Three double-dose reinforced hepatitis B revaccination scheme for patients with cirrhosis unresponsive to the standard regimen: an open-label randomised clinical trial.

OBJECTIVE: We aimed to compare the response rates between two different hepatitis B virus vaccination schedules for cirrhotic subjects who were non-responders to the first three 40 µg doses (month 0-1-2), and identify factors associated with the final response. DESIGN: A total of 120 cirrhotic patients (72.5% decompensated) were randomised at a 1:1 ratio to receive a single 40 µg booster vaccination at month 6 (classical arm) versus an additional round of three new 40 µg doses administered at monthly intervals (experimental arm). The main outcome was the rate of postvaccinal anti-hepatitis B surface antibodies levels ≥10 mIU/mL. RESULTS: Efficacy by ITT analysis was higher in the experimental arm (46.7%) than in the classical one (25%); OR 2.63, p=0.013. The experimental arm increased response rates compared with the classical one from 31% to 68% (OR 4.72; p=0.007), from 24.4% to 50% (OR 3.09; p=0.012) and from 24.4% to 53.8% (OR 3.62; p=0.007), in Child A, Model for End-Stage Liver Disease (MELD) <15 and MELD-Na<15 patients, respectively. Patients with more advanced liver disease did not benefit from the reinforced scheme. Both regimens showed similar safety profiles. Multivariable analysis showed that the experimental treatment was independently response associated when adjusted across three logistic regression models indicating equivalent cirrhosis severity. CONCLUSION: For cirrhotic patients, the revaccination of non-responders to the first three dose cycle, with three additional 40 µg doses, achieved significantly better response rates to those obtained with an isolated 40 µg booster dose. TRIAL REGISTRATION NUMBER: NCT01884415.

Decay kinetics of HIV-1-RNA in seminal plasma with dolutegravir/lamivudine versus dolutegravir plus emtricitabine/tenofovir alafenamide in treatment-naive people living with HIV.

BACKGROUND: This was a substudy of a Phase IV, randomized clinical trial (ClinicalTrials.gov identifier: NCT04295460) aiming to compare the activity of dolutegravir/lamivudine versus dolutegravir plus tenofovir alafenamide/emtricitabine (DTG + TAF/FTC) in the male genital tract. METHODS: Participants were asymptomatic adults without sexually transmitted diseases, treatment-naive people living with HIV (PLWH), with CD4+ T cell counts >200 cells/mm3 and plasma HIV-1-RNA levels >5000 and <500 000 copies/mL, randomized (1:1) to DTG + TAF/FTC or dolutegravir/lamivudine. Blood plasma (BP) and seminal plasma (SP) were collected at baseline and Weeks 4, 8, 12 and 24. HIV-1-RNA was measured in BP and SP using the Cobas 6800 system (Roche Diagnostics) with a lower detection limit of 20 copies/mL. The primary efficacy endpoint was the proportion of subjects with undetectable SP HIV-1-RNA at Week 12 by intention-to-treat analysis. RESULTS: Fifteen participants in the DTG + TAF/FTC and 16 in the dolutegravir/lamivudine arms were analysed, with basal SP viral load of 4.81 (4.30-5.43) and 4.76 (4.09-5.23), P = 0.469, respectively. At Week 12, only one participant in each treatment arm had a detectable SP HIV-1-RNA (DTG + TAF/FTC, 141 copies/mL; dolutegravir/lamivudine, 61 copies/mL). Based on the estimated means, there was no significant difference in the decay of HIV-1-RNA in both BP and SP over time between the two arms of treatment (F = 0.452, P = 0.662, and F = 1.147, P = 0.185, respectively). CONCLUSIONS: After 12 weeks of treatment, there were no differences in the percentage of undetectable SP HIV-1-RNA in naive PLWH who started dolutegravir/lamivudine compared with DTG + TAF/FTC.

A data mining based clinical decision support system for survival in lung cancer.

BACKGROUND: A clinical decision support system (CDSS ) has been designed to predict the outcome (overall survival) by extracting and analyzing information from routine clinical activity as a complement to clinical guidelines in lung cancer patients. MATERIALS AND METHODS: Prospective multicenter data from 543 consecutive (2013-2017) lung cancer patients with 1167 variables were used for development of the CDSS. Data Mining analyses were based on the XGBoost and Generalized Linear Models algorithms. The predictions from guidelines and the CDSS proposed were compared. RESULTS: Overall, the highest (> 0.90) areas under the receiver-operating characteristics curve AUCs for predicting survival were obtained for small cell lung cancer patients. The AUCs for predicting survival using basic items included in the guidelines were mostly below 0.70 while those obtained using the CDSS were mostly above 0.70. The vast majority of comparisons between the guideline and CDSS AUCs were statistically significant (p < 0.05). For instance, using the guidelines, the AUC for predicting survival was 0.60 while the predictive power of the CDSS enhanced the AUC up to 0.84 (p = 0.0009). In terms of histology, there was only a statistically significant difference when comparing the AUCs of small cell lung cancer patients (0.96) and all lung cancer patients with longer (≥ 18 months) follow up (0.80; p < 0.001). CONCLUSIONS: The CDSS successfully showed potential for enhancing prediction of survival. The CDSS could assist physicians in formulating evidence-based management advice in patients with lung cancer, guiding an individualized discussion according to prognosis.

Late toxicity for prostate cancer patients treated with hypofractionated helical tomotherapy.

AIM: The purpose of this study is to evaluate the long term tolerability of hypofractionated helical tomotherapy (HT) in localized prostate cancer patients. BACKGROUND: Previous hypofractionated schedules with conventional RT were associated with excessive toxicity, likely due to inadequate sophistication of treatment delivery. There are few data about late toxicity after HT. MATERIALS AND METHODS: We evaluated 38 patients with primary adenocarcinoma of the prostate. There were 9 (24%), 15 (39%), and 14 (37%) patients with high, intermediate, and low risk, respectively. Patients were treated with hypofractionated HT from May 2008 to February 2011. Hypofractionation regimens included: 68.04 Gy at 2.52 Gy/fraction (N = 25; 66%), 70 Gy at 2.5 Gy/fraction (N = 4; 11%) and 70.2 Gy at 2.6 Gy/fraction (N = 9; 23%). Late genitourinary (GU) and gastrointestinal (GI) toxicity was scored using the Radiation Therapy Oncology Group scoring system. RESULTS: Median age at diagnosis was 70 years (range 49-80) and median follow-up, 5.8 years. Late grade 1, 2 and 3 GI toxicity were 13%, 24%, and 2.6%, respectively. Late grade 1, 2, 3 GU toxicity were 29%, 21%, and 8%, respectively. Sexual toxicity was evaluated in 19 patients to be grade 1, 2 in 11% and grade 3 in 16%. Multivariate analysis showed that patients with higher values of rectum V50 associated with late GI toxicity (P = 0.025). Patients with PSA ≤8 (P = 0.048) or comorbidities (P = 0.013) at diagnosis were associated with higher late GU toxicity. Additionally, PSA ≤8 also associated with moderate (grade ≥2) late GU toxicity in the multivariate analysis (P = 0.028). CONCLUSIONS: Hypofractionated HT can be delivered safely with limited rates of moderate and severe late toxicity. The proportion of the rectum that receives a moderate and high dose, having comorbidities, and PSA at diagnosis seem to associate with long term toxicity.

D-dimer and high-sensitivity C-reactive protein levels to predict venous thromboembolism recurrence after discontinuation of anticoagulation for cancer-associated thrombosis.

BACKGROUND: Optimal duration of anticoagulation for cancer-associated thrombosis (CAT) remains unclear. This study assessed D-dimer (DD) and high-sensitivity C-reactive protein (hs-CRP) levels after the withdrawal of anticoagulation treatment to predict the risk of venous thromboembolism (VTE) recurrence among patients with CAT. METHODS: Prospective, multicentre study to evaluate CAT with ≥3 months of anticoagulation that was subsequently discontinued. Blood samples were taken when patients stopped the anticoagulation and 21 days later to determine the DD and hs-CRP levels. All patients were followed up for 6 months to detect VTE recurrence. RESULTS: Between 2013 and 2015, 325 patients were evaluated and 114 patients were ultimately enrolled in the study. The mean age was 62 ± 14 years and nearly 40% had metastasis. Ten patients developed VTE recurrence within 6 months (8.8%, 95% confidence interval [CI]: 4.3-15.5%). The DD and hs-CRP levels after 21 days were associated with VTE recurrence. The subdistribution hazard ratios were 9.82 for hs-CRP (95% CI: 19-52) and 5.81 for DD (95% CI: 1.1-31.7). CONCLUSIONS: This study identified that hs-CRP and DD were potential biomarkers of VTE recurrence after discontinuation of anticoagulation in CAT. A risk-adapted strategy could identify low-risk patients who may benefit from discontinuation of anticoagulation.

Validity and Reliability of the Portuguese Version of the Connor-Davidson Resilience Scale of 10 Elements for Young University Students.

BACKGROUND: Resilience is an important aspect of mental health in young people, which has become more relevant after the COVID-19 pandemic. It is therefore of paramount importance to have valid and reliable instruments that measure the globality of this aspect. One of the instruments that has been shown to have good psychometric properties and which has been widely adapted in several languages is the Connor-Davidson resilience scale, composed of 10 elements (10-item CD-RISC). AIM: The aim of this study was to evaluate the validity and reliability of the Portuguese version of the 10-item CD-RISC among young university students. METHODS: a cross-sectional observational study of psychometric validation was conducted with a sample of 206 university students. RESULTS: Good and adequate fit indices were obtained for the confirmatory factor analysis (CFA): Standardized Root-Mean-Square Residual [SRMR] = 0. 056; comparative fit index [CFI] = 0.958; and the Tucker-Lewis index [TLI] = 0.946. It also showed an average degree of convergent validity with the Depression, Anxiety and Stress Scale (DASS-21) and the General Health Scale (SF-36), and its internal consistency was good (Cronbach's alpha = 0.842) with a range of factor loadings between 0.42 and 0.77. CONCLUSIONS: the results show that the 10-item CD-RISC is a valid, reliable scale to measure resilience among young Portuguese university students.

Cross-Cultural Adaptation and Validation of the Portuguese Version of the Multidimensional Scale of Dating Violence 2.0 in Young University Students.

BACKGROUND: Dating violence has become a problem of social relevance with short- and long-term health consequences. Nurses are in a privileged position to detect and address this problem in health facilities and as school nurses in schools, providing health education and detecting this violence correctly. AIM: The aim of this study was to evaluate the cross-cultural validation of the Portuguese version of the Multidimensional Scale of Dating Violence-Short (MSDV 2.0). METHODS: A validation investigation was carried out in two phases: (1) cross-cultural adaptation of the items and content validation of the Portuguese version of MSDV 2.0 and (2) psychometric validation. RESULTS: Phase (1): The items of the original version include a cross-cultural translation from Spanish to Portuguese and analysed by a group of experts in gender violence and by the authors of the original scale, then a back translation was made and again reviewed by the experts. Young university students also participated for face validity, and a pilot test was carried out. Phase (2): Confirmatory factor analysis was performed using the robust maximum-likelihood estimation method, which confirmed the five-dimensional structure, obtaining good fit rates (chi-square significance (χ2) = 187.860 (p < 0.0001); root mean square error of approximation (RMSEA) = 0.049; comparative fit index (CFI) = 0.937; Tucker-Lewis index (TLI) = 0.923). Reliability analysis indicated adequate internal consistency (Cronbach's alpha (α) = 0.88 to 0.70). Finally, scores of the Portuguese versions MSDV 2.0 were correlated, as expected, positively with the Depression, Anxiety, and Stress Scale (DASS-21) (r = 0.36 to 0.16) and negatively with the Medical Outcomes Study Questionnaire Short Form 36, Health Survey (SF-36) (r = -0.30 to -0.14). CONCLUSIONS: To date, it is the only instrument that measures dating violence in a multidimensional way validated in the Portuguese university context.

Association of human beta-defensin-2 serum levels and sepsis in preterm neonates*.

OBJECTIVES: To determine human beta-defensin-2 levels in term and preterm neonates at birth and to evaluate its impact on sepsis. DESIGN: Observational study. SETTING: Single tertiary care hospital. PATIENTS: Term neonates and preterm neonates were recruited and divided in groups according to important clinical events. INTERVENTIONS: Cord blood samples were drawn from all newborns immediately after birth. Human beta-defensin-2 levels were determined using enzyme-linked immunosorbent assay technology. All neonates were followed clinically during the first 30 days of life. MEASUREMENTS AND MAIN RESULTS: Forty-two term and 31 preterm neonates were enrolled. Human beta-defensin-2 levels in term neonates were higher compared with preterm infants (median, 1,882 vs 918 pg/mL; p = 0.003) and correlated with gestational age and birth weight. Of 31 preterm neonates, seven suffered from late-onset sepsis, and this was associated with lower human beta-defensin-2 levels (median, 513 vs 1,411 pg/mL; p = 0.006). CONCLUSION: Preterm neonates show lower human beta-defensin-2 levels in cord blood compared with term neonates. Low human beta-defensin-2 levels in preterm neonates might be associated with an increased risk of late-onset sepsis.

[Job satisfaction of nurses in the clinical management units]. / Satisfacción laboral de los profesionales de enfermería en las unidades de gestión clínica.

Clinical Management Unit (CMU) is currently set in the Andalusian health institutions as the model reference management. This management model aims to make all healthcare professionals a powerful idea: the best performance of health resources is performed to drive clinical practice using the least number of diagnostic and therapeutic resources. The CMU not only aims at saving money, in the Clinical Management Agreement [1] are measured all the dimensions that make up the UGC: research, training, clinical process, the portfolio of services, objectives, financial management and indicators to control and security. The CMU is to transfer more responsibilities to Health Care Professionals, involving them in the management of the Unit. The CMU sets new approaches that directly affect health professionals and presents advantages and disadvantages for the Doctors and the Nurses, involved in achieving excellence in care work. Nurse Practitioners shows expectant before the changes are generated in health institutions and appears a discussion of skills derived from the CMU. Some Nurses believe that the bur, den of care to which they are subjected in public institutions has increased since the onset of the CMU and yet others believe that they are motivated and rewarded for the results obtained with this model of management. In health institutions, some professionals are more motivated than others and this is found in the outcome of health care activity [2]. Given the positive and negative perceptions that arise in the CMU Professional Nurses, it is considered appropriate to focus the objective of this work in the search for factors that influence job satisfaction of nurses in the CMU. There are few studies about the CMU [3] but are absent when linked with nursing, so the pursuit of scientific knowledge related to nursing management model based on Clinical and Quality Care can lead to establish new concepts around the nursing profession, a profession in which major changes are foreseen when the Grade is effective.

Expression of CD81, SR-BI and LDLR in lymphocytes and monocytes from patients with classic and occult hepatitis C virus infection.

CD81, the scavenger receptor-BI (SR-BI) and the low-density lipoprotein receptor (LDLR) are involved in peripheral blood mononuclear cells (PBMCs) hepatitis C virus (HCV) entry. To investigate if these molecules are altered by HCV, 20 controls and 66 patients: 37 untreated and 29 sustained virological responders, were studied. CD81 and LDLR expression, measured the percentage of cells expressing the HCV-receptors and their mean fluorescence intensity (MFI), was analyzed on lymphocytes and monocytes, as well as SR-BI on monocytes by flow cytometry. RNA was extracted from PBMCs and detection of the HCV-RNA positive and negative strands was performed by strand-specific RT-PCR. A statistically significant increase of CD81 expression was observed on lymphocytes, a higher percentage of LDLR on lymphocytes and monocytes, as well as SR-BI on monocytes was found in the patients as compared to the controls (P < 0.05 in all cases). Untreated patients showed a higher percentage of LDLR(+) lymphocytes than sustained virological responders (P = 0.025). Nineteen sustained virological responders bore the HCV-RNA positive strand in PBMCs; nine of them the negative strand too. Sustained virological responders with occult infection and viral replication, showed a higher expression of LDLR on lymphocytes (P < 0.05) and a higher LDLR MFI on monocytes (P = 0.011) than those without viral replication. In conclusion, HCV exposure modifies expression levels of the receptors studied, being LDLR related with HCV replication, not only in the classic but also in the occult infection.

Nursing Students' Knowledge, Awareness, and Experiences of Emergency Contraception Pills' Use.

The emergency contraception pill (ECP) is a non-prescribed medication in Spain. However, there is not enough evidence of its use among young people to define sex education contents. The aims of this research were to describe the experiences of the use of the ECP in university students and analyze their knowledge, attitude, and awareness regarding the ECP. The cross-sectional, analytic study was conducted with nursing degree students at the University of Seville. A total of 478 students answered the questionnaire. All of the students (100%) had heard about the ECP and had a positive attitude towards this contraceptive. A total of 25.7% had used the ECP, mainly because a condom had failed or because they did not use any contraceptive at all. Deficiencies in knowledge are related with the ECPs' mechanism of action, efficacy after repeated use, and the type of ECP available. Female students who used no method at all or withdrawal, and who were over 20 years old, used ECP to a greater extent (p < 0.005). Further education initiatives focused on the use of the ECP, its efficacy, and typology are needed, particularly among future health professionals who will later educate other young people.

Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19.

IL-6 is one of the major mediators of the hyper-inflammatory responses with complex biological functions as it can signal via different modes of action. IL-6 by classical signalling has anti-inflammatory and antibacterial activities, while trans-signalling mediates pro-inflammatory effects. The net biological effect of IL-6 is established by multiple factors beyond its absolute concentration. Here, we assess the relationship between IL-6 signalling variables [IL-6, soluble IL-6R (sIL-6R) and soluble gp130 (sgp130)] and outcomes in a cohort of 366 COVID-19 patients. The potential trans-signalling was evaluated by a ratio between the pro-inflammatory binary IL-6:sIL-6R complex and the inactive ternary IL-6:sIL-6R:sgp130 complex (binary/ternary complex) and the fold molar excess of sgp130 over sIL-6R (FME). Our data provide new evidence that high levels of IL-6, sIL-6R, sgp130, binary/ternary complex ratio, and low FME are independent predictors of COVID-19 severity in survivor patients (without death), and the combination of IL-6 + sIL-6R + sgp130 exhibited the most robust classification capacity. Conversely, in a subgroup of patients with a very poor prognosis, we found that high levels of IL-6 and low levels of sIL-6R, sgp130, and binary/ternary complex ratio were predictors of death. In this context, the highest predictive capacity corresponded to the combined analysis of IL-6 + FME + lymphopenia + creatinine. Herein, we present IL-6 signalling variables as a helpful tool for the early identification and stratification of patients with clear implications for treatment and clinical decision-making.

Immunological and inflammatory changes after simplifying to dual therapy in virologically suppressed HIV-infected patients through week 96 in a randomized trial.

OBJECTIVES: To evaluate whether simplification of antiretroviral treatment to dual therapy (DT) negatively impacts immune recovery (IR), immune activation and inflammation (IA/I), and HIV reservoir. METHODS: An open-label, single-centre, randomized controlled trial conducted in adult virologically suppressed HIV-infected patients on triple therapy (TT) with elvitegravir-cobicistat, emtricitabine and tenofovir alafenamide or dolutegravir (DTG), abacavir, and lamivudine (3TC). Participants were randomized to continue TT or switch to DTG, or darunavir/cobicistat (DRVc) plus 3TC. IR was assessed by CD4+/CD8+ ratio at 48 and 96 weeks. Changes in immune activation, proliferation, exhaustion, senescence, and apoptosis in CD4+ and CD8+ T cells, plasma sCD14, hsCRP, D-dimers, ß2-microglobulin, IL-6, TNF-α and IP-10 levels, cell-associated HIV-DNA (CA-DNA), and unspliced HIV-RNA (usRNA) were also analysed. RESULTS: One hundred and fifty-one participants were enrolled. Fourteen patients did not complete the follow up. In the ITT and PP analysis, the IR was similar between the treatment arms. In the ITT analysis, the median increase in CD4+/CD8+ ratio was 0.10, 0.04, and 0.07 at week 48, and 0.09, 0.05, and 0.08 at week 96 for TT, DTG/3TC, and DRVc/3TC, respectively. After adjusting for confounding factors, the slopes of changes in CD4+/CD8+ ratio over time were independent of treatment (F = 1.699; p = 0.436) and related only to baseline values (F = 756.871; p = 0.000). There were no differences in IA/I, CA-DNA, or usRNA between treatment arms. DISCUSSION: Both IR and IA/I, CA-DNA, and usRNA were similar in the three treatment groups, regardless of maintaining TT or simplifying to DTG/3TC or DRVc/3TC in virologically suppressed HIV-infected patients.

Clinical, laboratory data and inflammatory biomarkers at baseline as early discharge predictors in hospitalized SARS-CoV-2 infected patients.

BACKGROUND: The SARS-CoV-2 pandemic has overwhelmed hospital services due to the rapid transmission of the virus and its severity in a high percentage of cases. Having tools to predict which patients can be safely early discharged would help to improve this situation. METHODS: Patients confirmed as SARS-CoV-2 infection from four Spanish hospitals. Clinical, demographic, laboratory data and plasma samples were collected at admission. The patients were classified into mild and severe/critical groups according to 4-point ordinal categories based on oxygen therapy requirements. Logistic regression models were performed in mild patients with only clinical and routine laboratory parameters and adding plasma pro-inflammatory cytokine levels to predict both early discharge and worsening. RESULTS: 333 patients were included. At admission, 307 patients were classified as mild patients. Age, oxygen saturation, Lactate Dehydrogenase, D-dimers, neutrophil-lymphocyte ratio (NLR), and oral corticosteroids treatment were predictors of early discharge (area under curve (AUC), 0.786; sensitivity (SE) 68.5%; specificity (S), 74.5%; positive predictive value (PPV), 74.4%; and negative predictive value (NPV), 68.9%). When cytokines were included, lower interferon-γ-inducible protein 10 and higher Interleukin 1 beta levels were associated with early discharge (AUC, 0.819; SE, 91.7%; S, 56.6%; PPV, 69.3%; and NPV, 86.5%). The model to predict worsening included male sex, oxygen saturation, no corticosteroids treatment, C-reactive protein and Nod-like receptor as independent factors (AUC, 0.903; SE, 97.1%; S, 68.8%; PPV, 30.4%; and NPV, 99.4%). The model was slightly improved by including the determinations of interleukine-8, Macrophage inflammatory protein-1 beta and soluble IL-2Rα (CD25) (AUC, 0.952; SE, 97.1%; S, 98.1%; PPV, 82.7%; and NPV, 99.6%). CONCLUSIONS: Clinical and routine laboratory data at admission strongly predict non-worsening during the first two weeks; therefore, these variables could help identify those patients who do not need a long hospitalization and improve hospital overcrowding. Determination of pro-inflammatory cytokines moderately improves these predictive capacities.

Role of radiation therapy in the multidisciplinary management of Ewing's Sarcoma of bone in pediatric patients: An effective treatment for local control.

BACKGROUND: Radiotherapy (RT) plays an important role in the multidisciplinary management of Ewing's Sarcoma (ES), especially in unresectable cases. AIM: Assessment of efficacy of RT in terms of local control in pediatric patients with primary ES of bone. MATERIALS AND METHODS: Thirty-six patients younger than 17 years old with ES treated with combined RT and chemotherapy with (N = 14) or without (N = 22) prior surgery from 1981 to 2008 were retrospectively reviewed. Since 1995, they were all treated according to the Spanish Society of Pediatric Oncology protocol (55.5% cases). Those patients received vincristine, ifosfamide, doxorubicin and etoposide. The TNM classification was as follows: 17 T1, 18 T2 and 1 T3; 36 N0; 29 M0, 5 M1a and 2 M1b. Analysis was stratified by treatment: definitive RT or pre/postoperative RT. RESULTS: The 36 patients (21 male; 15 female) had a median age of 10 years (range 2-17 years). Median follow-up of living patients was 105 months. The 2-year local control (LC) rate for all patients was 88%. Five-year LC rates for patients treated with definitive and pre/postoperative RT were 91% and 86%, respectively. Two-year overall survival and disease-free survival rates for all patients were 68% and 66%, respectively. Low phosphatase alkaline levels and local and distant recurrences were significantly predictive of worse prognosis (P = 0.021, P = 0.011, P = 0.007, respectively). CONCLUSION: Radiotherapy with and without surgery is a highly effective local treatment option in the multidisciplinary management of ES in pediatric patients.

Myeloablative therapy against high risk Ewing's sarcoma: A single institution experience and literature review.

BACKGROUND: Attempts to improve survival outcomes of patients with high risk Ewing's sarcoma (ES) have focused on chemotherapy dose intensification strategies. AIM: The objective of this study is to retrospectively evaluate clinical characteristics and outcome of pediatric patients with high risk ES treated at a single institution. MATERIALS AND METHODS: From 1995 to 2008, seventeen patients (male:female, 14:3) were treated with dose-intensive therapy in our institution. Median age at diagnosis was 10 years (range: 2-15). Seven patients had metastases at diagnosis (lung in 6 cases and bone in one case). Eleven patients presented with unresectable disease. Fifteen (88.2%) received the Spanish Society of Pediatric Oncology protocol which includes six cycles of vincristine, doxorubicin, ifosfamide and etoposide. Two out of the six cases that were resectable received postoperative radiation. In addition, eleven patients received definitive radiation therapy. Finally, twelve (70.5%) out of 17 patients received myeloablative therapy with melphalan/etoposide. The rest of patients (N = 5) received busulfan/melphalan. RESULTS: Median follow-up was 78 months (range: 15-155 months). Initial responses were complete in all patients, but 9 of them developed progression disease. Seven patients became long-term event-free survivors. No patient died of toxicity after transplantation. The 2- and 5-year overall survival rates for all patients were 93% and 73%, respectively. Event-free survival rates were 74% and 54% at 2 and 5 years, respectively. CONCLUSION: This single-institution experience suggests that myeloablative therapy against high risk ES is effective and safe.

Prognostic value of the TGFß1 rs4803455 single nucleotide polymorphism in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single nucleotide polymorphisms in heat shock protein ß1 (HSPB1) and transforming growth factor ß1 (TGFß1) and survival have been investigated. METHODS: A prospective multicenter study of 94 patients with SCLC treated between 2013 and 2016 was conducted. Clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFß1 gene and 5 of HSPB1 gene) variables were analyzed. RESULTS: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (twice-daily radiation in 42%). Forty-seven percent received concurrent platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis, the rs4803455:CA genotype of the TGFß1 gene showed a statistically significant association with lower disease-free survival (DFS; hazard ratio [HR] 3.13; confidence interval [CI] 1.19-8.17; p = 0.020) and higher local recurrence (HR 3.80; CI 1.37-10.5; p = 0.048), and a marginal association with lower OS (HR 1.94; CI 0.98-3.83; p = 0.057). A combined analysis showed that patients receiving PCI and carrying the rs4803455:CA genotype had statistically significant lower OS (p < 0.001) and DFS (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. CONCLUSIONS: Genetic analysis showed the CA genotype of TGFß1 SNP rs4803455 was associated with worse prognosis in patients with SCLC and could be considered as a potential biomarker.

Overexpression of Canonical Prefoldin Associates with the Risk of Mortality and Metastasis in Non-Small Cell Lung Cancer.

Canonical prefoldin is a protein cochaperone composed of six different subunits (PFDN1 to 6). PFDN1 overexpression promotes epithelial-mesenchymal transition (EMT) and increases the growth of xenograft lung cancer (LC) cell lines. We investigated whether this putative involvement of canonical PFDN in LC translates into the clinic. First, the mRNA expression of 518 non-small cell LC (NSCLC) cases from The Cancer Genome Atlas (TCGA) database was evaluated. Patients with PFDN1 overexpression had lower overall survival (OS; 45 vs. 86 months; p = 0.034). We then assessed the impact of PFDN expression on outcome in 58 NSCLC patients with available tumor tissue samples. PFDN1, 3, and 5 overexpression were found in 38% (n = 22), 53% (n = 31), and 41% (n = 24) of tumor samples. PFDN1, 3, and 5 overexpression were significantly associated with lower OS, lower disease-free survival (DFS), and lower distant metastasis-free survival (DMFS) for PFDN1 and 3 with a trend for PFDN5. In multivariate analysis, PFDN5 retained significance for OS (hazard ratio (HR) 2.56; p = 0.007) and PFDN1 for DFS (HR 2.53; p = 0.010) and marginally for DMFS (HR 2.32; p = 0.053). Our results indicate that protein response markers, such as PFDN1, 3, and 5, may complement mRNA signatures and be useful for determining the most appropriate therapy for NSCLC patients.

Correlation between short-term air pollution exposure and unprovoked lung embolism. Prospective observational (Contamina-TEP Group).

BACKGROUND: The aim was to analyze the temporal relationship between short-term air pollution exposure and acute symptomatic unprovoked pulmonary embolism (PE). PATIENTS/METHODS: We performed a prospective, multicenter study in consecutive patients diagnosed with acute symptomatic unprovoked PE from February 2012 to January 2013. We analyzed demographic and clinical data, patients' addresses, meteorological and air pollutants data (PM10, SO2, CO, NO2, ozone emission data). We considered the number of days the patient had symptoms, and the study period constituted the previous 30 days. Likewise, the mean annual data of the reference season were calculated as well as the data of the 30-day study period corresponding to the same dates in the previous 3 years in order to obtain the monthly mean of the different pollutants for each period. RESULTS: A total of 162 patients with acute symptomatic PE were recruited (43.2% unprovoked PE). The air pollutants could be determined in 50% of the patients with unprovoked PE, and a final analysis was performed in 35 patients. In the multiple comparison analysis to verify a possible correlation between the study period and the annual median, only NO2 showed a statistically significant association (p = 0.009). When comparing the study period with the previous 3 years, only NO2 maintained a statistically significant association for the 3 study periods. CONCLUSIONS: We found a relationship between short-term exposure to NO2 and the presence of unprovoked PE.

The single nucleotide variant rs2868371 associates with the risk of mortality in non-small cell lung cancer patients: A multicenter prospective validation.

BACKGROUND AND PURPOSE: Definitive radiation therapy (RT) with or without chemotherapy has become the standard treatment for non-metastatic unresectable non-small cell lung cancer (NSCLC). However, treatment outcomes can differ substantially and patients' genetic background could play a crucial role. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta-1 (HSPB1) and survival have been reported in prior single-institution retrospective reports. MATERIALS AND METHODS: The current assay aims to validate such connection in a prospective multicenter study in a European cohort including 181 NSCLC patients. Median follow-up time for all patients was 13 months (range, 3-57 months). RESULTS: The results obtained show an association between the rs2868371 GG genotype and better overall survival (HR: 0.35; 95%CI: 0.13-0.96; p = 0.042) in multivariate analysis. Two-year overall survival rate was 72% for patients carrying the rs2868371 GG genotype versus 36% for those patients harboring the rs2868371 CC/CG genotypes (p = 0.013). Additionally, the rs2868371 GG genotype was found to be associated with better disease-free survival in the multivariate analysis (HR: 0.36; 95%CI: 0.13-0.99; p = 0.048). In silico analysis of the potential functional SNP suggested significant difference in the affinity of the Glucocorticoid Receptor binding site between alternative allelic variants, confirmed by chromatin immunoprecipitation analysis displaying stronger affinity for the risk allele (C). Furthermore, our findings indicate that the rs2868371 influences (mRNA) HSPB1 expression, offering insight into the regulation of HSPB1 transcription. CONCLUSION: The functional HSPB1 rs2868371 promoter variant may affect lung cancer survival by regulation of HSPB1 expression levels through glucocorticoid receptor interaction.