RESUMEN
CD4(+)Foxp3(+) regulatory T cells (Treg) are critical regulators of immune homeostasis and self-tolerance. Whereas thymic-derived or natural Treg stably express Foxp3, adaptive or induced Treg (iTreg) generated from peripheral CD4 T cells are susceptible to inflammation-induced reversion to pathogenic effector T cells. Building upon our previous observations that T cell-expressed receptors for C3a (C3aR) and C5a (C5aR) drive Th1 maturation, we tested the impact of C3aR/C5aR signaling on induction and stability of alloreactive iTreg. We observed that genetic deficiency or pharmacological blockade of C3aR/C5aR signaling augments murine and human iTreg generation, stabilizes Foxp3 expression, resists iTreg conversion to IFN-γ/TNF-α-producing efffector T cells, and, as a consequence, limits the clinical expression of graft-versus-host disease. Taken together, the findings highlight the expansive role of complement as a crucial modulator of T cell alloimmunity and demonstrate proof-of-concept that targeting C3a/C3aR and C5a/C5aR interactions could facilitate iTreg-mediated tolerance to alloantigens in humans.
Asunto(s)
Complemento C3a/inmunología , Isoantígenos , Activación de Linfocitos/inmunología , Receptor de Anafilatoxina C5a/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citometría de Flujo , Técnicas de Silenciamiento del Gen , Humanos , Immunoblotting , Isoantígenos/inmunología , Ratones , Ratones Noqueados , Subgrupos de Linfocitos T/inmunologíaRESUMEN
BACKGROUND: For women with oestrogen receptor (ER)-positive early breast cancer, treatment with tamoxifen for 5 years substantially reduces the breast cancer mortality rate throughout the first 15 years after diagnosis. We aimed to assess the further effects of continuing tamoxifen to 10 years instead of stopping at 5 years. METHODS: In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial, 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control). Allocation (1:1) was by central computer, using minimisation. After entry (between 1996 and 2005), yearly follow-up forms recorded any recurrence, second cancer, hospital admission, or death. We report effects on breast cancer outcomes among the 6846 women with ER-positive disease, and side-effects among all women (with positive, negative, or unknown ER status). Long-term follow-up still continues. This study is registered, number ISRCTN19652633. FINDINGS: Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3428 women allocated to continue vs 711 in 3418 controls, p=0·002), reduced breast cancer mortality (331 deaths vs 397 deaths, p=0·01), and reduced overall mortality (639 deaths vs 722 deaths, p=0·01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0·90 [95% CI 0·791·02] during years 59 and 0·75 [0·620·90] in later years; breast cancer mortality RR 0·97 [0·791·18] during years 59 and 0·71 [0·580·88] in later years). The cumulative risk of recurrence during years 514 was 21·4% for women allocated to continue versus 25·1% for controls; breast cancer mortality during years 514 was 12·2% for women allocated to continue versus 15·0% for controls (absolute mortality reduction 2·8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1248 women with ER-negative disease, and an intermediate effect among 4800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6454 women allocated to continue versus 679 deaths in 6440 controls; RR 0·99 [0·891·10]; p=0·84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1·87 (95% CI 1·133·07, p=0·01 [including 0·2% mortality in both treatment groups]), stroke 1·06 (0·831·36), ischaemic heart disease 0·76 (0·600·95, p=0·02), and endometrial cancer 1·74 (1·302·34, p=0·0002). The cumulative risk of endometrial cancer during years 514 was 3·1% (mortality 0·4%) for women allocated to continue versus 1·6% (mortality 0·2%) for controls (absolute mortality increase 0·2%). INTERPRETATION: For women with ER-positive disease, continuing tamoxifen to 10 years rather than stopping at 5 years produces a further reduction in recurrence and mortality, particularly after year 10. These results, taken together with results from previous trials of 5 years of tamoxifen treatment versus none, suggest that 10 years of tamoxifen treatment can approximately halve breast cancer mortality during the second decade after diagnosis. FUNDING: Cancer Research UK, UK Medical Research Council, AstraZeneca UK, US Army, EU-Biomed.
Asunto(s)
Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/administración & dosificación , Adulto , Anciano , Neoplasias de la Mama/química , Quimioterapia Adyuvante , Femenino , Humanos , Persona de Mediana Edad , Receptores de Estrógenos/análisis , Factores de TiempoRESUMEN
Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4-cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. In support of this concept, augmenting DC C5a/C3a production bypasses the requirement for CD4- and CD40-dependent help to wild-type CD8(+) T cells. CD4-deficient recipients of allogeneic heart transplants prime weak CD8 responses and do not acutely reject their grafts. In contrast, CD4-deficient chimeric mice possessing decay accelerating factor deficient (Daf1(-/-)) bone marrow, in which DC C3a/C5a production is potentiated, acutely reject transplants through a CD8 cell-dependent mechanism. Furthermore, hearts transplanted into CD40(-/-) mice prime weak CD8-cell responses and survive indefinitely, but hearts transplanted into Daf1(-/-)CD40(-/-) recipients undergo CD8 cell-dependent rejection. Together, the data indicate that heightened production and activation of immune cell-derived complement bypasses the need for CD40/CD154 interactions and implicate antigen-presenting cell-produced C5a and C3a as molecular bridges linking CD4 help to CD8(+) T cells.
Asunto(s)
Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Proteínas del Sistema Complemento/metabolismo , Animales , Células de la Médula Ósea/citología , Antígenos CD40/metabolismo , Ligando de CD40/metabolismo , Células Cultivadas , Complemento C3a/metabolismo , Complemento C5a/metabolismo , Cruzamientos Genéticos , Células Dendríticas/citología , Ensayo de Inmunoadsorción Enzimática/métodos , Citometría de Flujo/métodos , Rechazo de Injerto , Trasplante de Corazón/métodos , Inmunohistoquímica/métodos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodosRESUMEN
PURPOSE: Performance of 3D-T1W-TSE has been proven superior to 3D-MP-GRE at 3 T on brain metastases (BM) contrast-enhanced (CE) MRI. However, its performance at 1.5 T is largely unknown and sparsely reported. This study aims to assess image quality, lesion detectability and conspicuity of 1.5 T 3D-T1W-TSE on planning MRI of frameless BM radiotherapy. METHODS: 94 BM patients to be treated by frameless brain radiotherapy were scanned using 3D-T1W-TSE with immobilization on multi-vendor 1.5 T MRI-simulators. BMs were jointly diagnosed by 4 reviewers. Enhanced lesion conspicuity was quantitatively assessed by calculating contrast ratio (CR) and contrast-to-noise ratio (CNR). Signal-to-noise ratio (SNR) reduction of white matter due to the use of flexible coil was assessed. Lesion detectability and conspicuity were compared between 1.5 T planning MRI and 3 T diagnostic MRI by an oncologist and a radiologist in 10 patients. RESULTS: 497 BMs were jointly diagnosed. The CR and CNR were 75.2 ± 39.9% and 14.2 ± 8.1, respectively. SNR reduced considerably from 31.7 ± 8.3 to 21.9 ± 5.4 with the longer distance to coils. 3 T diagnostic MRI and 1.5 T planning MRI yielded exactly the same detection of 84 BMs. Qualitatively, lesion conspicuity at 1.5 T was not inferior to that at 3 T. Quantitatively, lower brain SNR and lesion CNR were found at 1.5 T, while lesion CR at 1.5 T was highly comparable to that at 3 T. CONCLUSION: 1.5 T 3D-T1W-TSE planning MRI of frameless BM radiotherapy was comprehensively assessed. Highly comparable BM detectability and conspicuity were achieved by 1.5 T planning MRI compared to 3 T diagnostic MRI. 1.5 T 3D-T1W-TSE should be valuable for frameless brain radiotherapy planning.
Asunto(s)
Neoplasias Encefálicas , Oncología por Radiación , Encéfalo , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/radioterapia , Medios de Contraste , Humanos , Imagen por Resonancia Magnética/métodosRESUMEN
Decay-accelerating factor (DAF) is a cell surface regulator that accelerates the dissociation of C3/C5 convertases and thereby prevents the amplification of complement activation on self cells. In the context of transplantation, DAF has been thought to primarily regulate antibody-mediated allograft injury, which is in part serum complement-dependent. Based on our previously delineated link between DAF and CD4 T cell responses, we evaluated the effects of donor Daf1 (the murine homolog of human DAF) deficiency on CD8 T cell-mediated cardiac allograft rejection. MHC-disparate Daf1(-/-) allografts were rejected with accelerated kinetics compared with wild-type grafts. The accelerated rejection predominantly tracked with DAF's absence on bone marrow-derived cells in the graft and required allograft production of C3. Transplantation of Daf1(-/-) hearts into wild-type allogeneic hosts augmented the strength of the anti-donor (direct pathway) T cell response, in part through complement-dependent proliferative and pro-survival effects on alloreactive CD8 T cells. The accelerated allograft rejection of Daf1(-/-) hearts occurred in recipients lacking anti-donor Abs. The results reveal that donor DAF expression, by controlling local complement activation on interacting T cell APC partners, regulates the strength of the direct alloreactive CD8(+) T cell response. The findings provide new insights into links between innate and adaptive immunity that could be exploited to limit T cell-mediated injury to an allograft following transplantation.
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Antígenos CD55/genética , Rechazo de Injerto/inmunología , Trasplante de Corazón/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD55/biosíntesis , Antígenos CD55/fisiología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Células Cultivadas , Activación de Complemento/genética , Activación de Complemento/inmunología , Citotoxicidad Inmunológica/genética , Rechazo de Injerto/genética , Rechazo de Injerto/metabolismo , Rechazo de Injerto/patología , Trasplante de Corazón/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Proyectos Piloto , Linfocitos T/metabolismoRESUMEN
Dendritic cells (DC) obtained by culturing myeloid precursors in GM-CSF undergo maturation and induce an efficient T cell response when stimulated with microbial products. DC precursors themselves also recognize microbial products, and it remains unclear how these stimulated DC precursors modulate the immune response. We show here that M-CSF-conditioned human DC precursors responded to LPS, Mycobacteria bovis, and inflammatory cytokines by a rapid and robust production of IL-10, largely superior to that observed with immature DC or monocytes. The endogenous IL-10 restrained the DC precursors from converting into professional APC, as blocking the IL-10 receptor in the presence of LPS resulted in the formation of efficient T cell stimulators. LPS stimulation concomitant with DC differentiation gave rise to immature DC, which were tolerant to a secondary LPS exposure. Furthermore, the LPS-activated DC precursors reduced bystander DC maturation and anti-CD3/CD28-triggered T cell activation. These data suggest that when exposed to inflammatory or microbial signals, M-CSF-conditioned DC precursors can participate in the modulation of inflammation and immune response by rapid release of IL-10.
Asunto(s)
Células Dendríticas/citología , Tolerancia Inmunológica , Interleucina-10/metabolismo , Lipopolisacáridos/farmacología , Factor Estimulante de Colonias de Macrófagos/farmacología , Diferenciación Celular , Citocinas/farmacología , Células Dendríticas/inmunología , Humanos , Inmunidad , Inflamación/inmunología , Células Mieloides/citologíaRESUMEN
Large B cell lymphomas can comprise numerous CD14+ cells in the tumor stroma, which raises the question of whether monocytes can support B cell survival and proliferation. We show that the coculture of monocytes with B cells from peripheral blood or from diffuse large B cell lymphoma enabled prolonged B cell survival. Under these conditions, diffuse large lymphoma B cells proliferated, and addition of B cell-activating factor of the TNF family (BAFF) and IL-2 enhanced cell division. Monocytes and dendritic cells (DC) had similar antiapoptotic activity on healthy B cells but displayed differences with respect to B cell proliferation. Monocytes and cord blood-derived CD14+ cells promoted B cell proliferation in the presence of an anti-CD40 stimulus, whereas DC supported B cell proliferation when activated through the BCR. DC and CD14+ cells were able to induce plasmocyte differentiation. When B cells were activated via the BCR or CD40, they released the leukocyte attractant CCL5, and this chemokine is one of the main chemokines expressed in diffuse large B cell lymphoma. The data support the notion that large B cell lymphoma recruit monocytes via CCL5 to support B cell survival and proliferation.
Asunto(s)
Linfocitos B/metabolismo , Proliferación Celular , Ganglios Linfáticos/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Monocitos/metabolismo , Receptor del Factor Activador de Células B/metabolismo , Biomarcadores de Tumor/metabolismo , Antígenos CD40/metabolismo , Supervivencia Celular , Quimiocina CCL5 , Quimiocinas CC/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/patología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Humanos , Técnicas para Inmunoenzimas , Interleucina-2/metabolismo , Receptores de Lipopolisacáridos/metabolismo , Ganglios Linfáticos/patología , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/patología , Monocitos/citología , Células Mieloides/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: The incidence rate of breast cancer is rising rapidly in Hong Kong. Lymphedema is a serious long-term complication of breast cancer surgery and radiation therapy. OBJECTIVE: The objectives of this study were to evaluate risk factors associated with the development of lymphedema for patients with breast cancer who have had an axillary lymph node dissection and to explore potential factors associated with moderate to severe lymphedema. METHODS: This was a matched case-control study of 202 women undergoing a unilateral axillary dissection for breast cancer, consisting of 101 cases with lymphedema and 101 controls who matched cases in terms of surgery date, axillary radiotherapy, and cancer stage. Arm circumferences were measured to determine presence and severity of lymphedema. Potential risk factors were collected by using clinical data and a questionnaire. A multiple logistic regression was used to obtain the adjusted odds ratios for potential risk factors for developing lymphedema. Exploratory analysis was also performed to identify factors associated with the development of moderate to severe lymphedema. RESULTS: Adjusted odds ratios for the development of lymphedema were 3.80 (95% confidence interval [CI] = 1.84-7.87) for previous inflammation-infection and 1.06 (95% CI = 1.02-1.10) for an increase of 1 year of age at axillary dissection. On exploratory analysis, adjusted odds ratios for moderate to severe degree of lymphedema were 4.53 (95% CI = 2.16-9.52) for previous inflammation-infection, 2.94 (95% CI = 1.44-6.03) for operation on dominant arm, 1.11 (95% CI = 1.01-1.22) for an increase of 1 kg/m in body mass index (BMI) at recruitment, and 1.05 (95% CI = 1.01-1.10) for an increase of 1 year of age at recruitment time. DISCUSSION: Previous inflammation-infection and advanced age at axillary dissection are risk factors associated with the initiation of lymphedema. Previous inflammation-infection, operation on the side of the dominant hand, obesity, and aging are potential risk factors associated with the aggravation of lymphedema. Greater BMI is still a risk factor for lymphedema progression even in a lower BMI population.
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Neoplasias de la Mama/cirugía , Escisión del Ganglio Linfático/efectos adversos , Linfedema/etiología , Distribución por Edad , Análisis de Varianza , Antropometría , Axila , Índice de Masa Corporal , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/radioterapia , Estudios de Casos y Controles , Femenino , Hong Kong/epidemiología , Humanos , Incidencia , Estilo de Vida , Modelos Logísticos , Linfedema/diagnóstico , Linfedema/epidemiología , Persona de Mediana Edad , Evaluación en Enfermería , Investigación en Enfermería , Oportunidad Relativa , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.
Asunto(s)
Movimiento Celular/fisiología , Células Dendríticas/metabolismo , Células Dendríticas/fisiología , Histiocitosis de Células de Langerhans/metabolismo , Células de Langerhans/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Proto-Oncogénicas B-raf/metabolismo , Animales , Apoptosis/fisiología , Histiocitosis de Células de Langerhans/patología , Humanos , Células de Langerhans/fisiología , Ratones , Ratones Endogámicos C57BL , Mutación/fisiología , Fagocitosis/fisiologíaRESUMEN
Dendritic cells (DCs) are critical for the launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141+ DCs have an innate resistance to infection by a broad range of enveloped viruses, including HIV and influenza virus. In contrast, CD1c+ DCs are susceptible to infection, which enables viral antigen production but impairs their immune functions and survival. The ability of CD141+ DCs to resist infection is conferred by RAB15, a vesicle-trafficking protein constitutively expressed in this DC subset. We show that CD141+ DCs rely on viral antigens produced in bystander cells to launch cross-presentation-driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection.
RESUMEN
GM-CSF and transforming growth factor beta (TGFbeta ) are required for the generation of Langerhans cells (LC), members of the dendritic cell (DC) family. Tumor necrosis factor alpha (TNFalpha) and IL-4 can enhance LC differentiation from human monocytes or CD34(+) progenitors. Here, we show that M-CSF-cultured DC precursors derived from CD34(+) progenitors resemble dermal CD14(+) cells and readily convert to LC-like DC in GM-CSF/TGFbeta. The cells express Langerin, CD1a, and CCR6, migrate in response to CCR6 ligand CCL20, and contain Birbeck granules. TNFalpha and IL-4, added separately or together, have an inhibitory effect on LC differentiation. Cells differentiated in the presence of IL-4 and TNFalpha express low levels of CCR7. This suggests that M-CSF-conditioned DC precursors retain the capacity to efficiently undergo a differentiation program, giving rise to LC-like DC solely through the effect of GM-CSF and TGFbeta.
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Citocinas/farmacología , Dermis/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Células de Langerhans/citología , Antígenos CD , Antígenos CD1/análisis , Antígenos CD34/análisis , Antígenos de Superficie/análisis , Proteínas Portadoras/análisis , Diferenciación Celular , Quimiocina CCL20 , Quimiocinas CC/farmacología , Dermis/química , Dermis/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Células Madre Hematopoyéticas/química , Humanos , Interleucina-4/farmacología , Lectinas Tipo C/análisis , Receptores de Lipopolisacáridos/análisis , Factor Estimulante de Colonias de Macrófagos/farmacología , Proteínas Inflamatorias de Macrófagos/farmacología , Lectinas de Unión a Manosa/análisis , Glicoproteínas de Membrana/análisis , Ligando RANK , Receptor Activador del Factor Nuclear kappa-B , Receptores CCR6 , Receptores de Quimiocina/análisis , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
PURPOSE: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All patients were irradiated with the same RT technique to > or =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). RESULTS: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p > or = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). CONCLUSIONS: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Anciano , Carcinoma/patología , Cisplatino/administración & dosificación , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: To define the dose-response relationship of nasopharyngeal carcinoma (NPC) above the conventional tumoricidal dose level of 66 Gy when the basic radiotherapy (RT) course was given by the 2D Ho's technique. PATIENTS AND METHODS: Data from all five regional cancer centers in Hong Kong were pooled for this retrospective study. All patients (n = 2426) were treated with curative-intent RT with or without chemotherapy between 1996 and 2000 with the basic RT course using the Ho's technique. The primary endpoint was local control. The prognostic significance of dose-escalation ('boost') after 66 Gy, T-stage, N-stage, use of chemotherapy, sex and age (< or =40 years vs >40 years) was studied. Both univariate and multivariate analyses were performed. RESULTS: On multivariate analysis, T-stage (P < 0.01; hazard ratio [HR], 1.58) and optimal boost (P = 0.01; HR, 0.34) were the only significant factors affecting local failure for the whole study population, and for the population of patients treated by radiotherapy alone, but not for patients who also received chemotherapy. The following were independent determinants of local failure for patient groups with different T-stages treated by radiotherapy alone: use of a boost in T1/T2a disease (P = 0.01; HR, 0.33); use of a boost (P < 0.01; HR, 0.60) and age (P = 0.01; HR, 1.02) in T3/T4 tumors. Among patients with T2b tumors treated by radiotherapy alone and given a boost, the use of a 20 Gy-boost gave a lower local failure rate than a 10 Gy-boost. There was no apparent excess mortality attributed to RT complications. CONCLUSIONS: Within the context of a multi-center retrospective study, dose-escalation above 66 Gy significantly improved local control for T1/T2a and T3/4 tumors when the primary RT course was based on the 2D Ho's technique without additional chemotherapy. 'Boosting' in NPC warrants further investigation. Caution should be taken when boosting is considered because of possible increase in radiation toxicity.
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Carcinoma/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Adulto , Análisis de Varianza , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Carcinoma/mortalidad , Carcinoma/patología , Quimioterapia Adyuvante , Relación Dosis-Respuesta en la Radiación , Femenino , Estudios de Seguimiento , Hong Kong , Humanos , Registros Médicos , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Estadificación de Neoplasias , Radioterapia Adyuvante , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population. METHODS: Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured. RESULTS: A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations. CONCLUSIONS: The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Toma de Decisiones Clínicas/métodos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/estadística & datos numéricos , Femenino , Perfilación de la Expresión Génica/métodos , Hong Kong , Humanos , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Medición de Riesgo/métodos , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
PURPOSE: To determine whether therapy with a DNA methyltransferase inhibitor is effective in achieving demethylation and gene re-expression in tumor DNA in patients. METHODS: Biopsy specimens were obtained from patients with Epstein-Barr virus-associated tumors, enrolled on a clinical trial of 5-azacitidine, within 72 hours of the conclusion of the last infusion of the first cycle of therapy, and compared to pretreatment specimens. Methylation-specific polymerase chain reaction, bisulfite genomic sequencing, and immunohistochemistry were used to assess demethylation and gene re-expression. RESULTS: Substantial degrees of demethylation were detected in all latent and lytic Epstein-Barr virus promoters examined. Immunohistochemistry suggested activation of a previously silent viral antigen expression in one instance. CONCLUSION: Pharmacologic reversal of dense CpG methylation in tumor tissue can be achieved in patients.
Asunto(s)
Azacitidina/farmacología , Metilación de ADN , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/genética , Linfoma de Células B/genética , Neoplasias Nasofaríngeas/genética , Antígenos Virales de Tumores/metabolismo , Secuencia de Bases , ADN Viral/metabolismo , ADN-Citosina Metilasas , Inhibidores Enzimáticos/farmacología , Humanos , Linfoma de Células B/virología , Neoplasias Nasofaríngeas/virología , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras GenéticasRESUMEN
AIM: To investigate the age differences in the risk factors, clinicopathological characteristics and patterns of treatment of female breast cancer patients. METHODS: Seven thousand one hundred and fifty-two women with primary breast cancer from the Hong Kong Breast Cancer Registry were recruited after receiving patients' consent, they were asked to complete standardized questionnaires which captured their sociodemographic characteristics and risk factors associated with breast cancer development. Among them, clinicopathological data and patterns of treatment were further collected from medical records of 5523 patients with invasive breast cancers. Patients were divided into two groups according to the age at diagnosis: younger (< 40 years old) vs older patients (≥ 40 years old) for subsequent analyses. RESULTS: Analysis on the sociodemographic characteristics and exposure to risk factors were performed on 7152 women with primary breast cancer and the results revealed that younger patients were more likely to have unhealthy lifestyles; these include a lack of exercise (85.4% vs 73.2%, P < 0.001), having high stress in life (46.1% vs 35.5%, P < 0.001), having dairy/meat-rich diets (20.2% vs 12.9%, P < 0.001), having alcohol drinking habit (7.7% vs 5.2%, P = 0.002). Younger patients were also more likely to have hormone-related risk factors including nulliparity (43.3% vs 17.8%, P < 0.001) and an early age at menarche (20.7% vs 13.2%, P < 0.001). Analyses on clinicopathological characteristics and patterns of treatment were performed on 5523 women diagnosed with invasive breast cancer. The invasive tumours in younger patients showed more aggressive pathological features such as having a higher percentage of grade 3 histology (45.7% vs 36.5%, P < 0.001), having a higher proportion of tumours with lymphovascular invasion (39.6% vs 33.2%, P = 0.003), and having multifocal disease (15.7% vs 10.3%, P < 0.001); they received different patterns of treatment than their older counterparts. CONCLUSION: Younger patients in Hong Kong are more likely to encounter risk factors associated with breast cancer development and have more aggressive tumours than their older counterparts.
RESUMEN
Thymus-derived (natural) CD4(+) FoxP3(+) regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell-expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4(+)CD25(-) T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.
Asunto(s)
Receptor de Anafilatoxina C5a/metabolismo , Receptores de Complemento/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/prevención & control , Colitis/inmunología , Colitis/patología , Colitis/prevención & control , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Rechazo de Injerto/prevención & control , Inmunidad Innata , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Anafilatoxina C5a/deficiencia , Receptor de Anafilatoxina C5a/genética , Receptores de Complemento/deficiencia , Receptores de Complemento/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal/inmunología , Trasplante de Piel/inmunología , Trasplante de Piel/patología , Linfocitos T Reguladores/metabolismo , Trasplante HomólogoRESUMEN
Results of studies published since 2002 reveal that T cells and antigen-presenting cells (APCs) produce complement proteins. The immune cell-derived, alternative pathway complement components activate spontaneously, yielding local, but not systemic, production of C3a and C5a. These anaphylatoxins bind to their respective G-protein-coupled receptors, C3aR and C5aR, expressed on both partners. The resultant complement-induced T cell activation and APC activation drive T cell differentiation, expansion and survival. Complement deficiency or blockade attenuates T cell-mediated autoimmunity and delays allograft rejection in mice. Increasing complement activation, achieved by genetic removal of the complement regulatory protein decay-accelerating factor, enhances murine T cell immunity and accelerates allograft rejection. The findings support the need for design and testing of complement inhibitors in humans.
Asunto(s)
Proteínas del Sistema Complemento/inmunología , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , HumanosRESUMEN
Acute graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic cell transplantation (allo-HCT) that results from donor allogeneic T cell attack on host tissues. Based on previous work implicating immune cell-derived C3a and C5a as regulators of T cell immunity, we examined the effects of locally produced C3a and C5a on murine T cell-mediated GvHD. We found that total body irradiation, a conditioning regimen required to permit engraftment of allo-HCT, caused upregulation and activation of alternative pathway complement components by recipient APCs. Allo-HCT with decay accelerating factor-null (Daf1(-/-)) host BM and Daf1(-/-) donor lymphocytes led to exacerbated GvHD outcome and resulted in splenic and organ-infiltrating T cell expansion. T cells deficient in C3a receptor (C3aR) and/or C5a receptor (C5aR) responded weakly in allogeneic hosts and exhibited limited ability to induce GvHD. Using a clinically relevant treatment strategy, we showed that pharmacological C5aR blockade reduced GvHD morbidity. Our data mechanistically link APC-derived complement to T cell-mediated GvHD and support complement inhibition as a therapeutic strategy for GvHD in humans.
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Células Presentadoras de Antígenos/inmunología , Complemento C3a/inmunología , Complemento C5a/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/inmunología , Acondicionamiento Pretrasplante , Enfermedad Aguda , Animales , Células Presentadoras de Antígenos/patología , Complemento C3a/genética , Complemento C5a/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Enfermedad Injerto contra Huésped/terapia , Humanos , Ratones , Ratones Noqueados , Receptores de Complemento/genética , Receptores de Complemento/inmunología , Linfocitos T/patología , Trasplante Homólogo , Irradiación Corporal TotalRESUMEN
Acute graft-versus-host disease (GVHD) results from the attack of host tissues by donor allogeneic T cells and is the most serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Host antigen-presenting cells are thought to control the priming of alloreactive T cells and the induction of acute GVHD after allo-HCT. However, whereas the role of host DC in GVHD has been established, the contribution of host macrophages to GVHD has not been clearly addressed. We show that, in contrast to DC, reducing of the host macrophage pool in recipient mice increased donor T cell expansion and aggravated GVHD mortality after allo-HCT. We also show that host macrophages that persist after allo-HCT engulf donor allogeneic T cells and inhibit their proliferation. Conversely, administration of the cytokine CSF-1 before transplant expanded the host macrophage pool, reduced donor T cell expansion, and improved GVHD morbidity and mortality after allo-HCT. This study establishes the unexpected key role of host macrophages in inhibiting GVHD and identifies CSF-1 as a potential prophylactic therapy to limit acute GVHD after allo-HCT in the clinic.