High-dose-rate intraoperative radiation therapy: the nuts and bolts of starting a program.

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.

Clinicopathologic Comparison of High-Dose-Rate Endorectal Brachytherapy versus Conventional Chemoradiotherapy in the Neoadjuvant Setting for Resectable Stages II and III Low Rectal Cancer.

Purpose. To assess for differences in clinical, radiologic, and pathologic outcomes between patients with stage II-III rectal adenocarcinoma treated neoadjuvantly with conventional external beam radiotherapy (3D conformal radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT)) versus high-dose-rate endorectal brachytherapy (EBT). Methods. Patients undergoing neoadjuvant EBT received 4 consecutive daily 6.5 Gy fractions without chemotherapy, while those undergoing 3DRT or IMRT received 28 daily 1.8 Gy fractions with concurrent 5-fluorouracil. Data was collected prospectively for 7 EBT patients and retrospectively for 25 historical 3DRT/IMRT controls. Results. Time to surgery was less for EBT compared to 3DRT and IMRT (P < 0.001). There was a trend towards higher rate of pathologic CR for EBT (P = 0.06). Rates of margin and lymph node positivity at resection were similar for all groups. Acute toxicity was less for EBT compared to 3DRT and IMRT (P = 0.025). Overall and progression-free survival were noninferior for EBT. On MRI, EBT achieved similar complete response rate and reduction in tumor volume as 3DRT and IMRT. Histopathologic comparison showed that EBT resulted in more localized treatment effects and fewer serosal adhesions. Conclusions. EBT offers several practical benefits over conventional radiotherapy techniques and appears to be at least as effective against low rectal cancer as measured by short-term outcomes.

Aspirin for the older person: report of a meeting at the Royal Society of Medicine, London, 3rd November 2011.

On November 23rd 2011, the Aspirin Foundation held a meeting at the Royal Society of Medicine in London to review current thinking on the potential role of aspirin in preventing cardiovascular disease and reducing the risk of cancer in older people. The meeting was supported by Bayer Pharma AG and Novacyl.

A novel process for introducing a new intraoperative program: a multidisciplinary paradigm for mitigating hazards and improving patient safety.

BACKGROUND: Since the Institute of Medicine's report, To Err is Human, was published, numerous interventions have been designed and implemented to correct the defects that lead to medical errors and adverse events; however, most efforts were largely reactive. Safety, communication, team performance, and efficiency are areas of care that attract a great deal of attention, especially regarding the introduction of new technologies, techniques, and procedures. We describe a multidisciplinary process that was implemented at our hospital to identify and mitigate hazards before the introduction of a new technique: high-dose-rate intraoperative radiation therapy, (HDR-IORT). METHODS: A multidisciplinary team of surgeons, anesthesiologists, radiation oncologists, physicists, nurses, hospital risk managers, and equipment specialists used a structured process that included in situ clinical simulation to uncover concerns among care providers and to prospectively identify and mitigate defects for patients who would undergo surgery using the HDR-IORT technique. RESULTS: We identified and corrected 20 defects in the simulated patient care process before application to actual patients. Subsequently, eight patients underwent surgery using the HDR-IORT technique with no recurrence of simulation-identified or unanticipated defects. CONCLUSION: Multiple benefits were derived from the use of this systematic process to introduce the HDR-IORT technique; namely, the safety and efficiency of care for this select patient population was optimized, and this process mitigated harmful or adverse events before the inclusion of actual patients. Further work is needed, but the process outlined in this paper can be universally applied to the introduction of any new technologies, treatments, or procedures.

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein.

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists ("XAntag"; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC(50) in the range of 2 to 5 mumol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream "effector" caspases (caspase-3 and caspase-7) versus the upstream "initiator" caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation.

The heat shock response: role in radiation biology and cancer therapy.

Since prehistoric times, elevated temperatures have been used to treat cancer in a variety of forms. In modern times (the last 40 years) efforts have concentrated on combining heat with other anti-tumour modalities, principally ionizing radiation and some chemotherapeutic drugs. Despite the emphasis on combined therapy, rodent data relating to heat sensitivity and thermal tolerance development assumed principal importance. These considerations suggested treating at 43 degrees C as a target temperature and fractionation schemes emphasizing thermal tolerance avoidance. Concomitantly crucial data on heat-induced tumour reoxygenation and its temperature dependence were largely ignored. In reality these were unrealistic and undesirable goals. The preponderance of evidence now suggests that lower temperatures (40-42 degrees C) administered more frequently, optimally immediately before and during each administration of ionizing radiation, are likely to yield optimal results. Factoring in trimodality therapy and other combinations of chemotherapeutic drugs will require some modifications of such fractionation schemes.

Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.

CONTEXT: Plasma fibrinogen levels may be associated with the risk of coronary heart disease (CHD) and stroke. OBJECTIVE: To assess the relationships of fibrinogen levels with risk of major vascular and with risk of nonvascular outcomes based on individual participant data. DATA SOURCES: Relevant studies were identified by computer-assisted searches, hand searches of reference lists, and personal communication with relevant investigators. STUDY SELECTION: All identified prospective studies were included with information available on baseline fibrinogen levels and details of subsequent major vascular morbidity and/or cause-specific mortality during at least 1 year of follow-up. Studies were excluded if they recruited participants on the basis of having had a previous history of cardiovascular disease; participants with known preexisting CHD or stroke were excluded. DATA EXTRACTION: Individual records were provided on each of 154,211 participants in 31 prospective studies. During 1.38 million person-years of follow-up, there were 6944 first nonfatal myocardial infarctions or stroke events and 13,210 deaths. Cause-specific mortality was generally available. Analyses involved proportional hazards modeling with adjustment for confounding by known cardiovascular risk factors and for regression dilution bias. DATA SYNTHESIS: Within each age group considered (40-59, 60-69, and > or =70 years), there was an approximately log-linear association with usual fibrinogen level for the risk of any CHD, any stroke, other vascular (eg, non-CHD, nonstroke) mortality, and nonvascular mortality. There was no evidence of a threshold within the range of usual fibrinogen level studied at any age. The age- and sex- adjusted hazard ratio per 1-g/L increase in usual fibrinogen level for CHD was 2.42 (95% confidence interval [CI], 2.24-2.60); stroke, 2.06 (95% CI, 1.83-2.33); other vascular mortality, 2.76 (95% CI, 2.28-3.35); and nonvascular mortality, 2.03 (95% CI, 1.90-2.18). The hazard ratios for CHD and stroke were reduced to about 1.8 after further adjustment for measured values of several established vascular risk factors. In a subset of 7011 participants with available C-reactive protein values, the findings for CHD were essentially unchanged following additional adjustment for C-reactive protein. The associations of fibrinogen level with CHD or stroke did not differ substantially according to sex, smoking, blood pressure, blood lipid levels, or several features of study design. CONCLUSIONS: In this large individual participant meta-analysis, moderately strong associations were found between usual plasma fibrinogen level and the risks of CHD, stroke, other vascular mortality, and nonvascular mortality in a wide range of circumstances in healthy middle-aged adults. Assessment of any causal relevance of elevated fibrinogen levels to disease requires additional research.

Platelet aggregation in whole blood is a paradoxical predictor of ischaemic stroke: Caerphilly Prospective Study revisited.

The Caerphilly Prospective Study demonstrates a paradoxical association of increased ischaemic stroke risk with decreased whole blood adenosine diphosphate (ADP) induced platelet sensitivity. A reanalysis of this association examines whether other haematological indices and prevalent disease at baseline may explain this finding. There were 1506 men free of clinical cardiovascular disease at baseline, with 85 men manifesting a first ischaemic stroke event over 8.3 years of follow-up in this population-based prospective cohort study. Using two different approaches, the paradoxical findings are confirmed and associations are slightly stronger after accounting for red cell, platelet, and white cell indices. A U-shaped relation of stroke with platelet count is noted. These findings are consistent with the existence of sub-clinical endothelial disease and compensatory mechanisms down-regulating ADP-induced aggregation sensitivity. They support an allostasis model of causality for understanding the paradox. A public health approach to prevention could have measurable impact if intervention strategies can be developed to alter early stages of disease appropriate to such mechanisms of causation.

Sorting of the human folate receptor in MDCK cells.

The human folate receptor (hFR) is a glycosylphosphatidy-linositol (GPI) linked plasma membrane protein that mediates delivery of folates into cells. We studied the sorting of the hFR using transfection of the hFR cDNA into MDCK cells. MDCK cells are polarized epithelial cells that preferentially sort GPI-linked proteins to their apical membrane. Unlike other GPI-tailed proteins, we found that in MDCK cells, hFR is functional on both the apical and basolateral surfaces. We verified that the same hFR cDNA that transfected into CHO cells produces the hFR protein that is GPI-linked. We also measured the hFR expression on the plasma membrane of type III paroxysmal nocturnal hemoglobinuria (PNH) human erythrocytes. PNH is a disease that is characterized by the inability of cells to express membrane proteins requiring a GPI anchor. Despite this defect, and different from other GPI-tailed proteins, we found similar levels of hFR in normal and type III PNH human erythrocytes. The results suggest the hypothesis that there may be multiple mechanisms for targeting hFR to the plasma membrane.

Bleeding time, stroke and myocardial infarction: the Caerphilly prospective study.

The stressed bleeding time is a simple 'global' test of haemostasis, dependent upon platelet function, rheology, thrombosis and intimal function. It could be of considerable value in clinical practice if it were shown to be predictive of vascular disease events. A stressed bleeding time test was done on 1319 men aged 55-69 years in the Caerphilly Cohort Study of Heart Disease, Stroke and Cognitive Decline. The men were followed-up and during the following 7-10 years 155 men had a myocardial infarction (MI) and 72 an ischaemic stroke. The mean bleeding time was 323 (SD 113)s. This was shorter in men who smoked by an average of 45 s, and lengthened in men who took aspirin daily by 40s. After making statistical adjustments for numerous possible confounding factors, the relative odds (ROs) of an MI within the third of men with the longest bleeding times, compared to the third with the shortest times, was 0.90 (0.40-2.03). For ischaemic stroke, the ROs in the third of men with the longest times were 1.42 (0.39-5.21). The stressed bleeding time does not predict either MI or ischaemic stroke. It has no place in health screening.

Exposure to power frequency electric fields and the risk of childhood cancer in the UK.

The United Kingdom Childhood Cancer Study, a population-based case-control study covering the whole of Great Britain, incorporated a pilot study measuring electric fields. Measurements were made in the homes of 473 children who were diagnosed with a malignant neoplasm between 1992 and 1996 and who were aged 0-14 at diagnosis, together with 453 controls matched on age, sex and geographical location. Exposure assessments comprised resultant spot measurements in the child's bedroom and the family living-room. Temporal stability of bedroom fields was investigated through continuous logging of the 48-h vertical component at the child's bedside supported by repeat spot measurements. The principal exposure metric used was the mean of the pillow and bed centre measurements. For the 273 cases and 276 controls with fully validated measures, comparing those with a measured electric field exposure >/=20 V m(-1) to those in a reference category of exposure <10 V m(-1), odds ratios of 1.31 (95% confidence interval 0.68-2.54) for acute lymphoblastic leukaemia, 1.32 (95% confidence interval 0.73-2.39) for total leukaemia, 2.12 (95% confidence interval 0.78-5.78) for central nervous system cancers and 1.26 (95% confidence interval 0.77-2.07) for all malignancies were obtained. When considering the 426 cases and 419 controls with no invalid measures, the corresponding odds ratios were 0.86 (95% confidence interval 0.49-1.51) for acute lymphoblastic leukaemia, 0.93 (95% confidence interval 0.56-1.54) for total leukaemia, 1.43 (95% confidence interval 0.68-3.02) for central nervous system cancers and 0.90 (95% confidence interval 0.59-1.35) for all malignancies. With exposure modelled as a continuous variable, odds ratios for an increase in the principal metric of 10 V m(-1) were close to unity for all disease categories, never differing significantly from one.

Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue.

PURPOSE: A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low alpha/beta ratio), more typical of the surrounding late-responding normal tissue. METHODS AND MATERIALS: Earlier estimates of alpha/beta for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. RESULTS: The estimated value of alpha/beta from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This alpha/beta value is considerably less than typical values for tumors (> or =8 Gy), and more comparable to values in surrounding late-responding normal tissues. CONCLUSIONS: This analysis provides strong supporting evidence that alpha/beta values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.

Left ventricular hypertrophy and risk of fatal and non-fatal stroke. EUROSTROKE: a collaborative study among research centres in Europe.

BACKGROUND: This study investigated the association between electrocardiographically assessed left ventricular hypertrophy (LVH) and fatal, non-fatal, haemorrhagic and ischaemic stroke in four European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies to investigate differences in incidence of, and risk factors for, stroke between countries. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. LVH was assessed according to the Minnesota code or the automated diagnostic MEANS classification system. For this analysis, data on LVH and stroke were available from cohorts in Cardiff (84 cases/200 controls), Kuopio (60/116), Rotterdam (114/334), and Novosibirsk (62/168). Results are adjusted for age and sex. RESULTS: LVH was associated with a twofold increased risk of stroke (odds ratio 2.1 (95% CI 1.3 to 3.5). The risk was particularly pronounced for fatal stroke (4.0 (95% CI 2.1 to 7.9)), whereas the risk was non-significantly increased for non-fatal stroke (1.5 (95% CI 0.8 to 2.7)). The increased risk was more pronounced in smokers: for total stroke 3.5 (95% CI 1.5 to 8.1) versus 1.6 (95% CI 0.8 to 3.1) in non-smokers. Adjustment for systolic blood pressure and body mass index attenuated the associations. LVH was not preferentially associated with a particular type of stroke, although the association with cerebral infarction was stronger. CONCLUSION: This analysis of the EUROSTROKE project indicates that LVH assessed by electrocardiogram is a predictor of stroke. The association seems to be stronger for fatal stroke than for non-fatal stroke and is more pronounced in smokers.

Level of fibrinogen and risk of fatal and non-fatal stroke. EUROSTROKE: a collaborative study among research centres in Europe.

BACKGROUND: It is well established that raised levels of fibrinogen increase the risk of coronary heart disease. For stroke, however, data are much more limited and restricted to overall stroke. This study investigated the association between fibrinogen and fatal, non-fatal, haemorrhagic and ischaemic stroke in three European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European cohort studies on incidence and risk factors of stroke. EUROSTROKE is designed as a nested case-control study. For each stroke case, two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. Recently, data on stroke and fibrinogen became available from cohorts in Cardiff (79 cases/194 controls), Kuopio (74/124), and Rotterdam (62/203). Results were adjusted for age, sex, smoking, and systolic blood pressure. RESULTS: The risk of stroke gradually increased with increasing fibrinogen levels: the odds ratios per quartile increase were 1.08 (95% CI 0.63 to 1.84), 1.91 (1.12 to 3.26) and 2.78 (1.64 to 4.72), respectively. This association was similar for ischaemic (n=138) and haemorrhagic stroke (n=25). Associations between fibrinogen and stroke were similar across strata of smoking, diabetes mellitus, previous myocardial infarction, and HDL cholesterol. The odds ratio, however, tended to increase with increasing systolic blood pressure: from 1.21 among those with a systolic pressure <120 mm Hg to 1.99 among subjects with a systolic pressure of 160 mm Hg or above. CONCLUSION: This analysis of the EUROSTROKE project indicates that fibrinogen is a powerful predictor of stroke. Results did not disclose a differential in this relation of fibrinogen and fatal or non-fatal stroke, or with type of stroke (ischaemic or haemorrhagic).

Prediction of stroke in the general population in Europe (EUROSTROKE): Is there a role for fibrinogen and electrocardiography?

BACKGROUND: To decide whether a person with certain characteristics should be given any kind of intervention to prevent a cardiovascular event, it would be helpful to classify subjects in low, medium and high risk categories. The study evaluated which well known cerebrovascular and cardiovascular correlates, in particular fibrinogen level and ECG characteristics, are able to predict the occurrence of stroke in men of the general population using data from three European cohorts participating in EUROSTROKE. METHODS: EUROSTROKE is a collaborative project among ongoing European population based cohort studies and designed as a prospective nested case-control study. For each stroke case two controls were sampled. Strokes were classified according to MONICA criteria or reviewed by a panel of four neurologists. Complete data were available of 698 men (219 stroke events) from cohorts in Cardiff (84 cases/200 controls), Kuopio (74/148) and Rotterdam (61/131). Multivariable logistic regression modeling was used to evaluate which information from history, physical examination (for example, blood pressure), blood lipids, and fibrinogen and ECG measurements independently contributed to the prediction of stroke. The area under receiver operating characteristic curve (ROC area) was used to estimate the predictive ability of models. RESULTS: Independent predictors from medical history and physical examination were age, stroke history, medically treated hypertension, smoking, diabetes mellitus and diastolic blood pressure. The ROC area of this model was 0.69. After validating and transforming this model to an easy applicable rule, 40% of all future stroke cases could be predicted. Adding pulse rate, body mass index, blood lipids, fibrinogen level and ECG parameters did not improve the classification of subjects in low, medium and high risk. Results were similar when fibrinogen was dichotomised at the upper tertile or quintile. CONCLUSION: In the general male population the future occurrence of stroke may be predicted using easy obtainable information from medical history and physical examination. Measurement of pulse rate, body mass index, blood lipids, fibrinogen level and ECG characteristics do not contribute to the risk stratification of stroke and have no value in the screening for stroke in the general male population.

Exon 3 of the alpha folate receptor gene contains a 5' splice site which confers enhanced ovarian carcinoma specific expression.

The human folate receptor (FR) is overexpressed in ovarian carcinoma. FR transcripts are heterogeneous due to the use of two promoters, P1 and P4, and alternative splicing of exon 3. RNase protection assay and RT-PCR revealed higher levels of the transcripts that include exon 3 in lines and specimens from ovarian carcinoma. A P1-chloramphenicol acetyltransferase (CAT) construct containing exon 3 demonstrated efficient reporter expression only in ovarian carcinoma. 5' and 3' deleted variants of the P1-CAT construct were analyzed by RT-PCR of the exogenous transcripts and reporter activity. A 5' splice site and 35 bp downstream intronic region of exon 3 appeared to regulate enhanced FR expression in ovarian carcinoma.

The incidence and aetiology of stroke in the Caerphilly and Speedwell Collaborative Studies II: risk factors for ischaemic stroke.

Reduction of stroke burden requires preventive interventions targeted at important risk factors. This report presents the analysis of risk factors for ischaemic stroke from a representative cohort of middle aged men from South Wales and south-west England. Data on risk factors were collected through validated questionnaires and physical and clinical measurements. Details of possible cerebrovascular events were retrieved, classified into ischaemic, haemorrhagic and uncertain subtypes, and validated. The ratio of definite ischaemic to definite haemorrhagic strokes was calculated. This showed that the vast majority of strokes of unknown subtype were likely to ischaemic. After exclusion of known haemorrhagic strokes and subarrachnoid haemorrhages the remaining strokes were labelled ischaemic. Hazard ratios for possible risk factors were calculated for all ischaemic, and for fatal and non-fatal strokes. There were 293 ischaemic strokes. Statistically significant age-adjusted hazard ratios were: 1.50 (95% confidence interval 1.16-1.95) for being in a manual social class, 1.82 (1.24-2.67) if smoking >15 cigarettes/d at enrollment, 1.19 (1.13-1.24) and 1.23 (1.14-1.34) per 10 mmHg increase in systolic and diastolic blood pressure, respectively, 0.67 (0.46-0.96) for the top quintile high density lipoprotein-cholesterol:cholesterol ratio compared to the bottom quintile, 2.04 (1.40-2.99) for presence of angina, 3.90 (2.01-7.58) for presence of atrial fibrillation, and 3.35 (1.90-5.80) for presence of diabetes. Risk factors were more strongly associated with fatal than non-fatal strokes. Multivariate analyses revealed that, while there was some attenuation of the effect of social class, angina and elevated BP, the risks from atrial fibrillation and diabetes were increased.

Aspirin: past, present and future.

Many folk remedies used since pre-historic times have depended upon salicylates for their effect. One hundred years ago aspirin was formulated from salicylic and acetic acids. It was the first drug to be synthesised and its formulation is regarded as the foundation of the modern pharmaceutical industry. The benefit of low-dose aspirin as a prophylactic after a thrombotic event was first reported 25 years ago. Its use after coronary or cerebral thrombosis is virtually mandatory, unless there are signs of intolerance. A 'loading dose' of soluble aspirin should be given on first contact with a patient who may be suffering from myocardial infarction. Patients considered to be at increased risk of a vascular event should also be advised to carry their own aspirin and, if they experience sudden severe chest pain, to chew and swallow a 300 mg tablet or a soluble preparation immediately. The current phase of the aspirin story is, however, not over, and its possible value in a variety of conditions, including dementia and certain cancers, seems likely to ensure that it will long continue to play a remarkable part in clinical practice.