TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial.

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.

A combinatory vaccine with IMA950 plus varlilumab promotes effector memory T-cell differentiation in the peripheral blood of patients with low-grade gliomas.

BACKGROUND: Central nervous system (CNS) WHO grade 2 low-grade glioma (LGG) patients are at high risk for recurrence and with unfavorable long-term prognosis due to the treatment resistance and malignant transformation to high-grade glioma. Considering the relatively intact systemic immunity and slow-growing nature, immunotherapy may offer an effective treatment option for LGG patients. METHODS: We conducted a prospective, randomized pilot study to evaluate the safety and immunological response of the multipeptide IMA950 vaccine with agonistic anti-CD27 antibody, varlilumab, in CNS WHO grade 2 LGG patients. Patients were randomized to receive combination therapy with IMA950 + poly-ICLC and varlilumab (Arm 1) or IMA950 + poly-ICLC (Arm 2) before surgery, followed by adjuvant vaccines. RESULTS: A total of 14 eligible patients were enrolled in the study. Four patients received pre-surgery vaccines but were excluded from postsurgery vaccines due to the high-grade diagnosis of the resected tumor. No regimen-limiting toxicity was observed. All patients demonstrated a significant increase of anti-IMA950 CD8+ T-cell response postvaccine in the peripheral blood, but no IMA950-reactive CD8+ T cells were detected in the resected tumor. Mass cytometry analyses revealed that adding varlilumab promoted T helper type 1 effector memory CD4+ and effector memory CD8+ T-cell differentiation in the PBMC but not in the tumor microenvironment. CONCLUSION: The combinational immunotherapy, including varlilumab, was well-tolerated and induced vaccine-reactive T-cell expansion in the peripheral blood but without a detectable response in the tumor. Further developments of strategies to overcome the blood-tumor barrier are warranted to improve the efficacy of immunotherapy for LGG patients.

Dendritic Cell Vaccination in Conjunction with a TLR Agonist Polarizes Interferon Immune Responses in Malignant Glioma Patients.

Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01204684.

The state of art of awake craniotomy in Latin American countries: a scoping review.

BACKGROUND AND OBJECTIVE: Awake craniotomy (AC) is a valuable technique for surgical interventions in eloquent areas, but its adoption in low- and middle-income countries faces challenges like limited infrastructure, trained personnel shortage, and inadequate funding. This scoping review explores AC techniques in Latin American countries, focusing on patient characteristics, tumor location, symptomatology, and outcomes. METHODS: A scoping review followed PRISMA guidelines, searching five databases in English, Spanish, and Portuguese. We included 28 studies with 258 patients (mean age: 43, range: 11-92). Patterns in AC use in Latin America were analyzed. RESULTS: Most studies were from Brazil and Mexico (53.6%) and public institutions (70%). Low-grade gliomas were the most common lesions (55%), most of them located in the left hemisphere (52.3%) and frontal lobe (52.3%). Gross-total resection was achieved in 34.3% of cases. 62.9% used an Asleep-Awake-Asleep protocol, and 14.8% used Awake-Awake-Awake. The main complication was seizures (14.6%). Mean post-surgery discharge time was 68 h. Challenges included limited training, infrastructure, and instrumentation availability. Strategies discussed involve training in specialized centers, seeking sponsorships, applying for awards, and multidisciplinary collaborations with neuropsychology. CONCLUSION: Improved accessibility to resources, infrastructure, and adequate instrumentation is crucial for wider AC availability in Latin America. Despite disparities, AC implementation with proper training and teamwork yields favorable outcomes in resource-limited centers. Efforts should focus on addressing challenges and promoting equitable access to this valuable surgical technique in the region.

Current Role of Endoscopic Endonasal Approach for Craniopharyngiomas: A 10-Year Systematic Review and Meta-Analysis Comparison with the Open Transcranial Approach.

In recent years, the endoscopic endonasal approach (EEA) for craniopharyngiomas has proven to be a safe option for extensive tumor resection, with minimal or no manipulation of the optic nerves and excellent visualization of the superior hypophyseal branches when compared to the Transcranial Approach (TCA). However, there is an ongoing debate regarding the criteria for selecting different approaches. To explore the current results of EEA and discuss its role in the management of craniopharyngiomas, we performed MEDLINE, Embase, and LILACS searches from 2012 to 2022. Baseline characteristics, the extent of resection, and clinical outcomes were evaluated. Statistical analysis was performed through an X2 and Fisher exact test, and a comparison between quantitative variables through a Kruskal-Wallis and verified with post hoc Bonferroni. The tumor volume was similar in both groups (EEA 11.92 cm3, -TCA 13.23 cm3). The mean follow-up in months was 39.9 for EEA and 43.94 for TCA, p = 0.76). The EEA group presented a higher visual improvement rate (41.96% vs. 25% for TCA, p < 0.0001, OR 7.7). Permanent DI was less frequent with EEA (29.20% vs. 67.40% for TCA, p < 0.0001, OR 0.2). CSF Leaks occurred more frequently with EEA (9.94% vs. 0.70% for TCA, p < 0.0001, OR 15.8). Recurrence rates were lower in the EEA group (EEA 15.50% vs. for TCA 21.20%, p = 0.04, OR 0.7). Our results demonstrate that, in selected cases, EEA for resection of craniopharyngiomas is associated with better results regarding visual preservation and extent of tumor resection. Postoperative CSF leak rates associated with EEA have improved compared to the historical series. The decision-making process should consider each person's characteristics; however, it is noticeable that recent data regarding EEA justify its widespread application as a first-line approach in centers of excellence for skull base surgery.

Pulmonary and central nervous system nocardiosis: Alcoholism as an immunocompromising factor / Nocardiosis pulmonar y del sistema nervioso central: el alcoholismo como factor de inmunocompromiso

Nocardiosis is a disease with worldwide distribution. It is usually found in tropical areas and mainly affects immunocompromised patients, however, there are also cases where its infection has been reported in immunocompetent patients. This pathology is caused by bacteria known as Nocardia spp., which are gram-positive microorganisms and environmental saprophytes, and although exposure to Nocardia spp. is almost universal, only a small fraction of exposed people develops the disease. We present the case of a 47-year-old man, with no evidence of immunosuppression, from a rural area of Boyacá, who was admitted due to intense and intermittent headache accompanied by paresthesia and, finally, a decrease in consciousness. A brain magnetic resonance was performed and evidenced a fronto-temporo- occipital space-occupying lesion in the cortico-subcortical region with a compressive effect and displacement of the ventricular system cavities. It was suspected at first a neoplastic lesion or a brain abscess. The lesion was surgically resected, and its culture showed Nocardia africana/nova. In later studies a possible primary pulmonary focus was evidenced. Alcoholism was the only risk factor documented. The patient completed 6 weeks of hospital antibiotic treatment with favorable clinical and radiological evolution and was discharged with a 1-year plan of outpatient antibiotic therapy. Although Nocardia spp. mainly affects immunocompromised patients, evidence shows that this microorganism can also be a threat to individuals without traditional immunosuppression risk factors.

La nocardiosis es una enfermedad de distribución mundial; de forma habitual se encuentra en zonas tropicales y afecta principalmente a pacientes inmunocomprometidos, sin embargo, también existen casos reportados de infección en personas inmunocompetentes. Esta infección es causada por actinomicetos del género Nocardia spp. que son bacterias Gram positivas, saprófitos ambientales. Aunque la exposición a Nocardia spp. es casi universal, solo una pequeña fracción de las personas expuestas desarrollan la enfermedad. Se presenta el caso de un hombre de 47 años, sin dato de inmunosupresión, procedente de un área rural de Boyacá, que consultó por un cuadro clínico de cefalea intensa e intermitente, con parestesias y, finalmente, alteración del estado de conciencia. Se practicó una resonancia magnética cerebral, en la que se evidenció una lesión que ocupaba espacio de localización córtico-subcortical en la región fronto-témporo-parietal izquierda, con efecto compresivo y desplazamiento de las cavidades del sistema ventricular. Se sospechó, inicialmente, una lesión neoplásica o un absceso cerebral. El paciente fue sometido a una resección quirúrgica, y el cultivo de la lesión documentó Nocardia africana/nova; en estudios posteriores, se evidenció un posible foco pulmonar primario. Como único factor de riesgo en el paciente, se documentó alcoholismo. Completó seis semanas de tratamiento antibiótico intrahospitalario con evolución clínica y radiológica, y egresó con plan de un año de terapia antibiótica ambulatoria. Aunque la enfermedad por Nocardia spp. afecta principalmente a pacientes inmunocomprometidos, la "evidencia" clínica demuestra que este microorganismo también puede ser una amenaza para individuos sin los factores de riesgo tradicionales para inmunosupresión.

ASP-2/Trans-sialidase chimeric protein induces robust protective immunity in experimental models of Chagas' disease.

Immunization with the Amastigote Surface Protein-2 (ASP-2) and Trans-sialidase (TS) antigens either in the form of recombinant protein, encoded in plasmids or human adenovirus 5 (hAd5) confers robust protection against various lineages of Trypanosoma cruzi. Herein we generated a chimeric protein containing the most immunogenic regions for T and B cells from TS and ASP-2 (TRASP) and evaluated its immunogenicity in comparison with our standard protocol of heterologous prime-boost using plasmids and hAd5. Mice immunized with TRASP protein associated to Poly-ICLC (Hiltonol) were highly resistant to challenge with T. cruzi, showing a large decrease in tissue parasitism, parasitemia and no lethality. This protection lasted for at least 3 months after the last boost of immunization, being equivalent to the protection induced by DNA/hAd5 protocol. TRASP induced high levels of T. cruzi-specific antibodies and IFNγ-producing T cells and protection was primarily mediated by CD8+ T cells and IFN-γ. We also evaluated the toxicity, immunogenicity, and efficacy of TRASP and DNA/hAd5 formulations in dogs. Mild collateral effects were detected at the site of vaccine inoculation. While the chimeric protein associated with Poly-ICLC induced high levels of antibodies and CD4+ T cell responses, the DNA/hAd5 induced no antibodies, but a strong CD8+ T cell response. Immunization with either vaccine protected dogs against challenge with T. cruzi. Despite the similar efficacy, we conclude that moving ahead with TRASP together with Hiltonol is advantageous over the DNA/hAd5 vaccine due to pre-existing immunity to the adenovirus vector, as well as the cost-benefit for development and large-scale production.

Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma.

PURPOSE: To assess whether MUC1 peptide vaccine produces an immune response and prevents subsequent colon adenoma formation. PATIENTS AND METHODS: Multicenter, double-blind, placebo-controlled randomized trial in individuals age 40 to 70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0. RESULTS: Fifty-three participants received the MUC1 vaccine and 50 placebo. Thirteen of 52 (25%) MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range, 2.9-17.3) at week 12 versus 0/50 placebo recipients (one-sided Fisher exact P < 0.0001). Of 13 responders at week 12, 11 (84.6%) responded to a booster injection at week 52 with a ≥2-fold increase in MUC1 IgG measured at week 55. Recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group versus 27 of 48 (56.3%) in the MUC1 group [adjusted relative risk (aRR), 0.83; 95% confidence interval (CI), 0.60-1.14; P = 0.25]. Adenoma recurrence occurred in 3/11 (27.3%) immune responders at week 12 and week 55 (aRR, 0.41; 95% CI, 0.15-1.11; P = 0.08 compared with placebo). There was no difference in serious adverse events. CONCLUSIONS: An immune response was observed only in vaccine recipients. Adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence compared with placebo was observed in participants who had an immune response at week 12 and with the booster injection.

Nocardiosis pulmonar y del sistema nervioso central: el alcoholismo como factor de inmunocompromiso / Pulmonary and central nervous system nocardiosis: Alcoholism as an immunocompromising factor

La nocardiosis es una enfermedad de distribución mundial; de forma habitual se encuentra en zonas tropicales y afecta principalmente a pacientes inmunocomprometidos, sin embargo, también existen casos reportados de infección en personas inmunocompetentes. Esta infección es causada por actinomicetos del género Nocardia spp. que son bacterias Gram positivas, saprófitos ambientales. Aunque la exposición a Nocardia spp. es casi universal, solo una pequeña fracción de las personas expuestas desarrollan la enfermedad. Se presenta el caso de un hombre de 47 años, sin dato de inmunosupresión, procedente de un área rural de Boyacá, que consultó por un cuadro clínico de cefalea intensa e intermitente, con parestesias y, finalmente, alteración del estado de conciencia. Se practicó una resonancia magnética cerebral, en la que se evidenció una lesión que ocupaba espacio de localización córtico-subcortical en la región fronto-témporo-parietal izquierda, con efecto compresivo y desplazamiento de las cavidades del sistema ventricular. Se sospechó, inicialmente, una lesión neoplásica o un absceso cerebral. El paciente fue sometido a una resección quirúrgica, y el cultivo de la lesión documentó Nocardia africana/nova; en estudios posteriores, se evidenció un posible foco pulmonar primario. Como único factor de riesgo en el paciente, se documentó alcoholismo. Completó seis semanas de tratamiento antibiótico intrahospitalario con evolución clínica y radiológica, y egresó con plan de un año de terapia antibiótica ambulatoria. Aunque la enfermedad por Nocardia spp. afecta principalmente a pacientes inmunocomprometidos, la "evidencia" clínica demuestra que este microorganismo también puede ser una amenaza para individuos sin los factores de riesgo tradicionales para inmunosupresión.

Nocardiosis is a disease with worldwide distribution. It is usually found in tropical areas and mainly affects immunocompromised patients, however, there are also cases where its infection has been reported in immunocompetent patients. This pathology is caused by bacteria known as Nocardia spp., which are gram-positive microorganisms and environmental saprophytes, and although exposure to Nocardia spp. is almost universal, only a small fraction of exposed people develops the disease. We present the case of a 47-year-old man, with no evidence of immunosuppression, from a rural area of Boyacá, who was admitted due to intense and intermittent headache accompanied by paresthesia and, finally, a decrease in consciousness. A brain magnetic resonance was performed and evidenced a fronto-temporo- occipital space-occupying lesion in the cortico-subcortical region with a compressive effect and displacement of the ventricular system cavities. It was suspected at first a neoplastic lesion or a brain abscess. The lesion was surgically resected, and its culture showed Nocardia africana/nova. In later studies a possible primary pulmonary focus was evidenced. Alcoholism was the only risk factor documented. The patient completed 6 weeks of hospital antibiotic treatment with favorable clinical and radiological evolution and was discharged with a 1-year plan of outpatient antibiotic therapy. Although Nocardia spp. mainly affects immunocompromised patients, evidence shows that this microorganism can also be a threat to individuals without traditional immunosuppression risk factors.

A Pilot Machine Learning Study Using Trauma Admission Data to Identify Risk for High Length of Stay.

INTRODUCTION: Trauma patients have diverse resource needs due to variable mechanisms and injury patterns. The aim of this study was to build a tool that uses only data available at time of admission to predict prolonged hospital length of stay (LOS). METHODS: Data was collected from the trauma registry at an urban level one adult trauma center and included patients from 1/1/2014 to 3/31/2019. Trauma patients with one or fewer days LOS were excluded. Single layer and deep artificial neural networks were trained to identify patients in the top quartile of LOS and optimized on area under the receiver operator characteristic curve (AUROC). The predictive performance of the model was assessed on a separate test set using binary classification measures of accuracy, precision, and error. RESULTS: 2953 admitted trauma patients with more than one-day LOS were included in this study. They were 70% male, 60% white, and averaged 47 years-old (SD: 21). 28% were penetrating trauma. Median length of stay was 5 days (IQR 3-9). For prediction of prolonged LOS, the deep neural network achieved an AUROC of 0.80 (95% CI: 0.786-0.814) specificity was 0.95, sensitivity was 0.32, with an overall accuracy of 0.79. CONCLUSION: Machine learning can predict, with excellent specificity, trauma patients who will have prolonged length of stay with only physiologic and demographic data available at the time of admission. These patients may benefit from additional resources with respect to disposition planning at the time of admission.

Exploring the relationship between physical literacy levels, engagement and emotionality in physical education classes / Explorando a relação entre os níveis de alfabetização física, engajamento e emotividade nas aulas de educação física

ABSTRACT For the researchers, physical literacy (AFi) is the objective to be achieved in Physical Education, for seeking competent subjects, capable of adhering to physical activity throughout their lives, with continuous personal, social, affective, and physical development. Quantitative, descriptive-correlational research was carried out, with a non-experimental design and a non-probabilistic sample of 322 subjects, students from 12 to 18 years old from private, public, and subsidized schools in Talca, Chile. The aim was to relate the level of AFi, engagement and perceived emotionality. Data were collected by the Perceived Physical Literacy Instrument (PPLI), Behavioral Engagement Questionnaire (BEQ) and Scale for Mood Assessment (EVEA). A positive relationship was identified with a higher level of physical literacy, higher levels of happiness (r=0.37) and emotional engagement (r=0.54), decreasing the indexes of hostility (r=-0.25) and the private establishments reach the highest levels of anxiety (X̅=3.2). It is concluded that the higher the level of AFi, the greater the commitment and the greater the regulation of emotional factors.

RESUMO A alfabetização física (AFi) é o objetivo para os pesquisadores na Educação Física, buscando sujeitos competentes e capazes de aderir à atividade física ao longo de suas vidas, com desenvolvimento contínuo pessoal, social, afetivo e físico. Esta pesquisa é de natureza quantitativa, descritiva-correlacional, com um desenho não experimental e uma amostra não probabilística de 322 sujeitos, estudantes de 12 a 18 anos de escolas particulares, municipais e subsidiadas na cidade de Talca, Chile. O objetivo foi relacionar o nível de AFi, comprometimento e emocionalidade percebida. Os dados foram coletados por meio do Perceived Physical Literacy Instrument (PPLI), Behavioral Engagement Questionnaire (BEQ) e Escala de Avaliação do Estado de Ânimo (EVEA). Identificou-se uma relação positiva com um maior nível de alfabetização física, maior nível de alegria (r=0,37) e comprometimento emocional (r=0,54), diminuindo os índices de hostilidade (r=-0,25). As escolas particulares atingem os níveis mais altos de ansiedade (X̅=3,2). Conclui-se que um maior nível de AFi está associado a um maior comprometimento e maior regulação dos fatores emocionais.

Effect of implementing an enhanced recovery protocol for pediatric colorectal surgery on complication rate, length of stay, and opioid use in children.

Introduction In the past two decades, Enhanced Recovery After Surgery (ERAS) pathways for adults have improved efficiency of care and decreased length of stay (LOS) without increasing postoperative complications. The effects of enhanced recovery pathways for children are less well known. In this retrospective cohort study, we evaluated the effects of an enhanced recovery protocol (ERP) implementation in children undergoing colorectal surgery. Methods We introduced a colorectal ERP in 2017. Children and young adults (ages 2-22 years) were divided into pre-intervention (2014-2016) and post-intervention groups (2017-2019) for analysis. We abstracted data, including demographics, primary surgery, LOS, postoperative pain scores, and postoperative complications. Results A total of 432 patients were included. Of those,148 (34%) were pre-ERP implementation and 284 (66%) were post-ERP implementation. Post-ERP patients experienced significantly shorter LOS (5.7 vs. 8.3 days, p<0.01); required less intraoperative local anesthetic (9.5% vs. 38.5%, p<0.01) because 55% of patients received an epidural and 18% received an abdominal plane block; and used less postoperative opioid (62.5% vs. 98.7%, p<0.01) than did pre-ERAS patients. After protocol implementation, average pain scores were lower on postoperative day 1 (3.6 vs. 4.5, p<0.05) and across the hospitalization (3.0 vs. 4.0, p<0.01). Conclusion Enhanced recovery pathways decrease LOS, opioid use, and postoperative pain scores for children undergoing colorectal surgery and should be considered for this patient population.

The administration of a pre-digested fat-enriched formula prevents necrotising enterocolitis-induced lung injury in mice.

Necrotising enterocolitis (NEC) is a devastating gastrointestinal disease of prematurity that typically develops after the administration of infant formula, suggesting a link between nutritional components and disease development. One of the most significant complications that develops in patients with NEC is severe lung injury. We have previously shown that the administration of a nutritional formula that is enriched in pre-digested Triacylglyceride that do not require lipase action can significantly reduce the severity of NEC in a mouse model. We now hypothesise that this 'pre-digested fat (PDF) system' may reduce NEC-associated lung injury. In support of this hypothesis, we now show that rearing newborn mice on a nutritional formula based on the 'PDF system' promotes lung development, as evidenced by increased tight junctions and surfactant protein expression. Mice that were administered this 'PDF system' were significantly less vulnerable to the development of NEC-induced lung inflammation, and the administration of the 'PDF system' conferred lung protection. In seeking to define the mechanisms involved, the administration of the 'PDF system' significantly enhanced lung maturation and reduced the production of reactive oxygen species (ROS). These findings suggest that the PDF system protects the development of NEC-induced lung injury through effects on lung maturation and reduced ROS in the lung and also increases lung maturation in non-NEC mice.

Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas.

BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.

Migración de la malla a la unión gastroesofágica: una complicación infrecuente de la reparación de una hernia hiatal gigante / Mesh migration into the gastroesophageal junction: a rare complication of giant hiatal hernia repair

Resumen El reparo de la hernia hiatal es un tema de debate debido a las posibles complicaciones asociadas que han cambiado a través de los años. En la literatura se reportan complicaciones asociadas al procedimiento hasta en un 30 % de los casos. Las complicaciones diferentes a la recurrencia y a largo plazo son infrecuentes, reportadas en menos del 9 % de los casos. La inclusión de la malla protésica en el esófago es una rara complicación y solo se han reportado pocos casos sobre esta. Entre los factores asociados a este desenlace se encuentran descritos: el material protésico, la técnica quirúrgica y la tensión de la malla sobre el tejido intervenido; sin embargo, es difícil establecer asociaciones directas de cada factor dado que la literatura actual solo cuenta con reportes de casos. A continuación, se muestra el caso clínico de un paciente, quien, después de una reparación de hernia hiatal con malla, presenta la inclusión de material protésico en el esófago; se aborda el diagnóstico y el manejo de la misma.

Abstract Hiatal hernia repair has been a subject of debate due to the possible associated complications that have changed over the years. The literature reports up to 30% of cases with complications associated with the procedure. Complications other than recurrence and long-term complications are rare and reported in less than 9% of cases. The migration of the prosthetic mesh into the esophagus is a rare complication and only a few cases have been reported. The factors associated with this outcome include prosthetic material, surgical technique, and mesh tension on the intervened tissue. However, it is difficult to establish direct associations of each factor since the current literature has only case reports. The following is a clinical case of a patient in whom the prosthetic material migrated into the esophagus after a hiatal hernia repair with mesh. The diagnosis and treatment offered are discussed.

Vaccine nanodiscs plus polyICLC elicit robust CD8+ T cell responses in mice and non-human primates.

Conventional cancer vaccines based on soluble vaccines and traditional adjuvants have produced suboptimal therapeutic efficacy in clinical trials. Thus, there is an urgent need for vaccine technologies that can generate potent T cell responses with strong anti-tumor efficacy. We have previously reported the development of synthetic high-density protein (sHDL) nanodiscs for efficient lymph node (LN)-targeted co-delivery of antigen peptides and CpG oligonucleotides (a Toll-like receptor-9 agonist). Here, we performed a comparative study in mice and non-human primates (NHPs) to identify an ideal vaccine platform for induction of CD8+ T cell responses. In particular, we compared the efficacy of CpG class B, CpG class C, and polyICLC (a synthetic double-stranded RNA analog, a TLR-3 agonist), each formulated with antigen-carrying sHDL nanodiscs. Here, we report that sHDL-Ag admixed with polyICLC elicited robust Ag-specific CD8+ T cell responses in mice, and when used in combination with α-PD-1 immune checkpoint inhibitor, sHDL-Ag + polyICLC eliminated large established (~100 mm3) MC-38 tumors in mice. Moreover, sHDL-Gag + polyICLC induced robust Simian immunodeficiency virus Gag-specific, polyfunctional CD8+ T cell responses in rhesus macaques and could further amplify the efficacy of recombinant adenovirus-based vaccine. Notably, while both sHDL-Ag-CpG-B and sHDL-Ag-CpG-C generated strong Ag-specific CD8+ T cell responses in mice, their results were mixed in NHPs. Overall, sHDL combined with polyICLC offers a strong platform to induce CD8+ T cells for vaccine applications.

IFN-γ- and IL-17-producing CD8+ T (Tc17-1) cells in combination with poly-ICLC and peptide vaccine exhibit antiglioma activity.

BACKGROUND: While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based immunotherapy for central nervous system (CNS) tumors, such as glioblastoma (GBM), still needs to overcome multiple challenges, including effective homing and persistence of T-cells. Based on previous observations that interleukin (IL)-17-producing T-cells can traffic to the CNS in autoimmune conditions, we evaluated CD8+ T-cells that produce IL-17 and interferon-γ (IFN-γ) (Tc17-1) cells in a preclinical GBM model. METHODS: We differentiated Pmel-1 CD8+ T-cells into Tc17-1 cells and compared their phenotypic and functional characteristics with those of IFN-γ-producing CD8+ T (Tc1) and IL-17-producing CD8+ T (Tc17) cells. We also evaluated the therapeutic efficacy, persistence, and tumor-homing of Tc17-1 cells in comparison to Tc1 cells using a mouse GL261 glioma model. RESULTS: In vitro, Tc17-1 cells demonstrated profiles of both Tc1 and Tc17 cells, including production of both IFN-γ and IL-17, although Tc17-1 cells demonstrated lesser degrees of antigen-specific cytotoxic activity compared with Tc1 cells. In mice-bearing intracranial GL261-Quad tumor and treated with temozolomide, Tc1 cells, but not Tc17-1, showed a significant prolongation of survival. However, when the T-cell transfer was combined with poly-ICLC and Pmel-1 peptide vaccine, both Tc1 and Tc17-1 cells exhibited significantly prolonged survival associated with upregulation of very late activation antigen-4 on Tc17-1 cells in vivo. Glioma cells that recurred following the therapy lost the susceptibility to Pmel-1-derived cytotoxic T-cells, indicating that immuno-editing was a mechanism of the acquired resistance. CONCLUSIONS: Tc17-1 cells were equally effective as Tc1 cells when combined with poly-ICLC and peptide vaccine treatment.

Intratumoral (Poly-ICLC) Therapy for Dogs with Advanced Cancers: First Report on Clinical Effectiveness, Quality of Life, and Adverse Events.

Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded viral RNA analog widely tested as a component of human therapeutic cancer vaccines and as a standalone agent for treating human cancers. However, there are no reports on the use of poly-ICLC for treating canine cancers. This study aimed to investigate the clinical efficacy, quality of life (QL), and adverse events of poly-ICLC treatment in dogs with advanced cancers. The treatment protocol consisted of weekly intratumoral doses of poly-ICLC. The canine patients underwent clinical, laboratory, and imaging tests, and their owners answered weekly QL questionnaires. Fourteen canine patients with different types of spontaneous advanced tumors were enrolled. Most dogs had received prior conventional therapies. Five dogs received at least 12 doses of poly-ICLC: the injected tumor was stable in three dogs, there was a partial response in one, and the injected tumor significantly enlarged in the other. The QL scoring remained stable or increased in most cases. Mild adverse events related to poly-ICLC were observed in 10 of the 14 patients. The data showed that intratumoral poly-ICLC therapy was well tolerated in dogs with advanced cancers, with clinical benefit and improved QL scores observed in some dogs.