Avatrombopag for severe refractory thrombocytopenia in a pediatric patient with ALL following allogeneic hematopoietic stem cell transplantation: A case report.

Patients who receive allogeneic hematopoietic stem cell transplantation (alloHSCT) are at risk for developing persistent thrombocytopenia. Here, we describe treatment with avatrombopag, a thrombopoietin receptor agonist, in a pediatric patient with chronic, severe, transfusion-dependent thrombocytopenia (<10 × 103/µL) post-alloHSCT that was persistent despite treatment with romiplostim, another thrombopoietin receptor agonist. Following the granting of a compassionate use investigational new drug authorization, avatrombopag treatment was initiated, and the patient's platelet count increased. To date, the patient has maintained a platelet count >100 × 103/µL. No adverse events or medication toxicities have been reported, and he has resumed his pre-alloHSCT activities.

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Treatment of newly diagnosed severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.

Treatment of relapsed/refractory severe aplastic anemia in children: Evidence-based recommendations.

Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with relapsed or refractory SAA.

RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Pathobiological signatures of dysbiotic lung injury in pediatric patients undergoing stem cell transplantation.

Hematopoietic cell transplantation (HCT) uses cytotoxic chemotherapy and/or radiation followed by intravenous infusion of stem cells to cure malignancies, bone marrow failure and inborn errors of immunity, hemoglobin and metabolism. Lung injury is a known complication of the process, due in part to disruption in the pulmonary microenvironment by insults such as infection, alloreactive inflammation and cellular toxicity. How microorganisms, immunity and the respiratory epithelium interact to contribute to lung injury is uncertain, limiting the development of prevention and treatment strategies. Here we used 278 bronchoalveolar lavage (BAL) fluid samples to study the lung microenvironment in 229 pediatric patients who have undergone HCT treated at 32 children's hospitals between 2014 and 2022. By leveraging paired microbiome and human gene expression data, we identified high-risk BAL compositions associated with in-hospital mortality (P = 0.007). Disadvantageous profiles included bacterial overgrowth with neutrophilic inflammation, microbiome contraction with epithelial fibroproliferation and profound commensal depletion with viral and staphylococcal enrichment, lymphocytic activation and cellular injury, and were replicated in an independent cohort from the Netherlands (P = 0.022). In addition, a broad array of previously occult pathogens was identified, as well as a strong link between antibiotic exposure, commensal bacterial depletion and enrichment of viruses and fungi. Together these lung-immune system-microorganism interactions clarify the important drivers of fatal lung injury in pediatric patients who have undergone HCT. Further investigation is needed to determine how personalized interpretation of heterogeneous pulmonary microenvironments may be used to improve pediatric HCT outcomes.

Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells.

The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRß repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.

Vaccines: a promising therapy for myelodysplastic syndrome.

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.

mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors.

BACKGROUND: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors. METHODS: Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models. RESULTS: Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated. CONCLUSIONS: We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

Cirugía de revascularización de miocardio usando arteria mamaria interna bilateral. Resultados a corto plazo / Coronary artery bypass graft surgery with bilateral internal mammary artery. Short-term results

Resumen Introducción: La cirugía de revascularización de miocardio (RVM) sigue siendo el gold standard en el tratamiento de la enfermedad coronaria multiarterial. Se ha demostrado que la RVM con ambas arterias mamarias internas (AMI) tiene mejor resultado de sobrevida a largo plazo. Metodología: Investigación retrospectiva de las cirugías de RVM con AMI bilateral, realizadas en el Instituto Nacional Cardiovascular-INCOR-EsSalud entre enero de 2012 a diciembre de 2015. Los objetivos fueron determinar la mortalidad por cualquier causa y los eventos cardiovasculares mayores a 30 días de seguimiento. Resultados: Treinta y seis pacientes fueron operados con AMI bilateral. No tuvimos mortalidad a 30 días. Los eventos cardiovasculares mayores se presentaron en el 5.56% de los pacientes (stroke 0%, infarto de miocardio posquirúrgico 5.56%, necesidad de nueva intervención coronaria 0%). La incidencia de mediastinitis y/o reconstrucción esternal fue de 0%. Siete pacientes tuvieron infección superficial de la herida, no hubo diferencia significativa entre los diabéticos y los no diabéticos (25% vs. 16.66%, OR: 3.3, p = 0.88) o entre los pacientes con o sin sobrepeso (19.23% vs. 20%, respectivamente, OR: 0.95, IC 95%, p = 0.68) para presentar infección de herida. Conclusiones: La RVM con AMI bilateral es un procedimiento seguro, con bajas tasas de mortalidad y de eventos cardiovasculares mayores a corto plazo. © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Publicado por Masson Doyma México S.A. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Abstract Introduction: Coronary artery bypass graft (CABG) surgery remains the reference standard in the treatment of multivessel coronary disease. Several studies have shown that CABG with bilateral internal mammary arteries (BIMA) has better results in long-term survival. Methodology: A retrospective study was conducted on CABG surgeries with BIMA from January 2012 to December 2015 in the National Cardiovascular Institute, INCOR, EsSalud, Peru. The objectives were to determine the mortality and major cardiovascular events at 30 days followup. Results: Of the 36 patients subjected to CABG surgery with BIMA, the 30-day mortality was 0%, with major cardiovascular events occurring in 5.56% of patients (Stroke 0%, postoperative myocardial infarction 5.56%, need of new coronary intervention 0%). The incidence of mediastinitis and/or sternal reconstruction was 0%. Superficial wound infection was observed in 7 patients, with there being no significant difference between diabetics and non-diabetics (25% vs. 16.66%, OR = 3.3, P = .88), or between patients with or without overweight (19.23% vs. 20%, respectively,OR = .95; 95% CI, P = .68). Conclusions: CABG surgery with BIMA is a safe procedure, with low rates of mortality and major cardiovascular events in the short-term. © 2016 Instituto Nacional de Cardiología Ignacio Chávez. Published by Masson Doyma México S.A. This is an open access article under the CC BY-NC-ND license (https://creativecommons.org/licenses/by-nc-nd/4.0/).

Evolución de los pacientes sometidos a cirugía de revascularización de miocardio con doble arteria mamaria interna en el Instituto Nacional Cardiovascular en el periodo 2012-2015 / Evolution of the patients undergoing to surgery of revascularization of myocardium with internal mammary artery double at the National Institute Cardiovascular in the period 2012-2015

Introducción: La revascularización de miocardio con utilización de una arteria mamaria interna es considerada actualmente el tratamiento quirúrgico de elección de la enfermedad isquémica coronaria multiarterial severa. Ya que la aplicación de esta técnica se ha asociado con resultados clínicos superiores en comparación con otros injertos, múltiples investigadores reportan que el empleo de doble arteria mamaria interna (AMI) podría mejorar dichos resultados. Metodología: La presente investigación es de tipo transversal en donde se revisaron historias clínicas. La población estuvo conformada por 36 pacientes con enfermedad isquémica coronaria multiarterial crónica quienes cumplieron con los criterios de selección. Resultados: La mortalidad a 30 días fue 0 por ciento. Se presentaron dos casos (5.56 por ciento) de infarto agudo de miocardio perioperatorio. No se presentó ningún caso de stroke ni de reintervención coronaria a 30 días. El 19.44 por ciento del total presentó infección de herida esternal superficial. Se presentaron 5 casos (13.88 por ciento) de sangrado postoperatorio excesivo. Conclusiones: La revascularización de miocardio con doble AMI no incrementa la mortalidad ni la incidencia de complicaciones mayores a 30 días. No existen diferencias significativas en la incidencia de infección de herida esternal tanto en el grupo de pacientes diabéticos/no diabéticos como en el grupo de pacientes con sobrepeso/IMC normal.

Introduction: Myocardial revascularization using internal mammary artery is currently considered the treatment of choice for severe multi-vessel ischemic coronary disease. Since the application of this technique has been associated with superior clinical outcomes compared with other grafts, multiple researchers report that the use of double internal mammary artery (IMA) could improve those results. Methodology: The current research is a cross-sectional study where medical records were reviewed. The population consisted of 36 patients who were diagnosed with multi-vessel chronic ischemic coronary disease who met the selection criteria. Results: The 30-day mortality was 0 per cent. Two cases (5.56 per cent) of acute perioperative myocardial infarction occurred. There were not any cases of stroke or coronary re-intervention after 30 days. 19.44 per cent of the total presented sternal wound infection. There were 5 cases (13.88 per cent) of excessive postoperative bleeding. Conclusion: Myocardial revascularization with double IMA does not increase mortality or the incidence of major complications after 30 days. There are no significant differences in the incidence of sternal wound infection both in the group of diabetic/non diabetic patients and in the group of overweight/normal BMI patients.