Reduction in calcium excretion in women with breast cancer and bone metastases using the oral bisphosphonate pamidronate.

The bisphosphonate pamidronate (3 amino-1, 1-hydroxypropylidene bisphosphonate (APD), Ciba-Geigy) is a powerful inhibitor of osteoclast function and has been shown to significantly reduce osteolysis associated with bone metastases in breast cancer. Until recently, however, only an intravenous preparation has been readily available. We have evaluated the toxicity and effect on urinary calcium excretion of an enteric-coated oral preparation of pamidronate in a phase I/II trial in patients with bone metastases from breast cancer. Sixteen women with progressive disease and evidence of active bone resorption with an elevated calcium excretion (fasting urine calcium/creatinine ratio greater than 0.4 (mmol mmol-1) on two occasions prior to treatment) were studied. Four were given 150 mg daily; four 300 mg daily; four 450 mg daily and four 600 mg daily. Urinary calcium/creatinine (Ca2+/Cr) ratios were measured on all patients after an overnight fast. In patients on 150 mg daily the mean ratio fell from 0.65 (range 0.57-0.72) before treatment to 0.13 (0.02-0.19) after three weeks treatment. Mean values at entry for patients on 300, 450 and 600 mg were 1.18 (0.72-2.1), 0.76 (0.42-1.5) and 0.63 (0.52-0.82) respectively and after treatment these fell to 0.11 (0.05-0.18), 0.37 (0.14-0.68) and 0.17 (0.06-0.25). There were no significant differences in efficacy between treatment groups. Oral, enteric-coated disodium pamidronate is non-toxic and effectively reduces calcium excretion, raised in association with metastatic bone disease at doses of 150 mg or above. At the doses used to date it is as effective as weekly treatments with 30 mg of the intravenous preparation. Further studies are required in order to determine its value for preventing complications of bone disease and possibly as an adjuvant to surgery for breast cancer

High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer.

Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100 mg m-2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 5 1/2 months and the median survival was 18 1/2 months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 days) and mean time to absolute neutrophil count recovery (ANC > 1,000 x 10(6) litre) from the start of treatment was 11 days. Moderate to severe epithelial toxicity (WHO grade 3 or 4) accompanied 43% of courses and was dose limiting. Conclusion: High dose, dose intensive chemotherapy has an excellent initial therapeutic effect in advanced breast cancer but does not prolong duration of remission or overall survival beyond that of standard treatment. Although subcutaneous rG-CSF curtailed the expected duration of neutropenia substantially, the overall incidence of neutropenia and of infections requiring intravenous antibiotics was high. Furthermore, almost half of the courses were complicated by moderate to severe oral mucositis and/or mild to moderate palmar and plantar inflammation. The lack of survival benefit and excess toxicity seriously limits the wider application of this regime. It should not be used in place of standard dose palliative chemotherapy for metastatic breast cancer

Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration

Patients with bone metastases from breast cancer often experience substantial skeletal complications – including debilitating bone pain – which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting in breast cancer patients with ⩾1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label infusions in the community or hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst pain (P=0.008) and average pain in the last 7 days (P=0.039), and interference with general activity (P=0.012). In each case, there were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital crossover setting for worst pain (P=0.021), average pain (P=0.003), and interference with general activity (P=0.001). Overall global health status showed a significant median improvement of 8.3% (P=0.013) at study end. Physical, emotional, and social functioning also showed significant overall improvement (P=0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P=0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in the community setting

Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study

This study was originally designed as a phase I/II study, with a dose escalation of docetaxel in combination with epirubicin 50 mg m⁻² and 5-fluorouracil (5-FU) 200 mg m⁻² day⁻¹. However, as dose escalation was not possible, the study is reported as a phase II study of the combination to assess response and toxicity. A total of 51 patients with locally advanced or metastatic breast cancer were treated on this phase II study, with doses of docetaxel 50 mg m⁻², epirubicin 50 mg m⁻² and infusional 5-FU 200 mg m⁻² day⁻¹ for 21 days. The main toxicity of this combination was neutropenia with 89% of patients having grade 3 and 4 neutropenia, and 39% of patients experiencing febrile neutropenia. Nonhaematological toxicity was mild. The overall response rate in the assessable patients was 64%, with median progression-free survival of 38 weeks, and median survival of 70 weeks. The ETF regimen was found to be toxic, and it was not possible to escalate the dose of docetaxel above the first dose level. This regimen has therefore not been taken any further, but as a development of this a new study is ongoing, combining 3-weekly epirubicin, weekly docetaxel and capecitabine, days 1-14

Diagnosing Stagnant Gas Bubbles in a Polymer Electrolyte Membrane Water Electrolyser using Acoustic Emission

The use of acoustic emission as a low-cost, non-destructive, and operando diagnostic tool has been demonstrated for a range of electrochemical energy conversion and storage devices, including polymer electrolyte membrane water electrolysers (PEMWEs) and fuel cells. In this work, an abrupt change in acoustic regime is observed during operation of a PEMWE as the current density is increased from 0.5 to 1.0 A cm^{-2}. This regime change is marked by a sudden drop in the number of acoustic hits, while hit duration, amplitude, and energy increase significantly. It is found that the change in acoustic regime coincides with a significant extension of the stagnant bubble region in the flow channels of the PEMWE, observed with high-speed optical imaging. These results demonstrate that acoustic emission can be used effectively as an operando diagnostic tool to monitor bubble formation (two-phase flow conditions) in PEMWEs, facilitating rapid testing or prototyping, and contributing to operational safety

Mapping midwifery and obstetric units in England

OBJECTIVE: to describe the configuration of midwifery units, both alongside&free-standing, and obstetric units in England. DESIGN: national survey amongst Heads of Midwifery in English Maternity Services SETTING: National Health Service (NHS) in England PARTICIPANTS: English Maternity Services Measurements descriptive statistics of Alongside Midwifery Units and Free-standing Midwifery Units and Obstetric Units and their annual births/year in English Maternity Services FINDINGS: alongside midwifery units have nearly doubled since 2010 (n = 53-97); free-standing midwifery units have increased slightly (n = 58-61). There has been a significant reduction in maternity services without either an alongside or free-standing midwifery unit (75-32). The percentage of all births in midwifery units has trebled, now representing 14% of all births in England. This masks significant differences in percentage of all births in midwifery units between different maternity services with a spread of 4% to 31%. KEY CONCLUSIONS: In some areas of England, women have no access to a local midwifery unit, despite the National Institute for Health&Clinical Excellence (NICE) recommending them as an important place of birth option for low risk women. The numbers of midwifery units have increased significantly in England since 2010 but this growth is almost exclusively in alongside midwifery units. The percentage of women giving birth in midwifery units varies significantly between maternity services suggesting that many midwifery units are underutilised. IMPLICATIONS FOR PRACTICE: Both the availability and utilisation of midwifery units in England could be improved

Surgery of the primary tumour in women with metastatic breast cancer at diagnosis in England and Wales – how do treatment rates vary at an individual and regional level?

BACKGROUND: Surgery to the primary tumour in women with metastatic breast cancer (MBC) has traditionally been reserved for palliative purposes, and European guidelines suggest it should be performed on an individualised basis1. A lack of consensus on the effectiveness of a procedure can lead to treatment variation in clinical practice. We examined what proportion of women with MBC aged 50+yrs received surgery to the primary tumour, and explored what patient and clinical characteristics influence receipt of surgery, as part of the National Audit of Breast Cancer in Older Patients (NABCOP). METHODS: Details of the NABCOP are available at www.nabcop.org.uk. Data on women aged 50+yrs newly diagnosed with MBC at diagnosis between January 2014 and December 2018 in England and Wales were obtained from national cancer registry datasets linked to routine hospital episodes. Receipt of surgery up to 3 years from diagnosis was examined using Kaplan Meier estimates, both nationally and between Cancer Alliances. The relationship between patient/tumour factors and time to surgery was analysed using log rank tests and a flexible parametric regression model (FPM). RESULTS: Between 2014 and 2018, 7316 women aged 50+yrs with MBC at diagnosis were identified. Overall, 18.7% women had surgery to the primary tumour within 1 year from diagnosis. Having surgery at 1 year was more common among younger women (50–59 yrs vs 80+yrs: 29.8% vs 8.6%, adjusted HR 1.79), those with T1/T2 tumours (T1/T2 vs T3/T4: 33.1% vs 20.8%, adjusted HR 1.72), and positive nodal stage (N0 vs N+: 19.3% vs 29.1%, adjusted HR 1.54). Rates of surgery within 1 year from diagnosis reduced over time, from 23.7% in 2014 to 15.7% in 2018, but to a greater degree among women aged 50–69 yrs (34.8% in 2014 to 21.1% in 2018) compared with women aged 70+yrs: 15.6% to 11.5%. Overall rates of surgery varied from 11.6% to 32.2% between the 20 Cancer Alliance/regions across England and Wales. CONCLUSIONS: Almost 20% of women aged 50+yrs with MBC at diagnosis received breast surgery within 1 year from diagnosis, but this varied between regions in England and Wales, and the use of surgery has decreased in recent years. Research is required to understand why treatment variation exists as well as to generate better evidence on the value of surgery in patients with MBC

Radiotherapy following breast-conserving surgery for screen-detected ductal carcinoma in situ: indications and utilisation in the UK. Interim findings from the Sloane Project

Use of radiotherapy (RT) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) varies according to country, precedent and prejudice. Results from a preliminary analysis of the data available within the UK Sloane Project can be appreciated in the context of the uncertainty concerning the selection of adjuvant RT following BCS for DCIS. There was a marked geographical variation in the use of RT within the United Kingdom. However, overall, patients with DCIS treated with BCS were significantly more likely to have RT planned (and given) if they had large (⩾15 mm), intermediate or high-grade tumours or if central comedo-type necrosis was present. Unexpectedly, margin width did not appear to have a significant effect on the decision-making process. However, the Van Nuys Prognostic Index did significantly affect the chances of getting planned RT in the univariate analysis, suggesting that clinicians may be starting to use this scoring system in routine practice to assist in decision making

Surgical decisions in older women with early breast cancer: patient and disease factors.

BACKGROUND: Studies reporting lower rates of surgery for older women with early invasive breast cancer have focused on women with oestrogen receptor (ER)-positive tumours. This study examined the factors that influence receipt of breast surgery in older women with ER-positive and ER-negative early invasive breast cancer . METHODS: Women aged 50 years or above with unilateral stage 1-3A early invasive breast cancer diagnosed in 2014-2017 were identified from linked English and Welsh cancer registration and routine hospital data sets. Logistic regression analysis was used to evaluate the influence of tumour and patient factors on receipt of surgery. RESULTS: Among 83 188 women, 86.8 per cent had ER-positive and 13.2 per cent had ER-negative early invasive breast cancer. These proportions were unaffected by age at diagnosis. Compared with women with ER-negative breast cancer, a higher proportion of women with ER-positive breast cancer presented with low risk tumour characteristics: G1 (20.0 versus 1.5 per cent), T1 (60.8 versus 44.2 per cent) and N0 (73.9 versus 68.8 per cent). The proportions of women with any recorded co-morbidity (13.7 versus 14.3 per cent) or degree of frailty (25 versus 25.8 per cent) were similar among women with ER-positive and ER-negative disease respectively. In women with ER-positive early invasive breast cancer aged 70-74, 75-79 and 80 years or above, the rate of no surgery was 5.6, 11.0 and 41.9 per cent respectively. Among women with ER-negative early invasive breast cancer, the corresponding rates were 3.8, 3.7 and 12.3 per cent. The relatively lower rate of surgery for ER-positive breast cancer persisted in women with good fitness. CONCLUSION: The reasons for the observer differences should be further explored to ensure consistency in treatment decisions