Risk factors for delay in symptomatic presentation: a survey of cancer patients.

BACKGROUND: Delay in symptomatic presentation leading to advanced stage at diagnosis may contribute to poor cancer survival. To inform public health approaches to promoting early symptomatic presentation, we aimed to identify risk factors for delay in presentation across several cancers. METHODS: We surveyed 2371 patients with 15 cancers about nature and duration of symptoms using a postal questionnaire. We calculated relative risks for delay in presentation (time from symptom onset to first presentation >3 months) by cancer, symptoms leading to diagnosis and reasons for putting off going to the doctor, controlling for age, sex and deprivation group. RESULTS: Among 1999 cancer patients reporting symptoms, 21% delayed presentation for >3 months. Delay was associated with greater socioeconomic deprivation but not age or sex. Patients with prostate (44%) and rectal cancer (37%) were most likely to delay and patients with breast cancer least likely to delay (8%). Urinary difficulties, change of bowel habit, systemic symptoms (fatigue, weight loss and loss of appetite) and skin symptoms were all common and associated with delay. Overall, patients with bleeding symptoms were no more likely to delay presentation than patients who did not have bleeding symptoms. However, within the group of patients with bleeding symptoms, there were significant differences in risk of delay by source of bleeding: 35% of patients with rectal bleeding delayed presentation, but only 9% of patients with urinary bleeding. A lump was a common symptom but not associated with delay in presentation. Twenty-eight percent had not recognised their symptoms as serious and this was associated with a doubling in risk of delay. Embarrassment, worry about what the doctor might find, being too busy to go to the doctor and worry about wasting the doctor's time were also strong risk factors for delay, but were much less commonly reported (<6%). INTERPRETATION: Approaches to promote early presentation should aim to increase awareness of the significance of cancer symptoms and should be designed to work for people of the lowest socioeconomic status. In particular, awareness that rectal bleeding is a possible symptom of cancer should be raised.

Breast cancer survival and stage at diagnosis in Australia, Canada, Denmark, Norway, Sweden and the UK, 2000-2007: a population-based study.

BACKGROUND: We investigate whether differences in breast cancer survival in six high-income countries can be explained by differences in stage at diagnosis using routine data from population-based cancer registries. METHODS: We analysed the data on 257,362 women diagnosed with breast cancer during 2000-7 and registered in 13 population-based cancer registries in Australia, Canada, Denmark, Norway, Sweden and the UK. Flexible parametric hazard models were used to estimate net survival and the excess hazard of dying from breast cancer up to 3 years after diagnosis. RESULTS: Age-standardised 3-year net survival was 87-89% in the UK and Denmark, and 91-94% in the other four countries. Stage at diagnosis was relatively advanced in Denmark: only 30% of women had Tumour, Nodes, Metastasis (TNM) stage I disease, compared with 42-45% elsewhere. Women in the UK had low survival for TNM stage III-IV disease compared with other countries. CONCLUSION: International differences in breast cancer survival are partly explained by differences in stage at diagnosis, and partly by differences in stage-specific survival. Low overall survival arises if the stage distribution is adverse (e.g. Denmark) but stage-specific survival is normal; or if the stage distribution is typical but stage-specific survival is low (e.g. UK). International differences in staging diagnostics and stage-specific cancer therapies should be investigated.

Transverse tubules are a common feature in large mammalian atrial myocytes including human.

Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca(2+) channels on t tubules with the sarcoplasmic reticulum (SR) constitutes a "calcium release unit" and allows close coupling of excitation to the rise in systolic Ca(2+). T tubules are virtually absent in the atria of small mammals, and therefore Ca(2+) release from the SR occurs initially at the periphery of the cell and then propagates into the interior. Recent work has, however, shown the occurrence of t tubules in atrial myocytes from sheep. As in the ventricle, Ca(2+) release in these cells occurs simultaneously in central and peripheral regions. T tubules in both the atria and the ventricle are lost in disease, contributing to cellular dysfunction. The aim of this study was to determine if the occurrence of t tubules in the atrium is restricted to sheep or is a more general property of larger mammals including humans. In atrial tissue sections from human, horse, cow, and sheep, membranes were labeled using wheat germ agglutinin. As previously shown in sheep, extensive t-tubule networks were present in horse, cow, and human atrial myocytes. Analysis shows half the volume of the cell lies within 0.64 ± 0.03, 0.77 ± 0.03, 0.84 ± 0.03, and 1.56 ± 0.19 µm of t-tubule membrane in horse, cow, sheep, and human atrial myocytes, respectively. The presence of t tubules in the human atria may play an important role in determining the spatio-temporal properties of the systolic Ca(2+) transient and how this is perturbed in disease.

Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995-2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data.

BACKGROUND: Cancer survival is a key measure of the effectiveness of health-care systems. Persistent regional and international differences in survival represent many avoidable deaths. Differences in survival have prompted or guided cancer control strategies. This is the first study in a programme to investigate international survival disparities, with the aim of informing health policy to raise standards and reduce inequalities in survival. METHODS: Data from population-based cancer registries in 12 jurisdictions in six countries were provided for 2·4 million adults diagnosed with primary colorectal, lung, breast (women), or ovarian cancer during 1995-2007, with follow-up to Dec 31, 2007. Data quality control and analyses were done centrally with a common protocol, overseen by external experts. We estimated 1-year and 5-year relative survival, constructing 252 complete life tables to control for background mortality by age, sex, and calendar year. We report age-specific and age-standardised relative survival at 1 and 5 years, and 5-year survival conditional on survival to the first anniversary of diagnosis. We also examined incidence and mortality trends during 1985-2005. FINDINGS: Relative survival improved during 1995-2007 for all four cancers in all jurisdictions. Survival was persistently higher in Australia, Canada, and Sweden, intermediate in Norway, and lower in Denmark, England, Northern Ireland, and Wales, particularly in the first year after diagnosis and for patients aged 65 years and older. International differences narrowed at all ages for breast cancer, from about 9% to 5% at 1 year and from about 14% to 8% at 5 years, but less or not at all for the other cancers. For colorectal cancer, the international range narrowed only for patients aged 65 years and older, by 2-6% at 1 year and by 2-3% at 5 years. INTERPRETATION: Up-to-date survival trends show increases but persistent differences between countries. Trends in cancer incidence and mortality are broadly consistent with these trends in survival. Data quality and changes in classification are not likely explanations. The patterns are consistent with later diagnosis or differences in treatment, particularly in Denmark and the UK, and in patients aged 65 years and older. FUNDING: Department of Health, England; and Cancer Research UK.

The National Awareness and Early Diagnosis Initiative in England: assembling the evidence.

A National Awareness and Early Diagnosis Initiative (NAEDI) has been established in England as part of the Government's strategy to improve cancer outcomes. One of the early priorities for this initiative has been to assemble the diverse evidence linking late diagnosis with poor survival and avoidable deaths. This supplement brings together new perspectives on existing research in this area together with findings from recently commissioned research. This paper describes a provisional model, the 'NAEDI pathway', for testing hypotheses relating to late diagnosis and its impact. Key findings from other papers in this supplement are also highlighted.

The size of the prize for earlier diagnosis of cancer in England.

BACKGROUND: This supplement presents a wide range of observations, reviews, novel research and analyses underpinning the National Awareness and Early Diagnosis Initiative (NAEDI). The preceding three papers present and discuss different aspects of the data from European cancer survival comparison studies. I conclude here by attempting to quantify the extent to which delayed diagnosis in England accounts for observed survival differences and by outlining areas for further research. METHODS: Analysis of indirect evidence related to late diagnosis, surgical intervention rates and utilisation of radiotherapy and chemotherapy in England and other European countries in the late 1990s for breast, colorectal and lung cancer. RESULTS: Late diagnosis was almost certainly a major contributor to poor survival in England for all three cancers. Low surgical intervention rates are very likely to have contributed to low survival rates for lung cancer and possibly for the other two cancers. Any differences in the use of radiotherapy or chemotherapy are likely to have had only a minor impact on survival differences. CONCLUSION: Between 5000 and 10000 deaths within 5 years of diagnosis could be avoided every year in England if efforts to promote earlier diagnosis and appropriate primary surgical treatment are successful. Detailed international benchmarking studies are to be recommended.

Determination of inorganic pharmaceutical counterions using hydrophilic interaction chromatography coupled with a Corona CAD detector.

A simple generic approach was investigated for the determination of inorganic pharmaceutical counterions in drug substances using conventional high performance liquid chromatographic (HPLC) instruments. An intuitive approach combined Corona charged aerosol detection (CAD) with a polymer-based zwitterionic stationary phase in the hydrophilic interaction chromatography (HILIC) mode. Two generic methods based on this HILIC/CAD technique were developed to quantitate counterions such as Cl-, Br-, SO(4)(2-), K+, Ca2+ and Mg2+ in different pharmaceutical compounds. The development and capability of this HILIC/CAD technique analysis were examined. HILIC/CAD was compared to ion chromatography (IC), the most commonly used methodology for pharmaceutical counterion analysis. HILIC/CAD was found to have significant advantages in terms of: (1) being able to quantitate both anions and cations simultaneously without a need to change column/eluent or detection mode; (2) imposing much less restriction on the allowable organic percentage of the eluents than IC, and therefore being more appropriate for analysis of counterions of poorly water-soluble drugs; (3) requiring minimal training of the operating analysts. The precision and accuracy of counterion analysis using HILIC/CAD was not compromised. A typical precision of <2.0% was observed for all tested inorganic counterions; the determinations were within 2.0% relative to the theoretical counterion amount in the drug substance. Additionally, better accuracy was shown for Cl- in several drug substances as compared to IC. The main drawback of HILIC/CAD is its unsuitability for many of the current silica-based HILIC columns, because slight dissolution of silica leads to high baseline noise in the CAD detector. As a result of the universal detection characteristics of Corona CAD and the unique separation capabilities of a zwitterionic stationary phase, an intuitive and robust HPLC method was developed for the generic determination of various counterions in different drug substances. HILIC/CAD technique is a useful alternative methodology, particularly for determination of counterions in low-solubility drugs.

Growth factors differentially regulate neuronal Cav channels via ERK-dependent signalling.

Voltage-gated calcium channels (Ca(v)) are tonically up-regulated via Ras/extracellular signal-regulated kinase (ERK) signalling in sensory neurones. However, the mechanisms underlying the specificity of cellular response to this pathway remain unclear. Neurotrophic factors are attractive candidates to be involved in this process as they are key regulators of ERK signalling and have important roles in neuronal survival, development and plasticity. Here, we report that in rat dorsal root ganglion neurones, endogenous nerve growth factor (NGF), glial derived neurotrophic factor (GDNF) and epidermal growth factor (EGF) are all involved in tonic ERK-dependent up-regulation of Ca(v) channels. Chronic (overnight) deprivation of growth factors inhibits total Ca(v) current according to developmental changes in expression of the cell surface receptors for NGF, GDNF and EGF. Whilst EGF specifically regulates transcriptional expression of Ca(v)s, NGF and GDNF also acutely modulate Ca(v) channels within a rapid ( approximately 10min) time-frame. These acute effects likely involve changes in the biophysical properties of Ca(v)s, including altered channel gating rather than changes in surface expression. Furthermore, NGF, GDNF and EGF differentially regulate specific populations of Ca(v)s. Thus, ERK-dependent regulation of Ca(v) activity provides an elegant and extremely flexible system with which to tailor calcium influx to discrete functional demands.

Why do older women delay presentation with breast cancer symptoms?

Women who delay their presentation with breast cancer for three months or longer are more likely to be diagnosed with later stage disease and have poorer survival. Older women, who are at greater risk of developing breast cancer, are also more likely to delay their presentation. Factors associated with delayed presentation were assessed in 69 women (>65 years) with breast cancer. Previous factors identified for women of all ages were confirmed (having a non-lump symptom p=0.003) or strengthened (non-disclosure of symptom discovery to a relative or close friend p=0.001). Additional factors for delay in this older group included reservations about seeing their GP (p=0.02) and fear of the consequences of cancer (p=0.04). These factors should inform the design of interventions to reduce delays.

A population study to define the incidence and survival of multiple myeloma in a National Health Service Region in UK.

Epidemiology data on multiple myeloma (MM) occurrence and outcome is inconsistent whilst a major limitation of randomized controlled trials is selection bias. We present a population-based analysis of patients diagnosed with MM in the South Thames area, which comprises 5.4 million adult inhabitants. A total of 855 cases of MM were ascertained between 1999 and 2000 in a collaborative project involving haematologists and the Thames Cancer Registry. The age-standardized rate was 3.29 per 100 000 and 4.82 cases per 100 000 (World Standard and European Population respectively). The median age was 73 years. The median survival for the whole group was 24 months whist it was 42 and 18 months in those aged less than 65 years and greater than 65 years respectively (P < 0.001). This population study has shown a higher incidence than previously reported in the UK and Europe and provides a benchmark for future studies. If survival is to be improved, future clinical trials and health care planning should consider patients over 65 years of age.

Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme.

This study aimed to develop an epirubicin dose modification scheme in women with breast cancer and liver dysfunction. We first identified target areas under the concentration-time curve (AUCs) of 2400 and 1600 ng/ml.h from pharmacokinetic studies in 15 women with normal liver tests. In a second group of 16 women with abnormal liver biochemistry, the relationship between raised asparate aminotransferase (AST) and epirubicin clearance was: dose=AUC (97.5-34.2xlog AST). Adaptive dosing was evaluated prospectively in a third group of 41 women with serum AST > or =2xnormal+/-raised bilirubin. The median AUCs were 2444 and 1608 ng/ml.h, close to the high and low target AUCs, respectively. Variability in AUC was lower with adaptive dosing than in a fourth group given an unadjusted dose of epirubicin (coefficient of variation=25.8, 30.0 and 46.5%, respectively; P=0.06). Epirubicin dosing based on AST is safe and may reduce pharmacokinetic variability.

Mantle-circulation models with sequential data assimilation: inferring present-day mantle structure from plate-motion histories.

Data assimilation is an approach to studying geodynamic models consistent simultaneously with observables and the governing equations of mantle flow. Such an approach is essential in mantle circulation models, where we seek to constrain an unknown initial condition some time in the past, and thus cannot hope to use first-principles convection calculations to infer the flow history of the mantle. One of the most important observables for mantle-flow history comes from models of Mesozoic and Cenozoic plate motion that provide constraints not only on the surface velocity of the mantle but also on the evolution of internal mantle-buoyancy forces due to subducted oceanic slabs. Here we present five mantle circulation models with an assimilated plate-motion history spanning the past 120 Myr, a time period for which reliable plate-motion reconstructions are available. All models agree well with upper- and mid-mantle heterogeneity imaged by seismic tomography. A simple standard model of whole-mantle convection, including a factor 40 viscosity increase from the upper to the lower mantle and predominantly internal heat generation, reveals downwellings related to Farallon and Tethys subduction. Adding 35% bottom heating from the core has the predictable effect of producing prominent high-temperature anomalies and a strong thermal boundary layer at the base of the mantle. Significantly delaying mantle flow through the transition zone either by modelling the dynamic effects of an endothermic phase reaction or by including a steep, factor 100, viscosity rise from the upper to the lower mantle results in substantial transition-zone heterogeneity, enhanced by the effects of trench migration implicit in the assimilated plate-motion history. An expected result is the failure to account for heterogeneity structure in the deepest mantle below 1500 km, which is influenced by Jurassic plate motions and thus cannot be modelled from sequential assimilation of plate motion histories limited in age to the Cretaceous. This result implies that sequential assimilation of past plate-motion models is ineffective in studying the temporal evolution of core-mantle-boundary heterogeneity, and that a method for extrapolating present-day information backwards in time is required. For short time periods (of the order of perhaps a few tens of Myr) such a method exists in the form of crude 'backward' convection calculations. For longer time periods (of the order of a mantle overturn), a rigorous approach to extrapolating information back in time exists in the form of iterative nonlinear optimization methods that carry assimilated information into the past through the use of an adjoint mantle convection model.

Circumcerebral application of weak complex magnetic fields with derivatives and changes in electroencephalographic power spectra within the theta range: implications for states of consciousness.

Relative power within the delta, theta, low-alpha, high-alpha, and gamma electroencephalographic spectra of 8 human volunteers was recorded over the left and right frontal, temporal, parietal, and occipital lobes during and after the circumcerebral application through an array of 8 solenoids of 6 different configurations of weak (5 to 10 microTesla) magnetic fields. The solenoids were equally spaced around the subject's head along a horizontal plane above the ears. An approximately 30% increase in power within the theta band occurred transcerebrally during the application of a specific configuration, previously shown to affect subjective time, involving 20-msec. rates of change in the duration of delivery of the magnetic fields to each successive solenoid. Compared to the left hemisphere, the right hemisphere displayed a 20% increase in power within the 5.0- to 5.9-Hz range for all 6 configurations. The results suggest that very complex magnetic fields with the appropriate temporal parameters rotated around and within brain space can interact with the cerebral processes, measured as specific hands of frequencies, generating consciousness. Implications for the roles of hippocampal theta activity, cortical resonance, and Goldstone bosons in these processes are discussed.

Does the method of detection of breast cancer affect subsequent psychiatric morbidity?

The aim of this prospective study was to compare the prevalence of psychiatric morbidity following diagnosis of breast cancer between a group of women presenting with screen-detected cancer and a group presenting with symptomatic disease. Psychiatric symptoms were elicited using the Structured Clinical Interview (SCID) and classified according to DSM-III criteria. 61 (46%) of 132 women interviewed experienced an episode of psychiatric disorder between 1 month before diagnosis and 12 months post-diagnosis. There was no association between detection by screening of breast cancer and psychiatric disorder (Odds Ratio (OR) 0.8, 95% Confidence Interval (CI) 0.4-1.8 P=0.7). The occurrence of an episode of psychiatric disorder was associated with a previous history of treatment for psychological problems (OR 2.4, 95% CI 1.1-5.5, P=0.02). The results suggest there is no increased risk of developing psychiatric morbidity associated with the detection of cancer through the National Breast Screening Programme.

Women's knowledge and beliefs regarding breast cancer.

Approximately 20-30% of women delay for 12 weeks or more from self-discovery of a breast symptom to presentation to a health care provider, and such delay intervals are associated with poorer survival. Understanding the factors that influence patient delay is important for the development of an effective, targeted health intervention programme to shorten patient delay. The aim of the study was to elicit knowledge and beliefs about breast cancer among a sample of the general female population, and examine age and socio-economic variations in responses. Participants were randomly selected through the Postal Address File, and data were collected through the Office of National Statistics. Geographically distributed throughout the UK, 996 women participated in a short structured interview to elicit their knowledge of breast cancer risk, breast cancer symptoms, and their perceptions of the management and outcomes associated with breast cancer. Women had limited knowledge of their relative risk of developing breast cancer, of associated risk factors and of the diversity of potential breast cancer-related symptoms. Older women were particularly poor at identifying symptoms of breast cancer, risk factors associated with breast cancer and their personal risk of developing the disease. Poorer knowledge of symptoms and risks among older women may help to explain the strong association between older age and delay in help-seeking. If these findings are confirmed they suggest that any intervention programme should target older women in particular, given that advancing age is a risk factor for both developing breast cancer and for subsequent delayed presentation.

Chemotherapy for advanced breast cancer: what influences oncologists' decision-making?

Chemotherapy is widely used in the management of patients with advanced breast cancer. However, a considerable proportion of patients experience toxic side effects without gaining benefit. This study aimed to elicit oncologists' views of the goals of chemotherapy for patients with advanced breast cancer and to elicit which factors are important in decisions to recommend chemotherapy to such patients. 30 oncologists underwent a semi-structured interview to examine their views of 5 goals of chemotherapy and of various disease, treatment and patient-related factors that might influence decisions to offer treatment. The clinicians also made decisions regarding treatment in relation to a hypothetical patient scenario under varying clinical conditions. Relief of symptoms and improvement of activity were rated as the most valuable and achievable goals of treatment. The patient's performance status, frailty and their wishes regarding treatment were the most important patient-related factors in determining decision-making. The most important disease/treatment-related factors were pace of the disease, previous poor response to chemotherapy, co-existing symptoms and concurrent medical conditions. The hypothetical scenario revealed that co-existing medical conditions, adverse previous response, increased age and depression would decrease the likelihood of recommending chemotherapy, whereas key symptoms (e.g. breathlessness) and the patient's goals would increase the likelihood. The findings suggest that British oncologists primarily aim to improve patients' physical function, although subjective factors, such as a patient's desire for anti-cancer treatment and their future goals, also influence decisions to offer treatment.

How many deaths have been avoided through improvements in cancer survival?

OBJECTIVE: To estimate how many deaths from cancer have been avoided in England and Wales because of recent improvements in survival. DESIGN: Analysis of national statistics. SETTING: England and Wales. SUBJECTS: 1.5 million adults with diagnosis of one of 47 different cancers during 1981-5 or 1986-90. MAIN OUTCOME MEASURES: Reduction in number of cancer deaths within five years of diagnosis among patients with cancer diagnosed during 1986-90 compared with patients with cancer diagnosed during 1981-5. RESULTS: 17 041 deaths were avoided within five years of diagnosis among patients with cancer diagnosed during 1986-90. This represents 3.3% of the cancer deaths that would have been expected if survival had been the same as for patients with cancer diagnosed during 1981-5. Two thirds of the avoided deaths arose from improvements in survival for just five cancers: female breast cancer (4822), cancers of the colon (2560), rectum (1090), and bladder (1157), and melanoma of the skin (1098). The largest proportionate reductions in excess deaths were for melanoma of the skin (23%) and cancers of the testis (17%) and bone (17%). About 12 000 (70%) of the avoided deaths arose among adults aged under 75 at death. Improvements in survival from cancers of lung, prostate, stomach, ovary, and brain were small: they accounted for 33% of all cancers but only 11% of avoided deaths. CONCLUSIONS: Small gains in survival from common cancers save more lives than larger gains for uncommon cancers. If recent rates of improvement in cancer survival continue, about 24 000 deaths within five years of diagnosis would be avoided in patents aged under 75 by the year 2010, representing about a quarter of the government's overall target of 100 000 fewer cancer deaths.