Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials

Background: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.
Methods: We undertook a meta-analysis of individual patient data for 10?801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.
Findings: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (=20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.
Interpretation: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.
Funding: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.

Vitamin D, calcium and dairy intake, and risk of oesophageal adenocarcinoma and its precursor conditions

Evidence is accumulating that vitamin D may be protective against carcinogenesis, although exceptions have been observed for some digestive tract neoplasms. The aim of the present study was to explore the association between dietary vitamin D and related nutrients and the risk of oesophageal adenocarcinoma and its precursor conditions, Barrett's oesophagus and reflux oesophagitis. In an all-Ireland case-control study conducted between March 2002 and July 2005, 218 oesophageal adenocarcinoma patients, 212 Barrett's oesophagus patients, 208 reflux oesophagitis patients and 252 population-based controls completed a 101-item FFQ, and provided lifestyle and demographic information. Multiple logistic regression analysis was applied to examine the association between dietary intake and disease risk. Oesophageal adenocarcinoma risk was significantly greater for individuals with the highest compared with the lowest tertile of vitamin D intake (OR 1·99, 95 % CI 1·03, 3·86; P for trend = 0·02). The direct association could not be attributed to a particular vitamin D food source. Vitamin D intake was unrelated to Barrett's oesophagus and reflux oesophagitis risk. No significant associations were observed for Ca or dairy intake and oesophageal adenocarcinoma, Barrett's oesophagus or reflux oesophagitis development. High vitamin D intake may increase oesophageal adenocarcinoma risk but is not related to reflux oesophagitis and Barrett's oesophagus. Ca and dairy product intake did not influence the development of these oesophageal lesions. These findings suggest that there may be population subgroups at an increased risk of oesophageal adenocarcinoma if advice to improve vitamin D intake from foods is implemented. Limited work has been conducted in this area, and further research is required.

Wavelet analysis of bender element signals

Accurate determination of shear wave arrival time using bender elements may be severely affected by a combination of near-field effects and reflected waves. These may mask the first arrival of the shear wave, making its detection difficult in the time domain. This paper describes an approach for measuring the shear wave arrival time through analysis of the output signal in the time-scale domain using a multi-scale wavelet transform. The local maxima lines of the wavelet transform modulus are observed at different scales, and all singularities are mathematically characterised, allowing subsequent detection of the singularity relating to the first arrival. Examples of the use of this approach on typical synthetic and experimental bender element signals are also supplied, and these results are compared with those from other time and frequency domain approaches. The wavelet approach is not affected by near-field effects, but instead is characterised by a relatively consistent singularity related to the shear wave arrival time, across a range of frequencies and noise levels.

Diagnostic accuracy and clinical management by realtime teledermatology. Results from the Northern Ireland arms of the UK Multicentre Teledermatology Trial

Diagnostic accuracy and management recommendations of realtime teledermatology consultations using low-cost telemedicine equipment were evaluated. Patients were seen by a dermatologist over a video-link and a diagnosis and treatment plan were recorded. This was followed by a face-to-face consultation on the same day to confirm the earlier diagnosis and management plan. A total of 351 patients with 427 diagnoses participated. Sixty-seven per cent of the diagnoses made over the video-link agreed with the face-to-face diagnosis. Clinical management plans were recorded for 214 patients with 252 diagnoses. For this cohort, 44% of the patients were seen by the same dermatologist at both consultations, while 56% were seen by a different dermatologist. In 64% of cases the same management plan was recommended at both consultations; a sub-optimum treatment plan was recommended in 8% of cases; and in 9% of cases the video-link management plans were judged to be inappropriate. In 20% of cases the dermatologist was unable to recommend a suitable management plan by video-link. There were significant differences in the ability to recommend an optimum management plan by video-link when a different dermatologist made the reference management plan. The results indicate that a high proportion of dermatological conditions can be successfully managed by realtime teledermatology.

Finite dimensional semigroup quadratic algebras with the minimal number of relations

A quadratic semigroup algebra is an algebra over a field given by the generators x_1, . . . , x_n and a finite set of quadratic relations each of which either has the shape x_j x_k = 0 or the shape x_j x_k = x_l x_m . We prove that a quadratic semigroup algebra given by n generators and d=(n^2+n)/4 relations is always infinite dimensional. This strengthens the Golod–Shafarevich estimate for the above class of algebras. Our main result however is that for every n, there is a finite dimensional quadratic semigroup algebra with n generators and d_n relations, where d_n is the first integer greater than (n^2+n)/4 . That is, the above Golod–Shafarevich-type estimate for semigroup algebras is sharp.

Role of basal extracellular Ca2+ entry during 5-HT-induced vasoconstriction of canine pulmonary arteries.

1. Measurements of artery contraction, cytosolic [Ca(2+)], and Ca(2+) permeability were made to examine contractile and cytosolic [Ca(2+)] responses of canine pulmonary arteries and isolated cells to 5-hydroxytryptamine (5-HT), and to determine the roles of intracellular Ca(2+) release and extracellular Ca(2+) entry in 5-HT responses. 2. The EC(50) for 5-HT-mediated contractions and cytosolic [Ca(2+)] increases was approximately 10(-7) M and responses were inhibited by ketanserin, a 5-HT(2A)-receptor antagonist. 3. 5-HT induced cytosolic [Ca(2+)] increases were blocked by 20 microM Xestospongin-C and by 2-APB (IC(50)=32 microM inhibitors of InsP(3) receptor activation. 4. 5-HT-mediated contractions were reliant on release of InsP(3) but not ryanodine-sensitive Ca(2+) stores. 5. 5-HT-mediated contractions and cytosolic [Ca(2+)] increases were partially inhibited by 10 microM nisoldipine, a voltage-dependent Ca(2+) channel blocker. 6. Extracellular Ca(2+) removal reduced 5-HT-mediated contractions further than nisoldipine and ablated cytosolic [Ca(2+)] increases and [Ca(2+)] oscillations. Similar to Ca(2+) removal, Ni(2+) reduced cytosolic [Ca(2+)] and [Ca(2+)] oscillations. 7. Mn(2+) quench of fura-2 and voltage-clamp experiments showed that 5-HT failed to activate any significant voltage-independent Ca(2+) entry pathways, including store-operated and receptor-activated nonselective cation channels. Ni(2+) but not nisoldipine or Gd(3+) blocked basal Mn(2+) entry. 8. Voltage-clamp experiments showed that simultaneous depletion of both InsP(3) and ryanodine-sensitive intracellular Ca(2+) stores activates a current with linear voltage dependence and a reversal potential consistent with it being a nonselective cation channel. 5-HT did not activate this current. 9. Basal Ca(2+) entry, rather than CCE, is important to maintain 5-HT-induced cytosolic [Ca(2+)] responses and contraction in canine pulmonary artery.

Chlorobenzenes in rivers draining industrial catchments

Eleven chlorobenzenes (out of a total of 12 in the congener series) were monitored weekly on four industrialized rivers (Aire, Calder, Don and Trent) of the Southern Humber Catchment in whole water samples. 1,2- and 1,4-dichlorobenzene were present at relatively high levels on both the Aire and Calder, having mean concentrations of approximately 30 ng/l. They were both at lower concentrations on the Don and Trent, although the 1,4-isomer dominated. All other chlorobenzenes monitored were routinely found on all the rivers, with the exception of hexachlorobenzene, which was only regularly detected on the Trent. Again, the rivers fell into two classes with respect to their total chlorobenzene concentrations, with the Aire and Calder being more polluted. The higher levels of chlorobenzenes (excluding hexachlorobenzene which was used widely as a agricultural pesticide) on the Aire and Calder, and the dominance of the 1,4-dichlorobenzene congener (accounting for 60-70% of sigma chlorobenzenes) on the Don and Trent, indicated that the Aire and Calder were predominately contaminated with chlorobenzenes through industrial sources, while the Don and Trent were mainly contaminated through domestic sources (1,4-dichlorobenzene is widely used as a toilet deodorant). 1,4-Dichlorobenzene dominated flux, with the Aire, Don and Trent exporting 52.5 kg/year into the Humber estuary, followed by the 1,2-dichlorobenzene at 38.8 kg/year. Sigma chlorobenzenes exported to the Humber was 133 kg/year. This is the first study to calculate chlorobenzene fluxes to the North Sea from a UK catchment.