Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.

BACKGROUND: Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. PATIENTS AND METHODS: c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). RESULTS: Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. CONCLUSIONS: c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Regularization of a Mathematical Model of the Wheatley Heart Valve.

This note considers the mathematical model published in the Journal of Biomechanical Engineering by McKee et al. [McKee, S., Cuminato, J. A., Stewart, I. W., and Wheatley, D. J., 2021, "A Mathematical Representation of the Wheatley Heart Valve," ASME J. Biomech. Eng., 143(8), p. 081006]. The model presented there suffers from the fact that there is a line discontinuity in the first derivative producing what appears to be a kink in each of the leaflets. This note is concerned with regularizing the shape of the valve while holding to Wheatley's essential idea [Wheatley, D. J., 2016, "Heart Valve," U.S. Patent No. 9,259,313, UK Patent No. 2,982,340 (2017), European Patent No. 2,979,666 (2017)].

Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to Implementation.

INTRODUCTION: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule. IPSILATERAL BREAST TUMOUR RELAPSE (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4-3.1), 1.7% (1.2-1.6) after 27 Gy and 1.4% (0.2-2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-mastectomy. NORMAL TISSUE EFFECTS: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or adjuvant chemotherapy. RADIOBIOLOGICAL CONSIDERATIONS: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in α/ß estimate for the late normal tissue effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation. CONCLUSION: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.

A Mathematical Representation of the Wheatley Heart Valve.

Starting from a hand-drawn contour plot, this note develops a set of intersecting and contiguous circles whose perimeter, upon extending appropriately to three dimensions, can be seen to be a natural mathematical representation of the Wheatley heart valve.

Percutaneous heart valves; past, present and future.

Percutaneous heart valves provide a promising future for patients refused surgery on the grounds of significant technical challenges or high risk for complications. Since the first human intervention more than 10 years ago, over 50 different types of valves have been developed. The CoreValve and Edwards SAPIEN valves have both experienced clinical trials and the latter has gained FDA approval for implantation in patients considered inoperable. Current complications, such as major vascular bleeding and stroke, prevent these valves from being commonly deployed in patients considered operable in conventional surgery. This review focuses on the past and present achievements of these valves and highlights the design considerations required to progress development further. It is envisaged that, with continued improvement in valve design and with increased clinical and engineering experience, percutaneous heart valve replacement may one day be a viable option for lower-risk operable patients.

Breast radiotherapy: less is more?

A 3 week schedule of whole breast radiotherapy is firmly established in the UK and is becoming more accepted internationally, especially as accelerated partial breast radiotherapy regimens become more common. It seems that a 3 week schedule is unlikely to be the lower limit of whole breast hypofractionation and the partial breast may even be adequately treated with just a single treatment. It is, however, essential that these hypotheses are rigorously tested within well-designed trials to ensure the highest quality of radiotherapy. This overview will address the rationale for hypofractionation in breast cancer, discuss past trials and outline the design of current studies.

Using bevacizumab to treat metastatic cancer: UK consensus guidelines.

Concise guidance is lacking for the use of bevacizumab by practicing oncologists. Eight oncologists with experience of bevacizumab were joined by a cardiologist interested in treating hypertension to develop practical guidelines for managing patients receiving bevacizumab, using available clinical data.

The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer.

BACKGROUND: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT+/-ZOL (CT+ZOL, n=102; CT, n=103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n=195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT+ZOL groups were 27.4 and 15.5 mm, respectively, giving a difference in means of 12 mm (95% confidence interval: 3.5-20.4 mm; P=0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT+ZOL group (P=0.146). There was no difference in axillary nodal involvement (P=0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Prevention of febrile neutropenia: use of granulocyte colony-stimulating factors.

There is good evidence to suggest that dose intensity is important when considering the effectiveness of adjuvant chemotherapy in patients with breast cancer. However, the development of chemotherapy-induced febrile neutropenia can lead to reduction in dose intensity and other treatment modifications, which may negatively affect patient outcomes. Febrile neutropenia can be prevented by the use of primary prophylactic treatment, notably with granulocyte colony-stimulating factors. This practice is supported by international guidelines, all of which recommend that primary prophylaxis with granulocyte colony-stimulating factors should be used with chemotherapy where the risk of febrile neutropenia is 20% or greater.

Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest.

Human hepatocellular carcinoma (HCC) has an elevated requirement for arginine in vitro, and pegylated recombinant human arginase I (rhArg-PEG), an arginine-depleting enzyme, can inhibit the growth of arginine-dependent tumors. While supplementation of the culture medium with ornithine failed to rescue Hep3B cells from growth inhibition induced by rhArg-PEG, citrulline successfully restored cell growth. The data support the roles previously proposed for ornithine transcarbamylase (OTC) in the arginine auxotrophy and rhArg-PEG sensitivity of HCC cells. Expression profiling of argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and OTC in 40 HCC tumor biopsy specimens predicted that 16 of the patients would be rhArg-sensitive, compared with 5 who would be sensitive to arginine deiminase (ADI), another arginine-depleting enzyme with anti-tumor activity. Furthermore, rhArg-PEG-mediated deprivation of arginine from the culture medium of different HCC cell lines produced cell cycle arrests at the G(2)/M or S phase, possibly mediated by transcriptional modulation of cyclins and/or cyclin dependent kinases (CDKs). Based on these results, together with further validation of the in vivo efficacy of rhArg-PEG against HCC, we propose that the application of rhArg-PEG alone or in combination with existing chemotherapeutic drugs may represent a specific and effective therapeutic strategy against HCC.

An audit of follow-up clinics for breast cancer patients in Cornwall: is the time and effort worth it?

This paper's aims were to investigate the time and costs of healthcare professionals involved with follow-up clinics for breast cancer patients; and to quantify the numbers of local recurrences detected. An audit of breast cancer patients diagnosed with disease recurrence was conducted, and data were collected from the cancer audit system and from an analysis of relevant case notes. Costs of the time spent in follow-up clinics by clinical staff were also collected. The study found that sixty-nine breast cancer patients were diagnosed with local recurrence between 1 January 1999 and 31 December 2004. Only 15% (10) of recurrences were detected at routine follow up, 48% were first noticed by patients themselves, and 37% were detected at routine mammography. Six separate follow-up clinics were scheduled each week. This involved a total clinic time of approximately 20 h, and a total weekly cost of around pound 4857, with an annual cost of pound 252,564. Our recommendation is that alternative methods of follow up need to be implemented so that healthcare professionals have more time for newly diagnosed patients, those on active treatment and those with relapsed disease.

Microvascular preconditioning is not detectable by corrosion casting in the isolated perfused rat heart after 30 minutes of ischaemia.

OBJECTIVE: Ischaemic preconditioning protects the myocardium from ischaemic injury and may also protect the vascular endothelium from the deleterious effects of ischaemia and reperfusion. We examined the possibility that ischaemic preconditioning might preserve the integrity of the coronary microcirculation following ischaemia and reperfusion. METHODS: Isolated rat hearts were perfused in Langendorff mode for 30 minutes and then subjected to 30 minutes of global ischaemia with or without ischaemic preconditioning (threexthree minute cycles). Some hearts underwent an additional 60 minutes of reperfusion. At the end of each protocol, microvascular corrosion casts were made by methylmethacrylate injection. RESULTS: Median left ventricular capillary density [interquartile range] after ischaemia was slightly but not significantly better with preconditioning at 6.8 [4.0-14.7]x10(-2) mm3.mg(-1) vs. 5.2 [2.6-7.1]x10(-2) mm3.mg(-1) (p=0.13). After 60 min of reperfusion, capillary density in preconditioned left ventricles was 20.7 [10.7-22.8]x10(-2) mm3.mg(-1) vs. 16.0 [10.2-23.0]x10(-2) mm3.mg(-1) for untreated ventricles (p=0.47). Coronary blood flow and heart rate were unchanged from before ischaemia. CONCLUSIONS: Ischaemia for 30 minutes induced global left ventricular capillary loss which was unmodified by preconditioning. We did not demonstrate vascular preconditioning using this model.

Dynamic modelling of prosthetic chorded mitral valves using the immersed boundary method.

Current artificial heart valves either have limited lifespan or require the recipient to be on permanent anticoagulation therapy. In this paper, effort is made to assess a newly developed bileaflet valve prosthesis made of synthetic flexible leaflet materials, whose geometry and material properties are based on those of the native mitral valve, with a view to providing superior options for mitral valve replacement. Computational analysis is employed to evaluate the geometric and material design of the valve, by investigation of its mechanical behaviour and unsteady flow characteristics. The immersed boundary (IB) method is used for the dynamic modelling of the large deformation of the valve leaflets and the fluid-structure interactions. The IB simulation is first validated for the aortic prosthesis subjected to a hydrostatic loading. The predicted displacement fields by IB are compared with those obtained using ANSYS, as well as with experimental measurements. Good quantitative agreement is obtained. Moreover, known failure regions of aortic prostheses are identified. The dynamic behaviour of the valve designs is then simulated under four physiological pulsatile flows. Experimental pressure gradients for opening and closure of the valves are in good agreement with IB predictions for all flow rates for both aortic and mitral designs. Importantly, the simulations predicted improved physiological haemodynamics for the novel mitral design. Limitation of the current IB model is also discussed. We conclude that the IB model can be developed to be an extremely effective dynamic simulation tool to aid prosthesis design.

Interventional versus conservative treatment in acute non-ST elevation coronary syndrome: time course of patient management and disease events over one year in the RITA 3 trial.

OBJECTIVE: To determine whether, in acute non-ST elevation coronary syndrome, the benefit from early invasive coronary intervention compared with a conservative strategy of later symptom-guided intervention varies over time. METHODS: In RITA 3 (Randomised Intervention Trial of unstable Angina 3) patients were randomly assigned to coronary angiography (median 2 days after randomisation) and appropriate intervention (n = 895) or to a symptom-guided conservative strategy (n = 915). RESULTS: In the first week patients in both groups were at highest risk of death, myocardial infarction (MI) or refractory angina (incidence rate 40 times higher than in months 5-12 of follow up). There were 22 MIs and 6 deaths in the intervention group (largely due to procedure-related events, 14 MIs and 3 deaths) versus 17 MIs and 3 deaths in the conservative group. In the rest of the year there were an additional 12 versus 27 MIs, respectively (treatment-time interaction p = 0.021). Over one year in the intervention group there was a 43% reduction in refractory angina; 22% of patients underwent coronary artery bypass surgery and 35% underwent percutaneous coronary intervention only, which reduced refractory angina but provoked some early MIs; and 43% were still treated medically, mostly because of a favourable initial angiogram. CONCLUSION: Any intervention policy needs to recognise the high risk of events in the first week and the substantial minority of patients not needing intervention. Intervention may be best targeted at higher risk patients, as the early hazards of the procedure are then offset by reduced subsequent events.

"Fathers" and "sons" of theories in cell physiology: the membrane theory.

The last 50 years in the history of life sciences are remarkable for a new important feature that looks as a great threat for their future. A profound specialization dominating in quickly developing fields of science causes a crisis of the scientific method. The essence of the method is a unity of two elements, the experimental data and the theory that explains them. To us, "fathers" of science, classically, were the creators of new ideas and theories. They were the true experts of their own theories. It is only they who have the right to say: "I am the theory". In other words, they were carriers of theories, of the theoretical knowledge. The fathers provided the necessary logical integrity to their theories, since theories in biology have still to be based on strict mathematical proofs. It is not true for sons. As a result of massive specialization, modern experts operate in very confined close spaces. They formulate particular rules far from the level of theory. The main theories of science are known to them only at the textbook level. Nowadays, nobody can say: "I am the theory". With whom, then is it possible to discuss today on a broader theoretical level? How can a classical theory--for example, the membrane one--be changed or even disproved under these conditions? How can the "sons" with their narrow education catch sight of membrane theory defects? As a result, "global" theories have few critics and control. Due to specialization, we have lost the ability to work at the experimental level of biology within the correct or appropriate theoretical context. The scientific method in its classic form is now being rapidly eroded. A good case can be made for "Membrane Theory", to which we will largely refer throughout this article.

5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial.

BACKGROUND: The long-term outcome of an interventional strategy in patients with non-ST-elevation acute coronary syndrome is unknown. We tested whether an interventional strategy (routine angiography followed by revascularisation) was better than a conservative strategy (ischaemia-driven or symptom-driven angiography) over 5 years' follow-up. METHODS: In a multicentre randomised trial, 1810 patients (from 45 hospitals in England and Scotland, UK) with non-ST-elevation acute coronary syndrome were randomly assigned to receive an early intervention (n=895) or a conservative strategy (n=915) within 48 h of the index episode of cardiac pain. In each group, the aim was to provide the best medical treatment, and also to undertake coronary arteriography within 72 h in the interventional strategy with subsequent management guided by the angiographic findings. Analysis was by intention to treat and the primary outcome (composite of death or non-fatal myocardial infarction) had masked independent adjudication. RITA 3 has been assigned the International Standard Randomised Control Trial Number ISRCTN07752711. FINDINGS: At 1-year follow-up, rates of death or non-fatal myocardial infarction were similar. However, at a median of 5 years' follow-up (IQR 4.6-5.0), 142 (16.6%) patients with intervention treatment and 178 (20.0%) with conservative treatment died or had non-fatal myocardial infarction (odds ratio 0.78, 95% CI 0.61-0.99, p=0.044), with a similar benefit for cardiovascular death or myocardial infarction (0.74, 0.56-0.97, p=0.030). 234 (102 [12%] intervention, 132 [15%] conservative) patients died during follow-up (0.76, 0.58-1.00, p=0.054). The benefits of an intervention strategy were mainly seen in patients at high risk of death or myocardial infarction (p=0.004), and for the highest risk group, the odds ratio of death or non-fatal myocardial infarction was 0.44 (0.25-0.76). INTERPRETATION: In patients with non-ST-elevation acute coronary syndrome, a routine invasive strategy leads to long-term reduction in risk of death or non-fatal myocardial infarction, and this benefit is mainly in high-risk patients. The findings provide support for national and international guidelines in the need for more robust risk stratification in acute coronary syndrome.

The future role of surgery in ischaemic heart disease.

The ability to restore myocardial perfusion in ischaemic heart disease has been one of the triumphs of surgery. Alternative, less invasive catheter-based methods have now taken the lead as favoured treatment. The resultant threat to surgical practice, as well as societal and organisational issues that impact on the life of surgeons, have caused many to question the future role of surgery in ischaemic heart disease. In spite of general awareness of risk factors, there is little to suggest that coronary disease will soon disappear; rather, obesity and unfavourable life-style of many will continue to recruit further patients and, additionally, an epidemic of heart failure is anticipated. At the same time, rapid advance in knowledge of the underlying disease is opening the prospect for more effective intervention for unstable coronary plaque. Of great relevance to the surgeon are recent advances in knowledge and technology that will lead to gene and cell-based therapy for ischaemic heart disease. The ability to modify or augment activity of myocytes in heart failure, and to promote angiogenesis, offers hope for repair of ischaemically damaged hearts undreamed of only a few years ago. Tissue engineering, encompassing gene and cell-based therapy, holds promise of reconstruction of the myocardium and its vasculature. Temporary cardiovascular support to enable application of these techniques will very likely provide one role for surgery. More importantly, the need to ensure optimal anatomic and functional repair will surely give rise to a new generation of surgeons with much expanded scientific and technical support to draw upon, and will ensure an important role for surgery in ischaemic heart disease for decades to come.