Changing presentation of prostate cancer in a UK population--10 year trends in prostate cancer risk profiles in the East of England.

BACKGROUND: Prostate cancer incidence is rising in the United Kingdom but there is little data on whether the disease profile is changing. To address this, we interrogated a regional cancer registry for temporal changes in presenting disease characteristics. METHODS: Prostate cancers diagnosed from 2000 to 2010 in the Anglian Cancer Network (n=21,044) were analysed. Risk groups (localised disease) were assigned based on NICE criteria. Age standardised incidence rates (IRs) were compared between 2000-2005 and 2006-2010 and plotted for yearly trends. RESULTS: Over the decade, overall IR increased significantly (P<0.00001), whereas metastasis rates fell (P<0.0007). For localised disease, IR across all risk groups also increased but at different rates (P<0.00001). The most striking change was a three-fold increase in intermediate-risk cancers. Increased IR was evident across all PSA and stage ranges but with no upward PSA or stage shift. In contrast, IR of histological diagnosis of low-grade cancers fell over the decade, whereas intermediate and high-grade diagnosis increased significantly (P<0.00001). CONCLUSION: This study suggests evidence of a significant upward migration in intermediate and high-grade histological diagnosis over the decade. This is most likely to be due to a change in histological reporting of diagnostic prostate biopsies. On the basis of this data, increasing proportions of newly diagnosed cancers will be considered eligible for radical treatment, which will have an impact on health resource planning and provision.

A personalised approach to prostate cancer screening based on genotyping of risk founder alleles.

BACKGROUND: To evaluate whether genotyping for 18 prostate cancer founder variants is helpful in identifying high-risk individuals and for determining optimal screening regimens. METHODS: A serum PSA level was measured and a digital rectal examination (DRE) was performed on 2907 unaffected men aged 40-90. Three hundred and twenty-three men with an elevated PSA (≥4 ng ml⁻¹) or an abnormal DRE underwent a prostate biopsy. All men were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA and C61G), for four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395 and I157T), for one allele in NBS1 (657del5), for one allele in HOXB13 (G84E), and for nine low-risk single-nucleotide polymorphisms (SNPs). RESULTS: On the basis of an elevated PSA or an abnormal DRE, prostate cancer was diagnosed in 135 of 2907 men (4.6%). In men with a CHEK2 missense mutation I157T, the cancer detection rate among men with an elevated PSA or an abnormal DRE was much higher (10.2%, P=0.0008). The cancer detection rate rose with the number of SNP risk genotypes observed from 1.2% for men with no variant to 8.6% for men who carried six or more variants (P=0.04). No single variant was helpful on its own in predicting the presence of prostate cancer, however, the combination of all rare mutations and SNPs improved predictive power (area under the curve=0.59; P=0.03). CONCLUSION: These results suggest that testing for germline CHEK2 mutations improves the ability to predict the presence of prostate cancer in screened men, however, the clinical utility of incorporating DNA variants in the screening process is marginal.

Lifetime body mass index, other anthropometric measures of obesity and risk of knee or hip osteoarthritis in the GOAL case-control study.

OBJECTIVE: To examine the risk of large joint osteoarthritis (OA) in those becoming overweight during early adult life, and to assess the risks associated with high body mass index (BMI) and other anthropometric measures of obesity. METHODS: BMI, waist and hip circumference were measured in the GOAL case-control study comprising hip OA cases (n=1007), knee OA cases (n=1042) and asymptomatic controls (n=1121). Retrospective estimates of lifetime weight, body shape and other risk factors were collected using an interview-lead questionnaire. Odds ratios (ORs), adjusted OR (aOR), 95% confidence intervals (CIs) and P values were calculated using logistic regression analysis. RESULTS: BMI was associated with knee OA (aOR 2.68, 95% CI 2.33-3.09, P-trend<0.001) and hip OA (aOR 1.65, 95% CI 1.46-1.87, P-trend<0.001). Those who became overweight earlier in adulthood showed higher risks of lower limb OA (P-trend<0.001 for knee OA and hip OA). Self-reported body shape was also associated with knee OA and hip OA, following a similar pattern to current and life-course BMI measures. Waist:hip ratio (WHR) at time of examination did not associate with OA independently of BMI, except in women-only analysis. Waist circumference was associated with lower limb OA risk. CONCLUSIONS: Becoming overweight earlier in adult life increased the risks of knee OA and hip OA. Different distribution patterns of adiposity may be related to OA risk in women.

Incident knee pain in the Nottingham community: a 12-year retrospective cohort study.

OBJECTIVES: To determine the community incidence of knee pain and associated risk factors over a 12-year period in people over the age of 40 years. METHOD: A cohort study of knee pain was undertaken in 2156 people from four general practices in North Nottinghamshire, UK. Knee pain was defined as 'pain around the knee for most days of at least a month'. Cumulative incidence over 12 years and person-year incidence rate of knee pain were estimated. Survival analysis was undertaken for time to the onset of knee pain. Hazard ratio (HR) and 95% confidence interval (CI) were estimated for relative risk between exposure and non-exposure. Cox regression model was used to adjust for confounding factors. RESULTS: The 12-year cumulative incidence of knee pain was 34.4% (32% for men and 35% for women), corresponding to an average incidence rate of 32 (31 for men and 34 for women)/1000 person-years. Incident knee pain was associated with female gender (HR 1.27, 95% CI 1.08, 1.49), obesity (1.80; 95% CI 1.37, 2.38), varus (1.68, 95% CI 1.15, 2.47) and valgus (1.83, 95% CI 1.05, 3.20) mal-alignment, and knee injury (2.37, 95% CI 2.98, 2.85). CONCLUSIONS: For people over age 40, one in three will develop knee pain within 12 years. On average, the risk of knee pain was 32/1000 person-years. This risk is associated with a variety of constitutional and environmental biomechanical insults to the knee. Some of these could be modified to possibly reduce the incidence of the condition.

Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis.

OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1ß (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.

A meta-analysis of interleukin-6 promoter polymorphisms on risk of hip and knee osteoarthritis.

OBJECTIVE: Interleukin-6 is a pro-inflammatory cytokine involved in the pathogenesis of osteoarthritis (OA). We investigated the role of two single nucleotide polymorphisms (SNPs) mapping to the promoter of the IL-6 gene on genetic susceptibility to hip and knee OA. METHODS: The -174G/C (rs1800795) and -597G/A (rs1800797) SNPs, implicated in the literature in risk of hip and hand OA, were genotyped in 2511 controls, 1101 hip OA cases and 1904 knee OA cases from four cohorts from the UK and Estonia. Data were analysed in conjuntion with published data on rs1800797 from the Genetics of OA and Lifestyle study (UK) on 791 controls, 1034 knee and 997 hip OA cases and rs1800795 data on 75 hip OA cases and 96 controls from Italy. Cases included both radiographic OA only and radiographic and symptomatic OA. Fixed and random-effects meta-analysis models were tested. RESULTS: No significant association was found with hip OA or knee OA with either SNP nor with the haplotypes formed by them. For individual SNPs the smallest P-value for hip OA was observed using a random-effects model for rs1800795 OR(Gallele)=1.066 (95% CI 0.89-1.28) P<0.49, and significant heterogeneity between cohorts (I(2)=65%, P<0.034) was detected. For knee OA the smallest P-value was seen for rs1800797 OR(Aallele)=1.055 (95%CI 0.98-1.12) P<0.18, no significant heterogeneity was observed (I(2)=0%, P<0.68). CONCLUSIONS: Our data do not support a role for the -174 and -597 IL-6 promoter polymorphisms in genetic susceptibility to knee or hip OA in Caucasian populations.

Attempt to replicate published genetic associations in a large, well-defined osteoarthritis case-control population (the GOAL study).

OBJECTIVE: Published studies have tested over 90 genes for association with osteoarthritis (OA), but few positives reported have been independently replicated. Using a new case-control study, our aim was to attempt the replication of findings from 12 genes reported to have significant genetic association with OA and to further examine the role of genetic variation in six of these genes. METHODS: A case-control study was undertaken in Nottingham, UK. Hospital-referred index cases with symptomatic, radiographic OA (ROA) of the knee (n=1040) or hip (n=1004) were recruited. Asymptomatic controls (n=1123) were recruited from intravenous urography waiting lists and screened for radiographic hip and knee OA. Sixty-eight polymorphisms were genotyped in IL1A, IL1B, IL1RN, IL4R, IL6, COL2A1, ADAM12, ASPN, IGF1, TGFB1, ESR1 and VDR. Statistical analysis compared allele or genotype frequencies of these polymorphisms in all asymptomatic controls and the subset of controls without ROA vs all OA, knee OA and hip OA. The analyses were adjusted for age, gender and body mass index. RESULTS: We were unable to replicate any of the published genetic associations investigated. Our extended exploratory analyses identified some associations between polymorphisms in TGFB1, IGF1 and IL1RN and OA; but the strength of evidence varied with the control group used. CONCLUSION: Lack of replication is common and could be due to differences in study design, phenotype, populations examined or the occurrence of false positives in the initial study. Variants within TGFB1, IGF1 and IL1RN could have a role in OA susceptibility; however, replication of these findings is required in an independent study.

Radiographic assessment of the index to ring finger ratio (2D:4D) in adults.

The smaller index to ring finger (2D:4D) ratio has been considered as a 'male finger pattern' and is associated with sporting ability and a number of conditions. However, the ratio may vary according to what is measured, the hand selected and the method used. This study aimed to determine: (1) which bones (phalanges, metacarpals or both) account for variation in the 2D:4D ratio; (2) whether the ratio shows right-left symmetry or relates to hand dominance; and (3) the correlation between visual classification and measured determinations of the ratio based on radiographs. Hand radiographs obtained as part of a large osteoarthritis genetic study were examined. Each hand was classified visually into three types according to the relative length of the index and ring finger: Type 1 (index longer than ring), Type 2 (index = ring) and Type 3 (index shorter than ring). For both index and ring fingers we measured (1) from base of proximal to tip of distal phalanx and (2) metacarpal length. Reproducibility of the classification and measurements were examined using kappa and intraclass correlation coefficient; symmetry between left and right hands was examined using Bland and Altman's agreement analysis; and correlation between visual classification and 2D:4D ratio data was analysed using the anova linearity test. Data were obtained from 3172 radiographs (1636 men, 1536 women; mean age 67 +/- 7.9 years, range 45-86 years). Prevalence of Type 3 hand was 61% in men and 37% in women (P < 0.001). Men had smaller 2D:4D ratios than women for phalanges (0.908 versus 0.922, P < 0.01), metacarpals (1.152 versus 1.157, P < 0.01) and the sum of phalanges plus metacarpals (1.005 versus 1.015, P < 0.01). The mean difference between right and left was -0.001 (95% limit of agreement -0.035, 0.032) for the phalangeal ratio and 0.003 (95% limit of agreement -0.051 to 0.057) for the metacarpal ratio. The 2D:4D ratio did not associate with handedness or age. There was a linear trend between the visual classification of hand type and the 2D:4D ratio data (P < 0.001). More technical difficulties (due to positioning, finger trauma, osteoarthritis) were encountered with the phalangeal ratio and visual categorization than with the metacarpal ratio: the latter could be measured in 98.7% of the study population. We concluded that measured 2D:4D ratios and visual categorization can be derived from hand radiographs. The phalanges and metacarpals both contribute to the variation in 2D:4D ratio with smaller ratios observed in men than in women. The ratio is symmetrical with only very small differences between right and left hands. Visual classification may be a useful simple tool for future epidemiological studies but is more prone to bias from positioning than direct measurement. If radiographs are used for this purpose, we recommend the metacarpal ratio with measurement of a single index hand or an average of both as it is least affected by bias from malpositioning, trauma or common joint disease.

Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene.

BACKGROUND: Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK1 ). SP and NK1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA. METHODS: Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed. RESULTS: Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10-4 , OR = 0.79 95% 0.68-0.90 after meta-analysis). CONCLUSIONS: This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA. SIGNIFICANCE: This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested.

Assigning exposure to pesticides and solvents from self-reports collected by a computer assisted personal interview and expert assessment of job codes: the UK Adult Brain Tumour Study.

OBJECTIVES: To compare assignment of occupational pesticide and solvent exposure using self-reported data collected by a computer assisted personal interview (CAPI) with exposure based on expert assessment of job codes. To discuss the advantages and disadvantages of using a CAPI to collect individual occupational exposure data. METHODS: Between 2001 and 2004, 1495 participants were interviewed using a CAPI for a case-control study of adult brain tumours and acoustic neuromas. Two types of occupational data were collected: (1) a full history, including job title from which a job code was assigned from the Standard Occupational Classification; and (2) specific details on pesticide and solvent exposure reported by participants. Study members' experiences of using the CAPI were recorded and advantages and disadvantages summarised. RESULTS: Of 7192 jobs recorded, the prevalence of self-reported exposure was 1.3% for pesticides and 11.5% for solvents. Comparing this with exposure expertly assessed from job titles showed 53.6% and 45.8% concordance for pesticides and solvents respectively. Advantages of the CAPI include no data entry stage, automatic input validation, and a reduction in interviewer bias. Disadvantages include an adverse effect on study implementation as a consequence of resources required for programming and difficulties encountered with data management prior to analysis. CONCLUSIONS: Different methods of exposure assessment derive different exposure levels for pesticide and solvent exposure at work. Agreement between self-reported and expert assessment of exposure was greater for pesticides compared to solvents. The advantages of using a CAPI for the collection of complex data outweigh the disadvantages for interviewers and data quality but using such a method requires extra resources at the study outset.

'Clustering'--real or apparent? Probability maps of childhood cancer in the West Midlands Health Authority region.

The West Midlands Regional Children's Tumour Registry collects detailed information on all cases of childhood cancer in the West Midlands Health Authority Region (WMHAR). The distribution by electoral ward of all cases diagnosed in the WMHAR between 1980 and 1984 has been determined. Analysis has also been performed for leukaemias/non-Hodgkin's lymphomas alone. We suggest that this latter grouping should be universally employed, owing to the difficulty of accurately separating out cases of leukaemia. Both spatial analyses showed several wards with significantly excessive rates on the basis of their cumulative Poison probability. Observed/expected ratios of 3-35 were seen for cases in significant wards, which are similar to the ratios seen in analysis of incidence around nuclear installations. However, further detailed consideration of these individual significance levels in the light of the number of statistically significant wards which would occur by chance alone, due to the multiple use of the test, accounted completely for the number of wards obtained in each of the groups considered. Thus, apparent 'clustering' of cases could be mere statistical artefact. In the WMHAR, therefore, using the technique of probability mapping, no true spatial pattern of incidence was found, other than that which would occur by chance alone. This, in a large area without nuclear installations and an even mix of rural and industrialised regions, could be seen as control data for those studies which have considered cases of childhood leukaemia around nuclear facilities, where the observation of single point clusters associated with suspected sites restricts assessments of spatial pattern in the rest of the area.(ABSTRACT TRUNCATED AT 250 WORDS)

Retrospective study of prognostic value of DNA ploidy and proliferative activity in neuroblastoma.

AIM: To assess the prognostic value of age and stage at diagnosis, site of primary tumour, cell ploidy and N-myc copy number in children with neuroblastoma. METHODS: Flow cytometry was used to determine the cellular DNA content of paraffin wax embedded archival material from 69 cases of neuroblastoma and was successful in 52. RESULTS: The age, stage, and survival distribution of the sampled cases was not significantly different from that in a larger population based series. There were seven diploid ("non-aneuploid") and 45 aneuploid (including two tetraploid and four triploid) tumours. The 10 year survival was significantly better for cases of aneuploid rather than diploid tumours (p < 0.05). An important new finding was that 10 year survival was also significantly better for tumours with a low percentage of cells in S phase (p < 0.03). CONCLUSION: The percentage of cells in S phase, a measure of the proliferative activity of the tumour, correlated with prognosis in neuroblastoma. This should be measured with other biological features of the disease, such as N-myc copy number, when prognostic indicators are being assessed.

Congenital mesoblastic nephroma: possible prognostic and management value of assessing DNA content.

The case records and pathology of all children with kidney tumours treated in the West Midlands Health Authority Region (WMHAR) from 1957 to 1986 were reviewed. The histology was reviewed by a panel of three paediatric pathologists. Thirteen (6%) out of 211 cases were considered to have congenital mesoblastic nephroma (CMN). Nine were of the conventional type, three of the atypical cellular type, and one mixed. DNA ploidy was investigated and showed two of the tumours to be aneuploid and nine diploid (tissue was not available in the two other cases). The two aneuploid tumours were of atypical cellular and mixed histology, respectively; the diploid tumours were of the conventional type in eight cases and atypical cellular in one. The atypical cellular type has been reported to behave more aggressively, but the benefit of additional treatment after surgery to prevent recurrence remains unclear. Measurement of DNA content by flow cytometry, together with histological subclassification, may be useful in selecting patients who will benefit from further treatment after surgery.

Immunophenotypic analysis of childhood Burkitt's lymphoma in the West Midlands 1957-1986.

AIMS: To analyse the immunophenotype of a large number of non-endemic Burkitt's lymphomas to determine whether a B cell phenotype is consistently recognisable using formalin fixed, paraffin wax embedded archival material and a standard panel of commercially available antibodies. METHODS: Archival material was obtained from 30 cases of childhood Burkitt's lymphoma registered with the West Midlands Regional Children's Tumour Research Group. These were analysed by a standard avidin biotin complex immunoperoxidase method using antibodies to CD45, CD43, CD30, CD20, CD15, and immunoglobulin heavy and light chains. RESULTS: There was a high incidence of the CD45RB and CD20 immunophenotypes, with a clearly recognisable B cell lineage even in archival material. IgM was identifiable in 13 of the 23 (56.5%) cases tested. Only three of 17 (18%) cases expressed CD30. Positive membrane staining with CD45RO was observed in two (6.7%) cases. CONCLUSIONS: A B cell lineage can be identified in Burkitt's lymphoma in formalin fixed, paraffin wax embedded material, even in archival tissue. There was a low incidence of membrane staining with CD45RO which is a potential source of diagnostic confusion.

Stress, social support, and stopping smoking after myocardial infarction in England.

STUDY OBJECTIVE: To examine the effect on mortality of stopping smoking after myocardial infarction and the psychosocial factors that influence the decision to stop. DESIGN: Analysis of smokers in a large prospective study. Self completed questionnaires provided information on psychosocial factors. SETTING: Coronary care units at six English hospitals participating in a multicentre clinical trial. SUBJECTS: These comprised consenting myocardial infarction survivors who had been identified as smokers and who completed questionnaires within seven days of infarct at six hospitals participating in the Anglo-Scandinavian study of early thrombolysis. The 532 patients identified have been followed for over five and a half years. The main outcome measure was five year all cause mortality. MAIN RESULTS: Smokers who stopped within one month showed significantly reduced mortality compared with those who persisted, adjusting for other prognostic indicators (odds ratio 0.56, 95% confidence interval 0.33, 0.98). Overall, 74% stopped smoking. Being married, low life stress levels before infarct, and higher social class were associated with stopping smoking but the differentials were small. Of the clinical variables, a final diagnosis of definite myocardial infarction was associated with stopping smoking. All associations remained after multiple logistic regression. CONCLUSION: Smoking cessation can halve the smokers' odds of dying after myocardial infarction and psychosocial factors play a small but important role in the important decision to stop smoking. Health professionals should continue to stress the importance of stopping smoking to all patients as there is little evidence to support specific directing of advice to relatively "stress or "socially isolated" groups.

Conservatively managed tibial shaft fractures in Nottingham, UK: are pain, osteoarthritis, and disability long-term complications?

OBJECTIVES: To investigate longterm pain and disability subsequent to a tibial shaft fracture treated conservatively. DESIGN AND SETTING: Subjects who had sustained a tibial shaft fracture more than 27 years ago were compared with those who had not. SUBJECTS: 572 fracture patients (identified from the records of the plaster room) aged over 16 at the time of injury were contracted and were compared with 2285 randomly selected subjects matched for age, sex, and general practice. MAIN OUTCOME MEASURES: Self reported knee pain; self reported GP's diagnosis of osteoarthritis; ability to climb stairs, walk 100 yards, to bend, kneel, or stoop; and SF-36 physical functioning score. RESULTS: Subjects were reviewed between 27 and 41 years after tibial shaft fracture (mean 35 years). Fracture patients were more likely to suffer chronic knee pain (odds ratio 1.23; 95% confidence interval (CI) 1.00, 1.51) and report being given a diagnosis of osteoarthritis by their GP (odds ratio 1.46; 95% CI 1.08, 1.97). The ability to climb stairs, walk 100 yards, and bend, kneel, or stoop was less in the fracture group than the other subjects. The SF-36 physical function score was significantly lower in the fracture group. CONCLUSIONS: More than 27 years after a tibial shaft fracture, subjects have more knee pain than the rest of the population. They also have greater difficulty performing everyday physical activities. The excess morbidity may be due to injury factors or treatment factors, and further research is needed to investigate this important association further.

Long-term outcome after tibial shaft fracture: is malunion important?

BACKGROUND: Fractures of the shaft of the tibia often heal with some angulation. Although there is biomechanical evidence that such angulation alters load transmission through the joints of the lower limb, it is not clear whether it can eventually lead to osteoarthritis. METHODS: One hundred and sixty-four individuals who had sustained a tibial shaft fracture were assessed in a research clinic thirty to forty-three years after the injury. The subjects were evaluated with regard to self-reported lower limb joint pain, stiffness, and disability (assessed with the Western Ontario and McMaster Universities [WOMAC] osteoarthritis questionnaire); clinical signs of osteoarthritis; and radiographic evidence of osteophytes and joint-space narrowing in the knees, ankles, and subtalar joints. RESULTS: Twenty-two (15%) of the 151 subjects who reported no other knee injury reported at least moderate knee pain, and eight (6%) of the 145 subjects who reported no other ankle injury reported at least moderate ankle pain. Seventeen (13%) of the 135 subjects who reported no other knee or ankle injury reported at least moderate disability. The ipsilateral side demonstrated a higher prevalence than the contralateral side in terms of pain with passive ankle movement (nineteen versus nine subjects, p = 0.02), pain with passive subtalar movement (fifteen versus four subjects, p = 0.01), and radiographic signs of ankle joint space narrowing (twelve subjects versus one subject, p = 0.0055). Knee osteoarthritis was frequently bilateral. Forty-seven fractures (29%) healed with coronal angulation of > or = 5 degrees. Apart from an association between shortening of > or = 10 mm and self-reported knee pain (p = 0.016), there were no significant univariate associations between these malunions and the development of osteoarthritis. Seventeen (15%) of 114 eligible subjects had overall malalignment of the lower limb, defined as a hip-knee-ankle angle outside the normal range of 6.25 degrees of varus to 4.75 degrees of valgus. This malalignment was due to the fracture malunion in nine subjects and predated the fracture in eight. In limbs with varus or valgus malalignment, there was an excess of subtalar stiffness (p = 0.04) and a nonsignificant trend toward more frequent knee pain. In limbs with varus malalignment, there was a nonsignificant trend toward more frequent radiographic evidence of osteoarthritis in the medial compartment of the knee joint. Most of the subjects in whom osteoarthritis was observed had normal overall alignment of the lower limb. CONCLUSIONS: The thirty-year outcome after a tibial shaft fracture is usually good, although mild osteoarthritis is common. Fracture malunion is not the cause of the higher prevalence of symptomatic ankle and subtalar osteoarthritis on the side of the fracture. Although varus malalignment of the lower limb occurs occasionally and may cause osteoarthritis in the medial compartment of the knee, other factors are more important in causing osteoarthritis after a tibial shaft fracture.

Childhood cancer in the West Midlands: incidence and survival, 1980-1984, in a multi-ethnic population.

The purpose of this study is to describe the incidence and survival of childhood cancer in the West Midlands for the period 1980-1984. Proportional breakdown by Asian subgroup is also considered. A total of 587 patients were registered, 49 of them of Asian origin. Breakdown to Asian versus non-Asian subgroups by diagnosis revealed comparatively high rates for Hodgkin's disease, retinoblastoma and neuroblastoma in the Asian patients. However, a deficit of cases was seen for CNS tumours. Comparison of overall age-standardized rates (ASR) for all cancers revealed a substantially lower value compared to that reported for the USA white population but a similar value to the USA black and UK white populations. Diagnostic breakdown revealed that the major difference between the West Midlands Regional Children's Tumour Research Group (WMRCTRG) and the USA white ASR was in the leukaemia and lymphoma group. Overall survival for the series was 56% at 5 years. The poorest prognosis was found in acute myeloid leukaemia, with only 23% of patients surviving at 5 years, against 62% in acute lymphoblastic leukaemia. CNS tumours also had a poor outcome, with an overall survival rate of 47%, although certain individual diagnoses were more favourable. We observed a 100% survival rate in Hodgkin's disease up to 5 years from diagnosis, and both Wilms' tumour and retinoblastoma had 90% survival rates.

Descriptive epidemiology of primary central nervous system tumours in children: a population-based study.

This study was undertaken to investigate the incidence, outcome and referral patterns of central nervous system tumours in a defined childhood population over a recent 5-year period. The study incorporated pathological review of all available diagnostic material and follow-up assessed survival at a minimum of 5 years from diagnosis. One hundred and forty-seven cases were reviewed, representing an annual incidence of 26.5 per million children aged less than 15 years. The distribution of individual diagnoses by age, sex and anatomical site was similar to comparable data collected previously in the United Kingdom and North America, but the inclusion of 28 cases (19%) without biopsy suggested that the wider use of computed tomography might account for a small increase in incidence over previous estimates. Analysis of referral to the Regional Paediatric Oncology Unit showed that the patients referred were younger than those not referred and were over-represented amongst the diagnoses of medulloblastoma, ependymoma and brain stem glioma, which carry the worst prognosis. Survival for all diagnoses together was 51% at 5 years, ranging from 13% for unbiopsied brain stem gliomas to 100% for juvenile astrocytomas. Referral to the Regional Unit appeared to have some survival advantage for children with medulloblastoma, although this was not statistically significant. Accurately reviewed data such as these are essential in order to assess current workload and treatment success, in addition to enabling investigation of future diagnostic and treatment strategies.