Estimating a normal reference range for serum B-cell maturation antigen levels for multiple myeloma patients.

The serum B-cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right-tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78-180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non-parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml.

Normalization of serum B-cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment.

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B-cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression-free survival (PFS; P = 0·0398) and overall survival (OS; P = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.

JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression.

Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo.

The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.

Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients.

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P<0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; P<0.001), clinical status (complete response vs partial response, P=0.0374; complete response vs progressive disease, P<0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (P=0.0006) and overall survival (P=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (P=0.0043) or a new salvage therapy (P=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum ß2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients.

Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

[Factors associated with level of knowledge and attitudes toward research among medical students in Peru, 2011]. / Factores asociados con el nivel de conocimientos y la actitud hacia la investigación en estudiantes de medicina en Perú, 2011.

OBJECTIVE: To identify the factors associated with level of knowledge and attitudes toward research among undergraduate medical students in Peru. METHODS: In this analytical cross-sectional study, a validated questionnaire on knowledge, attitudes, and practices related to research was applied to a representative sample of students at 17 Peruvian medical schools. The categorical and quantitative variables were subjected to simple two-factor analysis with adjustment for intraclass correlation. Prevalence ratios were derived on the basis of generalized linear models using bifactorial and multifactorial analysis. RESULTS: Questionnaires from 1 554 students (51.0% women) with an average age of 20.5 ± 2.86 years were analyzed. Only 46.7% of the respondents had a good level of knowledge and 37.7% had appropriate attitudes toward research. The variables that correlated with a good level of knowledge were the respondent having completed at least four years of academic study, belonging to a research group, and having an adviser. Having appropriate attitudes toward research correlated with being a woman and having an adviser. No differences were found between the level of knowledge and attitudes of the students at the universities studied. CONCLUSIONS: In general, the level of knowledge about research was unsatisfactory and the attitudes toward it were inappropriate. In order to change this situation, it will be critical to make changes in the curriculum to ensure that students engage in research from the beginning of their academic careers and develop research skills in their final years of study.

[Differences by socioeconomic and school level in food acquisition of Mexican population]. / Diferencias por nivel socioeconómico y escolar en la adquisición de alimentos de la población mexicana.

Introduction: Introduction: social or school factors influence the acquisition and selection of foods to be consumed. Objective: identifying the socioeconomic or school level that has the greatest weight in the acquisition of food in Mexican households. Methods: cross-sectional, retrospective and comparative study based on the database of the 2018 National Household Expenditure-Income Survey of Mexico. We worked with the national total of 73,274 Mexican households. The variables considered were: expenditure module of food and beverages, school grade of the head of the family and socioeconomic status to which the household belongs. For the statistical analysis, the following tests were used: linear regression analysis, as well as variance analysis, Snedecor's F test, post-hoc test and Schefé's confirmatory test. Results: socioeconomic status has a greater weight (p < .001) for food acquisition. Sugary drinks were the most widely acquired in all social and school levels. The lowest social level is the one who acquires the most cereals, fats, sugars and legumes, while for high school levels animal foods and processed meats are the ones most frequently acquired. Conclusion: the socioeconomic level has a great weight in the acquisition and variety of foods, although this does not mean that foods obtained are the healthiest. Therefore, public policies are urgently required in favor of nutritional education at all school levels, which promote the purchase of healthy foods and compete with commercial advertising strategies.

Introducción: Introducción: los factores sociales o escolares influyen en la adquisición y selección de alimentos a consumir. Objetivo: identificar el nivel socioeconómico o escolar que tenga mayor peso en la adquisición de alimentos en hogares mexicanos. Métodos: estudio transversal, retrospectivo y comparativo a partir de la base de datos de la Encuesta Nacional de Ingreso-Gasto en Hogares de México de 2018. Se trabajó con el total nacional de 73.274 hogares mexicanos. Las variables consideradas fueron: módulo de gasto de alimentos y bebidas, grado escolar del jefe de familia y condición socioeconómica a la que pertenece el hogar. Para el análisis estadístico se utilizó análisis de regresión lineal, así como análisis de varianza, prueba F de Snedecor, prueba post-hoc y confirmatoria de Schefé. Resultados: el nivel socioeconómico tiene un mayor peso (p < ,001) para la adquisición de los alimentos. Las bebidas azucaradas fueron las de mayor adquisición en todos los niveles sociales y escolares. El nivel social más bajo es el que adquiere la mayor cantidad de cereales, grasas, azucares y leguminosas, mientras que en los niveles escolares altos son los alimentos de origen animal y carnes procesadas los más adquiridos. Conclusión: el nivel socioeconómico tiene mayor peso en la adquisición y variedad de los alimentos, aunque esto no quiere decir que por ello se obtengan los más saludables. Por lo tanto, se requiere urgentemente de políticas públicas en favor de una educación nutricional en todos los niveles escolares, que promueva la compra de alimentos saludables y que compita con las estrategias publicitarias comerciales.

18F-FDG PET Visualizes Systemic STING Agonist-Induced Lymphocyte Activation in Preclinical Models.

Stimulator of interferon genes (STING) is a mediator of immune recognition of cytosolic DNA, which plays important roles in cancer, cytotoxic therapies, and infections with certain pathogens. Although pharmacologic STING activation stimulates potent antitumor immune responses in animal models, clinically applicable pharmacodynamic biomarkers that inform of the magnitude, duration, and location of immune activation elicited by systemic STING agonists are yet to be described. We investigated whether systemic STING activation induces metabolic alterations in immune cells that can be visualized by PET imaging. Methods: C57BL/6 mice were treated with systemic STING agonists and imaged with 18F-FDG PET after 24 h. Splenocytes were harvested 6 h after STING agonist administration and analyzed by single-cell RNA sequencing and flow cytometry. 18F-FDG uptake in total splenocytes and immunomagnetically enriched splenic B and T lymphocytes from STING agonist-treated mice was measured by γ-counting. In mice bearing prostate or pancreas cancer tumors, the effects of STING agonist treatment on 18F-FDG uptake, T-lymphocyte activation marker levels, and tumor growth were evaluated. Results: Systemic delivery of structurally distinct STING agonists in mice significantly increased 18F-FDG uptake in the spleen. The average spleen SUVmax in control mice was 1.90 (range, 1.56-2.34), compared with 4.55 (range, 3.35-6.20) in STING agonist-treated mice (P < 0.0001). Single-cell transcriptional and flow cytometry analyses of immune cells from systemic STING agonist-treated mice revealed enrichment of a glycolytic transcriptional signature in both T and B lymphocytes that correlated with the induction of immune cell activation markers. In tumor-bearing mice, STING agonist administration significantly delayed tumor growth and increased 18F-FDG uptake in secondary lymphoid organs. Conclusion: These findings reveal hitherto unknown functional links between STING signaling and immunometabolism and suggest that 18F-FDG PET may provide a widely applicable approach toward measuring the pharmacodynamic effects of systemic STING agonists at a whole-body level and guiding their clinical development.

Intra- and Interspecies Differences of Two Cecropia Species from Tabasco, Mexico, Determined through the Metabolic Analysis and 1H-NMR-Based Fingerprinting of Hydroalcoholic Extracts.

The genus Cecropia is used in the traditional medicine of Tabasco, Mexico, in diabetes and hypertension treatments, mainly without distinction of the species. This contribution aimed to carry out the metabolic analysis and Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy-based fingerprinting of the hydroalcoholic leaf extracts of Cecropia peltata (Cp) and Cecropia obtusifolia (Co) collected in five sub-regions of the State of Tabasco (Cp1, "Centro"; Cp2, "Chontalpa"; Cp3, "Pantanos"; Cp4, "Ríos" and Co5, "Sierra"). Firstly, the extracts were evaluated for their Total Phenol Content (TPC) and Total Flavonoid Content (TFC) by spectrophotometric methods. In addition, metabolic analysis was performed using High-Performance Liquid Chromatography with Diode-Array Detection HPLC-DAD, which allowed the quantification of the chemical markers: chlorogenic acid, isoorientin, and orientin, as well as a vitexin analog. Finally, metabolomic analysis was carried out based on the 1H-NMR spectra. The Cp4 extract (C. peltata from the "Ríos" sub-region) presented the highest values of TPC (155 ± 9.1 mg GAE/g E) and TFC (724 ± 22.2 mg RE/g E). The metabolic analysis was similar among the five samples; the highest concentrations of the four chemical markers were found in Cp3 (C. peltata from the "Pantanos" sub-region) for chlorogenic acid (39.8 ± 2.3 mg/g) and isoorientin (51.5 ± 2.9 mg/g), in Cp4 for orientin (49.9 ± 0.6 mg/g), and in Cp2 (C. peltata from the "Chontalpa" sub-region) for the vitexin analog (6.2 ± 0.2 mg/g). The metabolic analysis and the 1H-NMR fingerprint analysis showed intraspecies differences among the C. peltata samples and interspecies between C. peltata and C. obtusifolia, which were attributed to variations in the metabolite groups as well as in the proportion of sugars such as glucose and xylose.

Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival.

Although TNFRSF17 (also designated as B-cell maturation antigen (BCMA)) is expressed on tumour cells in B-cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma (MM) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients (n = 209), monoclonal gammopathy of undetermined significance (MGUS) individuals (n = 23) and age-matched controls (n = 40). BCMA was detected in the serum of untreated MM patients (n = 50) and levels were higher than in MGUS patients (P = 0·0157) and healthy subjects (P < 0·0001). Serum BCMA levels were higher among patients with progressive disease (n = 80) compared to those with responsive disease (n = 79; P = 0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median (P = 0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA, and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients.

Getting Ahead: A Resident Led Quality Improvement Project to Increase Diabetic Nephropathy Screening in an Underserved Hispanic-Predominant Population.

Introduction: Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States (US), with 37 million having chronic kidney disease. Despite national guidelines recommendations for diabetic nephropathy screening with urine albumin-to-creatinine ratio (UACR), less than 50% receive full screening.Our Internal Medicine residents led a quality improvement project to increase diabetic nephropathy screening rate with UACR in our resident clinic by 50% in one academic year. Methods: We conducted the resident-led quality improvement project from July 2021 to April 2022. We reviewed the electronic medical records (EMR) from our clinic pre-intervention July 2020 to June 2021 and compared this to post intervention July 2021 to March 2022 determining the nephropathy screening rates in patients with diabetes. Our interventions included resident education, pre and post surveys to test foundational knowledge, adding UACR in the affordable laboratory order form and establishing normal reference range of UACR in the EMR. Results: We collected 217 patients with diabetes, 27% were uninsured, 38% had Medicare/Medicaid and 90% identified as Hispanic. Comparing pre to post intervention, there was a significant change of 45 (20.7%) vs 71 (32.7%) patients screened for diabetic nephropathy with a UACR. The correct average score of knowledge-based questions was 82% on the pre survey, which increased to 88% in the post survey. Conclusion: Our study showed promising results on improving diabetic nephropathy screening. The comprehensive approach including resident education about diabetic nephropathy screening with UACR and more so facilitating the order set in the EMR were key to achieve this goal.

Efficacy and Safety of Extracorporeal Membrane Oxygenation in Patients under Mechanical Ventilation with COVID-19 and Severe Acute Respiratory Distress Syndrome: A Health Technology Assessment.

We aimed to assess the efficacy and safety of extracorporeal membrane oxygenation (ECMO) in patients under mechanical ventilation with COVID-19 and severe acute respiratory distress syndrome (ARDS). A systematic review of the literature published in PubMed, Cochrane Library and LILACS databases, was performed. A manual search was also conducted using the reference lists of the studies included in the full-text assessment, as well as a grey-literature search on Google. Additionally, websites of state institutions and organizations developing clinical practice guidelines and health technology assessments were reviewed. The ClinicalTrials.gov website was screened along with the websites of the International Clinical Trial Registry Platform and the National Registry of Health Research Projects of the Peruvian National Institute of Health. No restrictions were applied in terms of language, time, or country. A total of 13 documents were assessed, which included 7 clinical practice guidelines, 3 health technology assessments, 1 systematic review, 1 randomized clinical trial, and 1 observational study. A critical appraisal was conducted for each document. After this, we considered that the currently available evidence is insufficient for a conclusion supporting the use of ECMO in patients under mechanical ventilation with severe ARDS associated to COVID-19 in terms of mortality, safety, and quality of life.

Preliminary Phytochemical Profile and Bioactivity of Inga jinicuil Schltdl & Cham. ex G. Don.

Several Mesoamerican cultures have used Inga jinicuil as traditional medicine for the treatment of gastrointestinal, inflammatory, and infectious issues. The aims of this contribution were to elucidate the phytochemical profile of the organic extracts from the bark and leaves of I. jinicuil and to assess the anti-inflammatory and antibacterial properties of these extracts. The preliminary chemical profile was determined by HPLC-PDA and GC-MS; the anti-inflammatory activity was evaluated with a mouse ear edema model, whereas the antibacterial activity was screened against several bacteria. The phytochemical profile of both organs (bark and leaves) of I. jinicuil led to the identification of 42 compounds, such as polyphenolic, flavonoids, triterpenes, prenol-type lipids, and aliphatic and non-aliphatic esters. This molecular diversity gave moderate anti-inflammatory activity (67.3 ± 2.0%, dichloromethane bark extract) and excellent antibacterial activity against Pseudomona aeruginosa and methicillin-resistant Sthaphylococcus aureus (MIC values of ˂3.12 and 50 µg/mL, respectively). These results contribute to the chemotaxonomic characterization and the rational use in traditional medicine of Inga jinicuil Schltdl & Cham. ex G. Don.

Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis.

Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.

Chalcogenide glass microlenses by inkjet printing.

We demonstrate micrometer scale mid-IR lenses for integrated optics, using solution-based inkjet printing techniques and subsequent processing. Arsenic sulfide spherical microlenses with diameters of 10-350 µm and focal lengths of 10-700 µm have been fabricated. The baking conditions can be used to tune the precise focal length.

The co.LAB Generic Framework for Collaborative Design of Serious Games: Development Study.

BACKGROUND: Serious games are increasingly used at all levels of education. However, research shows that serious games do not always fulfill all the targeted pedagogical objectives. Designing efficient and engaging serious games is a difficult and multidisciplinary process that requires a collaborative approach. Many design frameworks have been described, most of which are dedicated to the development of specific types of serious games and take the collaborative dimension into account only to a limited extent. OBJECTIVE: Our aim was to create a generic serious game design framework that could be adapted to all kinds of serious games and implemented in a collaborative web platform. METHODS: We combined the results of a literature review with our experience in serious game design and development to determine the basic building blocks of a collaborative design framework. We then organized these building blocks into categories and determined the features that a generic design framework should include. Finally, based on the paradigm of complex systems and systemic modelling, we created the co.LAB generic design framework and specifications to allow its implementation in a collaborative web platform. RESULTS: Based on a total of 10 existing design methodologies or frameworks, 23 building blocks were identified and represent the foundation of the co.LAB framework. These blocks were organized into 5 categories: "context and objectives," "game design," "mechanics," "learning design," and "assessment." The arrangement by categories provides a structure that can be visualized in multiple and complementary ways. The classical view links game and learning design while other views offer project, systemic, and process visualizations. For the implementation of the co.LAB framework in a web platform, we propose to convert the building blocks into "cards." Each card would constitute a collaborative working space for the design of the corresponding block. To make the framework adaptive, cards could be added, adapted, or removed according to the kind of serious game intended. Enhancing the visualization of relationships between cards should support a systemic implementation of the framework. CONCLUSIONS: By offering a structured view of the fundamental design elements required to create serious games, the co.LAB framework can facilitate the design and development of such games by virtue of a collaborative, adaptive, and systemic approach. The different visualizations of the building blocks should allow for a shared understanding and a consistent approach throughout the design and development process. The implementation of the co.LAB framework in a collaborative web platform should now be performed and its actual usability and effectiveness tested.

Risk factors for mortality in hospitalized patients with COVID-19 from three hospitals in Peru: a retrospective cohort study.

BACKGROUND: Peru was one of the countries with the highest COVID-19 mortality worldwide during the first stage of the pandemic. It is then relevant to evaluate the risk factors for mortality in patients hospitalized for COVID-19 in three hospitals in Peru in 2020, from March to May, 2020.  Methods: We carried out a retrospective cohort study. The population consisted of patients from three Peruvian hospitals hospitalized for a diagnosis of COVID-19 during the March-May 2020 period. Independent sociodemographic variables, medical history, symptoms, vital functions, laboratory parameters and medical treatment were evaluated. In-hospital mortality was assessed as the outcome. We performed Cox regression models (crude and adjusted) to evaluate risk factors for in-hospital mortality. Hazard ratios (HR) with their respective 95% confidence intervals (95% CI) were calculated.  Results: We analyzed 493 hospitalized adults; 72.8% (n=359) were male and the mean age was 63.3 ± 14.4 years. COVID-19 symptoms appeared on average 7.9 ± 4.0 days before admission to the hospital, and the mean oxygen saturation on admission was 82.6 ± 13.8. While 67.6% (n=333) required intensive care unit admission, only 3.3% (n=16) were admitted to this unit, and 60.2% (n=297) of the sample died. In the adjusted regression analysis, it was found that being 60 years old or older (HR=1.57; 95% CI: 1.14-2.15), having two or more comorbidities (HR=1.53; 95% CI: 1.10-2.14), oxygen saturation between 85-80% (HR=2.52; 95% CI: 1.58-4.02), less than 80% (HR=4.59; 95% CI: 3.01-7.00), and being in the middle (HR=1.65; 95% CI: 1.15-2.39) and higher tertile (HR=2.18; 95% CI: 1.51-3.15) of the neutrophil-to-lymphocyte ratio, increased the risk of mortality.  Conclusions: The risk factors found agree with what has been described in the literature and allow the identification of vulnerable groups in whom monitoring and early identification of symptoms should be prioritized in order to reduce mortality.

The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan.

The anti-multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP-18770 which has shown anti-MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP-18770 in multiple MM models and in combination with conventional anti-MM therapies has not been evaluated. Herein, we show that CEP-18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone. Single agent CEP-18770 PO also showed marked anti-MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.

Vorinostat enhances the antimyeloma effects of melphalan and bortezomib.

OBJECTIVES: Examine the antitumor activity of the histone deacetylase inhibitor vorinostat's antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model. METHODS: RPMI8226, U266, and MM1S cells were cultured for 48 h in the presence of media, vorinostat, melphalan, or bortezomib alone, or combinations of vorinostat with melphalan or bortezomib. Cell proliferation was measured using the MTS [3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfphophenyl)-2H-tetrazolium, inner salt] assay. Severe combined immunodeficient mice bearing LAGkappa-1B tumors were treated with vorinostat [30, 60, or 100 mg/kg daily for five consecutive days per week (qdx5d), 100 or 300 mg/kg daily for 2 d/wk (qdx2d)], melphalan (1, 3, or 10 mg/kg qdx1d), bortezomib (0.25 or 0.5 mg/kg qdx2d), or combinations thereof for 35 d. Tumor growth was determined via measurement of human immunoglobulin G (hIgG) levels and tumor volume. RESULTS AND CONCLUSIONS: Vorinostat enhanced the anti-MM effects of melphalan and bortezomib in vitro. Synergism was observed with vorinostat and melphalan in RPMI8226 and U266 cell lines. Vorinostat 100 mg/kg in combination with melphalan 3 mg/kg resulted in significant inhibition of tumor growth in vivo, compared with control (tumor volume P = 0.0001; hIgG P = 0.0001), single-agent vorinostat (tumor volume P = 0.0025; hIgG P = 0.0137), and single-agent melphalan (tumor volume P = 0.0043; hIgG P = 0.0426). Vorinostat also enhanced the antimyeloma effects of bortezomib in vivo. Vorinostat enhances the anti-MM activity of melphalan and bortezomib in vitro and in vivo. This study provides rationale for further evaluation of vorinostat in combination with chemotherapeutic agents and bortezomib for the treatment of MM.