Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening.

BACKGROUND: Malignancy risks in patients with neurofibromatosis 1 (NF1) are increased, but those occurring outside of the nervous system have not been clearly defined. AIM: To evaluate the risk of breast cancer in women with NF1 in a population-based study. METHODS: The risk of breast cancer in a cohort of 304 women with NF1 aged >or=20 years was assessed and compared with population risks over the period 1975-2005 using a person-years-at-risk analysis. RESULTS: There were 14 cases of breast cancers in the follow-up period, yielding a standardised incidence ratio (SIR) of 3.5 (95% CI 1.9 to 5.9). However, six breast cancers occurred in women in their 40s, and the SIR of breast cancer in women aged <50 years was 4.9 (95% CI 2.4 to 8.8). INTERPRETATION: Women with NF1 aged <50 years have a fivefold risk of breast cancer, are in the moderate risk category and should be considered for mammography from 40 years of age.

Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening.

BACKGROUND: The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at-risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high-risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds. METHODS: 277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population. RESULTS: Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative. CONCLUSION: In high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.

Increased incidence of renal parenchymal carcinoma in the Northern and Yorkshire region of England, 1978-1997.

Kidney cancer remains relatively rare, but incidence and mortality rates are reported to be rising steadily across the world. To determine if such increases were occurring in the UK, we examined the rates of incidence and mortality in different histological subtypes of kidney cancer in the Northern and Yorkshire region of England. Details of all 8741 cases diagnosed between 1978 and 1997 were extracted from the population-based Northern and Yorkshire Cancer Registry. For all types of tumour, both incidence and mortality rates increased over the study period. Overall age-standardised incidence rates increased by 86% for renal parenchymal carcinoma (RPC) (80% for males, 90% for females) from 2.8 to 5.2 cases per 100000 (3.8-6.8 male, 2.0-3.8 female). There were incidence increases in all age groups, all Carstairs index groups and in both urban and rural populations. Although increased incidental detection of kidney tumours by improved investigational techniques may account for some of this rise, we believe it unlikely that it accounts for all of the increase observed. Potential aetiological causes for the increased rates include hypertension, smoking, a diet lacking fruit and vegetables, analgesic use and, particularly, obesity.

A study of the morbidity, mortality and long-term survival following radical cystectomy and radical radiotherapy in the treatment of invasive bladder cancer in Yorkshire.

OBJECTIVES: To study the morbidity of radical cystectomy and radical radiotherapy in the treatment of patients with invasive carcinoma of the bladder and to report the long-term survival following these treatments. PATIENT AND METHODS: 398 patients with invasive carcinoma of the bladder treated between 1993 and 1996 in the Yorkshire region were studied. Of 398 patients studied, 302 patients received radical radiotherapy and 96 underwent radical cystectomy. A retrospective review of patients' case notes was performed to construct a highly detailed database. Crude estimates of survival differences were derived using Kaplan-Meier methods. Log-rank tests (or, where appropriate, Wilcoxon tests) were used to test for the equality of these survivor functions. These functions were produced as all-cause survival. The proportional hazards regression modelling was used to assess the impact of definitive treatment on survival. A backwards-stepwise approach was used to derive a final predictive model of survival, with likelihood ratio tests to assess the statistical significance of variables to be included in the model. RESULTS: The patients undergoing radiotherapy were significantly older (mean age: 71 years versus 66 years), but no difference was identified in the distribution of American Society of Anaesthesiologists (ASA) grades in the two treatment groups. The stage distribution of cases in the treatment groups was not significantly different. Significant treatment delays were observed in both treatment groups. The median time from being seen in the clinic to transurethral resection of bladder tumour (TURBT) and subsequent radical treatment (cystectomy or radiotherapy) was 4.3 and 9 weeks, respectively. Age was the most significant independent factor accounting for treatment delays (p < 0.001). The 30-day and 3-month treatment-associated mortality for radical cystectomy and radiotherapy was 3.1% and 8.3% and 0.3% and 1.65%. Of the patients who received radiotherapy, 57 (18.8%) were subsequently subjected to a salvage cystectomy. For these 57 patients, 30-day and 3-month mortality after the salvage cystectomy were 8.8% and 15.7%. Gastrointestinal complications were the major source of early morbidity after primary and salvage cystectomy. Bowel leakage occurred in 3% following radical and 8.7% after salvage cystectomy. Bowel complications (leakage and obstruction) were the major cause of death following salvage cystectomy. No specific cause was predominant in those undergoing radical cystectomy with intestinal anastomotic leakage and urinary leakage accounting for one death each. Exacerbation of co-morbid conditions accounted for the remaining causes of mortality. Urinary leakage occurred in 4% following both forms of cystectomy. Recurrent pyelonephritis and intestinal obstruction were responsible for the majority of complications in the follow-up period. Bladder and gastrointestinal complications accounted for the majority of complications following radical radiotherapy. Some degree of irritative bladder and rectal were noted commonly. Severe bladder problems, which rendered the bladder non-functional or required surgical correction, occurred in 6.3% of patients. 2.3% of patients underwent surgery for bowel obstruction related to radiotherapy induced bowel strictures. Following radiotherapy, 43.6% of patients had a recurrence in the bladder at varying intervals post-treatment. Of these, 40% had > or =T2 disease. The 5-year survival following radiotherapy (with or without salvage cystectomy) was 37.4% while 36.5% of patients were alive 5 years after radical cystectomy. There was no statistically significant difference in the overall 5-year survival figures between the two primary treatments. Tumour stage, ASA grade and sex were the only independent predictors of 5-year survival on multivariate analysis. CONCLUSIONS: This retrospective regional study shows that there is no significant difference in the 5-year survival of patients with invasive bladder cancer treated with either radical radiotherapy or radical cystectomy. All forms of radical treatment for bladder cancer are associated with a significant treatment-associated morbidity and mortality. Gastrointestinal complications were responsible for the majority of complications. The treatment-associated mortality at 3 months was two- or three-fold higher than the 30-day mortality; emphasising its importance as an indicator of the true risks of cystectomy. The clinical T stage, the sex and the ASA grade of the patient were the only independent predictors of survival. The data in this series suggests that radical radiotherapy and radical cystectomy should be both considered as valid primary treatment options for the management of invasive bladder cancer.

Tirilazad for acute ischaemic stroke.

BACKGROUND: Tirilazad mesylate is neuroprotective in experimental models of ischaemic stroke suggesting it might be of benefit clinically. OBJECTIVES: To assess whether tirilazad mesylate is safe and effective at improving outcome in patients with acute ischaemic stroke. SEARCH STRATEGY: Trials of tirilazad were identified from searches of the Cochrane Stroke Group Specialised Trials Register (last searched: May 2001) and the Cochrane Controlled Trials Register (CENTRAL/CCTR). In addition, we contacted the Pharmacia & Upjohn company, the manufacturer of tirilazad, to identify unpublished studies and further information. SELECTION CRITERIA: Truly and quasi-randomised unconfounded placebo or open controlled trials of tirilazad administered within 24 hours onset of suspected or proven acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Data relating to early and end-of-trial case fatality, disability (Barthel Index and Glasgow Outcome Scale), phlebitis, and QTc were extracted by treatment group from published data and company reports. MAIN RESULTS: Six trials (four published, two unpublished) assessing tirilazad in 1757 patients with presumed acute ischaemic stroke were identified; all were double-blind and placebo-controlled in design. Tirilazad did not alter early case fatality (odds ratio, OR 1.11, 95% confidence intervals, 95% CI 0.79 to 1.56) or end-of-trial case fatality (OR 1.12, 95% CI 0.88 to 1.44). Tirilazad increased the odds of being dead or disabled by about one fifth, though the result was only just statistically significant; the odds ratios were similar whether the expanded Barthel Index or Glasgow Outcome Scale were used to assess outcome (OR 1.23, 95% CI 1.01 to 1.51; OR 1.23, 95% CI 1.01 to 1.50 respectively). Tirilazad significantly increased the rate of infusion site phlebitis (OR 2.81, 95% CI 2.14 to 3.69). Functional outcome (EBI) was significantly worse in prespecified subgroups of patients: females (OR 1.46, 95% CI 1.08 to 1.98) and subjects receiving low dose tirilazad (OR 1.31, 95% CI 1.03 to 1.67); a non-significant worse outcome was also seen in patients with mild-moderate stroke (OR 1.40, 95% CI 0.99 to 1.98). REVIEWER'S CONCLUSIONS: Tirilazad mesylate increased the combined end-point of 'death or disability' by about one-fifth, but did not alter case fatality, when given to patients with acute ischaemic stroke. Although further trials of tirilazad are now not warranted, analysis of individual patient data from the trials may help elucidate why tirilazad appears to worsen outcome in acute ischaemic stroke.

The effect of transdermal glyceryl trinitrate, a nitric oxide donor, on blood pressure and platelet function in acute stroke.

BACKGROUND AND PURPOSE: Hypertension is a common medical complication in acute stroke and is associated with a poor outcome. However, no large trials have assessed the effect of lowering blood pressure (BP) on outcome, and it remains unclear how BP should be managed in acute stroke. We assessed, in a double-blind randomised controlled trial, whether the nitric oxide (NO) donor glyceryl trinitrate (GTN, a known systemic and cerebral vasodilator), would lower BP and alter platelet function. METHODS: Thirty-seven patients with recent (< 5 days) ischaemic or haemorrhagic stroke were randomised by minimisation to 12 days of daily treatment with transdermal GTN or matching placebo patches. Twenty-four-hour ambulatory BP was measured before and during GTN treatment at days 0, 1 and 8. Platelet aggregation and expression of adhesion molecules were assessed at the same time points. Functional outcome (Rankin scale) and case fatality were assessed at 3 months. Analysis was by intention-to-treat. RESULTS: GTN significantly lowered BP by 13.0/5.2 mm Hg at day 1 and 9.3/5.0 mm Hg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to GTN was developing. Non-significant falls of 0.9/0.6 and 3.8/0.0 mm Hg occurred at days 1 and 8, respectively, in the placebo group. GTN had no effect on heart rate, or platelet aggregation or expression of platelet adhesion molecules, including glycoproteins Ia, Ib, IIIa and P-selectin. Additionally, GTN did not alter case fatality or dependency, although the study was not powered for these outcomes. CONCLUSIONS: Transdermal GTN, an NO donor, lowered BP by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke. However, GTN had no effect on platelet aggregation or expression of adhesion molecules. Since NO donors increase cerebral blood flow in patients with acute ischaemic stroke, GTN may be an appropriate drug for testing the effect of lowering BP on functional outcome.

Low-molecular-weight heparins and heparinoids in acute ischemic stroke : a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Low-molecular-weight heparins and heparinoids (LMWHs) are superior to unfractionated heparin in the prevention and treatment of venous thromboembolism and acute coronary syndromes. We performed a systematic review of randomized controlled trials (RCTs) to examine the safety and efficacy of LMWH in acute ischemic stroke. METHODS: Randomized, controlled, and nonconfounded trials of LMWH in acute ischemic stroke were identified from the Cochrane Library (version 2, 1999), previous systematic reviews, and a review of publication quality relating to acute stroke trials. The authors each independently extracted data by treatment group and assessed trial quality using Cochrane Collaboration criteria. RESULTS: Eleven completed RCTs involving 3048 patients were identified; data were available from 10 of these. Four trials explicitly excluded patients with presumed cardioembolic stroke. Treatment with LMWH was associated with significant reductions in prospectively identified deep vein thrombosis (OR 0.27, 95% CI 0.08 to 0.96) and symptomatic pulmonary embolism (OR 0.34, 95% CI 0.17 to 0.69) and with increased major extracranial hemorrhage (OR 2.17, 95% 1.10 to 4.28). Nonsignificant increases in end-of-treatment (OR 1.20, 95% CI 0.86 to 1.69) and end-of-trial (OR 1.05, 95% CI 0.83 to 1.32) case fatality and symptomatic intracranial hemorrhage (OR 1.77, 95% CI 0. 95 to 3.31) were observed. End-of-trial death and disability was nonsignificantly reduced (OR 0.87, 95% CI 0.72 to 1.06). CONCLUSIONS: ++LMWHs reduce venous thromboembolic events in patients with acute ischemic stroke and increase the risk of extracranial bleeding. A nonsignificant reduction in combined death and disability and nonsignificant increases in case fatality and symptomatic intracranial hemorrhage were also observed. On the basis of the current evidence, LMWH should not be used in the routine management of patients with ischemic stroke.