Rethinking neoadjuvant chemotherapy for breast cancer

Breast cancer is the most common cancer in women worldwide. In 2014, 55 000 women in the UK were given the diagnosis of breast cancer, and 11 000 died.1 Early breast cancer is traditionally treated with surgery, plus radiotherapy and adjuvant systemic therapy as required. Neoadjuvant chemotherapy for breast cancer is a new strategy that was introduced towards the end of the 20th century with the aim of reducing tumour size. It has four main rationales. Firstly, it should render an otherwise inoperable tumour operable or, secondly, allow more conservative surgery. Thirdly, starting systemic treatment preoperatively was hoped to lead to improved overall survival in patients with locally advanced cancers, who are at high risk of having distant disease. Finally, unlike adjuvant chemotherapy given in the absence of any measurable disease, neoadjuvant chemotherapy gives us the opportunity to observe the tumour shrink both palpably and on imaging, enabling a rapid assessment of clinical response. This could help test responses in vivo to new drug regimens, which could then be used as adjuvant therapies, in so called window of opportunity studies. A survey of multidisciplinary teams in Australia, Germany, Italy, the UK, and the US found that 7-27% of new breast cancers are treated with neoadjuvant chemotherapy (Saunders C, Cody H, Kolberg HC, et al, personal communication, 2017). With 1.7 million women receiving diagnoses annually, this translates into 120 000-460 000 women receiving neoadjuvant chemotherapy worldwide.1 Although data indicate that the first rationale remains valid, the others have not led to the desired outcomes. More conservative surgery after neoadjuvant chemotherapy can result in a higher rate of local recurrence, and, despite the earlier initiation of systemic treatment, no improvement in survival has been seen.234 Furthermore, neoadjuvant chemotherapy may not help test novel chemotherapies—although primary tumour response is a good indicator of prognosis for a particular treatment, it is counterintuitively a poor surrogate marker for the overall survival benefit when evaluating novel chemotherapy regimens. Finally, for 40-80% of patients, even the best neoadjuvant chemotherapy regimens extend the period the cancer remains in the breast and can make surgery more difficult, as the tumour is less easily palpable and the axillary lymph nodes are less distinct. We question the wisdom of the current widespread use of neoadjuvant chemotherapy

An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial)

BACKGROUND: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. OBJECTIVE: To compare TARGIT within a risk-adapted approach with whole breast external beam radiotherapy over several weeks (EBRT). DESIGN AND SETTING: The TARGIT-A trial was a pragmatic, prospective, international, multicenter, non-inferiority, non-blinded, randomised (1:1 ratio), clinical trial from 33 centres in 11 countries. Originally, randomisation occurred before initial lumpectomy (prepathology) and if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added, in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but needed a reoperation to reopen the wound to give TARGIT as delayed procedure. Risk-adapted approach meant that in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, then EBRT was recommended. Pragmatically, this reflected how TARGIT would be practiced in the real world. PARTICIPANTS: Women who were >=45 years of age with unifocal invasive ductal carcinoma preferably <= 3.5cm in size; 3451 patients were recruited between March 2000 and June 2012. OUTCOMES: Primary: absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary: included toxicity, breast cancer specific and non-breast-cancer mortality. RESULTS: Values below are 5-year Kaplan-Meier rates for TARGIT vs. EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall (3·3%(2·1–5·1) vs. 1·3%(0·7–2·5),p=0.04,Pnoninferiority =0.00000012) and in the prepathology stratum(n=2298) when TARGIT was given concurrently with lumpectomy(2·1%(1·1–4·2) vs. 1·1%(0·5–2·5),p=0.31,Pnoninferiority =0.0000000013). With delayed TARGIT postpathology,(n=1153) the between-group difference was larger than 2·5% and non-inferiority was not established for this stratum((5·4%(3·0–9·7) vs. 1·7%(0·6–4·9),p=0.069,Pnoninferiority= 0.06640). The local-recurrence-free survival when TARGIT was given with lumpectomy was 93.9%(95%CI 90.9 – 95.9) vs. EBRT: 92.5%(95%CI 89.7 – 94.6),p=0.35. In a planned subgroup analysis, progesterone (PgR) receptor status was found to be the only predictor of outcome - hormone responsive patients (PgRpositive) had similar 5-year local recurrence with TARGIT during lumpectomy 1.4%(0.5-3.9) vs. EBRT 1.2%(0.5-2.9),p=0.77. Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (2·6%[1·5–4·3] vs. 1·9%[1·1–3·2];p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5%[2·3–5·2];p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm 37 deaths, 3·9%(2·7–5·8) vs. 51 deaths, 5·3%(3·9–7·3),p=0.099). Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar QALYs, had a positive incremental Net Monetary Benefit that was borderline statistically significant from zero, and had a probability of over 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health care providers by £8 million to £9.1 million each year. This does not include environmental, patient and societal costs. LIMITATIONS: The number of local recurrences is small however, the number of events for local-recurrence-free survival is not small (59 vs. 61); Occurrence of only a few events implies that the treatments are effective and any difference is unlikely to be large. The follow up not all 3451 patients is 5 years, although the number required to answer the main trial question (n=585) have more than 5 years follow up. FUTURE WORK: We shall repeat the analyses with longer follow up. Although this may not change the primary result, the larger number of events may confirm the effect on mortality and allow more detailed subgroup analyses. The TARGIT-B trial is testing whether TARGIT-Boost is superior to EBRT boost. CONCLUSION: For patients with breast cancer (women who are 45 years of age and older with hormone sensitive invasive ductal carcinoma that is up to 3.5cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective, safer and less expensive alternative to postoperative EBRT. TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov NCT00983684

Iterative Approximate Consensus in the presence of Byzantine Link Failures

This paper explores the problem of reaching approximate consensus in synchronous point-to-point networks, where each directed link of the underlying communication graph represents a communication channel between a pair of nodes. We adopt the transient Byzantine link failure model [15, 16], where an omniscient adversary controls a subset of the directed communication links, but the nodes are assumed to be fault-free. Recent work has addressed the problem of reaching approximate consen- sus in incomplete graphs with Byzantine nodes using a restricted class of iterative algorithms that maintain only a small amount of memory across iterations [22, 21, 23, 12]. However, to the best of our knowledge, we are the first to consider approximate consensus in the presence of Byzan- tine links. We extend our past work that provided exact characterization of graphs in which the iterative approximate consensus problem in the presence of Byzantine node failures is solvable [22, 21]. In particular, we prove a tight necessary and sufficient condition on the underlying com- munication graph for the existence of iterative approximate consensus algorithms under transient Byzantine link model. The condition answers (part of) the open problem stated in [16].Comment: arXiv admin note: text overlap with arXiv:1202.609

Thermo-optic measurements and their inter-dependencies for delineating cancerous breast biopsy tissue from adjacent normal

The histopathological diagnosis of cancer is the current gold standard to differentiate normal from cancerous tissues. We propose a portable platform prototype to characterize the tissue's thermal and optical properties, and their inter-dependencies to potentially aid the pathologist in making an informed decision. The measurements were performed on 10 samples from five subjects, where the cancerous and adjacent normal were extracted from the same patient. It was observed that thermal conductivity (k) and reduced-scattering-coefficient (μ's) for both the cancerous and normal tissues reduced with the rise in tissue temperature. Comparing cancerous and adjacent normal tissue, the difference in k and μ's (at 940 nm) were statistically significant (p = 7.94e-3), while combining k and μ's achieved the highest statistical significance (6.74e-4). These preliminary results promise and support testing on a large number of samples for rapidly differentiating cancerous from adjacent normal tissues

Recent advances in biosensing approaches for point-of-care breast cancer diagnostics: challenges and future prospects

Timely and accurate diagnosis of breast cancer is essential for efficient treatment and the best possible survival rates. Biosensors have emerged as a smart diagnostic platform for the detection of biomarkers specific to the onset, recurrence, and therapeutic drug monitoring of breast cancer. There have been exciting recent developments, including significant improvements in the validation, sensitivity, specificity, and integration of sample processing steps to develop point-of-care (POC) integrated micro-total analysis systems for clinical settings. The present review highlights various biosensing modalities (electrical, optical, piezoelectric, mass, and acoustic sensing). It provides deep insights into their design principles, signal amplification strategies, and comparative performance analysis. Finally, this review emphasizes the status of existing integrated micro-total analysis systems (μ-TAS) for personalized breast cancer therapeutics and associated challenges and outlines the approach required to realize their successful translation into clinical settings

Ultracold atomic gases in optical lattices: mimicking condensed matter physics and beyond

We review recent developments in the physics of ultracold atomic and molecular gases in optical lattices. Such systems are nearly perfect realisations of various kinds of Hubbard models, and as such may very well serve to mimic condensed matter phenomena. We show how these systems may be employed as quantum simulators to answer some challenging open questions of condensed matter, and even high energy physics. After a short presentation of the models and the methods of treatment of such systems, we discuss in detail, which challenges of condensed matter physics can be addressed with (i) disordered ultracold lattice gases, (ii) frustrated ultracold gases, (iii) spinor lattice gases, (iv) lattice gases in "artificial" magnetic fields, and, last but not least, (v) quantum information processing in lattice gases. For completeness, also some recent progress related to the above topics with trapped cold gases will be discussed.Comment: Review article. v2: published version, 135 pages, 34 figure

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Hybrid Spectral-IRDx: Near-IR and Ultrasound Attenuation System for Differentiating Breast Cancer from Adjacent Normal Tissue

OBJECTIVE: While performing surgical excision for breast cancer (lumpectomy), it is important to ensure a clear margin of normal tissue around the cancer to achieve complete resection. The current standard is histopathology; however, it is time-consuming and labour-intensive requiring skilled personnel. METHOD: We describe a Hybrid Spectral-IRDx - a combination of the previously reported Spectral-IRDx tool with multimodal ultrasound and NIR spectroscopy techniques. We show how this portable, cost-effective, minimal-contact tool could provide rapid diagnosis of cancer using formalin-fixed (FF) and deparaffinized (DP) breast biopsy tissues. RESULTS: Using this new tool, measurements were performed on cancerous/fibroadenoma and its adjacent normal tissues from the same patients (N=14). The acoustic attenuation coefficient () and reduced scattering coefficient (s) (at 850, 940, and 1060 nm) for the cancerous/fibroadenoma tissues were reported to be higher compared to adjacent normal tissues, a basis of delineation. Comparing FF cancerous and adjacent normal tissue, the difference in s at 850 nm and 940 nm were statistically significant (p=3.17e-2 and 7.94e-3 respectively). The difference in between the cancerous and adjacent normal tissues for DP and FF tissues were also statistically significant (p=2.85e-2 and 7.94e-3 respectively). Combining multimodal parameters and s (at 940 nm) show highest statistical significance (p=6.72e-4) between FF cancerous/fibroadenoma and adjacent normal tissues. CONCLUSION: We show that Hybrid Spectral-IRDx can accurately delineate between cancerous and adjacent normal breast biopsy tissue. SIGNIFICANCE: The results obtained establish the proof-of-principle and large-scale testing of this multimodal breast cancer diagnostic platform for core biopsy diagnosis

Search for supersymmetry in events with four or more leptons in √s =13 TeV pp collisions with ATLAS

Results from a search for supersymmetry in events with four or more charged leptons (electrons, muons and taus) are presented. The analysis uses a data sample corresponding to 36.1 fb −1 of proton-proton collisions delivered by the Large Hadron Collider at s √ =13 TeV and recorded by the ATLAS detector. Four-lepton signal regions with up to two hadronically decaying taus are designed to target a range of supersymmetric scenarios that can be either enriched in or depleted of events involving the production and decay of a Z boson. Data yields are consistent with Standard Model expectations and results are used to set upper limits on the event yields from processes beyond the Standard Model. Exclusion limits are set at the 95% confidence level in simplified models of General Gauge Mediated supersymmetry, where higgsino masses are excluded up to 295 GeV. In R -parity-violating simplified models with decays of the lightest supersymmetric particle to charged leptons, lower limits of 1.46 TeV, 1.06 TeV, and 2.25 TeV are placed on wino, slepton and gluino masses, respectively

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level