Socio-demographic variation in stage at diagnosis of breast, bladder, colon, endometrial, lung, melanoma, prostate, rectal, renal and ovarian cancer in England and its population impact.

BACKGROUND: Stage at diagnosis strongly predicts cancer survival and understanding related inequalities could guide interventions. METHODS: We analysed incident cases diagnosed with 10 solid tumours included in the UK government target of 75% of patients diagnosed in TNM stage I/II by 2028. We examined socio-demographic differences in diagnosis at stage III/IV vs. I/II. Multiple imputation was used for missing stage at diagnosis (9% of tumours). RESULTS: Of the 202,001 cases, 57% were diagnosed in stage I/II (an absolute 18% 'gap' from the 75% target). The likelihood of diagnosis at stage III/IV increased in older age, though variably by cancer site, being strongest for prostate and endometrial cancer. Increasing level of deprivation was associated with advanced stage at diagnosis for all sites except lung and renal cancer. There were, inconsistent in direction, sex inequalities for four cancers. Eliminating socio-demographic inequalities would translate to 61% of patients with the 10 studied cancers being diagnosed at stage I/II, reducing the gap from target to 14%. CONCLUSIONS: Potential elimination of socio-demographic inequalities in stage at diagnosis would make a substantial, though partial, contribution to achieving stage shift targets. Earlier diagnosis strategies should additionally focus on the whole population and not only the high-risk socio-demographic groups.

Geographic variation in the use of lymphadenectomy and external-beam radiotherapy for endometrial cancer: a cross-sectional analysis of population-based data.

OBJECTIVE: To quantify geographic variation in the use of lymphadenectomy and/or external-beam radiotherapy (EBRT) for endometrial cancer in England. DESIGN: Cross-sectional analysis of population-based data. SETTING: English cancer registry data, linked to chemotherapy, radiotherapy and hospital episodes statistics data. POPULATION: Twenty-two thousand four hundred and eighty-three women with endometrial cancer presenting without clinical or radiological evidence of distant metastatic spread, diagnosed in England from 2013 to 2016. METHODS: Proportions of patients receiving lymphadenectomy and/or EBRT were compared across 19 Cancer Alliances, to identify variations in clinical practice. Two separate logistic regression models assessed the impact on variation of adjustment for tumour and patient characteristics. MAIN OUTCOME MEASURES: Receipt of lymphadenectomy, receipt of EBRT. RESULTS: There was substantial variation by Cancer Alliance in the adjusted proportion of women with endometrial cancer receiving lymphadenectomy (range 5% [95% CI 4-6%] to 48% [95% CI 45-52%]) and EBRT (range 10% [95% CI 7-12%] to 31% [95% CI 28-33%]), after adjusting for variation in pathological grade, age, comorbidities, deprivation, ethnic group and (EBRT only) FIGO stage. Different approaches to clinical practice were identified; (i) one Cancer Alliance had significantly higher than average lymphadenectomy and significantly lower than average EBRT use, (ii) three had high use of both lymphadenectomy and EBRT, (iii) one had low lymphadenectomy use and high EBRT use, and (iv) three had low use of both lymphadenectomy and EBRT. CONCLUSIONS: Lymphadenectomy is probably used to triage for EBRT when lymphadenectomy use is high and EBRT use is low. This is probably a result of variation in local endometrial cancer management guidelines, suggesting that UK recommendations should be clarified. TWEETABLE ABSTRACT: There is geographic variation in England in the use of lymphadenectomy and radiotherapy to treat endometrial cancer.

Stage at diagnosis and early mortality from cancer in England.

BACKGROUND: Stage at diagnosis is a key predictor of overall cancer outcome. For the first time, stage completeness is high enough for robust analysis for the whole of England. METHODS: We analysed data from the National Cancer Registration Service's (NCRS) Cancer Analysis System on persons diagnosed with breast, colorectal, lung, prostate or ovarian cancers in England in 2012. One-year relative survival (followed-up to the end of 2013) was calculated along with adjusted excess rate ratios, for mortality within 1 year. RESULTS: One-year relative survival decreased with increasing stage at diagnosis. For breast, prostate and colorectal cancers survival showed a major reduction for stage 4 cancers, whereas for lung and ovarian cancers there were substantial decreases in relative survival for each level of increase in stage. Excess rate ratios for mortality within 1 year of diagnosis showed that stage and age were the most important cofactors, but they also identified the statistically significant effects of sex, income deprivation and geographic area of residence. CONCLUSIONS: Further reductions in mortality may be most effectively achieved by diagnosing all cancers before they progress to stage 4, but for lung and ovarian cancers there is also a need for a stage shift to earlier stages together with efforts to improve stage-specific survival at all stages.

Vulval cancer incidence, mortality and survival in England: age-related trends.

OBJECTIVE: To explore the trends and age characteristics of vulval cancer incidence, mortality, survival and stage of disease. DESIGN: Retrospective population-based observational study based on cancer registry and Office for National Statistics data. SETTING: England. POPULATION: All women diagnosed with vulval cancer, defined by the site of the tumour (ICD-10 code C51). METHODS: Including all C51 cases, Poisson regression was used to test for trends in incidence and mortality rates, and generalised linear modelling was used to test for trends in relative survival. Excluding women with melanomas, basal cell carcinomas and Paget disease, stage was investigated as a percentage of staged data by age. MAIN OUTCOME MEASURES: Age-standardised incidence and mortality rates, relative survival rates and stage of disease at diagnosis. RESULTS: From 1990, there was a statistically significant increase in overall incidence (P = 0.018) and decrease in mortality (P < 0.001). In addition, there were statistically significant increases in overall survival (1-year, P < 0.001; 5-year, P < 0.001). However, from 1990, incidence increased in women aged 20-39 years (P = 0.002), 40-49 and 50-59 years (both P < 0.001) and 60-69 years (P = 0.030) and decreased in women aged 80 years and above (P < 0.001). There were statistically significant decreases in mortality in women aged ≥60 years (P < 0.001), and statistically significant increases in 1-year survival in women aged ≥40 years (P ≤ 0.047) and in 5-year survival in women aged 40-49 and ≥60 years (P ≤ 0.011). Stage patterns by age highlight diagnosis at an earlier stage in younger women and more advanced stage diagnosis in older women. CONCLUSION: Survival from vulval cancer has improved and mortality has decreased since 1990. The overall incidence of disease has increased as a result of more new diagnoses in the under 70-year age group.

Socio-demographic inequalities in stage of cancer diagnosis: evidence from patients with female breast, lung, colon, rectal, prostate, renal, bladder, melanoma, ovarian and endometrial cancer.

BACKGROUND: Understanding socio-demographic inequalities in stage at diagnosis can inform priorities for cancer control. PATIENTS AND METHODS: We analysed data on the stage at diagnosis of East of England patients diagnosed with any of 10 common cancers, 2006-2010. Stage information was available on 88 657 of 98 942 tumours (89.6%). RESULTS: Substantial socio-demographic inequalities in advanced stage at diagnosis (i.e. stage III/IV) existed for seven cancers, but their magnitude and direction varied greatly by cancer: advanced stage at diagnosis was more likely for older patients with melanoma but less likely for older patients with lung cancer [odds ratios for 75-79 versus 65-69 1.60 (1.38-1.86) and 0.83 (0.77-0.89), respectively]. Deprived patients were more likely to be diagnosed in advanced stage for melanoma, prostate, endometrial and (female) breast cancer: odds ratios (most versus least deprived quintile) from 2.24 (1.66-3.03) for melanoma to 1.31 (1.15-1.49) for breast cancer. In England, elimination of socio-demographic inequalities in stage at diagnosis could decrease the number of patients with cancer diagnosed in advanced stage by ∼5600 annually. CONCLUSIONS: There are substantial socio-demographic inequalities in stage at diagnosis for most cancers. Earlier detection interventions and policies can be targeted on patients at higher risk of advanced stage diagnosis.

Variation in advanced stage at diagnosis of lung and female breast cancer in an English region 2006-2009.

BACKGROUND: Understanding variation in stage at diagnosis can inform interventions to improve the timeliness of diagnosis for patients with different cancers and characteristics. METHODS: We analysed population-based data on 17,836 and 13,286 East of England residents diagnosed with (female) breast and lung cancer during 2006-2009, with stage information on 16,460 (92%) and 10,435 (79%) patients, respectively. Odds ratios (ORs) of advanced stage at diagnosis adjusted for patient and tumour characteristics were derived using logistic regression. RESULTS: We present adjusted ORs of diagnosis in stages III/IV compared with diagnosis in stages I/II. For breast cancer, the frequency of advanced stage at diagnosis increased stepwise among old women (ORs: 1.21, 1.46, 1.68 and 1.78 for women aged 70-74, 75-79, 80-84 and ≥85, respectively, compared with those aged 65-69 , P<0.001). In contrast, for lung cancer advanced stage at diagnosis was less frequent in old patients (ORs: 0.82, 0.74, 0.73 and 0.66, P<0.001). Advanced stage at diagnosis was more frequent in more deprived women with breast cancer (OR: 1.23 for most compared with least deprived, P=0.002), and in men with lung cancer (OR: 1.14, P=0.011). The observed patterns were robust to sensitivity analyses approaches for handling missing stage data under different assumptions. CONCLUSION: Interventions to help improve the timeliness of diagnosis of different cancers should be targeted at specific age groups.

How safe is it to transplant organs from deceased donors with primary intracranial malignancy? An analysis of UK Registry data.

Patients dying from primary intracranial malignancy are a potential source of organs for transplantation. However, a perceived risk of tumor transfer to the organ recipient has limited their use. We evaluated the risk of tumor transmission by reviewing the incidence in patients transplanted in the UK. Information from the UK Transplant Registry was combined with that from the national cancer registries of England, Wales and Northern Ireland to identify all organ donors between 1985 and 2001 inclusive with a primary intracranial malignancy and to identify the occurrence of posttransplant malignancy in the recipients of the organs transplanted. Of 11,799 organ donors in the study period, 179 were identified as having had a primary intracranial malignancy, including 33 with high-grade malignancy (24 grade IV gliomas and 9 medulloblastomas). A total of 448 recipients of 495 organs from 177 of these donors were identified. No transmission of donor intracranial malignancy occurred. Organs from patients dying from primary intracranial malignancy, including those with high-grade tumors, should be considered for transplantation and the small risk of tumor transmission should be balanced against the likely mortality for potential recipients who remain on the transplant waiting list.

Legal and ethical issues in the use of anonymous images in pathology teaching and research.

The privacy of patients' health information is of paramount importance. However, it is equally important that medical staff and students have access to photographs and video recordings of real patients for training purposes. Where the patient can be identified from such images, his or her consent is clearly required to both obtain the image and to use it in this way. However, the need for consent, both legally and ethically, is much less convincing where the patient cannot, by the very nature of the image, be identified from it. This is the case for many images used in the teaching of clinical medicine, such as videos taken of laparoscopies, images of internal organs and unlabelled X-rays.

Lysosome-endosome fusion and lysosome biogenesis.

Recent data both from cell-free experiments and from cultured cells have shown that lysosomes can fuse directly with late endosomes to form a hybrid organelle. This has a led to a hypothesis that dense core lysosomes are in essence storage granules for acid hydrolases and that, when the former fuse with late endosomes, a hybrid organelle for digestion of endocytosed macromolecules is created. Lysosomes are then re-formed from hybrid organelles by a process involving condensation of contents. In this Commentary we review the evidence for formation of the hybrid organelles and discuss the current status of our understanding of the mechanisms of fusion and lysosome re-formation. We also review lysosome biosynthesis, showing how recent studies of lysosome-like organelles including the yeast vacuole, Drosophila eye pigment granules and mammalian secretory lysosomes have identified novel proteins involved in this process.

Characterization of a fourth adaptor-related protein complex.

Adaptor protein complexes (APs) function as vesicle coat components in different membrane traffic pathways; however, there are a number of pathways for which there is still no candidate coat. To find novel coat components related to AP complexes, we have searched the expressed sequence tag database and have identified, cloned, and sequenced a new member of each of the four AP subunit families. We have shown by a combination of coimmunoprecipitation and yeast two-hybrid analysis that these four proteins (epsilon, beta4, mu4, and sigma4) are components of a novel adaptor-like heterotetrameric complex, which we are calling AP-4. Immunofluorescence reveals that AP-4 is localized to approximately 10-20 discrete dots in the perinuclear region of the cell. This pattern is disrupted by treating the cells with brefeldin A, indicating that, like other coat proteins, the association of AP-4 with membranes is regulated by the small GTPase ARF. Immunogold electron microscopy indicates that AP-4 is associated with nonclathrin-coated vesicles in the region of the trans-Golgi network. The mu4 subunit of the complex specifically interacts with a tyrosine-based sorting signal, indicating that, like the other three AP complexes, AP-4 is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs. AP-4 is of relatively low abundance, but it is expressed ubiquitously, suggesting that it participates in a specialized trafficking pathway but one that is required in all cell types.

Failure of BQ123, a more potent antagonist of sarafotoxin 6b than of endothelin-1, to distinguish between these agonists in binding experiments.

1. In homogenates of human saphenous vein, [125I]-ET-1 and [125I]-S6b each labelled a single population of high affinity binding sites with K(D) values of 0.64 +/- 0.11 nM and 0.55 +/- 0.08 nM respectively. Hill slopes were close to one. However, the density of receptors labelled by [125I]-ET-1 was significantly greater than that by [125I]-S6b (187.6 +/- 23.0 compared to 91.7 +/- 23.6 fmol mg-1 protein, P < 0.02). 2. BQ123, an ET(A-)selective antagonist, inhibited specific [125I]-ET-1 and [125I]-S6b binding with equal affinity. BQ123 competed in a biphasic manner for both [125I]-ET-1 (0.1 nM) and [125I]-S6b (0.1 nM) with ET(A) K(D) values of 0.55 +/- 0.17 nM and 0.52 +/- 0.02 nM and ET(B) K(D) values of 14.4 +/- 2.60 microM and 11.2 +/- 0.31 microM respectively. S6b monophasically inhibited 0.1 nM [125I]-ET-1 (K(D) 1.16 +/- 0.9 nM) but competed for 0.25 nM [125I]-ET-1 in a biphasic manner (K(D) high affinity site 1.99 +/- 0.84 nM, K(D) low affinity site 0.68 +/- 0.63 microM, ratio 67% : 33%). 3. BQ123 antagonized the vasoconstrictor responses of ET-1 with a pK(B) value of 6.47 whereas BQ123 exhibited 50 fold higher affinity against S6b-mediated vasoconstriction with a pK(B) value of 8.18. Regression slopes were 0.80 +/- 0.13 and 1.08 +/- 0.11 respectively. 4. In desensitization experiments, S6b (300 nM) did not contract preparations which were no longer responsive to ET-1 whereas a small contraction to ET-1 (300 nM) was obtained in preparations rendered unresponsive to S6b. 5. Medial sections of non-diseased human aorta, which express only ET(A) receptors, were used to compare dissociation rates of the two agonists. The time course for the dissociation of [125I]-ET-1 and [125I]-S6b was similar with 20-30% of each ligand dissociating at 4 h. 6. These data suggest that whilst BQ123, in common with other endothelin antagonists, is a much more potent blocker of S6b contractile responses than of ET-1 contractile responses, this is not reflected by the equal affinity of BQ123 determined in competition binding experiments against both [125I]-ET-1 and [125I]-S6b. This discrepancy in antagonist potency is probably not due to a marked difference in the rate of dissociation of [125I]-ET-1 and [125I]-S6b from endothelin receptors. One possible explanation is that ET-1 is activating an additional population of receptors which may have lower affinity for BQ123. This is suggested by the discrepancy in receptor density identified by [125I]-ET-1 and [125I]-S6b.

Some aspects of the pathophysiology of semicarbazide-sensitive amine oxidase enzymes.

The widespread distribution of enzymes classed as semicarbazide-sensitive amine oxidases (SSAO enzymes) throughout a very wide range of eukaryotic as well as prokaryotic organisms encourages the aspirations of those who wish to demonstrate physiological, pathological or pharmacological importance. Such enzymes are found in several tissues of mammals, both freely soluble, as in blood plasma, and membrane-bound, for example, in smooth muscle and adipose tissue. While they are capable of deaminating many amines with the production of an aldehyde and hydrogen peroxide, doubt still surrounds the identity of the most important endogenous substrates for these enzymes. At present, methylamine and aminoacetone appear to head the list of candidates. The possibility that SSAO enzymes can convert amine substrates to highly toxic metabolites is illustrated by the production of acrolein from the xenobiotic amine, allylamine and formaldehyde and methylglyoxal from methylamine and aminoacetone, respectively. Activities of SSAO enzymes may be influenced by physiological changes, such as pregnancy or pathologically by disease states, including diabetes, tumours and burns. Increased deamination of aminoacetone by tissue and plasma SSAO enzymes as a result of its increased production from L-threonine in conditions such as exhaustion, starvation and diabetes mellitus may be harmful. Such dangers could be mitigated either physiologically by a compensatory reduction in SSAO activity or pharmacologically by treatment with inhibitors of SSAO.