Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study.

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

Time to diagnosis in systemic lupus erythematosus: Associated factors and its impact on damage accrual and mortality. Data from a multi-ethnic, multinational Latin American lupus cohort.

BACKGROUND: Systemic lupus erythematosus (SLE) often mimics symptoms of other diseases, and the interval between symptom onset and diagnosis may be long in some of these patients. Aims: To describe the characteristics associated with the time to SLE diagnosis and its impact on damage accrual and mortality in patients with SLE from a Latin American inception cohort. METHODS: Patients were from a multi-ethnic, multi-national Latin-American SLE inception cohort. All participating centers had specialized lupus clinics. Socio-demographic, clinical/laboratory, disease activity, damage, and mortality between those with a longer and a shorter time to diagnosis were compared using descriptive statistical tests. Multivariable Cox regression models with damage accrual and mortality as the end points were performed, adjusting for age at SLE diagnosis, gender, ethnicity, level of education, and highest dose of prednisone for damage accrual, plus highest dose of prednisone, baseline SLEDAI, and baseline SDI for mortality. RESULTS: Of the 1437 included in these analyses, the median time to diagnosis was 6.0 months (Q1-Q3 2.4-16.2); in 721 (50.2%) the time to diagnosis was longer than 6 months. Patients whose diagnosis took longer than 6 months were more frequently female, older at diagnosis, of Mestizo ethnicity, not having medical insurance, and having "non-classic" SLE symptoms. Longer time to diagnosis had no impact on either damage accrual (HR 1.09, 95% CI 0.93-1.28, p = 0.300) or mortality (HR 1.37, 95% CI 0.88-2.12, p = 0.200). CONCLUSIONS: In this inception cohort, a maximum time of 24 months with a median of 6 months to SLE diagnosis had no apparent negative impact on disease outcomes (damage accrual and mortality).

Role of PATJ in stroke prognosis by modulating endothelial to mesenchymal transition through the Hippo/Notch/PI3K axis.

Through GWAS studies we identified PATJ associated with functional outcome after ischemic stroke (IS). The aim of this study was to determine PATJ role in brain endothelial cells (ECs) in the context of stroke outcome. PATJ expression analyses in patient's blood revealed that: (i) the risk allele of rs76221407 induces higher expression of PATJ, (ii) PATJ is downregulated 24 h after IS, and (iii) its expression is significantly lower in those patients with functional independence, measured at 3 months with the modified Rankin scale ((mRS) ≤2), compared to those patients with marked disability (mRS = 4-5). In mice brains, PATJ was also downregulated in the injured hemisphere at 48 h after ischemia. Oxygen-glucose deprivation and hypoxia-dependent of Hypoxia Inducible Factor-1α also caused PATJ depletion in ECs. To study the effects of PATJ downregulation, we generated PATJ-knockdown human microvascular ECs. Their transcriptomic profile evidenced a complex cell reprogramming involving Notch, TGF-ß, PI3K/Akt, and Hippo signaling that translates in morphological and functional changes compatible with endothelial to mesenchymal transition (EndMT). PATJ depletion caused loss of cell-cell adhesion, upregulation of metalloproteases, actin cytoskeleton remodeling, cytoplasmic accumulation of the signal transducer C-terminal transmembrane Mucin 1 (MUC1-C) and downregulation of Notch and Hippo signaling. The EndMT phenotype of PATJ-depleted cells was associated with the nuclear recruitment of MUC1-C, YAP/TAZ, ß-catenin, and ZEB1. Our results suggest that PATJ downregulation 24 h after IS promotes EndMT, an initial step prior to secondary activation of a pro-angiogenic program. This effect is associated with functional independence suggesting that activation of EndMT shortly after stroke onset is beneficial for stroke recovery.

The Real-World Study of Immunogenicity and Safety of the Adjuvant Recombinant Vaccine against Varicella Zoster Virus in Patients with Immune-Mediated Inflammatory Diseases Treated with Janus Kinase Inhibitors.

Background. The risk of herpes zoster reactivation is increased in immunocompromised patients, especially in those with immune-mediated inflammatory diseases (IMIDs) on Janus kinase inhibitor (JAKi) treatment. The recombinant subunit herpes zoster vaccine (RZV) is a non-live vaccine, recently approved for this subgroup of patients, which shows high rates of vaccine effectiveness, with few adverse effects reported in clinical trials. Purpose. The aim of this real-world study was to determine the immunogenicity and safety of RZV in IMID patients on JAKi treatment. Methods. The increase in the concentration of anti-gE antibody for varicella zoster virus post-vaccination, compared to the pre-vaccination concentration, was analyzed to test the humoral immune response. Adverse effects after the first and second vaccine doses were registered. Results. In total, 49 patients were analyzed, and a fourfold increase in antibody concentration was achieved in almost 40% of subjects, with only one serious local adverse effect. Discussion. The resulting immunogenicity was lower than that observed in clinical trials, probably due to the presence of immune disease and immunosuppressive treatment, and to the fact that this was a real-world study. No differences in response according to age, previous virus zoster reactivation, or concomitant treatments were found. Conclusions. RZV was well tolerated and reached the immune response objective in 40% of patients. These results reinforce the importance of including RZV vaccination for immunosuppressed patients. Real-world studies regarding vaccine effectiveness are still needed in order to gain a full understanding of the response to RZV in this group of patients.

Estilos y enfoques de aprendizaje en estudiantes de Estomatología y relación con el rendimiento académico en Farmacología

Fundamento: los estilos y enfoques de aprendizaje permiten conocer cómo el estudiante enfrenta este proceso y el modo en que procesa la información que debe ser asimilada. Objetivo: identificar los estilos y enfoques de aprendizaje que utilizan estudiantes de Estomatología y su relación con el rendimiento académico en la disciplina Farmacología. Métodos: estudio descriptivo-transversal, con enfoque cualicuantitativo, realizado de noviembre 2021 a enero 2022. La muestra, no probabilística, fue de 28 estudiantes (90,3 %) de segundo año de la carrera de Estomatología impartida en la Facultad de Estomatología de La Habana. A los participantes se les aplicaron dos instrumentos: cuestionario Honey y Alonso sobre estilos de aprendizaje y cuestionario Enfoques e Inventario de Habilidades de Estudio de los Estudiantes. Las dimensiones del rendimiento académico fueron excelente, bueno, y regular. Resultados: predominó la preferencia muy alta/alta en el estilo teórico (67,86 %) y la preferencia moderada en el reflexivo (67,86 %). Se encontró relación significativa entre la cantidad de estilos de aprendizaje de preferencia muy alta/alta y el rendimiento académico (p=0,044), y entre el estilo reflexivo y el rendimiento académico (p=0,024). También, se encontró relación significativa entre el rendimiento académico y el enfoque de aprendizaje estratégico (p=0,008) y la preferencia por la transmisión de la información (p=0,028). Conclusiones: en los estudiantes existen estilos y enfoques de aprendizaje que se relacionan con el rendimiento académico en Farmacología; se muestran aspectos que se deben considerar para el mejoramiento del proceso docente de esta disciplina en Estomatología.

Foundation: the learning styles and approaches allow us to know how the student faces this process and the way in which they process the information that must be assimilated. Objective: to identify the learning styles and approaches used by Dentistry students and their relationship with academic performance in the Pharmacology discipline. Methods: a descriptive-cross-sectional study, with a qualitative-quantitative approach, carried out from November 2021 to January 2022. The non-probabilistic sample consisted of 28 students (90.3%) in the second year of the Dentistry course taught at the Havana Dentistry Faculty. Two instruments were applied to the participants: the Honey and Alonso questionnaire on learning styles and the Approaches and Inventory of Student Study Skills questionnaire. The dimensions of academic performance were excellent, good, and regular. Results: the very high/high preference predominated in the theoretical style (67.86%) and the moderate preference in the reflective style (67.86%). A significant relationship was found between the number of very high/high preference learning styles and academic performance (p=0.044), and between the reflective style and academic performance (p=0.024). Also, a significant relationship was found between academic performance and the strategic learning approach (p=0.008) and the preference for the transmission of information (p=0.028). Conclusions: there are learning styles and approaches among students that are related to academic performance in Pharmacology; Aspects that should be considered for the improvement of the teaching process of this discipline in Dentistry are shown.

Trap and ambush therapy using sequential primary and tumor escape-selective oncolytic viruses.

In multiple models of oncolytic virotherapy, it is common to see an early anti-tumor response followed by recurrence. We have previously shown that frontline treatment with oncolytic VSV-IFN-ß induces APOBEC proteins, promoting the selection of specific mutations that allow tumor escape. Of these mutations in B16 melanoma escape (ESC) cells, a C-T point mutation in the cold shock domain-containing E1 (CSDE1) gene was present at the highest frequency, which could be used to ambush ESC cells by vaccination with the mutant CSDE1 expressed within the virus. Here, we show that the evolution of viral ESC tumor cells harboring the escape-promoting CSDE1C-T mutation can also be exploited by a virological ambush. By sequential delivery of two oncolytic VSVs in vivo, tumors which would otherwise escape VSV-IFN-ß oncolytic virotherapy could be cured. This also facilitated the priming of anti-tumor T cell responses, which could be further exploited using immune checkpoint blockade with the CD200 activation receptor ligand (CD200AR-L) peptide. Our findings here are significant in that they offer the possibility to develop oncolytic viruses as highly specific, escape-targeting viro-immunotherapeutic agents to be used in conjunction with recurrence of tumors following multiple different types of frontline cancer therapies.

Caracterización epidemiológica de pacientes con COVID-19 en la Región Sanitaria de Francisco Morazán, Honduras / Epidemiological characterization of patients with COVID-19 in the Sanitary Region of Francisco Morazán, Honduras

Antecedentes: La infección por el virus SARS- CoV-2 causa la enfermedad por coronavirus 2019 ( COVID-19). Objetivo: Caracterizar epidemiológicamente al paciente con COVID-19, Región Sanitaria Departamental de Francisco Morazán (RSDFM), Honduras, marzo 2020-enero 2021. Métodos: Estudio descriptivo retrospectivo. Incluyó n=11,401 usuarios a quienes se les realizó confirmación diagnóstica en la RSDFM. Se calculó incidencia general y mensual de COVID-19 como tasas por 10,000 habitantes, tasas de incidencia municipal (casos positivos/10,000) y tasa de letalidad (fallecidos/100 casos positivos). Resultados: Del total de 3,680 usuarios, el promedio de edad de los casos positivos fue 36.8 años (DS+/-17.9); sexo femenino 53.3% (1,962), procedencia Valle de Ángeles 20.4% (752). El nexo epidemiológico fue contacto con familiar o amigo positivo o fallecido por COVID-19 en 96.3% (3,544). La tasa general de incidencia fue 92.4/10,000. El municipio de Valle de Ángeles presentó la tasa de incidencia más elevada 366.1/10,000. La tasa de letalidad fue 1.8% (68/3680). Discusión: Los hallazgos de este estudio son compatibles con otros autores con respecto a las características epidemiológicas y sintomatología, identificando mayor riesgo de mortalidad en los individuos con edad ≥60 años (35/418 vs <60 años 32/3194; p=0.000, OR: 8.60, IC95%: 5.15-14.37), así como para el sexo masculino (48/1670 vs 20/1942; p=0.000, OR:2.79, IC95%: 1.61- 4.89). Los meses de mayor incidencia de casos en la RSDFM fueron los meses de junio a julio del 2020 y diciembre del 2020 a enero del 2021. Estudios de este tipo fortalecen el abordaje epidemiológico de las epidemias/pandemias...(AU)

Infección por SARS-CoV-2 y grupos sanguíneos en pacientes cubanos diagnosticados con la COVID-19

Introducción: Diferentes estudios han propuesto la relación entre los grupos sanguíneos del sistema ABO y la susceptibilidad a la COVID-19 y su importancia en el curso de la enfermedad. Objetivo: Determinar la frecuencia fenotípica de grupos sanguíneos ABO y RhD en un grupo de pacientes con infección activa por SARS-CoV-2. Métodos: Se realizó un estudio descriptivo, transversal y caso control en el Hospital Docente Clínico Quirúrgico "Freyre Andrade" de La Habana, para determinar la frecuencia fenotípica ABO y RhD en un grupo de pacientes con enfermedad activa por la COVID-19. Se estudiaron 928 muestras de sangre de pacientes con diagnóstico de COVID-19 y 1050 muestras pertenecientes a individuos sanos como grupo control. El grupo sanguíneo ABO y RhD se determinó por método de aglutinación en tubo con sueros hemoclasificadores anti-A, anti-B, anti-A+B, yanti-D. Los resultados fueron expresados en frecuencias absolutas y relativas y se determinó la asociación del grupo sanguíneo con la gravedad de la enfermedad por medio de la prueba no paramétrica de χ2 con un nivel de significación de p ≤ 0,05. Resultados: Se observó predominio del fenotipo O (49,24 %) seguido del A (35,79 %), B (12,68 %) y AB (2,27 %) respectivamente. Los fenotipos O y B presentaron significación estadística para la ocurrencia de la COVID-19, con valores de p < 0,05. No se encontró significación estadística en cuanto al predominio de un fenotipo particular y la necesidad de cuidados intensivos. Conclusiones: La relación del grupo sanguíneo ABO en la infectividad por SARS-CoV-2 y la gravedad de la enfermedad por la COVID-19 requiere estudios adicionales ya que los actuales no son concluyentes.

Introduction: Different studies have proposed the relationship between the blood groups of ABO system and the susceptibility to COVID-19 and its importance in the course of the disease. Objective: To determine the phenotypic frequency of ABO and RhD blood groups in a group of patients with active SARS-CoV-2 infection. Methods: A descriptive, cross-sectional, case-control study was conducted to determine the ABO and RhD phenotypic frequency in a group of patients with COVID-19 active disease. Nine hundred twenty eight blood samples and 1050 samples belonging to healthy individuals as control group were studied. The ABO and RhD blood group was determined by the tube agglutination method with anti-A, anti-B, anti-A+B, and anti-D blood classifying sera. The results were expressed in absolute and relative frequencies and the association of the blood group with the severity of the disease was determined by the non-parametric χ2 test with a significance level of p ≤ 0.05. Results: A predominance of phenotype O (49.24%) was observed, followed by A (35.79%), B (12.68%) and AB (2.27%) respectively. The O and B phenotypes showed statistical significance for the occurrence of COVID-19, with p values < 0.05. No statistical significance was found regarding the prevalence of a particular phenotype and the need for intensive care. Conclusions: The relationship of the ABO blood group in the infectivity of SARS-CoV-2 and the severity of the disease by COVID-19 requires additional studies, since the current ones are not conclusive.

Real-world safety and effectiveness of cenobamate in patients with focal onset seizures: Outcomes from an Expanded Access Program.

OBJECTIVE: This study investigated early, real-world outcomes with cenobamate (CNB) in a large series of patients with highly drug-resistant epilepsy within a Spanish Expanded Access Program (EAP). METHOD: This was a multicenter, retrospective, observational study in 14 hospitals. Inclusion criteria were age ≥18 years, focal seizures, and EAP authorization. Data were sourced from patient clinical records. Primary effectiveness endpoints included reductions (100%, ≥90%, ≥75%, and ≥50%) or worsening in seizure frequency at 3-, 6-, and 12-month visits and at the last visit. Safety endpoints included rates of adverse events (AEs) and AEs leading to discontinuation. RESULTS: The study included 170 patients. At baseline, median epilepsy duration was 26 years and median number of seizures/month was 11.3. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 12 and 3, respectively. Mean CNB dosages/day were 176 mg, 200 mg, and 250 mg at 3, 6, and 12 months. Retention rates were 98.2%, 94.5%, and 87% at 3, 6, and 12 months. At last available visit, the rate of seizure freedom was 13.3%; ≥90%, ≥75%, and ≥50% responder rates were 27.9%, 45.5%, and 63%, respectively. There was a significant reduction in the number of seizures per month (mean: 44.6%; median: 66.7%) between baseline and the last visit (P < 0.001). Responses were maintained regardless of the number of prior or concomitant ASMs. The number of concomitant ASMs was reduced in 44.7% of patients. The cumulative percentage of patients with AEs and AEs leading to discontinuation were 68.2% and 3.5% at 3 months, 74.1% and 4.1% at 6 months, and 74.1% and 4.1% at 12 months. The most frequent AEs were somnolence and dizziness. SIGNIFICANCE: In this highly refractory population, CNB showed a high response regardless of prior and concomitant ASMs. AEs were frequent but mostly mild-to-moderate, and few led to discontinuation.

Predictors of severe hemolytic anemia and its impact on major outcomes in systemic lupus erythematosus: Data from a multiethnic Latin American cohort.

OBJECTIVE: To determine the predictors of the occurrence of severe autoimmune hemolytic anemia (AIHA) and its impact on damage accrual and mortality in SLE patients. METHODS: Factors associated with time to severe AIHA (hemoglobin level ≤7 g/dL) occurring from the onset of SLE symptoms were examined by Cox proportional hazards regressions. The association of severe AIHA with mortality was examined by logistic regression analyses while its impact on damage was by negative binomial regression. RESULTS: Of 1,349 patients, 49 (3.6%) developed severe AIHA over a mean (SD) follow-up time of 5.4 (3.8) years. The median time from the first clinical manifestation to severe AIHA was 111 days (IQR 43-450). By multivariable analysis, male sex (HR 2.26, 95% CI 1.02-4.75, p = 0.044), and higher disease activity at diagnosis (HR 1.04, 95% CI 1.01-1.08, p = 0.025) were associated with a shorter time to severe AIHA occurrence. Of the SLEDAI descriptors, only hematologic (leukopenia and/or thrombocytopenia) showed a certain trend toward significance in the multivariable analysis (HR 2.36, 95% CI 0.91-6.13, p = 0.0772). Severe AIHA contributed neither to damage nor to mortality. CONCLUSIONS: Severe AIHA occurs during the early course of SLE. Male sex and higher disease activity at diagnosis emerged as independent predictors of a shorter time to severe AIHA occurrence. Although not statistically significant, hematological abnormalities at SLE diagnosis could predict the occurrence of severe AIHA in a shorter time. Damage and mortality did not seem to be impacted by the occurrence of severe AIHA.

Biallelic TET2 mutations confer sensitivity to 5'-azacitidine in acute myeloid leukemia.

Precision medicine can significantly improve outcomes for patients with cancer, but implementation requires comprehensive characterization of tumor cells to identify therapeutically exploitable vulnerabilities. Here, we describe somatic biallelic TET2 mutations in an elderly patient with acute myeloid leukemia (AML) that was chemoresistant to anthracycline and cytarabine but acutely sensitive to 5'-azacitidine (5'-Aza) hypomethylating monotherapy, resulting in long-term morphological remission. Given the role of TET2 as a regulator of genomic methylation, we hypothesized that mutant TET2 allele dosage affects response to 5'-Aza. Using an isogenic cell model system and an orthotopic mouse xenograft, we demonstrate that biallelic TET2 mutations confer sensitivity to 5'-Aza compared with cells with monoallelic mutations. Our data argue in favor of using hypomethylating agents for chemoresistant disease or as first-line therapy in patients with biallelic TET2-mutated AML and demonstrate the importance of considering mutant allele dosage in the implementation of precision medicine for patients with cancer.

Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.

Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.