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BACKGROUND: Limited data are available regarding the real-world effectiveness and safety of Cyclin Dependent Kinase 4/6 inhibitor (CDK4/6i) (palbociclib/ribociclib) just as a first-line treatment for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2â) metastatic breast cancer (MBC). OBJECTIVE: To assess whether clinical or demographic characteristics limit access to first-line CDK4/6i treatment in clinical practice in the Autonomous Community of Andalusia (Spain) between November 2017 and April 2020. In addition, effectiveness will be described in an exploratory analysis. METHODS: Physicians from 12 centers participated in selecting demographic and clinical characteristics, treatment, and outcome data from women with HR + /HER2- MBC treated with or without CDK4/6i in addition to hormonal in the first-line setting, in a 3:1 proportion. Kaplan-Meier analysis estimated progression-free rates (PFRs) and survival rates (SRs). RESULTS: A total of 212 patients were included, of whom 175 (82.5%) were in the CDK4/6i treatment group and 37 (17.5%) were in the non-CDK4/6i treatment group (control group). Patients in the CDK 4/6i treatment group were younger (p = 0.0011), the biopsies of the metastatic site at the moment of the relapse were most commonly performed (p = 0.0454), and had multiple metastatic sites (p = 0.0025). The clinical benefit rate (CBR) was 82.3% in the CDK4/6i group and 67.8% in the control group. Median time to a progression event or death (PFS) was 20.4 months (95%CI 15.6-28) in the CDK4/6i group and 12.1 months (95%CI 7.9-not reached) in the control group. CONCLUSIONS: Younger patients, biopsies of metastatic disease and with multiple metastatic sites were more frequently treated with CDK4/6i in our daily clinical practice.
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OBJECTIVE: To determine whether adenomyosis is present in the cornual portion of hysterectomies of symptomatic sterilization device users and in patients hysterectomized for different benign causes and who presented with pelvic pain and/or menstrual alterations. METHODS: An observational, analytical, cross-sectional, single-center, retrospective cohort study was conducted in a secondary level hospital. Cohort 1 consisted of women who had Essure® hysteroscopic sterilization devices inserted between 2009 and 2017, who developed gynecologic symptoms (pelvic pain, heavy menstrual bleeding, and/or abnormal uterine bleeding) and who underwent a hysterectomy for explantation of the devices. Cohort 2 consisted of women with the same gynecologic symptoms, who underwent a hysterectomy for other benign causes. All surgeries were performed by the gynecology team between 2018 and 2022. A descriptive and comparative analysis of sociodemographic, clinical characteristics, and pathologic findings between cohorts was made. RESULTS: In total, 96 patients were studied (cohort 1 included 34 women, cohort 2 included 62 women). Pelvic pain was found to be more frequent in the cohort of Essure users (76.47% vs. 50%, P = 0.012), with a ratio of three times higher in this group (odds ratio 3.25, 95% confidence interval 1.27-8.28). Adenomyosis was more frequently found in the Essure group, both at corporal and cornual portions, the latter being five times higher in this cohort (relative risk = 5.47; 95% confidence interval 1.17-25.64). CONCLUSIONS: The present study may be the first to describe cornual adenomyosis related to Essure devices. These devices may play a role in the development of adenomyosis and, consequently, pelvic pain. However, causality is difficult to establish.
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PURPOSE: HER2-targeted therapies have dramatically improved outcomes of patients with HER2-positive breast cancer (BC), as demonstrated in neoadjuvant trials. This study aims to provide real-world evidence on the use and effectiveness of combined pertuzumab, trastuzumab and chemotherapy (CT) in early-stage HER2-positive BC. METHODS: A retrospective, multicentre study was conducted on patients diagnosed with HER2-positive early BC treated with neoadjuvant pertuzumab and trastuzumab plus CT at 13 Spanish sites. The primary endpoint was pathological complete response (pCR). RESULTS: A total of 310 patients were included. Pertuzumab and trastuzumab were combined with anthracyclines and taxanes, carboplatin and docetaxel, and taxane-based CT in 77.1%, 16.5%, and 6.5% of patients, respectively. Overall, the pCR rate was 62.2%. The pCR was higher amongst patients with hormone receptor-negative tumours and with tumours expressing higher levels of Ki-67 (> 20%). After postoperative adjuvant treatment, 13.9% of patients relapsed. Those patients who did not achieve pCR, with tumours at advanced stages (III), and with node-positive disease were more likely to experience distant relapse. Median overall survival (OS) and distant disease-free survival (D-DFS) were not reached at the study end. The estimated mean OS and D-DFS times were 7.5 (95% CI 7.3-7.7) and 7.3 (95% CI 7.1-7.5) years, respectively (both were significantly longer amongst patients who achieved pCR). Grade 3-4 anti-HER2 related toxicities were reported in six (1.9%) patients. CONCLUSION: Neoadjuvant pertuzumab and trastuzumab plus CT achieve high pCR rates in real-life patients with HER2-positive early BC, showing an acceptable safety profile. Innovative adjuvant strategies are essential in patients at high risk of distant disease recurrence.
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The persistence of fetal cells in the mother (fetal microchimerism (FMc)) has been described in maternal tissues essential to the newborn. FMc is associated with several diseases that start or worsen in pregnancy or postpartum. This exploratory study reports-for the first time-the presence of FMc in the olfactory neuroepithelium (ON) of both healthy and depressed women with male offspring. However, depressed women had fewer microchimeric cells (digital PCR). The existence of FMc in the ON could facilitate mother-child bonding. These findings open new pathways to study FMc in the ON, female depression, and mother-child bonding.
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PURPOSE: To analyze the results of the telemedicine screening program for diabetic retinopathy (DR) in patients with type 1 diabetes conducted by the Endocrinology and Nutrition Management Unit of Virgen del Rocío University Hospital. METHODS: This cross-sectional study comprised patients with type 1 diabetes mellitus (DM) in our DR screening program from January 2018 to November 2020. Fundus photographs are performed by trained nurses and reviewed by a trained endocrinologist. Those suggestive of pathology are sent to ophthalmology through a telematic program for review. RESULTS: Of the 995 fundus photographs evaluated, 646 (65.3%) showed no evidence of DR, 327 (33.1%) presented possible DR, and 16 (1.6%) were not gradable. The diagnosis was confirmed in 254 patients after reviewing by ophthalmology, and the screening program achieved a positive predictive value for DR of 77.7%. Seventy-three were excluded by ophthalmology due to the absence of DR (false positive rate - 22.3%). In 92.5% of the cases classified by the ophthalmologist, the degree of DR was mild or very mild. CONCLUSION: Our telemedicine screening program for DR in patients with type 1 DM is consistent with the literature. Effective screening for DR is performed, with patients diagnosed in the early stages. Telemedicine programs facilitate efficient communication among healthcare personnel.
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Diabetes Mellitus Tipo 1 , Retinopatía Diabética , Telemedicina , Humanos , Diabetes Mellitus Tipo 1/complicaciones , Retinopatía Diabética/diagnóstico , Estudios Transversales , Telemedicina/métodos , Tamizaje Masivo/métodosRESUMEN
INTRODUCTION: In severe forms of obesity there is a high prevalence of psychopathological comorbidity. Psychiatric evaluation is an important component of comprehensive obesity care and contributes to optimizing therapeutic results after bariatric surgery. OBJECTIVE: To assess the effectiveness of psychometric tests used in the protocol for selecting patients for bariatric surgery. MATERIAL AND METHODS: Retrospective naturalistic observational study of 100 patients who were candidates for bariatric surgery. Patients who complete the psychometric protocol and the psychiatric interview between January 2019 and June 2021 are included. Two groups are formed: those considered unfit for any psychopathological reason and those considered fit. To evaluate the effectiveness of the tests used, ROC curves will be used. The sensitivity and specificity values of each test used will be obtained. RESULTS: 97 patients included, aged between 20 and 61 years, 64.9% women. 51.5% had a family history and 38.1% a personal history of any psychiatric disorder. Regarding the area under the curve, the scales that presented a value greater than 0.7 were the YFAS total score (0.771), HADS-D (0.757), the Edinburgh Bulimia total score (0.747), the severity score of YFAS (0.722) and Edinburgh Bulimia Severity Score (0.705). The most frequent diagnoses as a cause of exclusion were Food Addiction 8 (20.5%) and Generalized Anxiety Disorder (GAD) 6 (15.5%). CONCLUSIONS: The YFAS, BITE and HADS-A scales were useful to discriminate those patients considered unsuitable for bariatric surgery for any psychopathological cause.
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Cirugía Bariátrica , Bulimia , Obesidad Mórbida , Humanos , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Selección de Paciente , Bulimia/psicología , Obesidad Mórbida/cirugía , Obesidad Mórbida/epidemiología , Psicometría , Estudios Retrospectivos , Obesidad/cirugía , Encuestas y CuestionariosRESUMEN
BACKGROUND: Although there is scientific evidence of the presence of immunometabolic alterations in major depression, not all patients present them. Recent studies point to the association between an inflammatory phenotype and certain clinical symptoms in patients with depression. The objective of our study was to classify major depression disorder patients using supervised learning algorithms or machine learning, based on immunometabolic and oxidative stress biomarkers and lifestyle habits. METHODS: Taking into account a series of inflammatory and oxidative stress biomarkers (C-reactive protein (CRP), tumor necrosis factor (TNF), 4-hydroxynonenal (HNE) and glutathione), metabolic risk markers (blood pressure, waist circumference and glucose, triglyceride and cholesterol levels) and lifestyle habits of the participants (physical activity, smoking and alcohol consumption), a study was carried out using machine learning in a sample of 171 participants, 91 patients with depression (71.42% women, mean age = 50.64) and 80 healthy subjects (67.50% women, mean age = 49.12). The algorithm used was the support vector machine, performing cross validation, by which the subdivision of the sample in training (70%) and test (30%) was carried out in order to estimate the precision of the model. The prediction of belonging to the patient group (MDD patients versus control subjects), melancholic type (melancholic versus non-melancholic patients) or resistant depression group (treatment-resistant versus non-treatment-resistant) was based on the importance of each of the immunometabolic and lifestyle variables. RESULTS: With the application of the algorithm, controls versus patients, such as patients with melancholic symptoms versus non-melancholic symptoms, and resistant versus non-resistant symptoms in the test phase were optimally classified. The variables that showed greater importance, according to the results of the area under the ROC curve, for the discrimination between healthy subjects and patients with depression were current alcohol consumption (AUC = 0.62), TNF-α levels (AUC = 0.61), glutathione redox status (AUC = 0.60) and the performance of both moderate (AUC = 0.59) and vigorous physical exercise (AUC = 0.58). On the other hand, the most important variables for classifying melancholic patients in relation to lifestyle habits were past (AUC = 0.65) and current (AUC = 0.60) tobacco habit, as well as walking routinely (AUC = 0.59) and in relation to immunometabolic markers were the levels of CRP (AUC = 0.62) and glucose (AUC = 0.58). In the analysis of the importance of the variables for the classification of treatment-resistant patients versus non-resistant patients, the systolic blood pressure (SBP) variable was shown to be the most relevant (AUC = 0.67). Other immunometabolic variables were also among the most important such as TNF-α (AUC = 0.65) and waist circumference (AUC = 0.64). In this case, sex (AUC = 0.59) was also relevant along with alcohol (AUC = 0.58) and tobacco (AUC = 0.56) consumption. CONCLUSIONS: The results obtained in our study show that it is possible to predict the diagnosis of depression and its clinical typology from immunometabolic markers and lifestyle habits, using machine learning techniques. The use of this type of methodology could facilitate the identification of patients at risk of presenting depression and could be very useful for managing clinical heterogeneity.
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Trastorno Depresivo Mayor , Factor de Necrosis Tumoral alfa , Aprendizaje Automático , Biomarcadores , Proteína C-Reactiva , Nicotiana , GlutatiónRESUMEN
OBJECTIVES: To evaluate clinical data in women who underwent Essure® hysteroscopic sterilization and to determine whether this sterilization technique plays a role in developing new-onset symptoms. STUDY DESIGN: An observational, retrospective, single-center study. It was conducted in a secondary level hospital. It included 804 women who had Essure® hysteroscopic sterilization from 2009 to 2017. Charts from these women were reviewed from June 2009 to November 2019, searching for the development of gynecological symptoms (pelvic pain and bleeding disorders) and non-gynecological symptoms (bloating, joint pain, fatigue, headache, alopecia, allergy and depression). The sample was divided into two groups depending on whether they had developed gynecological symptoms (symptomatic group) or not (asymptomatic group), and a descriptive and comparative analysis was made between them. The impact of the global social alarm in 2015 regarding adverse events attributed to the devices, the development of non-gynecological symptoms, and the treatments required, including conservative and surgical options, were also described. RESULTS: Out of 804 women who had Essure® devices placed, 541(67.29%) remained asymptomatic, 263(32.71%) developed gynecological symptoms, and 41 of these (15.5% of the total sample) requested Essure® surgical removal. Pelvic pain was the most frequent symptom and the main reason for surgical removal. Bleeding alterations were the second most frequent symptom. Up to 55.89% described the symptoms after the social alarm. Non-gynecological symptoms were statistically significantly more frequent in the symptomatic group. CONCLUSIONS: More than a half of the women who underwent Essure® sterilization remained asymptomatic. The new-onset symptoms attributed to the devices are the minority and causality is difficult to establish. IMPLICATIONS STATEMENT: Our research provides new follow-up data about Essure® hysteroscopic sterilization. Association between gynecological symptoms and Essure® devices is difficult to demonstrate and some confounding factors may be implicated. The results we described, may guide and counsel medical-patient decisions for the treatment of symptoms related to the devices, including surgical removal.
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Esterilización Tubaria , Embarazo , Femenino , Humanos , Esterilización Tubaria/efectos adversos , Histeroscopía/efectos adversos , Histeroscopía/métodos , Estudios Retrospectivos , Dolor Pélvico/etiología , Dolor Pélvico/cirugía , EsterilizaciónRESUMEN
BACKGROUND: Alterations in cognitive performance have been described in patients with major depressive disorder (MDD). However, the specific risk factors of these changes are not yet known. This study aimed to explore whether inmunometabolic parameters are related to cognitive performance in MDD in comparison to healthy controls (HC) METHODS: Sample consisted of 84 MDD patients and 78 HC. Both groups were compared on the results of cognitive performance measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB), the presence of metabolic syndrome (MetS) and an inflammatory/oxidative index calculated by a principal component analysis of peripheral biomarkers (tumor necrosis factor, C-reactive protein and 4-hydroxynonenal). A multiple linear regression was carried out, to study the relationship between inmunometabolic variables and the global cognitive performance, being the latter the dependent variable. RESULTS: Significant differences were obtained in the inflammatory/oxidative index between both groups (F(1157)= 12.93; p < .001), also in cognitive performance (F(1157)= 56.75; p < .001). The inmunometabolic covariate regression model (i.e., condition (HC/MDD), sex, age and medication loading, MetS, inflammatory/oxidative index and the interaction between MetS and inflammatory/oxidative index) was statistically significant (F(7157)= 11.24; p < .01) and explained 31% of variance. The condition, being either MDD or HD, (B=-0.97; p < .001), age (B=-0.28; p < .001) and the interaction between inflammatory/oxidative index and MetS (B=-0.38; p = .02) were factors associated to cognitive performance. LIMITATIONS: Sample size was relatively small. The cross-sectional design of the study limits the possibilities of analysis. CONCLUSIONS: Our results provide evidence on the conjoint influence of metabolic and inflammatory dysregulation on cognitive dysfunction in MDD patients. In this way, our study opens a line of research in immunometabolic agents to deal with cognitive decline associated with MDD.
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Disfunción Cognitiva , Trastorno Depresivo Mayor , Cognición , Disfunción Cognitiva/complicaciones , Estudios Transversales , Depresión , HumanosRESUMEN
In the international context of a progress toward more inclusive educational systems and practices, the role of Special Education teachers is being transformed. From an inclusive perspective, these professionals increasingly support students and their teachers in the mainstream classroom, avoiding segregation. However, Special Education teachers often struggle to reach and support all students with special needs and their teachers to provide quality inclusive education. For this reason, more research is still needed on in-service training strategies for the inclusion of students with special needs that effectively translate into evidence-based school practices that improve the education of all students. This article analyses the impact of two evidence-based dialogic training programs of Special Education teachers working in mainstream schools carried out in Mexico during the 2018-2019 school year. Through in-depth interviews with participants, it was identified how, after the training, teachers increasingly grounded their actions on scientific evidence and promoted interactive learning environments that improved the educational inclusion of their students with special needs. This training also became the venue to make evidence-based educational actions available to other students without special needs, improving the quality of education provided to all students.
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BACKGROUND: Cognitive impairment has been reported in patients with Major Depressive Disorder (MDD). This study aims to explore the association between lifestyle habits and health-related factors and the presence of cognitive symptoms in MDD patients. METHODS: Demographic, clinical, health-related variables and cognitive scores measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB) were compared between 74 patients with current MDD and 68 healthy controls (HC). To test the hypothesis of associated factors to cognitive symptoms, multivariate backward stepwise linear regression models were run. RESULTS: Significant neuropsychological deficits were evident in MDD compared with HC in the global cognitive index (F=8.29; df=1, 140; p=0.005). In the regression analysis performed on MDD and HC, years of schooling (ß=-0.11; p=<0.001), job status (ß=-0.50; p=0.016), physical activity (ß=-0.25; p=0.04) and age at illness onset (ß=0.17; p=0.017) were statistically significant factors associated to cognitive impairment. The regression model ran in HC showed that only years of schooling were significant (ß=-0.07; p=<0.001) in this group. LIMITATIONS: Sample size was relatively small. Everyday cognitive skills were not evaluated. CONCLUSIONS: MDD patients have cognitive deficits. These deficits are linked with the years of education, job status, age of onset of the disease and the performance of physical activity. These results support the importance of the implementation of interventions targeting the cognitive reserve and lifestyle habits of MDD patients, in addition to the conventional therapeutic approach focused on symptoms control.
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Disfunción Cognitiva , Trastorno Depresivo Mayor , Cognición , Disfunción Cognitiva/epidemiología , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/epidemiología , Ejercicio Físico , Humanos , Pruebas NeuropsicológicasRESUMEN
OBJECTIVE: The primary objective of the study is to compare the effectiveness of trastuzumab-chemotherapy with and without pertuzumab. As a secondary objective, we seek to evaluate the cardiac safety of the treatment. METHOD: Retrospective observational study including all patients treated with either pertuzumab-trastuzumab-chemotherapy (n = 10) or trastuzumab-chemotherapy (n = 13) (January 2015-December 2018) in a specialty hospital, which met the criteria established by the Commission Central for the Optimization and Harmonization of the pharmacotherapy of the Andalusian Health Service for the use of pertuzumab in neoadjuvance: HER2 positive tumor, negative hormonal receptors, with high risk of relapse (tumor > 2 cm or lymph node involvement). To assess effectiveness, the complete pathological response was used. For cardiac safety, the decrease in left ventricular ejection fraction greater than 10% was employed. RESULTS: Complete pathological response was superior in the pertuzumab group (70.0% vs. 30.8%). Cardiac safety was similar in both. CONCLUSIONS: For patients with HER2 positive tumors and negative hormonal receptors with high risk criteria that receive pertuzumab, the complete pathological response is superior, with no increase in cardiac toxicity.
Objetivo: El objetivo primario del estudio es comparar la efectividad trastuzumab-quimioterapia con y sin pertuzumab. Como objetivo secundario se busca evaluar la seguridad cardiaca del tratamiento.Método: Estudio observacional retrospectivo que incluyó todas las pacientes tratadas con pertuzumab-trastuzumab-quimioterapia (n = 10) o trastuzumab-quimioterapia (n = 13) (enero 2015-diciembre 2018) en un hospital de especialidades, que cumplían los criterios establecidos por la Comisión Central para la Optimización y Armonización de la farmacoterapia del Servicio Andaluz de Salud para uso de pertuzumab en neoadyuvancia: tumor HER2 positivo, receptores hormonales negativos, con alto riesgo de recaída (tumor > 2 cm o afectación ganglionar). Para valorar la efectividad se utilizó la respuesta completa patológica, y para la seguridad cardiaca, el descenso de la fracción de eyección del ventrículo izquierdo superior al 10%.Resultados: La respuesta completa patológica fue superior en el grupo con pertuzumab (70,0% versus 30,8%). La seguridad cardiaca fue similar en ambos.Conclusiones: Para las pacientes con tumores HER2 positivo y receptores hormonales negativos con criterios de alto riesgo que reciben pertuzumab, la respuesta completa patológica resulta superior, sin observarse incremento de la toxicidad cardiaca.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Trastuzumab/administración & dosificación , Trastuzumab/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Femenino , Cardiopatías/inducido químicamente , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Receptor ErbB-2/genética , Estudios Retrospectivos , Riesgo , Volumen Sistólico/efectos de los fármacos , Trastuzumab/efectos adversosRESUMEN
OBJECTIVE: The transforming growth factor ß (TGFß) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGFß and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease. METHODS: Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGFß mAb. RESULTS: Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGFß activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls). CONCLUSION: These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.
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Anticuerpos Monoclonales/farmacología , Artritis Experimental/inmunología , Artritis Psoriásica/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proteínas de la Membrana/antagonistas & inhibidores , Psoriasis/inmunología , Adyuvantes Inmunológicos/toxicidad , Animales , Artritis Psoriásica/inducido químicamente , Linfocitos T CD4-Positivos/inmunología , Colágeno Tipo II , Modelos Animales de Enfermedad , Imiquimod/toxicidad , Interleucina-17/inmunología , Interleucina-2/inmunología , Mananos , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Noqueados , Saccharomyces cerevisiae , Piel/efectos de los fármacos , Piel/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Factor de Crecimiento Transformador beta/efectos de los fármacos , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND: CD6 is a lymphocyte surface co-receptor physically associated with the T-cell receptor (TCR)/CD3 complex at the center of the immunological synapse. There, CD6 assists in cell-to-cell contact stabilization and modulation of activation/differentiation events through interaction with CD166/ALCAM (activated leukocyte cell adhesion molecule), its main reported ligand. While accumulating evidence is attracting new interest on targeting CD6 for therapeutic purposes in autoimmune disorders, little is known on its potential in cancer. In an attempt to elucidate the in vivo relevance of blocking CD6-mediated interactions in health and disease, we explored the consequences of expressing high circulating levels of a soluble form CD6 (sCD6) as a decoy receptor. METHODS: High sCD6 serum levels were achieved by using transgenic C57BL/6 mice expressing human sCD6 under the control of lymphoid-specific transcriptional elements (shCD6LckEµTg) or wild type either transduced with hepatotropic adeno-associated virus coding for mouse sCD6 or undergoing repeated infusions of recombinant human sCD6 protein. Characterization of sCD6-induced changes was performed by ex vivo flow cytometry and functional analyses of mouse lymphoid organ cells. The in vivo relevance of those changes was explored by challenging mice with subcutaneous or metastatic tumors induced by syngeneic cancer cells of different lineage origins. RESULTS: Through a combination of in vitro and in vivo studies, we show that circulating sCD6 expression induces defective regulatory T cell (Treg) generation and function, decreased CD166/ALCAM-mediated tumor cell proliferation/migration and impaired galectin-induced T-cell apoptosis, supporting the fact that sCD6 modulates antitumor lymphocyte effector function and tumorigenesis. Accordingly, sCD6 expression in vivo resulted in delayed subcutaneous tumor growth and/or reduced metastasis on challenge of mice with syngeneic cancer cells. CONCLUSIONS: Evidence is provided for the disruption of CD6 receptor-ligand interactions as a feasible immunomodulatory approach in cancer.
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Antígenos CD/sangre , Antígenos de Diferenciación de Linfocitos T/sangre , Neoplasias Pulmonares/inmunología , Linfoma de Células T/inmunología , Melanoma Experimental/inmunología , Sarcoma Experimental/inmunología , Linfocitos T Reguladores/inmunología , Molécula de Adhesión Celular del Leucocito Activado/inmunología , Molécula de Adhesión Celular del Leucocito Activado/metabolismo , Animales , Antígenos CD/administración & dosificación , Antígenos CD/biosíntesis , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/administración & dosificación , Antígenos de Diferenciación de Linfocitos T/biosíntesis , Antígenos de Diferenciación de Linfocitos T/genética , Apoptosis/fisiología , Diferenciación Celular/fisiología , Línea Celular Tumoral , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Linfoma de Células T/metabolismo , Masculino , Melanoma Experimental/sangre , Melanoma Experimental/patología , Melanoma Experimental/terapia , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangre , Proteínas Recombinantes/genética , Sarcoma Experimental/sangre , Sarcoma Experimental/patología , Linfocitos T Reguladores/metabolismoRESUMEN
PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina/uso terapéutico , Quimioterapia Adyuvante/métodos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Adulto JovenRESUMEN
OBJECTIVE: The present study describes an ambulatory, free skin micrograft technique with cyanoacrylate as a coadjuvant venous leg ulcer (VLU) healing strategy and its outcomes after one month. METHODS: This prospective study involved Comprehensive Classification System for Chronic Venous Disorders (CEAP) stage C6 patients with good granulation tissue and negative culture results, consecutively recruited in January 2017 in the Hospital Clinico San Carlos. A skin micrograft was harvested from the anterior surface of the patient's thigh with a 0.4cm punch (0.12cm2). The graft was adhered to the ulcer bed with cyanoacrylate. Anti-adherent dressing and double-layer bandaging was applied, with weekly replacements. Measurements were obtained of the surface of the VLU and graft progression (in cm2) using a photographic grid. RESULTS: A total of 12 VLUs in 12 patients were included, with a mean treated surface of 20.32±13.9cm2. A total of 18 grafts were placed and all were found to be viable after one week. Average graft growth was not noticeable after one week but was found to be 0.25±0.08cm2 after week two, 0.41±0.98cm2 after week three, and 0.70±0.15cm2 after week four (p<0.001). There were no complications in the donor zone. CONCLUSION: The findings of this study show that free skin micrografting with cyanoacrylate as outpatient treatment for VLUs was simple, rapid and without complication in this study, and may contribute to its wider application in clinical use.