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Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.

Background The search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator. Methods Blood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations. Results In this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival. Conclusions In conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.

Clinical trials show that nivolumab has remarkable activity against relapsed/refractory classical Hodgkin lymphoma (cHL). However, the role of allogeneic hematopoietic stem cell transplantation (alloHSCT) as consolidation therapy in these patients remains controversial. We performed a retrospective analysis of data from 74 patients treated with nivolumab. The overall response rate was 58% (30.6% complete responses). Treatment-related adverse events were reported in 56.8% of patients (grade =3 in 9.4%). The main reasons for nivolumab discontinuation were referral for transplantation (41.7% patients) and disease progression (37.5%). The 2 year overall survival (OS) rate was 52% for the whole series. Ultimately, 39 patients received alloHSCT. The cumulative incidence of grade II-IV acute graft-versus-host disease was 33.3% (grade III-IV in two patients). The cumulative incidence of non-relapse mortality was 13.2%. Among nivolumab responding patients, 2 year OS and progression free survival (PFS) were higher for patients who underwent consolidation with alloHSCT (77.5% vs. 42.6%, p=0.126; and 73.9% vs. 27.2%, p=0.025, respectively). Thus, efficacy and safety of nivolumab is comparable with that reported in previous clinical trials. The percentage of patients who bridged to transplantation was high, indicating a preference for Spanish physicians. These results suggest that consolidation alloHSCT increases OS and PFS.

Background: the application of specialized nutritional support (SNE) is difficult at the organizational level due to the complexity of clinical practice guidelines and we do not know the degree of adherence to the published nutritional recommendations. The aim of this study was to assess the degree of adherence to the recommendations of high impact and "do not do" within our environment, in order to show areas for improvement. Methods: survey of nine questions agreed by experts and carried out in different ICUs of our environment, which reflected the recommendations in SNE. Data related to the organizational characteristics and the healthcare provider that indicated the nutritional support were collected. The differences regarding the degree of adherence between the level of care and the presence of an expert in these units were analyzed. Results: thirty-seven ICUs participated, which corresponded mostly to second level hospitals and polyvalent ICUs with an SNE indicated by intensivists. The adherence to the recommendations was > 80%, with three exceptions associated with issues related to the refeeding syndrome (70.3%), the caloric-protein adjustment of nutrition according to the patient's evolutionary phase (51.4%) and the adjustment of protein intake in patients with renal failure (40.5%). There were no differences according to the level of care or the presence of an expert in these ICUs. Only a greater availability of local nutrition protocols was observed in those ICUs with an expertise. Conclusions: there is a high theoretical adherence to the majority of recommendations in the nutritional field, with exceptions that could correspond to areas where there is an opportunity for improvement.

PurposeEnteral feeding intolerance (EFI) is a frequent problem in the intensive care unit (ICU), but current prokinetic agents have uncertain efficacy and safety profiles. The current study compared the efficacy and safety of ulimorelin, a ghrelin agonist, with metoclopramide in the treatment of EFI.MethodsOne hundred twenty ICU patients were randomized 1:1 to ulimorelin or metoclopramide for 5days. EFI was diagnosed by a gastric residual volume (GRV) 500ml. A volume-based feeding protocol was employed, and enteral formulas were standardized. The primary end point was the percentage daily protein prescription (%DPP) received by patients over 5days of treatment. Secondary end points included feeding success, defined as 80% DPP; gastric emptying, assessed by paracetamol absorption; incidences of recurrent intolerance (GRV500ml); vomiting or regurgitation; aspiration, defined by positive tracheal aspirates for pepsin; and pulmonary infection.ResultsOne hundred twenty patients were randomized and received the study drug (ulimorelin 62, metoclopramide 58). Mean APACHE II and SOFA scores were 21.6 and 8.6, and 63.3% of patients had medical reasons for ICU admission. Ulimorelin and metoclopramide resulted in comparable %DPPs over 5days of treatment (median [Q1, Q3]: 82.9% [38.4%, 100.2%] and 82.3% [65.6%, 100.2%], respectively, p=0.49). Five-day rates of feeding success were 67.7% and 70.6% when terminations unrelated to feeding were excluded, and there were no differences in any secondary outcomes or adverse events between the two groups.ConclusionsBoth prokinetic agents achieved similar rates of feeding success, and no safety differences between the two treatment groups were observed.

Multiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits. © 2018 The Authors

One of the main reasons for failure in Software Process Improvement (SPI) initiatives is the lack of motivation of the professionals involved. Therefore, motivation should be encouraged throughout the software process. Gamification allows us to define mechanisms that motivate people to develop specific tasks. A gamification framework was adapted to the particularities of an organization and software professionals to encourage motivation. Thus, it permitted to facilitate the adoption of SPI improvements and a higher success rate. The objective of this research was to validate the framework presented and increase the actual implementation of gamification in organizations. To achieve this goal, a qualitative research methodology was employed through interviews that involved a total of 29 experts in gamification and SPI. The results of this study confirm the validity of the framework presented, its relevance in the field of SPI and its alignment with the standard practices of gamification implementation within organizations.

BACKGROUND: Extracorporeal shockwave treatment (ESWT) and ultrasound-guided percutaneous lavage (UGPL) are two effective ways of treating rotator cuff calcific tendinopathy (RCCT). AIM: The aim of the present study was to compare the effectiveness of these techniques in the treatment of RCCT. DESIGN: Prospective, randomized, controlled trial. SETTING: Patients treated in our sports medicine and rehabilitation center (Centro Médico Deyre, Madrid. Spain) between January 2007 and December 2013. METHODS: This randomized study compares the results achieved with these techniques over one year following their use to treat the above condition. Eighty patients received ESWT and 121 received UGPL. A visual analogue scale was used to measure pain, and ultrasound to determine the extent of calcification, at 3, 6, and 12 months after treatment. RESULTS: Pain and the amount of calcification were significantly reduced by both techniques at 3, 6 and 12 months (P

High flow nasal cannula (HFNC) is a new therapeutic approach to patients with several forms of respiratory failure. Studies have shown that HFNC generates a low level of positive airway pressure, improves oxygenation, increases the end-expiratory lung volume, reduces airway resistance, increases functional residual capacity and alveolar recruitment and flushes nasopharyngeal dead space, thus helping to decrease the work of breathing. There is a better control of FiO2 and the gas humidification ensures a better patient tolerance and comfort. Due to a better mucociliary clearance, pulmonary defense mechanisms are restored. The low levels of pressure generated by HFNC may suggest that perhaps could play a role in the treatment of sleep apnea. Some studies have demonstrated a positive effect of HFNC on the apnea-hypopnea index showing us that HFNC could be an alternative to conventional treatment of obstructive sleep apnea in children and adults with fruitful results. We present a review of available evidence.

La ventilación mecánica es capaz de producir y agravar el daño pulmonar y contribuir a la aparición de fracaso multiorgánico. Uno de los mecanismos descritos es la hiperoxia alveolar que, en modelos experimentales, conlleva una producción de radicales libres de oxígeno (O2) que exceden las posibilidades de defensa celular, y dan lugar a inflamación, a sobreexpresión genética y a daño celular directo con fenómenos de necrosis y apoptosis. Los hallazgos en humanos no son tan concluyentes, sí está claramente demostrada una alteración funcional debida a la exposición a la fracción inspiratoria de O2 (FiO2) elevada y a un mayor desreclutamiento pulmonar en los pacientes con lesión pulmonar, y que tanto la FiO2 empleada como la presión arterial de oxígeno conseguida en las primeras 24h de ingreso están relacionadas con la mortalidad. Sería necesario realizar ensayos clínicos que evalúen cuál es el umbral de la FiO2 y de la saturación de O2 seguro. Mechanical ventilation may cause and aggravate lung damage and contribute to the appearance of multiorgan failure. One of the mechanisms that has been described is alveolar hyperoxia. In experimental models, it has lead to the production of free oxygen radicals that exceed the cell defense capacity, giving rise to inflammation, cell damage and gene overexpression with necrosis and apoptosis phenomenon. However, these findings in humans are not as conclusive, although a functional alteration due to the exposure to high FiO2, and greater lung de-recruitment in patients with lung injury has been clearly demonstrated. Moreover, both the FiO2 used as well as the PaO2 achieved in the first 24h of admission are associated with mortality. Clinical trials are needed that assess the threshold of the safe oxygen level for FiO2 and oxygen saturation.