Leishmania (L.) amazonensis LaLRR17 increases parasite entry in macrophage by a mechanism dependent on GRP78.

Leishmaniases affect 12 million people worldwide. They are caused by Leishmania spp., protozoan parasites transmitted to mammals by female phlebotomine flies. During the life cycle, promastigote forms of the parasite live in the gut of infected sandflies and convert into amastigotes inside the vertebrate macrophages. The parasite evades macrophage's microbicidal responses due to virulence factors that affect parasite phagocytosis, survival and/or proliferation. The interaction between Leishmania and macrophage molecules is essential to phagocytosis and parasite survival. Proteins containing leucine-rich repeats (LRRs) are common in several organisms, and these motifs are usually involved in protein­protein interactions. We have identified the LRR17 gene, which encodes a protein with 6 LRR domains, in the genomes of several Leishmania species. We show here that promastigotes of Leishmania (L.) amazonensis overexpressing LaLRR17 are more infective in vitro. We produced recombinant LaLRR17 protein and identified macrophage 78 kDa glucose-regulated protein (GRP78) as a ligand for LaLRR17 employing affinity chromatography followed by mass spectrometry. We showed that GRP78 binds to LaLRR17 and that its blocking precludes the increase of infection conferred by LaLRR17. Our results are the first to report LRR17 gene and protein, and we hope they stimulate further studies on how this protein increases phagocytosis of Leishmania.

Immunogenicity of COVID-19 vaccines in lung cancer patients.

OBJECTIVE: Patients with lung cancer are at increased risk of SARS-CoV-2 infection and severe complications from COVID-19, but information on the efficacy of anti-SARS-CoV-2 vaccine in these patients is scarce. We aimed at evaluating the safety and immunogenicity of COVID-19 vaccines in this population. PATIENTS AND METHODS: The prospective, nationwide SOLID substudy, enrolled adults with lung cancer who were fully vaccinated against COVID-19. Serum anti-SARS-CoV-2 IgG antibody levels were quantitatively assessed two weeks and six months after receipt of the last dose using a chemiluminescent microparticle immunoassay. Multivariate odds ratios for the association between demographic and clinical factors and seronegativity after vaccination were estimated. RESULTS: 1973 lung cancer patients were enrolled. Most patients had stage IV disease (66%) and were receiving active cancer treatment (82.7%). No significant differences were found in the probability of being seronegative for anti-SARS-CoV-2 IgG antibodies after full vaccination between patients who were receiving active cancer treatment and those who were not (p = 0.396). The administration of immunotherapy or oral targeted therapy and immunization with mRNA-1273 COVID-19 vaccine were factors independently associated with increased odds of being seropositive after vaccination. From all patients, 1405 received the second dose of vaccine and high levels of antibody titers were observed in 93.6% of patients two weeks after second dose. At six months, multivariate logistic regression analysis showed that performance status ≥ 2 was independently associated with a higher probability of being seronegative after full vaccination with an OR 4.15. On the other hand, received chemotherapy or oral target therapy and vaccination with mRNA-1273 were a factor independently associated with lower odds of being seronegative after full vaccination with an OR 0.52, 0.37 and 0.34, respectively. CONCLUSIONS: Lung cancer patients can safely achieve a strong immune response against SARS-CoV-2 after full vaccination, regardless of the cancer treatment received. TRIAL REGISTRATION: NCT04407143.

Changes in Faecal and Plasma Amino Acid Profile in Dogs with Food-Responsive Enteropathy as Indicators of Gut Homeostasis Disruption: A Pilot Study.

Dogs suffering from food-responsive enteropathy (FRE) respond to an elimination diet based on hydrolysed protein or novel protein; however, studies regarding the amino acid profile in FRE dogs are lacking. The aim of this pilot study was to evaluate whether the plasma and faecal amino acid profiles differed between control and FRE dogs and whether these could serve as indicators of severity of illness. Blood, faecal samples, body condition score, and severity of clinical signs based on the canine inflammatory bowel disease activity index were collected before starting the elimination diet. FRE dogs had lower proportions of plasma Asparagine, Histidine, Glycine, Cystine, Leucine, and branched-chain/aromatic amino acids; however, Phenylalanine increased. In faecal samples, Cystine was greater whereas Phenylalanine was lesser in sick dogs compared to control. Leucine correlated negatively with faecal humidity (r = -0.66), and Leucine and Phenylalanine with faecal fat (r = -0.57 and r = -0.62, respectively). Faecal Phenylalanine (r = 0.80), Isoleucine (r = 0.75), and Leucine (r = 0.92) also correlated positively with total short-chain fatty acids, whereas a negative correlation was found with Glycine (r = -0.85) and Cystine (r = -0.61). This study demonstrates the importance of Leucine and Phenylalanine amino acids as indicators of the disease severity in FRE dogs.

Revisiting phylogeny, systematics, and biogeography of a Pleistocene radiation.

PREMISE: Pilosocereus (Cactaceae) is an important dry forest element in all subregions and transitional zones of the neotropics, with the highest diversity in eastern Brazil. The genus is subdivided into informal taxonomic groups; however, most of these are not supported by recent molecular phylogenetic inferences. This lack of confidence is probably due to the use of an insufficient number of loci and the complexity of cactus diversification. Here, we explored the species relationships in Pilosocereus in more detail, integrating multilocus phylogenetic approaches with the assessment of the ancestral range and the effect of geography on diversification shifts. METHODS: We used 28 nuclear, plastid, and mitochondrial loci from 54 plant samples of 31 Pilosocereus species for phylogenetic analyses. We used concatenated and coalescent phylogenetic trees and Bayesian models to estimate the most likely ancestral range and diversification shifts. RESULTS: All Pilosocereus species were clustered in the same branch, except P. bohlei. The phylogenetic relationships were more associated with the geographic distribution than taxonomic affinities among taxa. The genus began diversifying during the Plio-Pleistocene transition in the Caatinga domain and experienced an increased diversification rate during the Calabrian age. CONCLUSIONS: We recovered a well-supported multispecies coalescent phylogeny. Our results refine the pattern of rapid diversification of Pilosocereus species across neotropical drylands during the Pleistocene and highlight the need for taxonomic rearrangements in the genus. We recovered a pulse of diversification during the Pleistocene that was likely driven by multiple dispersal and vicariance events within and among the Caatinga, Cerrado, and Atlantic Forest domains.

Monitoring of Circulating Tumor DNA Predicts Response to Treatment and Early Progression in Follicular Lymphoma: Results of a Prospective Pilot Study.

PURPOSE: Follicular lymphoma (FL) is the most frequent indolent non-Hodgkin lymphoma. Around 20% of patients suffer early disease progression within 24 months (POD24) of diagnosis. This study examined the significance of circulating tumor DNA (ctDNA) in predicting response to therapy and POD24 in patients with FL. EXPERIMENTAL DESIGN: We collected 100 plasma samples, before and during the treatment, from 36 patients with FL prospectively enrolled in 8 Spanish hospitals. They were treated with a chemotherapy-rituximab regimen and followed up for a median of 3.43 years. We performed targeted deep sequencing in cell-free DNA (cfDNA) and tumor genomic DNA from 31 diagnostic biopsy samples. RESULTS: Of the alterations detected in the diagnostic tissue samples, 73% (300/411) were also identified in basal cfDNA. The mean numbers of alterations per basal cfDNA sample in patients who suffered progression of disease within 24 months (POD24-pos) or did not achieve complete response (non-CR) were significantly higher than in POD24-neg or CR patients (unpaired samples t test, P = 0.0001 and 0.001, respectively). Pretreatment ctDNA levels, as haploid genome equivalents per milliliter of plasma, were higher in patients without CR (P = 0.02) and in POD24-pos patients compared with POD24-neg patients (P < 0.001). Dynamic analysis showed that ctDNA levels decreased dramatically after treatment, although the reduction was more significant in patients with CR and POD24-neg patients. CONCLUSIONS: Basal ctDNA levels are associated with the risk of early progression and response to treatment in FL. cfDNA monitoring and genotyping during treatment and follow-up predict response to treatment and early progression.

Análise de complicações de lipoenxertias realizadas em hospital público universitário entre 2015 e 2018: estudo retrospectivo transversal / Analysis of complications from fat grafting performed at a public university hospital between 2015 and 2018: a cross-sectional retrospective study

Introdução: A lipoenxertia consiste no processo de coleta de gordura de uma área doadora de gordura por meio de lipoaspiração seguida da realocação desse tecido em área receptora por meio de seringas e cânulas. É um processo seguro utilizado em cirurgias estéticas e reconstrutivas, de acordo com a literatura. O objetivo é avaliar as taxas de complicações dos procedimentos de lipoenxertia realizados em um hospital público universitário no período de 2015 a 2018, em comparação com dados previamente relatados na literatura. Métodos: Estudo observacional retrospectivo desenvolvido em hospital universitário público de Campinas - SP a partir da revisão de prontuários de pacientes submetidos a lipoenxertia nesta instituição de 2015 a 2018. Resultados: Em relação às complicações, a grande maioria correspondeu à reabsorção de gordura (62%). O hematoma correspondeu ao segundo mais comum (38% dos casos), seguido do edema (19%). Dor e discromia vieram em seguida, com 10% e 7% dos casos, respectivamente. Apenas um caso de infecção de ferida operatória foi descrito. Outras complicações menos frequentes foram hiperemia (5%), assimetrias (5%), descamação (2%), parestesia local (3%) e lesão cutânea (2%). Nenhuma outra complicação maior foi relatada, como embolia gordurosa ou complicações cirúrgicas graves como sangramento, sepse, anafilaxia, entre outras. Conclusão: Os procedimentos de lipoaspiração para coleta de gordura e lipoenxertia mostraram-se seguros e com baixo índice de complicações na amostra estudada, concordando com dados da literatura.

Introduction: Fat grafting consists of collecting fat from one fat donor area via liposuction, then reallocating this tissue into a receptor area through syringes and cannulas. According to the literature, it is a safe process used in aesthetic and reconstructive surgeries. The objective is to evaluate complication rates of fat grafting procedures performed in a public university hospital from 2015 to 2018 in comparison with data previously reported in the literature. Methods: A retrospective observational study developed at a public university hospital in Campinas-SP based on the revision of medical records of patients who underwent the fat grafting procedure in this institution from 2015 to 2018. Results: Regarding the complications, the vast majority corresponded to fat reabsorption (62%). Bruise corresponded to the second most common (38% of cases), followed by edema (19%). Pain and dyschromia followed next, with 10% and 7% of cases, respectively. Only one case of operative wound infection was described. Other less frequent complications included hyperemia (5%), asymmetries (5%), desquamation (2%), local paraesthesia (3%) and skin lesion (2%). No other larger complication was reported, such as fat embolism or severe surgical complications such as bleeding, sepsis, or anaphylaxis. Conclusion: The procedures of liposuction for fat collection and fat grafting were proved to be safe, yielding low complication rates in the studied sample, which agrees with data reported in the literature.

Perfil epidemiológico dos pacientes submetidos à cirurgia para tratamento de fratura de face em um hospital universitário / Epidemiological profile of patients undergoing surgery to treat facial fractures in a university hospital

Introdução: Trauma facial apresenta relevância estética, social e econômica. Conhecer sua epidemiologia permite formular medidas de prevenção, educação e sistematização de atendimento. Métodos: Triagem, através do sistema de informação hospitalar, buscando pacientes que necessitaram de cirurgia para fratura de face entre abril de 2015 e abril de 2020. Foram, então, coletados dados epidemiológicos. Resultados: Foram selecionados 141 pacientes. A média de idade foi 34 anos, com maioria do sexo masculino (85%). A etiologia predominante foi acidente com veículo automotor e a fratura cirúrgica mais prevalente foi a de órbita (67%). A mediana de tempo entre o trauma e a cirurgia foi de 18 dias. Sessenta pacientes apresentaram lesões associadas à fratura de face, com destaque para as ortopédicas e neurológicas. Conclusão: A etiologia mais comum de fraturas faciais cirúrgicas foi acidente de trânsito, sendo o sexo masculino mais afetado. As fraturas de órbita foram as mais tratadas cirurgicamente.

Introduction: Facial trauma presents aesthetic, social and economic relevance. Knowing its epidemiology makes it possible to formulate measures for prevention, education and systematization of care. Methods: Research through the hospital information system, looking for patients who needed to undergo surgery for face fracture between April 2015 and April 2020. Epidemiological data were then collected. Results: 141 patients were selected. The average age was 34 years, with most males (85%). The predominant etiology was motor vehicle accidents, and the most prevalent surgical fracture was orbit (67%). The median time between trauma and surgery was 18 days. Sixty patients had injuries associated with facial fractures, especially orthopedic and neurological injuries. Conclusion: The most common etiology of surgical facial fractures was a traffic accident, predominantly among men. Orbit fractures were the most surgically treated.

Overall Survival and Biomarker Analysis of Neoadjuvant Nivolumab Plus Chemotherapy in Operable Stage IIIA Non-Small-Cell Lung Cancer (NADIM phase II trial).

PURPOSE: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported. METHODS: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial. RESULTS: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72). CONCLUSION: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

Bcl-2 Immunoexpression in Feline Epitheliotropic Intestinal T-Cell Lymphomas.

Lymphoma is the most common malignant hematopoietic neoplasm in domestic felines. Twenty-two cases of feline epitheliotropic duodenal T-cell lymphoma were characterized morphologically and immunohistochemically (CD3, Pax5, Ki-67), and Bcl-2 immunoexpression was established. Most cases were in domestic shorthair cats (88.2%), with a mean age of 11.2 years. All lymphomas were CD3+, with a low-to-moderate expression of Ki-67 (<30%). A correlation between the tumoral pattern of infiltration in the lamina propria and the intraepithelial distribution of the neoplastic lymphocytes was established (p = 0.0155). Intraepithelial nests of neoplastic lymphocytes were predominantly observed in lymphomas with a patchy distribution in the lamina propria, whereas intraepithelial plaques were seen in lymphomas with an obliteration pattern. Bcl-2 was expressed in neoplastic cells in all cases, and a higher expression was associated with increased villous stunting (p = 0.0221), and tended to be present in those cases with increased epithelial damage. The expression of Bcl-2 and the degree of epitheliotropism were correlated with neoplastic progression in epitheliotropic intestinal T-cell lymphomas; those displaying high Bcl-2 immunoexpression showed increased villous stunting and epithelial damage, suggesting that Bcl-2 is overexpressed in advanced tumor stages, and may be used as a predictor of tumoral behavior in feline epitheliotropic intestinal T-cell lymphomas. This entity showed many similarities with human MEITL, so the latter entity should be considered in further lymphoma classifications of domestic animals.

Seroprevalence and immunological memory against SARS-CoV-2 in lung cancer patients: the SOLID study.

BACKGROUND: At present, we did not find any articles that studied seroprevalence and its persistence several months later in lung cancer patients in the setting of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with coronavirus disease 2019 (COVID-19) go on to develop antibodies (Abs) against viral proteins. However, it is not known how long these Abs last nor whether cancer treatments could affect the duration of immune response. METHODS: This prospective, longitudinal, multicenter serological study in the setting of SARS-CoV-2 infection was carried out in 50 Spanish hospitals. Eligibility criterion was the diagnosis of any lung cancer. The determination of anti-SARS-CoV-2 IgG Abs was performed by qualitative immuno-enzymatic assay using enzyme-linked immunosorbent assay (ELISA) kit from NovaLisa whose Abs target the recombinant antigen N of the nucleocapsid of SARS-CoV-2. The first Ab determination was performed between April 21 and June 3, 2020. The second Ab determination was performed in all previously seropositive patients, between September 10 and November 20, 2020. Study objectives were to prospectively determine seroprevalence in unselected lung cancer patients during the first wave of the pandemic; the persistence of immunity; protection or lack thereof against reinfection; and the influence of treatments on maintenance or loss of immunity. RESULTS: Of 1,500 patients, 128 were seropositive, overall prevalence of 8.5% seropositivity [95% confidence interval (CI): 7.2-10.1%]. Seventy-five percent were in active cancer treatment. Forty-seven point seven percent of IgG positive participants had experienced a symptomatic illness suspected of being infected with SARS-CoV-2 (95% CI: 38.8-56.6%). A second determination was performed on average 4.5 months later [interquartile range (IQR), 4.0-5.0 months] and obtained for 104 of the initially seropositive patients (81%), it could not be obtained in 24 patients, the majority due to death caused by disease progression (73%). In the second determination, IgG was not detected in 30.8% of patients. The severity of the infection, the need for hospitalization (P=0.032) and the presence of symptoms at diagnosis (P=0.02) were associated with persistence of immunity in the second determination. No variables or treatments received were associated with Abs loss. CONCLUSIONS: Immunity against SARS-CoV-2 does not appear to be compromised by treatment and persists beyond 4 months. Neither do mortality rates appear to be particularly high in this unselected population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04407143.

Use of immune checkpoint inhibitors in patients with solid tumors and pre-existing autoimmune or inflammatory disease: real-world data.

AIM: Immune checkpoint inhibitors (ICIs) are a cornerstone in cancer treatment but they can induce immune-related adverse events (irAEs). Furthermore, patients with pre-existing autoimmune and/or inflammatory disease (AID) have been excluded from clinical trials. The objective of this study is to evaluate the efficacy and safety of ICIs in patients with cancer and AID. MATERIALS & METHODS: This is an observational, retrospective study carried out at the Medical Oncology Department of Hospital Universitario Puerta de Hierro, Majadahonda, Madrid between January 2016 and December 2018. RESULTS: A total of 202 cancer patients treated with ICIs were included, 15 (7, 4%) of them had pre-existing autoimmune diseases. The most frequent pre-existing AID were thyroid diseases (33.3%): autoimmune hypothyroidism, Graves-Basedow disease and Hashimoto's thyroiditis. Three patients had psoriasis, two antinuclear antiboides + polyarthritis, one rheumatoid arthritis, another latent autoimmune diabetes in adults, another systemic lupus erythematosus and the last one, a polymyalgia rheumatica. In this series, the majority of patients (73.33%) did not experience any flare up of their autoimmune disease. In patients who had AID flare up, this was treated with corticosteroids. The most frequent cause of immunotherapy discontinuation was tumor progression (40%). A total of 20% of patients had to discontinue immunotherapy due to toxicity. CONCLUSION: In our series, AID flare ups or irAEs in patients with pre-existing AID who receive immunotherapy are not very common and can often be controlled without interrupting treatment. Prospective studies are needed to establish the incidence of irAEs in patients with pre-existing autoimmune conditions, evaluate risk-benefit and elaborate management clinical guidelines in this population.

Prognostic model of long-term advanced stage (IIIB-IV) EGFR mutated non-small cell lung cancer (NSCLC) survivors using real-life data.

BACKGROUND: There is a lack of useful diagnostic tools to identify EGFR mutated NSCLC patients with long-term survival. This study develops a prognostic model using real world data to assist clinicians to predict survival beyond 24 months. METHODS: EGFR mutated stage IIIB and IV NSCLC patients diagnosed between January 2009 and December 2017 included in the Spanish Lung Cancer Group (SLCG) thoracic tumor registry. Long-term survival was defined as being alive 24 months after diagnosis. A multivariable prognostic model was carried out using binary logistic regression and internal validation through bootstrapping. A nomogram was developed to facilitate the interpretation and applicability of the model. RESULTS: 505 of the 961 EGFR mutated patients identified in the registry were included, with a median survival of 27.73 months. Factors associated with overall survival longer than 24 months were: being a woman (OR 1.78); absence of the exon 20 insertion mutation (OR 2.77); functional status (ECOG 0-1) (OR 4.92); absence of central nervous system metastases (OR 2.22), absence of liver metastases (OR 1.90) or adrenal involvement (OR 2.35) and low number of metastatic sites (OR 1.22). The model had a good internal validation with a calibration slope equal to 0.781 and discrimination (optimism corrected C-index 0.680). CONCLUSIONS: Survival greater than 24 months can be predicted from six pre-treatment clinicopathological variables. The model has a good discrimination ability. We hypothesized that this model could help the selection of the best treatment sequence in EGFR mutation NSCLC patients.

A construção histórica do conceito de enzima e sua abordagem em livros didáticos de biologia / Historical construction of the concept of the enzyme and approaches in biology textbooks

Resumo O uso de história e filosofia da ciência no ensino-aprendizagem é comumente negligenciado, linear e/ou descontextualizado nos livros didáticos. Isso aconteceria com a história do conceito de enzimas? Este trabalho busca investigar essa questão. Para a fundamentação teórica, foi realizada breve revisão bibliográfica, investigando-se como o conceito de enzimas é apresentado em nove livros didáticos, seguindo três categorias de análise. Encontrou-se, de forma geral, falta de interconexão nos assuntos de bioquímica, sendo as enzimas usualmente apresentadas apenas pelo modelo "chave-fechadura", que hoje não é representativo da complexidade do fenômeno. Além disso, foram observados limites conceituais decorrentes da ausência ou deficiência na contextualização histórica presente no material didático.

Abstract The use of the history and philosophy of science in teaching and learning is commonly neglected, linear, and/or out of context in textbooks. This article investigates whether this also occurs with the concept of enzymes. A brief review of the literature establishes the theoretical foundation to investigate how the concept of enzymes is presented in nine textbooks, following three different lines of analysis. A general lack of interconnection was seen in biochemistry topics, with enzymes usually only presented via the "lock-and-key" model, which does not best represent their complexity. Furthermore, conceptual limitations resulting from a lack of historical contextualization (partial or complete) were also observed.

Clinical and molecular parameters associated to pneumonitis development in non-small-cell lung cancer patients receiving chemoimmunotherapy from NADIM trial.

BACKGROUND: Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy. METHODS: In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days. RESULTS: Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR). CONCLUSIONS: Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy.

Blood biomarkers associated to complete pathological response on NSCLC patients treated with neoadjuvant chemoimmunotherapy included in NADIM clinical trial.

BACKGROUND: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR. METHODS: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed. RESULTS: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4+ PD-1+ cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4+ CD25hi+ cells and CD69 expression on intermediate monocytes; but lower levels of CD3+ CD56- CTLA-4+ cells, CD14++ CD16+ CTLA-4+ cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR. CONCLUSIONS: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses.

Epidemiology, treatment, and survival in small cell lung cancer in Spain: Data from the Thoracic Tumor Registry.

BACKGROUND: Small-cell lung cancer (SCLC) is an aggressive disease with high metastatic potential and poor prognosis. Due to its low prevalence, epidemiological and clinical information of SCLC patients retrieved from lung cancer registries is scarce. PATIENTS AND METHODS: This was an observational multicenter study that enrolled patients with lung cancer and thoracic tumors, recruited from August 2016 to January 2020 at 50 Spanish hospitals. Demographic and clinical data, treatment patterns and survival of SCLC patients included in the Thoracic Tumor Registry (TTR) were analyzed. RESULTS: With a total of 956 cases, the age of 64.7 ± 9.1 years, 78.6% were men, 60.6% smokers, and ECOG PS 0, 1 or ≥ 2 in 23.1%, 53.0% and 23.8% of cases, respectively. Twenty percent of patients had brain metastases at the diagnosis. First-line chemotherapy (CT), mainly carboplatin or cisplatin plus etoposide was administered to >90% of patients. In total, 36.0% and 13.8% of patients received a second and third line of CT, respectively. Median overall survival was 9.5 months (95% CI 8.8-10.2 months), with an estimated rate of 70.3% (95% CI 67.2-73.4%), 38.9% (95% CI 35.4-42.4%), and 14.8% (95% CI 11.8-17.8%) at 6, 12 and 24 months respectively. Median progression-free survival was 6.3 months. Higher mortality and progression rates were significantly associated with male sex, older age, smoking habit, and ECOG PS 1-2. Long-term survival (> 2 years) was confirmed in 6.6% of patients, showing a positive correlation with better ECOG PS, poor smoking and absence of certain metastases at diagnosis. CONCLUSION: This study provides an updated overview of the clinical situation and treatment landscape of ES-SCLC in Spain. Our results might assist oncologists to improve current clinical practice towards a better prognosis for these patients.

Hybrid Closed-Loop System Achieves Optimal Perioperative Glycemia in a Boy With Type 1 Diabetes: A Case Report.

The goal in type 1 diabetes (T1D) therapy is to maintain optimal glycemic control under any circumstance. Diabetes technology is in continuous development to achieve this goal. The most advanced Food and Drug Administration- and European Medicines Agency-approved devices are hybrid closed-loop (HCL) systems, which deliver insulin subcutaneously in response to glucose levels according to an automated algorithm. T1D is frequently encountered in the perioperative period. The latest international guidelines for the management of children with diabetes undergoing surgery include specific adjustments to the patient's insulin therapy, hourly blood glucose monitoring, and intravenous (IV) insulin infusion. However, these guidelines were published while the HCL systems were still marginal. We present a case of a 9-year-old boy with long-standing T1D, under HCL system therapy for the last 9 months, and needing surgery for an appendectomy. We agreed with the family, the surgical team, and the anesthesiologists to continue HCL insulin infusion, without further adjustments, hourly blood glucose checks or IV insulin, while monitoring closely. The HCL system was able to keep glycemia within range for the total duration of the overnight fast, the surgery, and the initial recovery, without any external intervention or correction bolus. This is, to the best of our knowledge, the first reported pediatric case to undergo major surgery using a HCL system, and the results were absolutely satisfactory for the patient, his family, and the medical team. We believe that technology is ripe enough to advocate for a "take your pump to surgery" message, minimizing the impact and our interventions. The medical team may discuss this possibility with the family and patients.

Cancer and SARS-CoV-2 Infection: A Third-Level Hospital Experience.

INTRODUCTION: Madrid has been the epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in Spain. We analyzed our experience with SARS-CoV-2 infected and cancer patients. PATIENTS AND METHODS: We included patients from March 1 to April 30 2020 at Hospital Universitario Puerta de Hierro, Majadahonda, Madrid (Spain). The inclusion criteria were diagnosis of SARS-CoV-2 infection made by reverse transcription polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in cancer patients who were admitted to the hospital due to the need for respiratory support. The exclusion criteria were suspected cases not confirmed. The primary objective was to analyze the mortality rates of patients with cancer, especially those with lung cancer and COVID-19. RESULTS: Overall in-hospital mortality of cancer patients with coronavirus disease 2019 (COVID-19) was 15.2% similar to 12.7% of the global COVID-19 hospitalized population (p=0.615) and greater than that of patients admitted without SARS-CoV-2 infection during the same period 4.3% (p<0.001). Among 653 patients receiving active cancer therapy during the study period, 24 (3.7%) developed COVID-19 and required admission, 4.2% of those receiving chemotherapy, 9.5% immunotherapy and 2.1% targeted therapies. Lung and breast cancer were the most frequent cancer types (26.1%), followed by colorectal cancer (19.6%). Mortality in patients with lung cancer was 25%. The univariate analysis comparing patients who developed a serious event to those who did not showed that the higher Brescia index, CURB-65 scale, lactate dehydrogenase (LDH) or C-reactive protein (CRP) were the risk factors of developing severe complications. CONCLUSION: Patients with cancer, especially lung cancer, and SARS-CoV-2 infection have a worse overall prognosis than the general population.

Lung cancer patients with COVID-19 in Spain: GRAVID study.

INTRODUCTION: Patients with cancer may be at increased risk of more severe COVID-19 disease; however, prognostic factors are not yet clearly identified. The GRAVID study aimed to describe clinical characteristics, outcomes, and predictors of poor outcome in patients with lung cancer and COVID-19. METHODS: Prospective observational study that included medical records of patients with lung cancer and PCR-confirmed COVID-19 diagnosis across 65 Spanish hospitals. The primary endpoint was all-cause mortality; secondary endpoints were hospitalization and admission to intensive care units (ICU). RESULTS: A total of 447 patients with a mean age of 67.1 ± 9.8 years were analysed. The majority were men (74.3 %) and current/former smokers (85.7 %). NSCLC was the most frequent type of cancer (84.5 %), mainly as adenocarcinoma (51.0 %), and stage III metastatic or unresectable disease (79.2 %). Nearly 60 % of patients were receiving anticancer treatment, mostly first-line chemotherapy. Overall, 350 (78.3 %) patients were hospitalized for a mean of 13.4 ± 11.4 days, 9 (2.0 %) were admitted to ICU and 146 (32.7 %) died. Advanced disease and the use of corticosteroids to treat COVID-19 during hospitalization were predictors of mortality. Hospitalized, non-end-of-life stage patients with lymphocytopenia and high LDH had an increased risk of death. Severity of COVID-19 correlated to higher mortality, ICU admission, and mechanical ventilation rates. CONCLUSIONS: Mortality rate was higher among patients treated with corticosteroids during hospitalization, while anticancer therapy was not associated with an increased risk of hospitalization or death. Tailored approaches are warranted to ensure effective cancer management while minimizing the risk of exposure to SARS-CoV-2.

Multicenter Study of the Seroprevalence of Antibodies against Covid-19 in Patients with Lymphoma: An Analysis of the Oncological Group for the Treatment and Study of Lymphomas (Gotel).

The new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) coronavirus has generated a pandemic, in which there are population groups at higher risk and who are potentially fatal victims of the disease. Cancer patients have been considered a group with special susceptibility, particularly patients with lung tumour involvement and haematological neoplasms. The Spanish Lymphoma Oncology Group (GOTEL) carried out a multicenter study of SARS-CoV-2 seroprevalence in patients with lymphoma. Results: A total of 150 patients were included between 22 May and 11 June 2020. The mean age was 65 years (range 17-89), 70 women (46.5%) and 80 men (53, 5%). At the time of diagnosis of lymphoma, 13 cases were stage I (9%), 27 (18%) stage II, 37 (24.5%) stage III, and 73 (48.5%) stage IV, while 6.6% had a primary extranodal origin. A total of 10 cases with positive serology for SARS-CoV-2 were identified, which is a prevalence of 6% in this population. None of the patients required intensive care unit management and all fully recovered from the infection. Conclusion: IgG antibody seroprevalence in lymphoma patients appears similar to that of the general population and does not show greater aggressiveness.