CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

BACKGROUND: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy. METHODS: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment. Baseline and on-treatment plasma and PBMC samples were analyzed by multiplex protein assay and mass cytometry, respectively. RESULTS: In this Phase 1B study (NCT02298959), ten patients with advanced PD-1-resistant melanoma were treated with a combination of ziv-aflibercept (at 2-4 mg/kg) plus pembrolizumab (at 2 mg/kg), administered intravenously every 2 weeks. Two patients (20%) achieved a partial response, and two patients (20%) experienced stable disease (SD) as the best response. The two responders had mucosal melanoma, while both patients with SD had ocular melanoma. The combination therapy demonstrated clinical activity and acceptable safety, despite the occurrence of adverse events. Changes in plasma analytes such as platelet-derived growth factor and PD-L1 were explored, indicating potential alterations in myeloid cell function. Higher levels of circulating CXCL10 in non-responding patients may reflect pro-tumor activity. Specific subsets of γδ T cells were associated with poor clinical outcomes, suggesting impaired γδ T-cell function in non-responding patients. CONCLUSIONS: Although limited by sample size and follow-up, these findings highlight the potential of the combination of ziv-aflibercept antiangiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment and the need for further research to improve outcomes in anti-PD-1-resistant melanoma. TRIAL REGISTRATION NUMBER: NCT02298959.

Profiling of Natural Killer Interactions With Cancer Cells Using Mass Cytometry.

We developed a comprehensive method for functional assessment of the changes in immune populations and killing activity of peripheral blood mononuclear cells after cocultures with cancer cells using mass cytometry. In this study, a 43-marker mass cytometry panel was applied to a coculture of immune cells from healthy donors' peripheral blood mononuclear cells with diverse cancer cell lines. DNA content combined with classical CD45 surface staining was used as gating parameters for cocultures of immune cells (CD45high/DNAlow) with hematological (CD45low/DNAhigh) and solid cancer cell lines (CD45neg/DNAhigh). This strategy allows for universal discrimination of cancer cells from immune populations without the need for a specific cancer cell marker and simultaneous assessment of phenotypical changes in both populations. The use of mass cytometry allows for simultaneous detection of changes in natural killer, natural killer T cell, and T cell phenotypes and degranulation of immune populations upon target recognition, analysis of target cells for cytotoxic protein granzyme B content, and cancer cell death. These findings have broad applicability in research and clinical settings with the aim to phenotype and assess functional changes following not only NK-cancer cell interactions but also the effect of those interactions on other immune populations.

Protocol for the Request of Knee Magnetic Resonance Imaging in Elderly Patients with Suspected Osteoarthritis: Reduction in Test Requests and Impact on Management and Diagnosis.

Objective To develop an evidence-based protocol to guide magnetic resonance imaging (MRI) requests in elderly patients with suspected knee osteoarthrosis and to evaluate its effectiveness after implementation. Methods The institutional protocol was developed after reviewing the literature during the first semester of 2018. The control group was defined as patients cared for in the first semester of 2018, before the implementation/dissemination of the institutional protocol, and the study group was composed by patients cared for during the second semester of 2018 after the standardization of MRI requests for suspected knee osteoarthrosis. Results Our sample included 826 patients undergoing knee MRI, with a mean age of 69.3 years. Protocol implementation decreased MRI requests and increased radiograph requests ( p < 0.001). After the implementation of the protocol, the MRI changed the diagnosis or treatment in only 11.2% of the cases. Conclusion Protocol implementation resulted in a 47.5% reduction in the number of requests for knee MRI, with most (89%) patients with alteration in diagnosis or treatment. Level of evidence: case-control study (IIIB).

Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations.

Protocol for the Request of Knee Magnetic Resonance Imaging in Elderly Patients with Suspected Osteoarthritis: Reduction in Test Requests and Impact on Management and Diagnosis / Protocolo de solicitação de ressonância magnética do joelho em pacientes idosos com suspeita de osteoartrose: Redução da solicitação de exames e o impacto na conduta e no diagnóstico

Abstract Objective To develop an evidence-based protocol to guide magnetic resonance imaging (MRI) requests in elderly patients with suspected knee osteoarthrosis and to evaluate its effectiveness after implementation. Methods The institutional protocol was developed after reviewing the literature during the first semester of 2018. The control group was defined as patients cared for in the first semester of 2018, before the implementation/dissemination of the institutional protocol, and the study group was composed by patients cared for during the second semester of 2018 after the standardization of MRI requests for suspected knee osteoarthrosis. Results Our sample included 826 patients undergoing knee MRI, with a mean age of 69.3 years. Protocol implementation decreased MRI requests and increased radiograph requests (p < 0.001). After the implementation of the protocol, the MRI changed the diagnosis or treatment in only 11.2% of the cases. Conclusion Protocol implementation resulted in a 47.5% reduction in the number of requests for knee MRI, with most (89%) patients with alteration in diagnosis or treatment. Level of evidence: case-control study (IIIB).

Resumo Objetivo Desenvolver um protocolo, baseado em evidências, para guiar a solicitação de exames de ressonância magnética (RM) em pacientes idosos com suspeita de osteoartrose do joelho e avaliar a sua eficácia após implementação. Métodos O protocolo institucional foi desenvolvido após revisão da literatura durante o primeiro semestre do ano de 2018. Definiu-se como grupo de controle os pacientes do primeiro semestre de 2018, antes da aplicação/divulgação do protocolo institucional, e o grupo de estudo foi composto por pacientes atendidos no segundo semestre do mesmo ano após a padronização dos pedidos de RM para a suspeita de osteoartrose do joelho. Resultados Nossa amostra contou com 826 pacientes submetidos a RM do joelho, com média de idade de 69,3 anos. Após a implementação do protocolo, houve um decréscimo das solicitações de RM e um aumento no número de solicitações de radiografias (p < 0,001). Após a implementação do protocolo, a RM alterou o diagnóstico ou a conduta do médico em apenas 11,2% dos casos. Conclusão Após a introdução do protocolo, encontrou-se uma redução de 47,5% no número de pedidos de RM do joelho, sendo que a maioria (89%) dos pacientes não tiveram suas condutas ou diagnóstico alterados. Nível de evidência: estudo caso-controle (IIIB).

EXTRACORPOREAL SHOCKWAVE THERAPY IN SHOULDER INJURIES: PROSPECTIVE STUDY.

OBJECTIVE: To evaluate the functional results after the use of extracorporeal shockwave therapy (ESWT) in four groups of patients: tendinopathy, partial rotator cuff injury, adhesive capsulitis and calcareous tendinopathy of the rotator cuff at one month and three months after the end of treatment. METHODS: Case series in which patients were evaluated according to the VAS of pain, range of motion of the shoulder, and functional questionnaires DASH and modified UCLA. RESULTS: There was a significant increase in the measure of flexion, lateral rotation and shoulder abduction in the evaluations after treatment in relation to the baseline measurement (p < 0.001) and no evidence of significant difference was found between the post-treatment evaluations at one month and three months follow-up (p > 0.05). There was a significant reduction in the VAS score, increase in the UCLA score and a significant reduction in the DASH score in the post-treatment evaluations in relation to the baseline score (p < 0.001) and a significant improvement in the three-month evaluation in relation to one month (p < 0.05). CONCLUSION: Extracorporeal shockwave therapy proved to be efficient and safe in the treatment of shoulder pathologies, improving pain, range of motion and functional scores in all groups of patients evaluated in the study. Level of Evidence IV, Case series.

OBJETIVO: Avaliar os resultados funcionais após uso de terapia de ondas de choque (TOC) em quatro grupos de pacientes: tendinopatia, lesão parcial de manguito rotador, capsulite adesiva e tendinopatia calcária do manguito rotador com 1 mês e 3 meses após término do tratamento. MÉTODOS: Série de casos, na qual os pacientes foram avaliados de acordo com a EVA da dor, amplitude de movimento do ombro, e questionários funcionais DASH e UCLA modificados. RESULTADOS: Houve aumento significativo das medidas de flexão, rotação lateral e abdução do ombro nas avaliações após tratamento, em relação à medida basal (p < 0,001) e não houve evidências de variação significativa entre as avaliações pós-tratamento com 1 mês e 3 meses de acompanhamento (p°> 0,05). Houve redução significativa do escore EVA, aumento do escore UCLA e redução significativa do escore DASH nas avaliações após tratamento em relação ao escore basal (p < 0,001) e melhora significativa na avaliação de três meses em relação a um mês (p < 0,05). CONCLUSÃO: A terapia de ondas de choque mostrou-se uma terapia eficiente e segura no tratamento das patologias do ombro, com melhora da dor, arco de movimento e escores funcionais em todos os grupos de pacientes avaliados no estudo. Nível de Evidência IV, Série de casos.

Extracorporeal shockwave therapy in shoulder injuries: prospective study / Uso de terapia de ondas de choque em doenças ortopédicas do ombro: estudo prospectivo

ABSTRACT Objective: To evaluate the functional results after the use of extracorporeal shockwave therapy (ESWT) in four groups of patients: tendinopathy, partial rotator cuff injury, adhesive capsulitis and calcareous tendinopathy of the rotator cuff at one month and three months after the end of treatment. Methods: Case series in which patients were evaluated according to the VAS of pain, range of motion of the shoulder, and functional questionnaires DASH and modified UCLA. Results: There was a significant increase in the measure of flexion, lateral rotation and shoulder abduction in the evaluations after treatment in relation to the baseline measurement (p < 0.001) and no evidence of significant difference was found between the post-treatment evaluations at one month and three months follow-up (p > 0.05). There was a significant reduction in the VAS score, increase in the UCLA score and a significant reduction in the DASH score in the post-treatment evaluations in relation to the baseline score (p < 0.001) and a significant improvement in the three-month evaluation in relation to one month (p < 0.05). Conclusion: Extracorporeal shockwave therapy proved to be efficient and safe in the treatment of shoulder pathologies, improving pain, range of motion and functional scores in all groups of patients evaluated in the study. Level of Evidence IV, Case series.

RESUMO Objetivo: Avaliar os resultados funcionais após uso de terapia de ondas de choque (TOC) em quatro grupos de pacientes: tendinopatia, lesão parcial de manguito rotador, capsulite adesiva e tendinopatia calcária do manguito rotador com 1 mês e 3 meses após término do tratamento. Métodos: Série de casos, na qual os pacientes foram avaliados de acordo com a EVA da dor, amplitude de movimento do ombro, e questionários funcionais DASH e UCLA modificados. Resultados: Houve aumento significativo das medidas de flexão, rotação lateral e abdução do ombro nas avaliações após tratamento, em relação à medida basal (p < 0,001) e não houve evidências de variação significativa entre as avaliações pós-tratamento com 1 mês e 3 meses de acompanhamento (p°> 0,05). Houve redução significativa do escore EVA, aumento do escore UCLA e redução significativa do escore DASH nas avaliações após tratamento em relação ao escore basal (p < 0,001) e melhora significativa na avaliação de três meses em relação a um mês (p < 0,05). Conclusão: A terapia de ondas de choque mostrou-se uma terapia eficiente e segura no tratamento das patologias do ombro, com melhora da dor, arco de movimento e escores funcionais em todos os grupos de pacientes avaliados no estudo. Nível de Evidência IV, Série de casos.

Corporate Social Responsibility Practices of Colombian Companies as Perceived by Industrial Engineering Students.

This work describes the perceptions that Industrial Engineering students have regarding Colombian firms' corporate social responsibility (CSR) practices. It also explores the incidence of gender, academic level, work experience and entrepreneurial intention on students' vision. A survey with 70 CSR practices was designed based on previous research. Practices were grouped in ten dimensions: shareholders, customers, employees, suppliers, stakeholders, ethics, environment, legal, human rights and society. A representative sample of 142 students was used. Results show that students perceive a higher commitment of Colombian companies with the shareholders dimension, while a lower with the society, ethics and environmental CSR practices. Work experience and entrepreneurial intention are the only variables affecting the identified perceptions. Thus, as they gain experience, their perceptions become more favorable. On the other hand, potential entrepreneurs have a more critical view on the companies' commitment. Additionally, the fact that the academic level does not impact students' perceptions constitutes a challenge for the academic program, since it is expected that this will affect the vision of future engineers. This is the first study that evaluates perceptions of Industrial Engineering students, who, given their object of study, will be responsible for designing and managing production processes in organizations of the future. Results respond to a specific context (students at a Colombian public university), therefore further research to explore the subject is recommended.