The Practice of Paediatric Radiation Oncology in Low- and Middle-income Countries: Outcomes of an International Atomic Energy Agency Study.

AIMS: Childhood cancer survival is suboptimal in most low- and middle-income countries (LMICs). Radiotherapy plays a significant role in the standard care of many patients. To assess the current status of paediatric radiotherapy, the International Atomic Energy Agency (IAEA) undertook a global survey and a review of practice in eight leading treatment centres in middle-income countries (MICs) under Coordinated Research Project E3.30.31; 'Paediatric radiation oncology practice in low and middle income countries: a patterns-of-care study by the International Atomic Energy Agency.' MATERIALS AND METHODS: A survey of paediatric radiotherapy practices was distributed to 189 centres worldwide. Eight leading radiotherapy centres in MICs treating a significant number of children were selected and developed a database of individual patients treated in their centres comprising 46 variables related to radiotherapy technique. RESULTS: Data were received from 134 radiotherapy centres in 42 countries. The percentage of children treated with curative intent fell sequentially from high-income countries (HICs; 82%) to low-income countries (53%). Increasing deficiencies were identified in diagnostic imaging, radiation staff numbers, radiotherapy technology and supportive care. More than 92.3% of centres in HICs practice multidisciplinary tumour board decision making, whereas only 65.5% of centres in LMICs use this process. Clinical guidelines were used in most centres. Practice in the eight specialist centres in MICs approximated more closely to that in HICs, but only 52% of patients were treated according to national/international protocols whereas institution-based protocols were used in 41%. CONCLUSIONS: Quality levels in paediatric radiotherapy differ among countries but also between centres within countries. In many LMICs, resources are scarce, coordination with paediatric oncology is poor or non-existent and access to supportive care is limited. Multidisciplinary treatment planning enhances care and development may represent an area where external partners can help. Commitment to the use of protocols is evident, but current international guidelines may lack relevance; the development of resources that reflect the capacity and needs of LMICs is required. In some LMICs, there are already leading centres experienced in paediatric radiotherapy where patient care approximates to that in HICs. These centres have the potential to drive improvements in service, training, mentorship and research in their regions and ultimately to improve the care and outcomes for paediatric cancer patients.

Infection-related complications during treatment for childhood acute lymphoblastic leukemia.

Background: Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking. Patients and methods: We evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period. Results: Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n = 389), followed by ear (n = 151), bloodstream (n = 147), and gastrointestinal tract (n = 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n = 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P = 0.002) during induction and febrile neutropenia and documented infection (both P < 0.001) during later continuation. White race was associated with documented infection (P = 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P < 0.001) and documented infections (P = 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P < 0.001). Conclusions: The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

A revised definition for cure of childhood acute lymphoblastic leukemia.

With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).

Treatment of childhood acute lymphoblastic leukemia in central America: a lower-middle income countries experience.

BACKGROUND: Five Asociación de Hemato-Oncología de Centroamérica (AHOPCA) countries have used an adapted BFM-based protocol for childhood acute lymphoblastic leukemia (ALL). PROCEDURE: In the AHOPCA-ALL 2008 protocol, patients were stratified by age, white blood cell count, immunophenotype, central nervous system involvement, day 8 prednisone response, and morphologic bone marrow response to induction therapy. Patients at Standard Risk (SR) received a three-drug induction regimen, a reinduction phase, and maintenance with protracted intrathecal therapy. Those at Intermediate (IR) and High Risk (HR) received, in addition, daunorubicin during induction therapy, a consolidation phase and two or three reinduction phases respectively. RESULTS: From August 2008 through July 2012, 1,313 patients were enrolled: 353 in SR, 548 in IR, 412 in HR. During induction therapy, 3.0% of patients died, 2.7% abandoned treatment, 1.1% had resistant ALL, and 93.2% achieved morphological complete remission (CR). Deaths and abandonment in first CR occurred in 2.7% and in 7.0% of patients, respectively. The relapse rate at a median observation time of 2.1 years was 15.0%. At 3 years, the event-free survival (EFS) and overall survival (OS), with abandonment considered as an event, were 59.4% (SE 1.7) and 68.2% (SE 1.6). Three-year EFS was 68.5% (SE 3.0), 62.1% (SE 2.6), and 47.8% (SE 3.2) for SR, IR, and HR groups. Adolescents had a significantly higher relapse rate (P = 0.001). CONCLUSIONS: This experience shows that common international studies are feasible in lower-middle income countries. Toxic deaths, abandonment of treatment, and relapses remain major obstacles to the successful treatment. Alternative treatment strategies may be beneficial.

ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy.

ETV6-RUNX1 fusion is the most common genetic aberration in childhood acute lymphoblastic leukemia (ALL). To evaluate whether outcomes for this drug-sensitive leukemia are improved by contemporary risk-directed therapy, we studied clinical features, response and adverse events of 168 children with newly diagnosed ETV6-RUNX1-positive ALL on St Jude Total Therapy studies XIIIA (N=36), XIIIB (N=38) and XV (N=94). Results were compared with 494 ETV6-RUNX1-negative B-precursor ALL patients. ETV6-RUNX1 was associated with age 1-9 years, pre-treatment classification as low risk and lower levels of minimal residual disease (MRD) on day 19 of therapy (P<0.001). Event-free survival (EFS) or overall survival (OS) did not differ between patients with or without ETV6-RUNX1 in Total XIIIA or XIIIB. By contrast, in Total XV, patients with ETV6-RUNX1 had significantly better EFS (P=0.04; 5-year estimate, 96.8±2.4% versus 88.3±2.5%) and OS (P=0.04; 98.9±1.4% versus 93.7±1.8%) than those without ETV6-RUNX1. Within the ETV6-RUNX1 group, the only significant prognostic factor associated with higher OS was the treatment protocol Total XV (versus XIIIA or XIIIB) (P=0.01). Thus, the MRD-guided treatment schema including intensive asparaginase and high-dose methotrexate in the Total XV study produced significantly better outcomes than previous regimens and demonstrated that nearly all children with ETV6-RUNX1 ALL can be cured.

Safety of central venous catheter placement at diagnosis of acute lymphoblastic leukemia in children.

BACKGROUND: Central venous catheters (CVC) facilitate the management of patients with cancer. Optimal timing for placement of a CVC is controversial. We sought to determine whether early placement in children with acute lymphoblastic leukemia (ALL), a group at high risk for infection and thrombosis, was associated with an increased rate of surgical complications. PROCEDURE: We evaluated the incidence and risk factors for early surgical complications in children with ALL diagnosed between 2004 and 2009 at a single pediatric cancer center. RESULTS: One hundred seventy-two patients were studied. There were 17 episodes of bloodstream infection, for a 30-day incidence of 9.8% (95% CI, 5.9-15%). There were no surgical site infections and no CVC was removed due to infection. Early thrombosis occurred in only one patient, 3 days after CVC placement. Infection was not influenced by catheter type, patient age, body mass index, or fever at the time of placement. The infection rate was not statistically higher when the ANC was <500/mm(3) at the time of CVC placement (14.2% vs. 6.8%; P = 0.12). CONCLUSION: Early CVC placement at the time of diagnosis of ALL was associated with a low surgical complication rate with no catheters requiring removal due to infection. Utilizing our current methods of preoperative preparation, surgical management and postoperative CVC care, early placement of a CVC is safe in children with ALL even when their ANC is <500/mm(3) , but larger cohort studies would be helpful to further clarify this issue.

Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma.

BACKGROUND: Children with recurrent or refractory malignant lymphoma generally have a poor prognosis. There is a need for new active drug combinations for this high-risk group of patients. PATIENTS AND METHODS: This study evaluated the activity and toxicity of the methotrexate, ifosfamide, etoposide and dexamethasone (MIED) regimen for childhood refractory/recurrent non-Hodgkin's lymphoma (NHL) or Hodgkin's lymphoma (HL). From 1991 through 2006, 62 children with refractory/recurrent NHL (n = 24) or HL (n = 38) received one to six cycles of MIED. Based on MIED response, intensification with hematopoietic stem cell transplantation (HSCT) was considered. RESULTS: There were 10 complete (CR) and 5 partial responses (PR) among the 24 children with NHL [combined response rate, 63%; 95% confidence interval (CI) 38% to 73%]. There were 13 CR and 18 PR among the 37 assessable children with HL (combined response rate, 84%; 95% CI, 68% to 94%). Although 59% courses were associated with grade IV neutropenia, treatment was well tolerated and without toxic deaths. CONCLUSIONS: MIED is an effective regimen for refractory/recurrent childhood malignant lymphoma, permitting a bridge to intensification therapy with HSCT.

Long-term results of St Jude Total Therapy Studies 11, 12, 13A, 13B, and 14 for childhood acute lymphoblastic leukemia.

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.

Reproducibility of measures of visit-to-visit variability in blood pressure after transient ischaemic attack or minor stroke.

BACKGROUND: In certain patients in routine practice, blood pressure (BP) measurements differ substantially from week to week or month to month. Although often assumed to be random, such variability could provide information on underlying pathology or prognosis. In order to be informative, however, visit-to-visit BP variability would have to be neither random (i.e. it should be reproducible over time within individuals) nor artefactual (i.e. it should not be an artefact of the method/timing of measurement, for example). METHODS: We quantified visit-to-visit variability in BP and explored potential confounding factors by analysing repeat measurements obtained every few months during follow-up in two large trials in patients with a transient ischaemic attack (TIA) or minor ischaemic stroke: the UK-TIA Aspirin Trial (effect of aspirin, effect of season and day of the week of measurement) and the European Carotid Surgery Trial (ECST - effect of carotid endarterectomy). By comparing different periods of follow-up, we also determined the reproducibilities of mean and several different measures of variability for both systolic (SBP) and diastolic BP (DBP). RESULTS: The mean absolute difference between adjacent SBP readings was 14.7 mm Hg in the UK-TIA Trial and 16.0 mm Hg in ECST. Visit-to-visit variability in both SBP and DBP were independent of the potentially confounding factors studied, but reproducibility of all the variability measures was statistically significantly greater than zero. Reproducibility (intraclass correlation) of standard deviation of SBP was 0.32 (p < 0.0001) in the UK-TIA Trial and 0.18 (p = 0.0007) in ECST. Consequently, classification of patients with high (top quintile) or low (bottom quintile) variability was consistent over time (observed/expected = 2.21, 95% confidence interval 1.71-2.85, p < 0.0001, and 1.65, 1.23-2.21, p = 0.0007, respectively). Reproducibility increased with the number of measurements used to calculate variability, and was independent of any correlation with mean BP. CONCLUSIONS: Visit-to-visit variability in BP in these populations was reproducible, independently of any correlation with mean BP, demonstrating that visit-to-visit intra-individual BP variability is not random.

Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1.

To evaluate the impact of contemporary therapy on the clinical outcome of children with pre-B acute lymphoblastic leukemia (ALL) and the t(1;19)/TCF3/PBX1, we analyzed 735 patients with B-cell precursor ALL treated in four successive protocols at St Jude Children's Research Hospital. The 41 patients with the t(1;19) had a comparable event-free survival to that of the 694 patients with other B-cell precursor ALL (P=0.63; 84.2+/-7.1% (s.e.) vs 84.0+/-1.8% at 5 years). However, patients with the t(1;19) had a lower cumulative incidence of any hematological relapse (P=0.06; 0 vs 8.3+/-1.2% at 5 years) but a significantly higher incidence of central nervous system (CNS) relapse (P<0.001; 9.0+/-5.1% vs 1.0+/-0.4% at 5 years). In a multivariate analysis, the t(1;19) was an independent risk factor for isolated CNS relapse. These data suggest that with contemporary treatment, patients with the t(1;19) and TCF3/PBX1 fusion have a favorable overall outcome but increased risk of CNS relapse.

Incidence and predictors of treatment-related mortality in paediatric acute leukaemia in El Salvador.

Survival rates among children with leukaemia in low-income countries are lower than those in high-income countries. This has been attributed in part to higher treatment-related mortality (TRM). We examined the demographics, treatment, and outcomes of paediatric patients in El Salvador with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) to determine the incidence, causes, and risk factors for TRM. Two trained data managers collected data prospectively; no patients were excluded. Biological, socioeconomic and nutritional predictors were examined. A total of 469 patients with ALL and 78 patients with AML were included. The 2-year cumulative incidence of TRM was significantly higher among children with AML (35.4+/-6.4%) than those with ALL (12.5+/-1.7%; P<0.0001). However, the proportion of deaths attributable to the toxicity of treatment did not differ significantly between AML (25/47, 53.2%) and ALL (55/107, 51.4%; P=0.98). Among children with ALL, low monthly income (P=0.04) and low parental education (P=0.02) significantly increased the risk of TRM. Among children with AML, biological, socioeconomic, and nutritional variables were not associated with TRM. In this low-income country, toxic death significantly contributes to mortality in both ALL and AML. A better understanding of the effect of socioeconomic status on TRM may suggest specific strategies for patients with ALL.

Clinical consequences of hyperglycemia during remission induction therapy for pediatric acute lymphoblastic leukemia.

Hyperglycemia adversely affects outcome in adult patients with acute lymphoblastic leukemia (ALL), but its impact on children with this disease is unknown. We evaluated the relationship between hyperglycemia during remission induction therapy and clinical outcomes among pediatric patients with ALL. We reviewed the records of patients enrolled on four consecutive ALL protocols (Total Therapy protocols XIIIA, XIIIB, XIV and XV) at St Jude Children's Research Hospital from 1991 to 2007 and identified those who experienced hyperglycemia (glucose >or=200 mg per 100 ml) during remission induction. Complete remission (CR) rates at the end of induction, event-free survival (EFS), overall survival (OS), cumulative incidence of relapse and occurrence of infections were compared between those who did and did not experience hyperglycemia. Of 871 patients analyzed, 141 (16%) experienced hyperglycemia during remission induction. Patients with hyperglycemia were significantly older than the other patients (P<0.0001). There was no significant difference in CR rate (P=0.92), EFS (P=0.80), OS (P=0.28), cumulative incidence of relapse (P=0.59) or in the probability or types of infection between patients who did and did not experience hyperglycemia. Pediatric patients with or without hyperglycemia during remission induction for ALL have similar clinical outcome. Occurrence of hyperglycemia does not warrant alteration of the antileukemic regimen.

Effect of age and glycaemic control on the association between fibrinogen and risk of acute coronary events after transient ischaemic attack or stroke.

BACKGROUND: Fibrinogen is an independent risk factor for acute vascular events, but there is uncertainty as to whether it is causal. One potential causal mechanism is the formation of low permeability fibrin clot in association with raised fibrinogen. We hypothesised that if this effect of fibrinogen were causally related to risk of vascular events, the risk relationship would be affected by the two other factors that affect fibrin clot permeability - age and glycaemic control. METHODS: We studied the relationship between fibrinogen and risk of incident coronary events by age and baseline glucose levels in pooled data from three cohorts of patients with known cerebrovascular disease (UK-TIA Aspirin trial; Dutch TIA trial; Oxford TIA Study) during 23,272 patient-years of follow-up. RESULTS: Risk of coronary events increased linearly with fibrinogen, but there was a significant interaction with age (p = 0.01 across tertiles of age), with the association being strongest for individuals aged <60 years (upper fibrinogen quintile hazard ratio = 3.95, 95% CI = 2.67-5.85, p < 0.0001). The risk relation was diminished in individuals with impaired glucose tolerance or diabetes. The effects of age and glycaemic control were independent, such that there was an almost fivefold increase in risk across quintiles of fibrinogen in patients aged <60 years with below median normal glucose levels (upper quintile hazard ratio = 4.90, 95% CI = 2.79-8.58, p < 0.0001). CONCLUSIONS: The effect of age and glycaemic control on the relationship between fibrinogen and risk of acute coronary events supports the hypothesis of a causal effect of fibrinogen mediated via the permeability of fibrin clot.

Apolipoproteins as predictors of ischaemic stroke in patients with a previous transient ischaemic attack.

BACKGROUND: Weak associations between total and LDL cholesterol and ischaemic stroke compared with coronary heart disease (CHD) are at odds with the similar effectiveness of statin drugs in preventing ischaemic stroke and CHD, suggesting that other lipid sub-fractions that are affected by statins might be better predictors of ischaemic stroke. Apolipoprotein B levels are reduced by statins and are a stronger predictor of CHD than total and LDL cholesterol in patients both on and off statins. However, there are very few published data on apolipoproteins and stroke risk and no studies in patients with previous transient ischaemic attack (TIA). METHODS: We performed a prospective cohort study of the associations of baseline total cholesterol, LDL, HDL, apolipoproteins A1 and B (apo A1; apo B) and risk of ischaemic stroke in 261 patients with previous TIA. Cox proportional hazards models were used to determine crude and multivariate-adjusted hazard ratios (HR) above versus below median values at 10-years follow-up. RESULTS: The apo B/apo A1 ratio was the strongest independent predictor of ischaemic stroke (HR=2.94, 95% CI 1.43-5.88, p=0.003) followed by apo B (HR=2.26, 95% CI 1.16-4.38, p=0.02). The associations between total cholesterol, LDL, HDL, LDL/HDL ratio and apo A1 and ischaemic stroke risk did not reach statistical significance. CONCLUSIONS: Apo B and the apo B/apo A1 ratio are predictive of ischaemic stroke in patients with previous TIA. Further studies are required to determine whether the prognostic value of apolipoprotein levels is maintained in patients on statins.

Overt testicular disease at diagnosis of childhood acute lymphoblastic leukemia: lack of therapeutic role of local irradiation.

To assess the prognosis of overt testicular disease at diagnosis of acute lymphoblastic leukemia, and any therapeutic role of irradiation for this involvement, we reviewed the data of 811 boys treated on St Jude studies Total X--XI (early period) and Total XII-XIV (recent period). In all, 19 boys (2.3%) had testicular disease at diagnosis. In the early period, patients with testicular leukemia had a poorer overall survival (OS) (P=0.003), event-free survival (EFS) (P=0.064), and higher cumulative incidence of relapse (P=0.041) than did other patients. During the recent period, patients with and without overt testicular leukemia did not differ in OS (P=0.257), EFS (P=0.102), or cumulative incidence of relapse (P=0.51). In a multivariate analysis, OS was lower for patients with testicular disease than for those without the involvement in the early period (P=0.047) but not in the recent one (P=0.75). Both patients who received irradiation for residual testicular disease at the end of induction subsequently died of leukemia. Of the other 17 patients who did not receive irradiation, only one developed testicular relapse in combination with bone marrow relapse. In conclusion, the prognostic impact of overt testicular disease has diminished. Irradiation appears to provide no survival advantage to this patient population.

Association between tea ingestion and invasive Bacillus cereus infection among children with cancer.

Bacillus cereus is an emerging pathogen that causes invasive disease in immunocompromised hosts. A case-control study, prompted by a clinical case, demonstrated an association between dietary tea ingestion and B. cereus bacteremia. Policies designed to interrupt transmission of this pathogen to susceptible patients should be considered.

Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study).

BACKGROUND: The incidence of stroke is predicted to rise because of the rapidly ageing population. However, over the past two decades, findings of randomised trials have identified several interventions that are effective in prevention of stroke. Reliable data on time-trends in stroke incidence, major risk factors, and use of preventive treatments in an ageing population are required to ascertain whether implementation of preventive strategies can offset the predicted rise in stroke incidence. We aimed to obtain these data. METHODS: We ascertained changes in incidence of transient ischaemic attack and stroke, risk factors, and premorbid use of preventive treatments from 1981-84 (Oxford Community Stroke Project; OCSP) to 2002-04 (Oxford Vascular Study; OXVASC). FINDINGS: Of 476 patients with transient ischaemic attacks or strokes in OXVASC, 262 strokes and 93 transient ischaemic attacks were incident events. Despite more complete case-ascertainment than in OCSP, age-adjusted and sex-adjusted incidence of first-ever stroke fell by 29% (relative incidence 0.71, 95% CI 0.61-0.83, p=0.0002). Incidence declined by more than 50% for primary intracerebral haemorrhage (0.47, 0.27-0.83, p=0.01) but was unchanged for subarachnoid haemorrhage (0.83, 0.44-1.57, p=0.57). Thus, although 28% more incident strokes (366 vs 286) were expected in OXVASC due to demographic change alone (33% increase in those aged 75 or older), the observed number fell (262 vs 286). Major reductions were recorded in mortality rates for incident stroke (0.63, 0.44-0.90, p=0.02) and in incidence of disabling or fatal stroke (0.60, 0.50-0.73, p<0.0001), but no change was seen in case-fatality due to incident stroke (17.2% vs 17.8%; age and sex adjusted relative risk 0.85, 95% CI 0.57-1.28, p=0.45). Comparison of premorbid risk factors revealed substantial reductions in the proportion of smokers, mean total cholesterol, and mean systolic and diastolic blood pressures and major increases in premorbid treatment with antiplatelet, lipid-lowering, and blood pressure lowering drugs (all p<0.0001). INTERPRETATION: The age-specific incidence of major stroke in Oxfordshire has fallen by 40% over the past 20 years in association with increased use of preventive treatments and major reductions in premorbid risk factors.

Regression dilution of systolic and diastolic blood pressure in patients with established cerebrovascular disease.

BACKGROUND AND OBJECTIVE: Blood pressure (BP) is a major risk factor for stroke and cardiovascular events. To quantify its effect, it is necessary to correct for regression dilution bias (RDB). RDB has been estimated from repeated measurements of BP in population-based studies, but there are no data in patients with established vascular disease. METHOD: We analyzed repeat measurements of BP from three large studies of patients with cerebrovascular disease: UK-TIA trial (n=2098), Dutch TIA trial (n=2953), and the European Carotid Surgery Trial (n=2646). The regression dilution ratio (RDR) was estimated by parametric and nonparametric methods at follow-up intervals ranging from 4 months to 6 years. RESULTS: After an interval of only 4-5 months, nonparametric RDRs of 0.56, 0.40, and 0.45 for systolic BP and 0.45, 0.33, and 0.31 for diastolic BP were observed in the three studies, respectively. These values are much smaller than those reported in population-based studies, indicating greater within-person variability in BP. CONCLUSION: RDRs from population-based studies cannot necessarily be applied to cohorts with established vascular disease.