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ABSTRACT: Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Prognóstico , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Europa (Continente)RESUMO
ABSTRACT: Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Adulto , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Europa (Continente) , Gerenciamento Clínico , Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , PrognósticoRESUMO
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.
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The objective of this guideline, prepared by the ALL subgroup of the Advanced Cell Therapy Sub-Committee of BSBMTCT (British Society of Blood and Marrow Transplantation), is to provide healthcare professionals with practical guidance on the preparation of children and young adults with B-acute lymphoblastic leukaemia from the point of referral to that of admission for CAR T-cell treatment. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.
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Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Criança , Imunoterapia Adotiva/métodos , Adulto Jovem , Adolescente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adulto , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
PURPOSE: Report the rate and severity of degenerative disc disease (DDD) in non-surgical adolescent idiopathic scoliosis (AIS) patients and correlate these findings with patient-reported symptomatology scores. Additionally, to quantify the rate of concurrent pathological radiological findings in this group. METHODS: This was a retrospective chart review study at a single tertiary centre. AIS patients aged 10-16 who had received a whole spine MRI between September 2007 and January 2019 and who had not received surgical intervention to their spine were included. MRI scan reports were screened to extract those who had evidence of DDD. These were then reviewed by a blinded second reviewer who graded every disc using the Pfirrmann grading system. SRS-22 scores were extracted for patients when available. RESULTS: In total, 968 participants were included in the study. Of these, 93 (9.6%) had evidence of DDD, which was Pfirrmann grade ≥ 3 in 28 (2.9%). The most commonly affected level was L5/S1 (59.1% of DDD cases). A total of 55 patients (5.7%) had evidence of syringomyelia, 41 (3.4%) had evidence of spondylolisthesis (all L5/S1), 14 (1.4%) had bilateral L5 pars defects, and 5 (0.5%) had facet joint degeneration. Spondylolisthesis and bilateral pars defects were more common in patients with DDD identified on MRI scan (p < 0.001 and p = 0.04, respectively). Function (p = 0.048) and pain (p = 0.046) scores were worse in patients with DDD. CONCLUSION: We present a baseline for the rate and severity of DDD in the non-operative AIS cohort. This should assist in decision-making and counselling of patients prior to surgery. LEVEL OF EVIDENCE: III.
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Degeneração do Disco Intervertebral , Escoliose , Espondilolistese , Humanos , Adolescente , Escoliose/complicações , Escoliose/diagnóstico por imagem , Degeneração do Disco Intervertebral/complicações , Degeneração do Disco Intervertebral/diagnóstico por imagem , Estudos Retrospectivos , Dor , Medidas de Resultados Relatados pelo PacienteRESUMO
Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.
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Proteínas de Fusão bcr-abl/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transcriptoma , Adolescente , Adulto , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-bcr/genética , Medição de Risco , Adulto JovemRESUMO
PURPOSE: To address the anatomical challenges facing complex and revision spinal surgery, patient-specific 3D-printed models (3D-PMs) have received growing attention worldwide, primarily in adults. We report the use of a 3D-PM in the treatment of a case of wound breakdown over a component of a VEPTR (Vertical Expandable Prosthetic Titanium Rib; DePuy-Synthes) system, requiring replacement of Dunn-McCarthy hook and sleeve with components contoured to a patient-specific 3D-PM of the spine. METHOD: A two-year-old born with myelomeningocele (MMC), repaired at birth, developed progressive MMC-associated kyphoscoliosis. Elective insertion of a rib-to-pelvis 'Eiffel Tower' bilateral VEPTR growing rods construct was performed without initial complication. Prominence of the right VEPTR sleeve and Dunn-McCarthy hook side-to-side connector resulted in breakdown of overlying poor-quality soft tissues, necessitating washout, partial implant removal, intravenous antibiotic therapy and delayed primary wound closure. A patient-specific 3D-PM, utilising pre-operative CT spine and pelvis 3D-reconstructions, allowed pre-operative formation of a contoured implant, which was inserted without need for further revision. RESULTS: The patient underwent further VEPTR lengthening without recurrent infection, wound breakdown or implant failure at 24-month follow-up. Satisfactory control of the deformity has been achieved with continued improvement in sitting height and radiographic indices. CONCLUSION: This case illustrates the possibility, in certain cases, of using 3D-PM to develop complex components of spinal implant systems pre-operatively, removing the time and difficulty of intra-operative contouring. Consequently, custom-contoured implants may be produced, sterilised and implanted. This technique may be an option, in infants, including MMC-associated kyphoscoliosis, where midline fixation is not possible.
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Escoliose , Titânio , Recém-Nascido , Humanos , Lactente , Pré-Escolar , Costelas/diagnóstico por imagem , Costelas/cirurgia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/cirurgia , Escoliose/diagnóstico por imagem , Escoliose/cirurgia , Escoliose/etiologia , Próteses e Implantes/efeitos adversos , Pelve/cirurgia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Germline mutations in CDKN2A, encoding the tumor suppressor p16, are responsible for a large proportion of familial melanoma cases and also increase risk of pancreatic cancer. We identified four families through pancreatic cancer probands that were affected by both cancers. These families bore a germline missense variant of CDKN2A (47T>G), encoding a p16-L16R mutant protein associated with high cancer occurrence. Here, we investigated the biological significance of this variant. When transfected into p16-null pancreatic cancer cells, p16-L16R was expressed at lower levels than wild-type (WT) p16. In addition, p16-L16R was unable to bind CDK4 or CDK6 compared with WT p16, as shown by coimmunoprecipitation assays and also was impaired in its ability to inhibit the cell cycle, as demonstrated by flow cytometry analyses. In silico molecular modeling predicted that the L16R mutation prevents normal protein folding, consistent with the observed reduction in expression/stability and diminished function of this mutant protein. We isolated normal dermal fibroblasts from members of the families expressing WT or L16R proteins to investigate the impact of endogenous p16-L16R mutant protein on cell growth. In culture, p16-L16R fibroblasts grew at a faster rate, and most survived until later passages than p16-WT fibroblasts. Further, western blotting demonstrated that p16 protein was detected at lower levels in p16-L16R than in p16-WT fibroblasts. Together, these results suggest that the presence of a CDKN2A (47T>G) mutant allele contributes to an increased risk of pancreatic cancer as a result of reduced p16 protein levels and diminished p16 tumor suppressor function.
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Ciclo Celular , Inibidor p16 de Quinase Dependente de Ciclina/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Heterozigoto , Melanoma/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Neoplasias Pancreáticas/genética , LinhagemRESUMO
Despite being predominantly a childhood disease, the incidence of acute lymphoblastic leukemia (ALL) has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterization to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next-generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1-positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and <1% of patients, respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile was identified in over a third (28/77) of cases of B-cell precursor ALL. The genetic good-risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP arrays and 9% (2/23) of NGS samples, and represent novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with 5-year event-free and overall survival rates of 17% and 24%, respectively, across the cohort, indicating a need for novel therapeutic strategies.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Idoso , Criança , Estudos de Coortes , Rearranjo Gênico , Genômica , Humanos , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , PrognósticoRESUMO
The modulation of GLI2, an oncogenic transcription factor commonly upregulated in cancer, is in many cases not due to genetic defects, suggesting dysregulation through alternative mechanisms. The identity of these molecular events remains for the most part unknown. Here, we identified TFII-I as a novel repressor of GLI2 expression. Mapping experiments suggest that the INR region of the GLI2 promoter is necessary for GLI2 repression. ChIP studies showed that TFII-I binds to this INR. TFII-I knockdown decreased the binding of NELF-A, a component of the promoter-proximal pausing complex at this site, and enriched phosphorylated RNAPII serine 2 in the GLI2 gene body. Immunoprecipitation studies demonstrate TFII-I interaction with SPT5, another pausing complex component. TFII-I overexpression antagonized GLI2 induction by TGFß, a known activator of GLI2 in cancer cells. TGFß reduced endogenous TFII-I binding to the INR and increased RNAPII SerP2 in the gene body. We demonstrate that this regulatory mechanism is not exclusive of GLI2. TGFß-induced genes CCR7, TGFß1 and EGR3 showed similar decreased TFII-I and NELF-A INR binding and increased RNAPII SerP2 in the gene body post-TGFß treatment. Together these results identify TFII-I as a novel repressor of a subset of TGFß-responsive genes through the regulation of RNAPII pausing.
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Proteínas Nucleares/metabolismo , RNA Polimerase II/metabolismo , Fatores de Transcrição TFII/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Células Hep G2 , Humanos , Regiões Promotoras Genéticas , Proteínas Repressoras/fisiologia , Transcrição Gênica , Ativação TranscricionalRESUMO
BACKGROUND: It is unclear whether traditional growing rod (TGR) treatment outcomes vary by early-onset scoliosis (EOS) subtype. The goal of this study was to compare radiographic outcomes and complications of TGR treatment by EOS subtype. METHODS: We queried an international database of EOS patients from 20 centers to identify "graduates" who had (1) undergone primary TGR treatment from 1993 to 2014; (2) completed TGR treatment; and (3) had an uneventful clinical examination within 6 months after completion of TGR treatment with no anticipated further intervention. We included 202 patients in 4 etiologic subgroups: neuromuscular (n=65), syndromic (n=57), idiopathic (n=52), and congenital (n=28). Mean age at surgery was 7.1 years (range, 1.6 to 14.9 y); mean duration of follow-up was 8 years (range, 2 to 18.6 y). The groups did not differ by mean age, body mass index, sex, number of lengthenings, or duration of follow-up. The following preoperative differences were significant: (1) greater mean major curve in the neuromuscular versus idiopathic subgroup; (2) shorter spinal height (T1-S1) in the congenital versus idiopathic subgroup; and (3) smaller proportion of ambulatory patients in the neuromuscular subgroup versus all other subgroups. RESULTS: We found no significant differences among subgroups in mean major curve correction or changes in thoracic height (T1-T12), spinal height, or global kyphosis at any point. Rates of deep surgical site infection, implant-related complications, and neurological complications were not different among subgroups. The medical complication rate was significantly lower in the idiopathic group compared with the other groups. CONCLUSIONS: Major curve correction and spinal and thoracic height increases did not differ significantly at any point by EOS subtype. Rates of deep surgical site infection, implant-related complications, and neurological complications did not differ by subtype. Except for the lower rate of medical complications in the idiopathic group, our findings suggest that, after TGR treatment, patients can expect similar outcomes regardless of their EOS subtype. LEVEL OF EVIDENCE: Level III, therapeutic.
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Cifose , Escoliose , Fusão Vertebral , Humanos , Estudos Retrospectivos , Escoliose/diagnóstico por imagem , Escoliose/etiologia , Escoliose/cirurgia , Coluna VertebralRESUMO
The ß- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid ß peptide, which is believed to be the main driver of neurodegeneration in Alzheimer's disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid ß aggregation, widely neglecting the potential meaning of very early generation of amyloid ß inside the cell. In the last few years, the importance of intracellular amyloid ß (iAß) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAß is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAß through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAß generation and point out future directions urgently needed to manifest the potential relevance of iAß in Alzheimer's disease.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biomarcadores , Placa AmiloideRESUMO
The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.
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Cromatina/genética , Elementos Reguladores de Transcrição , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Proteína GLI1 em Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , DNA/metabolismo , Células HEK293 , Humanos , Domínios Proteicos , Mapas de Interação de Proteínas , Fatores de Transcrição/química , Ativação Transcricional , Proteína GLI1 em Dedos de Zinco/químicaRESUMO
BACKGROUND: Patients with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. METHODS: The efficacy of inotuzumab ozogamicin (InO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open-label, randomized, phase 3 study 1022 (INO-VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO. RESULTS: In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64-2.14]). The probability of being event-free (progression-free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%). CONCLUSION: Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD-directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors.
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Inotuzumab Ozogamicina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , RecidivaRESUMO
AIMS: The diagnostic and clinical significance of granulomas in gastrointestinal (GI) biopsies from haematopoietic transplant patients remains disputed, especially following the proposal of cord colitis syndrome (CCS) as a new entity. The aim of the following study was to explore this controversy by identifying such biopsies with granulomas and detailing their clinicopathological associations. METHODS AND RESULTS: Twelve patients with granuloma-containing biopsies were identified from across three scenarios: prospectively during a GI pathologist's routine practice over a period of 5 years; retrospectively from a cohort of transplant patients with clinically validated GI graft versus host disease (GVHD); and retrospectively from a cohort of patients who had received umbilical cord blood (UCB). Their clinicopathological assessments (which included unique long-term patient follow-up) showed that granulomas are only rarely seen across all GI biopsies from haematopoietic transplant patients, and may uncommonly constitute a histological feature of GI GVHD. Granulomas-and especially well-defined, non-cryptolytic ones-are more commonly present in GI biopsies from UCB recipients, but do not show any accompanying histological features that are different from those seen in granuloma-containing biopsies from other patient groups. Furthermore, the three UCB recipients with granuloma-containing biopsies were clinically diagnosed with GVHD rather than CCS. Finally, polymorphic post-transplant lymphoproliferative disorder (PTLD) can present histologically as GI granulomatous inflammation that mimics Crohn's disease. CONCLUSIONS: Granulomas in GI biopsies of haematopoietic transplant patients may often indicate a treatable aetiology such as GVHD or PTLD. Granulomas are more commonly seen in GI biopsies from UCB recipients, but do not necessarily indicate a diagnosis of CCS.
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Biópsia , Granuloma , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adulto , Idoso , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença de Crohn/diagnóstico , Doença de Crohn/patologia , Diagnóstico Diferencial , Feminino , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/patologia , Granuloma/diagnóstico , Granuloma/patologia , Humanos , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.
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Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Pancreáticas/metabolismo , Rabdomiossarcoma/metabolismo , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de Zinco/metabolismo , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Multimerização Proteica , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/genéticaRESUMO
This study computationally assesses the accuracy of an instantaneous wave-free ratio (iFR) threshold range compared to standard modalities such as fractional flow reserve (FFR) and coronary flow reserve (CFR) for multiple intermediate lesions near the left main (LM) coronary bifurcation. iFR is an adenosine-independent index encouraged for assessment of coronary artery disease (CAD), but different thresholds are debated. This becomes particularly challenging in cases of multivessel disease when sensitivity to downstream lesions is unclear. Idealized LM coronary arteries with 34 different intermediate stenoses were created and categorized (Medina) as single and multiple lesion groups. Computational fluid dynamics modeling was performed with physiologic boundary conditions using an open-source software (simvascular1) to solve the time-dependent Navier-Stokes equations. A strong linear relationship between iFR and FFR was observed among studied models, indicating computational iFR values of 0.92 and 0.93 are statistically equivalent to an FFR of 0.80 in single and multiple lesion groups, respectively. At the clinical FFR value (i.e., 0.8), a triple-lesion group had smaller CFR compared to the single and double lesion groups (e.g., triple = 3.077 versus single = 3.133 and double = 3.132). In general, the effect of additional intermediate downstream lesions (minimum lumen area > 3 mm2) was not statistically significant for iFR and CFR. A computational iFR of 0.92 best predicts an FFR of 0.80 and may be recommended as threshold criteria for computational assessment of LM stenosis following additional validation using patient-specific models.
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Reserva Fracionada de Fluxo MiocárdicoRESUMO
BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n = 30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n = 13), diffuse large B cell lymphoma (n = 7), low-grade non-Hodgkin lymphoma (n = 16), mantle cell lymphoma (n = 10), and T cell lymphoma (n = 6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n = 3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n = 21), matched unrelated donors (MUD) (n = 24), miss-matched unrelated donors (MMUD) (n = 6), and syngeneic (n = 1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n = 32), and 29% (n = 15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1 × 106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P = .035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P = .021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P = .001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma , Adulto , Alemtuzumab/uso terapêutico , Quimerismo , Humanos , Incidência , Linfócitos , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Transplante AutólogoRESUMO
Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSCs) may be effective against acute graft-versus-host disease (aGVHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid-refractory aGVHD (NCT00366145). In total, 260 patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009 and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGVHD symptoms for any period of at least 28 days after beginning treatment. Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% versus 30%; P = 0.42). In post hoc analyses, patients with liver involvement who received at least 1 infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% versus 5%; P = .047). Among high-risk patients (aGVHD grades C and D), remestemcel-L demonstrated significantly higher OR at day 28 than placebo (58% versus 37%; P = 0.03). Furthermore, pediatric patients had a higher OR with MSCs compared with placebo (64% versus 23%; P = .05). Similar rates of adverse events were observed between treatment groups. Remestemcel-L was safe and well tolerated. Results of this study did not demonstrate superior DCR compared with placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Doença Aguda , Adulto , Criança , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Esteroides/uso terapêuticoRESUMO
The American Society for Transplantation and Cellular Therapy (ASTCT) published its first white paper on indications for autologous and allogeneic hematopoietic cell transplantation (HCT) in 2015. It was identified at the time that periodic updates of indications would be required to stay abreast with state of the art and emerging indications and therapy. In recent years the field has not only seen an improvement in transplantation technology, thus widening the therapeutic scope of HCT, but additionally a whole new treatment strategy using modified immune effector cells, including chimeric antigen receptor T cells and engineered T-cell receptors, has emerged. The guidelines review committee of the ASTCT deemed it optimal to update the ASTCT recommendations for indications for HCT to include new data and to incorporate indications for immune effector cell therapy (IECT) where appropriate. The guidelines committee established a multiple stakeholder task force consisting of transplant experts, payer representatives, and a patient advocate to provide guidance on indications for HCT and IECT. This article presents the updated recommendations from the ASTCT on indications for HCT and IECT. Indications for HCT/IECT were categorized as (1) Standard of care, where indication is well defined and supported by evidence; (2) Standard of care, clinical evidence available, where large clinical trials and observational studies are not available but have been shown to be effective therapy; (3) Standard of care, rare indication, for rare diseases where demonstrated effectiveness exists but large clinical trials and observational studies are not feasible; (4) Developmental, for diseases where preclinical and/or early-phase clinical studies show HCT/IECT to be a promising treatment option; and (5) Not generally recommended, where available evidence does not support the routine use of HCT/IECT. The ASTCT will continue to periodically review these guidelines and update them as new evidence becomes available.