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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%; I2 = 41%; P = .17). The incidence of grade ≥ 3 irAEs was 27.0% (95% CI, 20%-35%; I2 = 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.

Background Although presurgical nasal decontamination with mupirocin (NDM) has been advocated as a measure for preventing postsurgical mediastinitis (PSM) due to Staphylococcus aureus, this strategy is not universally recommended due to lack of robust supporting evidence. We aimed to evaluate the role of preoperative NDM in the annual incidence of S. aureus PSM at our institution. Methods An interrupted time-series analysis, with an autoregressive error model, was applied to our single-center cohort by comparing preintervention (1990–2003) and postintervention (2005–2018) periods. Logistic regression was performed to analyze risk factors for S. aureus PSM. Results 12 236 sternotomy procedures were analyzed (6370 [52.1%] and 5866 [47.9%] in the pre- and postintervention periods, respectively). The mean annual percentage adherence to NDM estimated over the postintervention period was 90.2%. Only 4 of 127 total cases of S. aureus PSM occurred during the 14-year postintervention period (0.68/1000 sternotomies vs 19.31/1000 in the preintervention period; P Conclusions Our experience suggests the implementation of preoperative NDM significantly reduces the incidence of S. aureus PSM.

Background and objectives Heart failure (HF) is a frequent condition that deteriorates quality of life and results in high morbidity and mortality. A considerable number of studies have been implemented in recent years to determine the factors that affect the prognosis of HF; however, few studies have assessed the prognosis of patients hospitalised for their first episode of HF. The aim of our study was to analyse the prognostic impact of renal function on patients hospitalised for a first episode of HF. Material and Methods We recruited 600 patients hospitalised for a first episode of HF in 3 tertiary Spanish hospitals. We analysed the mortality risk during the first year of follow-up according to renal function at the time of admission. Results The patients with the highest degree of kidney failure at admission were older (p Conclusions The presence of kidney failure at admission was a marker of poor prognosis in our cohort of patients hospitalised for a first episode of HF

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 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.

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.

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; P =0.005) and an appropriate grade of decongestion (CCSP 83 mmol/L 2 hours after FST had a 96% sensitivity to predict an NT-proBNP reduction ≥30% and 95% to predict a CCS 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.

Purpose Heart failure (HF) is a chronic, frequent and disabling condition but with a modifiable course and a large potential for improving. The aim of this study was to validate the two available clinical prediction rules for mortality at one year in patients with primo-hospitalization for decompensated HF: PREDICE and AHEAD. The secondary aim was to evaluate in our setting the changes in the clinical pattern of HF in the last decade in patients hospitalized for a first episode of the disease. Patients and methods A prospective multicenter cohort study, which included 180 patients hospitalized with "de novo" HF was conducted to validate the PREDICE score. Calibration and discrimination measurements were calculated for the PREDICE model and the PREDICE score (using the validation cohort of the PREDICE) and the AHEAD score (using both the development and the validation cohort of the PREDICE). Results For the PREDICE models, the area under the curve (AUC) was 0.68 (95% confidence interval [CI]: 0.57-0.79) and the calibration slope 0.65 (95% CI: 0.21-1.20). For the PREDICE score AUC was 0.59 (95% CI: 0.47-0.71) and slope 0.42 (95% CI: -0.20-1.17). For the AHEAD score the AUC was 0.68 (95% CI: 0.62-0.73) and slope 1.38 (95% CI: 0.62-0.73) when used the development cohort of PREDICE and the AUC was 0.58 (95% CI: 0.49-0.67), and slope 0.68 (95% CI: -0.06 to 1.47) when used its validation cohort. Conclusion The present study shows that the two risk scores available for patients with primo-hospitalization for decompensated HF (PREDICE and AHEAD) are not currently valid for predicting mortality at one-year. In our setting the clinical spectrum of hospitalized patients with new-onset HF has been modified over time. The study underscores the need to validate the prognostic models before clinical implementation.

Following a parathyroidectomy there is a bone mineral density (BMD) improvement in patients with primary hyperparathyroidism. However, data of bone microarchitecture are scarce. Trabecular bone score (TBS) estimates bone microarchitecture and could provide valuable information in those patients. The aim of this study is to assess TBS changes 2 years after successful surgery in a group of patients with primary hyperparathyroidism and correlate these results with changes in BMD and bone turnover markers. This is a prospective study including 32 patients. In all participants BMD and TBS were measured, before and 24 months after surgery. Biochemical data: serum calcium, PTH, 25-OH-vitamin D, beta-crosslaps, bone alkaline phosphatase, and osteocalcin. 25 female and 7 male patients, mean age 64.6±12.4 years, were included in the study. At baseline, BMD was low at: lumbar spine (T-score −2.19±1.31), total hip (−1.33±1.12), femoral neck (−1.75±0.84), and distal one-third radius (−2.74±1.68). Baseline TBS showed partially degraded microarchitecture (1.180±0.130). After parathyroidectomy lumbar spine BMD increased significantly (5.3±13.0%, p

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

Background: 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.Materials and Methods: 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).Results: 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).Conclusions: 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.

AIMS This systematic review aims to evaluate the effect of continuous glucose monitoring (CGM) on maternal and neonatal outcomes in gestational diabetes mellitus (GDM). METHODS Two authors conducted a systematic search using PubMed, Embase, CENTRAL, CINAHL, Scopus, Web of Science, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform. The inclusion criteria for the systematic review were randomized clinical trials that compared the effects of CGM and blood glucose monitoring (BGM) in women with GDM. A restricted maximum likelihood random-effects model was used for the meta-analysis. The measures of effect were risk ratios for categorical data and mean differences for continuous data. RESULTS Of the 457 studies reviewed, six randomized clinical trials met the inclusion criteria. A total of 482 patients were included in the meta-analysis. The use of CGM was associated with lower HbA1c levels at the end of pregnancy (mean difference: -0.22; 95%CI -0.42 to -0.03) compared to BGM. Women using CGM also had less gestational weight gain (mean difference: -1.17, 95%CI -2.15 to -0.19), and their children had lower birth weight (mean difference: -116.26, 95%CI -224.70 to -7.81). No differences were observed in the other outcomes evaluated. CONCLUSION Women with GDM using CGM may achieve lower average blood glucose levels, lower maternal weight gain and infant birth weight than women using BGM. Nevertheless, current evidence is limited by the low number of studies and the small sample sizes of these studies. Larger clinical trials are needed to better understand the effects of CGM in GDM. REGISTRATION PROSPERO registration ID CRD42021225651.

Objective Acromegaly is associated with increased vertebral fracture (VFs) risk not correlated to bone mineral density (BMD). Trabecular bone score (TBS), related to bone microarchitecture, provides information on bone strength. This cross-sectional study considered the usefulness of TBS and BMD to assess bone status in long-term controlled acromegalic patients. Design, patients, measurements 26 acromegaly patients (14 female and 12 males) were included in the study. A further 117 subjects were recruited as controls (58 females and 57 males). BMD was measured using dual-energy X-ray absorptiometry (DXA), TBS was obtained applying Medimaps software 2.0. Biochemical parameters were determined by standardized techniques. Results 73% of patients with acromegaly exhibited normal lumbar spine (LS) BMD. TBS was normal in 38% of acromegalic patients and partially degraded or degraded in 31% of patients, respectively. No differences were found in LS BMD between acromegalic patients and controls. TBS values were significantly lower in patients with acromegaly (1.27 ± 0.13 vs. 1.35 ± 0.17, p = .01). Postsurgical remission was associated with higher TBS values (1.35 ± 0.10 vs. 1.23 ± 0.13, p = .02) and pituitary radiotherapy treatment with lower TBS values (1.18 ± 0.12 vs. 1.31 ± 0.12, p = .004). On multivariate analysis, age, BMI and LS BMD were predictors of TBS changes in patients with acromegaly (p Conclusions Patients with long-term controlled acromegaly can exhibit deterioration of bone microstructure measured with TBS, despite BMD measurement not showing bone loss. Our study suggests that TBS is useful for monitoring the bone status changes in acromegalic patients.

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.

Background: There are no immunological data on SARS-CoV-2 heterologous vaccinations schedules in humans. We assessed the immunogenicity and reactogenicity of BNT162b2 (Comirnaty, BioNTech) administered as second dose in participants primed with ChAdOx1-S (Vaxzevria, Astra Zeneca). Methods: We did a phase 2, open-label, adaptive, randomised, controlled clinical trial on adults under 60 years old, vaccinated with a single dose of ChAdOx1-S between 8 and 12 weeks before screening, and no history of SARS-CoV-2 infection (EudraCT No. 2021-001978-37 and NCT04860739). Participants were randomly assigned (2:1) to receive BNT162b2 (0.3 mL, single intramuscular injection) or observation. The primary outcomes were 7-day reactogenicity and 14-day anti-spike IgG response, measured by immunoassays covering SARS-CoV-2 trimeric spike protein and receptor binding domain (RBD). Antibodies functionality and cellular immune response were assessed using a pseudovirus neutralization assay and IFN-gamma immunoassay, respectively. Findings: Between April 24 and April 30, 2021, 676 individuals were randomized (n=450 intervention group, n=226 control group) at 5 sites in Spain, and 663 (441 and 222, respectively) completed the study up to day 14 (mean age 44 [SD 9], 56·5% female). In the intervention group, geometric mean titres (GMT) of IgG-RBD increased from 71·46 BAU/mL (95% CI 59·84-85·33) at baseline to 7756·68 (7371·53; 8161·96) at day 14 (p < 0·0001). IgG against trimeric spike-protein increased from 98·4 [85.69–112.99] to 3684·87 [3429·87–3958·83]). 100% participants exhibited neutralizing antibodies 14 days after BNT162b2 administration, in comparison to 34.1% at enrolment. A 4-fold increase in cellular immune response was also observed. Reactions were predominantly mild (68·3%) or moderate (29·9%), and consisted more frequently on injection site pain (88·2%), induration (35·5%), headache (44·4%) and myalgia (43·3%). 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. Clinical Trial Registration Details: EudraCT No. 2021-001978-37 and NCT04860739. Funding Information: Funded by Instituto de Salud Carlos III (ISCIII). Declaration of Interests: CB is the Deputy General Manager of the ISCIII. JRA has received fees from Janssen, outside of the submitted work. AMB is principal investigator of clinical trials sponsored by GSK, Daiichi-Sankyo, Janssen and Farmalider, outside of the submitted work. The other authors declare no competing interests. Ethics Approval Statement: All the participants provided written informed consent before enrolment. The trial complies with the principles of the Declaration of Helsinki and Good Clinical Practice. This study was approved by the Spanish Agency of Medicines and Healthcare Products (AEMPS) and by the Ethics Committee at University Hospital La Paz.

[Abstract] Background. Available information about prognostic implications of potassium levels alteration in the setting of acute heart failure (AHF) is scarce. Objectives. We aim to describe the prevalence of dyskalemia (hypo or hyperkalemia), its dynamic changes during AHF-hospitalization, and its long-term clinical impact after hospitalization. Methods. We analyzed 1779 patients hospitalized with AHF who were included in the REDINSCOR II registry. Patients were classified in three groups, according to potassium levels both on admission and discharge: hypokalemia (potassium 5 mEq/L). Results. The prevalence of hypokalemia and hyperkalemia on admission was 8.2 and 4.6%, respectively, and 6.4 and 2.7% at discharge. Hyperkalemia on admission was associated with higher in-hospital mortality (OR = 2.32 [95% CI: 1.04–5.21] p = 0.045). Among patients with hypokalemia on admission, 79% had normalized potassium levels at discharge. In the case of patients with hyperkalemia on admission, 89% normalized kalemia before discharge. In multivariate Cox regression, dyskalemia was associated with higher 12-month mortality, (HR = 1.48 [95% CI, 1.12–1.96], p = 0.005). Among all patterns of dyskalemia persistent hypokalemia (HR = 3.17 [95% CI: 1.71–5.88]; p

Background The impact of late-onset cytomegalovirus (CMV) infection (LOCI) on cardiac allograft vasculopathy (CAV) has yet to be established. Methods A retrospective study was performed for patients who had undergone heart transplantation (HT) between January 1995 and October 2017 to analyze epidemiology of LOCI (any positive level of CMV pp65 antigenemia or DNAemia after 100 days, without previous CMV replication) and its association with CAV. Our main hypothesis was that LOCI causes less direct and indirect effects compared to early onset infection (EOCI). Results Late-onset cytomegalovirus infection developed in 57 of 410 patients (13.9%) in a median time of 4.7 months post-transplant. CAV at 10 years was diagnosed in 31.6% of patients with LOCI, 34.6% with EOCI, and in 19.3% of CMV-uninfected patients. In the multivariate analysis, EOCI was an independent variable for developing CAV (HR 1.8, 95% CI 1.13-2.82, P = .01). Patients with LOCI showed a trend toward a higher risk of CAV, but the difference was not statistically significant (HR 1.7, 95% CI 0.95-3.08, P = .07). In the complementary log-log model, LOCI and EOCI had a similar CAV-free survival, and a higher probability of developing CAV than CMV-uninfected patients (P = .02). Conclusions Cytomegalovirus infection after HT may result in the same long-term events regardless of its onset, with a higher risk of developing CAV at 10 years than patients without CMV.

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 PaO2/FiO2 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. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02748-2.

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; p-value for difference between subgroups

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.

OBJECTIVES Imported Chagas disease (CD) is an emerging health problem in Europe due to immigration from endemic countries. Although WHO currently recommends two different serological methods to establish diagnosis, new tools like the ARCHITECT Chagas assay have potential for use as a single diagnostic test. Our objective was to determine an optimal signal-to-cut-off (S/CO) value for the ARCHITECT Chagas assay to diagnose CD with a single test. METHODS A retrospective study conducted at the 12 de Octubre University Hospital (Madrid, Spain). All patients with requests for Chagas screening between January 2014 and August 2017 were consecutively included. All samples were routinely tested with the ARCHITECT assay. Negative samples (S/CO

The effect of above-normal body mass index (BMI) on health outcomes is controversial because it is difficult to distinguish from the effect due to BMI-associated cardiovascular risk factors. The objective was to analyze the impact on 10-year incidence of cardiovascular disease, cancer deaths and overall mortality of the interaction between cardiovascular risk factors and BMI. We conducted a pooled analysis of individual data from 12 Spanish population cohorts with 10-year follow-up. Participants had no previous history of cardiovascular diseases and were 35-79years old at basal examination. Body mass index was measured at baseline being the outcome measures ten-year cardiovascular disease, cancer and overall mortality. Multivariable analyses were adjusted for potential confounders, considering the significant interactions with cardiovascular risk factors. We included 54,446 individuals (46.5% with overweight and 27.8% with obesity). After considering the significant interactions, the 10-year risk of cardiovascular disease was significantly increased in women with overweight and obesity [Hazard Ratio=2.34 (95% confidence interval: 1.19-4.61) and 5.65 (1.54-20.73), respectively]. Overweight and obesity significantly increased the risk of cancer death in women [3.98 (1.53-10.37) and 11.61 (1.93-69.72)]. Finally, obese men had an increased risk of cancer death and overall mortality [1.62 (1.03-2.54) and 1.34 (1.01-1.76), respectively]. In conclusion, overweight and obesity significantly increased the risk of cancer death and of fatal and non-fatal cardiovascular disease in women; whereas obese men had a significantly higher risk of death for all causes and for cancer. Cardiovascular risk factors may act as effect modifiers in these associations.

We present a historic cohort study with 57 patients diagnosed with mycosis fungoides in early stages during the years 1999 to 2002. Our group performed a cDNA microarray on the diagnosis skin biopsies samples with the CNIO (oncologic investigation national center of Spain) Onco-Chip. This chip includes 6386 cancer-related clones. Since the samples were processed in two deferent years the initial set of 57 patients was divided in two groups of 29 and 28 patients due to the heterogeneity of the sample array results. The patients had a medium of 14 years of follow-up and were divided in two groups: progression (development of tumor, nodes, erythroderma, blood involvement or metastasis) and no progression. And we performed volcano pot analysis and GSEA to determine whether there are different genes expressions at diagnosis that determine prognosis. Several pathways were up and down regulated differently in patients progressing. We performed a GSEA analysis with the following results. Pathways related with progression: CXCR4 pathway (p=0.000) Normalized Enrichment Score (NES) 1.91 and FDR 0.027; genes: BCAR1, PXN, PIK3CA, PTK2, PIK3R1, PRKCA, HRAS, RAF1, CXCL12, PIK3C2G, GNB1. Other pathways with p

The aim of this study was to report the clinical outcome and toxicity of radiochemotherapy in locally advanced gastric cancer (LAGC) patients treated according to the Intergroup 116 trial protocol in our institution. We retrospectively reviewed 105 patients with LAGC treated with radical surgery and adjuvant radiochemotherapy. We analyzed overall survival (OS), disease-free survival (DFS), locoregional failure-free survival (LFS), prognostic factors and toxicity. The mean follow-up was 96.48 months. The majority of tumors were T3–T4 (75%) and 86.6% had nodal metastases. The OS, DFS and LFS rates to 3 years were 53.48%, 52.75% and 81.65%, respectively and to 5 years 40%, 46.73% and 76.77% respectively. The univariate analysis showed that N stage < N2, TN stage < IIIA, R0 resection and N‑ratio < 3 were statistically significant prognostic factors for OS and DFS, T stage < T4 for OS and N‑ratio < 3 for LFS. The group with D2 lymphadenectomy had worse LFS than the D1 group (65.2% vs 88.1%, respectively, p = 0.039) probably due to a significant difference in the proportion node positive patients in the D2 group (94% vs. 78%; p = 0.027). In the multivariate analysis, only R0 resection was statistically significant factor for improved OS (p = 0.018). Acute grade III–IV gastrointestinal and hematologic toxicity rates were 8.5% and 15.2%, respectively and 89.5% completed treatment as planned. Our results are consistent with those of the Intergroup-0116 trial for LAGC in terms of survival. This regimen is well tolerated and with acceptable toxicity. An R0 resection was an independent prognostic factor for improved OS.

Objective To determine the presence of human papillomavirus (HPV) in head and neck squamous cell carcinoma, specifically in the larynx without the bias of other sublocations, and to describe the different serotypes of HPV and their impact on overall and disease-free survival after 10-year follow-up. Study Design Retrospective case series with chart review of ear, nose, and throat oncologic database. Setting Academic tertiary care hospital. Subjects A total of 123 samples of larynx squamous cell carcinoma were included, only from the glottis and treated only with surgery between 1977 and 2005. Methods DNA extraction was carried out by polymerase chain reaction, and subsequent visualization was performed in low-density arrays. Results were compared with histologic, clinicopathologic, and survival parameters, with a 10-year follow-up. Results HPV DNA was detected in 22.76% (n = 28) of the samples. Eleven genotypes were detected, 2 of which had never been described in the larynx (HPV43 and HPV62). No increasing trend of HPV was observed over time. HPV presence did not correlate with better survival during the follow-up. Smoking was proven as an independent factor in relation to the presence of HPV. Conclusion HPV may represent a notable factor in the development of a subset of laryngeal squamous cell carcinoma without significant influence on overall and disease-free survival. More studies, including oncogene transcription proteins, would be necessary to draw more relevant conclusions about the relevance of HPV infection in the larynx.

BackgroundTumor 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.MethodsWe 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.ResultsBoth 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 =55), 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.ConclusionsBoth 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.

Aim: Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and/or gestational morbidity in patients with antiphospholipid autoantibodies (aPL). Over recent years, IgA anti-beta2-glycoprotein I (B2GPI) antibodies (IgA aB2GPI) have reached similar clinical relevance as IgG or IgM isotypes. We recently described the presence of immune complexes of IgA bounded to B2GPI (B2A-CIC) in the blood of patients with antecedents of APS symptomalology. However, B2A-CIC's clinical associations with thrombotic events (TEV) have not been described yet. Methods: A total of 145 individuals who were isolate positive for IgA aB2GPI were studied: 50 controls without any APS antecedent, 22 patients with recent TEV (Group-1), and 73 patients with antecedents of old TEV (Group-2). Results: Mean B2A-CIC levels and prevalence in Group-1 were 29.6 ± 4.1 AU and 81.8%, respectively, and were significantly higher than those of Group-2 and controls (p < 0.001). In a multivariable analysis, positivity of B2A-CIC was an independent variable for acute thrombosis with a 22.7 odd ratio (confidence interval 5.1 –101.6, 95%, p < 0.001). Levels of B2A-CIC dropped significantly two months after the TEV. B2A-CIC positive patients had lower platelet levels than B2A-CIC-negative patients (p < 0.001) and more prevalence of thrombocytopenia (p < 0.019). Group-1 had no significant differences in C3 and C4 levels compared with other groups. Conclusion: B2A-CIC is strongly associated with acute TEV. Patients who did not develop thrombosis and were B2A-CIC positive had lower platelet levels, which suggest a hypercoagulable state. This mechanism is unrelated to complement-fixing aPL. B2A-CIC could potentially select IgA aB2GPI-positive patients at risk of developing a thrombotic event.

High incidence and prognostic relevance of thromboembolic disease in patients with ALK-rearranged NSCLCs

// Alberto Carretero-Gonzalez 1 , David Lora 2 , Ismael Ghanem 3 , Jon Zugazagoitia 1 , Daniel Castellano 1 , Juan M. Sepulveda 1 , Jose A. Lopez-Martin 1 , Luis Paz-Ares 1 and Guillermo de Velasco 1 1 Medical Oncology Service, University Hospital 12 de Octubre, Madrid, Spain 2 Clinical Research Unit (imas12-CIBERESP), University Hospital 12 de Octubre, Madrid, Spain 3 Medical Oncology Service, University Hospital La Paz, Madrid, Spain Correspondence to: Guillermo de Velasco, email: gdvelasco.gdv@gmail.com Keywords: AntiPD1/PDL1; nivolumab; pembrolizumab; atezolizumab; response rate Received: September 11, 2017 Accepted: January 13, 2018 Published: January 20, 2018 ABSTRACT 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.

Background: lung transplantation (LTx) is a viable option for most patients with end-stage lung diseases. Esophageal motor disorders (EMD) are frequent in candidates for LTx, but there is very little data about changes in esophageal motility post-LTx. Aim: the aim of our study was to assess esophageal motor disorders by high resolution manometry (HRM) both pre-LTx and six months post-LTx in patients with and without organ rejection. Study: HRM (Manoscan(r)) was performed in 57 patients both pre-LTx and six months post-LTx. HRM plots were analyzed according to the Chicago classification 3.0. Results: EMD were found in 33.3% and in 49.1% of patients pre-LTx and post-LTx, respectively, and abnormal peristalsis was more frequently found post-LTx (p = 0.018). Hypercontractile esophagus was frequently found post-LTx (1.8% and 19.3% pre-LTx and post-LTx, respectively). Esophagogastric junction (EGJ) morphology changed significantly pre-LTx and post-LTx; type I (normal) was more frequent post-LTx (63-2% and 82.5% respectively, p = 0.007). EMD were more frequent post-LTx in both the non-rejection and rejection group, although particularly in the rejection group (43.2% and 69.2% respectively, p = 0.09). EMD such as distal spasm, hypercontractile esophagus and EGJ outflow obstruction were also observed more frequently post-LTx in the rejection group. Conclusion: significant changes in esophageal motility were observed pre-LTx and particularly post-LTx; hypercontractile esophagus was a frequent EMD found post-LTx. EMD were more frequent in the group of patients that experienced organ rejection compared to the non-rejection group. EMD leading to an impaired esophageal clearance should be considered as an additional factor that contributes to LTx failure.

BACKGROUND/AIMS The body position can influence esophageal motility data obtained with high-resolution manometry (HRM). To examine whether the body position influences HRM diagnoses in patients with esophageal dysphagia and gastroesophageal reflux disease (GERD). METHODS HRM (Manoscan) was performed in 99 patients in the sitting and supine positions; 49 had dysphagia and 50 had GERD as-sessed by 24-hour pH monitoring. HRM plots were analyzed according to the Chicago classification. RESULTS HRM results varied in the final diagnoses of the esophageal body (EB) in patients with dysphagia (P = 0.024), the result being more distal spasm and weak peristalsis while sitting. In patients with GERD, the HRM diagnoses of the lower esophageal sphinc-ter (LES), the esophagogastric junction (EGJ) morphology, and EB varied depending on the position; (P = 0.063, P = 0.017, P = 0.041 respectively). Hypotensive LES, EGJ type III (hiatal hernia), and weak peristalsis were more frequently identified in the sitting position. The reliability (kappa) of the position influencing HRM diagnoses was similar in dysphagia and GERD ("LES diagnosis": dysphagia 0.32 [0.14-0.49] and GERD 0.31 [0.10-0.52], P = 0.960; "EB diagnosis": dysphagia 0.49 [0.30-0.69] and GERD 0.39 [0.20-0.59], P = 0.480). The reliability in "EGJ morphology" studies was higher in dysphagia 0.81 (0.68-0.94) than in GERD 0.55 (0.37-0.73), P = 0.020. CONCLUSIONS HRM results varied according to the position in patients with dysphagia and GERD. Weak peristalsis was more frequently diagnosed while sitting in dysphagia and GERD. Hypotensive LES and EGJ type III (hiatal hernia) were also more frequently diagnosed in the sitting position in patients with GERD.

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.

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-s2 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

Background Concerns have arisen regarding the optimal antifungal regimen for Candida parapsilosis bloodstream infection (BSI) in view of its reduced susceptibility to echinocandins. Methods The Prospective Population Study on Candidemia in Spain (CANDIPOP) is a prospective multicenter, population-based surveillance program on Candida BSI conducted through a 12-month period in 29 Spanish hospitals. Clinical isolates were identified by DNA sequencing, and antifungal susceptibility testing was performed by the European Committee on Antimicrobial Susceptibility Testing methodology. Predictors for clinical failure (all-cause mortality between days 3 to 30, or persistent candidemia for ≥72 hours after initiation of therapy) in episodes of C. parapsilosis species complex BSI were assessed by logistic regression analysis. We further analyzed the impact of echinocandin-based regimen as the initial antifungal therapy (within the first 72 hours) by using a propensity score approach. Results Among 752 episodes of Candida BSI identified, 200 (26.6%) were due to C. parapsilosis species complex. We finally analyzed 194 episodes occurring in 190 patients. Clinical failure occurred in 58 of 177 (32.8%) of evaluable episodes. Orotracheal intubation (adjusted odds ratio [AOR], 2.81; P = .018) and septic shock (AOR, 2.91; P = .081) emerged as risk factors for clinical failure, whereas early central venous catheter removal was protective (AOR, 0.43; P = .040). Neither univariate nor multivariate analysis revealed that the initial use of an echinocandin-based regimen had any impact on the risk of clinical failure. Incorporation of the propensity score into the model did not change this finding. Conclusions The initial use of an echinocandin-based regimen does not seem to negatively influence outcome in C. parapsilosis BSI.

Background: High-resolution manometry (HRM) is a breakthrough in the morphological study of the gastroesophageal junction (GEJ) and its degrees of disruption. Objectives: a) Assessment of risk factors involved in the disruption of the GEJ in patients with gastroesophageal reflux (GER) symptoms; b) the relationship between the type of GEJ and GER demonstrated by 24 hours pH-monitoring; and c) identification of the alterations in the manometric parameters related to the morphology of the GEJ. Methods: One hundred and fifteen patients with symptoms of GER studied with HRM and classified by the type of GEJ (type I: Normal; type II: Sliding; type III: Hiatal hernia). Twenty four hour pH-monitoring without proton pump inhibitors was performed in all of them. Epidemiological aspects, manometric parameters (Chicago 2012 classification) and the pH-monitoring results were evaluated. Results: Age (OR 1.033 [1.006-1.060]; p = 0.16), BMI (OR 1.097 [1.022-1.176]; p = 0. 01) and abdominal perimeter (OR 1.034 [1.005-1.063]; p = 0.0215) were independent risk factors for the GEJ type III (area under the curve 0.70). Disruption of the GEJ was associated with a lower resting pressure (p = 0.006), greater length (p < 0.001) and greater esophageal shortening (p < 0.001). Abnormal acidic reflux was found in the total period (p = 0.015), standing (p = 0.022) and supine (p = 0.001) in patients with GEJ type II and III with respect to type I. Conclusions: Increased age, overweight and central obesity pose a higher risk of GEJ type III (hiatal hernia). The greater disruption of the GEJ is associated with lower resting pressure, esophageal shortening, and higher acid exposure in the pH-monitoring.

IgA anti-beta-2-glycoprotein I (aB2GPI) antibodies have been related to vascular pathology in the general population and mainly in hemodialyzed patients (prevalence 33%) in whom an elevated incidence of thrombosis and mortality is found. In this paper we have studied the presence of IgA aB2GPI antibodies at pretransplant and their evolution after transplantation with a cross-sectional-based follow-up study of a cohort of 288 endstage renal disease (ESRD) patients treated with kidney transplantation. Pretransplant IgA aB2GPI levels were elevated31.7±4.2 U/mL without differences in age or type of dialysis. Patients with different etiologies of ESRD showed higher levels of IgA aB2GPI than blood donors, except the groups of non-IgA glomerular disease and systemic erythematosus lupus, whose nonsignificant differences were observed. IgA aB2GPI antibodies dropped immediately after transplantation (10.7±1.0 U/mL,P<0.0001), coinciding with a high degree of immunosuppression, and remained significantly lower than that observed in pretransplant status. Prevalence of patients with elevated antibodies was also less in transplanted patients (8.9% versus 30.4%,P<0.0001). Among, positivity for IgA aB2GPI was higher than in patients who had received their first transplant that those were retransplanted. This finding could have important clinical implications and can suggest new therapeutic strategies in patients with IgA aB2GPI antibodies.

6617 Background: Retrospective database studies have suggested that statins and vitamin D have a positive impact on prostate cancer survival and specifically in mCRPC patients (pt). Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with abiraterone (AA) and/or Prednisone (P) on two randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins and vitamin D in overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Independent predictors were investigated using Cox regression analysis. This study, carried out under YODA Project #2016-1136, used data obtained from the Yale University Open Data Access Project. Results: These two studies included 2280 patients (1340 treated with AA/P and 640 with P). Use of Statin + vitamin D was associated with a 38% reduction in mortality in the postdocetaxel setting and 32% in the predocetaxel setting in patients treated with abiraterone (Table 1 and 2). No significant reduction in the rate of skeletal-related events was seen in patients treated with vitamin D or statins. Conclusions: To our knowledge this is the first report suggesting the impact of vitamin D+statin in mCPRC treated with abiraterone. The potential benefits of vitamin D do not seem to be secondary to concomitant statin use in this population. Further studies are needed to confirm these results. [Table: see text][Table: see text]

Objective To externally validate the prognostic models for predicting the time-dependent outcome in patients with locally advanced cervical cancer (LACC) who were treated with concurrent chemoradiotherapy in an independent cohort. Methods A historical cohort of 297 women with LACC who were treated with radical concurrent chemoradiotherapy from 1999 to 2014 at the 12 de Octubre University Hospital (H12O), Madrid, Spain. The external validity of prognostic models was quantified regarding discrimination, calibration, measures of overall performance, and decision curve analyses. Results The review identified 8 studies containing 13 prognostic models. Different (International Federation of Gynecology and Obstetrics [FIGO] stages, parametrium involvement, hydronephrosis, location of positive nodes, and race) but related cohorts with validation cohort (5-year overall survival [OS]=70%; 5-year disease-free survival [DFS]=64%; average age of 50; and over 79% squamous cell) were evaluated. The following models exhibited good external validity in terms of discrimination and calibration but limited clinical utility: the OS model at 3 year from Kidd et al.'s study (area under the receiver operating characteristic curve [AUROC]=0.69; threshold of clinical utility [TCU] between 36% and 50%), the models of DFS at 1 year from Kidd et al.'s study (AUROC=0.64; TCU between 24% and 32%) and 2 years from Rose et al.'s study (AUROC=0.70; TCU between 19% and 58%) and the distant recurrence model at 5 years from Kang et al.'s study (AUROC=0.67; TCU between 12% and 36%). Conclusion The external validation revealed the statistical and clinical usefulness of 4 prognostic models published in the literature.

Urinary tract infections (UTI) are common in emergency departments (ED), and at least 15% of them are bacteremic. However, there are few data on how to predict which patients are at high risk of developing bacteremic UTI (b-UTI). We performed a retrospective observational cohort study including patients diagnosed with UTI who were admitted to the ED of a tertiary-care hospital in Spain. We included only those patients in whom blood cultures were performed. A nomogram for b-UTI was developed as visualizations of a logistic regression model. Two hundred and thirteen patients with UTI were finally included, 108 of them developed b-UTI (50.7%). The mean age was 60.5 ± 21.4 years. A previous urologic disease was present in 45.5%, 12 out of 213 patients (5.6%) had a urologic tumor (10.2% in b-UTI group vs. 1% in non b-UTI, p = 0.003), and 4.2% were kidney transplant recipients. In a multivariate analysis, variables associated with b-UTI were: solid organ malignancy (OR 3.19; CI 95% 1.01–10.03, p = 0.04), elevated neutrophil count (more than 80% of neutrophils) (OR 5.84; CI 95% 2.13–15.99, p = 0.0006), elevated C reactive protein (OR 1.046; CI 95% 1.006–1.087, p = 0.022), and pyuria (presence of ≥50 white cells per high-power field of urine) (OR 4.43; CI 95% 1.94–10.11, p = 0.0004). The presence of solid tumor, elevated neutrophil count, elevated C reactive protein, and pyuria are independent risk factors that could be useful in anticipating the development of bacteremia in patients with UTI seen in the ED.

Background The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable. Objective To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort. Methods Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer's Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries. Results 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%-31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p > 0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative). Conclusions Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials.

OBJECTIVES To determine the impact of the expression of epidermal growth factor receptor (EGFR) on disease-free survival (DFS) and on pelvic relapse in patients with advanced cancer of the cervix receiving concurrent chemoradiotherapy. METHODS In 112 consecutive patients with advanced cancer of the cervix (11 stage IB2-IIA, 25 IIB, 63 IIIB, 13 IVA) treated with chemoradiotherapy between December 1994 and September 2004, the expression of EGFR using histoimmunochemistry was measured and used in univariate and multivariate analysis, along with variables such as age, International Federation of Gynecology and Obstetrics Staging System for Epithelial Ovarian Cancer (FIGO) stage, histology, Eastern Cooperative Oncology Group (ECOG), tumor size, and ganglia involvement diagnosed with computerized axial tomography, treatment with cisplatin to evaluate its impact on DFS and pelvic relapse. RESULTS Of the 112 biopsies, 32 (28.6%) were negative or slightly positive (EGFR±) and 80 (71.4%) were moderate or intensely positive (EGFR++/+++). The overexpression of EGFR (++/+++) was significantly associated with an epidermoid histology (P < 0.0001), with a higher rate of pelvis relapse and a decreased DFS (hazard ratio [HR]: 2.31 [1.08-4.96]; P = 0.03). Overall, treatment with cisplatin increased DFS (HR: 0.51 [0.26-0.97]; P = 0.04). CONCLUSIONS Patients with tumors of the cervix and overexpression of the EGFR++/+++ show a higher probability of pelvic relapses and a decreased disease-free survival. The poor prognosis of these tumors may be a consequence of an increase in radio-resistance.

Summary The aim of this study was to investigate the effect of risedronate (RIS) on bone loss and bone turnover markers after liver transplantation (LT). Patients with osteopenia or osteoporosis within the first month after LT were randomized to receive RIS 35 mg/week plus calcium 1000 mg/day and vitamin D3 800 IU/day (n = 45) or calcium and vitamin D3 at same dosages (n = 44). Primary endpoint was change in bone mineral density (BMD) 6 and 12 months after LT. Secondary endpoints included changes in serum β-CrossLaps (β-CTX) and procollagen type 1 amino-terminal peptide (P1NP) and fracture rate. Spine X-rays were obtained at baseline and after 12 months. There was no significant difference in BMD changes between both treatment groups at any sites; either at 6 or 12 months. Spine BMD increased in both groups at 12 months vs. baseline (P = 0.001). RIS patients had a significant increase in intertrochanteric BMD at 12 months (P

230 Background: Retrospective database studies have suggested that statins may have a positive impact on some mCRPC pts treated with prednisone (P)/abiraterone (AA) Methods: We conducted a post-hoc analysis of individual pt data of mCRPC pts treated with AA and/or P on randomized phase III clinical trials COU -AA-301 and COU-AA-302 to analyze the impact of statins on overall survival (OS). Statistical analyses were performed using the Kaplan Meier method and Cox regression adjusted for known prognostic factors. This study, was carried out under YODA Project #2016-1136 Results: 458 (41%) prechemotherapy pts and 348 (29%) postchemotherapy pts were statins users (Table). Improved OS was observed for mCPRC pts who were statins users in the postdocetaxel setting [HR: 0.82 (95% CI: 0.71 to 0.94); p = 0.006], and there was a trend towards a prolonged OS in the predocetaxel setting [HR: 0.89 (95% CI: 0.77 to 1.03); p = 0.13] adjusted by interventional treatment (AA and/or P). In the predocetaxel setting there were no significant differences in OS between the groups AA/P/non-statin users and placebo/P/statin users (p=0.3). In the multivariate analysis, patients randomized to AA/P who were statins users and presenting ECOG

Objectives: To determine the impact of c-erb-B2 overexpression on disease-free survival (DFS) and local relapse in patients with advanced cervical cancer (CC) receiving concurrent chemoradiotherapy treatment. Methods: A total of 136 patients with advanced CC (FIGO stage: IB2-IIA [12]; IIB [34]; IIIB [71]; IVA [19]; including both epidermoid [86] and adenocarcinoma [14]) were analyzed to determine c-erb-B2 levels by immunohistochemistry (c-erb-B2 antibody; Dako, Glostrup, Denmark). Only c-erb-B2+++ biopsies were considered positive. All patients received pelvic radiotherapy, brachytherapy, and concurrent chemotherapy with 2 different regimens: 48 patients were treated with tegafur (800 mg/d orally) and 88 with tegafur (same doses) plus 5 cycles of weekly cisplatin 40 mg/m2/wk intravenously. Results: A total of 32 (23.5%) biopsies were considered c-erb-B2-positive. Three-year and 5-year DFS were 61% and 58% for c-erb-B2-negative patients and 36% and 36% for c-erB2-positive patients, respectively (P = 0.02). Patients were stratified in 4 groups according to their c-erb-B2 status and whether they received cisplatin. The group of patients with c-erb-B2 overexpression that did not receive platinum treatment had a higher rate of pelvic relapse (P Conclusions: c-erb-B2 overexpression may imply a poor prognosis for patients with advanced CC. Treatment with cisplatin-based radiochemotherapy improved outcome in these patients.

The cannabinoid receptor-1 (CNR-1) and endogenous agonists of this receptor are present in the central and peripheral nervous systems including the gastrointestinal nervous system. The surgically rejected specimens of human colorectal cancers and paired normal tissues were studied to detect mutations in the CNR1 gene by sequencing method. The results were compared to clinicopathological parameters and correlated with overall survival time. Sixty-three colorectal cancer patients, who underwent surgical excision of colorectal carcinoma, were included in this study. The coding region of the CNR1 gene was studied: a nucleotide change (G→A) at position 1359 was identified by direct sequencing of PCR. Thirty-eight patients had the G/G genotype (wild type) in tumor areas and 25 patients had G/A heterozygous or A/A homozygous genotype. Univariate analysis revealed 2 independent variables associated with CNR1 gene mutation. The results show that the patients with Dukes stage C and D had a 2.9 times (p = 0.04) and patients that were lymph node positive had 2.8 times (p = 0.05) greater probability of nucleotide change in CNR1 gene. Genotype G/A plus A/A had a shorter overall survival time than G/G wild-type patients (p < 0.05). Indeed nontumor paired colorectal tissues showed nucleotide change. A large number of patients with mutation in the CNR1 gene were observed. These preliminary findings highlight the importance of further studies in the use of cannabinoid analogs as receptor ligands to analyze potential therapeutic effects.

e21683 Background: Reported rates of FN with docetaxel (DTX) in PC patients are variable. This creates uncertainty regard the use of granulocyte colony-stimulating factor primary prophylaxis (G-CSF) in this setting. We conducted a meta-analysis of randomized clinical trials to determine the relative risk (RR) of FN in patients receiving DTX. Methods: To perform this analysis we systematically searched in PUBMED and MEDLINE database the following terms: “DTX”, “randomized clinical trial” and “prostate cancer” only for articles published between January 1996 and August 2016. Phase II-III clinical studies comparing DTX to non-DTX control arms (best supportive care [BSC] including non-cytotoxic therapy or mitoxantrone) for PC were included. The meta-analyses were performed by computing RRs with 95% confidence intervals (CI) using fixed-effects model with the Mantel-Haenszel method. Results: Seven studies (N = 5088 patients) were included. The global incidence of FN in patients treated with DTX was 10.7%. The RR of FN was higher in patients receiving DTX compared to patients did not receive DTX (RR 16.8 [95% CI 10.7; 26.4] p < 0.0001). 6.6% of patients with metastatic castration resistant prostate cancer (CRPC) treated with DTX developed FN, the RR of FN with DTX compared to mitoxantrone was 28.6 (95% CI 5.6; 145.1). 12.4% of patients with hormone-sensitive prostate cancer (HSPC) treated with DTX developed FN, the RR of FN was 15.3 (95% CI 9.6; 24.6) compared to BSC. There was no statistically significant differences in the rate of FN according to the hormone sensitivity (HSPC vs CRPC) (p = 0.7). In most studies the use of G-CSF was at the discretion of the investigator. Conclusions: This meta-analysis shows that DTX is associated with a significant increase in the relative risk of FN in patients with PC. The effectiveness of primary prophylactic G-CSF in this setting has not been fully established. The incidence reported here does not meet the threshold recommended by ESMO and ASCO guidelines for the use of prophylactic G-CSF. Special attention should be given to high risk groups for FN, including elderly patients and those with bone marrow involvement or previous radiotherapy/chemotherapy.

AIM To analyse the impact of octogenarian donors in liver transplantation. METHODS We present a retrospective single-center study, performed between November 1996 and March 2015, that comprises a sample of 153 liver transplants. Recipients were divided into two groups according to liver donor age: recipients of donors ≤ 65 years (group A; n = 102), and recipients of donors ≥ 80 years (group B; n = 51). A comparative analysis between the groups was performed. Quantitative variables were expressed as mean values and SD, and qualitative variables as percentages. Differences in properties between qualitative variables were assessed by χ2 test. Comparison of quantitative variables was made by t-test. Graft and patient survivals were estimated using the Kaplan-Meier method. RESULTS One, 3 and 5-year overall patient survival was 87.3%, 84% and 75.2%, respectively, in recipients of younger grafts vs 88.2%, 84.1% and 66.4%, respectively, in recipients of octogenarian grafts (P = 0.748). One, 3 and 5-year overall graft survival was 84.3%, 83.1% and 74.2%, respectively, in recipients of younger grafts vs 84.3%, 79.4% and 64.2%, respectively, in recipients of octogenarian grafts (P = 0.524). After excluding the patients with hepatitis C virus cirrhosis (16 in group A and 10 in group B), the 1, 3 and 5-year patient (P = 0.657) and graft (P = 0.419) survivals were practically the same in both groups. Multivariate Cox regression analysis demonstrated that overall patient survival was adversely affected by cerebrovascular donor death, hepatocarcinoma, and recipient preoperative bilirubin, and overall graft survival was adversely influenced by cerebrovascular donor death, and recipient preoperative bilirubin. CONCLUSION The standard criteria for utilization of octogenarian liver grafts are: normal gross appearance and consistency, normal or almost normal liver tests, hemodynamic stability with use of < 10 μg/kg per minute of vasopressors before procurement, intensive care unit stay < 3 d, CIT < 9 h, absence of atherosclerosis in the hepatic and gastroduodenal arteries, and no relevant histological alterations in the pre-transplant biopsy, such as fibrosis, hepatitis, cholestasis or macrosteatosis > 30%.

Background Pretransplantation anti-major histocompatibility complex class I chain-related molecule A (MICA) sensitization is an uncommon event and its role on kidney graft evolution is not completely defined. Methods A retrospective study of patients transplanted between 2005 and 2011 in our center (n=727) was performed. Recipients were classified in four groups, according either to multiplexed flow cytometry-recorded anti-human leukocyte antigen (HLA) and anti-MICA antibodies or to percent panel-reactive antibody (PRA; by complement-dependent cytotoxicity) and anti-MICA antibodies. Results In the total cohort, 52 (7.15%) patients had preformed anti-MICA antibodies, and these were not related with anti-HLA, previous transplantations, or recipient female sex (potential pregnancies). Kaplan-Meier curves showed global allograft survival differences (P=0.042) mostly due to pronounced decrease in PRA+MICA+ group early after transplantation. Biopsy-proven allograft rejection rate increased after month 12 in PRA+MICA- group and was higher early after transplantation in PRA+MICA+ group (P=0.033). In paired comparisons, rejection incidence was superior in PRA+MICA- versus PRA-MICA- patients (17% vs. 7%; P=0.007) at 24 months, confirming the widely reported deleterious effect of PRA+ status, but at 3 months rejection was higher in PRA+MICA+ versus PRA-MICA- patients (14% vs. 2%; P=0.009). Among patients categorized according anti-HLA and anti-MICA antibodies, the most striking difference in rejection was observed at 3 months (8% in HLA-MICA+ vs. 2% in HLA-MICA- patients; P=0.032). In the multivariate analysis, HLA-MICA+ status at 3 months independently conferred the highest risk for rejection (odds ratio, 5.07; P=0.049). Conclusions Pretransplantation sensitization against MICA and HLA are independent events. Preformed anti-MICA antibodies independently increase risk for kidney rejection and enhance the deleterious effect of PRA+ status early after transplantation.