Mesothelial-to-Mesenchymal Transition and Exosomes in Peritoneal Metastasis of Ovarian Cancer

Most patients with ovarian cancer (OvCA) present peritoneal disseminated disease at the time of diagnosis. During peritoneal metastasis, cancer cells detach from the primary tumor and disseminate through the intraperitoneal fluid. The peritoneal mesothelial cell (PMC) monolayer that lines the abdominal cavity is the first barrier encountered by OvCA cells. Subsequent progression of tumors through the peritoneum leads to the accumulation into the peritoneal stroma of a sizeable population of carcinoma-associated fibroblasts (CAFs), which is mainly originated from a mesothelial-to-mesenchymal transition (MMT) process. A common characteristic of OvCA patients is the intraperitoneal accumulation of ascitic fluid, which is composed of cytokines, chemokines, growth factors, miRNAs, and proteins contained in exosomes, as well as tumor and mesothelial suspended cells, among other components that vary in proportion between patients. Exosomes are small extracellular vesicles that have been shown to mediate peritoneal metastasis by educating a pre-metastatic niche, promoting the accumulation of CAFs via MMT, and inducing tumor growth and chemoresistance. This review summarizes and discusses the pivotal role of exosomes and MMT as mediators of OvCA peritoneal colonization and as emerging diagnostic and therapeutic targets

Parvovirus B19 en mujer con tiroiditis autoinmune: reporte de caso

Introducción: El parvovirus B19 es un virus de ADN pequeño que presenta patrones de infección en su mayoría asintomáticos durante el brote. Usualmente se contagia por via aérea, siendo una infección más incidente en la infancia. Infecta principalmente a las células progenitoras eritroides mediante el antígeno P e induce su apoptosis. Produce eritema infeccioso, artropatía. Por otra parte, la tiroiditis autoinmune, es una inflamación crónica, de origen autoinmune que produce, de forma gradual, hipotiroidismo. Reporte: Se presenta el caso de una mujer de 46 años con hipotiroidismo subclínico de dos años que ingresa a emergencia por exantema facial y de extremidades con artralgias múltiples, evolucionando con hepatopatía. Se le detectaron IgM anti-parvovirus B19 y anticuerpos anti-TPO durante la estancia hospitalaria. Conclusión: La infección por parvovirus ha sido poco o nada estudiada en el medio trujillano y debido a las manifestaciones exantémicas y artropatías suele confundirse con enfermedades autoinmunitarias.PALABRAS CLAVE  Parvovirus B19 Humano (DeCS); Tiroiditis Autoinmune (DeCS)DOI: http://dx.doi.org/10.17268/rmt.2020.v15i01.0

Combined Immune Defect in B-Cell Lymphoproliferative Disorders Is Associated with Severe Infection and Cancer Progression

This research received no external funding. K.G.-H is supported by The European Social Fund (ESF) through a Río Ortega Grant for Health Research Projects by the Carlos III Health Institute (ISCIII) (CM20/00098).B cell chronic lymphoproliferative diseases (B-CLPD) are associated with secondary antibody deficiency and other innate and adaptive immune defects, whose impact on infectious risk has not been systematically addressed. We performed an immunological analysis of a cohort of 83 B-CLPD patients with recurrent and/or severe infections to ascertain the clinical relevance of the immune deficiency expression. B-cell defects were present in all patients. Patients with combined immune defect had a 3.69-fold higher risk for severe infection (p = 0.001) than those with predominantly antibody defect. Interestingly, by Kaplan–Meier analysis, combined immune defect showed an earlier progression of cancer with a hazard ratio of 3.21, than predominantly antibody defect (p = 0.005). When B-CLPD were classified in low-degree, high-degree, and plasma cell dyscrasias, risk of severe disease and cancer progression significantly diverged in combined immune defect, compared with predominantly antibody defect (p = 0.001). Remarkably, an underlying primary immunodeficiency (PID) was suspected in 12 patients (14%), due to prior history of infections, autoimmune and granulomatous conditions, atypical or variegated course and compatible biological data. This first proposed SID classification might have relevant clinical implications, in terms of predicting severe infections and cancer progression, and might be applied to different B-CLPD entities.Depto. de Inmunología, Oftalmología y ORLFac. de MedicinaTRUEpu

Perfiles moleculares y patrones de recaída en cáncer de ovario

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 16-07-2018Esta tesis tiene embargado el acceso al texto completo hasta el 16-01-2020El cáncer de ovario es una enfermedad que condiciona una importante morbimortalidad en la mujer, ya que suele diagnosticarse en estadios avanzados, generalmente con ascitis y diseminación peritoneal. El tratamiento se basa invariablemente en la cirugía y la quimioterapia basada en taxanos y platino. A pesar de que en la última década se han definido algunos subtipos moleculares (destacando el fenotipo asociado a mutación de BRCA), en la práctica clínica el manejo no ha cambiado significativamente. En este trabajo hemos realizado el estudio de una serie de marcadores inmunohistoquímicos sencillos y accesibles en la práctica clínica, además del estudio de mutaciones en PIK3CA, que pudieran definir unos fenotipos clínicos diferenciados con un pronóstico determinado. Por otra parte, se ha hipotetizado sobre la existencia de un subtipo clínico, definido por una primera recaída “ganglionar”, con evolución y pronóstico diferente. En el estudio se han incluido y recogido datos clínicos de 206 pacientes diagnosticadas de carcinoma de ovario de tres hospitales de Madrid. Se disponía de material quirúrgico de 144 de ellas para realizar el análisis de marcadores inmunohistoquímicos y el estudio de ADN para la detección de mutaciones en PIK3CA usando una PCR a tiempo real. Los resultados obtenidos nos han permitido describir 4 perfiles moleculares asociados a diferente comportamiento clínico en cáncer de ovario: “Stem”, “Ciclo celular”, “Dormancy”, y “PIK3CA mutado”. Cada uno de estos perfiles se asocia a unas características clínicas determinadas. Asimismo, hemos definido un subgrupo con “recaída ganglionar” con diferente evolución clínica y mejor pronóstico a largo plaz

Usefulness and real-world outcomes of next generation sequencing testing in patients with cancer: an observational study on the impact of selection based on clinical judgementResearch in context

Summary: Background: Next Generation Sequencing (NGS) panels are increasingly used in advanced patients with cancer to guide therapy. There is, however, controversy about when should these panels be used, and about their impact on the clinical course. Methods: In an observational study of 139 patients with cancer having an NGS test [from January 1st, 2017 to December 30th, 2020, in two hospitals (Hospital Universitario de La Princesa and Hospital Universitario Quironsalud Madrid) from Spain], we evaluated whether the clinical course (progression-free survival, PFS) was influenced by drug-based criteria [druggable alterations, receiving a recommended drug, having a favourable ESCAT category (ESMO Scale for Clinical Actionability of molecular Targets)] or clinical judgement criteria. Findings: In 111 of 139 cases that were successfully profiled, PFS was not significantly influenced by either having druggable alterations [median PFS for patients with druggable alterations was 170 (95% C.I.: 139–200) days compared to 299 (95% C.I.: 114–483) for those without; p = 0.37], receiving a proposed matching agent [median PFS for patients receiving a genomics-informed drug was 195 days (95% C.I.: 144–245), compared with 156 days for those that did not (95% C.I.: 85–226); p = 0.50], or having favourable ESCAT categories [median PFS for patients with ESCAT I-III was 183 days (95% C.I.: 104–261), compared with 180 (95% C.I.:144–215) for patients with ESCAT IV-X; p = 0.87]. In contrast, NGS testing performed within clinical judgement showed a significantly improved PFS [median PFS for patients that were profiled under the recommended scenarios was 319 days (95% C.I.: 0–658), compared to 123 days (95% C.I.: 89–156) in the non-recommended categories; p = 0.0020]. Interpretation: According to our data, real-world outcomes after NGS testing provide evidence of the benefit of clinical judgement in patients with either advanced cancers that routinely need multiple genetic markers, patients with advanced rare cancers, or patients that are screened for molecular clinical trials. By contrast, NGS does not seem to be valuable when performed in cases with a poor PS, rapidly progressing cancer, short expected lifetime, or cases with no standard therapeutic options. Funding: RC, NR-L and MQF are recipients of the PMP22/00032 grant, funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF). The study also received funds from the CRIS Contra el Cancer Foundation

Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with negative axillary involvement at initial diagnosis

Objetivo: valorar la tasa de detección de ganglio centinela tras quimioterapia neoadyuvante en pacientes con cáncer infiltrante de mama y axila clínicamente negativa previa al tratamiento y analizar su supervivencia global y supervivencia libre de enfermedad. Material y métodos: estudio observacional retrospectivo. Se incluyeron las pacientes con cáncer de mama tratadas con quimioterapia neoadyuvante en el Hospital Universitario Quironsalud Madrid entre los años 2008-2014. A todas se les practicó cirugía conservadora o radical junto con biopsia selectiva de ganglio centinela posneoadyuvancia. Se recogió información correspondiente a características sociodemográficas, variables relacionadas con el tratamiento quirúrgico y médico, evolución, características del tumor, supervivencia global y supervivencia libre de enfermedad. Resultados: se incluyeron en el estudio 112 pacientes (116 tumores, 4 de ellos bilaterales). De los 112 tumores unilaterales, 98 (84,5%) estaban en estadios iniciales. La mediana de tamaño tumoral fue 20 mm (15-30). La práctica totalidad (97,4%) eran carcinomas ductales infiltrantes. La quimioterapia se basó en antraciclinas y taxanos con adición de carboplatino en los casos triple negativo y de trastuzumab en Her-2/neu sobreexpresado. Se realizó cirugía conservadora en el 59,5%. La tasa de detección de ganglio centinela fue del 100% con un valor predictivo negativo del 99,1% (110/111), al encontrar una sola recidiva axilar en los 111 ganglios centinela negativos, y se obtuvo respuesta completa patológica en el 52,6%, mayoritariamente en los tumores Her-2 puros y triples negativos con diferencia estadísticamente significativa (p:0.018). La supervivencia global fue del 99,1% con mediana de seguimiento de 53 meses, observando eventos de recaída en 10 pacientes de las cuales solo 2 fueron axilares. Conclusiones: en nuestra experiencia, la biopsia selectiva de ganglio centinela sistemática posneoadyuvancia en pacientes con axila negativa al inicio presenta una excelente tasa de detección, sin aumentar el número de recidivas axilares de forma significativa ni la supervivencia global de estas pacientes. Consideramos, por tanto, esta estrategia la mejor opción para la estadificación quirúrgica de estos tumores.Objective: To assess sentinel lymph node biopsy rate after neoadjuvant chemotherapy in breast cancer patients with negative axillary nodes at diagnosis and to analize their disease free interval and overall survival. Material and methods: Retrospective observational study including breast cancer patients with neoadjuvant chemotherapy at the Hospital Universitario Quironsalud Madrid between 2008-2014. Post chemotherapy, all patients underwent conservative or radical surgery along with a systematic sentinel lymph node biopsy. Patients data was collected and included sociodemographic characteristics, variables regarding surgical and medical treatment, follow-up, tumor characteristics, overall and disease-free survival. Results: The study included 112 patients (116 tumors, 4 of them bilateral). Of the 112 unilateral tumors, 98 (84.5%) were early stages. The median tumor size was 20 mm (15-30) and the majority (97,4%) were invasive ductal carcinoma chemotherapy was based on anthracyclines and taxanes with addition of carboplatin in triple negative cases and trastuzumab in Her-2/neu positive tumors. Conservative procedures were performed in 59,5% of cases. Sentinel lymph node detection rate reached 100% with a negative predictive value of 99,1% (110/111) finding only one axillary recurrence among 111 SLNB. We achieved pathological complete response in 52,6% of tumors in the breast, and more specifically in pure Her2/neu positive and triple negative surrogates (p:0.018). Overall survival was 99,1% with median follow-up of 53 months and 10 patients had a relapse, with only two patients with axillary involvement. Conclusions: In our experience, sentinel lymph node biopsy performed systematically after neoadjuvant treatment in clinically node negative patients have an excellent detection rate without increasing the axillary recurrence rate nor decreasing overall survival in this group of patients. We consider this strategy the best option for the surgical staging of this tumors after chemotherapy.Sin financiaciónNo data JCR 20190.123 SJR (2019) Q4, 152/185 Obstetrics and GynecologyNo data IDR 2019UE

Clinical characteristics and outcomes among hospitalized adults with severe COVID-19 admitted to a tertiary medical center and receiving antiviral, antimalarials, glucocorticoids, or immunomodulation with tocilizumab or cyclosporine: A retrospective obsertional study (COQUIMA cohort)

Background The COVID-19 outbreak challenges the Spanish health system since March 2020. Some available therapies (antimalarials, antivirals, biological agents) were grounded on clinical case observations or basic science data. The aim of this study is to describe the characteristics and impact of different therapies on clinical outcomes in a cohort of severe COVID-19 patients. Methods In this retrospective, single-center, observational study, we collected sequential data on adult patients admitted to Hospital Universitario Quironsalud Madrid. Eligible patients should have a microbiological (positive test on RT-PCR assay from a nasal swab) or an epidemiological diagnosis of severe COVID-19. Demographic, baseline comorbidities, laboratory data, clinical outcomes, and treatments were compared between survivors and non-survivors. We carried out univariate and multivariate logistic regression models to assess potential risk factors for in-hospital mortality. Findings From March 10th to April 15th, 2020, 607 patients were included. Median age was 69 years [interquartile range, {IQR} 22; 65% male). The most common comorbidities were hypertension (276 [46·94%]), diabetes (95 [16·16%]), chronic cardiac (133 [22·62%]) and respiratory (114 [19·39%]) diseases. 141 patients (23·2%) died. In the multivariate model the risk of death increased with older age (odds ratio, for every year of age, 1·15, [95% CI 1·11 - 1·2]), tocilizumab therapy (2·4, [1·13 - 5·11]), C-reactive protein at admission (1·07, per 10 mg/L, [1·04 - 1·10]), d-dimer > 2·5 μg/mL (1·99, [1·03 - 3·86]), diabetes mellitus (2·61, [1·19 - 5·73]), and the PaO2/FiO2 at admission (0·99, per every 1 mmHg, [0·98 - 0·99]). Among the prescribed therapies (tocilizumab, glucocorticoids, lopinavir/ritonavir, hydroxychloroquine, cyclosporine), only cyclosporine was associated with a significant decrease in mortality (0·24, [0·12 - 0·46]; p<0·001). Interpretation In a real-clinical setting, inhibition of the calcineurin inflammatory pathway, NF-κΒ, could reduce the hyperinflammatory phase in COVID-19. Our findings might entail relevant implications for the therapy of this disease and could boost the design of new clinical trials among subjects affected by severe COVID-19.Sin financiaciónNo data JCR 20201.915 SJR (2020) Q1, 165/2447 Medicine (miscellaneous)No data IDR 2020UE

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study)

Introduction: Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. Material and methods: We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. Results: A total of 114 patients were included (March–July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1–3 N0–1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. Conclusion: The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data

Plitidepsin for the management of a cancer patient infected with SARS-CoV-2 while receiving chemotherapy

Sin financiación51.769 Q1 JCR 2021UE