Trial supports targeted radiotherapy for early breast cancer but protocol still requires 3 weeks of daily therapy

Commentary on: Coles CE, Griffin CL, Kirby AM, et al. IMPORT Trialists. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet 2017;390:1048–60. Context The evidence-based local treatment for early breast cancer is breast-conserving surgery and radiotherapy, requiring 3–6 weeks of daily whole breast external beam radiation therapy, which is inconvenient for patients and expensive. The suggestion that targeted radiation to the tumour bed with modern techniques may be adequate was proposed in 1995.1 This was heralded as a new standard2 with the publication of the TARGIT-A trial3 4 of single-dose targeted intraoperative radiotherapy (TARGIT-IORT), later confirmed by other European studies using brachytherapy5 that requires 5 days of inpatient stay or EBRT.6 Methods In this study,7 in 30 UK centres, from 2007 to 2010, women aged ≥50 years, who had undergone breast-conserving surgery for unifocal invasive ductal carcinoma ≤3 cm in size with a 2 mm non-cancerous excision margin, were randomly assigned (1:1:1) to receive daily over 3 weeks one of three regimens: (1) 40 Gy whole breast irradiation (WBI); (2) 36 Gy WBI with 40 Gy partial breast irradiation (PBI); or (3) 40 Gy PBI targeted to the tumour bed. The primary endpoint was ipsilateral local relapse with a non-inferiority margin of 2.5% at 5 years. For quality of life, 72 different patient-reported outcome measures (PROM) were analysed and radiotherapy toxicity was assessed by photographs and clinicians. Neither patients, clinicians nor data analysts were masked to treatment allocation. Findings Five-year estimated incidence of local relapse was 1.1% (95% CI 0.5 to 2.3) with WBI (n=674) and 0.5% (0.2–1.4) with PBI (n=669); non-inferiority was confirmed. Unlike in prior trials,3–6 radiotherapy toxicity was not reduced. Of the 72 PROMs assessed, only two (breast appearance and texture) were reported to have better cumulative scores with PBI. The incidence of only one PROM (‘breast appearance changed’) was reduced at 5 years (from 27% to 15%). Commentary IMPORT-LOW provides further mature randomised evidence supporting PBI. However, PBI with IMPORT-LOW protocol offers little advantage to patients or the healthcare system. The 2 mm clear margins this protocol requires render many patients ineligible; acceptable margins are currently much smaller, for example, >0 mm in USA.8 The authors emphasise the benefit in two quality of life domains, although 72 were tested, with 5-year benefit seen in only one. Clearly, IMPORT-LOW patients had considerably better prognosis cancers than in other trials that have proven non-inferiority of targeted radiation to whole breast radiation. Compared with TARGIT-A, for example, only 3% versus 16% were node positive, and 9% versus 15% were grade 3. Therefore, the low recurrence rate is not surprising. Who benefits from the IMPORT-LOW protocol? For patients and healthcare systems, the 3-week daily regimen has adverse physical, social, financial9 and environmental impacts10 and offers no advantage over conventional radiation. PBI using IMPORT-LOW is also resource consuming (and therefore expensive), and keeps radiotherapy departments very busy. Conversely, TARGIT-IORT delivered during the operation enables over 80% of patients to avoid visiting the radiotherapy centre at all. The relevance here is that although published twice in The Lancet, with an independent editorial concluding that it should be offered as an alternative to conventional EBRT, TARGIT-IORT is not even mentioned in the IMPORT-LOW paper. We find this surprising since the number of patients with a median follow-up of 5–6 years is similar (~1200 vs 1300), and both proved non-inferiority. Implications for practice Targeted radiation methods range from the 3-week daily course required for IMPORT-LOW with 16 hospital visits, to the single-dose TARGIT-IORT given during lumpectomy. Several other approaches are also available,5 6 and as all are effective, patients are entitled to choose what is right for them, based on convenience, personal cost, quality of life and side effects. Acknowledgments We thank Professor Michael Baum, Professor Michael Douek, Mr Nathan Coombs, Professor Max Bulsara, Dr Julian Singer, Dr David Morgan, Dr Shiroma D’Silva and Ms Marcelle Bernstein for valuable discussion about this manuscript

The unimolecular decomposition of dimethoxymethane: channel switching as a function of temperature and pressure

Branching ratios of competing unimolecular reactions often exhibit a complicated temperature and pressure dependence that makes modelling of complex reaction systems in the gas phase difficult. In particular, the competition between steps proceeding via tight and loose transition states is known to present a problem. A recent example from the field of combustion chemistry is the unimolecular decomposition of CH$_3$OCH$_2$OCH$_3$ (DMM), which is discussed as an alternative fuel accessible from sustainable sources. It is shown by a detailed master equation analysis with energy- and angular-momentum-resolved specific rate coefficients from RRKM theory and from the simplified statistical adiabatic channel model, how channel switching of DMM depends on temperature and pressure, and under which experimental conditions which channels prevail. The necessary molecular and energy data were obtained from quantum-chemical calculations at the CCSD(F12*)(T*)/cc-pVQZ-F12//B2PLYP-D3/def2-TZVPP level of theory. A parameterization describing the channel branching over extended ranges of temperature and pressure is derived, and the model is used to simulate shock tube experiments with detection by atomic resonance absorption spectroscopy and time-of-flight mass spectrometry. The agreement between the simulated and experimental concentration–time profiles is very good. The temperature and pressure dependence of the channel branching is rationalized, and the data are presented in a form that can be readily implemented into DMM combustion models

Dopant-controlled single-electron pumping through a metallic island

We investigate a hybrid metallic island / single dopant electron pump based on fully-depleted silicon on insulator technology. Electron transfer between the central metallic island and the leads is controlled by resonant tunneling through single phosphorus dopants in the barriers. Top gates above the barriers are used control the resonance conditions. Applying radio frequency signals to the gates, non-adiabatic quantized electron pumping is achieved. A simple deterministic model is presented and confirmed by comparing measurements with simulations

Machine Learning for the Prediction of Converged Energies from Ab Initio Nuclear Structure Calculations

The prediction of nuclear observables beyond the finite model spaces that are accessible through modern ab initio methods, such as the no-core shell model, pose a challenging task in nuclear structure theory. It requires reliable tools for the extrapolation of observables to infinite many-body Hilbert spaces along with reliable uncertainty estimates. In this work we present a universal machine learning tool capable of capturing observable-specific convergence patterns independent of nucleus and interaction. We show that, once trained on few-body systems, artificial neural networks can produce accurate predictions for a broad range of light nuclei. In particular, we discuss neural-network predictions of ground-state energies from no-core shell model calculations for 6Li, 12C and 16O based on training data for 2H, 3H and 4He and compare them to classical extrapolations.Comment: 7 pages, 5 figures, 1 tabl

Controlling the error mechanism in a tunable-barrier non-adiabatic charge pump by dynamic gate compensation

Single-electron pumps based on tunable-barrier quantum dots are the most promising candidates for a direct realization of the unit ampere in the recently revised SI: they are simple to operate and show high precision at high operation frequencies. The current understanding of the residual transfer errors at low temperature is based on the evaluation of backtunneling effects in the decay cascade model. This model predicts a strong dependence on the ratio of the time dependent changes in the quantum dot energy and the tunneling barrier transparency. Here we employ a two-gate operation scheme to verify this prediction and to demonstrate control of the backtunneling error. We derive and experimentally verify a quantitative prediction for the error suppression, thereby confirming the basic assumptions of the backtunneling (decay cascade) model. Furthermore, we demonstrate a controlled transition from the backtunneling dominated regime into the thermal (sudden decoupling) error regime. The suppression of transfer errors by several orders of magnitude at zero magnetic field was additionally verified by a sub-ppm precision measurement

Development of a Scalable Fabrication Concept for Sustainable, Programmable Shape‐Morphing Metamaterials

Programmable materials are a novel development, in which specialized production processes are used to introduce a framework of information capabilities into the inner structure of materials. Since the design and fabrication of programmable materials are still challenging, this aims to introduce a design and fabrication concept to pave the way toward industrial application. Herein, complex shape morphing has been implemented in the sense that the shape changes in response to external conditions, following a predefined program. First, the feasibility of a fabrication concept for uniform metamaterials with auxetic behavior is presented. A material with a predetermined nonuniform inner structure that deforms to a symmetrical shape has been developed and fabricated according to this concept. More complex behavior can be implemented by facilitating optimization methods to find inner structures according to a target shape. Lastly, an optimized and producible design for asymmetrical shape morphing is described to demonstrate the applicability of the approach