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Precise manipulation of flexible surgical tools is crucial in minimally invasive surgical procedures, necessitating a miniature and flexible robotic probe that can precisely direct the surgical instruments. In this work, we developed a polymer-based robotic fiber with a thermal actuation mechanism by local heating along the sides of a single fiber. The fiber robot was fabricated by highly scalable fiber drawing technology using common low-cost materials. This low-profile (below 2 millimeters in diameter) robotic fiber exhibits remarkable motion precision (below 50 micrometers) and repeatability. We developed control algorithms coupling the robot with endoscopic instruments, demonstrating high-resolution in situ molecular and morphological tissue mapping. We assess its practicality and safety during in vivo laparoscopic surgery on a porcine model. High-precision motion of the fiber robot delivered endoscopically facilitates the effective use of cellular-level intraoperative tissue identification and ablation technologies, potentially enabling precise removal of cancer in challenging surgical sites.
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Laparoscopía , Procedimientos Quirúrgicos Robotizados , Robótica , Porcinos , Animales , Procedimientos Quirúrgicos Robotizados/métodos , Laparoscopía/métodos , Procedimientos Quirúrgicos Mínimamente InvasivosRESUMEN
Magnusiomyces clavatus is a rare yeast-like fungus that can cause opportunistic infections in immunocompromised patients. Here, we present a 14-year-old patient who was followed up with the diagnosis of acute lymphoblastic leukemia, developed skin rashes, and Magnusiomyces clavatus infection detected. The patient died shortly after the infection was diagnosed.
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Exantema , Leucemia-Linfoma Linfoblástico de Células Precursoras , Saccharomycetales , Niño , Humanos , Adolescente , Hongos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Exantema/etiologíaRESUMEN
Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.
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Canalopatías , Humanos , Autopsia , Canalopatías/diagnóstico , Canalopatías/genética , Canalopatías/complicaciones , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/patología , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Arritmias Cardíacas/complicaciones , MutaciónRESUMEN
BACKGROUND: Purine nucleoside phosphorylase (PNP) deficiency is a rare autosomal recessive combined immunodeficiency. The phenotype is profound T cell deficiency with variable B and NK cell functions and results in recurrent and persistent infections that typically begin in the first year of life. Neurologic findings occur in approximately two-thirds of patients. The mechanism of neurologic abnormalities is unclear. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for PNP deficiency. METHODS: We report here six patients from five unrelated families with PNP deficiency treated in two centers in Turkey. We evaluated the neurological status of patients and compared to post-transplantation period if available. Then, we performed PubMed, Google Scholar, and Researchgate searches using the terms "PNP" and "hematopoietic stem cell transplantation" to find all reported cases of PNP transplantation and compared to our cohort. RESULTS: Six patients were treated in two centers in Turkey. One patient died from post-transplant complications. The other four patients underwent successful HSCT with good immune reconstitution after transplantation (follow-up 21-48 months) and good neurological outcomes. The other patient with a new mutation is still waiting for a matching HLA donor. DISCUSSION: In PNP deficiency, clinical manifestations are variable, and this disease should be considered in the presence of many different clinical findings. Despite the comorbidities that occurred before transplantation, HSCT currently appears to be the only treatment option for this disease. HSCT not only cures immunologic disorders, but probably also improves or at least stabilizes the neurologic status of patients.
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Trasplante de Células Madre Hematopoyéticas , Enfermedades de Inmunodeficiencia Primaria , Errores Innatos del Metabolismo de la Purina-Pirimidina , Humanos , Purina-Nucleósido Fosforilasa/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedades de Inmunodeficiencia Primaria/diagnóstico , Enfermedades de Inmunodeficiencia Primaria/terapia , Enfermedades de Inmunodeficiencia Primaria/etiología , Errores Innatos del Metabolismo de la Purina-Pirimidina/terapiaRESUMEN
Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome with diverse clinical manifestations leading to major diagnostic and therapeutic difficulties. This study aimed to evaluate clinical manifestations, prognostic factors, and long-term outcomes in children with primary HLH. Forty-one patients diagnosed with primary HLH were retrospectively evaluated for patient characteristics, HLH gene mutations, clinical and laboratory manifestations, prognostic factors, and long-term outcomes. The median age of the patients at the time of diagnosis was 3 months (minimum to maximum: 1 to 144 mo). There were 23 patients who had HLH mutation analysis performed, 10 patients with PRF1 mutation, 6 with STX11 mutation, and 7 with UNC13D mutation. Thirteen patients (31.7%) had central nervous system involvement. No correlation was found between overall survival and central nervous system involvement. The estimated 5-year overall survival for the patient who had hematopoietic stem cell transplantation was 9.4 times better than the patients who did not receive hematopoietic stem cell transplantation (81.3% vs 16.7%; P = 0.001). Median serum sodium and blood urea nitrogen levels were significantly higher in deceased HLH patients compared with surviving HLH patients ( P = 0.043, and P = 0.017, respectively). Primary HLH has a poor outcome with high mortality, which necessitates well-designed and international clinical trials to improve diagnosis, therapy, and long-term outcomes.
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Linfohistiocitosis Hemofagocítica , Niño , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/terapia , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Pronóstico , Estudios Retrospectivos , Perforina/genética , Mutación , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: Respiratory viral infections (RVIs) are important complications in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT); however, risk factors for lower respiratory tract infections (LRTIs) are not well characterized. The aim of this study was to determine risk factors for the progression to LRTIs in pediatric patients with respiratory symptoms who underwent HSCT. PATIENTS AND METHODS: This retrospective study included 87 pediatric patients with respiratory symptoms who underwent HSCT. Respiratory viral polymerase chain reaction samples were obtained from all patients. The evaluated data included risk factors to progression to LRTIs, long-term pulmonary complications, transplantation-related mortality, and overall survival. RESULTS: Viral pathogens were detected in 31 (48.4%) patients with upper respiratory tract infections and 13 (56.5%) patients with LRTIs. There was a statistically significant difference between the groups in engraftment delay and lymphocytopenia. Also it was determined that engraftment delay (odds ratio: 7.46 [95% CI, 1.99 to 27.86]; P = 0.003) and COVID-19 infection had statistically significant effects on overall survival in general (odds ratio: 8.06 [95% CI, 2.63 to 24.64]; P <0.001]). CONCLUSION: Not only host and transplant-related factors but also viral agent type were found to be effective in progression to LRTIs. As the available therapy for respiratory viral infections remains limited, the focus should be on the prevention of infection.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Infecciones del Sistema Respiratorio , Humanos , Niño , Estudios Retrospectivos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de RiesgoRESUMEN
Multisystem inflammatory syndrome in children (MIS-C) is rare, however, severe hyperinflammatory condition in children generally weeks after acute SARS-CoV-2 infection. A subset of MIS-C patients is presented with severe heart failure. We hereby report 8-year-old girl presenting acute severe left ventricular failure. Various medical treatments including inotropic agents and drugs related to SARS-CoV-2 infection and MIS-C were applied. However, venoarterial extracorporeal membrane oxygenation (ECMO) was needed to be performed. Due to unsuccessful attempts for ECMO weaning, left ventricular assist device was implanted to the patient with temporary right ventricular support from ECMO.
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COVID-19 , Insuficiencia Cardíaca , Corazón Auxiliar , COVID-19/complicaciones , Niño , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/terapia , Humanos , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Síndrome de Respuesta Inflamatoria Sistémica/terapiaRESUMEN
OBJECTIVES: Sinusoidal obstruction syndrome/venoocclusive disease is a significant complication of hematopoietic stem cell transplantation. Due to high mortality rates, new treatment strategies have been investigated. Here, we have presented outcomes of therapeutic plasma exchange performed on patients with sinusoidal obstruction syndrome/veno-occlusive disease. MATERIAL AND METHODS: Our study included 70 pediatric patients diagnosed with sinusoidal obstruction syndrome/veno-occlusive disease. Therapeutic plasma exchange procedures in patients were evaluated retrospectively. RESULTS: There were 9 mild (12.9%), 9 moderate (12.9%), 21 severe (30%), and 31 very severe (44.2%) cases of sinusoidal obstruction syndrome/venoocclusive disease. Therapeutic plasma exchange was performed in 31 of the 70 study patients (59.6%). Moreover, 10/21 patients with severe (47.6%) and 21/31 patients with very severe (67.7%) disease underwent plasma exchange. Mean time from diagnosis of sinusoidal obstruction syndrome/venoocclusive disease to therapeutic plasma exchange initiation was 2.3 days. The 31 patients who received therapeutic plasma exchange had a total of 146 sessions. Overall survival rates at 100 days were 87.1% and 92.3% for patients who did and did not undergo therapeutic plasma exchange, respectively. When patients with mild and moderate disease who were not expected to undergo plasma exchange were excluded (n = 52), 100-day overall survival rates were 87.1% and 90.5% for those who did and did not undergo plasma exchange, respectively. When we compared severe versus very severe groups, no significant difference was found. CONCLUSIONS: Plasmapheresis had no positive effect on survival. However, overall survival in all groups was higher than that in the literature, despite the high number of patients with severe and very severe disease. Interpretation of the results is limited by the retrospective nature of the study. Thus, prospective, randomized controlled trials with larger numbers of patients are necessary to investigate the role of therapeutic plasma exchange in patients with sinusoidal obstruction syndrome/veno-occlusive disease.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/terapia , Humanos , Intercambio Plasmático/efectos adversos , Plasmaféresis/efectos adversos , Estudios Prospectivos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
INTRODUCTION: In highly sensitized patients who have panel reactive antibodies (PRAs) before hematopoietic stem cell transplantation, primary graft failure risk may increase. In this study, we aimed to determine the association of PRA with engraftment, and graft versus host disease (GVHD) in pediatric patients. MATERIALS AND METHODS: Forty-three PRA-positive and 42 PRA-negative patients were taken into study. Both groups were compared in terms of graft failure, acute GVHD, viral infection and survival rates. PRA-positive group was also divided into 2 according to treatment modality (steroid-only group/combination therapy) and compared for the same parameters. RESULTS: There was no difference in PRA-positive and negative patients in terms of graft failure, acute GVHD and viral infections. Analysis of the PRA-positive group in itself showed that there was also no difference in terms of graft failure and viral infection frequency. The only difference is that acute grade 3 to 4 GVHD was higher in the steroid-only group. The 100-day overall survival was 90.2% and 90.4% for the PRA-positive and negative groups, respectively. CONCLUSIONS: Different treatment strategies like plasmapheresis, steroid, rituximab, or combination therapies can be used for the desensitization of PRA-positive patients before hematopoietic stem cell transplantation. Patient-specific treatment modality for sensitized patients before transplant can increase the success rate.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Niño , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA , Prueba de Histocompatibilidad , HumanosRESUMEN
OBJECTIVES: The mostimportant problems thatlimitthe effectiveness of allogeneic hematopoietic stem cell transplantation in patients with severe aplastic anemia are graft failure and graft-versus-host disease. Mesenchymal stem cells can support normal hematopoiesis and prevent graft-versus-host disease. We aimed to analyze the effects of combined transplant of human umbilical cord-derived mesenchymal stem cells and matched donor allogeneic hematopoietic stem cells in children with severe aplastic anemia. MATERIALS AND METHODS: We retrospectively examined 15 pediatric patients with severe aplastic anemia who received fludarabine-based reduced intensity conditioning regimen and intravenously infused human umbilical cord-derived mesenchymal stem cells at a dose of 1 × 106/kg recipient body weight within 12 to 18 hours before hematopoietic stem cells infusion. We evaluated the engraftment rate, the frequency and severity of graft-versus-host disease, and the overall survival rate. RESULTS: No patients had adverse events related to intravenously human umbilical cord-derived mesenchymal stem cells infusion. All patients achieved successful engraftment and sustained donor chimerism. The median time for neutrophil and platelet engraftment was 14 and 25 days,respectively. The frequency was 20% for grade III/IV acute graftversus- host disease and 15.3% for chronic graftversus-host disease. Patients were followed-up for a median of 33 months (range, 2-89 months). The 5-year overall survival rate was 80%. CONCLUSIONS: Combined transplant of matched donor hematopoietic stem cells with human umbilical cord-derived mesenchymal stem cells is safe in pediatric patients with severe aplastic anemia. The achievement of engraftment in all of our patients and the acceptable frequency of acute and chronic graft-versus-host disease and survival rate are encouraging.
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Anemia Aplásica , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Células Madre Mesenquimatosas , Humanos , Niño , Anemia Aplásica/diagnóstico , Anemia Aplásica/cirugía , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Aguda , Cordón UmbilicalRESUMEN
BACKGROUND/AIMS: The aim of this study is to share autopsy findings of COVID-19-positive cases and autopsy algorithms for safely handling of suspicious bodies during this pandemic. METHODS: COVID-19-positive cases of Istanbul Morgue Department were retrospectively analyzed. Sampling indications for PCR tests in suspicious deaths, macroscopic and microscopic findings obtained in cases with positive PCR tests were evaluated. RESULTS: In the morgue department, 345(25.8%) of overall 1336 autopsy cases were tested for COVID-19. PCR test was found positive in 26 cases. Limited autopsy procedure was performed in 7 cases, while the cause of death was determined by external examination in the remaining 19 cases. Male-to-female ratio was found 3.3:1 and mean age was 60.0 ± 13.6 among all PCR-positive cases. Cause of death was determined as viral pneumonia in fully autopsied cases. Most common findings were sticky gelatinous fluid in cavities and firm and swollen lungs, varying degrees of consolidation. In microscopy, diffuse alveolar epithelial damage, type-II pneumocyte hyperplasia, hyaline membrane formation, fibrinous exudate, and fibrinous plaques in the alveoli were the most common findings. CONCLUSIONS: In COVID-19 autopsies, pulmonary findings were found to be prominent and the main pathology was pneumonia. Older age and findings of chronic diseases indicate that the cases were in the multirisk group in terms of COVID-19 mortality.
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COVID-19 , Neumonía Viral , Anciano , Autopsia , Femenino , Humanos , Pulmón/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , SARS-CoV-2RESUMEN
BACKGROUND: Haploidentical HSCT is a good option for children with PIDs lacking an HLA-matched donor. Co-transplantation of MSCs during haploidentical HSCT in patients with PIDs may enhance engraftment, decrease the risk of GVHD, and ensure stable donor chimerism. METHODS: Twenty-seven pediatric patients (median age, 1.4 years; range, .3-10.9) with PIDs undergoing thirty haploidentical HSCT with TCR αß depletion and co-transplantation of MSCs were enrolled to study. Most patients (73.3%) received myeloablative conditioning consisting of treosulfan or busulfan, fludarabine, and thiotepa. The median duration of follow-up was 14.3 months (range, 1-69 months). RESULTS: Acute GVHD occurred in 7 patients (grade I-II n = 5, grade III-IV n = 2). Chronic GVHD was observed in only one patient. Twenty-one patients (70.2%) had 100% donor chimerism in all cell lines including T-cell and B-cell lineages. Primary graft failure was observed in 7 patients (25.9%). The cumulative incidences of TRM were 20% at day 100, and 26.7% at one year and five years. Probabilities of OS were 80% at day 100, and 71.9% at 1 year and 5 years. Infants transplanted younger than 6 months of age had the highest 5-year survival rate (85.7%). CONCLUSION: We conclude that use of TCR αß depleted haploidentical transplantation with MSCs may ensure a rapid engraftment rate, low incidence of significant acute and chronic GVHD, and acceptable post-transplantation morbidity, especially in patients diagnosed with SCID and may be considered in children with PIDs. In younger patients (≤6 months), survival is comparable between HLA-matched graft and CD3+ TCRαß depleted HLA-mismatched graft recipients.
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Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Mesenquimatosas , Enfermedades de Inmunodeficiencia Primaria/terapia , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Acondicionamiento Pretrasplante/métodos , Niño , Preescolar , Femenino , Rechazo de Injerto , Humanos , Lactante , MasculinoRESUMEN
Objective: This study aimed to evaluate systemic thrombolysis experiences with recombinant tissue plasminogen activator (rtPA). Materials and Methods: Retrospective data were collected from 13 Turkish pediatric hematology centers. The dose and duration of rtPA treatment, concomitant anticoagulant treatment, complete clot resolution (CCR), partial clot resolution (PCR), and bleeding complications were evaluated. Low-dose (LD) rtPA treatment was defined as 0.01-0.06 mg/kg/h and high-dose (HD) rtPA as 0.1-0.5 mg/kg/h. Results: Between 2005 and 2019, 55 thrombotic episodes of 54 pediatric patients with a median age of 5 years (range: 1 day to 17.75 years) were evaluated. These patients had intracardiac thrombosis (n=16), deep vein thrombosis (DVT) (n=15), non-stroke arterial thrombosis (n=14), pulmonary thromboembolism (PE) (n=6), and stroke (n=4). The duration from thrombus detection to rtPA initiation was a median of 12 h (range: 2-504 h) and it was significantly longer in cases of DVT and PE compared to stroke, non-stroke arterial thrombosis, and intracardiac thrombosis (p=0.024). In 63.6% of the episodes, heparin was initiated before rtPA treatment. LD and HD rtPA were administered in 22 and 33 of the episodes, respectively. Concomitant anticoagulation was used in 90% and 36% of the episodes with LD and HD rtPA, respectively (p=0.0001). Median total duration of LD and HD rtPA infusions was 30 h (range: 2-120 h) and 18 h (2-120 h), respectively (p=0.044). Non-fatal major and minor bleeding rates were 12.5% and 16.7% for LD and 3.2% and 25.8% for HD rtPA, respectively. At the end of the rtPA infusions, CCR and PCR were achieved in 32.7% and 49.0% of the episodes, respectively. The most successful site for thrombolysis was intracardiac thrombosis. HD versus LD rtPA administration was not correlated with CCR/PCR or bleeding (p>0.05). Conclusion: Systemic thrombolytic therapy may save lives and organs effectively if it is used at the right indications and the right times in children with high-risk thrombosis by experienced hematologists with close monitoring of recanalization and bleeding.
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Terapia Trombolítica , Trombosis , Activador de Tejido Plasminógeno , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Estudios Retrospectivos , Trombosis/tratamiento farmacológico , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
BACKGROUND: Anti-human T-lymphocyte immunoglobulin is commonly used as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. The studies according to optimum dose of ATLG especially in pediatric patients are limited. PATIENTS AND METHODS: Outcomes of 99 pediatric patients diagnosed with nonmalignant diseases, who received ATLG as GVHD prophylaxis for matched unrelated donor HSCT at a dose of 10 mg/kg (group 1), 20 mg/kg (group 2), and 30 mg/kg (group 3), were analyzed retrospectively. RESULTS: The incidences of acute and chronic GVHD were statistically not different between three groups (p = .20 and p = .13), but we did not observe chronic GVHD in group 3 patients. Cox regression analysis showed that ATLG dose of 10 mg/kg (p = .007) and severe acute GVHD (p = .001) were significant prognostic factors for inferior overall survival. Although ATLG dose of 10 mg/kg is effective in pediatric patients on acute and chronic GVHD prevention, TRM and overall survival were superior in ATLG doses ≥20 mg/kg (p = .04 and p = .037) with no difference between 20 and 30 mg/kg. CONCLUSION: Although ATLG dose of 10 mg/kg is effective in pediatric patients on acute and chronic GVHD prevention and safe from the point of infection, TRM and OS were superior in ATLG doses ≥20 mg/kg with no difference between 20 and 30 mg/kg. These observations should be supported with other multicenter prospective studies including larger patient population.
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Suero Antilinfocítico/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Donante no EmparentadoRESUMEN
Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.
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PURPOSE: Patients with heterozygous gain-of-function (GOF) mutations in STAT1 frequently exhibit chronic mucocutaneous candidiasis (CMC), immunodeficiency and autoimmune manifestations. Several treatment options including targeted therapies and hematopoietic stem cell transplantation (HSCT) are available for STAT1 GOF patients but modalities and outcomes are not well established. Herein, we aimed to unravel the effect of ruxolitinib as a bridge therapy in a patient with sporadic STAT1 T385M mutation to manage infections and other disease manifestations. METHODS: Peripheral blood mononuclear cells were isolated from the patient prior to, during ruxolitinib treatment and 6 months after HSCT. IFN-ß-induced STAT1 phosphorylation/dephosphorylation levels and PMA/ionomycin-stimulated intracellular IL-17A/IFN-γ production in CD4+ T cells were evaluated. Differentially expressed genes between healthy controls and the patient prior to, during ruxolitinib treatment and post-transplantation were investigated using Nanostring nCounter Profiling Panel. RESULTS: Ruxolitinib provided favorable responses by controlling candidiasis and autoimmune hemolytic anemia in the patient. Dysregulation in STAT1 phosphorylation kinetics improved with ruxolitinib treatment and was completely normalized after transplantation. TH17 deficiency persisted after ruxolitinib treatment, but normalized following HSCT. Consistent with the impairment in JAK/STAT signaling, multiple immune related pathways were found to be dysregulated in the patient. At baseline, genes related to type I IFN-related pathways, antigen processing, T-cell and B-cell functions were upregulated, while NK-cell function and cytotoxicity related genes were downregulated. Dysregulated gene expression was partially improved with ruxolitinib treatment and normalized after transplantation. CONCLUSION: Our findings suggest that improved disease management and immune dysregulatory profile can be achieved with ruxolitinib treatment before transplantation and this would be beneficial to reduce the risk of adverse outcome of HSCT.
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Mutación con Ganancia de Función , Trasplante de Células Madre Hematopoyéticas , Enfermedades del Sistema Inmune/etiología , Enfermedades del Sistema Inmune/terapia , Inhibidores de las Cinasas Janus/uso terapéutico , Nitrilos/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Factor de Transcripción STAT1/genética , Alelos , Preescolar , Terapia Combinada , Citocinas/metabolismo , Diagnóstico Diferencial , Femenino , Genotipo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Enfermedades del Sistema Inmune/diagnóstico , Inmunofenotipificación , Fenotipo , Fosforilación , Factor de Transcripción STAT1/metabolismo , Resultado del TratamientoRESUMEN
Mesenchymal stem cells (MSCs) have been used systemically or locally in many chronic and nonhealing skin lesions in recent years. In this study, umbilical cord-derived MSCs (UC-MSCs)-seeded fibrin matrix was used as a wound dressing in pediatric patients with stage 4 acute graft-versus-host disease (aGVHD)-induced desquamated skin lesions. This is the first study in which the UC-MSCs-seeded fibrin matrix was used as a wound dressing in aGVHD. A total of 14 times the MSCs-seeded fibrin matrix were applied to 9 patients as a wound dressing. On the seventh day, epithelialization and clinical response were evaluated. According to the size of the skin defect min: 1, max: 6 pieces were applied at a time. After 48 to 72 hours, it was observed that all of the MSCs-seeded fibrin matrixes adhered to the skin and the crustation started in 6 (43%) applications, whereas liquefaction was detected under all of them in 7 (50%) applications. Complete response was obtained in 6 applications (43%), partial response in 1 (7%), and no response in 7 applications (50%). This study showed that the MSCs-seeded fibrin matrix can be used effectively and safely in the matrix in the local treatment of aGVHD-induced skin wounds in pediatric patients.
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Fibrina/química , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre Mesenquimatosas , Andamios del Tejido/química , Cordón Umbilical/citología , Adolescente , Vendajes , Células Cultivadas , Niño , Preescolar , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Masculino , Células Madre Mesenquimatosas/citología , Estudios Prospectivos , Piel/patología , Cicatrización de HeridasRESUMEN
BACKGROUND: Post-transplant relapse has a dismal prognosis in children with acute leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Data on risk factors, treatment options, and outcomes are limited. PROCEDURE: In this retrospective multicenter study in which a questionnaire was sent to all pediatric transplant centers reporting relapse after allo-HSCT for a cohort of 938 children with acute leukemia, we analyzed 255 children with relapse of acute leukemia after their first allo-HSCT. RESULTS: The median interval from transplantation to relapse was 180 days, and the median follow-up from relapse to the last follow-up was 1844 days. The 3-year overall survival (OS) rate was 12.0%. The main cause of death was disease progression or subsequent relapse (82.6%). The majority of children received salvage treatment with curative intent without a second HSCT (67.8%), 22.0% of children underwent a second allo-HSCT, and 10.2% received palliative therapy. Isolated extramedullary relapse (hazard ratio (HR): 0.607, P = .011) and relapse earlier than 365 days post-transplantation (HR: 2.101, P < .001 for 0-180 days; HR: 1.522, P = .041 for 181-365 days) were found in multivariate analysis to be significant prognostic factors for outcome. The type of salvage therapy in chemosensitive relapse was identified as a significant prognostic factor for OS. CONCLUSION: A salvage approach with curative intent may be considered for patients with post-transplant relapse, even if they relapse in the first year post-transplantation. For sustainable remission, a second allo-HSCT may be recommended for patients who achieve complete remission after reinduction treatment.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia/mortalidad , Leucemia/terapia , Enfermedad Aguda , Adolescente , Niño , Preescolar , Terapia Combinada , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Recién Nacido , Leucemia/diagnóstico , Masculino , Pronóstico , Recurrencia , Estudios Retrospectivos , Terapia Recuperativa , Análisis de Supervivencia , Trasplante Homólogo , Turquía/epidemiología , Adulto JovenRESUMEN
We examined outcomes of 51 pediatric patients with relapsed acute leukemia (AL) who underwent a second allogeneic hematopoietic stem cell transplantation (alloHSCT). After a median follow-up of 941 days (range, 69-2842 days), leukemia-free survival (LFS) and overall survival (OS) at 3 years were 26.6% and 25.6%, respectively. The nonrelapse mortality rate (NMR) and cumulative incidence of relapse (CIR) were 36.4% and 42.4%, respectively. The Cox regression analysis demonstrated that the risk factors at second transplantation for predicting limited LFS were active disease (hazard ratio (HR) = 5.1), reduced intensity conditioning (RIC) (HR = 5.0), matched unrelated donor (MUD) (HR = 3.4) and performance score <80 (HR = 3.2). Pediatric patients with AL who relapsed after their first alloHSCT may survive with a second alloHSCT. Disease status, conditioning intensity, donor type, and performance score at the second transplantation are the relevant risk factors. A score based on these factors may predict the results of the second transplantation.