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.

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.

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.

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.

A detailed map of the 660-kilometer discontinuity beneath the izu-bonin subduction zone.

Dynamical processes in the Earth's mantle, such as cold downwelling at subduction zones, cause deformations of the solid-state phase change that produces a seismic discontinuity near a depth of 660 kilometers. Observations of short-period, shear-to-compressional wave conversions produced at the discontinuity yield a detailed map of deformation beneath the Izu-Bonin subduction zone. The discontinuity is depressed by about 60 kilometers beneath the coldest part of the subducted slab, with a deformation profile consistent with the expected thermal signature of the slab, the experimentally determined Clapeyron slope of the phase transition, and the regional tectonic history.

Flood basalts and hot-spot tracks: plume heads and tails.

Continental flood basalt eruptions have resulted in sudden and massive accumulations of basaltic lavas in excess of any contemporary volcanic processes. The largest flood basalt events mark the earliest volcanic activity of many major hot spots, which are thought to result from deep mantle plumes. The relative volumes of melt and eruption rates of flood basalts and hot spots as well as their temporal and spatial relations can be explained by a model of mantle plume initiation: Flood basalts represent plume "heads" and hot spots represent continuing magmatism associated with the remaining plume conduit or "tail." Continental rifting is not required, although it commonly follows flood basalt volcanism, and flood basalt provinces may occur as a natural consequence of the initiation of hot-spot activity in ocean basins as well as on continents.

A mantle plume initiation model for the wrangellia flood basalt and other oceanic plateaus.

The vast Wrangellia terrane of Alaska and British Columbia is an accreted oceanic plateau with Triassic strata that contain a 3- to 6-kilometers thick flood basalt, bounded above and below by marine sedimentary rocks. This enormous outpouring of basalt was preceded by rapid uplift and was followed by gradual subsidence of the plateau. The uplift and basalt eruptions occurred in less than approximately 5 million years, and were not accompanied by significant extension or rifting of the lithosphere. This sequence of events is predicted by a mantle plume initiation, or plume head, model that has recently been developed to explain continental flood volcanism. Evidence suggests that other large oceanic basalt plateaus, such as the Ontong-Java, Kerguelen, and Caribbean, were formed as the initial outbursts of the Louisville Ridge, Kerguelen, and Galapagos hot spots, respectively. Such events may play an important role in the creation and development of both oceanic and continental crust.

Synchrony and causal relations between permian-triassic boundary crises and siberian flood volcanism.

The Permian-Triassic boundary records the most severe mass extinctions in Earth's history. Siberian flood volcanism, the most profuse known such subaerial event, produced 2 million to 3 million cubic kilometers of volcanic ejecta in approximately 1 million years or less. Analysis of (40)Ar/(39)Ar data from two tuffs in southern China yielded a date of 250.0 +/- 0.2 million years ago for the Permian-Triassic boundary, which is comparable to the inception of main stage Siberian flood volcanism at 250.0 +/- 0.3 million years ago. Volcanogenic sulfate aerosols and the dynamic effects of the Siberian plume likely contributed to environmental extrema that led to the mass extinctions.

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.

A mathematical model relating response durations to amount of subclinical resistant disease.

A mathematical model is presented which seeks to determine, from examination of the response durations of a group of patients with malignant disease, the mean and distribution of the resistant tumor volume. The mean tumor-doubling time and distribution of doubling times are also estimated. The model assumes that in a group of patients there is a log-normal distribution both of resistant disease and of tumor-doubling times and implies that the shapes of certain parts of an actuarial response-duration curve are related to these two factors. The model has been applied to data from two reported acute leukemia trials: (a) a recent acute myelogenous leukemia trial was examined. Close fits were obtained for both the first and second remission-duration curves. The model results suggested that patients with long first remissions had less resistant disease and had tumors with slower growth rates following second line treatment; (b) an historical study of maintenance therapy for acute lymphoblastic leukemia was used to estimate the mean cell-kill (approximately 10(4) cells) achieved with single agent, 6-mercaptopurine. Application of the model may have clinical relevance, for example, in identifying groups of patients likely to benefit from further intensification of treatment.

Combination chemotherapy versus melphalan and prednisolone in the treatment of multiple myeloma: an overview of published trials.

PURPOSE: A meta-analysis was performed to compare survival after treatment with melphalan and prednisolone (M + P) with that after combination chemotherapy (CCT) in patients with multiple myeloma. METHODS: Meta-analysis was performed on 18 published trials comprising 3,814 patients comparing M + P with CCT. Two-year survival percentages with observed and expected deaths at 2 years were calculated for each trial, and the overview methodology was applied to these figures. RESULTS: Overall results from the 18 trials suggest that there is no difference in efficacy between the two treatments. This finding, however, masks a highly significant correlation between 2-year survival rates for M + P-treated patients in individual studies and the difference between the M + P and CCT 2-year survival rates for that study (r = .69; P = .0008). In separate overviews, those studies with a high M + P 2-year survival rate showed a survival difference in favor of M + P (P = .02), whereas those with a low rate suggested a difference in favor of CCT (P V .07). Comparison of the 2-year survival rates in the M + P treatment arms of each of the studies with available data showed an inverse correlation between survival and the proportion of patients with either poor performance status (P less than .001) or immunoglobulin A (IgA) M band (P = .02). CONCLUSIONS: These results imply that M + P is superior for patients with an intrinsically good prognosis and inferior for those patients with a poor prognosis. If reliable prognostic factors can be established for this disease, they could be used to select therapy for individual patients.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.

Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry.

Adjuvant systemic therapy for women with node-negative breast cancer is most easily justified for those patients at highest risk of relapse. We have examined the impact of tumor size, histologic grade, estrogen receptor (ER) status, tumor ploidy, and S-phase fraction (SPF) on relapse-free survival (RFS) for 169 patients with node-negative breast cancer in order to identify groups of patients at high and low risk of relapse. Patients with small tumors (less than or equal to 1.0 cm) had a significantly better RFS than those with larger tumors (P = .005), with 96% remaining relapse-free at 5 years. Patients with tumors less than or equal to 1.0 cm were thus excluded from analysis when attempting to define a group with a poor prognosis. Within the group of patients with tumors greater than 1.0 cm, tumor ploidy (P = .63), ER status (P = .3), or progesterone receptor (PgR) status (P = .24) did not predict for RFS. Patients with grade 1 or 2 infiltrating ductal tumors had a significantly better prognosis than those with grade 3 tumors (P = .04). The prognostic factor that gave the widest separation between subgroups, however, was SPF. Patients whose tumors were greater than 1.0 cm with an SPF less than or equal to 10% had a 5-year RFS of 78% compared with a 5-year RFS of 52% for those with an SPF greater than 10% (P = .006). We have combined tumor size and SPF to identify three prognostic groups: (1) tumor less than or equal to 1.0 cm, 5-year RFS 96%; (2) tumor greater than 1.0 cm plus SPF less than or equal to 10%, 5-year RFS 78%; 3) tumor greater than 1.0 cm plus SPF greater than 10%, 5-year RFS 52%. These prognostic groupings may help identify patients most suitable for adjuvant therapy.

Short-term therapy for acute myelogenous leukemia.

Since 1978, 187 patients (age range, 15 to 59, median 44 years) have received short-term chemotherapy as part of three sequential open studies (B-IX, X, Xb) or a randomized clinical trial (B-XI). An intended six cycles of Adriamycin (ADR) (doxorubicin; Adria Laboratories, Columbus, OH), cytarabine (ara-C), and thioguanine (TG) were administered with as short an intercycle time as possible. No further therapy was administered. Complete remission (CR) was achieved in 118 of 187 patients (63%). On univariate and multivariate analyses achievement of CR correlated adversely with a low serum albumin at presentation and an antecedent marrow disorder. Forty-five patients continue in first remission between 15 months and 8 1/2 years, no relapses being seen after 3 1/2 years (median follow-up, 3 1/2 years). The median duration of remission was 1 year. M3 morphology, a blast count less than 100 x 10(9)/L, and absence of hepatosplenomegaly correlated favorably with remission duration. There was no difference in duration of remission between patients receiving 3, 4, 5, or 6 cycles. The best results overall were achieved in patients under the age of 40, with 43% projected to remain free of disease at 5 years. Fifty patients remain alive between 17 months and 9 years, the predicted actuarial survival being 25% at 5 years.

Follicular lymphoma: prognostic factors for response and survival.

One hundred forty-eight patients with newly diagnosed follicular lymphoma were treated over a 12-year period. Twenty-two patients received radiotherapy for stage I and II disease, followed by adjuvant chemotherapy in 14 patients. One hundred thirteen were treated at presentation with short courses of chemotherapy, most often with single-agent chlorambucil for bulky stage II and stages III and IV disease. Thirteen patients were managed expectantly until there was evidence of disease progression. The median survival was 9 years. Patients treated with radiotherapy for stage I and II disease had an 83% relapse-free survival, but those with bulky stage II or stages III and IV disease treated with chemotherapy pursued a remitting and relapsing course with a 70% response rate at initial and subsequent retreatments, but a median duration of remission of 4 years in stage III and 1 year in stage IV disease (P = .041). Patients were observed in relapse and retreatment was administered as appropriate, once every 33 months on average. Poor prognosis patients could be identified by a combination of the presentation characteristics: B symptoms, hepatosplenomegaly, anemia, and abnormal liver function. These factors predicted a poor response to treatment and correlated with a short survival. Histologic subgroups were not associated with differences in survival, but transformation to a diffuse high-grade lymphoma was observed in 23 of the 72 patients (32%) at risk, with a median follow-up of 6 years and 6 months, and was associated with a very poor prognosis. The present treatment strategy has proved successful for most patients with localized disease and those older patients with indolent small volume disseminated follicular lymphoma. New approaches are being investigated for the younger poor prognosis patients.

Failure of acute intravascular volume expansion to alter plasma vasopressin in the nonhuman primate, Macaca fascicularis.

Experiments were carried out in the anesthetized monkey to determine the influence of acute hypervolemia on plasma vasopressin (ADH) concentration. The administration of an isotonic-isooncotic high molecular weight dextran infusion in two steps, each in an amount equal to 15% of the estimated blood volume, produced substantial elevations of left ventricular end diastolic pressure (17.1 cm H2O); however, no consistent change in mean plasma ADH concentration or mean arterial pressure occurred. The results support the position that in the primate, arterial blood pressure rather than blood volume is the major modulator of ADH secretion when blood volume is increased isoosmotically.

Liver metastases from breast cancer: the relationship between clinical, biochemical and pathological features and survival.

The clinical records of 312 consecutive patients with liver metastases from breast cancer were reviewed. The primary tumours were commonly poorly differentiated, although the majority were steroid receptor positive. At diagnosis of liver metastases, 60% of patients had hepatomegaly, 13% were jaundiced and 7% had ascites. A raised serum aspartate transaminase (AST) was the most common biochemical abnormality (84%), with 54% of patients having an AST of more than twice the upper limit of normal. The median survival from the time of diagnosis of liver metastases was 3.8 months. No feature existing prior to the development of liver metastases influenced subsequent survival. The presence of jaundice (P less than 0.001), ascites (P = 0.01) or hepatomegaly (P = 0.01) were all associated with a particularly poor prognosis. While any degree of elevation of bilirubin (P less than 0.001) or alkaline phosphatase (P = 0.003) was unfavourable, a raised AST alone was not predictive of shorter survival. AST only influenced survival significantly when above twice the upper limit of normal (P less than 0.001), with prognosis then progressively worsening the more elevated the level. Multivariate analysis using the Cox model suggested that the degree of elevation of AST was the single most important prognostic factor for survival after the diagnosis of liver metastases.