RESUMEN
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for refractory/relapsed (R/R) hematologic malignancies, with six products approved for B-cell tumors and multiple myeloma as of the end of 2023. However, adoptive cell therapy (ACT) for solid tumors is hindered by critical challenges in multiple areas, including (1) lack of appropriate tumor-specific antigens, (2) inefficient T-cell trafficking and infiltration into the tumor microenvironment, and (3) immunosuppressive signals within the tumor milieu that induce T-cell dysfunction. This review examines the existing clinical trial data on ACT for solid tumors to elucidate the current landscape of ACT development for solid tumors. It also outlines the trajectory of ACT for solid tumors and integrative approaches to overcoming the complex tumor microenvironment.
Asunto(s)
Neoplasias , Microambiente Tumoral , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Microambiente Tumoral/inmunología , Inmunoterapia Adoptiva/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Linfocitos T/inmunología , Ensayos Clínicos como Asunto , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.
RESUMEN
INTRODUCTION: Although the prognosis of Langerhans cell histiocytosis (LCH) is excellent, the high recurrence rate and permanent consequences, such as central diabetes insipidus and LCH-associated neurodegenerative diseases, remain to be resolved. Based on previous reports that patients with high-risk multisystem LCH show elevated levels of inflammatory molecules, we hypothesised that dexamethasone would more effectively suppress LCH-associated inflammation, especially in the central nervous system (CNS). We further hypothesised that intrathecal chemotherapy would effectively reduce CNS complications. We administer zoledronate to patients with multifocal bone LCH based on an efficacy report from a small case series. METHODS AND ANALYSIS: This phase II study (labelled the LCH-19-MSMFB study) is designed to evaluate the significance of introducing dexamethasone and intrathecal chemotherapy for multisystem disease and zoledronate for multifocal bone disease in previously untreated, newly diagnosed children, adolescents (under 20 years) and adults under 40 years. The primary endpoint is the 3-year event-free survival rate by risk group of under 20 years and the 3-year event-free survival rate of 20 years and over. ETHICS AND DISSEMINATION: This study was approved by the Central Review Board of the National Hospital Organisation Nagoya Medical Centre (Nagoya, Japan) on 21 January 2022 and was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp/en-latest-detail/jRCTs041210027). Written informed consent will be obtained from all patients and/or their guardians. TRIAL REGISTRATION NUMBER: jRCTs041210027.
Asunto(s)
Dexametasona , Histiocitosis de Células de Langerhans , Ácido Zoledrónico , Humanos , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/mortalidad , Niño , Adolescente , Japón , Adulto , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Adulto Joven , Ácido Zoledrónico/uso terapéutico , Masculino , Femenino , Ensayos Clínicos Fase II como Asunto , Preescolar , Conservadores de la Densidad Ósea/uso terapéuticoRESUMEN
When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 4 , Humanos , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , Niño , Masculino , Femenino , Preescolar , Hibridación Fluorescente in Situ , Adolescente , Trastornos Linfoproliferativos/virología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , ARN Viral/análisis , Citometría de Flujo/métodos , Linfocitos B/virología , Adulto , Sensibilidad y Especificidad , Lactante , Células Asesinas Naturales/virologíaRESUMEN
Alemtuzumab is used with reduced-toxicity conditioning (RTC) in allogeneic hematopoietic cell transplantation (HCT), demonstrating efficacy and feasibility for patients with inborn errors of immunity (IEI) in Western countries; however, the clinical experience in Asian patients with IEI is limited. We retrospectively analyzed patients with IEI who underwent the first allogeneic HCT with alemtuzumab combined with RTC regimens in Japan. A total of 19 patients were included and followed up for a median of 18 months. The donors were haploidentical parents (n = 10), matched siblings (n = 2), and unrelated bone marrow donors (n = 7). Most patients received RTC regimens containing fludarabine and busulfan and were treated with 0.8 mg/kg alemtuzumab with intermediate timing. Eighteen patients survived and achieved stable engraftment, and no grade 3-4 acute graft-versus-host disease was observed. Viral infections were observed in 11 patients (58%) and 6 of them presented symptomatic. The median CD4+ T cell count was low at 6 months (241/µL) but improved at 1 year (577/µL) after HCT. Whole blood cells continued to exhibit > 80% donor type in most cases; however, 3/10 patients exhibited poor donor chimerism only among T cells and also showed undetectable levels of T-cell receptor recombination excision circles (TRECs) at 1 year post-HCT. This study demonstrated the efficacy and safety of alemtuzumab; however, patients frequently developed viral infections and slow reconstitution or low donor chimerism in T cells, emphasizing the importance of monitoring viral status and T-cell-specific chimerism. (238 < 250 words).
Asunto(s)
Alemtuzumab , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Trasplante Homólogo , Humanos , Alemtuzumab/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Masculino , Femenino , Acondicionamiento Pretrasplante/métodos , Preescolar , Niño , Lactante , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Pueblo Asiatico , Resultado del Tratamiento , AdolescenteAsunto(s)
Histiocitosis de Células de Langerhans , Niño , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Histiocitosis de Células de Langerhans/diagnóstico por imagen , Histiocitosis de Células de Langerhans/patología , Pulmón/diagnóstico por imagen , Pulmón/patología , Tomografía Computarizada por Rayos XRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of behavioral flexibility and stereotyped language. Food selectivity is common among children with ASD because of their persnickety nature. A prolonged unbalanced diet results in an increased risk of several diseases, such as iron deficiency anemia, scurvy, rickets, dry eye, and Wernicke encephalopathy. However, no cases of megaloblastic anemia have been reported to date. We report the case of an 11-year-old boy with ASD who developed megaloblastic anemia due to vitamin B12 deficiency. He had a prolonged history of selective eating for more than 10 years. His nutritional status on admission was poor, and he had low weight and short stature. His food selectivity was so strong that intervention to expand diet variety was unsuccessful. A developmental-behavioral pediatrician found that the patient had visual dominance and could take some medications when suffering from a minor illness. Nutritional supplements were selected after consultation with a nutritionist. Although compulsory treatment was necessary during the acute phase, the therapy was continued at home. With multidisciplinary intervention tailored to the patient and his parents' characteristics, his nutritional status improved in a few months.
Asunto(s)
Anemia Megaloblástica , Trastorno del Espectro Autista , Deficiencia de Vitamina B 12 , Humanos , Masculino , Niño , Anemia Megaloblástica/etiología , Trastorno del Espectro Autista/complicaciones , Deficiencia de Vitamina B 12/complicaciones , Dieta , Suplementos DietéticosRESUMEN
Turner syndrome (TS) patients with Y chromosome material face an increased risk of gonadal germ cell tumors (GCTs). This case report discusses the challenges in decision-making regarding prophylactic gonadectomy, considering the risk of malignancy and the desire to preserve fertility. We report a case of a 12-year-old female with mosaic TS and Y chromosome material who initially presented with short stature and obesity. Karyotype analysis showed a mixed cell line (45X and 46XY). Counseling about the increased risk of developing GCT and preservation of gonadal function was provided, and we decided to delay gonadectomy until the age of 12. Prophylactic bilateral gonadectomy revealed dysgerminoma associated with GB at the age of 12. Fortunately, the patient was asymptomatic, with no additional therapy required due to the early stage of the disease. The case highlights the dilemma in managing TS patients with Y chromosome material, where the risk of GCT varies depending on the type of difference in sex development and gonadal function. The decision to delay gonadectomy reflects the emphasis on preservation of ovarian, although it poses a risk of malignancy. This case underscores the importance of individualized care in TS patients with Y chromosome material, balancing the risk of malignancy against preservation of ovarian. It emphasizes the need for timely and personalized decision-making in prophylactic gonadectomy.
RESUMEN
X-linked inhibitor of apoptosis protein (XIAP) deficiency is an inborn error of immunity (IEI). Allogeneic hematopoietic cell transplantation (HCT) is currently the only curative therapy available for XIAP deficiency. Granulomatous and lymphocytic interstitial lung disease (GLILD) is a common immune-related lung complication of IEIs. We present a 6-year-old boy with XIAP deficiency and GLILD. Computed tomography showed lung nodes but no symptoms. Before HCT, GLILD was not managed with immunosuppressive therapy, because he was asymptomatic. The HCT procedure was subsequently performed. The post-HCT course was uneventful; follow-up computed tomography on day 46 showed nodules had disappeared. HCT could potentially ameliorate GLILD like other inflammatory processes associated with the underlying IEIs.
Asunto(s)
Inmunodeficiencia Variable Común , Enfermedades Genéticas Ligadas al Cromosoma X , Trasplante de Células Madre Hematopoyéticas , Enfermedades Pulmonares Intersticiales , Trastornos Linfoproliferativos , Masculino , Humanos , Niño , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/terapia , Trastornos Linfoproliferativos/terapia , Trastornos Linfoproliferativos/complicaciones , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunodeficiencia Variable Común/complicacionesRESUMEN
Histiocytoses, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), are inflammatory myeloid tumors in which monocyte lineage cells aggregate in various organs, causing tissue damage. Most of these tumors harbor oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes, typified by BRAFV600E. Some patients with LCH develop bilateral symmetrical cerebellar lesions and brain atrophy several years after diagnosis when the initial symptoms disappear, leading to cerebellar ataxia and higher cerebral dysfunction. A similar neurological disorder has also been reported in ECD. This neurological disorder can be improved with MAPK inhibitors. When patients with this neurological disorder are identified among neurodegeneration of unknown etiology or histiocytosis patients and treated early with MAPK inhibitors, the disorder can be reversible.
Asunto(s)
Encefalopatías , Enfermedad de Erdheim-Chester , Histiocitosis de Células de Langerhans , Neoplasias , Humanos , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/patología , Enfermedad de Erdheim-Chester/diagnóstico , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/patología , MutaciónRESUMEN
PURPOSE: To confirm the hypothesis that brain white matter damage is involved in the pathogenesis and disease progression of Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND), we aimed to analyze pediatric patients with LCH using diffusion tensor imaging (DTI). METHODS: We enrolled 33 patients with LCH and obtained 33 DTI datasets. Using DTI-based tractography, fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were measured in the cerebral and cerebellar white matter tracts. The participants were divided into three groups-non-ND, ND without clinical symptoms (r-ND), and ND with clinical symptoms (c-ND)-according to their clinical status during the examination with DTI. We compared the DTI parameters in white matter tracts were compared among the three groups. RESULTS: In the order of non-ND, r-ND, and c-ND groups, the FA in superior cerebellar peduncle (SCP) and middle cerebellar peduncle (MCP) significantly decreased, the ADC, AD, and RD of MCP, and the RD of SCP were significantly elevated (FA-SCP; p < 0.001, FA-MCP; p = 0.026, ADC-MCP; p < 0.001, AD-MCP; p = 0.002, RD-MCP; p = 0.003, and RD-SCP; p = 0.018). Furthermore, in the simple linear regression analysis, the FA, ADC, AD, and RD values in the MCP and the FA value in the SCP were significantly influenced by the presence of neurological symptoms and ND findings on MRI (all p < 0.001). CONCLUSION: In LCH-ND, we identified microstructural damage in the SCP and MCP. DTI parameters in these tracts may help monitor LCH-ND; therefore, future studies are required to validate these results in a large cohort.
Asunto(s)
Enfermedades Neurodegenerativas , Sustancia Blanca , Humanos , Niño , Imagen de Difusión Tensora/métodos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/patología , Cerebelo/patología , Imagen de Difusión por Resonancia Magnética , AnisotropíaRESUMEN
OBJECTIVE: Hepatic steatosis is a key initiating event in the pathogenesis of alcohol-associated liver disease (ALD), the most detrimental organ damage resulting from alcohol use disorder. However, the mechanisms by which alcohol induces steatosis remain incompletely understood. We have previously found that alcohol binging impairs brain insulin action, resulting in increased adipose tissue lipolysis by unrestraining sympathetic nervous system (SNS) outflow. Here, we examined whether an impaired brain-SNS-adipose tissue axis drives hepatic steatosis through unrestrained adipose tissue lipolysis and increased lipid flux to the liver. METHODS: We examined the role of lipolysis, and the brain-SNS-adipose tissue axis and stress in alcohol induced hepatic triglyceride accumulation in a series of rodent models: pharmacological inhibition of the negative regulator of insulin signaling protein-tyrosine phosphatase 1ß (PTP1b) in the rat brain, tyrosine hydroxylase (TH) knockout mice as a pharmacogenetic model of sympathectomy, adipocyte specific adipose triglyceride lipase (ATGL) knockout mice, wildtype (WT) mice treated with ß3 adrenergic agonist or undergoing restraint stress. RESULTS: Intracerebral administration of a PTP1b inhibitor, inhibition of adipose tissue lipolysis and reduction of sympathetic outflow ameliorated alcohol induced steatosis. Conversely, induction of adipose tissue lipolysis through ß3 adrenergic agonism or by restraint stress worsened alcohol induced steatosis. CONCLUSIONS: Brain insulin resistance through upregulation of PTP1b, increased sympathetic activity, and unrestrained adipose tissue lipolysis are key drivers of alcoholic steatosis. Targeting these drivers of steatosis may provide effective therapeutic strategies to ameliorate ALD.
Asunto(s)
Hígado Graso Alcohólico , Hígado Graso , Hepatopatías Alcohólicas , Ratas , Ratones , Animales , Lipólisis , Roedores/metabolismo , Hígado Graso/patología , Insulina/metabolismo , Etanol/efectos adversos , Ratones Noqueados , ObesidadAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Linfohistiocitosis Hemofagocítica , Humanos , Niño , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/etiología , Etopósido/uso terapéutico , Palmitatos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , DexametasonaRESUMEN
Langerhans cell histiocytosis-associated neurodegenerative disease (LCH-ND) is the most serious late complication secondary to LCH and is gradually progressive, destructive, and irreversible. Detection of the BRAF V600E mutation in peripheral blood mononuclear cells (PBMCs), even in the absence of active LCH lesions, is considered a sign of clinical LCH-ND, presenting with both abnormal imaging findings and neurological symptoms. However, the detection of the BRAF V600E mutation in PBMCs of patients with asymptomatic radiological LCH-ND (rLCH-ND) without active LCH lesions who present only with abnormal imaging findings is unknown. In this study, we analyzed the BRAF V600E mutations in PBMCs and cell-free DNA (cfDNA) of patients with rLCH-ND without active LCH lesions (n = 5) using a droplet digital polymerase chain reaction (ddPCR) assay. The BRAF V600E mutation in PBMCs was detected in three out of five (60%) cases. The mutant allele frequencies in the three positive cases were 0.049%, 0.027%, and 0.015%, respectively. However, the cfDNA BRAF V600E mutation remained undetected in all patients. Detection of the BRAF V600E mutant allele in PBMCs may be helpful in identifying asymptomatic rLCH-ND in patients at high risk for developing LCH-ND, including those with relapses at CNS risk sites or central diabetes insipidus.
Asunto(s)
Histiocitosis de Células de Langerhans , Enfermedades Neurodegenerativas , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Leucocitos Mononucleares/patología , Mutación , Histiocitosis de Células de Langerhans/diagnóstico por imagen , Histiocitosis de Células de Langerhans/genética , Reacción en Cadena de la PolimerasaRESUMEN
STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades Inflamatorias del Intestino , Linfohistiocitosis Hemofagocítica , Humanos , Masculino , Diarrea , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/terapia , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/terapia , Proteínas Munc18/genética , MutaciónRESUMEN
We assessed relapse patterns in paediatric patients with relapsed Langerhans cell histiocytosis (LCH) who were initially treated with the JLSG-96/02 protocol. We analysed 187 relapse events in 101 relapsed LCH patients [31 with multifocal bone (MFB) and 70 with multisystem (MS) at LCH diagnosis] among a total 317 patients enrolled in JLSG-96/-02 studies. Relapse of LCH was defined as an exacerbation of the non-active disease (NAD) condition. Of the 317 patients, 101 (31.9%) had the first relapse at 1.5 years after initiation of therapy. The first relapse and subsequent relapses did not differ between patients with MFB and MS disease. Of the 187 relapse events, relapse occurred as a single-system disease (n = 159; 85%), in which isolated bone relapse (n = 104; 55%) was the most common. Relapse at MS disease with the risk of organ involvement is extremely rare. After relapse(s), most patients underwent chemotherapy (122/187; 65%) and 87% of them achieved NAD status again. The incidence of permanent consequences was significantly higher in patients with relapses than in those without relapses. In the JLSG cohort, bone relapse most occurred in both MFB and MS patients. Most relapses could be effectively controlled by repeated administration of the initial chemotherapy.
Asunto(s)
Histiocitosis de Células de Langerhans , NAD , Niño , Humanos , Lactante , Resultado del Tratamiento , NAD/uso terapéutico , Recurrencia , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Análisis de Datos , Estudios RetrospectivosRESUMEN
METHODS AND ANALYSIS: This study was a non-blinded, multicenter, single-arm study. Recurrent (relapsed) LCH is defined as the appearance of new lesions or the enlargement of preexisting lesions due to LCH. In this study, all patients received hydroxyurea, and if the treatment response was unsatisfactory, methotrexate was added. The duration of treatment was 48 weeks. The primary endpoint was the rate of non-active disease achievement, which was 24 weeks after initiating hydroxyurea administration. No active disease is defined as the resolution of all the signs and symptoms related to LCH.
Asunto(s)
Histiocitosis de Células de Langerhans , Metotrexato , Humanos , Metotrexato/uso terapéutico , Hidroxiurea/efectos adversos , Proyectos Piloto , Histiocitosis de Células de Langerhans/diagnóstico , RecurrenciaRESUMEN
Foot-and-mouth disease (FMD) is a contagious disease affecting cloven-hoofed animals. Its transmissibility and antigenic variety make this disease difficult to control. Antiviral agents are expected to have an immediate effect that is independent of viral antigenicity; thus, they can serve as effective tools for inhibiting the spread of the causative agent, the FMD virus (FMDV), from infected animals. In this study, we investigated the antiviral activity of a pyrazinecarboxamide derivative, T-1105, against FMDV. Cytopathic effect inhibition assays revealed that T-1105 strongly inhibited the replication of 28 reference strains of all seven FMDV serotypes at non-cytotoxic concentrations. The antiviral effect of T-1105 against FMDV was also evaluated by experimental infection of domestic pigs. T-1105 was administered orally to pigs starting 1 h before or 6 h after the inoculation of a porcinophilic FMDV serotype O, topotype CATHAY. None of the pigs administered with T-1105 showed clinical signs of FMD. Moreover, no infectious FMDVs or FMDV-specific genes were detected in their sera, oral and nasal discharges, or tissues collected 48 h after virus inoculation. These findings strongly suggest that administration of T-1105 is effective in controlling the spread of FMDV in pigs.