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Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (4170 patients). An updated archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower eGFR, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR respectively diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
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OBJECTIVE: The pathophysiology of Meniere's Disease (MD) involves endolymphatic hydrops (ELH) of the inner ear. Magnetic Resonance Imaging (MRI) has been shown to detect ELH, but changes in ELH have been poorly described using this modality. Our objective was to review MRI-measured changes in ELH over time and after medical and/or surgical intervention in patients with MD. We secondarily aim to associate changes in ELH with changes in MD symptomatology. DATABASES REVIEWED: Medline, Web of Science, and Embase databases. METHODS: A systematic review of articles was performed to identify studies utilizing MRI to measure ELH changes over time, and after medical or surgical treatment. Articles on non-human subjects and without direct measurement of ELH were excluded. RESULTS: Of 532 studies identified, 12 were included, involving 170 patients (mean age 56.3 years). Ten studies were prospective; two were retrospective. Five studies strictly utilized medical means of intervention, four utilized surgical treatments, one utilized both, and two observed temporal changes without treatment. Across all interventions, 72.1 % of patients exhibited the same or worsening ELH on imaging. In studies reporting vertigo outcomes, 95.9 % of patients exhibited improvement after the treatment period. CONCLUSION: Medical and surgical interventions often yield symptomatic relief of vertigo in MD patients despite stable or increasing ELH volume. MRI may have greater clinical utility in diagnosing ELH as opposed to assessing treatment response.
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Hidropesía Endolinfática , Enfermedad de Meniere , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Hidropesía Endolinfática/diagnóstico por imagen , Hidropesía Endolinfática/patología , Enfermedad de Meniere/complicaciones , Enfermedad de Meniere/diagnóstico por imagen , Enfermedad de Meniere/patología , Vértigo , Imagen por Resonancia Magnética/métodosRESUMEN
The optimum approach towards immunosuppression withdrawal following kidney transplant failure is unclear. Prolonged weaning may be associated with reduced sensitization, less graft nephrectomy and greater likelihood of retransplantation, but conversely increased risk of infection, malignancy and death. We conducted a single-centre retrospective analysis of patients experiencing graft failure between 2007 and 2017, comparing rates of sensitization, retransplantation, nephrectomy, infection, malignancy and death between patients who had immunosuppression weaned over <90 vs. 90-180 vs. >180 days. Patient survival after immunosuppression withdrawal over <90 vs. 90-180 vs. >180 days was 73.3%, 72.1% and 80.4%, respectively (P = 0.35), with no differences in cPRA (80.06 vs. 81.21 vs. 85.42, P = 0.66) or retransplantation rate [24/31 (77.4%) vs. 21/35 (60.0%) vs. 22/36 (61.1%), P = 0.13]. There was significantly less nephrectomy after late immunosuppression cessation [10/42 (23.8%) vs. 7/42 (16.7%) vs. 3/43 (7.0%), P = 0.01] but no differences in infections or malignancy. On competing risk regression (death as competing risk) controlling for cofactors including age, nephrectomy and rejection, prolonged immunosuppression did not predict likelihood of retransplantation (SHR 1.000, P = 0.88). Prolonged immunosuppression withdrawal does not reduce sensitization or improve retransplantation rates but is associated with less nephrectomy. Immunosuppression withdrawal should be tailored to individual circumstances after graft failure.
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Trasplante de Riñón , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Terapia de Inmunosupresión , Trasplante de Riñón/efectos adversos , Reoperación , Estudios RetrospectivosRESUMEN
INTRODUCTION: Cochlear implantation (CI) is a reliable and safe means by which sensorineural hearing loss can be ameliorated in the elderly population. However, a high degree of variation exists in postimplantation hearing outcomes for which some modifiable factors of the daily natural auditory environment may be contributory. In this study, we analyze the relationship between cochlear implant patient age, natural auditory environment, and postimplantation speech perception among older adults. METHODS: Data log from automatic environment classification enabled sound processors of postlingually deafened CI recipients ≥50 years old (n = 115) were obtained retrospectively and analyzed for time spent (hours per day) in listening environment and loudness (SPL dB). Speech perception testing was assessed in a subset of patients (n = 27) using open-set word recognition in quiet Consonant-Nucleus-Consonant in the short and intermediate postoperative period. RESULTS: The mean subject age was 70 years (range, 53-99 years). Average daily implant use was 10.8 h and was not significantly correlated with age (p = 0.23, Spearman's rho). Age was positively correlated with the percentage of hours spent at <40 and 40-50 dB and negatively correlated to proportional CI use at higher volume (60-70, 70-80, and >80 dB; rs = 0.21, 0.20, -0.20, -0.35, -0.43; p = 0.021, 0.036, 0.033, <0.001, <0.001, respectively). Age was positively correlated with CI use in the quiet scene (rs = 0.26, p = 0.006) and negatively correlated with scenes containing speech and noise (rs = -0.19, -0.25; p = 0.046, 0.007). Total hours of device use and time spent at <40, 40-50 dB, and quiet environments were significantly correlated with improved CNC word scores (rs = 0.48, 0.48, 0.51; p = 0.01, 0.01, <0.01, Spearman's rho). While all speech (speech in noise + speech) was not significantly correlated to improvements in speech perception, a medium effect size was observed (rs = 0.37, p = 0.057). DISCUSSION/CONCLUSION: This study supports a relationship between auditory environment and age, with older CI recipients spending a greater proportion of time in quiet. Older CI users demonstrated greater improvements in speech perception with longer daily device use. Additional examination of the relationship between auditory environment and speech perception is necessary to conclusively guide future auditory rehabilitation efforts.
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Implantación Coclear , Implantes Cocleares , Pérdida Auditiva Sensorineural , Percepción del Habla , Anciano , Anciano de 80 o más Años , Pérdida Auditiva Sensorineural/cirugía , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Many models are published which predict outcomes in hospitalized COVID-19 patients. The generalizability of many is unknown. We evaluated the performance of selected models from the literature and our own models to predict outcomes in patients at our institution. METHODS: We searched the literature for models predicting outcomes in inpatients with COVID-19. We produced models of mortality or criticality (mortality or ICU admission) in a development cohort. We tested external models which provided sufficient information and our models using a test cohort of our most recent patients. The performance of models was compared using the area under the receiver operator curve (AUC). RESULTS: Our literature review yielded 41 papers. Of those, 8 were found to have sufficient documentation and concordance with features available in our cohort to implement in our test cohort. All models were from Chinese patients. One model predicted criticality and seven mortality. Tested against the test cohort, internal models had an AUC of 0.84 (0.74-0.94) for mortality and 0.83 (0.76-0.90) for criticality. The best external model had an AUC of 0.89 (0.82-0.96) using three variables, another an AUC of 0.84 (0.78-0.91) using ten variables. AUC's ranged from 0.68 to 0.89. On average, models tested were unable to produce predictions in 27% of patients due to missing lab data. CONCLUSION: Despite differences in pandemic timeline, race, and socio-cultural healthcare context some models derived in China performed well. For healthcare organizations considering implementation of an external model, concordance between the features used in the model and features available in their own patients may be important. Analysis of both local and external models should be done to help decide on what prediction method is used to provide clinical decision support to clinicians treating COVID-19 patients as well as what lab tests should be included in order sets.
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COVID-19 , China , Hospitalización , Humanos , Pandemias , Estudios Retrospectivos , SARS-CoV-2RESUMEN
PURPOSE: To assess the safety of using a microdrill in endoscopic vs microscopic stapes surgery. MATERIALS AND METHODS: A retrospective review of 29 adult ears with otosclerosis who underwent either an endoscopic or microscopic approach to microdrill stapedotomy. PRIMARY OUTCOME: Determine if transcanal endoscopic stapes surgery with the microdrill is as safe as microscopic stapes surgery. Secondary outcome: Bone and air pure-tone averages, air-bone gap, speech discrimination, overall surgical cost, and operative time were measured and analyzed. Complications such as post-operative dysgeusia, vertigo, readmission, revision and hearing loss were noted. RESULTS: 29 patients with otosclerosis were retrospectively reviewed, in total 14 endoscopic and 15 microscopic approaches were included, all performed over one-year period. None of the endoscopic surgeries require conversion to the microscope. No statistically significant audiometric differences between the endoscopic vs microscopic approaches in air pure-tone averages and air-bone gap. There were 82.8% air-bone gap closure to <15 dB with no significant difference in the percent of such closures between the endoscopic (85.7%) and microscopic groups (80%, P = .68). Three prostheses were used: 4.25 mm (17.2%), 4.5 mm (58.6%) and the 4.75 mm (24.1%) smart/eclipse. Endoscopic median operative time was 51 min vs 42 min for microscopic approach (P =.004). CONCLUSIONS: The endoscopic with microdrill approach is criticized to lack depth perception, especially when using a microdrill to perform in stapedotomies. Our study showcases that using the microdrill use produces minimal differences in outcomes, cost, and is a safe modality to stapes surgery in both approaches.
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Endoscopía/instrumentación , Mandrillus , Microcirugia/instrumentación , Otosclerosis/cirugía , Cirugía del Estribo/instrumentación , Estribo , Animales , Endoscopía/métodos , Femenino , Humanos , Masculino , Microcirugia/métodos , Persona de Mediana Edad , Tempo Operativo , Estudios Retrospectivos , Seguridad , Cirugía del Estribo/métodos , Resultado del TratamientoRESUMEN
Monocyte-derived dendritic cells (moDCs) dramatically increase in numbers upon infection and inflammation; accordingly, we found that this also occurs during allogeneic responses. Despite their prominence, how emergent moDCs and resident conventional DCs (cDCs) divide their labor as APCs remain undefined. Hence, we compared both direct and indirect presentation by murine moDCs versus cDCs. We found that, despite having equivalent MHC class II expression and in vitro survival, moDCs were 20-fold less efficient than cDCs at inducing CD4(+) T cell proliferation through both direct and indirect Ag presentation. Despite this, moDCs were more potent at inducing Th1 and Th17 differentiation (e.g., 8-fold higher IFN-γ and 2-fold higher IL-17A in T cell cocultures), whereas cDCs induced 10-fold higher IL-2 production. Intriguingly, moDCs potently reduced the ability of cDCs to stimulate T cell proliferation in vitro and in vivo, partially through NO production. We surmise that such division of labor between moDCs and cDCs has implications for their respective roles in the immune response.
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Diferenciación Celular/inmunología , Células Dendríticas/citología , Células Dendríticas/inmunología , Activación de Linfocitos/inmunología , Monocitos/citología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Presentación de Antígeno/inmunología , Linaje de la Célula , Proliferación Celular , Técnicas de Cocultivo , Citometría de Flujo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T Colaboradores-Inductores/citologíaRESUMEN
Although the mechanisms governing the innate recognition of pathogen-associated molecular patterns have been well defined, how allogeneic cellular stimuli evoke innate responses remains less so. In this article, we report that upon i.v. transfer (to avoid major iatrogenic interference), allogeneic but not syngeneic leukocytes could induce a rapid (after 1 d) accumulation of host monocyte-derived dendritic cells (moDCs) without any increase in conventional DCs. This occurred in various donor-host strain combinations, did not require MHC mismatch, and could be induced by various donor cell types including B cells, T cells, or NK cells. Using RAG(-/-)γc(-/-) and scid γc(-/-)mice with different MHC, we found that the presence of either donor or host lymphoid cells was required. Alloinduced moDC accumulation was significantly reduced when splenocytes from mice deficient in NK cells by genetic ablation were used as donors. A major component of this moDC accumulation appears to be recruitment. Our findings provide new insights into how the innate and adaptive immune system may interact during allogeneic encounters and thus transplant rejection.
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Células Dendríticas/fisiología , Inmunidad Innata , Monocitos/fisiología , Animales , Células Dendríticas/inmunología , Rechazo de Injerto , Células Asesinas Naturales/inmunología , Ratones , Ratones SCID , Monocitos/inmunología , Linfocitos T/inmunologíaRESUMEN
Dendritic cells (DCs) are professional antigen-presenting cells that consist of functionally and phenotypically heterogeneous populations. Monocyte-derived DCs (moDCs) are a DC subset that have been attracting increasing interest owing to their potent influence on adaptive immune function and their rapid accumulation upon an inflammatory stimulus. Although early studies on moDCs mainly addressed infection, their emergence and function in other settings such as autoimmunity and allogeneic organ transplantation are now being increasingly appreciated. In this review, the relationship between murine monocyte subsets and the moDCs that arise from them is discussed. Their role in initiating and modulating innate and adaptive immune responses in various pathophysiological scenarios is also explored, including how they may separate their labour from conventional DCs. How these findings might relate to their human counterparts is also discussed. Overall, monocytes and moDCs exhibit complex and heterogeneous behaviours that are critical in responses against microbial invasion, autoimmunity and allograft rejection.
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Diferenciación Celular , Células Dendríticas/citología , Monocitos/citología , Animales , Enfermedad , Humanos , InmunidadRESUMEN
Glioblastoma is a devastating cancer with universally poor outcomes in spite of current standard multimodal therapy. Immunotherapy is an attractive new treatment modality given its potential for exquisite specificity and its favorable side effect profile; however, clinical trials of immunotherapy in GBM have thus far shown modest benefit. Optimally combining radiation with immunotherapy may be the key to unlocking the potential of both therapies given the evidence that radiation can enhance anti-tumor immunity. Here we review this evidence and discuss considerations for combined therapy.
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Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inmunoterapia/métodos , Radioterapia/métodos , Neoplasias Encefálicas/inmunología , Terapia Combinada , Glioblastoma/inmunología , HumanosRESUMEN
The Na(+) /K(+) -translocating adenosine triphosphatase (ATPase) transports sodium and potassium across the plasma membrane and represents a potential target in cancer chemotherapy. Na(+) /K(+) -ATPase belongs to the P-type ATPase family (also known as E1-E2 ATPase), which is involved in transporting certain ions, metals, and lipids across the plasma membrane of mammalian cells. In humans, the Na(+) /K(+) -ATPase is a binary complex of an α-subunit that has four isoforms (α1 -α4 ) and a ß-subunit that has three isoforms (ß1 -ß3 ). This review aims to update our knowledge on the role of Na(+) /K(+) -ATPase in cancer development and metastasis, as well as on how Na(+) /K(+) -ATPase inhibitors kill tumour cells. The Na(+) /K(+) -ATPase has been found to be associated with cancer initiation, growth, development, and metastasis. Cardiac glycosides have exhibited anticancer effects in cell-based and mouse studies via inhibition of the Na(+) /K(+) -ATPase and other mechanisms. Na(+) /K(+) -ATPase inhibitors may kill cancer cells via induction of apoptosis and autophagy, radical oxygen species production, and cell cycle arrest. They also modulate multiple signalling pathways that regulate cancer cell survival and death, which contributes to their antiproliferative activities in cancer cells. The clinical evidence supporting the use of Na(+) /K(+) -ATPase inhibitors as anticancer drugs is weak. Several phase I and phase II clinical trials with digoxin, Anvirzel, and huachansu (an intravenous formulated extract of the venom of the wild toad), either alone or more often in combination with other anticancer agents, have shown acceptable safety profiles but limited efficacy in cancer patients. Well-designed randomized clinical trials with reasonable sample sizes are certainly warranted to confirm the efficacy and safety of cardiac glycosides for the treatment of cancer.
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Antineoplásicos/farmacología , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , ATPasa Intercambiadora de Sodio-Potasio/químicaRESUMEN
BACKGROUND AIMS: Outcomes for patients with glioblastoma remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL) 13Rα2, human epidermal growth factor receptor 2, epidermal growth factor variant III or erythropoietin-producing hepatocellular carcinoma A2 has shown promise for the treatment of glioma in preclinical models. On the basis of IL13Rα2 immunotoxins that contain IL13 molecules with one or two amino acid substitutions (IL13 muteins) to confer specificity to IL13Rα2, investigators have constructed CARS with IL13 muteins as antigen-binding domains. Whereas the specificity of IL13 muteins in the context of immunotoxins is well characterized, limited information is available for CAR T cells. METHODS: We constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo. RESULTS: T cells expressing all four CARs recognized IL13Rα1 or IL13Rα2 recombinant protein in contrast to control protein (IL4R) as judged by interferon-γ production. IL13 protein produced significantly more IL2, indicating that IL13 mutein-CAR T cells have a higher affinity to IL13Rα2 than to IL13Rα1. In cytotoxicity assays, CAR T cells killed IL13Rα1- and/or IL13Rα2-positive cells in contrast to IL13Rα1- and IL13Rα2-negative controls. Although we observed no significant differences between IL13 mutein-CAR T cells in vitro, only T cells expressing IL13 mutein-CARs with an E13K amino acid substitution had anti-tumor activity in vivo that resulted in a survival advantage of treated animals. CONCLUSIONS: Our study highlights that the specificity/avidity of ligands is context-dependent and that evaluating CAR T cells in preclinical animal model is critical to assess their potential benefit.
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Glioblastoma/terapia , Inmunoterapia , Subunidad alfa2 del Receptor de Interleucina-13/genética , Linfocitos T/inmunología , Sustitución de Aminoácidos , Animales , Regulación Neoplásica de la Expresión Génica/inmunología , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Inmunotoxinas/genética , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa1 del Receptor de Interleucina-13/inmunología , Subunidad alfa2 del Receptor de Interleucina-13/inmunología , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.
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Terapia Genética/métodos , Glioblastoma/terapia , Inmunoterapia/métodos , Receptor EphA2/genética , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Línea Celular Tumoral , Vectores Genéticos , Humanos , Interferón gamma/metabolismo , Interleucina-2/metabolismo , Células K562 , Masculino , Ratones , Ratones SCID , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Retroviridae/genética , Transducción GenéticaRESUMEN
Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.
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Fibroblastos/inmunología , Gelatinasas/inmunología , Proteínas de la Membrana/inmunología , Neoplasias/inmunología , Receptores de Antígenos/inmunología , Serina Endopeptidasas/inmunología , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Citocinas/biosíntesis , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Endopeptidasas , Fibroblastos/metabolismo , Gelatinasas/genética , Gelatinasas/metabolismo , Expresión Génica , Orden Génico , Vectores Genéticos , Humanos , Inmunoterapia , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/metabolismo , Neoplasias/mortalidad , Neoplasias/patología , Receptores de Antígenos/genética , Receptores de Antígenos/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Serina Endopeptidasas/genética , Serina Endopeptidasas/metabolismo , Linfocitos T/metabolismoRESUMEN
Preclinical and early clinical studies have demonstrated that chimeric antigen receptor (CAR)-redirected T cells are highly promising in cancer therapy. We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens. Combinational targeting of these tumor-associated antigens could therefore offset this escape mechanism. We studied the single-cell coexpression patterns of HER2, IL-13Rα2, and EphA2 in primary GBM samples using multicolor flow cytometry and immunofluorescence, and applied a binomial routine to the permutations of antigen expression and the related odds of complete tumor elimination. This mathematical model demonstrated that cotargeting HER2 and IL-13Rα2 could maximally expand the therapeutic reach of the T cell product in all primary tumors studied. Targeting a third antigen did not predict an added advantage in the tumor cohort studied. We therefore generated bispecific T cell products from healthy donors and from GBM patients by pooling T cells individually expressing HER2 and IL-13Rα2-specific CARs and by making individual T cells to coexpress both molecules. Both HER2/IL-13Rα2-bispecific T cell products offset antigen escape, producing enhanced effector activity in vitro immunoassays (against autologous glioma cells in the case of GBM patient products) and in an orthotopic xenogeneic murine model. Further, T cells coexpressing HER2 and IL-13Rα2-CARs exhibited accentuated yet antigen-dependent downstream signaling and a particularly enhanced antitumor activity.
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Traslado Adoptivo , Antígenos de Neoplasias/metabolismo , Glioblastoma/terapia , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Animales , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Línea Celular Tumoral , Terapia Combinada , Glioblastoma/inmunología , Glioblastoma/patología , Células HEK293 , Humanos , Subunidad alfa2 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/inmunología , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Ratones , Ratones SCID , Modelos Biológicos , Receptor ErbB-2/genética , Receptor ErbB-2/inmunología , Receptor ErbB-2/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Células Tumorales Cultivadas , Escape del Tumor , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Antiphospholipid syndrome (APS) may occur in isolation or in association with systemic lupus erythematosus (SLE), with the potential to cause renal failure via several distinct pathologies. Renal transplantation in the presence of APS carries a risk of early graft loss from arterial or venous thrombosis, or thrombotic microangiopathy (TMA). Whilst perioperative anticoagulation reduces the risk of large vessel thrombosis, it may result in significant haemorrhage, and its efficacy in preventing post-transplant TMA is uncertain. Here, we report a patient with end-stage kidney disease (ESKD) due to lupus nephritis and APS, in whom allograft TMA developed soon after transplantation despite partial anticoagulation. TMA resolved with plasma exchange-based therapy albeit with some irreversible graft damage and renal impairment. We discuss the differential diagnosis of post-transplant TMA, and current treatment options.
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Síndrome Antifosfolípido/complicaciones , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Nefritis Lúpica/complicaciones , Microangiopatías Trombóticas/etiología , Adulto , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/diagnóstico , Síndrome Antifosfolípido/tratamiento farmacológico , Biopsia , Diagnóstico Diferencial , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Nefritis Lúpica/diagnóstico , Masculino , Intercambio Plasmático , Valor Predictivo de las Pruebas , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/terapia , Resultado del TratamientoRESUMEN
Background: The emergency personnel who responded to the World Trade Center (WTC) attacks endured severe occupational exposures, yet the prevalence of cognitive impairment remains unknown among WTC-exposed-FDNY-responders. The present study screened for mild and severe cognitive impairment in WTC-exposed FDNY responders using objective tests, compared prevalence rates to a cohort of non-FDNY WTC-exposed responders, and descriptively to meta-analytic estimates of MCI from global, community, and clinical populations. Methods: A sample of WTC-exposed-FDNY responders (n = 343) was recruited to complete an extensive battery of cognitive, psychological, and physical tests. The prevalences of domain-specific impairments were estimated based on the results of norm-referenced tests, and the Montreal Cognitive Assessment (MoCA), Jak/Bondi criteria, Petersen criteria, and the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria were used to diagnose MCI. NIA-AA criteria were also used to diagnose severe cognitive impairment. Generalized linear models were used to compare prevalence estimates of cognitive impairment to a large sample of WTC-exposed-non-FDNY responders from the General Responder Cohort (GRC; n = 7102) who completed the MoCA during a similar time frame. Result: Among FDNY responders under 65 years, the unadjusted prevalence of MCI varied from 52.57% to 71.37% depending on the operational definition of MCI, apart from using a conservative cut-off applied to MoCA total scores (18 < MoCA < 23), which yielded a markedly lower crude prevalence (24.31%) compared to alternative criteria. The prevalence of MCI was higher among WTC-exposed-FDNY-responders, compared to WTC-exposed-non-FDNY-GRC-responders (adjusted RR = 1.53, 95% C.I . = [1.24, 1.88], p < .001) and meta-analytic estimates from different global, community, and clinical populations. Following NIA-AA diagnostic guidelines, 4.96% of WTC-exposed-FDNY-responders met the criteria for severe impairments (95% CI = [2.91% to 7.82%]), a prevalence that remained largely unchanged after excluding responders over the age of 65 years. Discussion: There is a high prevalence of mild and severe cognitive impairment among WTC-responders highlighting the putative role of occupational/environmental and disaster-related exposures in the etiology of accelerated cognitive decline.
RESUMEN
BACKGROUND: Optimal management of children with centrally located low-grade glioma (LGG) is unclear. Initial interventions in most children are chemotherapy in younger and radiation therapy (RT) in older children. A better understanding of the inherent risk factors along with the effects of interventions on long-term outcome can lead to reassessment of the current approaches to minimize long-term morbidity. METHODS: To reassess the current treatment strategies of centrally located LGG, we compared the long-term survival and morbidity of different treatment regimens. Medical records of patients primarily treated at Texas Children's Cancer and Hematology Centers between 1987 and 2008 were reviewed. RESULTS: Forty-seven patients with a median follow-up of 79 months were included in the analysis. The 5-year overall survival and progression-free survival (PFS) for all patients were 96% and 53%, respectively. The 5-year PFS for those treated initially with RT (12 patients; median age, 11 years [range, 3-15 years]) and with chemotherapy (28 patients; median age, 2 years [range 0-8 years]) were 76% and 37%, respectively (log-rank test P = .02). Among children who progressed after chemotherapy, the 5-year PFS after salvage RT was 55%. Patients diagnosed at a younger age (<5 years) were more likely to experience endocrine abnormalities (Fisher exact test; P<.00001). CONCLUSIONS: Effective and durable tumor control was obtained with RT as initial treatment. In younger patients, chemotherapy can delay the use of RT; however, frequent progression and long-term morbidity are common. More effective and less toxic therapies are required in these patients, the majority of whom are long-term survivors.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Glioma/patología , Glioma/terapia , Proteínas de Fusión Oncogénica/análisis , Adolescente , Síntomas Afectivos/epidemiología , Síntomas Afectivos/etiología , Astrocitoma/patología , Astrocitoma/terapia , Neoplasias Encefálicas/química , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Niño , Preescolar , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/etiología , Supervivencia sin Enfermedad , Enfermedades del Sistema Endocrino/epidemiología , Enfermedades del Sistema Endocrino/etiología , Femenino , Glioma/química , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/radioterapia , Humanos , Hibridación Fluorescente in Situ , Lactante , Estimación de Kaplan-Meier , Masculino , Registros Médicos , Clasificación del Tumor , Enfermedades del Sistema Nervioso/epidemiología , Enfermedades del Sistema Nervioso/etiología , Dosificación Radioterapéutica , Estudios Retrospectivos , Sobrevivientes/estadística & datos numéricos , Texas/epidemiología , Resultado del Tratamiento , Trastornos de la Visión/epidemiología , Trastornos de la Visión/etiologíaRESUMEN
T-cell therapy with genetically modified T cells targeting CD19 or CD20 holds promise for the immunotherapy of hematologic malignancies. These targets, however, are only present on B cell-derived malignancies, and because they are broadly expressed in the hematopoietic system, their targeting may have unwanted consequences. To expand T-cell therapies to hematologic malignancies that are not B cell-derived, we determined whether T cells can be redirected to CD70, an antigen expressed by limited subsets of normal lymphocytes and dendritic cells, but aberrantly expressed by a broad range of hematologic malignancies and some solid tumors. To generate CD70-specific T cells, we constructed a chimeric antigen receptor (CAR) consisting of the CD70 receptor (CD27) fused to the CD3-ζ chain. Stimulation of T cells expressing CD70-specific CARs resulted in CD27 costimulation and recognition of CD70-positive tumor cell lines and primary tumor cells, as shown by IFN-γ and IL-2 secretion and by tumor cell killing. Adoptively transferred CD70-specific T cells induced sustained regression of established murine xenografts. Therefore, CD70-specific T cells may be a promising immunotherapeutic approach for CD70-positive malignancies.
Asunto(s)
Ligando CD27/inmunología , Inmunoterapia , Linfoma no Hodgkin/terapia , Linfocitos T/inmunología , Animales , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Citocinas/inmunología , Humanos , Inmunoterapia/métodos , Interleucina-2/inmunología , Activación de Linfocitos , Linfoma no Hodgkin/inmunología , Ratones , Ratones SCID , Linfocitos T/trasplante , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
INTRODUCTION: Augmentative and alternative communication (AAC) encompasses all forms of unaided and aided modes of communication, but typically excludes codified language such as spoken words or American Sign Language (ASL). In pediatric patients with a documented additional disability (population of interest), deficits in communication may pose a barrier to language development. While forms of AAC are frequently mentioned in the literature, recent innovations have permitted the use of high-tech AAC in the rehabilitation process. Our objective was to review the implementation of AAC in pediatric cochlear implant recipients with a documented additional disability. METHODS: A scoping review of existing literature examining the use of AAC in pediatric CI recipients was conducted in the PubMed/MEDLINE and Embase databases. Studies with pediatric cochlear implant recipients with a concomitant diagnosis requiring additional therapeutic intervention outside the scope of standard post-CI follow-up care and rehabilitation from 1985 to 2021 met inclusion criteria (population of interest). Studies limited to spoken or formal sign language (e.g., American Sign Language, ASL) as communication modalities were excluded. RESULTS: Four hundred twenty studies were screened of which 29 were included. 13 were prospective, 10 were retrospective, 1 was cross-sectional, and 5 were case reports. Of these 29 studies, 378 patients met the inclusion criteria (age <18, CI user, additional disability, utilized AAC). Fewer studies (n = 7) utilized AAC as the primary intervention for investigation. Autism spectrum disorder, learning disorder, and cognitive delay were frequently mentioned as additional disabilities in conjunction with AAC. Unaided forms of AAC included gesture/behavior, informal sign, and signed exact English, while aided AAC included a Picture Exchange Communication System (PECS), Voice Output Communication Aids (VOCA), and touchscreen programs such as TouchChat® HD. Various audiometric and language development outcome measures were mentioned, most commonly the Peabody Picture Vocabulary Test (PPVT) (n = 4) and the Preschool Language Scale, Fourth Edition (PLS-4) (n = 4). CONCLUSION: There is a gap in the literature regarding the use of aided and high-tech AAC in pediatric CI users with a documented additional disability. Given the use of multiple different outcome measures, additional exploration of the intervention of AAC is warranted.