RESUMEN
Epidemiological data have provided limited and inconsistent evidence on the relationship between radiation exposure and lymphoid neoplasms. We classified 553 lymphoid neoplasm cases diagnosed between 1950 and 1994 in the Life Span Study cohort of atomic bomb survivors into World Health Organization subtypes. Mature B-cell neoplasms represented 58%, mature T-cell and natural killer (NK)-cell neoplasms 20%, precursor cell neoplasms 5%, and Hodgkin lymphoma (HL) 3%, with the remaining 15% classified as non-Hodgkin lymphoid (NHL) neoplasms or lymphoid neoplasms not otherwise specified. We used Poisson regression methods to assess the relationship between radiation exposure and the more common subtypes. As in earlier reports, a significant dose response for NHL neoplasms as a group was seen for males but not females. However, subtype analyses showed that radiation dose was strongly associated with increased precursor cell neoplasms rates, with an estimated excess relative risk per Gy of 16 (95% Confidence interval: 7.0, >533) at age 50. The current data based primarily of tissue-based diagnoses suggest that the association between radiation dose and lymphoid neoplasms as a group is largely driven by the radiation effect on precursor cell neoplasms while presenting no evidence of a radiation dose response for major categories of mature cell neoplasms, either B- or T-/NK-cell, or more specific disease entities (diffuse large B-cell lymphoma, plasma cell myeloma, adult T-cell leukemia/lymphoma) or HL.
Asunto(s)
Supervivientes a la Bomba Atómica , Leucemia Linfoide/etiología , Linfoma/etiología , Neoplasias Inducidas por Radiación/etiología , Adolescente , Adulto , Femenino , Humanos , Incidencia , Leucemia Linfoide/patología , Linfoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/patología , Ceniza Radiactiva/efectos adversos , Riesgo , Organización Mundial de la Salud , Adulto JovenRESUMEN
The anti-cancer potential of dipyridamole has been suggested from experiments, but evidence from population-based studies is still lacking. We aimed to explore if dipyridamole use was related to a lower risk of lymphoid neoplasms. We identified individuals with prescription of aspirin after diagnosis of ischaemic cerebrovascular disease since 2006 by linking several Swedish registers. In these aspirin users, those with dipyridamole prescription were further identified as the study group and patients without dipyridamole were randomly selected as reference group with 1:1 ratio using a propensity score-matching approach. After a median of 6·67 years of follow-up, a total of 46 patients with dipyridamole use developed lymphoid neoplasms with an incidence rate of 0·49 per 1 000 person-years, while the rate in the matched group was 0·74 per 1 000 person-years. As compared to non-users, dipyridamole users were associated with a significantly decreased risk of lymphoid neoplasms [hazard ratio (HR) = 0·65; 95% confidence interval (CI) = 0·43-0·98]. Specifically, the reduced risk was observed for non-Hodgkin lymphomas (HR = 0·64; 95% CI = 0·42-0·94), especially B-cell lymphomas (HR = 0·56; 95% CI = 0·35-0·88). Dipyridamole use was related to a lower risk of lymphoid neoplasms, indicating a clinical potential of dipyridamole to be an adjunct anti-tumour agent against lymphoid neoplasms.
Asunto(s)
Dipiridamol/efectos adversos , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Linfoma/epidemiología , Linfoma/etiología , Inhibidores de Agregación Plaquetaria/efectos adversos , Anciano , Anciano de 80 o más Años , Aspirina/efectos adversos , Aspirina/uso terapéutico , Quimioprevención , Comorbilidad , Dipiridamol/uso terapéutico , Susceptibilidad a Enfermedades , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Leucemia Linfoide/prevención & control , Linfoma/prevención & control , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Vigilancia de la Población , Puntaje de Propensión , Modelos de Riesgos Proporcionales , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Suecia/epidemiologíaRESUMEN
Leukotoxin (LtxA) (Trade name, Leukothera) is a protein that is secreted from the oral bacterium Aggregatibacter actinomycetemcomitans, which targets and kills activated white blood cells (WBCs) by binding to lymphocyte function associated antigen-1 (LFA-1). Interaction between LtxA and Jurkat T-cells results in cell death and is characterized by increased intracellular Ca2+, activation of caspases, clustering of LtxA and LFA-1 within lipid rafts, and involvement of the Fas death receptor. Here, we show that LtxA can kill malignant lymphocytes via apoptotic and necrotic forms of cell death. We show that LtxA causes activation of caspases and PARP, cleavage of pannexin-1 (Panx1) channels, and expulsion of ATP, ultimately leading to cell death via apoptosis and necrosis. CRISPR-Cas9 mediated knockout (K/O) of Panx1 in Jurkat cells prevented ATP expulsion and resulted in resistance to LtxA for both apoptotic and necrotic forms of death. Resistance to necrosis could only be overcome when supplementing LtxA with endogenous ATP (bzATP). The combination of LtxA and bzATP promoted only necrosis, as no Panx1 K/O cells stained positive for phosphatidylserine (PS) exposure following the combined treatment. Inhibition of LtxA/bzATP-induced necrosis was possible when pretreating Jurkat cells with oATP, a P2X7R antagonist. Similarly, blockage of P2X7Rs with oATP prevented the intracellular mobilization of Ca2+, an important early step in LtxA induced cell death. We show that LtxA is able to kill malignant lymphocytes through an apoptotic death pathway which is potentially linked to a Panx1/P2X7R mediated necrotic form of death. Thus, inhibition of ATP release appears to significantly delay the onset of LtxA induced apoptosis while completely disabling the necrotic death pathway in T-lymphocytes, demonstrating the crucial role of ATP release in LtxA-mediated cell death.
Asunto(s)
Conexinas/metabolismo , Exotoxinas/metabolismo , Linfocitos/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Adenosina Trifosfato/metabolismo , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Muerte Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Conexinas/deficiencia , Exotoxinas/farmacología , Técnicas de Silenciamiento del Gen , Humanos , Células Jurkat , Leucemia Linfoide/etiología , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patología , Linfocitos/patología , Linfoma/etiología , Linfoma/metabolismo , Linfoma/patología , Proteínas del Tejido Nervioso/deficiencia , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Transducción de Señal/efectos de los fármacosAsunto(s)
Biomarcadores de Tumor , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/etiología , Linfoma/diagnóstico , Linfoma/etiología , Técnicas de Diagnóstico Molecular/métodos , Toma de Decisiones Clínicas , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Leucemia Linfoide/terapia , Linfoma/terapia , Técnicas de Diagnóstico Molecular/normasRESUMEN
BACKGROUND: The association between herpes zoster and the risk of lymphoid neoplasms in Asian populations has not yet been established. We performed a longitudinal follow-up study using a nationwide cohort to assess the risk of lymphoid neoplasms arising after herpes zoster infection in the adult Korean population. METHODS: Data from participants ≥20 years of age who were registered in the Korean National Health Insurance Service-National Sample Cohort database between 2002 and 2013 were collected. We extracted the data of participants with herpes zoster (n = 59,495) as well as those of matched references at a ratio of 1:4 (n = 237,980) and investigated the subsequent occurrence of lymphoid neoplasms. A stratified Cox proportional hazards model was used to calculate unadjusted hazard ratios (HRs) as well as those adjusted for the Charlson comorbidity index score. RESULTS: The rate of lymphoid neoplasms was higher in the herpes zoster group (0.15% [90/59,495]) than in the reference group (0.08% [212/237,980], P < 0.001). The unadjusted and adjusted HRs of herpes zoster in patients with lymphoid neoplasms were 1.68 (95% confidence interval [CI] = 1.31-2.15) and 1.58 (95% CI = 1.23-2.02), respectively (P < 0.001 for both). On subgroup analyses according to age and sex, herpes zoster was associated with an increased risk of lymphoid neoplasms in all subgroups; the adjusted HRs were 1.53 (95% CI = 1.05-2.24) for patients < 60 years old, 1.58 (95% CI = 1.14-2.20) for patients ≥60 years old, 1.64 (95% CI = 1.16-2.31) for men, and 1.51 (95% CI = 1.06-2.16) for women (P < 0.05 for all). On subgroup analysis of lymphoid neoplasm subtypes, herpes zoster was associated with the risk of Hodgkin's disease (adjusted HR: 3.23 [95% CI = 1.17-8.93]) and multiple myeloma/malignant plasma cell neoplasms (adjusted HR: 2.17 [95% CI = 1.33-3.54]) (P < 0.05 for both). CONCLUSION: Herpes zoster is associated with lymphoid neoplasm development in the Korean population irrespective of age and sex. The risks of Hodgkin's disease and plasma cell neoplasms are significantly elevated in patients with herpes zoster.
Asunto(s)
Herpes Zóster/complicaciones , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Linfoma/epidemiología , Linfoma/etiología , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Susceptibilidad a Enfermedades , Femenino , Estudios de Seguimiento , Herpes Zóster/virología , Herpesvirus Humano 3 , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Passive immunotherapy with therapeutic monoclonal antibodies (mAbs) has revolutionized the treatment of cancer, especially hematological malignancies over the last 20 years. While use of mAbs has improved outcomes, development of resistance is inevitable in most cases, hindering the long-term survival of cancer patients. This review focuses on the available data on mechanisms of resistance to rituximab and includes some additional information for other mAbs currently in use in hematological malignancies. RECENT FINDINGS: Mechanisms of resistance have been identified that target all described mechanisms of mAb activity including altered antigen expression or binding, impaired complement-mediated cytotoxicity (CMC) or antibody-dependent cellular cytotoxicity (ADCC), altered intracellular signaling effects, and inhibition of direct induction of cell death. Numerous approaches to circumvent identified mechanisms of resistance continue to be investigated, but a thorough understanding of which resistance mechanisms are most clinically relevant is still elusive. In recent years, a deeper understanding of the tumor microenvironment and targeting the apoptotic pathway has led to promising breakthroughs. Resistance may be driven by unique patient-, disease-, and antibody-related factors. Understanding the mechanisms of resistance to mAbs will guide the development of strategies to overcome resistance and re-sensitize cancer cells to these biological agents.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Resistencia a Antineoplásicos , Leucemia Linfoide/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacología , Antígenos de Neoplasias/inmunología , Antineoplásicos Inmunológicos/farmacología , Apoptosis , Proteínas del Sistema Complemento/inmunología , Resistencia a Antineoplásicos/genética , Humanos , Leucemia Linfoide/etiología , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patología , Linfoma/etiología , Linfoma/metabolismo , Linfoma/patología , Polimorfismo Genético , Receptores de IgG/metabolismo , Factores de Riesgo , Resultado del Tratamiento , Microambiente TumoralRESUMEN
Signals emanating from the B-cell receptor (BCR) promote proliferation and survival in diverse forms of B-cell lymphoma. Precision medicine strategies targeting the BCR pathway have been generally effective in treating lymphoma, but often fail to produce durable responses in diffuse large B-cell lymphoma (DLBCL), a common and aggressive cancer. New insights into DLBCL biology garnered from genomic analyses and functional proteogenomic studies have identified novel modes of BCR signaling in this disease. Herein, we describe the distinct roles of antigen-dependent and antigen-independent BCR signaling in different subtypes of DLBCL. We highlight mechanisms by which the BCR cooperates with TLR9 and mutant isoforms of MYD88 to drive sustained NF-κB activity in the activated B-cell-like (ABC) subtype of DLBCL. Finally, we discuss progress in detecting and targeting oncogenic BCR signaling to improve the survival of patients with lymphoma.
Asunto(s)
Leucemia Linfoide/etiología , Leucemia Linfoide/metabolismo , Linfoma/etiología , Linfoma/metabolismo , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de Señal , Animales , Autoantígenos/inmunología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Centro Germinal/patología , Humanos , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Receptores de Antígenos de Linfocitos B/genéticaRESUMEN
PURPOSE OF REVIEW: The outcome of patients with lymphoid malignancies has markedly improved in recent years which is likely due to a combination of advances in supportive care, and therapeutic options. In this article, we will provide an overview over the role PI3-kinase signalling, one of the most important dysregulated pathways in cancer, and its successful inhibition in lymphoma. RECENT FINDINGS: PI3-kinase inhibitors have shown remarkable activity in an increasing subset of patients with non-Hodgkin lymphomas. The first drug to be approved was idelalisib for patients with relapsed/refractory follicular lymphoma and CLL/SLL as monotherapy, or in combination with rituximab, respectively. After an initial setback related to increased toxicity including deaths observed in several upfront studies, there has been a resurgence in interest in this pathway following the promising efficacy of second-generation PI3K inhibitors including in patients with T cell lymphomas. PI3K inhibition continues to be an invaluable tool in the therapy of patients with lymphoid malignancies if managed cautiously. Preclinical models are helpful in predicting possible side effects and identifying new lymphoma subtypes that may be susceptible to this class of agents. The future will likely involve rationally designed combinatorial approaches to deepen the response rate and prevent the emergence of resistance.
Asunto(s)
Antineoplásicos/farmacología , Leucemia Linfoide/metabolismo , Linfoma/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Animales , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Isoenzimas , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/tratamiento farmacológico , Leucemia Linfoide/etiología , Linfoma/diagnóstico , Linfoma/tratamiento farmacológico , Linfoma/etiología , Terapia Molecular Dirigida/métodos , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
La leucemia linfoide crónica (LLC) es una neoplasia maligna que afecta principalmente a pacientes de mediana edad y ancianos. Se caracteriza por la proliferación de linfocitos morfológicamente maduros pero inmunoincompetentes que se acumulan en sangre periférica, médula ósea y tejido linfático. Presenta gran heterogeneidad clínica. Se describen diversos fenotipos, aunque predomina la expansión clonal de células B CD5+CD23+. Los factores pronósticos en la LLC incluyen el subgrupo citogenético, estado mutacional de inmunoglobulina, la expresión de ZAP-70, CD38 y CD49d. El tratamiento se basa en usar modernos algoritmos terapéuticos aprobados, que produzcan mayores respuestas y menores eventos secundarios, en lograr la remisión clínica completa y mejorar la calidad de vida de estos pacientes(AU)
Chronic lymphocytic leukemia (CLL) is a malignancy that mainly affects middle-aged and elderly patients. It is characterized by the proliferation of morphologically mature but immunoincompetent lymphocytes that accumulate in blood, bone marrow and lymphatic tissue. It presents great clinical heterogeneity. Several phenotypes are described, although the clonal expansion of CD5 + CD23 + B cells predominates. Prognostic factors include the cytogenetic subgroup, immunoglobulin mutational status, expression of ZAP-70, CD38, and CD49d. The treatment is based on using modern approved therapeutic algorithms that produce greater responses and minor secondary events, to achieve complete clinical remission and to improve the quality of life of these patients(AU)
Asunto(s)
Humanos , Leucemia Linfoide/genética , Inmunofenotipificación/métodos , Pronóstico , Leucemia Linfoide/etiología , Citometría de Flujo/métodos , Antígenos/metabolismoRESUMEN
Although a possible role of reproductive factors in lymphomagenesis has been hypothesized, results of epidemiological studies have been inconsistent. Here, we investigated the association between reproductive factors and the risk of lymphoid neoplasm and its subgroups. We used data from a large-scale, population-based prospective study in a Japanese cohort with 42 691 eligible women aged 40-69 years from 1990 to 1994. During a mean follow up of 18.7 years, we identified 176 cases of lymphoid neoplasm and 90 of non-Hodgkin lymphoma (NHL). A multivariable-adjusted Cox proportional hazards regression model was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for the risk of lymphoid neoplasms and its subgroups according to self-reported reproductive factors. Parous women had an increased risk of lymphoid neoplasm compared with nulliparous women (HR = 2.51, 95% CI, 1.03-6.13). An increased risk of lymphoid neoplasms was found in women with later onset of menarche (≤13 years old; reference: 14-15; HR = 1.75, 95% CI = 1.10-2.79: ≥16; HR = 1.93, 95% CI = 1.17-3.19: P-trend: 0.01) and a shorter menstrual cycle (28-29 days; reference: ≤27; HR = 1.60, 95% CI = 1.05-2.43, P-trend = 0.81). No association was observed between lymphoid neoplasms and other reproductive factors, including age at first birth, breastfeeding, type of menopause, or exogenous hormone use. Our study suggests that ever parity, late age at menarche and a short menstrual cycle length may be associated with the development of lymphoid neoplasms. The inconsistency seen in epidemiological research to date warrants further investigation.
Asunto(s)
Susceptibilidad a Enfermedades , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Linfoma/epidemiología , Linfoma/etiología , Historia Reproductiva , Adulto , Factores de Edad , Anciano , Femenino , Estudios de Seguimiento , Humanos , Japón/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Vigilancia en Salud Pública , Medición de Riesgo , Factores de RiesgoRESUMEN
OBJECTIVE: The main goal was to analyze the incidence of the morbidity in 1980, 1989, 2001, 2014 years and the structures of the absolute number of hematopoietic and lymphoid neoplasms cases during the period 1980-2014 on radiation contaminated and not contaminated territories in Cherkasy region. MATERIALS AND METHODS: The epidemiological indecies of hematological neoplasms were analyzed on radiation con taminated and not contaminated territories in Cherkasy region during the period from 1980 to 2014. Referring the territory in Cherkasy region to radiation contaminated is based on settlements dosimetry certification of Ukraine after the Chornobyl accident. 63 settlements were enrolled to radiation contaminated areas in Cherkasy region and 11 settlements assigned as not contaminated areas. RESULTS: The first positions in the list of the hematological neoplasms structure and frequency among new cases during 1980-2014 on not contaminated territories in Cherkasy region occupied by lymphoid leukemia, Hodgkin's lymphoma and myeloid leukemia and on the radiation contaminated territories - chronic, acute lymphoid and myeloid leukemia and lymphoma, diffuse large cell lymphoma. In the structure of hematological neoplasms record ed on the contaminated territories in Cherkasy region, there is a smaller proportion of Hodgkin's lymphoma cases (C81) than 0.84 fold (RR = 0.84; 95 % CI = 0.75-0.93) and more than 1.15 times (RR = 1.15; 95 % CI = 1.02-1.30) other unspecified malignant lymphoid and hematopoietic neoplasms. In 2001 on the radiation contaminated terri tories in Cherkasy region increase the incidence of acute and chronic myeloid leukemia in 2.46 times (p = 0.024) observed compared to non contaminated areas there (5.30 per 100 000, 95% CI = 3.03-8.33 versus 2.15 per 100,000, 95 % CI = 0.66-3.64). It was calculated that RR of acute and chronic myeloid leukemia (C92) in 2001 on radiation contaminated areas in Cherkasy region is 1.40 (95 % CI = 1.12-1.17) and Hodgkin's lymphoma (C81) on condition ally clean areas Cherkasy region - 1.70 (95 % CI = 1.36-2.12).
Asunto(s)
Accidente Nuclear de Chernóbil , Neoplasias Hematológicas/epidemiología , Enfermedad de Hodgkin/epidemiología , Leucemia Linfoide/epidemiología , Leucemia Mieloide/epidemiología , Linfoma de Células B Grandes Difuso/epidemiología , Exposición a la Radiación/efectos adversos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Niño , Preescolar , Enfermedad Crónica , Femenino , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/patología , Enfermedad de Hodgkin/etiología , Enfermedad de Hodgkin/patología , Humanos , Incidencia , Leucemia Linfoide/etiología , Leucemia Linfoide/patología , Leucemia Mieloide/etiología , Leucemia Mieloide/patología , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Dosis de Radiación , Contaminantes Radiactivos/efectos adversos , Radiometría , Población Rural , Sobrevivientes , Ucrania/epidemiología , Población UrbanaRESUMEN
Background: Dietary fat intake may contribute to non-Hodgkin lymphoma (NHL) pathogenesis by influencing carcinogen exposure or through immune modulation.Objective: We aimed to evaluate NHL risk associated with total and specific dietary fat intake.Design: We evaluated associations within the Nurses' Health Study (NHS) (n = 88,598) and the Health Professionals Follow-Up Study (HPFS) (n = 47,531) using repeated validated dietary assessments. We confirmed 1802 incident NHL diagnoses through 2010. Using multivariable Cox proportional hazards models, we estimated hazard ratios (HRs) for all NHL and common subtypes associated with a 1-SD increase in cumulative mean intakes of total, animal, saturated, trans, and vegetable fats and marine fatty acids. We pooled sex-specific HRs using random-effects meta-analysis.Results: Over 24-30 y of follow-up, neither total nor specific dietary fats were significantly associated with NHL risk overall. Higher total, animal, and saturated fat intakes were positively associated with the risk of the chronic lymphocytic leukemia/small lymphocytic lymphoma subtype among women only (253 cases; P-trend ≤ 0.05), driven by strong associations during 1980-1994. From baseline through 1994, among women and men combined, total fat intake was borderline-significantly positively associated with NHL overall (pooled HR per SD: 1.13; 95% CI: 0.99, 1.29) and was significantly associated with diffuse large B cell lymphoma (pooled HR per SD: 1.47; 95% CI: 1.06, 2.05), with similar trends for animal and saturated fat intake. For women only, trans fat was significantly positively associated with all NHL. In contrast, during 1994-2010, there was little evidence for associations of dietary fat intake with NHL overall or by subtype.Conclusion: Previous observations of an increased risk of NHL associated with intakes of total, animal, saturated, and trans fat with 14 y of follow-up did not persist with longer follow-up.
Asunto(s)
Dieta , Grasas de la Dieta/efectos adversos , Conducta Alimentaria , Linfoma no Hodgkin/etiología , Ácidos Grasos trans/efectos adversos , Adulto , Animales , Ingestión de Energía , Ácidos Grasos/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfoide/etiología , Linfoma de Células B/etiología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de RiesgoRESUMEN
We studied 140 families with two or more lymphoid cancers, including non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), for deviation from the population age of onset and lymphoid cancer co-occurrence patterns. Median familial NHL, HL, CLL and MM ages of onset are substantially earlier than comparable population data. NHL, HL and CLL (but not MM) also show earlier age of onset in later generations, known as anticipation. The co-occurrence of lymphoid cancers is significantly different from that expected based on population frequencies (p < .0001), and the pattern differs more in families with more affected members (p < .0001), suggesting specific lymphoid cancer combinations have a shared genetic basis. These families provide evidence for inherited factors that increase the risk of multiple lymphoid cancers. This study was approved by the BC Cancer Agency - University of British Columbia Clinical Research Ethics Board.
Asunto(s)
Familia , Leucemia Linfoide/epidemiología , Linfoma/epidemiología , Edad de Inicio , Anticipación Genética , Susceptibilidad a Enfermedades , Femenino , Predisposición Genética a la Enfermedad , Humanos , Leucemia Linfoide/etiología , Linfoma/etiología , Masculino , Linaje , Programa de VERFRESUMEN
OBJECTIVES: There is an ongoing debate on the possible association between infections in early childhood and subsequent cancer risk, but it remains unclear if a hospital admission for infection is associated with risk of childhood cancer diagnosis. We examined if a hospital-based diagnosis of pneumonia was a clinical marker of the three most common childhood cancers. DESIGN: Population-based cohort study. SETTING: Denmark, hospital diagnoses, 1994-2013. METHODS: Using national health registries, we compared the observed incidence of leukaemia, lymphoma and brain cancer among 83 935 children with a hospital-based pneumonia diagnosis with that expected among children in the general population. We calculated absolute cancer risks and standardised incidence ratios (SIRs) as a measure of relative risk. RESULTS: The cancer SIRs were substantially increased during the first 6 months of follow-up; lymphoid leukaemia: 6.2 (95% CI 3.5 to 10.3); myeloid leukaemia: 14.8 (95% CI 6.0 to 30.6); Hodgkin's lymphoma: 60.8 (95% CI 26.2 to 120), non-Hodgkin's lymphoma: 15.9 (95% CI 5.2 to 37.2) and brain cancer: 4.4 (95% CI 1.9 to 8.7). The 6-month absolute risks of leukaemia, lymphoma and brain cancer were all low, reaching 0.05% when combined. An increased risk persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the 5-year absolute cancer risk was 0.14%. CONCLUSIONS: The short-term incidence of leukaemia, lymphoma and brain cancer was higher than expected and persisted beyond 5 years for non-Hodgkin's lymphoma and brain cancer. However, the absolute cancer risk was low.
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Neoplasias Encefálicas/etiología , Leucemia/etiología , Linfoma/etiología , Neumonía/complicaciones , Adolescente , Neoplasias Encefálicas/epidemiología , Niño , Preescolar , Estudios de Cohortes , Dinamarca/epidemiología , Femenino , Enfermedad de Hodgkin/epidemiología , Enfermedad de Hodgkin/etiología , Hospitalización , Humanos , Incidencia , Lactante , Recién Nacido , Leucemia/epidemiología , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Leucemia Mieloide/epidemiología , Leucemia Mieloide/etiología , Linfoma/epidemiología , Linfoma no Hodgkin/epidemiología , Linfoma no Hodgkin/etiología , Masculino , Sistema de Registros , Factores de RiesgoRESUMEN
The NF-κB pathway, a critical regulator of apoptosis, plays a key role in many normal cellular functions. Genetic alterations and other mechanisms leading to constitutive activation of the NF-κB pathway contribute to cancer development, progression and therapy resistance by activation of downstream anti-apoptotic pathways, unfavorable microenvironment interactions, and gene dysregulation. Not surprisingly, given its importance to normal and cancer cell function, the NF-κB pathway has emerged as a target for therapy. In the review, we present the physiologic role of the NF-κB pathway and recent advances in better understanding of the pathologic roles of the NF-κB pathway in major types of lymphoid neoplasms. We also provide an update of clinical trials that use NF-κB pathway inhibitors. These trials are exploring the clinical efficiency of combining NF-κB pathway inhibitors with various agents that target diverse mechanisms of action with the goal being to optimize novel therapeutic opportunities for targeting oncogenic pathways to eradicate cancer cells.
Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Linfoide/tratamiento farmacológico , Leucemia Linfoide/metabolismo , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Terapia Molecular Dirigida , FN-kappa B/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos/farmacología , Biomarcadores de Tumor , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/etiología , Tejido Linfoide/efectos de los fármacos , Tejido Linfoide/metabolismo , Tejido Linfoide/patología , Linfoma/diagnóstico , Linfoma/etiología , Mutación , Resultado del Tratamiento , Microambiente TumoralRESUMEN
In hematological malignancies complex interactions exist between the immune system, microorganisms and malignant cells. On one hand, microorganisms can induce cancer, as illustrated by specific infection-induced lymphoproliferative diseases such as Helicobacter pylori-associated gastric mucosa-associated lymphoid tissue lymphoma. On the other hand, malignant cells create an immunosuppressive environment for their own benefit, but this also results in an increased risk of infections. Disrupted innate immunity contributes to the neoplastic transformation of blood cells by several mechanisms, including the uncontrolled clearance of microbial and autoantigens resulting in chronic immune stimulation and proliferation, chronic inflammation, and defective immune surveillance and anti-cancer immunity. Restoring dysfunction or enhancing responsiveness of the innate immune system might therefore represent a new angle for the prevention and treatment of hematological malignancies, in particular lymphoid malignancies and associated infections. Recently, it has been shown that cells of the innate immune system, such as monocytes/macrophages and natural killer cells, harbor features of immunological memory and display enhanced functionality long-term after stimulation with certain microorganisms and vaccines. These functional changes rely on epigenetic reprogramming and have been termed 'trained immunity'. In this review the concept of 'trained immunity' is discussed in the setting of lymphoid malignancies. Amelioration of infectious complications and hematological disease progression can be envisioned to result from the induction of trained immunity, but future studies are required to prove this exciting new hypothesis.
Asunto(s)
Inmunidad Innata , Memoria Inmunológica , Leucemia Linfoide/inmunología , Linfoma/inmunología , Inmunidad Adaptativa , Animales , Antígenos/inmunología , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Tolerancia Inmunológica , Terapia de Inmunosupresión , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Leucemia Linfoide/etiología , Leucemia Linfoide/metabolismo , Leucemia Linfoide/patología , Activación de Linfocitos/inmunología , Linfoma/etiología , Linfoma/metabolismo , Linfoma/patología , Transducción de SeñalRESUMEN
Nijmegen breakage syndrome (NBS, MIM #251260) is an autosomal recessive chromosomal instability disorder. Majority of patients affected are of Slavic origin and share the same founder mutation of 657del5 within the NBN gene encoding protein involved in DNA double-strand breaks repair. Clinically, this is characterized by a microcephaly, immunodeficiency and a high incidence of pediatric malignancies, mostly lymphomas and leukemias. Anticancer treatment among patients with NBS is challenging because of a high risk of life threatening therapy-related toxicity including severe infections, bone marrow failure, cardio- and nephrotoxicity and occurrence of secondary cancer. Based on systemic review of available literature and the Polish acute lymphoblastic leukemia database we concluded that among patients with NBS, these who suffered from clinically proven severe immunodeficiency are at risk of the complications associated with oncological treatment. Thus, in this group it reasonable to reduce chemotherapy up to 50% especially concerning anthracyclines methotrexate, alkylating agents and epipodophyllotoxines, bleomycin and radiotherapy should be omitted. Moreover, infection prophylaxis using intravenous immunoglobulin supplementation together with antifungal and antibacterial agent is recommended. To replace radiotherapy or some toxic anticancer agents targeted therapy using monoclonal antibodies and kinase inhibitors or bone marrow transplantation with reduced-intensity conditioning should be considered in some cases, however, this statement needs further studies.
Asunto(s)
Leucemia Linfoide/diagnóstico , Leucemia Linfoide/terapia , Linfoma/diagnóstico , Linfoma/terapia , Síndrome de Nijmegen/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Predisposición Genética a la Enfermedad , Humanos , Inmunoterapia/efectos adversos , Inmunoterapia/métodos , Infecciones/etiología , Leucemia Linfoide/epidemiología , Leucemia Linfoide/etiología , Linfoma/epidemiología , Linfoma/etiología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Síndrome de Nijmegen/complicaciones , Síndrome de Nijmegen/diagnóstico , Síndrome de Nijmegen/terapia , Fenotipo , Radioterapia/efectos adversos , Radioterapia/métodos , Riesgo , Resultado del TratamientoRESUMEN
B-cell receptor (BCR) signaling pathway plays a central role in B-lymphocyte development and initiation of humoral immunity. Recently, BCR signaling pathway has been shown as a major driver in the pathogenesis of B-cell malignancies. As a result, a vast array of BCR-associated kinases has emerged as rational therapeutic targets changing treatment paradigms in B cell malignancies. Based on high efficacy in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR signaling pathway. Here, we describe the essential components of BCR signaling, their function in normal and pathogenic signaling and molecular effects of their inhibition in vitro and in vivo.
Asunto(s)
Leucemia Linfoide/etiología , Receptores de Antígenos de Linfocitos B/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , Leucemia Linfoide/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Transducción de SeñalRESUMEN
Post-transplantation lymphoproliferative disorder (PTLD) is a significant complication of solid organ transplantation. Most PTLD is of the B-cell subtype, although T-cell subtype PTLD uncommonly occurs. T-cell PTLDs are usually aggressive neoplasms and shorten patient and allograft survivals significantly. We present a single-center case series of 4 patients who developed T-cell large granular lymphocytic (LGL) leukemia, a rare T-cell PTLD characterized by large granular lymphocytes that have characteristic azurophilic granules and a highly variable clinical course.