Monitoring with circulating tumor cells in the perioperative setting of patients with surgically treated stages I-IIIA NSCLC.

Background: Surgery is regarded as the treatment's cornerstone for early stage and locally advanced non-small cell lung cancer (NSCLC) whenever the tumor is considered resectable. Liquid biopsy is one of the most promising research areas in oncology in the last 10 years, providing a useful non-invasive tool to detect and monitor cancer. The prognostic value of circulating tumor cells (CTCs) has been studied in different cancer types and had been related with a higher risk of relapse and worse prognosis. The aim of this study is to evaluate the prognostic value of CTC detection in patients with stage I-IIIA NSCLC treated with surgery. Methods: We conducted a prospective, single-center study of 180 consecutive patients with resected and pathological confirmed stage I to IIIA (TNM AJCC/UICC 8th edition) NSCLC. Patients' blood samples were processed and CTCs were characterized before and after the surgery. A cohort of patients had CTC determination after chemotherapy and surgery. Cut-off points were established in 1 and 5 CTCs for statistical analysis. Results: A proportion of 76.7% had at least 1 CTC before the surgery, and 30.6% had 5 or more, while 55.9% had at least 1 CTC after surgery, and 8.3% had 5 or more. We found no correlation between preoperative CTC detection for a cut-off of 5 with neither overall survival (OS) [hazard ratio (HR): 0.99, P=0.887], disease-free survival (DFS) (HR: 0.95, P=0.39) nor relapse (32.7% vs. 28.8%, P=0.596). We also did not find a correlation between postoperative CTCs detection for a cut-off of 5 with either OS (HR: 1.01, P=0.808), DFS (HR: 0.95, P=0.952) or relapse (26.7% vs. 29.5%, P=0.83). The mean change in the number of CTCs over time between preoperative and postoperative samples was 2.13, with a standard deviation of 6.78. Conclusions: Despite the large cohort of patients included in this study, CTC monitoring in the perioperative setting was not correlated with relapse, DFS or OS in our study, and therefore cannot be recommended as a reliable biomarker for minimal residual disease (MRD) after surgery.

Atezolizumab Plus Bevacizumab as First-line Treatment for Patients With Metastatic Nonsquamous Non-Small Cell Lung Cancer With High Tumor Mutation Burden: A Nonrandomized Controlled Trial.

Importance: Antiangiogenic drug combinations with anti-programmed cell death 1 protein and anti-programmed cell death 1 ligand 1 (PD-L1) agents are a novel treatment option for lung cancer. However, survival remains limited, and the activity of these combinations for tumors with high tumor mutation burden (TMB) is unknown. Objective: To assess the clinical benefits and safety of atezolizumab plus bevacizumab for patients with high-TMB advanced nonsquamous non-small cell lung cancer (NSCLC). Design, Setting, and Participants: This multicenter, single-arm, open-label, phase 2 nonrandomized controlled trial (Atezolizumab Plus Bevacizumab in First-Line NSCLC Patients [TELMA]) included treatment-naive patients aged 18 years or older with confirmed stage IIIB-IV nonsquamous NSCLC with TMB of 10 or more mutations/megabase and no EGFR, ALK, STK11, MDM2, or ROS1 alterations. From May 2019 through January 2021, patients were assessed at 13 sites in Spain, with follow-up until February 28, 2022. Interventions: Participants were given atezolizumab, 1200 mg, plus bevacizumab, 15 mg/kg, on day 1 of each 21-day cycle. Treatment was continued until documented disease progression, unacceptable toxic effects, patient withdrawal, investigator decision, or death. Main Outcomes and Measures: The primary end point was 12-month progression-free survival (PFS) rate (according to Response Evaluation Criteria in Solid Tumours, version 1.1 criteria); PFS was defined as the time from enrollment to disease progression or death. Adverse events were monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: A total of 307 patients were assessed for trial eligibility, of whom 266 were ineligible for enrollment. Of the 41 patients enrolled, 3 did not fulfill all inclusion criteria and were excluded. The remaining 38 patients (28 [73.7%] male; mean [SD] age, 63.7 [8.3] years) constituted the per-protocol population. The 12-month PFS rate was 51.3% (95% CI, 34.2%-66.0%), which met the primary end point. The 12-month overall survival (OS) rate was 72.0% (95% CI, 54.1%-83.9%). The median PFS was 13.0 months (95% CI, 7.9-18.0 months), and the median OS was not reached. Of the 38 patients, 16 (42.1%) achieved an objective response and 30 (78.9%) achieved disease control. The median time to response was 2.8 months (IQR, 2.8-3.58 months), with a median duration of response of 11.7 months (range, 3.57-22.4 months; the response was ongoing at cutoff). Of 16 responses, 8 (50.0%) were ongoing. Most adverse events were grade 1 or 2. For atezolizumab, the most common adverse events were fatigue (6 [15.8%]) and pruritus (6 [15.8%]). For bevacizumab, they were hypertension (10 [26.3%]) and proteinuria (4 [10.5%]). Drug discontinuation occurred in 2 patients receiving atezolizumab (5.3%) and 3 patients receiving bevacizumab (7.9%). PD-L1 levels were not associated with response, PFS, or OS. Conclusions and Relevance: These findings suggest that atezolizumab with bevacizumab is a potential treatment for high-TMB nonsquamous NSCLC. Trial Registration: ClinicalTrials.gov Identifier: NCT03836066.

Patient-reported experience in lung and breast cancer through a patient journey.

OBJECTIVE: To analyse a patient journey based on the experience reported by  breast and lung cancer patients at Spanish hospital. Method: A mixed design was used, with interviews with 16 health  professionals and 25 patients (qualitative method) and a Net Promoter Score questionnaire to 127 patients (quantitative method). INCLUSION CRITERIA: oncology patients > 18 years treated in hospital between February-  May 2019. EXCLUSION CRITERIA: paediatric patients, in palliative care or who were  hospitalised at the time of the study. RESULTS: Six phases were identified from the data obtained in the qualitative method: my life before diagnosis; discovery; initiation; treatment;  followup; and my current life. In the my life before diagnosis phase, a  functional level of experience was established, as patients' lives met their  expectations. In the discovery phase, patients' expectations were observed to  be met, although several satellite experiences were found. In the initiation  phase, the experience tended to be negative due to long waiting times and  emotional and physical stress. The treatment phase was defined as a basic- poor experience, due to waiting times and lack of institutional support. The  experience in the follow-up phase was positive in terms of tests and visits, but  critical points were observed in waiting times. In the current phase, the effort  made by health professionals to ensure the best possible treatment and care  was mentioned. In terms of quantitative analysis, a positive score (46%) was obtained for the Net Promoter Score indicator, as 60% of patients were promoters, i.e. they were satisfied with the service offered by the hospital. CONCLUSIONS: This study provides insight into the experience of cancer patients in the six main stages of the disease. The most positive phases were "my life before diagnosis" and "follow-up" while the phases with a negative trend were "initiation" and "treatment" due to the waiting times  and the emotional burden on the patient.

OBJETIVO: Analizar la experiencia aportada por los pacientes con cáncer de  mama y pulmón utilizando la metodología del recorrido del paciente en un  hospital español. Método: Se empleó un diseño mixto, con entrevistas a 16 profesionales sanitarios y 25 pacientes (método cualitativo), y un cuestionario  basado en el indicador Net Promoter Score a 127 pacientes (método  cuantitativo). Criterios de inclusión: pacientes oncológicos > 18 años tratados  en el hospital entre febrero y mayo de 2019. Criterios de exclusión: pacientes pediátricos, en cuidados paliativos o que estaban hospitalizados en el  momento del estudio. RESULTADOS: Se identificaron seis fases a partir de los datos obtenidos en  el  método cualitativo: mi vida antes del diagnóstico, descubrir, comenzar, tratamiento, seguimiento y mi vida hoy. En la fase mi vida antes del  diagnóstico se estableció un nivel de experiencia funcional, ya que la vida  cumplía las expectativas de los pacientes. En la fase de descubrir se observó  que las expectativas de los pacientes se cumplían, aunque se  encontraron varias experiencias satélite. En la fase comenzar, la experiencia  tendió a ser negativa debido a los largos tiempos de espera y al estrés  emocional y físico. La fase de tratamiento se consideró como una experiencia  de nivel básico-deficiente, debido a los tiempos de espera y a la falta de apoyo  institucional. La experiencia en la fase de seguimiento fue positiva respecto   las pruebas y las visitas, pero se observaron puntos críticos en los tiempos de espera. en la fase mi vida hoy se mencionó el esfuerzo realizado  por  los profesionales sanitarios para garantizar el mejor tratamiento y  atención posibles. En cuanto al análisis cuantitativo, se obtuvo una puntuación positiva (46%) para el indicador Net Promoter Score, ya que el 60% de los  pacientes pertenecían a la categoría de promotores, es decir, estaban satisfechos con el servicio ofrecido por el hospital. CONCLUSIONES: Este estudio permite conocer la experiencia de los pacientes  oncológicos en las seis etapas principales de la enfermedad. Las fases más  positivas fueron "mi vida antes del diagnóstico" y "seguimiento", mientras que  las fases con tendencia negativa fueron "inicio" y "tratamiento" debido a los  tiempos de espera y la carga emocional que suponen para el paciente.

Deep metagenomics examines the oral microbiome during dental caries, revealing novel taxa and co-occurrences with host molecules.

Dental caries, the most common chronic infectious disease worldwide, has a complex etiology involving the interplay of microbial and host factors that are not completely understood. In this study, the oral microbiome and 38 host cytokines and chemokines were analyzed across 23 children with caries and 24 children with healthy dentition. De novo assembly of metagenomic sequencing obtained 527 metagenome-assembled genomes (MAGs), representing 150 bacterial species. Forty-two of these species had no genomes in public repositories, thereby representing novel taxa. These new genomes greatly expanded the known pangenomes of many oral clades, including the enigmatic Saccharibacteria clades G3 and G6, which had distinct functional repertoires compared to other oral Saccharibacteria. Saccharibacteria are understood to be obligate epibionts, which are dependent on host bacteria. These data suggest that the various Saccharibacteria clades may rely on their hosts for highly distinct metabolic requirements, which would have significant evolutionary and ecological implications. Across the study group, Rothia, Neisseria, and Haemophilus spp. were associated with good dental health, whereas Prevotella spp., Streptococcus mutans, and Human herpesvirus 4 (Epstein-Barr virus [EBV]) were more prevalent in children with caries. Finally, 10 of the host immunological markers were significantly elevated in the caries group, and co-occurrence analysis provided an atlas of potential relationships between microbes and host immunological molecules. Overall, this study illustrated the oral microbiome at an unprecedented resolution and contributed several leads for further study that will increase the understanding of caries pathogenesis and guide therapeutic development.

Progression-Free and Overall Survival for Concurrent Nivolumab With Standard Concurrent Chemoradiotherapy in Locally Advanced Stage IIIA-B NSCLC: Results From the European Thoracic Oncology Platform NICOLAS Phase II Trial (European Thoracic Oncology Platform 6-14).

INTRODUCTION: The NICOLAS study is the first completed single-arm phase II trial in stage III NSCLC evaluating hierarchically first the safety and then the efficacy of adding nivolumab concurrently to standard definitive concurrent chemoradiotherapy. The safety end point was reported earlier; here, we present the efficacy results. METHODS: Stage IIIA-B unresectable treatment-naive patients with NSCLC received three cycles of platinum-based chemotherapy and concurrent radiotherapy (66 Gy, 33 fractions), along with nivolumab (360 mg, 3-weekly). Nivolumab was continued as monotherapy consolidation for a maximum of 1 year (480 mg, 4-weekly). The primary end point was 1-year progression-free survival (PFS), with a target improvement compared with historical data of at least 15%, from 45% to 60%. To test this efficacy hypothesis, a sample size of 74 assessable patients provided a power of 83% with a one-sided alpha of 5%. RESULTS: A total of 79 patients were enrolled with a median follow-up of 21.0 months (interquartile range: 15.8-25.8 mo) for the primary PFS analysis. A total of 35.4% of the patients had stage IIIA, and 63.3% had stage IIIB disease. The 1-year PFS was 53.7% (95% confidence interval [CI]: 42.0%-64.0%) and the median PFS was 12.7 months (95% CI: 10.1-22.8 mo). Because 37 PFS events occurred in the first year posttreatment among the first 74 assessable patients, a 1-year PFS rate of at least 45% could not be rejected (p = 0.23). At an extended follow-up (median 32.6 mo), 37 deaths have been recorded, with a median overall survival (OS) of 38.8 months (95% CI: 26.8 mo-not estimable) and a 2-year OS rate of 63.7% (95% CI: 51.9%-73.4%). The OS of patients with stage IIIA disease was found to be significantly higher than patients with stage IIIB disease, with a 2-year OS of 81% and 56%, respectively (p = 0.037). CONCLUSIONS: PFS and OS are arithmetically higher in studies involving the same population. However, on the basis of the formal hierarchical efficacy analysis, we could not reject that the 1-year PFS rate is at least 45%.

Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis.

Anterior gradient 2 (AGR2) is a member of the protein disulfide isomerase (PDI) family, which plays a role in the regulation of protein homeostasis and the unfolded protein response pathway (UPR). AGR2 has also been characterized as a proto-oncogene and a potential cancer biomarker. Cellular localization of AGR2 is emerging as a key component for understanding the role of AGR2 as a proto-oncogene. Here, we provide evidence that extracellular AGR2 (eAGR2) promotes tumor metastasis in various in vivo models. To further characterize the role of the intracellular-resident versus extracellular protein, we performed a comprehensive protein-protein interaction screen. Based on these results, we identify AGR2 as an interacting partner of the mTORC2 pathway. Importantly, our data indicates that eAGR2 promotes increased phosphorylation of RICTOR (T1135), while intracellular AGR2 (iAGR2) antagonizes its levels and phosphorylation. Localization of AGR2 also has opposing effects on the Hippo pathway, spheroid formation, and response to chemotherapy in vitro. Collectively, our results identify disparate phenotypes predicated on AGR2 localization. Our findings also provide credence for screening of eAGR2 to guide therapeutic decisions.

JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines.

Mutations or deletions in exons 18-21 in the EGFR) are present in approximately 15% of tumors in patients with non-small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC50 from 49 nmol/L to 8 µmol/L (P < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC50 from 49 nmol/L to 2 nmol/L; P < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P < 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645-57. ©2017 AACR.

Evidence of eosinophil extracellular trap cell death in COPD: does it represent the trigger that switches on the disease?

In spite of the numerous studies on chronic obstructive pulmonary disease (COPD), the cellular and molecular basis of the disease's development remain unclear. Neutrophils and eosinophils are known to be key players in COPD. Recently, neutrophil extracellular trap cell death (NETosis), a mechanism due to decondensation and extrusion of chromatin to form extracellular traps, has been demonstrated in COPD. However, there is limited knowledge about eosinophil extracellular trap cell death (EETosis) and its role in the pathogenesis of COPD. The aim of this study was to evaluate EETosis in stable COPD. Induced sputum obtained from healthy smokers and low exacerbation risk COPD A or B group patients or high exacerbation risk COPD C or D group patients were included. Samples were examined using electron microscopy and immunofluorescence. Healthy smokers (n=10) and COPD A (n=19) group exhibited neutrophilic or paucigranulocytic phenotypes, with NETosis being absent in these patients. In contrast, COPD B (n=29), with eosinophilic or mixed phenotypes, showed EETosis and incipient NETosis. COPD C (n=18) and COPD D groups (n=13) were differentiated from low exacerbation rate-COPD group by the abundant cellular debris, with COPD C group having an eosinophilic pattern and numerous cells undergoing EETosis. A hallmark of this group was the abundant released membranes that often appeared phagocytosed by neutrophils, which coincidentally exhibited early NETosis changes. The COPD D group included patients with a neutrophilic or mixed pattern, with abundant neutrophil extracellular trap-derived material. This study is the first to demonstrate EETosis at different stages of stable COPD. The results suggest a role for eosinophils in COPD pathophysiology, especially at the beginning and during the persistence of the disease, regardless of whether the patient quit smoking, with EETosis debris probably triggering uncontrolled NETosis. The main target of these findings should be young smokers with the potential to develop COPD.

Diagrama A-D GOLD 2011 bajo el microscopio: Respondiendo a la fisiopatogénia de la EPOC con implicancias en el manejo de la enfermedad / GOLD 2011 A-D CHART under the microscope. Responding to COPD physiopathogeny with implications in disease management

El objetivo de este trabajo fue analizar el fenotipo celular en esputo de los pacientes con diagnóstico de EPOC clasificados según el diagrama A-D. Se reclutaron paciente ambos géneros, edad ≥ 60 años, ex fumadores de por lo menos 10 pack/año, con diagnóstico de EPOC en situación estable. Se los clasifico según GOLD 2011 en categorías clínicas A, B, C, D y se les analizó el patrón inflamatorio bronquial por medio de citología de esputo. Se estudiaron 85 pacientes con diagnóstico de EPOC distribuidos en categoría A (19), B (29), C (19) y D (18); la edad de estos últimos fue significativamente mayor que las del resto de los pacientes. El patrón predominante celular en esputo fue Eosinofílico (43), Neutrofílico (17), Mixto (9) y Paucigranulocítico (16). La distribución del patrón celular predominante en relación a cada grupo clínico de EPOC fue estadísticamente significativo p ≤ 0,001. El fenotipo celular Neutrofílico en el grupo A; eosinofílico y mixto en los grupos B y C y en el grupo D, aun presentes los eosinófilos predominó el patrón Neutrofílico. Concluimos que este estudio identificó patrones celulares inflamatorios que caracterizan cada grupo del diagrama A-D de la EPOC lo cual puede contribuir a explicar su carácter heterogéneo, personalizar el tratamiento y especialmente apunta a identificar tempranamente el paciente en riesgo de iniciar y perpetuar la enfermedad.

GOLD 2011 A-D CHART under the microscope: Responding to COPD physiopathogeny with implications in disease management

The purpose of this study was to analyze sputum cellular phenotype in patients with a diagnosis of COPD classified according to the A-D chart. We included patients of both genders, aged ≥ 60 years, who were former smokers of at least 10 packets/year, with a diagnosis of COPD under stable conditions. They were classified according to the 2011 GOLD criteria into clinical categories A, B, C, D and their bronchial inflammatory pattern was analyzed using sputum cytology. Eighty-five patients with a diagnosis of COPD were divided into category A (19), B (29), C (19) and D (18); the age of the latter was significantly higher than the rest of the patients. The predominant cellular pattern in sputum was eosinophilic (43), neutrophilic (17), mixed (9) and paucigranulocytic (16). The distribution of the predominant cellular pattern in connection with each COPD clinical group was statistically significant p ≤ 0.001. The neutrophilic cellular phenotype was predominant in group A; the eosinophilic and mixed phenotypes in groups B and C, and in group D, even though eosinophils were present, the predominant pattern was neutrophilic. We concluded that this study identified inflammatory cellular patterns that distinguish each group in the COPD A-D chart, which can contribute to explain their heterogeneous nature, customize treatment and, most of all, identify patients at risk of disease onset and perpetuation at an early stage.

Inhibition of IKK/NF-κB Signaling Enhances Differentiation of Mesenchymal Stromal Cells from Human Embryonic Stem Cells.

Embryonic stem cell-derived mesenchymal stromal cells (MSCs; also known as mesenchymal stem cells) represent a promising source for bone regenerative medicine. Despite remarkable advances in stem cell biology, the molecular mechanism regulating differentiation of human embryonic stem cells (hESCs) into MSCs remains poorly understood. Here, we report that inhibition of IκB kinase (IKK)/nuclear factor kappa B (NF-κB) signaling enhances differentiation of hESCs into MSCs by expediting the loss of pluripotent markers and increasing the expression of MSC surface markers. In addition, a significantly higher quantity of MSCs was produced from hESCs with IKK/NF-κB suppression. These isolated MSCs displayed evident multipotency with capacity to terminally differentiate into osteoblasts, chondrocytes, and adipocytes in vitro and to form bone in vivo. Collectively, our data provide important insights into the role of NF-κB in mesenchymal lineage specification during hESC differentiation, suggesting that IKK inhibitors could be utilized as an adjuvant in generating MSCs for cell-mediated therapies.

Single CD271 marker isolates mesenchymal stem cells from human dental pulp.

Mesenchymal stem cells (MSCs) are a promising tool in regenerative medicine due to their capacity to differentiate into multiple lineages. In addition to MSCs isolated from bone marrow (BMSCs), adult MSCs are isolated from craniofacial tissues including dental pulp tissues (DPs) using various stem cell surface markers. However, there has been a lack of consensus on a set of surface makers that are reproducibly effective at isolating putative multipotent dental mesenchymal stem cells (DMSCs). In this study, we used different combinations of surface markers (CD51/CD140α, CD271, and STRO-1/CD146) to isolate homogeneous populations of DMSCs from heterogeneous dental pulp cells (DPCs) obtained from DP and compared their capacity to undergo multilineage differentiation. Fluorescence-activated cell sorting revealed that 27.3% of DPCs were CD51(+)/CD140α(+), 10.6% were CD271(+), and 0.3% were STRO-1(+)/CD146(+). Under odontogenic conditions, all three subsets of isolated DMSCs exhibited differentiation capacity into odontogenic lineages. Among these isolated subsets of DMSCs, CD271(+) DMSCs demonstrated the greatest odontogenic potential. While all three combinations of surface markers in this study successfully isolated DMSCs from DPCs, the single CD271 marker presents the most effective stem cell surface marker for identification of DMSCs with high odontogenic potential. Isolated CD271(+) DMSCs could potentially be utilized for future clinical applications in dentistry and regenerative medicine.

Characterization of the osteogenic potential of mesenchymal stem cells from human periodontal ligament based on cell surface markers.

Mesenchymal stem cell (MSC)-mediated therapy has been shown to be clinically effective in regenerating tissue defects. For improved regenerative therapy, it is critical to isolate homogenous populations of MSCs with high capacity to differentiate into appropriate tissues. The utilization of stem cell surface antigens provides a means to identify MSCs from various tissues. However, few surface markers that consistently isolate highly regenerative MSCs have been validated, making it challenging for routine clinical applications and making it all the more imperative to identify reliable surface markers. In this study, we used three surface marker combinations: CD51/CD140α, CD271, and STRO-1/CD146 for the isolation of homogenous populations of dental mesenchymal stem cells (DMSCs) from heterogeneous periodontal ligament cells (PDLCs). Fluorescence-activated cell sorting analysis revealed that 24% of PDLCs were CD51(+)/CD140α(+), 0.8% were CD271(+), and 2.4% were STRO-1(+)/CD146(+). Sorted cell populations were further assessed for their multipotent properties by inducing osteogenic and chondrogenic differentiation. All three subsets of isolated DMSCs exhibited differentiation capacity into osteogenic and chondrogenic lineages but with varying degrees. CD271(+) DMSCs demonstrated the greatest osteogenic potential with strong induction of osteogenic markers such as DLX5, RUNX2, and BGLAP. Our study provides evidence that surface marker combinations used in this study are sufficient markers for the isolation of DMSCs from PDLCs. These results provide important insight into using specific surface markers for identifying homogenous populations of DMSCs for their improved utilization in regenerative medicine.

Niveles séricos de aluminio en pacientes con enfermedad de Alzheimer / Aluminium serum levels in Alzheimer disease patients

En la determinación de los niveles séricos de aluminio de los pacientes con enfermedad de Alzheimer(EA), ninguno presentó elevaciones de dicho metal por encima del límite permisible. Se observaron cifras superiores de aluminio en los pacientes con EA en comparación con el grupo control, además de ser significativamente mayores en el sexo femenino y en aquellos que consumían antiácidos...

Niveles de aluminio sérico en un grupo de pacientes con enfermedad de Alzheimer / Serum levels of aluminum in a group of patients with Alzheimer's disease / Níveis séricos de alumínio em um grupo de pacientes com doença de Alzheimer

La Enfermedad de Alzheimer (EA) es una patología neurodegenerativa frecuente en la población senil. Clínicamente se caracteriza por la pérdida progresiva de la memoria y otras habilidades cognitivas. Se han propuesto diversas causas como desencadenantes de la EA, entre las cuales se encuentran factores ambientales como malnutrición, lesiones a nivel craneal y exposición al aluminio (Al), debido a que este metal es una sustancia neurotóxica. El objetivo del presente estudio fue evaluar los niveles de aluminio sérico en pacientes con enfermedad de Alzheimer, internados en un geriátrico en el municipio Veroes, Estado Yaracuy, durante el período mayo-junio de 2013. La muestra estuvo conformada por 22 pacientes con EA, y el grupo control estuvo representado por 12 pacientes sin EA. Las concentraciones de aluminio sérico fueron determinadas por Espectrofotometría de Absorción Atómica Electrotérmica (ETAAS) con horno de grafito. Se obtuvieron valores de la mediana de aluminio sérico de 2,15 mg/L, con un máximo de elevación de 3,0 mg/L para el grupo con EA, mientras que el control fue de 1,60 mg/L, con un máximo de 3,30 mg/L. Ninguno de los pacientes presentaron niveles de Al sérico por encima del límite permisible. Se observaron cifras superiores de este metal en los pacientes con EA en comparación con el grupo control, además de ser significativamente mayores en el género femenino y en aquellos que consumían antiácidos.

Alzheimer's disease (AD) is a common neurodegenerative disorder in the elderly population. It is clinically characterized by progressive loss of memory and other cognitive skills. There are several proposed AD causes as triggers, among which are environmental factors including malnutrition, cranial injuries and exposure level aluminum (Al), because this metal is a neurotoxic substance. The aim of this study was to evaluate serum aluminum levels in patients with Alzheimer's disease, institutionalized in Veroes town, Yaracuy state during May-June 2013 period. The sample consisted of 22 patients with AD and the control group was represented by 12 patients without AD. Serum aluminum concentrations were determined by Electrothermal Atomic Absorption Spectrophotometry (ETAAS) with graphite furnace. Median values of serum aluminum of 2.15 mg/L, with a maximum height of 3.0 mg/L for the AD group were obtained, while the control was 1.60 mg/L, with a maximum of 3.30 mg/L. None of the patients had serum Al levels above the allowable limit. Higher figures of this metal were observed in patients with AD compared with the control group, as well as being significantly higher in females and in those eating antacids.

A doença de Alzheimer (DA) é uma desordem neurodegenerativa frequente na população idosa. Clinicamente caracteriza-se pela perda progressiva da memória e outras habilidades cognitivas. Várias causas têm sido propostas como gatilhos para DA, incluindo fatores ambientais tais como a desnutrição, lesões cranianas e exposição de alumínio (Al), devido a que este metal é uma substância neurotóxica. O objetivo deste estudo foi avaliar os níveis de alumínio sérico em pacientes com doença de Alzheimer, hospitalizados na cidade Veroes, Estado Yaracuy, durante o período maio-junho de 2013. A mostra consistiu de 22 pacientes com DA e o grupo controle foi representado por 12 pacientes sem DA. Concentrações de alumínio sérico foram determinadas por Espectrofotometria de Absorção Atômica Eletrotérmica (ETAAS) com forno de grafite. Os valores da mediana de alumínio sérico de 2,15 mg/L, com uma altura máxima de 3,0 mg/L para o grupo DA foram obtidos, enquanto que para o grupo controle foi de 1,60 mg/L, com um máximo de 3,30 mg/L. Nenhum dos pacientes tinha níveis séricos de Al acima do limite permitido. Foram observados valores mais elevados deste metal nos pacientes com DA em comparação com o grupo controle, além de ser significativamente maior no sexo feminino e nas pessoas que consumiam antiácidos.

Differences in cerebrospinal fluid inflammatory cell reaction of patients with leptomeningeal involvement by lymphoma and carcinoma.

Dissemination of neoplastic cells into the cerebrospinal fluid (CSF) and leptomeninges is a devastating complication in patients with epithelial cell neoplasia (leptomeningeal carcinomatosis [LC]) and lymphomas (lymphomatous meningitis [LyM]). Information about the surrounding inflammatory cell populations is scarce. In this study, flow cytometry immunophenotyping was used to describe the distribution of the main leukocyte populations in the CSF of 83 patients diagnosed with neoplastic meningitis (LC, n = 65; LyM, n = 18). These data were compared with those obtained in the CSF from 55 patients diagnosed with the same groups of neoplasia without meningeal involvement (solid tumors, n = 36; high-grade lymphoma, n = 19). Median (interquartile) rates of lymphocytes, monocytes, and polymorphonuclear (PMN) cells were 59.7% (range, 35-76.6%), 24% (range, 16-53%), and 1.5% (range, 0-7.6%) in LC, respectively, and 98.5% (range, 70.8-100%), 1.5% (range, 0-29.3%), and 0% in LyM, respectively (P < 0.001). No difference was observed between patients with breast adenocarcinoma (n = 30) and lung adenocarcinoma (n = 21), nor with different rates of malignant CSF involvement. Patients with lymphoma (with or without LyM) had a similar CSF leukocyte distribution, but cancer patients with LC and without LC had a distinctive PMN cell rate (P = 0.002). These data show that CSF samples from patients with LC have a greater number of inflammatory cells and a different leukocyte distribution than seen in the CSF from patients with LyM. Description of PMN cells is a distinctive parameter of patients with LC, compared with the CSF from patients with LyM and patients with cancer but without LC.

Evaluation of clinical use and effectiveness of darbepoetin alfa in cancer patients with chemotherapy-induced anemia.

PURPOSE: To investigate the patterns of use of darbepoetin alfa in Spanish centers, and to evaluate its effectiveness in the treatment of chemotherapy-induced anemia under clinical practice conditions. METHODS: This was an observational, retrospective, multicenter study in adult patients with non-myeloid malignancies who initiated chemotherapy and darbepoetin alfa. Data was collected for up to 16 weeks or until treatment discontinuation. RESULTS: A total of 685 patients (72.7% with solid tumors and 27.3% with hematologic malignancies) were included in the study. Median age was 64.7 years (range 18.5-88.9 years), 50.7% were women, 82.4% had ECOG status 0-1 and 80.5% had stage III/IV cancer. At darbepoetin initiation, mean hemoglobin (Hb) was 100 g/L (SD 10), with 11.0% and 23.1% of patients below 90 g/L in solid and hematologic malignancies, respectively. A decrease in transfusion requirements was observed between weeks 5-16 with respect to weeks 0-16 (13.3% [95% CI: 10.7 to 15.9] versus 19.0% [95% CI: 16.0 to 22.0]). Hb levels were significantly increased during the treatment (mean change of 10.4 g/L for solid tumors [p < 0.001], and 16.6 g/L for hematologic malignancies [p < 0.001]). The percentage of patients with baseline Hb level <110 g/L who achieved an Hb level ≥110 g/L during the study was 66.5% (95% CI: 62.5% to 70.5%). Six serious adverse reactions were considered related to darbepoetin alfa (thromboembolic events, 1.0%). CONCLUSIONS: With the limitation of a retrospective design, our results suggest that darbepoetin alfa is a well tolerated treatment that increases hemoglobin levels and reduces the need for transfusion in cancer patients receiving chemotherapy in clinical practice.

Toll-like receptors, inflammation, metabolism and obesity.

Obesity is a highly prevalent health problem in Western countries that leads to many important diseases such as type 2 diabetes and metabolic syndrome being now considered an inflammatory chronic disease. Adipocytes are no longer considered passive cells storing fat since they are major producers of inflammatory cytokines during obesity. Adipocytes and macrophages share many biological properties including the synthesis of similar molecules regulating inflammation. Fatty acid levels are elevated in obesity and induce inflammatory pathways by yet a mostly unknown mechanism, leading to the development of insulin and leptin resistance. Recent studies suggest that these effects could be mediated through the activation of toll-like receptors (TLR). TLR signalling pathways might contribute to the development of obesity-associated insulin resistance, thus representing a connection between innate immunity and metabolism. Here, we summarize the recent evidence for the important role that TLRs play in adipose tissue, obesity and insulin resistance.