RESUMEN
PURPOSE OF REVIEW: The systemic treatment of advanced hepatocellular carcinoma (HCC) has significantly evolved. Immune checkpoint inhibitors (ICIs) have demonstrated clinical efficacy and more favorable toxicity profiles compared to multikinase inhibitors. Combination therapy with ICIs may provide greater anti-tumor activity compared to ICI monotherapy. This review will discuss the current treatment landscape of advanced HCC, with a focus on recently completed and ongoing trials of ICI combinations, as well as future directions. RECENT FINDINGS: Atezolizumab/bevacizumab has been approved as first-line therapy in patients with advanced HCC based on its superiority over sorafenib in the pivotal IMbrave150 trial. Similarly, durvalumab/tremelimumab demonstrated an improvement in overall survival compared to sorafenib in the HIMALAYA trial. Other combinations of ICIs with targeted agents and dual immune checkpoint blockade are currently being investigated in large randomized Phase 3 trials for the first-line treatment of HCC. Results of several ICI combination trials have been reported or are anticipated in the next few years and may potentially expand the therapy options in this patient population. Further areas of exploration include the use of ICIs in earlier stages of disease, other immunotherapy approaches such as adoptive T cell therapy, and the identification of predictive biomarkers. These ongoing efforts will likely further improve patient outcomes in the future.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Sorafenib/uso terapéuticoAsunto(s)
Biomarcadores de Tumor/genética , Carcinoma Ductal Pancreático/cirugía , Daño del ADN , Mutación , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Reparación del ADN por Recombinación , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Humanos , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Immune-related adverse events (IRAEs) are becoming increasingly common as the use of immune checkpoint inhibitors expands into more tumor types and treatment settings. Although the majority of IRAEs are mild and can be managed in the outpatient setting by the medical oncologist, severe IRAEs can be life threatening and often require complex care coordination among multiple providers. These providers include a variety of non-oncology specialists who have interest and expertise in managing IRAEs. Multiple systems-based solutions have been proposed in the literature, but these need to be tailored to the needs and resources of each practice setting. In this article, we highlight the challenges of IRAE care by presenting an illustrative case from our institution. We then describe the format and structure of the IRAE Tumor Board established at the University of Washington/Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Finally, we discuss how this tumor board attempts to address clinical issues related to complex IRAE presentations and provide IRAE education.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/terapia , Neoplasias/complicaciones , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The recent accumulation of molecular profiling data for primary hepatobiliary malignancies, including hepatocellular carcinoma and biliary tract cancers, has led to a proliferation of promising therapeutic investigations in recent years. Treatment with pathway-specific targeted inhibitors and immunotherapeutic agents have demonstrated promising early clinical results. Key molecular alterations in common hepatobiliary cancers and ongoing interventional clinical trials of molecularly targeted systemic agents focusing on hepatocellular carcinoma and biliary tract cancer are reviewed.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Biomarcadores de Tumor/antagonistas & inhibidores , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5ß1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors. METHODS: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage. RESULTS: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5ß1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses. CONCLUSIONS: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/inmunología , Bevacizumab/administración & dosificación , Bevacizumab/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Integrina alfa5beta1/antagonistas & inhibidores , Integrina alfa5beta1/inmunología , Masculino , Persona de Mediana Edad , Neoplasias/inmunologíaRESUMEN
The tumor stroma is increasingly recognized as a key player in tumorigenesis through its effects on cell signaling, immune responses, and access of therapeutic agents. A major component of the extracellular matrix is hyaluronic acid (HA), which raises the interstitial gel fluid pressure within tumors and reduces drug delivery to malignant cells, and has been most extensively studied in pancreatic ductal adenocarcinoma (PDA). Pegylated recombinant human hyaluronidase (PEGPH20) is a novel agent that degrades HA and normalizes IFP to enhance the delivery of cytotoxic agents. It has demonstrated promising preclinical results and early clinical evidence of efficacy in the first-line treatment of metastatic PDA with acceptable tolerability. Moreover, intratumoral HA content appears to be a predictive biomarker of response. Phase 2 and 3 trials of PEGPH20 plus chemotherapy are ongoing in metastatic PDA, and it is also being evaluated in other malignancies and in combination with radiation and immunotherapy.
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Adenocarcinoma/tratamiento farmacológico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Ácido Hialurónico/genética , Hialuronoglucosaminidasa/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/aislamiento & purificación , Carcinogénesis/efectos de los fármacos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Sistemas de Liberación de Medicamentos , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Humanos , Ácido Hialurónico/aislamiento & purificación , Hialuronoglucosaminidasa/genética , Metástasis de la Neoplasia , Proteínas Recombinantes/genética , Células del Estroma/efectos de los fármacosRESUMEN
BACKGROUND: Adjuvant chemotherapy (ACT) improved survival in the NCIC Clinical Trials Group JBR.10 trial of resected stage IB/II non-small-cell lung cancer. A prognostic 15-gene expression signature was developed, which may also predict for benefit from ACT. An exploratory economic analysis was conducted to assess the potential cost-effectiveness of using the 15-gene signature in guiding ACT decisions. METHODS: A decision analytic model was populated by study patients with quantitative reverse transcription polymerase chain reaction tumor profiling, current costs, and quality-adjusted survival. Analysis was performed over the 6-year follow-up from the perspective of the Canadian public health care system in 2015 Canadian dollars (discounted 5%/year). Incremental cost-effectiveness and cost-utility ratios were determined for ACT versus observation using clinical stage, gene signature, or a combined approach to select treatment. RESULTS: The mean survival gain of ACT versus observation was higher using the gene signature (1.86 years) compared with clinical stage (1.28 years). Although more costly, ACT guided by the gene signature remained cost-effective at $10,421/life-year gained (95% confidence interval [CI], $466-$19,568 Canadian), comparable to stage-directed selection ($7081/life-year gained; 95% CI, -$2370 to $14,721; P = .52). Incremental cost-utility ratios were $13,452/quality-adjusted life-year (95% CI, $373-$31,949) and $9194/quality-adjusted life-year (95% CI, -$4104 to $23,952), respectively (P = .53). Comparing the standard and test-and-treat approaches, use of the gene signature did not significantly alter survival compared with the standard strategy, but it reduced the ACT rate by 25%. CONCLUSION: If validated, the use of the 15-gene expression signature to select patients for ACT may increase the survival gain of treatment in patients with high-risk stage IB/II non-small-cell lung cancer, while avoiding toxicities in low-risk patients.
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Adenocarcinoma/economía , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Carcinoma de Pulmón de Células no Pequeñas/economía , Carcinoma de Células Escamosas/economía , Análisis Costo-Beneficio , Neoplasias Pulmonares/economía , Guías de Práctica Clínica como Asunto , Transcriptoma , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Canadá , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante , Técnicas de Apoyo para la Decisión , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models. Gene expression microarray and gene set enrichment analyses were performed in cell lines to determine the expression profiles and pathways of sensitivity/resistance. Pharmacodynamic changes in treated-PDTX were also characterized. Results Pevonedistat effectively inhibited cell viability (IC50 < 0.3 µM) and induced apoptosis in a subset of melanoma cell lines. Sensitive and resistant cell lines exhibited distinct gene expression profiles; sensitive models were enriched for genes involved in DNA repair, replication and cell cycle regulation, while immune response and cell adhesion pathways were upregulated in resistant models. Pevonedistat also reduced tumor growth in melanoma cell line xenografts and PDTX with variable responses. An accumulation of pevonedistat-NEDD8 adduct and CDT1 was observed in sensitive tumors consistent with its mechanism of action. Conclusions This study provided preclinical evidence that NAE inhibition by pevonedistat has anti-tumor activity in melanoma and supports the clinical benefits observed in recent Phase 1 trials of this drug in melanoma patients. Further investigations are warranted to develop rational combinations and determine predictive biomarkers of pevonedistat.
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Antineoplásicos/farmacología , Ciclopentanos/farmacología , Melanoma/tratamiento farmacológico , Pirimidinas/farmacología , Enzimas Activadoras de Ubiquitina/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Melanoma/genética , Melanoma/metabolismo , Enzimas Activadoras de Ubiquitina/metabolismo , Ubiquitinación/efectos de los fármacosRESUMEN
BACKGROUND: Sizing of FMR1 trinucleotide repeats in the clinical laboratory requires the use of capillary sequencer by PCR, or by a labor intensive measurement using Southern blot method. Our aim was to validate an accurate and robust PCR assay for quantification of CGG repeats. METHODS: We performed an analytical and clinical validation of a new PCR-based method that utilizes a low-cost capillary electrophoresis instrument and the FragilEase™ reagent kit. First, analytical performance was demonstrated on 12 Coriell reference samples comprising normal through full mutations. Subsequently, a cohort of 112 archived clinical DNA samples, enriched for premutation and full mutations, was analyzed. RESULTS: All samples were amplified successfully. Quantification of repeat numbers was interpreted by the use of standards with known repeats. Twenty-five full-mutation samples were successfully amplified with the largest allele size measured at 1380 repeats. The repeat numbers from the new assay were concordant with those obtained with the reference method. The intra-assay (CV<2.5%) and inter-assay imprecision was within 1 CGG repeat. CONCLUSION: This new PCR-based method is reproducible and capable of identifying all Fragile X alleles. It is an accurate and robust method that facilitates Fragile X testing in a broader spectrum of clinical laboratories.
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Síndrome del Cromosoma X Frágil/genética , Reacción en Cadena de la Polimerasa/métodos , Repeticiones de Trinucleótidos/genética , Electroforesis , Femenino , Humanos , Masculino , Reacción en Cadena de la Polimerasa/economía , Reacción en Cadena de la Polimerasa/normas , Estándares de ReferenciaRESUMEN
Advances in our knowledge of the molecular pathogenesis of cancer have led to increased interest in molecularly targeted agents (MTAs), which target specific oncogenic drivers and are now a major focus of cancer drug development. MTAs differ from traditional cytotoxic agents in various aspects, including their toxicity profiles and the potential availability of predictive biomarkers of response. The landscape of phase I oncology trials is evolving to adapt to these novel therapies and to improve the efficiency of drug development. In this Review, we discuss new strategies used in phase I trial design, such as novel dose-escalation schemes to circumvent limitations of the classic 3 + 3 design and enable faster dose escalation and/or more-precise dose determinations using statistical modelling; improved selection of patients based on genetic or molecular biomarkers; pharmacokinetic and pharmacodynamic analyses; and the early evaluation of efficacy - in addition to safety. Indeed, new expedited approval pathways that can accelerate drug development require demonstration of efficacy in early phase trials. The application of molecular tumour profiling for matched therapy and the testing of drug combinations based on a strong biological rationale are also increasingly seen in phase I studies. Finally, the shift towards multi-institutional trials and centralized study management results in consequent implications for institutions and investigators. These issues are also highlighted herein.
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Antineoplásicos/uso terapéutico , Ensayos Clínicos Fase I como Asunto/métodos , Neoplasias/tratamiento farmacológico , Proyectos de Investigación/tendencias , Relación Dosis-Respuesta a Droga , Humanos , Dosis Máxima ToleradaRESUMEN
BACKGROUND: The purpose of this study was to compare the results of thoracic epidural analgesia (TEA) and parecoxib in controlling postoperative pain after the Nuss procedure. METHODS: Between August 2005 and July 2014, 120 adolescents and adults underwent Nuss procedures and received either TEA or parecoxib for postoperative pain control. Demographic data, preoperative preparation times, visual analog scale (VAS) pain scores from postoperative day 1 to day 5, medical costs of pain control, days to Foley catheter removal, days to being able to sit up, days to being able to walk, days of hospital stay, nausea/vomiting scores, and complications related to pain control were compared. RESULTS: A total of 106 patients received TEA, and 14 received parecoxib. No between-group differences in demographics were observed. Patients in the parecoxib group had shorter preparation times (p<0.001), lower VAS pain scores from postoperative day 2 to day 5 (day 2, p=0.006; day 3, p=0.006; day 4, p<0.001; day 5, p<0.001), shorter hospital stays (p<0.001), lower pain control costs (p<0.001), and lower nausea/vomiting scores (p=0.046). CONCLUSIONS: For adolescents and adults undergoing the Nuss procedure, parecoxib affords better pain control efficacy, a shorter hospital stay, lower medical pain control costs, and fewer side effects compared with TEA.
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Analgesia Epidural/métodos , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Tórax en Embudo/cirugía , Isoxazoles/uso terapéutico , Procedimientos Ortopédicos , Dolor Postoperatorio/tratamiento farmacológico , Adolescente , Adulto , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Tiempo de Internación , Masculino , Dimensión del Dolor , Dolor Postoperatorio/diagnóstico , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Antineoplásicos/administración & dosificación , Ensayos Clínicos Fase I como Asunto/métodos , Oncología Médica/tendencias , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Oncología Médica/métodos , Evaluación de Resultado en la Atención de Salud/métodos , Selección de Paciente , Proyectos de InvestigaciónRESUMEN
Brahma (BRM) has a key function in chromatin remodeling. Two germline BRM promoter insertion-deletion polymorphisms, BRM-741 and BRM-1321, have been previously associated with an increased risk of lung cancer in smokers and head and neck cancer. To further evaluate their role in cancer susceptibility particularly in early disease, we conducted a preplanned case-control study to investigate the association between the BRM promoter variants and stage I/II upper aerodigestive tract (UADT) cancers (i.e., lung, esophageal, head and neck), a group of early-stage malignancies in which molecular and genetic etiologic factors are poorly understood. The effects of various clinical factors on this association were also studied. We analyzed 562 cases of early-stage UADT cancers and 993 matched healthy controls. The double homozygous BRM promoter variants were associated with a significantly increased risk of early stage UADT cancers (adjusted odds ratio [aOR], 2.46; 95% confidence interval [CI], 1.7-3.8). This association was observed in lung (aOR, 2.61; 95% CI, 1.5-4.9) and head and neck (aOR, 2.75; 95% CI, 1.4-5.6) cancers, but not significantly in esophageal cancer (aOR, 1.66; 95% CI, 0.7-5.8). There was a nonsignificant trend for increased risk in the heterozygotes or single homozygotes. The relationship between the BRM polymorphisms and early-stage UADT cancers was independent of age, sex, smoking status, histology, and clinical stage. These findings suggest that the BRM promoter double insertion homozygotes may be associated with an increased risk of early-stage UADT cancers independent of smoking status and histology, which must be further validated in other populations.
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Neoplasias Esofágicas/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias Pulmonares/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Pronóstico , Regiones Promotoras Genéticas , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
Apoptosis serves as a protective mechanism by eliminating damaged cells through programmed cell death. After apoptotic cells pass critical checkpoints, including mitochondrial fragmentation, executioner caspase activation, and DNA damage, it is assumed that cell death inevitably follows. However, this assumption has not been tested directly. Here we report an unexpected reversal of late-stage apoptosis in primary liver and heart cells, macrophages, NIH 3T3 fibroblasts, cervical cancer HeLa cells, and brain cells. After exposure to an inducer of apoptosis, cells exhibited multiple morphological and biochemical hallmarks of late-stage apoptosis, including mitochondrial fragmentation, caspase-3 activation, and DNA damage. Surprisingly, the vast majority of dying cells arrested the apoptotic process and recovered when the inducer was washed away. Of importance, some cells acquired permanent genetic changes and underwent oncogenic transformation at a higher frequency than controls. Global gene expression analysis identified a molecular signature of the reversal process. We propose that reversal of apoptosis is an unanticipated mechanism to rescue cells from crisis and propose to name this mechanism "anastasis" (Greek for "rising to life"). Whereas carcinogenesis represents a harmful side effect, potential benefits of anastasis could include preservation of cells that are difficult to replace and stress-induced genetic diversity.
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Apoptosis/genética , Transformación Celular Neoplásica/genética , Daño del ADN , Animales , Animales Recién Nacidos , Antiinfecciosos Locales/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Transformación Celular Neoplásica/efectos de los fármacos , Células Cultivadas , Depsipéptidos/farmacología , Etanol/farmacología , Perfilación de la Expresión Génica , Células HeLa , Humanos , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Ratones Endogámicos BALB C , Microscopía Fluorescente , Miocitos Cardíacos/citología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Células 3T3 NIH , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma/efectos de los fármacos , Transcriptoma/genéticaRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) is commonly associated with hepatic complications. Patients with myelofibrosis (MF) often develop liver dysfunction in the early posttransplantation period; however, this has not yet been studied in a systematic fashion. We retrospectively evaluated 53 patients with MF who underwent HCT to assess the prevalence of acute liver toxicity and risk factors and the impact on survival. We compared the prevalence of acute hepatic complications in that group and a matched control group of 53 patients with myelodysplastic syndrome (MDS). In the MF group, during the first 6 weeks after HCT, the incidence of mild (34.2-102.6 µM), moderate (102.6-342 µM), and severe (>342 µM) hyperbilirubinemia was 34%, 40%, and 4%, respectively (normal, <22 µM). The incidence of mild/moderate transaminitis (2-10 times the upper limit of normal) was 23%, and that of severe transaminitis (>10 times the upper limit of normal) was 6%. Veno-occlusive disease as defined by the Baltimore criteria was observed in 19 patients (36%) in the MF group. Compared with MDS, MF was associated with a significantly higher incidence of moderate/severe hyperbilirubinemia (44% versus 21%; P = .02) and veno-occlusive disease (36% versus 19%; P = .05). A history of portal hypertension, biopsy-proven hepatic iron overload, or splanchnic vein thrombosis was a strong predictor of moderate/severe hyperbilirubinemia (P = .02). Acute hepatocellular injury with moderate/severe hyperbilirubinemia or transaminitis was associated with inferior survival at 12 months (P = .02) in the MF group. We conclude that patients with MF are at significant risk of early hepatotoxicity after HCT, which is associated with an adverse impact on survival.
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Trasplante de Células Madre Hematopoyéticas , Hiperbilirrubinemia/patología , Hígado/patología , Síndromes Mielodisplásicos/patología , Mielofibrosis Primaria/patología , Acondicionamiento Pretrasplante , Adulto , Anciano , Canadá/epidemiología , Femenino , Humanos , Hiperbilirrubinemia/epidemiología , Hiperbilirrubinemia/mortalidad , Hiperbilirrubinemia/terapia , Incidencia , Hígado/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/terapia , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Factores de Tiempo , Trasplante HomólogoAsunto(s)
Endocarditis Bacteriana/diagnóstico , Enfermedades de las Válvulas Cardíacas/diagnóstico , Infarto/etiología , Infecciones Estafilocócicas/diagnóstico , Adulto , Diagnóstico Diferencial , Ecocardiografía Transesofágica , Endocarditis Bacteriana/complicaciones , Fiebre/etiología , Enfermedades de las Válvulas Cardíacas/patología , Humanos , Infarto/diagnóstico , Masculino , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureusRESUMEN
Advances in next-generation sequencing technology are enabling the systematic analyses of whole cancer genomes, providing insights into the landscape of somatic mutations and the great genetic heterogeneity that defines the unique signature of an individual tumor. Moreover, integrated studies of the genome, epigenome, and transcriptome reveal mechanisms of tumorigenesis at multiple levels. Progress in sequencing technologies and bioinformatics will improve the costs, sensitivity, and accuracy of detecting somatic mutations, while large-scale projects are underway to coordinate cancer genome sequencing at the global level to facilitate the generation and dissemination of high-quality uniform genetic data. These developments will create opportunities for deeper studies of cancer genetics and the clinical application of genome sequencing, and will motivate further research in cancer pathogenesis.
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Neoplasias/genética , Epigenómica , Regulación Neoplásica de la Expresión Génica , Genoma Humano , Humanos , Mutación , Análisis de Secuencia de ADNRESUMEN
BACKGROUND & AIMS: This report describes the use of a novel sensitive and specific ELISA for the measurement of human fibrinogen-like protein 2 (FGL2/fibroleukin), a novel effector of natural regulatory T (Treg) cells, to predict the course of chronic hepatitis C viral infection (HCV). METHODS: Plasma levels of FGL2 were measured in HCV patients and compared to healthy controls and to patients with alcoholic liver disease. RESULTS: FGL2 levels were significantly higher in HCV patients (84.3+/-89.1 ng/ml, n=80) compared to healthy controls (36.4+/-21.9 ng/ml, n=30, p<0.001), to a subset of patients who cleared HCV following anti-viral treatment (16.6+/-19.7 ng/ml, n=32, p<0.001), and to patients with inactive alcoholic liver disease (18.8+/-17.4 ng/ml, n=24, p<0.001). Among HCV patients, plasma levels of FGL2 correlated significantly with the stage of fibrosis (p=0.001) and were significantly higher in patients with cirrhosis (164.1+121.8 ng/ml, n=60) compared to non-cirrhotics (57.7+/-52.8 ng/ml, n=20, p=0.001). Genotype 1 patients had significantly higher levels of FGL2 (98.1+/-100.3 ng/ml, n=60) compared to patients with genotype 2/3 (41.5+/-38.6 ng/ml, n=20, p=0.0008). Patients with genotype 2/3 had FGL2 levels similar to healthy controls (41.5+/-38.6 vs. 36.41+/-21.9 ng/ml, p=ns). Infiltrating lymphocytes in liver biopsies of HCV patients were positive for either FGL2 or FoxP3 (a marker of Treg cells) or expressed both markers. CONCLUSIONS: This report documents the development of a sensitive ELISA for measurement of plasma levels of FGL2 an effector Treg cells, which correlates with the severity of HCV infection.
Asunto(s)
Fibrinógeno/análisis , Hepatitis C Crónica/sangre , Hepatopatías Alcohólicas/sangre , Adulto , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Fibrinógeno/inmunología , Hepatitis C Crónica/inmunología , Humanos , Hepatopatías Alcohólicas/inmunología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
UNLABELLED: Fulminant viral hepatitis (FH) remains an important clinical problem in which the underlying pathogenesis is not well understood. Here, we present insight into the immunological mechanisms involved in FH caused by murine hepatitis virus strain 3 (MHV-3), indicating a critical role for CD4(+)CD25(+) regulatory T cells (Tregs) and production of the novel Treg effector molecule FGL2. Before infection with MHV-3, susceptible BALB/cJ mice had increased numbers of Tregs and expression of fgl2 messenger RNA (mRNA) and FGL2 protein compared with resistant A/J mice. After MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with increased percentage of Tregs. Treatment with anti-FGL2 antibody completely inhibited Treg activity and protected susceptible BALB/cJ mice against MHV-3-liver injury and mortality. Adoptive transfer of wild-type Tregs into resistant fgl2(-/-) mice increased their mortality caused by MHV-3 infection, whereas transfer of peritoneal exudate macrophages had no adverse effect. CONCLUSION: This study demonstrates that FGL2 is an important effector cytokine of Tregs that contributes to susceptibility to MHV-3-induced FH. The results further suggest that targeting FGL2 may lead to the development of novel treatment approaches for acute viral hepatitis infection.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Fibrinógeno/inmunología , Hepatitis Viral Animal/inmunología , Linfocitos T Reguladores/inmunología , Animales , Infecciones por Coronavirus/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Terapia de Inmunosupresión , Ratones , Ratones Endogámicos A/inmunología , Ratones Endogámicos BALB C , Virus de la Hepatitis Murina , Reacción en Cadena de la PolimerasaRESUMEN
Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.