RESUMEN
BACKGROUND: PLAnning Treatment For Oesophago-gastric Cancer: a Randomised Maintenance Therapy Trial (PLATFORM) is an adaptive phase II study assessing the role of maintenance therapies in advanced oesophago-gastric (OG) adenocarcinoma. We evaluated the role of the anti-programmed death-ligand 1 (PD-L1) inhibitor durvalumab in these patients. PATIENTS AND METHODS: Patients with human epidermal growth factor receptor 2-negative locally advanced or metastatic OG adenocarcinoma with disease control or response to 18 weeks of platinum-based first-line chemotherapy were randomised to active surveillance or maintenance durvalumab. The primary endpoint was progression-free survival (PFS). Safety was assessed in all patients who had commenced surveillance visits or received at least one dose of durvalumab. Exploratory survival analyses according to PD-L1 Combined Positive Score (CPS) and immune (biomarker-positive) or angiogenesis dominant (biomarker-negative) tumour microenvironment (TME) phenotypes were conducted. RESULTS: Between March 2015 and April 2020, 205 patients were randomised to surveillance (n = 100) and durvalumab (n = 105). No significant differences were seen in PFS [hazard ratio (HR) 0.84, P = 0.13] and overall survival (OS; HR 0.98, P = 0.45) between surveillance and durvalumab. Five patients randomised to durvalumab demonstrated incremental radiological responses compared with none with surveillance. Treatment-related adverse events occurred in 77 (76.2%) durvalumab-assigned patients. A favourable effect in OS with durvalumab over surveillance in CPS ≥5 and immune biomarker-positive patients was observed compared with CPS <5 and biomarker-negative subgroups, respectively: CPS ≥5 versus <5: HR 0.63, 95% confidence interval (CI) 0.32-1.22 versus HR 0.93, 95% CI 0.44-1.96; biomarker-positive versus negative: HR 0.60, 95% CI 0.29-1.23 versus HR 0.84, 95% CI 0.42-1.65. CONCLUSION: Maintenance durvalumab does not improve PFS in patients with OG adenocarcinoma who respond to first-line chemotherapy but induced incremental radiological responses in a subset of patients. TME characterisation could refine patient selection for anti-PD-L1 therapy above PD-L1 CPS alone.
Asunto(s)
Adenocarcinoma , Anticuerpos Monoclonales , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Gástricas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Adenocarcinoma/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Adulto , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Receptor ErbB-2/metabolismo , Anciano de 80 o más Años , Supervivencia sin ProgresiónRESUMEN
PATRIOT is a phase I study of the ATR inhibitor, AZD6738, as monotherapy, and in combination with palliative radiotherapy. Here, we describe the protocol for this study, which opened in 2014 and is currently recruiting and comprises dose escalation of both drug and radiotherapy, and expansion cohorts.
RESUMEN
Background: Targeted capture sequencing can potentially facilitate precision medicine, but the feasibility of this approach in gastrointestinal (GI) malignancies is unknown. Patients and methods: The FOrMAT (Feasibility of a Molecular Characterisation Approach to Treatment) study was a feasibility study enrolling patients with advanced GI malignancies from February 2014 to November 2015. Targeted capture sequencing (mainly using archival formalin-fixed paraffin-embedded diagnostic/resection samples) was carried out to detect mutations, copy number variations and translocations in up to 46 genes which had prognostic/predictive significance or were targets in current/upcoming clinical trials. Results: Of the 222 patients recruited, 215 patients (96.8%) had available tissue samples, 125 patients (56.3%) had ≥16 genes successfully sequenced and 136 patients (61.2%) had ≥1 genes successfully sequenced. Sample characteristics influenced the proportion of successfully sequenced samples, e.g. tumour type (colorectal 70.9%, biliary 52.6%, oesophagogastric 50.7%, pancreas 27.3%, P = 0.002), tumour cellularity (high versus low: 78.3% versus 13.3%, P ≤ 0.001), tumour content (high versus low: 78.6% versus 27.3%, P = 0.001) and type of sample (resection versus biopsy: 82.4% versus 47.6%, P ≤ 0.001). Currently, actionable alterations were detected in 90 (40.5%) of the 222 patients recruited (66% of the 136 patients sequenced) and 2 patients subsequently received a targeted therapy. The most frequently detected currently actionable alterations were mutations in KRAS, BRAF, TP53 and PIK3CA. For the 205 patients with archival samples, the median time to obtain sequencing results was 18.9 weeks, including a median of 4.9 weeks for sample retrieval and 5.1 weeks for sequencing. Conclusions: Targeted sequencing detected actionable alterations in formalin-fixed paraffin-embedded samples, but tissue characteristics are of critical importance in determining sequencing success. Routine molecular profiling of GI tumours outside of clinical trials is not an effective use of healthcare resources unless more targeted drugs become available. ClinicalTrials.gov identifier: NCT02112357.
Asunto(s)
Análisis Mutacional de ADN/métodos , Neoplasias Gastrointestinales/genética , Mutación , Análisis de Secuencia de ADN/métodos , ADN de Neoplasias/química , ADN de Neoplasias/genética , Estudios de Factibilidad , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , HumanosRESUMEN
BACKGROUND: EXPERT and EXPERT-C were phase II clinical trials of neoadjuvant chemotherapy (NACT) followed by chemoradiotherapy (CRT) in high-risk, locally advanced rectal cancer (LARC). DESIGN: We pooled individual patient data from these trials. The primary objective was overall survival (OS) in the intention-to-treat (ITT) population. Prognostic factors were also analysed. RESULTS: A total of 269 patients were included. Of these, 91.1% completed NACT, 88.1% completed CRT and 240 (89.2%) underwent curative surgery (R0/R1). After a median follow-up of 71.9 months, 5-year progression-free survival (PFS) and OS were 66.4% and 73.3%, respectively. In the group of R0/R1 resection patients, 5-year relapse-free survival (RFS) and OS were 71.6% and 77.2%, respectively, with local recurrence occurring in 5.5% and distant metastases in 20.6% of cases. Significant prognostic factors after multivariate analyses included age, tumour grade and MRI extramural venous invasion (mrEMVI) at baseline, MRI tumour regression grade (mrTRG) after CRT, ypT stage after surgery and adherence to study treatment. mrTRG after NACT was associated with PFS (P = 0.002) and OS (P = 0.018) and appeared to stratify patients based on the incremental benefit from sequential CRT. Among the outcome measures considered, in the subgroup of R0/R1 resection patients, ypT and ypStage had the highest predictive accuracy for RFS (concordance index: 0.6238 and 0.6252, respectively) and OS (concordance index: 0.6094 and 0.6132, respectively). CONCLUSIONS: Administering NACT before CRT could be a potential strategy for high-risk LARC. In this setting, mrTRG after CRT is an independent prognostic factor, while mrTRG after NACT should be tested as a parameter for treatment selection in trials of NACT ± CRT. ypT stage may be a valuable surrogate end point for future phase II trials investigating intensified neoadjuvant treatments in similar patient populations.
Asunto(s)
Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioradioterapia/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Resultado del TratamientoRESUMEN
BACKGROUND: The REAL-2 trial demonstrated that capecitabine and oxaliplatin were effective alternatives to fluorouracil and cisplatin, respectively, when used in triplet chemotherapy regimens for previously untreated oesophago-gastric cancer. The aim of the current analysis was to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in the REAL-2 cohort. MATERIAL AND METHODS: A post hoc exploratory analysis was carried out on REAL-2 patients with the available absolute neutrophil count and absolute lymphocyte count. A high NLR was defined using a cut-off value of >3.0. The NLR was then correlated with clinical outcomes including overall survival (OS), progression-free survival (PFS) and objective response rate. Survival curves were generated using the Kaplan-Meier method and comparison between groups was carried out using Cox regression. RESULTS: Data were available in 908 of the 1002 REAL-2 participants. Of these, 516 (56.8%) were deemed to have a high NLR. In univariate analysis, high NLR was associated with a hazard ratio (HR) for OS of 1.73 (1.50-2.00), P < 0.001, compared with low NLR, equating to median OS values of 9.1 [95% confidence interval (CI) 8.0-9.6] and 12.7 months (95% CI 10.8-14.4), respectively. The NLR remained highly significant for OS (P < 0.001) in a multivariate model including performance status, age, disease extent, presence of liver metastases and presence of peritoneal metastases. For PFS, high NLR was associated with an HR of 1.63 (1.41-1.87), P < 0.001, compared with low NLR in univariate analysis. No significant interaction was found between NLR status and treatment arm, 13% of all patients with low NLR achieving survival beyond 24 months compared with only 6% of patients with high NLR (P < 0.001). CONCLUSION: Our results confirm that high NLR status had a significant negative prognostic effect in the REAL-2 trial population. Based on the multivariate analysis, this effect was independent of other known prognostic factors.
Asunto(s)
Capecitabina/administración & dosificación , Neoplasias Esofágicas/tratamiento farmacológico , Compuestos Organoplatinos/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Neoplasias Esofágicas/sangre , Neoplasias Esofágicas/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Recuento de Linfocitos , Linfocitos/efectos de los fármacos , Linfocitos/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Oxaliplatino , Pronóstico , Neoplasias Gástricas/sangre , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. PATIENTS AND METHODS: We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. RESULTS: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). CONCLUSION: This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.
Asunto(s)
MicroARNs/genética , Terapia Neoadyuvante/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias del Recto/genética , Neoplasias del Recto/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Capecitabina/uso terapéutico , Cetuximab/uso terapéutico , Quimioradioterapia , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Marcadores Genéticos/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Polimorfismo de Nucleótido Simple/genética , Neoplasias del Recto/mortalidadRESUMEN
BACKGROUND: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial. METHODS: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed. RESULTS: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n=40; CAPOX-C, n=38). In this population, after a median follow-up of 63.8months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p=0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p=0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p=0.20). CONCLUSIONS: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mutación , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/genética , Proteínas ras/genética , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Capecitabina , Cetuximab , Quimioradioterapia , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias del Recto/mortalidad , Estudios Retrospectivos , Análisis de Secuencia de ADN , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/metabolismo , Adenocarcinoma/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Capecitabina , Cetuximab , Quimioradioterapia , Quimioterapia Adyuvante , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Modelos de Riesgos Proporcionales , Neoplasias del Recto/mortalidad , Estudios Retrospectivos , Método Simple Ciego , Resultado del TratamientoRESUMEN
BACKGROUND: Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer. METHODS: Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone. RESULTS: The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4). CONCLUSION: Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Epotilonas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Moduladores de Tubulina/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Diarrea/inducido químicamente , Epotilonas/efectos adversos , Femenino , Humanos , Letargia/inducido químicamente , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Moduladores de Tubulina/efectos adversosRESUMEN
BACKGROUND: The physician's global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment of response to omalizumab (XOLAIR®). This randomized, open-label, parallel-group study evaluated the persistency of treatment responder classification in patients receiving omalizumab added to optimized asthma therapy (OAT). METHODS: Patients (12-75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and omalizumab (n = 272) or OAT (n = 128) for 32 weeks. Response or nonresponse was evaluated at Weeks 16 and 32. Response was defined as an investigator's (physician's) GETE rating of excellent or good; nonresponse was defined as a rating of moderate, poor or worsening. RESULTS: Three hundred and forty-nine patients had GETE ratings available at Weeks 16 and 32 (omalizumab n = 258, OAT n = 91). Omalizumab responders of about 171/187 (91.4%)and 44/71 (62.0%) omalizumab nonresponders at Week 16 persisted as responders or nonresponders at Week 32. The investigator's GETE at Week 16 predicted persistency of response or nonresponse to omalizumab at Week 32 for 83.3% (215/258) of patients. OAT patients showed a lower persistency of response (18/28 [64.3%]) and a higher persistency of nonresponse (57/63 [90.5%]) than omalizumab patients. Excellent and good GETE ratings in omalizumab-treated patients were reflected by improvements in exacerbation rates (P < 0.001), severe exacerbation rates (P = 0.023), hospitalizations (P = 0.003), total emergency visits (P = 0.026) and Asthma Control Questionnaire overall score (P < 0.001). CONCLUSION: Response to omalizumab, as assessed by a physician's GETE at 16 weeks, is an effective predictor of continuing persistent response to omalizumab for the majority of patients.
Asunto(s)
Antiasmáticos/uso terapéutico , Anticuerpos Antiidiotipos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Asma/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados , Niño , Estudios de Seguimiento , Humanos , Inmunoglobulina E , Persona de Mediana Edad , Omalizumab , Factores de Tiempo , Resultado del TratamientoRESUMEN
Chronic tissue hypoxia may play a role in the pathogenesis of late radiation fibrosis. In order to investigate this hypothesis, the immunohistochemical distribution of pimonidazole hydrochloride (n = 14 patients) and carbonic anhydrase IX (CAIX) (n = 38 patients) was studied in samples of previously irradiated normal human tissue. One sample of irradiated breast tissue, which also showed marked histological features of radiation injury, stained positive for pimonidazole hydrochloride. No CAIX staining was seen in irradiated tissue other than some evidence of physiological hypoxia in the epidermis of two samples of irradiated skin; both were positive for pimonidazole and one was focally positive for CAIX. Pimonidazole hydrochloride staining of tissue with morphological changes of radiation injury could support a role for hypoxia in the pathogenesis of late normal tissue fibrosis in humans.
Asunto(s)
Antígenos de Neoplasias , Anhidrasas Carbónicas , Hipoxia de la Célula , Nitroimidazoles , Traumatismos por Radiación/diagnóstico , Adulto , Anhidrasa Carbónica IX , Anhidrasas Carbónicas/farmacocinética , Femenino , Humanos , Persona de Mediana Edad , Nitroimidazoles/farmacocinética , Traumatismos por Radiación/etiología , Radioterapia de Alta Energía/efectos adversos , Reino UnidoRESUMEN
BACKGROUND: Studies have linked asthma death to either increased or decreased use of medical services. METHODS: A population based case-control study of asthma deaths in 1994-8 was performed in 22 English, six Scottish, and five Welsh health authorities/boards. All 681 subjects who died were under the age of 65 years with asthma in Part I on the death certificates. After exclusions, 532 hospital controls were matched to 532 cases for age, district, and date of asthma admission/death. Data were extracted blind from primary care records. RESULTS: The median age of the subjects who died was 53 years; 60% of cases and 64% of controls were female. There was little difference in outpatient attendance (55% and 55%), hospital admission for asthma (51% and 54%), and median inpatient days (20 days and 15 days) in the previous 5 years. After mutual adjustment and adjustment for sex, using conditional logistic regression, three variables were independently associated with asthma death: fewer general practice contacts (odds ratio 0.82 (95% confidence interval (CI) 0.74 to 0.91) per 5 contacts) in the previous year, more home visits (1.14 (95% CI 1.08 to 1.21) per visit) in the previous year, and fewer peak expiratory flow recordings (0.83 (95% CI 0.74 to 0.92) per occasion) in the previous 3 months. These associations were similar after adjustment for markers of severity, psychosocial factors, systemic steroids, short acting bronchodilators and antibiotics, although the association with peak flow was weakened and just lost significance. CONCLUSION: Asthma death is associated with less use of primary care services. Both practice and patient factors may be involved and a better understanding of these may offer possibilities for reducing asthma death.
Asunto(s)
Asma/mortalidad , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Administración por Inhalación , Adulto , Antiasmáticos/uso terapéutico , Asma/terapia , Estudios de Casos y Controles , Femenino , Volumen Espiratorio Forzado/fisiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Aceptación de la Atención de Salud/estadística & datos numéricos , Ápice del Flujo Espiratorio/fisiología , Atención Primaria de Salud/estadística & datos numéricos , Esteroides/administración & dosificación , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Previous studies measuring the prevalence of allergen sensitization have been relatively small and used small numbers of allergens. To effectively evaluate children with atopic disease, we need an accurate knowledge of which allergens are important. OBJECTIVE: To measure the prevalence of sensitization within a large unselected birth cohort, to examine the associations between sensitization to different allergens and determine whether atopy can be defined by a small panel of allergens. METHODS: The Avon Longitudinal Study of Parents and Children is a population-based birth cohort of 13,638 singletons surviving to 4 weeks of age. The cohort was skin tested at 7 years of age to house dust mite (Dermatophagoides pteronyssinus), grass pollens, cat, peanuts, mixed tree nuts and egg and one of three other panels: animal danders, foods or aeroallergens. Sensitization was defined as a weal diameter of > or =3 mm. The strength of associations between sensitization to different allergens was tested by calculating the odds ratio adjusted for sensitization to D. pteronyssinus and grass pollen and gender. RESULTS: Valid data were obtained from 6412 singletons. Sensitization was most common to aeroallergens: grass pollens (8.5%), D. pteronyssinus (7.8%), cat (4.9%), D. farinae (3.6%), dog (2.7%), horse (1.4%), rabbit (1.4%). Of the foods tested, the most common sensitization was to peanut (1.4%) and mixed tree nuts (1.0%). More than 95% of subjects with sensitization to any of the 29 allergens tested were sensitized to one of grass, D. pteronyssinus or cat allergen. There were strong associations of multiple sensitizations both within and between different allergen classes (pollens, animals, foods, peanut and tree nuts). CONCLUSIONS: Seven-year-old children in the UK are primarily sensitized to aeroallergens, but also to peanuts and tree nuts. There are strong associations between sensitization within allergen groups as well as between allergen groups. Further studies are required to observe whether similar associations are seen with clinical allergy to these allergens.
Asunto(s)
Contaminación del Aire/efectos adversos , Alérgenos/inmunología , Hipersensibilidad/inmunología , Animales , Gatos , Niño , Perros , Inglaterra/epidemiología , Femenino , Hipersensibilidad a los Alimentos/epidemiología , Hipersensibilidad a los Alimentos/inmunología , Caballos/inmunología , Humanos , Hipersensibilidad/epidemiología , Masculino , Nueces/inmunología , Hipersensibilidad al Cacahuete/inmunología , Polen/inmunología , Prevalencia , Estudios Prospectivos , Pyroglyphidae/inmunología , Conejos , Pruebas CutáneasRESUMEN
BACKGROUND: The purpose of this study was to assess whether a short course of anthracycline containing chemotherapy followed by high dose therapy with autologous stem-cell support improves disease-free and overall survival as compared with conventional, anthracycline containing chemotherapy, in patients with primary breast cancer and four or more histologically involved lymph nodes. PATIENTS AND METHODS: Two hundred and eighty one patients entered into a randomised clinical trial were allocated to receive standard, conventional treatment (5-fluorouracil, epirubicin and cyclophosphamide-FEC for six cycles) or FEC for three cycles followed by high dose therapy consisting of cyclophosphamide, thiotepa and carboplatin and stem cell rescue (HDT). To be eligible, patients had to be free of overt metastatic disease and be < or =60 years of age. Analyses were according to intention to treat. RESULTS: At a median follow up of 68 months, 118 patients have experienced a relapse or death from breast cancer (62 in the FEC followed by HDT arm and 56 in the conventional FEC arm) and a total of 100 patients have died (54 in the FEC followed by HDT arm and 46 in the conventional FEC arm). No significant difference was observed in relapse-free survival [hazard ratio 1.06, 95% CI 0.74-1.52, p = 0.76] or overall survival [hazard ratio 1.18, 95% CI 0.80-1.75, p = 0.40]. Five patients died from treatment related causes, three as a consequence of HDT and two in the conventional FEC arm. CONCLUSIONS: At the present time, no benefit has been observed from replacing three cycles of conventional chemotherapy with the HDT regimen described here. Patients should continue to receive conventional chemotherapy as adjuvant therapy for breast cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Ganglios Linfáticos/patología , Recurrencia Local de Neoplasia/epidemiología , Trasplante de Células Madre/métodos , Adulto , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Terapia Combinada , Intervalos de Confianza , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Cooperación Internacional , Mastectomía Segmentaria , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Selección de Paciente , Probabilidad , Pronóstico , Modelos de Riesgos Proporcionales , Valores de Referencia , Medición de Riesgo , Tasa de Supervivencia , Trasplante Autólogo , Resultado del TratamientoRESUMEN
BACKGROUND: Uncontrolled studies suggest that psychosocial factors and health behaviour may be important in asthma death. METHODS: A community based case-control study of 533 cases, comprising 78% of all asthma deaths under age 65 years and 533 hospital controls individually matched for age, district and asthma admission date corresponding to date of death was undertaken in seven regions of Britain (1994-98). Data were extracted blind from anonymised copies of primary care records for the previous 5 years and non-blind for the earlier period. RESULTS: 60% of cases and 63% of controls were female. The median age in both groups was 53. Cases had an earlier age of asthma onset, more chronic obstructive lung disease, and were more obese. 48% of cases and 42% of controls had a health behaviour problem; repeated non-attendance/poor inhaler technique was related to increased risk of death. Overall, 85% and 86%, respectively, had a psychosocial problem. Four psychosocial factors were associated with increased risk of death (psychosis, alcohol/drug abuse, financial/employment problems, learning difficulties) and two with reduced risk (anxiety/prescription of antidepressant drugs and sexual problems). While alcohol/drug abuse lost significance after adjustment for psychosis, other associations appeared independent of each other and of indicators of severity and co-morbidity. None of the remaining 13 factors including family problems, domestic abuse, bereavement, and social isolation were significantly related to risk of asthma death. CONCLUSION: There was an apparently high burden of psychosocial problems in both cases and controls. The associations between health behaviour, psychosocial factors, and asthma death are varied and complex with a limited number of factors showing positive relationships.