Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study

PrefHer revealed compelling and consistent patient preference for subcutaneous (s.c.) trastuzumab, regardless of delivery by single-use injection device or hand-held syringe. s.c. trastuzumab was well-tolerated and safety data, including immunogenicity, were consistent with previous reports. No new safety signals were identified compared with the known intravenous trastuzumab profile in early breast cance

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

La infusión intracerebroventricular prolongada de líquido cefalorraquídeo procedente de pacientes con esclerosis lateral amiotrófica provoca cambios histológicos en el cerebro y la médula espinal de la rata similares a los hallados en la enfermedad

Resumen: Introducción: La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro. Material y métodos: Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados: Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobre expresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones: Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad. Abstract: Introduction: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. Material and methods: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43 days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82 days after surgery. Results: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. Conclusion: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease. Palabras clave: Esclerosis lateral amiotrófica, Modelo experimental ELA, Periferina, TDP-43, Enfermedades neurodegenerativas, Citotoxicidad, Keywords: Amyotrophic lateral sclerosis, ALS experimental model, Peripherin, TDP-43, Neurodegenerative diseases, Cytotoxicit

Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease

Introduction: Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons. Materials and methods: We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43 days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82 days after surgery. Results: Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatin C, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins. Conclusion: Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease. Resumen: Introducción: La exposición de líquido cefalorraquídeo (LCR) de pacientes con esclerosis lateral amiotrófica (ELA) induce efectos citotóxicos en cultivos celulares de neuronas motoras in vitro. Material y métodos: Se seleccionó LCR de 32 pacientes con ELA que previamente habían demostrado efectos citotóxicos. Se implantaron con minibombas osmóticas intracerebroventriculares (ICV) en 28 ratas macho adultas y se dividieron en 3 grupos: 9 ratas de LCR de pacientes no-ELA, 15 ratas de ELA-LCR citotóxico y 4 ratas de una solución salina fisiológica. El LCR se administró por vía ICV de forma continua durante periodos de 20 o 43 días. Se realizó la evaluación clínica, electromiográfica y análisis de tejidos después de sacrificio a los 20, 45 y 82 días tras la cirugía. Resultados: Los estudios inmunohistoquímicos muestran daño en los tejidos con características similares a las encontradas en formas esporádicas de ELA, tales como sobreexpresión de cistatina C, transferrina y la proteína en el TDP-43 citoplasmática. Los primeros cambios observados parecían jugar un papel protector por la sobreexpresión de periferina, panAKT, fosfoAKT y metalotioneínas; esta expresión habría disminuido al momento de analizar las ratas que se sacrificaron al día 82, en el que hay un aumento de apoptosis. Los primeros cambios celulares identificados fueron la constatación de activación de la microglía seguido por astrogliosis con sobreexpresión de GFAP y proteína S100B. Conclusiones: Nuestros datos parecen indicar que la ELA podría propagarse a través del LCR, y que la administración ICV de ELA-LCR citotóxico produce cambios similares a los encontrados en las formas esporádicas de la enfermedad. Keywords: Amyotrophic lateral sclerosis, ALS experimental model, Peripherin, TDP-43, Neurodegenerative diseases, Cytotoxicity, Palabras clave: Esclerosis lateral amiotrófica, Modelo experimental ELA, Periferina, TDP-43, Enfermedades neurodegenerativas, Citotoxicida