Trastuzumab (Herceptin (R)): Monoclonal antibody in the treatment of HER2/neu-overexpressing breast cancer in the metastatic and (neo)adjuvant situation

Trastuzumab (Herceptin (R)) is a humanized monoclonal antibody that specifically targets HER2/neu (human epidermal growth factor receptor-2) breast cancer cells, which are overexpressed in about 25-30% of breast carcinomas. After phase I and II trials, several phase III studies of trastuzumab alone or in combination with various chemotherapies were conducted. Patients with HER2/neu overexpression levels of 3+ determined by immunohistochemical assay or gene amplification (fluorescence in situ hybridization) derive most clinical benefit from trastuzumab. Taking into consideration efficacy and side effect profile, the combination of trastuzumab and paclitaxel showed an improvement of all clinical parameters, including overall survival, for the first time in the history of palliative breast cancer therapy. The application of trastuzumab has meanwhile become an established part of systemic therapy of metastastic breast cancer, and excellent data of its application in the adjuvant setting now exist (NSABP-B31, NCCTG-N9831, HERA), with significantly better relapse-free survival in the treatment arms with trastuzumab. Ongoing trials investigate the role of trastuzumab in the neoadjuvant setting. Trastuzumab is generally well tolerated. Cardiotoxicity is the main concern, thus monitoring of cardiac function is recommended

Trabalho em Saúde Mental Durante a COVID-19: Manejo de Pacientes com Risco

Health professional have been exposed to different stressors during the first two year of the COVID-19 pandemic. This situation may cause emotional symptoms besides influencing on the way they attended their patients. This article aimed to investigate how health professionals care for patients at risk of suicide and have experienced their work in the context of the COVID-19 pandemic. By using semi-structured interviewing, participants, from different areas from mental health field, reported their experiences that were analyzed by the technique of qualitative content analyses. The participants pointed out that they had to adapt to a new routine during the pandemic, what involved the services closure, team reduction, increasing of working hours, changings in the current working process, in addition to the risk of being contaminated, themselves or a familiar. All of participants had already lost patients to suicide and a large part of them kept to assisting patients at risk during this period. The risk assessment did not follow any pre-established protocol, but took place together with other professionals, and always in contact with the patients' families. Professionals had greater difficulty in referrals and decision-making, in addition to perceiving themselves more fearful in interventions and feeling more overwhelmed. We discuss the need to research and propose new strategies for intervention targeting mental health of these workers, especially preparing them for public health crisis situations.Los profesionales de la salud estuvieron expuestos a varios estresores en los primeros dos años de la pandemia de COVID-19, y estos factores pueden causar síntomas emocionales, además de influir en la forma en que cuidan a sus pacientes. Este artículo pretendía investigar cómo los profesionales de la salud trataron a los pacientes en riesgo de suicidio y vivieron su trabajo en el contexto de la pandemia de COVID-19. A través de entrevistas semiestructuradas, participantes de diferentes áreas de la salud mental relataron sus experiencias, las cuales fueron analizadas mediante la técnica de análisis de contenido cualitativo. Los participantes destacaron que debieron adaptarse a una nueva rutina durante la pandemia, que implicó cerrar servicios, reducir equipos, aumentar la carga de trabajo, cambiar el método de atención, además de tener que lidiar con el riesgo de ser contaminados o contaminados por sus conocidos y miembros de la familia. Todos ellos ya habían perdido pacientes por suicidio y gran parte de los participantes seguían viendo pacientes de riesgo durante este período. La valoración del riesgo no siguió ningún protocolo preestablecido, sino que se realizó junto con otros profesionales, y siempre en contacto con los familiares de los pacientes. Los profesionales tenían mayor dificultad en la derivación y toma de decisiones, además de percibirse más temerosos en las intervenciones y sentirse más agobiados. Se discute la necesidad de investigar y proponer nuevas estrategias de intervención y mejora en la salud mental de estos trabajadores, especialmente preparándolos para situaciones de crisis sanitaria.Profissionais da saúde estiveram expostos a diversos estressores nos dois primeiros anos da pandemia da COVID-19, e esses fatores podem ocasionar sintomas emocionais, além de influenciar na forma com que atenderam seus pacientes. Este artigo teve por objetivo investigar como os profissionais de saúde atenderam pacientes com risco de suicídio e vivenciaram seu trabalho no cenário da pandemia da COVID-19. Por meio de entrevistas semiestruturadas, os participantes de diferentes áreas da saúde mental relataram suas vivências, sendo analisadas com a técnica de análise de conteúdo qualitativa. Os participantes destacaram que tiveram que se adaptar com uma nova rotina durante a pandemia, que envolveu o fechamento de serviços, redução de equipes, aumento de carga horária, mudança no método do atendimento, além de precisarem lidar com o risco de se contaminar ou contaminar seus conhecidos e familiares. Todos já tinham perdido pacientes por suicídio e grande parte dos participantes seguiu atendendo pacientes em risco nesse período. A avaliação de risco não seguia nenhum protocolo pré-estabelecido, mas ocorreu em conjunto com outros profissionais, e sempre em contato com a família dos pacientes. Os profissionais tiveram uma maior dificuldade nos encaminhamentos e tomadas de decisão, além de se perceberem mais receosos nas intervenções e se sentirem mais sobrecarregados. Discute-se a necessidade de pesquisar e propor novas estratégias de intervenção e melhoria na saúde mental desses trabalhadores, especialmente preparando-os para situações de crises sanitárias

Exposure to avian coronavirus vaccines is associated with increased levels of SARS-CoV-2-cross-reactive antibodies.

BACKGROUND Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. METHODS We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. RESULTS A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared with pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared with pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. CONCLUSION We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings may be useful for further studies on the adaptive immunity against COVID-19

Exposure to avian coronavirus vaccines is associated with increased levels of SARS-CoV-2-cross-reactive antibodies

Background: Although avian coronavirus infectious bronchitis virus (IBV) and SARS-CoV-2 belong to different genera of the Coronaviridae family, exposure to IBV may result in the development of cross-reactive antibodies to SARS-CoV-2 due to homologous epitopes. We aimed to investigate whether antibody responses to IBV cross-react with SARS-CoV-2 in poultry farm personnel who are occupationally exposed to aerosolized IBV vaccines. Methods: We analyzed sera from poultry farm personnel, COVID-19 patients, and pre-pandemic controls. IgG levels against the SARS-CoV-2 antigens S1, RBD, S2, and N and peptides corresponding to the SARS-CoV-2 ORF3a, N, and S proteins as well as whole virus antigens of the four major S1-genotypes 4/91, IS/1494/06, M41, and D274 of IBV were investigated by in-house ELISAs. Moreover, live-virus neutralization test (VNT) was performed. Results: A subgroup of poultry farm personnel showed elevated levels of specific IgG for all tested SARS-CoV-2 antigens compared with pre-pandemic controls. Moreover, poultry farm personnel, COVID-19 patients, and pre-pandemic controls showed specific IgG antibodies against IBV strains. These antibody titers were higher in long-term vaccine implementers. We observed a strong correlation between IBV-specific IgG and SARS-CoV-2 S1-, RBD-, S2-, and N-specific IgG in poultry farm personnel compared with pre-pandemic controls and COVID-19 patients. However, no neutralization was observed for these cross-reactive antibodies from poultry farm personnel using the VNT. Conclusion: We report here for the first time the detection of cross-reactive IgG antibodies against SARS-CoV-2 antigens in humans exposed to IBV vaccines. These findings may be useful for further studies on the adaptive immunity against COVID-19. Keywords: COVID-19; IBV; SARS-CoV-2; cross-reactivity; neutralizatio

An artificial intelligence algorithm is highly accurate for detecting endoscopic features of eosinophilic esophagitis

The endoscopic features associated with eosinophilic esophagitis (EoE) may be missed during routine endoscopy. We aimed to develop and evaluate an Artificial Intelligence (AI) algorithm for detecting and quantifying the endoscopic features of EoE in white light images, supplemented by the EoE Endoscopic Reference Score (EREFS). An AI algorithm (AI-EoE) was constructed and trained to differentiate between EoE and normal esophagus using endoscopic white light images extracted from the database of the University Hospital Augsburg. In addition to binary classification, a second algorithm was trained with specific auxiliary branches for each EREFS feature (AI-EoE-EREFS). The AI algorithms were evaluated on an external data set from the University of North Carolina, Chapel Hill (UNC), and compared with the performance of human endoscopists with varying levels of experience. The overall sensitivity, specificity, and accuracy of AI-EoE were 0.93 for all measures, while the AUC was 0.986. With additional auxiliary branches for the EREFS categories, the AI algorithm (AI-EoE-EREFS) performance improved to 0.96, 0.94, 0.95, and 0.992 for sensitivity, specificity, accuracy, and AUC, respectively. AI-EoE and AI-EoE-EREFS performed significantly better than endoscopy beginners and senior fellows on the same set of images. An AI algorithm can be trained to detect and quantify endoscopic features of EoE with excellent performance scores. The addition of the EREFS criteria improved the performance of the AI algorithm, which performed significantly better than endoscopists with a lower or medium experience level

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms

Ex-vivo detection and quantification of autoreactive t-cells in multiple sclerosis patients and controls

GesamtdissertationDie Multiple Sklerose (MS) ist die häufigste chronisch-entzündliche Erkrankung des Zentralnervensystems. Man geht davon aus, dass eine durch aktivierte Myelin-spezifische T-Zellen hervorgerufene Entzündungsreaktion zur Demyelinisierung und zum Untergang von Axonen und Neuronen führt. Mit Hilfe eines IL-7 modifizierten Proliferationsassays konnte Myelinreaktivität auf MBP-Protein sowie andere eingesetzte Myelinantigene bei MS-Patienten und Kontrollen nachgewiesen werden, wobei auf einzelne Myelinpeptide häufiger Patienten reagierten. In einer Längsschnittuntersuchung zeigte sich ein höherer kumulativer Stimulationsindex auf MBP-Protein bei den MS-Patienten, was für eine höhere Aktivität Myelin-spezifischer T-Zellen bei der MS sprechen könnte. Ex-vivo, nach nur 6 stündiger Inkubationszeit mit Myelinantigen, konnte bei wenigen Patienten (3/33) und Kontrollen (2/26) eine Population IFN- gamma/TNF-alpha produzierender CD4+/CD69+ T-Zellen mit dem Durchflusszytometer detektiert werden. Es zeigte sich kein Unterschied hinsichtlich der Frequenz Myelin-spezifischer T-Zellen bei Patienten und KontrollenMultiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system. Activated myelin specific T cells are thought to mediate an inflammatory reaction leading to demyelination, axonal damage and loss of neurons. Using an IL-7 modified proliferation assay, myelin reactivity to MBP-protein and other myelin antigens was shown in MS patients and healthy controls. To some of the antigens patients reacted more frequently than volunteers. A longitudinal analysis revealed a higher cumulative stimulation index for MBP protein in MS patients, which may indicate a higher activity of myelin specific T cells in MS. An IFN-gamma/TNF-alpha producing CD4+/CD69+ T cell population was detected ex vivo only 6 hours after antigenic challenge by intracellular flow cytometry in 3/33 MS patients and 2/26 healthy controls. The calculated myelin specific T cell frequencies did not differ between patients and controls