/ijms22126396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232645PMC
June 2021

Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial.

Lancet 2021 07 25;398(10295):121-130. Epub 2021 Jun 25.

Servicio de Farmacología Clínica, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address:

Background: To date, no immunological data on COVID-19 heterologous vaccination schedules in humans have been reported. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech, Mainz, Germany) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, AstraZeneca, Oxford, UK).

Methods: We did a phase 2, open-label, randomised, controlled trial on adults aged 18-60 years, vaccinated with a single dose of ChAdOx1-S 8-12 weeks before screening, and no history of SARS-CoV-2 infection. Participants were randomly assigned (2:1) to receive either BNT162b2 (0·3 mL) via a single intramuscular injection (intervention group) or continue observation (control group). The primary outcome was 14-day immunogenicity, measured by immunoassays for SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibody functionality was assessed using a pseudovirus neutralisation assay, and cellular immune response using an interferon-γ immunoassay. The safety outcome was 7-day reactogenicity, measured as solicited local and systemic adverse events. The primary analysis included all participants who received at least one dose of BNT162b2 and who had at least one efficacy evaluation after baseline. The safety analysis included all participants who received BNT162b2. This study is registered with EudraCT (2021-001978-37) and ClinicalTrials.gov (NCT04860739), and is ongoing.

Findings: Between April 24 and 30, 2021, 676 individuals were enrolled and randomly assigned to either the intervention group (n=450) or control group (n=226) at five university hospitals in Spain (mean age 44 years [SD 9]; 382 [57%] women and 294 [43%] men). 663 (98%) participants (n=441 intervention, n=222 control) completed the study up to day 14. In the intervention group, geometric mean titres of RBD antibodies increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 BAU/mL (7371·53-8161·96) at day 14 (p<0·0001). IgG against trimeric spike protein increased from 98·40 BAU/mL (95% CI 85·69-112·99) to 3684·87 BAU/mL (3429·87-3958·83). The interventional:control ratio was 77·69 (95% CI 59·57-101·32) for RBD protein and 36·41 (29·31-45·23) for trimeric spike protein IgG. Reactions were mild (n=1210 [68%]) or moderate (n=530 [30%]), with injection site pain (n=395 [88%]), induration (n=159 [35%]), headache (n=199 [44%]), and myalgia (n=194 [43%]) the most commonly reported adverse events. No serious adverse events were reported.

Interpretation: BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response, with an acceptable and manageable reactogenicity profile.

Funding: Instituto de Salud Carlos III.

Translations: For the French and Spanish translations of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S0140-6736(21)01420-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233007PMC
July 2021

Potential Role of Natriuretic Response to Furosemide Stress Test During Acute Heart Failure.

Circ Heart Fail 2021 Jun 15;14(6):e008166. Epub 2021 Jun 15.

Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain (P.C.P., J.N., L.M.F., Z.B.-B., J.C.L.-A., J.d.J.B., M.D.G.-C.C., P.E.S., R.S.-B., F.A.Y., J.F.D.).

Background: Poor natriuresis has been associated with a poorer response to diuretic treatment and worse prognosis in acute heart failure. Recommendations on how and when to measure urinary sodium (UNa) are lacking. We aim to evaluate UNa quantification after a furosemide stress test (FST) capacity to predict appropriate decongestion during acute heart failure hospitalization.

Methods: Patients underwent an FST on day-1 of admission, and UNa was measured 2 hours after, dividing patients into low or high UNa based on the sample median value. A semiquantitative composite congestive score (CCS; 0-9) and NT pro-BNP (N-terminal pro-B-type natriuretic peptide) quantification were assessed before the FST and at day 5 after the FST.

Results: Median UNa after FST in the 65 patients included was 113 (97-122) mmol/L. At day 5, a lower proportion of patients with a low UNa reached a 30% decrease in NT-proBNP levels (21 [66%] for low UNa versus 31 [94%] for high UNa; =0.005) and an appropriate grade of decongestion (CCS<3) (20 [62%] for low UNa versus 32 [97%] for high UNa; <0.001). A UNa>83 mmol/L 2 hours after FST had a 96% sensitivity to predict an NT-proBNP reduction ≥30% and 95% to predict a CCS<3 at day 5. Low UNa patients presented a lower cumulative diuresis and weight loss and presented more often with prolonged hospitalization, worsening heart failure, and readmission because of acute heart failure or death at 6 months.

Conclusions: Low natriuresis after an FST identified patients at a higher risk of an inadequate diuretic response and an inappropriate decongestion. FST-guided diuretic treatment might help to improve decongestion, shorten hospitalizations, and to reduce adverse outcomes.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008166DOI Listing
June 2021

Presence of Extra-Criteria Antiphospholipid Antibodies Is an Independent Risk Factor for Ischemic Stroke.

Front Cardiovasc Med 2021 3;8:665741. Epub 2021 May 3.

Healthcare Research Institute, Hospital Universitario 12 de Octubre, Madrid, Spain.

Ischemic stroke is the most common and severe arterial thrombotic event in Antiphospholipid syndrome (APS). APS is an autoimmune disease characterized by the presence of thrombosis and antiphospholipid antibodies (aPL), which provide a pro-coagulant state. The aPL included in the classification criteria are lupus anticoagulant, anti-cardiolipin (aCL) and anti-β2-glycoprotein-I antibodies (aB2GPI) of IgG and IgM isotypes. Extra-criteria aPL, especially IgA aB2GPI and IgG/IgM anti-phosphatidylserine/prothrombin antibodies (aPS/PT), have been strongly associated with thrombosis. However, their role in the general population suffering from stroke is unknown. We aim (1) to evaluate the aPL prevalence in ischemic stroke patients, (2) to determine the role of aPL as a risk factor for stroke, and (3) to create an easy-to-use tool to stratify the risk of ischemic stroke occurrence considering the presence of aPL and other risk factors. A cohort of 245 consecutive ischemic stroke patients was evaluated in the first 24 h after the acute event for the presence of classic aPL, extra-criteria aPL (IgA aB2GPI, IgG, and IgM aPS/PT) and conventional cardiovascular risk factors. These patients were followed-up for 2-years. A group of 121 healthy volunteers of the same age range and representative of the general population was used as reference population. The study was approved by the Ethics Committee for Clinical Research (Reference numbers CEIC-14/354 and CEIC-18/182). The overall aPL prevalence in stroke patients was 28% and IgA aB2GPI were the most prevalent (20%). In the multivariant analysis, the presence of IgA aB2GPI (OR 2.40, 95% CI: 1.03-5.53), dyslipidemia (OR 1.70, 95% CI: 1.01-2.84), arterial hypertension (OR 1.82, 95% CI: 1.03-3.22), atrial fibrillation (OR 4.31, 95% CI: 1.90-9.78), and active smoking (OR 3.47, 95% CI: 1.72-6.99) were identified as independent risk factors for ischemic stroke. A risk stratification tool for stroke was created based on these factors (AUC: 0.75). IgA aB2GPI are an important independent risk factor for ischemic stroke. Evaluation of aPL (including extra-criteria) in cardiovascular risk factor assessment for stroke can potentially increase the identification of patients at risk of thrombotic event, facilitating a decision on preventive treatments.
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http://dx.doi.org/10.3389/fcvm.2021.665741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126615PMC
May 2021

Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB harmonization project comparing three NGS panels.

J Immunother Cancer 2021 May;9(5)

H12O-CNIO Lung Cancer Clinical Research Unit, Health Research Institute Hospital 12 de Octubre (imas12) / Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Background: Tumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.

Methods: We evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.

Results: Both panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.

Conclusions: Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.
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http://dx.doi.org/10.1136/jitc-2020-001904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108670PMC
May 2021

A predictive score at admission for respiratory failure among hospitalized patients with confirmed 2019 Coronavirus Disease: a simple tool for a complex problem.

Intern Emerg Med 2021 Apr 29. Epub 2021 Apr 29.

Department of Internal Medicine, University Hospital 12 de Octubre, Av Córdoba Km 5,400, 28041, Madrid, Spain.

Coronavirus Disease 2019 (COVID-19) pandemic has implacably stricken on the wellness of many countries and their health-care systems. The aim of the present study is to analyze the clinical characteristics of the initial wave of patients with COVID-19 attended in our center, and to identify the key variables predicting the development of respiratory failure. Prospective design study with concurrent data retrieval from automated medical records of all hospitalized adult patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rRT-PCR assay performed on respiratory samples from March 2nd to 18th, 2020. Patients were followed up to May 1st, 2020 or death. Respiratory failure was defined as a PaO/FiO ratio ≤ 200 mm Hg or the need for mechanical ventilation (either non-invasive positive pressure ventilation or invasive mechanical ventilation). We included 521 patients of whom 416 (81%) had abnormal Chest X-ray on admission. Median age was 64.6 ± 18.2 years. One hundred eighty-one (34.7%) developed respiratory failure after a median time from onset of symptoms of 9 days (IQR 6-11). In-hospital mortality was 23.8% (124/521). The modeling process concluded into a logistic regression multivariable analysis and a predictive score at admission. Age, peripheral pulse oximetry, lymphocyte count, lactate dehydrogenase and C-reactive protein were the selected variables. The model has a good discriminative capacity with an area under the ROC curve of 0.85 (0.82-0.88). The application of a simple and reliable score at admission seems to be a useful tool to predict respiratory failure in hospitalized COVID-19 patients.
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http://dx.doi.org/10.1007/s11739-021-02748-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082224PMC
April 2021

Efficacy and safety of anti-PD-1/PD-L1 combinations versus standard of care in cancer: a systematic review and meta-analysis.

Oncoimmunology 2021 02 23;10(1):1878599. Epub 2021 Feb 23.

Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain.

Immune checkpoint inhibitors (ICIs) as monotherapy in different solid tumors showed an early detrimental effect in a subset of patients reflected by the early crossover of the progression-free survival (PFS) curves. Currently, combination therapies with ICIs added to chemotherapy or targeted therapy are expanding the landscape of metastatic solid tumors. We have examined the benefits and risks of adding ICIs to the standard of care (SOC) versus SOC alone. A search of randomized clinical trials (RCTs) comparing ICIs combinations versus the corresponding SOC in different metastatic tumors according to the PRISMA guidelines was performed. Selected endpoints included PFS, time-to-response (TTR), overall survival (OS), overall response rate (ORR), and ≥ grade 3 adverse events (AEs). Subgroup analyses based on backbone treatment and tumor type were included. A total of 10536 patients (19 studies) were included (ICIs-arm: 5596 patients; SOC-arm: 4940 patients). Globally, PFS, OS, and ORR results favored ICIs-arm. No differences in terms of TTR were found between arms. ICI-arm was associated with a slight increase of ≥ G3 AEs (relative risk: 1.07). The results in multiple myeloma patients are controversial in favor of ICIs combinations. Adding ICIs to SOC benefits a greater number of patients, prolonging survival with no early detrimental effect. The toxicity profile is safe, with a mild increase of high-grade manageable AEs.
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http://dx.doi.org/10.1080/2162402X.2021.1878599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906255PMC
February 2021

Eradication of Staphylococcus aureus post-sternotomy mediastinitis following the implementation of universal pre-operative nasal decontamination with mupirocin: an interrupted time-series analysis.

Clin Infect Dis 2021 Jan 29. Epub 2021 Jan 29.

Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Complutense University, Madrid, Spain.

Background: Although pre-surgical nasal decontamination with mupirocin (NDM) has been advocated as a measure for preventing post-surgical mediastinitis (PSM) due to Staphylococcus aureus, this strategy is not universally recommended due to the lack of robust supporting evidence. We aimed to evaluate the role of pre-operative NDM in the annual incidence of S. aureus PSM at our institution.

Methods: An interrupted time-series analysis, with autoregressive error model, was applied to our single-center cohort by comparing pre-intervention (1990-2003) and post-intervention period (2005 to 2018). Logistic regression was performed to analyze risk factors for S. aureus PSM.

Findings: 12,236 sternotomy procedures were analyzed (6,370 [52.1%] and 5,866 [47.9%] in the pre-intervention and post-intervention periods, respectively). The mean annual percentage adherence to NDM estimated over the post-interventional period was 90.2%. Only four out of 127 total cases of S. aureus PSM occurred during the 14-years post-intervention period (0.68/1,000 sternotomies vs. 19.31/1,000 in pre-interventional period [p<0.0001]). Interrupted time-series analysis demonstrated a statistically significant annual reduction of S. aureus PSM trend of -9.85 cases per 1,000 sternotomies (-13.17 to -6.5, P-value< 0·0001) in 2005, with a decreasing trend maintained over the following five years with an estimated relative reduction of 84.8% (95% CI: 89·25 to 74·09). Chronic obstructive pulmonary disease was the single independent risk factor for S. aureus PSM (odds ratio: 3.7; 95% CI: 1.72-7.93) and was equally distributed in patients undergoing sternotomy during pre or post-intervention periods.

Interpretation: Our experience suggests that the implementation of pre-operative NDM reduces significantly the incidence of S. aureus PSM.
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http://dx.doi.org/10.1093/cid/ciab073DOI Listing
January 2021

Systemic Analysis and Review of Nivolumab-ipilimumab Combination as a Rescue Strategy for Renal Cell Carcinoma After Treatment With Anti-PD-1/PD-L1 Therapy.

Clin Genitourin Cancer 2021 04 15;19(2):95-102. Epub 2020 Oct 15.

Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain. Electronic address:

Nivolumab-ipilimumab has become the standard of care in the frontline setting for intermediate-/poor-risk metastatic renal cell carcinoma (mRCC). This regimen is associated with survival improvement but significant toxicity. Anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) monotherapy may provide response and offers a better safety profile. In this context, nivolumab-ipilimumab has been postulated as a rescue treatment after anti-PD-1/PD-L1 therapy. Recent retrospective data has shown positive results, and several nonrandomized clinical trials (NRCTs) have evaluated this strategy. Therefore, we performed a meta-analysis of available NRCTs to clarify the efficacy and safety of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 monotherapy. We searched PubMed, Medline, Embase, and the Cochrane Central Register of Controlled Trials to identify clinical trials investigating the efficacy and safety of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 in patients with mRCC. Only phase II NRCTs were available for the analysis. The pooled effect of single proportions with a 95% confidence interval (CI) was used as the measure of effect (overall response rate [ORR] and incidence of grade ≥ 3 adverse events). Four studies accounting for 237 patients were included. All patients received prior anti-PD-1/PD-L1 monotherapy. The pooled ORR of salvage nivolumab-ipilimumab after prior anti-PD-1/PD-L1 failure was 10.0% (95% CI, 6%-14%; I = 41%; P = .17). The incidence of grade ≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I = 0%; P = .56). The results of this analysis suggest that the use of salvage nivolumab-ipilimumab in mRCC after prior anti-PD-1/PD-L1 has limited activity with a 10% ORR, and a non-negligible toxicity with 1 of 4 patients developing grade ≥ 3 immune-related adverse events.
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http://dx.doi.org/10.1016/j.clgc.2020.10.004DOI Listing
April 2021

The Value of PD-L1 Expression as Predictive Biomarker in Metastatic Renal Cell Carcinoma Patients: A Meta-Analysis of Randomized Clinical Trials.

Cancers (Basel) 2020 Jul 17;12(7). Epub 2020 Jul 17.

Medical Oncology Department, University Hospital 12 de Octubre, 28041 Madrid, Spain.

Immune checkpoint inhibitors (ICIs) are soluble antibodies that have dramatically changed the outcomes including overall survival in a subset of kidney tumors, specifically in renal cell carcinoma (RCC). To date, there is no a single predictive biomarker approved to be used to select the patients that achieve benefit from ICIs targeting. It seems reasonable to analyze whether the programmed death-ligand 1 (PD-L1) expression could be useful. To assess the role of PD-L1 expression as a potential predictive biomarker for benefit of ICIs in RCC patients, we performed a search of randomized clinical trials (RCTs) comparing ICIs (monotherapy or in combination with other therapies) to standard of care in metastatic RCC patients according to PRISMA guidelines. Trials must have included subgroup analyses evaluating the selected outcomes (progression-free survival (PFS) and overall survival (OS)) in different subsets of patients according to PD-L1 expression on tumor samples. Hazard ratios with confidence intervals were used as the measure of efficacy between groups. A total of 4635 patients (six studies) were included (ICIs arm: 2367 patients; standard of care arm: 2268 patients). Globally, PFS and OS results favored ICIs. Differential expression of PD-L1 on tumor samples could select a subset of patients who could benefit more in terms of PFS (those with higher levels; -value for difference between subgroups: <0.0001) but it did not seem to impact in OS results (-value for difference: 0.63). As different methods to assess PD-L1 positivity were used among trials, this heterogeneity could have an influence on the results. PD-L1 could represent a biomarker to test PFS in clinical trials but its value for OS is less clear. In this meta-analysis, the usefulness of PD-L1 expression as a predictive biomarker to select treatment in metastatic RCC patients was not clearly shown.
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http://dx.doi.org/10.3390/cancers12071945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409133PMC
July 2020

Derivation and external validation of the SIMPLICITY score as a simple immune-based risk score to predict infection in kidney transplant recipients.

Kidney Int 2020 10 12;98(4):1031-1043. Epub 2020 Jun 12.

Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain. Electronic address:

Existing approaches for infection risk stratification in kidney transplant recipients are suboptimal. Here, we aimed to develop and validate a weighted score integrating non-pathogen-specific immune parameters and clinical variables to predict the occurrence of post-transplant infectious complications. To this end, we retrospectively analyzed a single-center derivation cohort of 410 patients undergoing kidney transplantation in 2008-2013 in Madrid. Peripheral blood lymphocyte subpopulations, serum immunoglobulin and complement levels were measured at one-month post-transplant. The primary and secondary outcomes were overall and bacterial infection through month six. A point score was derived from a logistic regression model and prospectively applied on a validation cohort of 522 patients undergoing kidney transplantation at 16 centers throughout Spain in 2014-2015. The SIMPLICITY score consisted of the following variables measured at month one after transplantation: C3 level, CD4 T-cell count, CD8 T-cell count, IgG level, glomerular filtration rate, recipient age, and infection within the first month. The discrimination capacity in the derivation and validation cohorts was good for overall (areas under the receiver operating curve of 0.774 and 0.730) and bacterial infection (0.767 and 0.734, respectively). The cumulative incidence of overall infection significantly increased across risk categories in the derivation (low-risk 13.7%; intermediate-risk, 35.9%; high-risk 77.6%) and validation datasets (10.2%, 28.9% and 50.4%, respectively). Thus, the SIMPLICITY score, based on easily available immune parameters, allows for stratification of kidney transplant recipients at month one according to their expected risk of subsequent infection.
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http://dx.doi.org/10.1016/j.kint.2020.04.054DOI Listing
October 2020

Systematic review and meta-analysis comparing Adjustable Transobturator Male System (ATOMS) and male Readjustment Mechanical External (REMEEX) system for post-prostatectomy incontinence.

World J Urol 2021 Apr 11;39(4):1083-1092. Epub 2020 Jun 11.

Instituto de Investigación Sanitaria Hospital "12 de Octubre" (i+12), CIBER de Epidemiología y Salud Pública (CIBERESP), Universidad Complutense de Madrid, 28041, Madrid, Spain.

Objective: To assess the efficacy and safety of Adjustable Transobturator Male System (ATOMS) compared to male Readjustment Mechanical External (REMEEX) system for post-prostatectomy incontinence (PPI).

Material And Methods: A systematic review and meta-analysis on adjustable device ATOMS compared to male REMEEX is presented. Studies on female or neurogenic incontinence were excluded. Primary objectives were evaluation of dryness (the proportion of patients with no-pad or one safety pad/day after device adjustment) and improvement between devices. Secondary objectives were complications and explant rate. They were estimated using a random-effect model. Statistical heterogeneity among studies was assessed using Cochran's Q test, Higgins's I statistics and tau2.

Results: Combined data of 29 observational studies with 1919 patients showed an equivalent proportion of patients treated with radical prostatectomy (p = .125) and previous radiation (p = .126). Dryness rate was 69.3% for ATOMS and 53.4% for male REEMEX (p = .008). Improvement rate was 90.8% for ATOMS and 80.2% for REMEEX (p = .007). Complication rate was 18.9% for ATOMS and 35.8% for REMEEX (p = .096) and explant rate was 5.5% for ATOMS and 13.9% for REMEEX (p = .027). Significant heterogeneity was evidenced, due to absence of randomized studies, variable incontinence severity baseline, difficulties for a common reporting of complications and difference in the follow-up. Differences observed between devices remained statistically significant when only studies with silicone-covered scrotal port (SSP) ATOMS and male REMEEX system II were considered.

Conclusions: Despite the absence of direct comparison and the limitations observed ATOMS appears more effective than male REMEEX to treat PPI, and with less explant rate as reported in the literature.
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http://dx.doi.org/10.1007/s00345-020-03300-1DOI Listing
April 2021

Endometrial scratch vs no intervention in egg donation cycles: the ENDOSCRATCH trial protocol.

BMC Pregnancy Childbirth 2020 May 30;20(1):333. Epub 2020 May 30.

Fetal Medicine Unit - Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016). Department of Obstetrics and Gynecology. University Hospital 12 de Octubre. 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Madrid, Spain.

Background: The effects of endometrial scratching (ES) on embryo implantation have been studied for many years. Several studies have shown better outcomes when performed on patients undergoing intrauterine insemination and in vitro fertilization (IVF) cycles, but many other reports have not been able to find these differences. As far as cycles with donor eggs are concerned, reported evidence is scarce. Our aim in this trial is to determine if ES is useful for those patients undergoing IVF cycles with donor eggs, in order to assure a greater homogeneity in embryo quality and endometrial preparation.

Methods: This single centre randomized controlled trial will include patients undergoing an egg donation cycle, meeting the inclusion criteria and who accept to participate in the study. Once informed consent is signed, patients will be randomly allocated to the study arm (group A) and then receive ES in the luteal phase of the cycle prior to embryo transfer, or the control arm (group B) without any intervention. All cycle data will be collected and analyzed to obtain the clinical pregnancy and the live birth rates in the two groups.

Discussion: Several studies have tried to determine the effectiveness of an ES in IVF cycles, but it is still unclear due to the heterogeneity of these reports. The aim of this study is to determine if there are differences in clinical pregnancy rate and live birth rate in egg donor cycles, when comparing an ES performed in the preceding luteal phase versus no intervention, given that embryo quality and endometrial preparation protocols will be comparable.

Trial Registration: Ethical approval of version 2.0 of this trial was obtained on the 13th January 2017. It was retrospectively registered on the 5th April 2017 as the ENDOSCRATCH Trial (NCT03108157) in ClinicalTrials.gov.
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http://dx.doi.org/10.1186/s12884-020-02958-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260784PMC
May 2020

Endometrial Scratching Effect on Clinical Pregnancy Rates in Patients Undergoing Egg Donor In Vitro Fertilization Cycles: the ENDOSCRATCH Randomized Clinical Trial (NCT03108157).

Reprod Sci 2020 10 28;27(10):1863-1872. Epub 2020 May 28.

Fetal Medicine Unit - Maternal and Child Health and Development Network (Red SAMID-RD12/0026/0016), Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute (imas12), Complutense University of Madrid, Avda. Andalucia s/n, Madrid, Spain.

The potential benefit of endometrial scratching (ES) on embryo implantation is still a controversial subject. At present, the single retrospective study in egg donor IVF cycles concluded that ES has no beneficial effect. Our objective was to determine if there are differences in clinical pregnancy rates (CPR) in egg donor cycles when an ES is performed. This is a randomized controlled trial (RCT) in egg donor IVF patients conducted at ProcreaTec Fertility Center in Madrid. Three hundred fifty-two patients were included in total. One hundred sixty-one patients completed the protocol in group A and 172 patients in group B. Patients allocated to group A received an ES in the luteal phase of the cycle preceding the embryo transfer cycle. Group B patients did not receive any intervention. Primary outcome of this RCT was CPR. Secondary outcomes were implantation (IR), miscarriage (MR), ongoing pregnancy (OPR), multiple pregnancy (MulPR), and live birth rates (LBR). CPR was 104 of 161 (64.6%) in group A and 102 of 172 (59.3%) in group B (RR 1.09, 95% confidence interval (CI) (0.92-1.29); p = 0.378). OPR, MR, MulPR, and LBR were also comparable. No major complications were detected after ES and pregnancy complications were comparable. Our results show that there is no beneficial role of ES in egg donor IVF cycles, considering these patients as the ideal model as they share homogeneous embryo quality and endometrial preparation protocols. This trial was registered on April 5, 2017, as the ENDOSCRATCH trial (NCT03108157).
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http://dx.doi.org/10.1007/s43032-020-00204-8DOI Listing
October 2020

A New Clinical and Immunovirological Score for Predicting the Risk of Late Severe Infection in Solid Organ Transplant Recipients: The CLIV Score.

J Infect Dis 2020 07;222(3):479-487

Unit of Infectious Diseases, Hospital Universitario "12 de Octubre," Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain.

Background: We aimed at constructing a composite score based on Epstein-Barr virus DNAemia (EBVd) and simple clinical and immunological parameters to predict late severe infection (LI) beyond month 6 in solid organ transplantation (SOT) recipients.

Methods: Kidney and liver transplant recipients between May 2014 and August 2016 at 4 participating centers were included. Serum immunoglobulins and complement factors, peripheral blood lymphocyte subpopulations, and whole blood EBVd were determined at months 1, 3, and 6. Cox regression analyses were performed to generate a weighted score for the prediction of LI.

Results: Overall, 309 SOT recipients were followed-up for a median of 1000 days from transplant (interquartile range, 822-1124). Late severe infection occurred in 104 patients (33.6%). The CLIV Score consisted of the following variables at month 6: high-level EBVd (>1500 IU/mL) and recurrent infection during the previous months (6 points); recipient age ≥70 years and chronic graft dysfunction (5 points); cytomegalovirus mismatch (4 points); and CD8+ T-cell count <400 cells/μL (2 points). The area under receiver operating characteristics curve was 0.77 (95% confidence interval, 0.71-0.84). The risk of LI at day 1000 was as follows: score 0, 12.6%; score 2-5, 25.5%; score 6-9, 52.7%; score ≥10, 73.5%.

Conclusions: While waiting for further external validation, the CLIV Score based on clinical and immune-virological parameters is potentially useful to stratify the risk of LI after SOT.
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http://dx.doi.org/10.1093/infdis/jiaa090DOI Listing
July 2020

Systematic review and meta-analysis comparing Adjustable Transobturator Male System (ATOMS) and Adjustable Continence Therapy (ProACT) for male stress incontinence.

PLoS One 2019 2;14(12):e0225762. Epub 2019 Dec 2.

Instituto de Investigación Sanitaria Hospital "12 de Octubre" (i+12), Madrid, Spain.

Background And Purpose: Urinary incontinence is one of the most serious complications of prostate cancer treatment. The objective of this study was to assess efficacy and safety of Adjustable Transobturator Male System (ATOMS) compared to Adjustable Continence Therapy (proACT) for male stress urinary incotinence according to literature findings.

Material And Methods: A systematic review and meta-analysis on adjustable devices ATOMS and ProACT is presented. Studies on female or neurogenic incontinence were excluded. Differences between ATOMS and proACT in primary objective: dryness status (no-pad or one safety pad/day) after initial device adjustment, and in secondary objectives: improvement, satisfaction, complications and device durability, were estimated using random-effect model. Statistical heterogeneity among studies included in the meta-analysis was assessed using tau2, Higgins´s I2 statistics and Cochran´s Q test.

Results: Combined data of 41 observational studies with 3059 patients showed higher dryness (68 vs. 55%; p = .01) and improvement (91 vs. 80%; p = .007) rate for ATOMS than ProACT. Mean pad-count (-4 vs. -2.5 pads/day; p = .005) and pad-test decrease (-425.7 vs. -211.4 cc; p < .0001) were also significantly lower. Satisfaction was higher for ATOMS (87 vs. 56%; p = .002) and explant rate was higher for proACT (5 vs. 24%; p < .0001). Complication rate for ProACT was also higher, but not statistically significant (17 vs. 26%; p = .07). Mean follow-up was 25.7 months, lower for ATOMS than ProACT (20.8 vs. 30.6 months; p = .02). The rate of working devices favoured ATOMS at 1-year (92 vs. 76; p < .0001), 2-years (85 vs. 61%; p = .0008) and 3-years (81 vs. 58%; p = .0001). Significant heterogeneity was evidenced, due to variable incontinence severity baseline, difficulties for a common reporting of complications, different number of adjustments and time of follow-up and absence of randomized studies.

Conclusions: Despite the limitations that studies available are exclusively descriptive and the follow-up is limited, literature findings confirm ATOMS is more efficacious, with higher patient satisfaction and better durability than ProACT to treat male stress incontinence.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886794PMC
March 2020

Reliable change indices for the 37-item version of the MMSE in Spanish older adults.

Clin Neuropsychol 2020 12 22;34(sup1):13-28. Epub 2019 Nov 22.

Faculty of Medicine, Complutense University, Madrid, Spain.

Objective: The aim of this study was to establish reliable change and regression-based change score norms on the 37-item version of MMSE in older Spanish adults at the three-year follow-up.

Method: All subjects of this research were selected from the Neurological Disorders in Central Spain (NEDICES), a prospective population-based cohort study of older adults (65 years and over). Of the 4208 individuals free from neurological disorders in this cohort, 2073 participants completed the MMSE-37 at baseline and at the three-year follow-up. Reliable Change Indices were computed for the 80, 90% and 95 confidence intervals (CIs). Multiple regression analyses were used to derive equations for predicting MMSE-37 post-test scores taking into account baseline scores, time to follow-up and sociodemographic factors.

Results: The MMSE-37 obtained a marginal test-retest reliability (.70). The results showed significant effects of education, age, and sex on the MMSE-37 change scores. After correcting for regression to the mean, at least a 6-point change on MMSE-37 (three-years follow-up) is required to be classified as reliable (90% CI).

Conclusions: These findings demonstrate that the MMSE-37 is a reliable test-retest measure whose change scores are significantly influenced by sociodemographic factors. Importantly, small changes on this measure require a cautious interpretation.
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http://dx.doi.org/10.1080/13854046.2019.1692077DOI Listing
December 2020

Development of a predictive model of hospitalization in primary care patients with heart failure.

PLoS One 2019 16;14(8):e0221434. Epub 2019 Aug 16.

Health Service Research Network for Chronic Diseases (Red de Investigación en Servicios de Salud en Enfermedades Crónicas/REDISSEC), Madrid, Spain.

Background: Heart failure (HF) is the leading cause of hospitalization in people over age 65. Predictive hospital admission models have been developed to help reduce the number of these patients.

Aim: To develop and internally validate a model to predict hospital admission in one-year for any non-programmed cause in heart failure patients receiving primary care treatment.

Design And Setting: Cohort study, prospective. Patients treated in family medicine clinics.

Methods: Logistic regression analysis was used to estimate the association between the predictors and the outcome, i.e. unplanned hospitalization over a 12-month period. The predictive model was built in several steps. The initial examination included a set of 31 predictors. Bootstrapping was used for internal validation.

Results: The study included 251 patients, 64 (25.5%) of whom were admitted to hospital for some unplanned cause over the 12 months following their date of inclusion in the study. Four predictive variables of hospitalization were identified: NYHA class III-IV, OR (95% CI) 2.46 (1.23-4.91); diabetes OR (95% CI) 1.94 (1.05-3.58); COPD OR (95% CI) 3.17 (1.45-6.94); MLHFQ Emotional OR (95% CI) 1.07 (1.02-1.12). AUC 0.723; R2N 0.17; Hosmer-Lemeshow 0.815. Internal validation AUC 0.706.; R2N 0.134.

Conclusion: This is a simple model to predict hospitalization over a 12-month period based on four variables: NYHA functional class, diabetes, COPD and the emotional dimension of the MLHFQ scale. It has an acceptable discriminative capacity enabling the identification of patients at risk of hospitalization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0221434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697326PMC
March 2020

Comparative safety analysis of immunotherapy combined with chemotherapy versus monotherapy in solid tumors: a meta-analysis of randomized clinical trials.

Oncotarget 2019 May 14;10(35):3294-3301. Epub 2019 May 14.

Medical Oncology Department, University Hospital 12 de Octubre, Madrid, Spain.

Combination treatment (chemotherapy plus immune checkpoint blockade [ICB]) has shown promising activity in terms of efficacy, but it has been suggested that its toxicity profile is less favorable compared to monotherapy. We conducted a meta-analysis of published randomized clinical trials comparing combination treatment to monotherapy (chemotherapy or ICB) in patients with metastatic solid tumors. Differences in rates of safety issues (all-grade adverse events, grade 3/4 adverse events, treatment-related deaths, treatment discontinuations) between groups were estimated. Subgroup analyses for the control group (chemotherapy or ICB as monotherapy) and immune checkpoint inhibitor (anti-CTLA-4 or anti-PD-1/PD-L1 antibodies) were performed. A total of 4379 patients (ten studies) were included (monotherapy: 2026 patients; combination treatment: 2353 patients). Combination treatment presented more grade 3/4 adverse events (RR 1.32, 95% CI 1.12-1.55) and discontinuations (RR 2.31, 95% CI 1.28-4.16). There were no differences in the mortality rate between groups. Subgroup analyses showed a potentially more toxic profile with anti-CTLA-4 agents. Combination treatment is associated with an increase in grade 3/4 adverse events and treatment discontinuations compared to monotherapy, but not increased mortality. The toxicity profile of combination therapy should be considered with regard to the overlapping safety profiles.
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http://dx.doi.org/10.18632/oncotarget.26908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524939PMC
May 2019

Impact of MBL2 gene polymorphisms on the risk of infection in solid organ transplant recipients: A systematic review and meta-analysis.

Am J Transplant 2019 04 7;19(4):1072-1085. Epub 2018 Dec 7.

Transplantation Center, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.

Mannose-binding lectin (MBL) is a soluble pattern recognition molecule involved in complement activation. Single nucleotide polymorphisms (SNPs) in the MBL2 gene have been associated with susceptibility to infection, although data in solid organ transplant recipients remains inconclusive. This meta-analysis was primarily aimed at investigating the association between posttransplant bacterial and fungal infection and variant alleles of MBL2 gene SNPs in the promoter/5' untranslated region and exon 1. Cytomegalovirus (CMV) infection and/or disease were considered secondary outcomes. PubMed, EMBASE, and Web of Knowledge were searched for relevant articles up to August 2018. Eleven studies (comprising 1858 patients) were included, with liver transplant (LT) recipients accounting for 80.4% of the pooled population. As compared to high-MBL expression haplotypes (YA/YA, YA/XA), any MBL-deficient haplotype was associated with an increased risk of posttransplant bacterial and fungal infections (risk ratio [RR]: 1.30; P = .04). Low/null-MBL expression haplotypes (XA/O, O/O) also increased the risk of primary outcome (RR: 1.51; P = .008) and CMV events (RR: 1.50; P = .006). No effect was observed for individual promoter SNPs. In conclusion, MBL-deficient haplotypes are associated with a significant, albeit moderate, increase in the risk of posttransplant infection, with this association being mainly restricted to LT recipients.
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http://dx.doi.org/10.1111/ajt.15160DOI Listing
April 2019

Final outcome trends in severe traumatic brain injury: a 25-year analysis of single center data.

Acta Neurochir (Wien) 2018 12 31;160(12):2291-2302. Epub 2018 Oct 31.

Department of Neurosurgery, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Avda Cordoba, SN, 28041, Madrid, Spain.

Background: Evidence from the last 25 years indicates a modest reduction of mortality after severe traumatic head injury (sTBI). This study evaluates the variation over time of the whole Glasgow Outcome Scale (GOS) throughout those years.

Methods: The study is an observational cohort study of adults (≥ 15 years old) with closed sTBI (GCS ≤ 8) who were admitted within 48 h after injury. The final outcome was the 1-year GOS, which was divided as follows: (1) dead/vegetative, (2) severely disabled (dependent patients), and (3) good/moderate recovery (independent patients). Patients were treated uniformly according to international protocols in a dedicated ICU. We considered patient characteristics that were previously identified as important predictors and could be determined easily and reliably. The admission years were divided into three intervals (1987-1995, 1996-2004, and 2005-2012), and the following individual CT characteristics were noted: the presence of traumatic subarachnoid or intraventricular hemorrhage (tSAH, IVH), midline shift, cisternal status, and the volume of mass lesions (A × B × C/2). Ordinal logistic regression was performed to estimate associations between predictors and outcomes. The patients' estimated propensity scores were included as an independent variable in the ordinal logistic regression model (TWANG R package).

Findings: The variables associated with the outcome were age, pupils, motor score, deterioration, shock, hypoxia, cistern status, IVH, tSAH, and epidural volume. When adjusting for those variables and the propensity score, we found a reduction in mortality from 55% (1987-1995) to 38% (2005-2012), but we discovered an increase in dependent patients from 10 to 21% and just a modest increase in independent patients of 6%.

Conclusions: This study covers 25 years of management of sTBI in a single neurosurgical center. The prognostic factors are similar to those in the literature. The improvement in mortality does not translate to better quality of life.
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http://dx.doi.org/10.1007/s00701-018-3705-7DOI Listing
December 2018

Longitudinal profile of circulating T follicular helper lymphocytes parallels anti-HLA sensitization in renal transplant recipients.

Am J Transplant 2019 01 25;19(1):89-97. Epub 2018 Jul 25.

Department of Immunology, Hospital 12 de Octubre, Madrid, Spain.

Antibody-mediated rejection is responsible for 30%-50% of renal graft failures. Differentiation of B cells into antibody-producing plasmablasts depends on the collaboration of follicular helper T cells (Tfh). We analyzed circulating Tfh (cTfh) in kidney recipients and studied cTfh relationship with anti-HLA antibody production and graft outcome. cTfh were longitudinally analyzed in a prospective cohort of patients (n = 206), pre- and posttransplantation. Clinical data, HLA sensitization, and cTfh function were recorded. Both pretransplant and 6-month posttransplant cTfh were able to derive IgG-producing plasmablasts. Pretransplant cTfh was decreased in patients, especially in those who received dialysis. However, these cells were increased in patients with previous allograft or transfusions and in HLA-sensitized recipients. After transplantation cTfh expanded, significantly more in patients who developed de novo anti-HLA antibodies than in patients who remained unsensitized. Augmented pretransplant cTfh positively correlated with higher intensity of pretransplant anti-HLA class I and with de novo anti-HLA class I and anti-HLA class II antibodies. Consistently, pretransplantation cTfh were higher in patients who experienced acute rejection (HR = 1.14 [1.04-1.25]). Thus, we show a role for Tfh in anti-HLA sensitization and rejection. Multicenter studies with additional patient cohorts are needed to validate these results. Immunosuppressive drugs targeting Tfh could be useful to improve outcomes.
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http://dx.doi.org/10.1111/ajt.14987DOI Listing
January 2019

Analysis of response rate with ANTI PD1/PD-L1 monoclonal antibodies in advanced solid tumors: a meta-analysis of randomized clinical trials.

Oncotarget 2018 Feb 20;9(9):8706-8715. Epub 2018 Jan 20.

Medical Oncology Service, University Hospital 12 de Octubre, Madrid, Spain.

Background: Anti-PD1/PD-L1 monoclonal antibodies (mAbs) increase overall survival compared to standard of care (SOC) in different tumors. However, a proportion of patients (pts) will have progressive disease (PD) as best response. We conducted a meta-analysis to study the rates of response comparing these antibodies with SOC.

Methods: A search of published trials in MEDLINE and EMBASE analyzing anti-PD1/PD-L1mAbs monotherapy compared to SOC. Relative risk (RR) with 95% confidence interval (CI) of response rates between groups was estimated. Subgroup analyses for location of primary tumor, number of previous treatment lines, selected population by PD-L1 expression and type of radiological assessment were made.

Results: Twelve studies accounting for 6,700 pts were included (anti-PD1/PD-L1 mAbs: 3,451 pts; SOC: 3,249 pts [2,823 pts: chemotherapy, 426 pts: targeted therapy]). Adjusted response rates were (N, %): Complete Response (CR) (69/3153, 2.19%), Partial Response (PR) (596/3153, 18.90%), Stable Disease (SD) (632/2463, 25.66%) and PD (1027/2463, 41.70%); and CR (16/2955, 0.54%), PR (263/2955, 8.90%), SD (835/2269, 36.80%) and PD (834/2269, 36.76%) with anti-PD1/PD-L1 mAbs and SOC, respectively. Anti-PD1/PD-L1 mAbs improved CR rate (RR 3.48) and PR rate (RR 2.27). There were no differences in the PD rate between groups (RR 1.10). Subgroup analyses showed an improvement in clinical benefit with anti-PD1/PD-L1 mAbs for melanoma (RR 1.59; 1.37-1.84 95% CI) and those treated in the first line setting (RR 1.57; 1.27-1.95 95% CI).

Conclusions: Anti-PD1/PD-L1 mAbs increase overall response rate compared to SOC without an increase in PD rate. Melanoma and pts treated in first line setting seem to have greater benefit with anti-PD1/PD-L1 mAbs.

Findings: In this systematic meta-analysis, anti-PD1/PD-L1 mAbs were associated with a greater overall response rate. Patients with melanoma and those managed in the first line setting seem to have an additional benefit with anti-PD1/PD-L1 mAbs.
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http://dx.doi.org/10.18632/oncotarget.24283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823578PMC
February 2018

Evaluation of the multiplex PCR Allplex-GI assay in the detection of bacterial pathogens in diarrheic stool samples.

J Microbiol Methods 2018 01 31;144:33-36. Epub 2017 Oct 31.

Servicio de Microbiología, Hospital Universitario 12 de Octubre, Madrid, Spain. Electronic address:

Rapid and accurate detection of the pathogens that cause gastrointestinal infection is important for appropriate therapy and proper infection control. This study assesses the performance of a new molecular assay for simultaneous detection of 13 different gastrointestinal bacteria in stool specimens. Using the Allplex GI-Bacteria (AGI-BI/AGI-BII) assay, a total of 394 stool samples were tested and the results were compared with culturing on selective differential followed by identification by mass spectroscopy. Discordant results were analyzed by a different multiplex PCR method, the Fast-Track Diagnostics Bacterial gastroenteritis (FTD-BG). The routine method (RM) detected 109 (27.7%) positive samples and the Allplex-GI assay, 261 (66.2%). Analysis of discordant results revealed that the molecular assay detected 44 pathogens that were not detected by the RM, including 23 Campylobacter spp., 11 Salmonella spp, 3 Y. enterocolitica, 2 EIEC/Shigella spp, 2 E. coli 0157, 2 C. difficile and 1 Aeromonas spp. Five cases not detected by the molecular method were detected by the RM (3 Aeromonas spp, 1 Salmonella spp and 1 Y. enterocolitica). For all targets, the percentages of sensitivity and specificity were >95%, except for Aeromonas spp., which were 81% and 99% respectively. This study suggests that Allplex-GI multiplex PCR is a sensitive and specific assay that enables a rapid and accurate diagnosis of bacterial gastrointestinal infections.
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http://dx.doi.org/10.1016/j.mimet.2017.10.016DOI Listing
January 2018

Herpes zoster in kidney transplant recipients: protective effect of anti-cytomegalovirus prophylaxis and natural killer cell count. A single-center cohort study.

Transpl Int 2018 02 11;31(2):187-197. Epub 2017 Oct 11.

Unit of Infectious Diseases, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (i+12), School of Medicine, Universidad Complutense, Madrid, Spain.

Despite its impact on quality of life and potential for complications, specific risk and protective factors for herpes zoster (HZ) after kidney transplantation (KT) remain to be clarified. We included 444 patients undergoing KT between November 2008 and March 2013. Peripheral blood lymphocyte subpopulations were measured at baseline and months 1 and 6. The risk factors for early (first post-transplant year) and late HZ (years 1-5) were separately assessed. We observed 35 episodes of post-transplant HZ after a median follow-up of 48.3 months (incidence rate: 0.057 per 1000 transplant-days). Median interval from transplantation was 18.3 months. Six patients (17.1%) developed disseminated infection. Postherpetic neuralgia occurred in 10 cases (28.6%). The receipt of anti-cytomegalovirus (CMV) prophylaxis with (val)ganciclovir decreased the risk of early HZ [adjusted hazard ratio (aHR): 0.08; 95% CI: 0.01-1.13; P-value = 0.062], whereas the natural killer (NK) cell at month 6 was protective for the occurrence of late HZ [aHR (per 10-cells/μl increase): 0.94; 95% CI: 0.88-1.00; P-value = 0.054]. In conclusion, two easily ascertainable factors (whether the patient is receiving anti-CMV prophylaxis and the NK cell count at month 6) might be potentially useful to tailor preventive strategies according to individual susceptibility to post-transplant HZ.
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http://dx.doi.org/10.1111/tri.13076DOI Listing
February 2018

Incidence of thromboembolic events in asymptomatic carriers of IgA anti ß2 glycoprotein-I antibodies.

PLoS One 2017 20;12(7):e0178889. Epub 2017 Jul 20.

Department of Immunology Instituto de Investigación, Hospital Universitario 12 de Octubre, Madrid, Spain.

Background: The antiphospholipid syndrome (APS) is defined by simultaneous presence of vascular clinical events and antiphospholipid antibodies (aPL). The aPL considered as diagnostics are lupus anticoagulant and antibodies anticardiolipin (aCL) and anti-ß2 glycoprotein-I (aB2GP1). During recent years, IgA aB2GP1 antibodies have been associated with thrombotic events both in patients positive, and mainly negative for other aPL, however its value as a pro-thrombotic risk-factor in asymptomatic patients has not been well defined.

Objective: To test the role of IgA anti B2GP1 as a risk factor for the development of APS-events (thrombosis or pregnancy morbidity) in asymptomatic population with a 5-year follow-up.

Methods: 244 patients isolated positive for anti-beta2-glycoprotein I IgA (Group-1 study) and 221 negative patients (Group-2 control) were studied. All the patients were negative for IgG and IgM aCL.

Results: During the follow-up, 45 patients (9.7%) had APS-events, 38 positive for IgA-aB2GP1 and 7 negative (15.6% vs 3.2%, p<0.001). The incidence rate of APS-events was 3.1% per year in IgA-aB2GP1 positive patients and 0.6% per year in the control group. Arterial thrombosis were the most frequent APS-events (N = 25, 55%) and were mainly observed in Group-1 patients (21 vs 4, p = 0.001). Multivariate analysis were shown as independent risk-factors for the development of APS-events, age, sex (men) and presence of IgA-aB2GP1 (odds ratio 5.25, 95% CI 2.24 to 12.32).

Conclusion: The presence of IgA-aB2GP1 in people with no history of APS-events is the main independent risk factor for the development of these types of events, mainly arterial thrombosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178889PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519006PMC
September 2017

Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine.

Nature 2017 06;546(7660):676-680

Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.

Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis. However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma. Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress. Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma. Still, the identities and prognostic value of lymphangiogenic mediators remain unclear. Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches. Injectable lymphatic tracers have been developed, but their limited diffusion precludes whole-body imaging at visceral sites. Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer. Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.
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http://dx.doi.org/10.1038/nature22977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6005659PMC
June 2017