SummaryBackgroundLocal cancer relapse risk after breast conservation surgery followed by radiotherapy has fallen sharply in many countries, and is influenced by patient age and clinicopathological factors. We hypothesise that partial-breast radiotherapy restricted to the vicinity of the original tumour in women at lower than average risk of local relapse will improve the balance of beneficial versus adverse effects compared with whole-breast radiotherapy.MethodsIMPORT LOW is a multicentre, randomised, controlled, phase 3, non-inferiority trial done in 30 radiotherapy centres in the UK. Women aged 50 years or older who had undergone breast-conserving surgery for unifocal invasive ductal adenocarcinoma of grade 1–3, with a tumour size of 3 cm or less (pT1–2), none to three positive axillary nodes (pN0–1), and minimum microscopic margins of non-cancerous tissue of 2 mm or more, were recruited. Patients were randomly assigned (1:1:1) to receive 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast radiotherapy and 40 Gy to the partial breast (reduced-dose group), or 40 Gy to the partial breast only (partial-breast group) in 15 daily treatment fractions. Computer-generated random permuted blocks (mixed sizes of six and nine) were used to assign patients to groups, stratifying patients by radiotherapy treatment centre. Patients and clinicians were not masked to treatment allocation. Field-in-field intensity-modulated radiotherapy was delivered using standard tangential beams that were simply reduced in length for the partial-breast group. The primary endpoint was ipsilateral local relapse (80% power to exclude a 2·5% increase [non-inferiority margin] at 5 years for each experimental group; non-inferiority was shown if the upper limit of the two-sided 95% CI for the local relapse hazard ratio [HR] was less than 2·03), analysed by intention to treat. Safety analyses were done in all patients for whom data was available (ie, a modified intention-to-treat population). This study is registered in the ISRCTN registry, number ISRCTN12852634.FindingsBetween May 3, 2007, and Oct 5, 2010, 2018 women were recruited. Two women withdrew consent for use of their data in the analysis. 674 patients were analysed in the whole-breast radiotherapy (control) group, 673 in the reduced-dose group, and 669 in the partial-breast group. Median follow-up was 72·2 months (IQR 61·7–83·2), and 5-year estimates of local relapse cumulative incidence were 1·1% (95% CI 0·5–2·3) of patients in the control group, 0·2% (0·02–1·2) in the reduced-dose group, and 0·5% (0·2–1·4) in the partial-breast group. Estimated 5-year absolute differences in local relapse compared with the control group were −0·73% (−0·99 to 0·22) for the reduced-dose and −0·38% (−0·84 to 0·90) for the partial-breast groups. Non-inferiority can be claimed for both reduced-dose and partial-breast radiotherapy, and was confirmed by the test against the critical HR being more than 2·03 (p=0·003 for the reduced-dose group and p=0·016 for the partial-breast group, compared with the ...

Background We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.Methods FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1-3, pN0-1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1•6% excess for five-fraction schedules (critical hazard ratio [HR] of 1•81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132. FindingsBetween Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71•5 months (IQR 71•3 to 71•7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0•86 (95% CI 0•51 to 1•44) for 27 Gy in five fractions and 0•67 (0•38 to 1•16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2•1% (1•4 to 3•1); estimated absolute differences versus 40 Gy in 15 fractions were -0•3% (-1•0 to 0•9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior fivefraction schedule: p=0•0022 vs 40 Gy in 15 fractions) and -0•7% (-1•3 to 0•3) for 26 Gy in five fractions (p=0•00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9•9%) 40 Gy patients, 155 (15•4%) of 1005 27 Gy patients, and 121 of 1020 (11•9%) 26 Gy patients. Across all clinician assessments from 1-5 years, odds ratios versus 40 Gy in 15 fractions were 1•55 (95% CI 1•32 to 1•83, p<0•0001) for 27 Gy in five fractions and 1•12 (0•94 to 1•34, p=0•20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.Interpretation 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant l...

The aim of this study was to determine the extent of ankle muscle weakness in children with cerebral palsy (CP) and to identify potential causes. Maximal voluntary contractions of plantar (PF) and dorsiflexors (DF) were determined at optimal angles in knee flexion and extension in both legs of 14 children with hemiplegia (7 males, 7 females) and 14 with diplegia (8 males, 6 females). Their results were compared to 14 age- and weight-matched control participants (5 males, 9 females). Muscle cross-sectional areas of soleus, posterior, and anterior compartment muscles were determined from MRIs in 14 children with CP (eight diplegia, six hemiplegia) and 18 control children. Specific tension (torque/unit area) of PF and DF was determined from torque and cross-sectional area results. Muscle volumes of PF and DF were also determined in both legs of five control children and five with hemiplegia. Muscle EMG was recorded from soleus, medial gastrocnemius, and tibialis anterior during each maximal voluntary contraction. Mean amplitude was significantly reduced in PF and DF in both CP groups and significantly higher levels of coactivation of antagonists were found compared to control participants. Strength of PF and DF was significantly reduced in both CP groups, but more importantly the muscles were found to be weak based on significantly reduced specific tensions. The PF were most affected, particularly in the group with hemiplegia. It is believed that an inability to maximally activate their muscles contributed to this weakness. A combination of incomplete activation and high levels of PF coactivation are thought to have contributed to DF weakness.

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The effect of osmotic cell swelling on the permeability of HeLa cells to a range of structurally unrelated solutes including taurine, sorbitol, thymidine, choline, and K+ (96Rb+) was investigated. For each solute tested, reduction in the osmolality of the medium from 300 to 200 mosmol/kgH2O caused a significant increase in the unidirectional influx rate. In each case, the osmotically activated transport component was nonsaturable up to external substrate concentrations of 50 mM. Inhibitors of the swelling-activated anion channel of HeLa cells [quinine, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, niflumate, 1,9-dideoxyforskolin, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), and tamoxifen] blocked the osmotically activated influx of each of the different substrates tested, as well as the osmotically activated efflux of taurine and I-. Tamoxifen and NPPB were similarly effective at blocking the osmotically activated efflux of 96Rb+. The simplest of several hypotheses consistent with the data is that the osmotically activated transport of the different solutes tested here is via a swelling-activated anion-selective channel that has a significant cation permeability and a minimum pore diameter of 8-9 A.

Summary To determine whether equine dysautonomia (ED) is associated with alterations in plasma amino acid metabolism, plasma amino acid profiles were determined for horses with acute (n = 10), subacute (n = 6) and chronic (n = 7) ED and for healthy cograzing horses (n = 6) and control horses (n = 10). Horses with acute ED had perturbations in plasma amino acid profiles resembling those of severe protein malnutrition. In addition, horses with ED and cograzing healthy horses had depletion of the plasma sulphur amino acids cyst(e)ine and methionine. As similar plasma amino acid perturbations occur in subacute/chronic cyanide toxicity, the role of cyanogenic glycosides in the aetiology of ED warrants further study. Unfortunately, amino acid analysis cannot be used as a definitive premortem diagnostic test for ED, since there was overlap in the individual amino acid levels of control, cograzing and ED horses.

Summary Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-' for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720mgday-' for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 gM on day 4 of all courses of treatment at both 480 and 720 mg day-'. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 JM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 gM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.