RESUMO
BACKGROUND: The first studies on patients with forkhead-box protein P1 (FOXP1) syndrome reported associated global neurodevelopmental delay, autism symptomatology, dysmorphic features and cardiac and urogenital malformations. The aim of this study was to assess the prevalence of congenital abnormalities in an unbiased cohort of patients with FOXP1 syndrome and to document rare complications. METHODS: Patients with FOXP1 syndrome were included, mostly diagnosed via whole-exome sequencing for neurodevelopmental delay. A parent-report questionnaire was used to assess medical signs and symptoms, including questions about features rated as most burdensome by patients and their family. RESULTS: Forty individuals were included, 20 females and 20 males. The mean age at assessment was 13.2 years (median 8.5 years; range 2-54 years; ≥18 years n = 7). Seven adults were included. All patients had developmental problems, including cognitive, communication, social-emotional and motor delays. The most prevalent medical signs and symptoms include delayed bladder control, sleeping problems, hypermetropia, strabismus, sacral dimple, undescended testes, abnormal muscle tone and airway infections. The most burdensome complaints for patients with FOXP1 syndrome, as perceived by parents, include intellectual disability, impaired communication, behaviour problems, lack of age-appropriate self-reliance, attention problems and anxiety. According to parents, patients have quite similar reported symptoms, although incontinence, obsessions and a complex sensory profile have a higher ranking. CONCLUSION: The results of this study may be used to further guide medical management and identify patient priorities for future research targeted on those features of FOXP1 syndrome that most impair quality of life of patients and their families.
Assuntos
Transtorno Autístico , Deficiência Intelectual , Masculino , Adulto , Feminino , Humanos , Adolescente , Qualidade de Vida , Proteínas Repressoras/genética , Fenótipo , Transtorno Autístico/genética , Fatores de Transcrição/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismoRESUMO
Immunodeficiency-Centromeric instability-Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003-2021, at median age 4.3 years (range 0.5-19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1-185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1-14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Pré-Escolar , Criança , Masculino , Feminino , Lactente , Adolescente , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/diagnóstico , Adulto Jovem , Síndromes de Imunodeficiência/terapia , Síndromes de Imunodeficiência/diagnóstico , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Doenças da Imunodeficiência Primária/terapia , Doenças da Imunodeficiência Primária/diagnósticoRESUMO
In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers.
Assuntos
Agamaglobulinemia , Transplante de Células-Tronco Hematopoéticas , Humanos , Rituximab/uso terapêutico , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoglobulina G , Imunoglobulina ARESUMO
Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only â¼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.
Assuntos
Ligante CD27/deficiência , Doenças Genéticas Inatas , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Doenças Genéticas Inatas/mortalidade , Doenças Genéticas Inatas/terapia , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/terapia , Lactente , Masculino , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Little is known about characteristics of seasonal human coronaviruses (HCoVs) (NL63, 229E, OC43, and HKU1) after allogeneic stem cell transplantation (allo-HSCT). METHODS: This was a collaborative Spanish and European bone marrow transplantation retrospective multicenter study, which included allo-HSCT recipients (adults and children) with upper respiratory tract disease (URTD) and/or lower respiratory tract disease (LRTD) caused by seasonal HCoV diagnosed through multiplex polymerase chain reaction assays from January 2012 to January 2019. RESULTS: We included 402 allo-HSCT recipients who developed 449 HCoV URTD/LRTD episodes. Median age of recipients was 46 years (range, 0.3-73.8 years). HCoV episodes were diagnosed at a median of 222 days after transplantation. The most common HCoV subtype was OC43 (nâ =â 170 [38%]). LRTD involvement occurred in 121 episodes (27%). HCoV infection frequently required hospitalization (18%), oxygen administration (13%), and intensive care unit (ICU) admission (3%). Three-month overall mortality after HCoV detection was 7% in the whole cohort and 16% in those with LRTD. We identified 3 conditions associated with higher mortality in recipients with LRTD: absolute lymphocyte count <0.1 × 109/mL, corticosteroid use, and ICU admission (hazard ratios: 10.8, 4.68, and 8.22, respectively; Pâ <â .01). CONCLUSIONS: Seasonal HCoV after allo-HSCT may involve LRTD in many instances, leading to a significant morbidity.
Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Adolescente , Adulto , Idoso , Betacoronavirus , Criança , Pré-Escolar , Coronavirus Humano 229E , Infecções por Coronavirus/mortalidade , Coronavirus Humano NL63 , Coronavirus Humano OC43 , Feminino , Hospitalização , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/mortalidade , Estudos Retrospectivos , Fatores de Risco , Estações do AnoRESUMO
Bloodstream infections and graft-versus-host disease are common complications after hematopoietic stem cell transplantation (HSCT) procedures, associated with the gut microbiota that acts as a reservoir for opportunistic pathogens. Selective gut decontamination (SGD) and total gut decontamination (TGD) during HSCT have been associated with a decreased risk of developing these complications after transplantation. However, because studies have shown conflicting results, the use of these treatments remains subject of debate. In addition, their impact on the gut microbiota is not well studied. The aim of this study was to elucidate the dynamics of the microbiota during and after TGD and to compare these with the dynamics of SGD. In this prospective, observational, single-center study fecal samples were longitudinally collected from 19 children eligible for allogenic HSCT (TGD, n=12; SGD, n=7), weekly during hospital admission and monthly after discharge. In addition, fecal samples were collected from 3 family stem cell donors. Fecal microbiota structure of patients and donors was determined by 16S rRNA gene amplicon sequencing. Microbiota richness and diversity markedly decreased during SGD and TGD and gradually increased after cessation of decontamination treatment. During SGD, gut microbiota composition was relatively stable and dominated by Bacteroides, whereas it showed high inter- and intraindividual variation and low Bacteroides abundance during TGD. In some children TGD allowed the genera Enterococcus and Streptococcus to thrive during treatment. A gut microbiota dominated by Bacteroides was associated with increased predicted activity of several metabolic processes. Comparing the microbiota of recipients and their donors indicated that receiving an SCT did not alter the patient's microbiota to become more similar to that of its donor. Overall, our findings indicate that SGD and TGD affect gut microbiota structure in a treatment-specific manner. Whether these treatments affect clinical outcomes via interference with the gut microbiota needs to be further elucidated.
Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/métodos , Microbiota/efeitos dos fármacos , Condicionamento Pré-Transplante/métodos , Adolescente , Criança , Pré-Escolar , Descontaminação , Feminino , Humanos , Masculino , Estudos ProspectivosAssuntos
Ataxia Telangiectasia , Transplante de Células-Tronco Hematopoéticas , Imunodeficiência Combinada Severa , Recém-Nascido , Humanos , Ataxia Telangiectasia/diagnóstico , Ataxia Telangiectasia/genética , Triagem Neonatal , Proteínas Mutadas de Ataxia Telangiectasia , Diagnóstico Precoce , Imunodeficiência Combinada Severa/diagnósticoRESUMO
Ewing sarcoma is an aggressive neoplasm predominantly occurring in adolescents and has a poor prognosis when metastasized. For patients with metastatic disease in particular, immunotherapy has been proposed as possible beneficial additive therapy. CCL21 activation-based immunotherapy was successful in preclinical studies in other tumor types; therefore, we investigated CCL21 expression in Ewing sarcoma as potential target for immunotherapy. The CCL21 RNA expression was determined in 21 Ewing sarcoma cell lines and 18 primary therapy-naive Ewing sarcoma samples. In the tumor samples, this was correlated with the number and CD4(+)/CD8(+) ratio of infiltrating T cells and clinical parameters. Higher RNA expression levels of CCL21 significantly correlated with a lower CD4(+)/CD8(+) T cell ratio (P = 0.009), good chemotherapeutic response (P = 0.01) and improved outcome (P < 0.001). In patients with metastases, CCL21 expression was significantly lower than in patients without (P < 0.0005). CCL21 expression was significantly higher in Ewing sarcoma tissue samples compared to cell lines (P < 0.01), implying the involvement of a stromal factor. Protein expression analysis of CCL21 and its receptor CCR7 in 24 therapy-naïve tumors showed that there was no expression in all bar one Ewing sarcoma cells. In conclusion, CCL21 is expressed in clinical Ewing sarcoma samples by nontumor-infiltrating immune cells. The observed positive correlation with survival implies that CCL21 might be a potential prognostic marker for Ewing sarcoma and marks the potential of CCL21 immunotherapy for use in Ewing sarcoma.
Assuntos
Neoplasias Ósseas/genética , Quimiocina CCL21/metabolismo , Sarcoma de Ewing/genética , Neoplasias Ósseas/patologia , Feminino , Humanos , Imunoterapia , Masculino , Sarcoma de Ewing/patologia , Microambiente TumoralRESUMO
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient's hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.
Assuntos
Agamaglobulinemia , Transplante de Células-Tronco Hematopoéticas , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Adolescente , Anemia Falciforme/terapia , Anemia Falciforme/imunologia , Linfócitos B/imunologia , Quimeras de Transplante , Antígenos HLA/imunologia , Antígenos HLA/genéticaRESUMO
Recombinase-activating gene (RAG)-deficient SCID patients lack B and T lymphocytes due to the inability to rearrange immunoglobulin and T cell receptor genes. The two RAG genes act as a required dimer to initiate gene recombination. Gene therapy is a valid treatment alternative for RAG-SCID patients who lack a suitable bone marrow donor, but developing such therapy for RAG1/2 has proven challenging. Using a clinically approved lentiviral vector with a codon-optimized RAG1 gene, we report here preclinical studies using CD34+ cells from four RAG1-SCID patients. We used in vitro T cell developmental assays and in vivo assays in xenografted NSG mice. The RAG1-SCID patient CD34+ cells transduced with the RAG1 vector and transplanted into NSG mice led to restored human B and T cell development. Together with favorable safety data on integration sites, these results substantiate an ongoing phase I/II clinical trial for RAG1-SCID.
RESUMO
High-grade osteosarcoma has a poor prognosis with an overall survival rate of about 60 percent. The recently closed European and American Osteosarcoma Study Group (EURAMOS)-1 trial investigates the efficacy of adjuvant chemotherapy with or without interferon-α. It is however unknown whether the interferon-signaling pathways in immune cells of osteosarcoma patients are functional. We studied the molecular and functional effects of interferon treatment on peripheral blood lymphocytes and monocytes of osteosarcoma patients, both in vivo and ex vivo. In contrast to other tumor types, in osteosarcoma, interferon signaling as determined by the phosphorylation of signal transducer and activator of transcription (STAT)1 at residue 701 was intact in immune cell subsets of 33 osteosarcoma patients as compared to 19 healthy controls. Also, cytolytic activity of interferon-α stimulated natural killer cells against allogeneic (n = 7 patients) and autologous target cells (n = 3 patients) was not impaired. Longitudinal monitoring of three osteosarcoma patients on interferon-α monotherapy revealed a relative increase in the CD16-positive subpopulation of monocytes during treatment. Since interferon signaling is intact in immune cells of osteosarcoma patients, there is a potential for indirect immunological effects of interferon-α treatment in osteosarcoma.
Assuntos
Neoplasias Ósseas/imunologia , Interferon-alfa/imunologia , Leucócitos Mononucleares/imunologia , Osteossarcoma/imunologia , Transdução de Sinais/imunologia , Adolescente , Adulto , Neoplasias Ósseas/tratamento farmacológico , Criança , Feminino , Humanos , Interferon-alfa/uso terapêutico , Células K562 , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Osteossarcoma/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Adulto JovemRESUMO
Ewing sarcoma is an aggressive round cell sarcoma with poor patient prognosis, particularly in cases of advanced-stage disease. Dynamic tumor-host immune interations within the tumor microenvironment may polarize in situ immune responses and shape tumor development and/or progression. To gain insight into the nature of tumour-host immune interactions within the Ewing sarcoma microenvironment, the presence and spatial distribution of infiltrating CD8(+) /CD4(+) T-lymphocytes were evaluated in therapy-naive Ewing sarcoma. Expression profiling of 40 different chemokines and several chemokine receptors was performed in therapy-naive tumours and cell lines by qPCR, immunohistochemistry, and flow cytometry. Considerable inter-tumour variation was observed regarding density, type, and distribution of infiltrating T-lymphocytes. Tumour-infiltrating T-cells contained significantly higher percentages of CD8(+) T-lymphocytes as compared to stroma-infiltrating cells, suggesting preferential migration of this T-cell type into tumour areas. Gene expression levels of several type 1-associated, pro-inflammatory chemokines (CXCR3- and CCR5-ligands CXCL9, CXCL10, and CCL5) correlated positively with infiltrating (CD8(+) ) T-lymphocyte numbers expressing corresponding chemokine receptors. Survival analyses demonstrated an impact of tumour-infiltrating, and not stroma-infiltrating, CD8(+) T-lymphocytes on tumour progression. At protein level, both tumour and stromal cells expressed the IFNγ-inducible chemokines CXCL9 and CXCL10. CCR5-ligand CCL5 was exclusively expressed by non-tumoural stromal/infiltrating cells. Together, our results indicate that an inflammatory immune microenvironment with high expression of type 1-associated chemokines may be critical for the recruitment of (CD8(+) ) T-lymphocytes expressing corresponding chemokine receptors. The observed impact of tumour-infiltrating (CD8(+) ) T-lymphocytes is consistent with a role for adaptive anti-tumour immunity in the prevention of Ewing sarcoma progression. Recognition of the merits and exploitation/induction of an inflammatory microenvironment may improve the efficacy of natural immune responses against, and (adoptive) immunotherapeutic approaches for, Ewing sarcoma.
Assuntos
Neoplasias Ósseas/imunologia , Mediadores da Inflamação/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Receptores de Quimiocinas/metabolismo , Sarcoma de Ewing/imunologia , Adolescente , Adulto , Linfócitos T CD8-Positivos/imunologia , Criança , Pré-Escolar , Progressão da Doença , Perfilação da Expressão Gênica/métodos , Humanos , Interferon gama/biossíntese , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase/métodos , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/imunologiaRESUMO
Treosulfan-based conditioning has gained popularity in pediatric allogeneic hematopoietic stem cell transplantation (HSCT) because of its presumed favorable efficacy and toxicity profile. Treosulfan is used in standardized dosing regimens based on body surface area. The relationships between systemic treosulfan exposure and early and long-term clinical outcomes in pediatric patients undergoing allogeneic HSCT for nonmalignant diseases remain unclear. In this a multicenter, prospective observational study, we assessed the association between treosulfan exposure and early and, in particular, long-term clinical outcomes. Our study cohort comprised 110 pediatric patients with nonmalignant diseases who underwent HSCT between 2011 and 2019 in Leiden, The Netherlands and Rome, Italy. Blood samples were collected, and treosulfan area under the receiver operating characteristic curve (AUC0-∞) was estimated as a measure of exposure. Cox proportional hazard survival analyses were performed to assess the relationships between treosulfan exposure and overall survival (OS) and event-free survival (EFS). The predictive value of systemic treosulfan exposure for the occurrence of toxicity within 28 days was evaluated using a multivariable logistic regression analysis. In the overall cohort, OS and EFS at 2 years were 89.0% and 75.3%, respectively, with an excellent OS of 97% in children age <2 years. The occurrence of grade II-IV acute graft-versus-host disease, the level of 1-year whole blood chimerism, and 2-year OS and EFS were not correlated with treosulfan exposure. The occurrence of skin toxicity (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.26-13.68; P = .02) and all-grade mucositis (OR, 4.43; 95% CI, 1.43-15.50; P = .02), but not grade ≥2 mucositis (OR, 1.51; 95% CI, 0.52 to 4.58; P = .46) was related to high treosulfan exposure (>1750 mg*h/L). Our study demonstrates that standardized treosulfan-based conditioning results in a favorable OS and EFS in infants and children with nonmalignant diseases, independent of interindividual variation in treosulfan exposure. These outcomes can be achieved without the need for therapeutic drug monitoring, thereby emphasizing the advantage of treosulfan use in this category of patients. Although higher treosulfan exposure increases the risk of skin toxicity, there is no absolute necessity for therapeutic drug monitoring if proper preventive skin measures are taken. More research is needed to assess whether deescalation of treosulfan doses is possible to minimize early and long-term toxicity without compromising efficacy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucosite , Bussulfano/análogos & derivados , Criança , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Mucosite/etiologia , Estudos Prospectivos , Condicionamento Pré-Transplante/efeitos adversosRESUMO
High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell-mediated therapies for chemotherapy-resistant and chemotherapy-sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell-mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell-mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient-derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell-activating agents in patients with high-grade osteosarcoma.
Assuntos
Neoplasias Ósseas/imunologia , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Osteossarcoma/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação de Linfócitos T/metabolismo , Neoplasias Ósseas/metabolismo , Separação Celular , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunoterapia Adotiva/métodos , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Osteossarcoma/metabolismo , Análise Serial de TecidosRESUMO
Up to 10% of hospitalized patients have an antibiotic allergy label in their medical file, most frequently concerning penicillins. However, the vast majority of reported allergies to antibiotics does not represent a "true" allergy but are due to drug intolerance, idiosyncratic reactions or symptoms of the concurrent infectious disease. Since antibiotic allergy labels result in deviation from first-choice antimicrobial therapy, tackling the issue of incorrect antibiotic allergy labelling, already at young age, is a core element of antibiotic stewardship. In this article, we describe the structured approach to the patient with a presumed antibiotic allergy with emphasis on key elements of allergy-specific history taking and the limited risk of cross-allergic reactions between beta-lactam subclasses.
Assuntos
Antibacterianos/efeitos adversos , Gestão de Antimicrobianos , Hipersensibilidade a Drogas/diagnóstico , Algoritmos , Criança , Pré-Escolar , Reações Cruzadas , Humanos , Hipersensibilidade Tardia/diagnóstico , Hipersensibilidade Imediata/diagnóstico , Anamnese/métodos , beta-Lactamas/efeitos adversosRESUMO
Reduced total and memory B-cell numbers in peripheral blood long term after hematopoietic stem cell transplantation (HSCT) are associated with an increased incidence of infections and immune complications. Using novel modelling strategies, baseline factors influencing B-cell reconstitution can be comprehensively studied. This study aims to investigate the numerical total and memory B-cell reconstitution in children and the association with baseline determinants 0.5-2 years after allogeneic HSCT. Eligible for inclusion were children transplanted in our center between 2004-2017 who received a first HSCT for malignant or non-malignant disorders. The continuous absolute counts of total and memory B-cells were evaluated as outcome measure. Exploratory analysis at one year was done to identify possible determinants. Linear mixed effect modelling was used to analyze the association of these determinants with total and memory B-cell reconstitution 0.5-2 years after HSCT. In a cohort of 223 evaluable patients analyzed at 1-year after HSCT donor age, stem cell source, donor type, recipient age and conditioning were identified as significant determinants for total and memory B-cell numbers. Multivariable analysis revealed that both donor and recipient age were inversely correlated with the size of total and memory B-cell reconstitution. In contrast, no correlation was found with stem cell source, donor type and conditioning. Making use of linear mixed modelling both stem cell donor and recipient age were identified as independent determinants of total and memory B-cell reconstitution 0.5-2 years after HSCT.
Assuntos
Linfócitos B/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Reconstituição Imune , Adolescente , Fatores Etários , Linfócitos B/metabolismo , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Lactente , Infecções/etiologia , Modelos Lineares , Masculino , Análise Multivariada , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosRESUMO
Treosulfan is increasingly used as myeloablative agent in conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). In our pediatric HSCT program, myalgia was regularly observed after treosulfan-based conditioning, which is a relatively unknown side effect. Using a natural language processing and text-mining tool (CDC), we investigated whether treosulfan compared with busulfan was associated with an increased risk of myalgia. Furthermore, among treosulfan users, we studied the characteristics of given treatment of myalgia, and studied prognostic factors for developing myalgia during treosulfan use. Electronic Health Records (EHRs) until 28 days after HSCT were screened using the CDC for myalgia and 22 synonyms. Time to myalgia, location of pain, duration, severity and drug treatment were collected. Pain severity was classified according to the WHO pain relief ladder. Logistic regression was performed to assess prognostic factors. 114 patients received treosulfan and 92 busulfan. Myalgia was reported in 37 patients; 34 patients in the treosulfan group and 3 patients in the busulfan group (p = 0.01). In the treosulfan group, median time to myalgia was 7 days (0-12) and median duration of pain was 19 days (4-73). 44% of patients needed strong acting opiates and adjuvant medicines (e.g. ketamine). Hemoglobinopathy was a significant risk factor, as compared to other underlying diseases (OR 7.16 95% CI 2.09-30.03, p = 0.003). Myalgia appears to be a common adverse effect of treosulfan in pediatric HSCT, especially in hemoglobinopathy. Using the CDC, EHRs were easily screened to detect this previously unknown side effect, proving the effectiveness of the tool. Recognition of treosulfan-induced myalgia is important for adequate pain management strategies and thereby for improving the quality of hospital stay.
Assuntos
Bussulfano/análogos & derivados , Mineração de Dados/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Mialgia/diagnóstico , Condicionamento Pré-Transplante/efeitos adversos , Adolescente , Bussulfano/efeitos adversos , Criança , Pré-Escolar , Registros Eletrônicos de Saúde/estatística & dados numéricos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Masculino , Mialgia/induzido quimicamente , Mialgia/epidemiologia , Medição da Dor/estatística & dados numéricos , Estudos Retrospectivos , Índice de Gravidade de Doença , Condicionamento Pré-Transplante/métodosRESUMO
Objective: Inborn errors of immunity (IEI) are a heterogeneous group of disorders, affecting different components of the immune system. Over 450 IEI related genes have been identified, with new genes continually being recognized. This makes the early application of next-generation sequencing (NGS) as a diagnostic method in the evaluation of IEI a promising development. We aimed to provide an overview of the diagnostic yield and time to diagnosis in a cohort of patients suspected of IEI and evaluated by an NGS based IEI panel early in the diagnostic trajectory in a multicenter setting in the Netherlands. Study Design: We performed a prospective observational cohort study. We collected data of 165 patients with a clinical suspicion of IEI without prior NGS based panel evaluation that were referred for early NGS using a uniform IEI gene panel. The diagnostic yield was assessed in terms of definitive genetic diagnoses, inconclusive diagnoses and patients without abnormalities in the IEI gene panel. We also assessed time to diagnosis and clinical implications. Results: For children, the median time from first consultation to diagnosis was 119 days versus 124 days for adult patients (U=2323; p=0.644). The median turn-around time (TAT) of genetic testing was 56 days in pediatric patients and 60 days in adult patients (U=1892; p=0.191). A definitive molecular diagnosis was made in 25/65 (24.6%) of pediatric patients and 9/100 (9%) of adults. Most diagnosed disorders were identified in the categories of immune dysregulation (n=10/25; 40%), antibody deficiencies (n=5/25; 20%), and phagocyte diseases (n=5/25; 20%). Inconclusive outcomes were found in 76/165 (46.1%) patients. Within the patient group with a genetic diagnosis, a change in disease management occurred in 76% of patients. Conclusion: In this cohort, the highest yields of NGS based evaluation for IEI early in the diagnostic trajectory were found in pediatric patients, and in the disease categories immune dysregulation and phagocyte diseases. In cases where a definitive diagnosis was made, this led to important disease management implications in a large majority of patients. More research is needed to establish a uniform diagnostic pathway for cases with inconclusive diagnoses, including variants of unknown significance.