Anti-PF4 immunothrombosis without proximate heparin or adenovirus vector vaccine exposure.

ABSTRACT: Platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies and anti-PF4 antibodies cause heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombocytopenia and thrombosis (VITT), respectively. Diagnostic and treatment considerations differ somewhat between HIT and VITT. We identified patients with thrombocytopenia and thrombosis without proximate heparin exposure or adenovirus-based vaccination who tested strongly positive by PF4/polyanion enzyme-immunoassays and negative/weakly positive by heparin-induced platelet activation (HIPA) test but strongly positive by PF4-induced platelet activation (PIPA) test (ie, VITT-like profile). We tested these patients by a standard chemiluminescence assay that detects anti-PF4/heparin antibodies found in HIT (HemosIL AcuStar HIT-IgG(PF4-H)) as well as a novel chemiluminescence assay for anti-PF4 antibodies found in VITT. Representative control sera included an exploratory anti-PF4 antibody-positive but HIPA-negative/weak cohort obtained before 2020 (n = 188). We identified 9 patients with a clinical-pathological profile of a VITT-like disorder in the absence of proximate heparin or vaccination, with a high frequency of stroke (arterial, n = 3; cerebral venous sinus thrombosis, n = 4), thrombocytopenia (median platelet count nadir, 49 × 109/L), and hypercoagulability (greatly elevated D-dimer levels). VITT-like serological features included strong reactivity by PIPA (aggregation <10 minutes in 9/9 sera) and positive testing in the novel anti-PF4 chemiluminescence assay (3/9 also tested positive in the anti-PF4/heparin chemiluminescence assay). Our exploratory cohort identified 13 additional patient sera obtained before 2020 with VITT-like anti-PF4 antibodies. Platelet-activating VITT-like anti-PF4 antibodies should be considered in patients with thrombocytopenia, thrombosis, and very high D-dimer levels, even without a proximate exposure to heparin or adenovirus vector vaccines.

Phase II trial of afatinib in patients with advanced urothelial carcinoma with genetic alterations in ERBB1-3 (LUX-Bladder 1).

BACKGROUND: Preclinical and early clinical data suggest that the irreversible ErbB family blocker afatinib may be effective in urothelial cancers harbouring ERBB mutations. METHODS: This open-label, phase II, single-arm trial (LUX-Bladder 1, NCT02780687) assessed the efficacy and safety of second-line afatinib 40 mg/d in patients with metastatic urothelial carcinoma with ERBB1-3 alterations. The primary endpoint was 6-month progression-free survival rate (PFS6) (cohort A); other endpoints included ORR, PFS, OS, DCR and safety (cohorts A and B). Cohort A was planned to have two stages: stage 2 enrolment was based on observed antitumour activity. RESULTS: Thirty-four patients were enroled into cohort A and eight into cohort B. In cohorts A/B, PFS6 was 11.8%/12.5%, ORR was 5.9%/12.5%, DCR was 50.0%/25.0%, median PFS was 9.8/7.8 weeks and median OS was 30.1/29.6 weeks. Three patients (two ERBB2-amplified [cohort A]; one EGFR-amplified [cohort B]) achieved partial responses. Stage 2 for cohort A did not proceed. All patients experienced adverse events (AEs), most commonly (any/grade 3) diarrhoea (76.2%/9.5%). Two patients (4.8%) discontinued due to AEs and one fatal AE was observed (acute coronary syndrome; not considered treatment-related). CONCLUSIONS: An exploratory biomarker analysis suggested that basal-squamous tumours and ERBB2 amplification were associated with superior response to afatinib. CLINICAL TRIAL REGISTRATION: NCT02780687.

Non-C19MC-altered embryonal tumor with multilayered rosettes in a young woman with DICER1 syndrome: case report and review of the literature.

Embryonal tumors with multilayered rosettes (ETMR) are highly aggressive and therapy-resistant pediatric central nervous system (CNS) tumors that have three histological patters: embryonal tumor with abundant neuropil and true rosettes, ependymoblastoma, and medulloepithelioma. We present a case of ETMR in an 18-year-old woman with DICER1 syndrome. This report confirms the important role of DNA-methylation analysis in the classification of CNS embryonal tumors and the importance of investigating somatic and germline DICER1 mutations in all CNS embryonal tumors.

Detection of autoantibodies using chemiluminescence technologies.

CONTEXT: Although autoantibody detection methods such as indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISAs) have been available for many years and are still in use the innovation of fast, fully automated instruments using chemiluminescence technology in recent years has led to rapid adoption in autoimmune disease diagnostics. In 2009, BIO-FLASH, a fully automated, random access chemiluminescent analyzer, was introduced, proceeded by the development of the QUANTA Flash chemiluminescent immunoassays (CIA) for autoimmune diagnostics. OBJECTIVE: To summarize the evolution of CIAs for the detection of autoantibodies and to review their performance characteristics. METHODS: Pubmed was screened for publications evaluating novel QUANTA Flash assays and how they compare to traditional methods for the detection of autoantibodies. In addition, comparative studies presented at scientific meetings were summarized. RESULTS: Several studies were identified that compared the novel CIAs with conventional methods for autoantibody detection. The agreements ranged from moderate to excellent depending on the assay. The studies show how the CIA technology has enhanced the analytical and clinical performance characteristics of many autoantibody assays supporting both diagnosis and follow-up testing. CONCLUSION: CIA has started to improve the diagnostic testing of autoantibodies as an aid in the diagnosis of a broad range of autoimmune diseases.

A Phase I, Open-Label, Dose Confirmation, Escalation, and Expansion Trial of BI 1810631 as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations.

BACKGROUND: BI 1810631 is a human HER2-selective tyrosine kinase inhibitor that covalently binds to both wild-type and mutated HER2 receptors, including exon 20 insertion mutations, whilst sparing EGFR signaling. This phase Ia/Ib, open-label, non-randomized study will determine the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of BI 1810631 in patients with HER2 aberration-positive solid tumors (NCT04886804). PATIENTS AND METHODS: In phase Ia, patients with histologically/cytologically confirmed HER2 aberration-positive advanced/metastatic solid tumors will receive BI 1810631 orally twice daily (BID) or once daily (QD) at escalating doses. Starting dose level is 15 mg BID; QD schedule will begin after one dose level above estimated therapeutic dose of BI 1810631 is determined safe by the Dose Escalation Committee. Dose escalation will continue until MTD/recommended phase II dose and preferred phase Ib schedule for each schedule is determined. In phase Ib, patients with HER2 tyrosine kinase domain (TKD) mutation-positive non-small cell lung cancer (NSCLC) who have previously received ≥1 line of systemic therapy will be enrolled initially, with possible inclusion of additional NSCLC cohorts in the future, including untreated patients. The primary endpoints will be MTD based on number of dose-limiting toxicities (DLTs)/number of patients with DLTs (phase Ia) and objective response (phase Ib). Secondary endpoints include PK parameters (phase Ia/Ib); duration of response, disease control, duration of disease control, and progression-free survival (phase Ib). CONCLUSIONS: BI 1810631 could be an effective and tolerable EGFR-sparing oral treatment for patients with HER2 mutation-positive NSCLC, including exon 20 insertion mutations. GOV IDENTIFIER: NCT04886804.

hTERT and IGF-1R Proteins Expression in Response to Treatment in Patients with HPV Alpha 9-Positive Cervical Cancer.

Human papillomavirus (HPV) infection is strongly associated with cervical cancer (CC). Genomic alterations caused by viral infection and subsequent dysregulation of cellular metabolism under hypoxic conditions could influence the response to treatment. We studied a possible influence of IGF-1Rb, hTERT, HIF1a, GLUT1 protein expression, HPV species presence and relevant clinical parameters on the response to treatment. In 21 patients, HPV infection and protein expression were detected using GP5+/GP6+PCR-RLB and immunohistochemistry, respectively. The worse response was associated with radiotherapy alone compared with chemoradiotherapy (CTX-RT), anemia and HIF1a expression. HPV16 type was the most frequent (57.1%) followed by HPV-58 (14.2%) and HPV-56 (9.5%). The HPV alpha 9 species was the most frequent (76.1%) followed by alpha 6 and alpha 7. IGF-1Rb (85.7%), HIF1a (61.9%), GLUT1 (52.3%), and hTERT expression [cytoplasm and nucleus (90.4%)] were detected. The MCA factorial map showed different relationships, standing out, expression of hTERT and alpha 9 species HPV, expression of hTERT and IGF-1Rb expression [Fisher's exact test (P = 0.04)]. A slight trend of association was observed between, GLUT1 and HIF1 a expression, hTERT and GLUT1 expression. A noteworthy finding was the subcellular localization of hTERT in the nucleus and cytoplasm of CC cells and its possible interaction with IGF-1R in presence of HPV alpha 9 species. Our findings suggest that the expression of HIF1a, hTERT, IGF-1Rb and GLUT1 proteins that interact with some HPV species may contribute to cervical cancer development, and the modu lation of treatment response.

Meaningful Learning Experiences in Everyday Life During Pandemics. A Qualitative Study.

The COVID-19 pandemic has drastically changed the lives of people all over the world. In particular, an unprecedented educational crisis has occurred due to the circumstances of physical distancing and remote learning. This article focuses specifically on the meaningful learning experiences in the everyday lives of adolescents during the pandemic. 72 meaningful learning experiences were identified from 11 participants who recorded their specific learning experiences for a week by a means of a journal recorded by themselves. A content analysis was undertaken in order to identify the ecology (what, how, where, and who with) of the different learning experiences. The results show a prevalence of personal and conceptual learning, a presence of both formal and specifically informal, everyday activities among the meaningful learning experiences detected, the importance of peers, teacher and "learning experiences while alone," and the use of digital technologies as learning resources; they also reveal the assistance of others in the learning process. The main contribution of this study illustrates how students in everyday life during pandemics are involved in a whole range of different activities both at school and at home.

[Standards for interoperability: new challenges]. / Estándares para la interoperabilidad: nuevos retos.

Strategies for implementation of information systems have mainly focused on the implementation of different models of electronic medical records systems and solutions for specific departments. The next step is to make these systems share and exchange information and assistance that generate accessible citizens. For it, must be structured in a coherent and give a semantic content to allow interoperability between systems. This can be done if it is based on the standards, since they ensure consistency, scientific support and critical mass. The Department of Health of the Generalitat of Catalonia, through the office of standards and interoperability TicSalut Foundation, carried out the deployment of standards that facilitate interoperability between the centers not only in Catalonia but also with a global vision.

Evolución a largo plazo y factores influyentes de los pacientes que ingresan con FANV en los servicios de Medicina Interna de Galicia / Long-term evolution and influential factors of patients admitted with NVAF in the Internal Medicine services of Galicia

Objectives: The objective of this study was to investigate the longterm evolution and influencing factors of patients with non-valvular atrial fibrillation (NVAF) admitted to internal medicine services. Patients and method: This is an observational and retrospective study of the evolution during five years of the patients admitted, between January-2016 and January-2017, with FANV in the Galician Internal Medicine services. For this end, it was quantified the emergency room visits, hospital admissions and survival. The factors with more influence over these variables were studied. Results: It was included 1.342 patients and followed for 5 years. There were 3.691 hospital admissions, and 8.687 visits to the emergency department (ED). They had a survival of 66,6%, with a median survival of 1.034,57 days. The univariate analysis found that age, antithrombotic treatment at discharge and Barthel's index influenced survival, but not sex. However, in the multivariate analysis only Barthel’s index was found to be independent variable that influence survival. Conclusions: Patients with NVAF admitted to internal medicine services constitute a subpopulation at high risk of hospital readmission and visits to the ED. A change in the model of transition to discharge and outpatient follow-up is necessary, through adapted proactive programs, capable of reducing hospital events and improving the quality of life of these patients and their caregivers. (AU)

Objetivos: Estudiar la evolución a lo largo plazo, así como los factores que influyen en la misma, de la población con fibrilación auricular no valvular (FANV) que ingresa en los servicios de Medicina Interna. Pacientes y método: Estudio observacional y retrospectivo de la evolución durante cinco años, de los pacientes ingresados con FANV en los servicios de Medicina Interna gallegos, entre enero-2016 y enero-2017. Para este fin se cuantificaron las visitas a urgencias, los ingresos hospitalarios y la supervivencia. Se estudiaron los factores que más influyeron en estas variables. Resultados: Se incluyeron 1.342 pacientes y se realizó un seguimiento durante 5 años. Se contabilizaron 3.691 ingresos hospitalarios, y 8.687 visitas al servicio de urgencias (SU). Tuvieron una supervivencia del 66,6%, con una mediana de supervivencia de 1.034,57 días. En el análisis univariante, la edad, el tratamiento antitrombótico al alta y el índice de Barthel influyeron en la supervivencia, no así el sexo. En el análisis multivariante, el índice de Barthel fue la única variable independiente que influyó en la supervivencia. Conclusiones: Los pacientes con FANV ingresados en los servicios de Medicina Interna, suponen una subpoblación de alto riesgo de reingreso hospitalario y visitas al SU. Es necesario un cambio en el modelo de transición al alta y de seguimiento ambulatorio, mediante programas proactivos adaptados, capaces de reducir eventos hospitalarios y mejorar la calidad de vida de estos pacientes y sus cuidadores. (AU)

Multicentre evaluation of IL Test Free PS: a fully automated assay to quantify free protein S.

Deficiency of the anticoagulant vitamin K-dependent protein S (PS) is associated with increased risk of venous thrombosis. In human plasma, PS circulates in two forms: as free protein (free PS) and PS bound to C4b-binding protein (C4BP), a regulator of the complement system. Assays for free PS have higher sensitivity and specificity for protein S deficiency than assays for total protein S. We have extensively evaluated the analytical performance of a novel assay for free PS, the IL Test Free Protein S, which takes advantage of the affinity of C4BP for free PS, and compared its performance to existing methods. IL Test Free Protein S is a rapid, fully automated turbidimetric assay consisting of two reagents: a C4BP coated latex and an anti-PS monoclonal antibody coated latex. The test range, precision and linearity were adequate and the assay tolerated high concentrations of interfering substances of clinical significance. The reference range agreed with previously published studies. The analysis of 903 patient samples belonging to 20 different clinical categories with the new assay yielded free PS results that agreed well with those obtained using the assays established in the participating laboratories. The study demonstrated the IL Test Free Protein S to be rapid, reliable and easy to perform.

Estándares para la interoperabilidad: nuevos retos / Standards for interoperability: new challenges

Las estrategias de implantación de los sistemas de información se han centrado principalmente en la implantación de diferentes modelos de historia clínica electrónica, así como sistemas específicos para soluciones departamentales. El siguiente paso es hacer que estos sistemas compartan e intercambien la información asistencial que generan y hacerla accesible al ciudadano. Para ello, se debe estructurar de una forma coherente y darle un contenido semántico que permita la interoperabilidad entre los sistemas. Esto se puede hacer si se fundamenta en los estándares, ya que garantizan una coherencia, respaldo científico y masa crítica. El Departamento de Salud de la Generalitat de Catalunya, a través de la oficina de estándares e interoperabilidad de la Fundación TicSalut, está llevando a cabo el despliegue de los estándares que facilitará la interoperabilidad no sólo entre los centros de Cataluña sino también con una visión global (AU)

Strategies for implementation of information systems have mainly focused on the implementation of different models of electronic medical records systems and solutions for specific departments. The next step is to make these systems share and exchange information and assistance that generate accessible citizens. For it, must be structured in a coherent and give a semantic content to allow interoperability between systems. This can be done if it is based on the standards, since they ensure consistency, scientific support and critical mass. The Department of Health of the Generalitat of Catalonia, through the office of standards and interoperability TicSalut Foundation, carried out the deployment of standards that facilitate interoperability between the centers not only in Catalonia but also with a global vision (AU)