Abrocitinibe, dupilumabe e upadacitinibe para o tratamento de adolescentes com dermatite atópica moderada a grave e dupilumabe para o tratamento de crianças com dermatite atópica grave / Abrocitinib, dupilumab, and upadacitinib for the treatment of adolescents with moderate to severe atopic dermatitis and dupilumab for the treatment of children with severe atopic dermatitis

INTRODUÇÃO: A dermatite atópica é uma condição crônica e inflamatória da pele. O sintoma mais comum é o prurido associado a lesões eritematosas e escamosas. Estima-se, no Brasil, uma taxa de prevalência de 2.664,44 por 100.000 pessoas. No SUS, o PCDT de dermatite atópica inclui dois tratamentos tópicos (dexametasona e acetato de hidrocortisona) e a ciclosporina oral. Quando um paciente não estiver bem controlado com as terapias tópicas e sistêmica, é indicada a introdução de terapias imunobiológicas e inibidores da Janus-quinase. Esses medicamentos não são disponibilizados, no SUS, para dermatite atópica. PERGUNTAS: Qual é a eficácia, a segurança e a custo-efetividade dos medicamentos abrocitinibe, dupilumabe e upadacitinibe (adolescentes); e dupilumabe (crianças) para o tratamento de pacientes com dermatite atópica moderada a grave com falha, intolerância ou contraindicação à ciclosporina e com indicação à terapia sistêmica? EVIDÊNCIAS CLÍNICAS: foi realizada uma busca sistematizada da literatura no dia 04 de janeiro de 2024. Foram identificadas 24 revisões sistemáticas de estudos clínicos randomizados (ECRs) que atenderam às perguntas de pesquisa. Aquela com a busca mais recente foi selecionada para a descrição detalhada dos resultados. Para adolescentes e crianças, os ensaios clínicos foram descritos de forma individual para cada tecnologia. Entre adolescentes com dermatite moderada a grave, quando comparadas a placebo, todas as tecnologias avaliadas (abrocitini

[Severe atopic dermatitis in childhood in the era of personalized medicine]. / Dermatitis atópica severa en la infancia en la era de la medicina personalizada.

Atopic dermatitis (AD) is a chronic, non-infectious inflammatory dermatosis, with increasing prevalence in recent decades. Due to its chronic and recurrent nature, it diminishes the quality of life of patients and their families. In recent years, advances in the understanding of AD's pathophysiology have driven the development of targeted therapies such as monoclonal antibodies (mAbs) and Janus kinase inhibitors (JAKis) which modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. Four targeted therapies have been approved in the USA for the treatment of severe/refractory cases: dupilumab, tralokinumab, abrocitinib, and upadacitinib. This manuscript aims to present an update on the pathophysiology of AD, describe the new treatments available, and provide an analysis of the initial results of the use of these treatments in the pediatric population. We concluded that the high cost of these treatments often limits their prescription to situations where cases of atopic dermatitis are resistant to other conventional therapeutic options or when the disease reaches a severe degree. This underscores the importance of careful and accurate decision-making in the medical management of AD to ensure the efficient use of these therapeutic resources.

Budget impact analysis of durvalumab consolidation therapy vs no consolidation therapy after chemoradiotherapy in stage III non-small cell lung cancer in the context of the Chilean health care system.

BACKGROUND: Durvalumab, used as consolidation immunotherapy, has shown to improve survival in patients with stage III non-small cell lung cancer who respond to chemoradiotherapy, based on the most recent follow-up of PACIFIC. The Chilean healthcare system provides access to certain immunotherapies for this condition. The present study sought to estimate the budget impact of durvalumab versus standard of care in the context of the Chilean healthcare system. RESEARCH DESIGN AND METHODS: A partitioned survival model was adapted to compare two strategies: durvalumab as consolidation therapy and standard of care for treating stage III NSCLC. The number of patients eligible for treatment was estimated using published incidence data and modeled for a 5-year time horizon. Model inputs were based on published literature, and the duration of treatment was estimated using survival curves obtained from PACIFIC. Costs were estimated in Chilean pesos (CLP) and converted to USD dollars using an exchange rate of USD 1 = CLP 827. Scenario analyses were performed to assess different subsequent therapy splits, variations in the target population and dosage of durvalumab. RESULTS: Durvalumab uptake projected total costs ranging from USD 1.27 in Year 1 to 8.5 million in Year 5 from the public perspective. From the private perspective, the budget impact for the first year is USD 1.3 million to USD 3 million for 2028. This difference relies mostly on the lower number of patients treated. Both perspectives anticipated cost savings over the time horizon through reduced monitoring, adverse events, and end-of-life expenses. CONCLUSIONS: This study demonstrates that the inclusion of Durvalumab for NSCLC in Chile represents an investment in the Chilean health system. The incremental costs align with clinical benefits and potential savings in healthcare resource utilization. However, a comprehensive cost-effectiveness analysis is needed to evaluate its economic value thoroughly.

Ultrafast and highly sensitive detection of SARS-CoV-2 spike protein by field-effect transistor graphene-based biosensors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), etiological agent for the coronavirus disease 2019 (COVID-19), has resulted in over 775 million global infections. Early diagnosis remains pivotal for effective epidemiological surveillance despite the availability of vaccines. Antigen-based assays are advantageous for early COVID-19 detection due to their simplicity, cost-effectiveness, and suitability for point-of-care testing (PoCT). This study introduces a graphene field-effect transistor-based biosensor designed for high sensitivity and rapid response to the SARS-CoV-2 spike protein. By functionalizing graphene with monoclonal antibodies and applying short-duration gate voltage pulses, we achieve selective detection of the viral spike protein in human serum within 100 µs and at concentrations as low as 1 fg ml-1, equivalent to 8 antigen molecules perµl of blood. Furthermore, the biosensor estimates spike protein concentrations in serum from COVID-19 patients. Our platform demonstrates potential for next-generation PoCT antigen assays, promising fast and sensitive diagnostics for COVID-19 and other infectious diseases.

Mouse and human immune responses share neutralization epitopes of HAstV-VA1.

Astroviruses are highly divergent and infect a wide variety of animal hosts. In 2009, a genetically divergent human astrovirus (HAstV) strain VA1 was first identified in an outbreak of acute gastroenteritis. This strain has also been associated with fatal central nervous system disease. In this work, we report the isolation of three high-affinity neutralizing monoclonal antibodies (Nt-MAbs) targeting the capsid spike domain of HAstV-VA1. These antibodies (7C8, 2A2, 3D8) were used to select individual HAstV-VA1 mutants resistant to their neutralizing activity and a HAstV-VA1 triple mutant that escapes neutralization from all three Nt-MAbs. Sequencing of the virus genome capsid region revealed escape mutations that map to the surface of the capsid spike domain, define three potentially independent neutralization epitopes, and help delineate four antigenic sites in human astroviruses. Notably, two of the escape mutations were found to be present in the spike sequence of the HAstV-VA1-PS strain isolated from an immunodeficient patient with encephalitis, suggesting that those mutations arose as a result of the immune pressure generated by the patient's immunotherapy. In agreement with this observation, human serum samples exhibiting strong neutralization activity against wild-type HAstV-VA1 had a 2.6-fold reduction in neutralization titer when evaluated against the triple-escape HAstV-VA1 mutant, suggesting that both mouse and human antibody responses target shared neutralization epitopes. The isolated Nt-MAbs reported in this work will help to characterize the functional domains of the virus during cell entry and have the potential for developing a specific antibody therapy for the neurological disease associated with HAstV-VA1. IMPORTANCE: Human astroviruses (HAstVs) have been historically associated with acute gastroenteritis. However, the genetically divergent HAstV-VA1 strain has been associated with central nervous system disease. In this work high-affinity neutralizing monoclonal antibodies directed to HAstV-VA1 were isolated and characterized. The proposed binding sites for these antibodies and for neutralizing antibodies against classical HAstVs suggest that there are at least four neutralization sites on the capsid spike of astroviruses. Our data show that natural infection with human astrovirus VA1 elicits a robust humoral immune response that targets the same antigenic sites recognized by the mouse monoclonal antibodies and strongly suggests the emergence of a variant HAstV-VA1 virus in an immunodeficient patient with prolonged astrovirus infection. The isolated Nt-MAb reported in this work will help to define the functional sites of the virus involved in cell entry and hold promise for developing a specific antibody therapy for the neurological disease associated with HAstV-VA1.

A Dual Strategy-In Vitro and In Silico-To Evaluate Human Antitetanus mAbs Addressing Their Potential Protective Action on TeNT Endocytosis in Primary Rat Neuronal Cells.

Tetanus disease, caused by C. tetani, starts with wounds or mucous layer contact. Prevented by vaccination, the lack of booster shots throughout life requires prophylactic treatment in case of accidents. The incidence of tetanus is high in underdeveloped countries, requiring the administration of antitetanus antibodies, usually derived from immunized horses or humans. Heterologous sera represent risks such as serum sickness. Human sera can carry unknown viruses. In the search for human monoclonal antibodies (mAbs) against TeNT (Tetanus Neurotoxin), we previously identified a panel of mAbs derived from B-cell sorting, selecting two nonrelated ones that binded to the C-terminal domain of TeNT (HCR/T), inhibiting its interaction with the cellular receptor ganglioside GT1b. Here, we present the results of cellular assays and molecular docking tools. TeNT internalization in neurons is prevented by more than 50% in neonatal rat spinal cord cells, determined by quantitative analysis of immunofluorescence punctate staining of Alexa Fluor 647 conjugated to TeNT. We also confirmed the mediator role of the Synaptic Vesicle Glycoprotein II (SV2) in TeNT endocytosis. The molecular docking assays to predict potential TeNT epitopes showed the binding of both antibodies to the HCR/T domain. A higher incidence was found between N1153 and W1297 when evaluating candidate residues for conformational epitope.

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. RESULTS: In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Dicloxacilina en infecciones producidas por estafilococo productor de penicilinasa / Dicloxacillin in infections caused by penicillinase-producing staphylococcus

INTRODUCCIÓN: El amplio arsenal terapéutico destinado al tratamiento de las enfermedades infecciosas disponible en la actualidad hace imprescindible la realización de una selección rigurosa del agente antimicrobiano que se va a utilizar según una serie de criterios que permitan un uso adecuado de éstos. En primer lugar, habría que valorar la necesidad de instaurar un tratamiento antibiótico de acuerdo con los hallazgos clínicos del paciente. Una vez considerada esta necesidad, los criterios de selección del antimicrobiano más adecuado se deben hacer en función de los siguientes criterios: gravedad y estado general de base del paciente, consideración de los microorganismos más probables según el foco de la infección, el conocimiento del estado actual de resistencias de los posibles microorganismos implicados, la farmacocinética y la farmacodinámica de los antibióticos, los efectos secundarios y el coste de los antimicrobianos, la vía de administración y la duración del tratamiento. Las infecciones de piel y partes blandas están entre las infecciones más frecuentes en Pediatría. Los microorganismos implicados con mayor frecuencia son Staphylococcus aureus (S. aureus) y Streptococcus pyogenes (S. pyogenes). En ciertas situaciones deberá sospecharse que el S. aureus sea resistente a la meticilina (SARM). Las infecciones bacterianas de la piel pueden ocurrir a diferentes niveles de profundidad implicando la epidermis (impétigo), la dermis (ectima, erisipela) o el tejido celular subcutáneo (celulitis, abscesos subcutáneos), mientras que las infecciones de partes blandas se extenderán a mayor profundidad y afectarán a la fascia (fascitis necrotizante) o el músculo (piomiositis). El tratamiento antibiótico se debe iniciar de forma empírica cubriendo S. aureus y S. pyogenes y añadiendo un antibiótico con actividad inhibidora de la síntesis de toxinas cuando sea necesario. OBJETIVO: Evaluar rapidamente los parâmetros de eficácia, seguridade, costos y recomendaciones disponibles acerca del empleo de Dicloxacilina sódica para el tratamiento de personas con infecciones por gérmenes gram positivos, incluyendo estafilococos produtores de betalactamasa. METODOLOGÍA: Se realizo uma búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también em sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologias sanitárias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnologia sanitária y guias de práctica clínica. CONCLUSIONES: La Dicloxacilina, un antibiótico de la clase de las penicilinas, ha demostrado ser efectiva en el tratamiento de diversas infecciones bacterianas. Su eficacia radica en su capacidad para inhibir la síntesis de la pared celular bacteriana, lo que lleva a la muerte de las bacterias sensibles. Se utiliza comúnmente para tratar infecciones causadas por bacterias grampositivas, como Staphylococcus aureus, que son resistentes a la penicilina debido a la producción de la enzima beta-lactamasa. La Dicloxacilina es especialmente útil en el tratamiento de infecciones de la piel y tejidos blandos, como celulitis, forúnculos y abscesos, así como infecciones de heridas quirúrgicas y estafilococos en la piel. Alrededor del 5% de los pacientes tratados pueden esperar reacciones adversas. Los efectos adversos más comunes son náuseas, vómitos y diarrea. Como con otras penicilinas, se han producido reacciones de hipersensibilidad (inmediatas o tardías). La mayoría de estas son leves, sin embargo, se han reportado reacciones de hipersensibilidad graves, incluida la muerte (Aunque en extremo raras). Al costo aportado en solicitud, la tecnología tiene un impacto presupuestario mayor que los códigos disponibles actualmente en el Listado Oficial de Medicamentos (LOM). Actualmente con la concentración solicitada (250 mg/5 mL) existen 5 registros sanitarios activos, aunque su corta vida media obliga a administrarla con estrechos intervalos de dosificación (cada 6 horas) y el sabor de la solución oral es muy desagradable, lo que dificulta mucho el cumplimiento del tratamiento.[1] Las Guías Clínicas de Pediatria consideran tanto Cefadroxilo y Dicloxacilina como opciones para infecciones de la piel y tejidos blancos, y en otras alternativas terapéuticas se consideran Amoxicilina + Ácido clavulánico, Clindamicina y Claritromicina. Para el tratamiento de infecciones causadas por bacterias productoras de penicilinasa, neumococos del grupo A-beta, estreptococos hemolíticos y cepas de estafilococos resistentes a la penicilina G, se pueden considerar varias opciones terapéuticas. Algunas de estas opciones incluyen: Antibióticos antiestafilocócicos: Entre ellos se incluyen la oxacilina, la meticilina, la nafcilina y doxiciclina. Estos antibióticos son resistentes a la acción de la penicilinasa, una enzima producida por las bacterias estafilococos que inactiva la penicilina. Son eficaces contra infecciones causadas por estafilococos resistentes a la penicilina y a la meticilina. Cefalosporinas de primera generación, como la cefalexina y la cefadroxilo, pueden ser una opción de tratamiento para infecciones causadas por estafilococos productores de penicilinasa, neumococos del grupo A-beta, estreptococos hemolíticos y algunas cepas de estreptococos resistentes a la penicilina G. Estas cefalosporinas tienen actividad contra una amplia variedad de bacterias grampositivas y algunas gramnegativas, y son especialmente útiles en infecciones leves a moderadas de la piel y tejidos blandos, infecciones del tracto urinario y faringitis estreptocócica. Cefalosporinas de segunda generación: Las cefalosporinas como la cefuroxima, la cefaclor y la cefprozil pueden ser efectivas contra estreptococos y algunos tipos de estafilococos resistentes a la penicilina. Sin embargo, su eficacia contra cepas productoras de penicilinasa puede ser limitada. Macrólidos: Los macrólidos como la eritromicina, la claritromicina y la azitromicina pueden ser útiles en el tratamiento de infecciones causadas por estreptococos y neumococos. Sin embargo, algunos estafilococos pueden desarrollar resistencia a estos antibióticos, por lo que su uso puede ser limitado en infecciones estafilocócicas graves. Vancomicina: La vancomicina es un antibiótico que se utiliza para tratar infecciones causadas por estafilococos resistentes a la meticilina y otros microorganismos grampositivos. Es un agente de reserva que se reserva para infecciones graves o resistentes a otros antibióticos. En el LOM, se encuentra al menos un representante de casi todos los grupos de antibióticos mencionados, con formulaciones pediátricas disponibles en jarabe o suspensión (Cefadroxilo, Claritromicina, Amoxicilina + ácido clavulánico). En los casos en que no se dispone de estas formulaciones, como con la doxiciclina para niños mayores de 8 años o clindamicina, se pueden emplear las presentaciones en tabletas o cápsulas. Además, algunas formulaciones endovenosas, como la clindamicina, oxacilina e incluso la vancomicina, están disponibles para su uso en casos que lo requieran.

Antibody Isolation in C. neoformans.

The importance of humoral immunity to fungal infections remains to be elucidated. In cryptococcosis, patients that fail to generate antibodies against antigens of the fungus Cryptococcus neoformans are more susceptible to the disease, demonstrating the importance of these molecules to the antifungal immune response. Historically, antibodies against C. neoformans have been applied in diagnosis, therapeutics, and as important research tools to elucidate fungal biology. Throughout the process of generating monoclonal antibodies (mAbs) from a single B-cell clone and targeting a single epitope, several immunization steps might be required for the detection of responsive antibodies to the antigen of interest in the serum. This complex mixture of antibodies comprises the polyclonal antibodies. To obtain mAbs, B-lymphocytes are harvested (from spleen or peripheral blood) and fused with tumor myeloma cells, to generate hybridomas that are individually cloned and specifically screened for mAb production. In this chapter, we describe all the necessary steps, from the immunization to polyclonal antibody harvesting, hybridoma generation, and mAb production and purification. Additionally, we discuss new cutting-edge approaches for generating interspecies mAbs, such as humanized mAbs, or for similar species in distinct host backgrounds.

Human antibodies in Mexico and Brazil neutralizing tick-borne flaviviruses.

Flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and yellow fever virus (YFV) are spread by mosquitoes and cause human disease and mortality in tropical areas. In contrast, Powassan virus (POWV), which causes severe neurologic illness, is a flavivirus transmitted by ticks in temperate regions of the Northern hemisphere. We find serologic neutralizing activity against POWV in individuals living in Mexico and Brazil. Monoclonal antibodies P002 and P003, which were derived from a resident of Mexico (where POWV is not reported), neutralize POWV lineage I by recognizing an epitope on the virus envelope domain III (EDIII) that is shared with a broad range of tick- and mosquito-borne flaviviruses. Our findings raise the possibility that POWV, or a flavivirus closely related to it, infects humans in the tropics.

Development and assessment of a virtual escape-room game for teaching industrial bioprocesses.

This article presents a study on the implementation of a virtual escape-room game as a novel teaching methodology in biochemistry education. The game aimed to engage students in producing monoclonal antibodies against SARS-CoV-2 while reinforcing theoretical concepts and fostering teamwork. Three versions of the game were tested, incorporating modifications to address student feedback on and improve the overall experience. The study employed a satisfaction survey to gather insights from students regarding their perception of the game. Results showed that the implementation of answer flexibility using RegEx had a significant positive impact on student satisfaction and motivation. The introduction of RegEx allowed for a more realistic and immersive gaming experience, as students could provide varied answers while still being evaluated correctly. Overall, the findings highlight the effectiveness of the game's design, the suitability of the Google Forms platform for distance learning, and the importance of incorporating answer flexibility through RegEx. These results provide valuable guidance for educators seeking to enhance student engagement and satisfaction through the use of escape-room games in biochemistry education.

Efficacy and Safety of Monoclonal Antibodies for the Treatment of Eosinophilic Esophagitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Monoclonal antibodies (MAbs) have clinical benefits for treating several atopic diseases. However, consensus on its use for eosinophilic esophagitis (EoE) is lacking. The present meta-analysis aimed to compare the efficacy and safety of MAbs versus placebo for treating EoE. METHODS: We searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcomes were changes in peak esophageal eosinophils count/high power field (HPF) and mean esophageal eosinophils count/HPF. The secondary outcomes were changes in the EoE-Histology Scoring System (EoE-HSS), Endoscopic Reference Score (EREFS), dysphagia score, and adverse events (AEs). We compared binary outcomes using risk ratio (RR) and continuous outcomes using mean difference (MD) or standardized mean difference (SMD), with 95% confidence interval (CI). Considering the diversity of mechanistic properties of MAbs, a pre-specified subgroup analysis by MAb mechanism of action was performed for all outcomes, provided that at least two studies were in each subgroup. Heterogeneity was assessed using Cochran's Q test and I2 statistics. RESULTS: 6 RCTs were included (533 patients). Compared to placebo, MAbs led to a significant reduction in peak esophageal eosinophils count/HPF (MD -0.78; CI 95% -0.87, -0.6801) and mean esophageal eosinophils count/HPF (SMD -0.79; CI 95% -1.5, -0.08). Moreover, MAbs significantly reduced EoE-HSS scores (grade score: SMD -9.31; 95% CI -13.95, -4.6701; stage score: SMD -10.18; 95% CI -15.06, -5.31), EREFS (SMD -5.95; CI 95% -9.19, -2.71) and dysphagia score (SMD -1.79; CI 95% -3.36, -0.23) without increasing AEs compared to placebo. Among those MAbs whose mechanism of action includes the blockage of the receptor for IL-13 (Dupilumab, QAX576, and RPC4046), the scores of EoE-HSS grade, EoE-HSS stage, EREFS, and dysphagia were significantly reduced, and they presented a similar risk of overall and serious AEs compared to placebo. CONCLUSION: MAbs seem effective and safe in reducing esophageal eosinophil infiltrate, EoE-HSS score, EREFS score, and dysphagia symptoms in patients with EoE. However, further evidence is needed to establish its place in EoE management.

Daratumumab más bortezomib más dexametasona en personas mayores de 18 años con diagnóstico de mieloma múltiple refractario a lenalidomida y con recaída a al menos una línea de terapia previa / Daratumumab plus bortezomib plus dexamethasone in people aged 18 years or older with a diagnosis of lenalidomide-refractory multiple myeloma and relapsed to at least one prior line of therapy

INTRODUCCIÓN: Cuadro clínico: El mieloma múltiple (MM) produce diversas manifestaciones clínicas como lesiones y fracturas óseas, insuficiencia renal, hipercalcemia, infecciones recurrentes y/o anemia. Esta condición representa uno de los cánceres hematológicos más frecuentes, con una incidencia estandarizada por edad de 1.92 por cada cien mil personas a nivel mundial. En Perú, el MM es el tercer cáncer hematológico más frecuente y con mayor mortalidad. Asimismo, se estima responsable de la pérdida de 5365 años de vida saludable al año, principalmente por su componente de muerte prematura. Tecnología sanitária: El daratumumab es un anticuerpo monoclonal que se une a la proteína CD38, expresada en alto nivel en las células tumorales del MM. Se encuentra indicado para uso combinado con bortezomib y dexametasona (D-Vd) en pacientes con MM tratados con al menos una línea de terapia previa. La dosis recomendada es 16 mg/kg de peso, administrados en ciclos semanales durante las primeras nueve semanas, cada tres semanas entre las semanas 10 y 24, y cada cuatro semanas a pa

International Cost-Effectiveness Analysis of Durvalumab in Stage III Non-Small Cell Lung Cancer.

Importance: Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems. Objective: To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain). Design, Setting, and Participants: In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023. Main Outcomes and Measures: Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed. Results: The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab. Conclusions and Relevance: In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.

Evaluation of the Inhibitory Potential of Synthetic Peptides Homologous to CDR3 Regions of a Monoclonal Antibody against Bothropic Venom Serine Proteases.

Snakebite accidents, neglected tropical diseases per the WHO, pose a significant public health threat due to their severity and frequency. Envenomation by Bothrops genus snakes leads to severe manifestations due to proteolytic enzymes. While the antibothropic serum produced by the Butantan Institute saves lives, its efficacy is limited as it fails to neutralize certain serine proteases. Hence, developing new-generation antivenoms, like monoclonal antibodies, is crucial. This study aimed to explore the inhibitory potential of synthetic peptides homologous to the CDR3 regions of a monoclonal antibody targeting a snake venom thrombin-like enzyme (SVTLE) from B. atrox venom. Five synthetic peptides were studied, all stable against hydrolysis by venoms and serine proteases. Impressively, four peptides demonstrated uncompetitive SVTLE inhibition, with Ki values ranging from 10-6 to 10-7 M. These findings underscore the potential of short peptides homologous to CDR3 regions in blocking snake venom toxins, suggesting their promise as the basis for new-generation antivenoms. Thus, this study offers potential advancements in combatting snakebites, addressing a critical public health challenge in tropical and subtropical regions.

Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review.

Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: -1.46, 95% confidence interval [CI]: -1.76 to -1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.