RESUMEN
Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-ß-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways.
Asunto(s)
Neoplasias Encefálicas/inmunología , Perfilación de la Expresión Génica/métodos , Glioblastoma/inmunología , Tolerancia Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Células Madre Neoplásicas/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Células Cultivadas , Estudios de Cohortes , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Redes Reguladoras de Genes/inmunología , Glioblastoma/genética , Glioblastoma/patología , Humanos , Tolerancia Inmunológica/genética , Células Asesinas Naturales/metabolismo , Células Madre Neoplásicas/metabolismo , Fenotipo , Pronóstico , Transducción de Señal/genética , Transducción de Señal/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Carcinoma of the penis is a rare tumour of the male urogenital tract, which may be treated by using several modalities. We present a single-centre experience of iridium-192 implantation. From 1980 to 1997, 31 patients with node-negative penile cancer were treated with an iridium-192 implant to the penis. A retrospective analysis of the case notes was made. Survival curves were estimated by the Kaplan-Meier method. The median age at treatment was 61.5 years. Twenty-seven patients presented with Jackson Stage I disease and four with Stage II disease. They were treated with an iridium-192 implant to the penis after biopsy (n = 25) or tumour excision (n = 6), with a 'watch and wait' policy for inguinal nodes. Four patients did not complete their implantation treatment and had additional external beam radiotherapy. The median follow-up was 61.5 months. The primary tumour was controlled in 25 of 31 patients (80.6%) by the implant. In all but one patient with primary relapse, surgical salvage was successful, although one patient died of septicaemia 3 weeks after surgery. Nodes were the initial site of relapse in seven patients, with associated relapse in the primary in one. The actuarial 5-year survival rates were as follows: overall survival 69.0 %, disease-specific survival (corrected for intercurrent deaths) 85.4%, relapse-free survival 57.8% and local relapse-free survival 75.6%. One patient underwent amputation for necrosis and 11 of 25 patients (44%) who achieved penile conservation required dilatation for urethral stenosis. In conclusion, iridium-192 implantation is a successful method of treatment for penile cancer in terms of local control, with preservation of function in the majority of patients. In those who do relapse at the primary site, surgical salvage is usually possible.
Asunto(s)
Braquiterapia/métodos , Carcinoma/radioterapia , Radioisótopos de Iridio/uso terapéutico , Ganglios Linfáticos/patología , Neoplasias del Pene/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma/patología , Progresión de la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias del Pene/patología , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Ninety patients with stage T3 Nx Mo carcinoma of the urinary bladder were treated with radical megavoltage external beam radiotherapy. Planning for treatment was undertaken on a treatment planning system utilizing CT scan slices to define the target volume and patient outline. All patients underwent a second CT scan half way through their course of treatment to assess any change in target volume and the continued adequacy of the original treatment plan. Seventy-two patients (80%) had no spatial shift in target volume, but, of the 18 patients with such a shift, treatment plans were changed in seven. The majority of patients had no delay in continuing their treatment after replanning, but one patient had a gap of 5 days before restarting treatment. An analysis of the factors possibly associated with a change in target volume showed that a primary tumour at the bladder base, rather than elsewhere in the bladder, was the single most important criterion for predicting target volume changes. There was no correlation between the size of the initial tumour, or the size of the prostate gland in male patients, and the occurrence of a shift in volume outside the initial target volume. Some method of regularly assessing the continued relevance of the target volume may be needed in this group of patients to improve the precision of treatment and also improve results.
Asunto(s)
Carcinoma de Células Transicionales/radioterapia , Neoplasias de la Vejiga Urinaria/radioterapia , Anciano , Carcinoma de Células Transicionales/diagnóstico por imagen , Femenino , Humanos , Masculino , Planificación de la Radioterapia Asistida por Computador , Radioterapia de Alta Energía , Tomografía Computarizada por Rayos X , Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/diagnóstico por imagenRESUMEN
Ninety-six patients with inoperable carcinoma of the bronchus were entered into a prospective study of the effectiveness of palliative radiotherapy. The median survival of the group as a whole was 38 weeks. Major symptoms such as cough, dyspnoea and haemoptysis were well controlled at 3 months and 6 months follow-up. There was no significant effect on performance status. Dysphagia and tiredness occurred in 81% of patients, but were classed as mild in 41% and 47% respectively, lasting less than 4 weeks in 86%. There was no correlation between the radiotherapy dose received and symptom control. Fourteen per cent of patients were dead within approximately 3 months of treatment and were unlikely to have benefited from therapy. Careful selection of patients for palliative radiotherapy is recommended.
Asunto(s)
Adenocarcinoma/radioterapia , Carcinoma Broncogénico/radioterapia , Carcinoma de Células Pequeñas/radioterapia , Carcinoma de Células Escamosas/radioterapia , Neoplasias Pulmonares/radioterapia , Cuidados Paliativos , Adenocarcinoma/mortalidad , Anciano , Carcinoma Broncogénico/mortalidad , Carcinoma de Células Pequeñas/mortalidad , Inglaterra , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/mortalidad , Masculino , Estudios ProspectivosRESUMEN
Thirty-five patients with Hodgkin's disease were staged with the aid of chest radiographs, bipedal lymphograms and computed tomography (CT) scans. Computed tomographic findings altered management in only two patients (6%) by indicating enlargement of their radiotherapy fields. After lymphography, five patients (14%) were changed from Stage II (clinical and CT staging) to Stage III, so altering their management. Because either technique may show more extensive disease, CT and lymphography are complementary. Computed tomography should be performed initially. If it reveals no abnormality in the lymphogram area, lymphography, too, should be undertaken. Inverted Y fields are easier to visualise and design from lymphograms than from CT sections.