Neoadjuvant Therapy in Early Breast Cancer:Treatment Considerations and Common Debates in Practice

Neoadjuvant treatment offers a number of benefits for patients with early breast cancer, and is an important option for consideration by multidisciplinary teams. Despite literature showing its efficacy, the use of neoadjuvant therapy varies widely. Here we discuss the clinical evidence supporting the use of neoadjuvant therapy in early stage breast cancer, including patient selection, monitoring response, surgery and radiotherapy considerations, with the aim of assisting multidisciplinary teams to determine patient suitability for neoadjuvant treatment

Regulatory capacity building and the governance of clinical stem cell research in China

While other works have explained difficulties in applying ‘international’ guidelines in the field of regenerative medicine in so-called low- and middle-income countries (LMICs) in terms of ‘international hegemony’, ‘political and ethical governance’ and ‘cosmopolitisation’, this article on stem cell regulation in China emphasises the particular complexities faced by large LMICs: the emergence of alternative regulatory arrangements made by stakeholders at a provincial level at home. On the basis of ethnographic and archival research of clinical stem cell research hubs, we have characterized six types of entrepreneurial ‘bionetworks’, each of which embodies a regulatory orientation that developed in interaction with China’s regulatory dilemmas. Rather than adopting guidelines from other countries, we argue that regulatory capacity building is more appropriately viewed as a relational concept, referring to the ability to develop regulatory requirements that can cater for different regulatory research needs on an international level and at home

Integrated care to address the physical health needs of people with severe mental illness : a rapid review

Background People with mental health conditions have a lower life expectancy and poorer physical health outcomes than the general population. Evidence suggests that this discrepancy is driven by a combination of clinical risk factors, socioeconomic factors and health system factors. Objective(s) To explore current service provision and map the recent evidence on models of integrated care addressing the physical health needs of people with severe mental illness (SMI) primarily within the mental health service setting. The research was designed as a rapid review of published evidence from 2013–15, including an update of a comprehensive 2013 review, together with further grey literature and insights from an expert advisory group. Synthesis We conducted a narrative synthesis, using a guiding framework based on nine previously identified factors considered to be facilitators of good integrated care for people with mental health problems, supplemented by additional issues emerging from the evidence. Descriptive data were used to identify existing models, perceived facilitators and barriers to their implementation, and any areas for further research. Findings and discussion The synthesis incorporated 45 publications describing 36 separate approaches to integrated care, along with further information from the advisory group. Most service models were multicomponent programmes incorporating two or more of the nine factors: (1) information sharing systems; (2) shared protocols; (3) joint funding/commissioning; (4) colocated services; (5) multidisciplinary teams; (6) liaison services; (7) navigators; (8) research; and (9) reduction of stigma. Few of the identified examples were described in detail and fewer still were evaluated, raising questions about the replicability and generalisability of much of the existing evidence. However, some common themes did emerge from the evidence. Efforts to improve the physical health care of people with SMI should empower people (staff and service users) and help remove everyday barriers to delivering and accessing integrated care. In particular, there is a need for improved communication between professionals and better information technology to support them, greater clarity about who is responsible and accountable for physical health care, and awareness of the effects of stigmatisation on the wider culture and environment in which services are delivered. Limitations and future work The literature identified in the rapid review was limited in volume and often lacked the depth of description necessary to acquire new insights. All members of our advisory group were based in England, so this report has limited information on the NHS contexts specific to Scotland, Wales and Northern Ireland. A conventional systematic review of this topic would not appear to be appropriate in the immediate future, although a more interpretivist approach to exploring this literature might be feasible. Wherever possible, future evaluations should involve service users and be clear about which outcomes, facilitators and barriers are likely to be context-specific and which might be generalisable

Implementing microbicides in low-income countries.

The magnitude of the global human immunodeficiency virus (HIV) epidemic is determined by women from lower income countries, specifically sub-Saharan Africa. Microbicides offer women who are unable to negotiate safe sex practices a self-initiated HIV prevention method. Of note, is its potential to yield significant public health benefits even with relatively conservative efficacy, coverage and user adherence estimates, making microbicides an effective intervention to invest scarce healthcare resources. Existing healthcare delivery systems provide an excellent opportunity to identify women at highest risk for infection and to also provide an access point to initiate microbicide use. Innovative quality improvement approaches, which strengthen existing sexual reproductive health services and include HIV testing, and linkages to care and treatment services, provide an opportunity to lay the foundations for wide-scale provision of microbicides. The potential to enhance health outcomes in women and infants and potentially affect rates of new HIV infection may soon be realised

An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving 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 (EBRT) over several weeks. Design: The TARGeted Intraoperative radioTherapy Alone (TARGIT-A) trial was a pragmatic, prospective, international, multicentre, non-inferiority, non-blinded, randomised (1 : 1 ratio) clinical trial. 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 which needed a reoperation to reopen the wound to give TARGIT as a delayed procedure. The risk-adapted approach meant that, in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, EBRT was recommended. Pragmatically, this reflected how TARGIT would be practised in the real world. Setting: Thirty-three centres in 11 countries. Participants: Women who were aged ≥ 45 years with unifocal invasive ductal carcinoma preferably ≤ 3.5 cm in size. Interventions: TARGIT within a risk-adapted approach and whole-breast EBRT. Main outcome measures: The primary outcome measure was absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary outcome measures included toxicity and breast cancer-specific and non-breast-cancer mortality. Results: In total, 3451 patients were recruited between March 2000 and June 2012. The following values are 5-year Kaplan–Meier rates for TARGIT compared with EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall [TARGIT 3.3%, 95% confidence interval (CI) 2.1% to 5.1% vs. EBRT 1.3%, 95% CI 0.7% to 2.5%; p = 0.04; Pnon-inferiority = 0.00000012] and in the prepathology stratum (n = 2298) when TARGIT was given concurrently with lumpectomy (TARGIT 2.1%, 95% CI 1.1% to 4.2% vs. EBRT 1.1%, 95% CI 0.5% to 2.5%; p = 0.31; Pnon-inferiority = 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 (TARGIT 5.4%, 95% CI 3.0% to 9.7% vs. EBRT 1.7%, 95% CI 0.6% to 4.9%; p = 0.069; Pnon-inferiority = 0.06640]. The local recurrence-free survival was 93.9% (95% CI 90.9% to 95.9%) when TARGIT was given with lumpectomy compared with 92.5% (95% CI 89.7% to 94.6%) for EBRT (p = 0.35). In a planned subgroup analysis, progesterone receptor (PgR) status was found to be the only predictor of outcome: hormone-responsive patients (PgR positive) had similar 5-year local recurrence with TARGIT during lumpectomy (1.4%, 95% CI 0.5% to 3.9%) as with EBRT (1.2%, 95% CI 0.5% to 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 (TARGIT 2.6%, 95% CI 1.5% to 4.3% vs. EBRT 1.9%, 95% CI 1.1% to 3.2%; p = 0.56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1.4%, 95% CI 0.8% to 2.5% vs. 3.5%, 95% CI 2.3% to 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 (3.9%, 95% CI 2.7% to 5.8% vs. 5.3%, 95% CI 3.9% to 7.3%; p = 0.099]. Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar quality-adjusted life-years, had a positive incremental net monetary benefit that was borderline statistically significantly different from zero and had a probability of \u3e 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 in the UK by £8–9.1 million each year. This does not include environmental, patient and societal costs. Limitations: The number of local recurrences is small but the number of events for local recurrence-free survival is not as small (TARGIT 57 vs. EBRT 59); occurrence of so few events (\u3c 3.5%) also implies that both treatments are effective and any difference is unlikely to be large. Not all 3451 patients were followed up for 5 years; however, more than the number of patients required to answer the main trial question (n = 585) were followed up for \u3e 5 years. Conclusions: For patients with breast cancer (women who are aged ≥ 45 years with hormone sensitive invasive ductal carcinoma that is up to 3.5 cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than and less expensive than postoperative EBRT. Future work: The analyses will be repeated with longer follow-up. Although this may not change the primary result, the larger number of events may confirm the effect on overall mortality and allow more detailed subgroup analyses. The TARGeted Intraoperative radioTherapy Boost (TARGIT-B) trial is testing whether or not a tumour bed boost given intraoperatively (TARGIT) boost is superior to a tumour bed boost given as part of postoperative EBRT. Trial registration: Current Controlled Trials ISRCTN34086741 and ClinicalTrials.gov NCT00983684. Funding: University College London Hospitals (UCLH)/University College London (UCL) Comprehensive Biomedical Research Centre, UCLH Charities, Ninewells Cancer Campaign, National Health and Medical Research Council and German Federal Ministry of Education and Research (BMBF). From September 2009 this project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 73. See the NIHR Journals Library website for further project information

The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies

Background: Shedding of Salmonella Typhi or Paratyphi in the stool or urine leads to contamination of food or water, which is a prerequisite for transmission of enteric fever. Currently, there are limited data on the effect of vaccination or prior exposure on stool shedding. Methods: Six Salmonella Typhi or Paratyphi human challenge studies were conducted between 2011 and 2017. Participants were either unvaccinated or vaccinated with 1 of 4 vaccines: Vi-polysaccharide (Vi-PS), Vi-tetanus-toxoid conjugate vaccine (Vi-TT), live oral Ty21a vaccine, or an experimental vaccine (M01ZH09). Daily stool cultures were collected for 14 days after challenge. Results: There were 4934 stool samples collected from 430 volunteers. Participants who received Vi-PS or Vi-TT shed less than unvaccinated participants (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.15-0.77; P = .010 and OR, 0.41; 95% CI, 0.19-0.91, P = .029 for Vi-PS and Vi-TT, respectively). Higher anti-Vi immunoglobulin G titers were associated with less shedding of S. Typhi (P < .0001). A nonsignificant reduction in shedding was associated with Ty21a vaccine (OR, 0.57; 95% CI, 0.27-1.20; P = .140). Individuals previously exposed to S. Typhi shed less than previously unexposed individuals (OR, 0.30; 95% CI, 0.1-0.8; P = .016). Shedding of S. Typhi was more common than S. Paratyphi. Conclusions: Prior vaccination with Vi vaccines, or natural infection, reduces onward transmission of S. Typhi. Field trials of Vi-TT should be designed to detect indirect protection, reflecting the consequence of reduced stool shedding observed in the human challenge model

Surgical wounds healing by secondary intention: characterising and quantifying the problem, identifying effective treatments, and assessing the feasibility of conducting a randomised controlled trial of negative pressure wound therapy versus usual care

Background: Most surgical incisions heal by primary intention (i.e. wound edges are apposed with sutures, clips or glue); however some heal by secondary intention (i.e. the wound is left open and heals by formation of granulation tissue). There is, however, a lack of evidence regarding the epidemiology, management, and impact on patients’ quality of life of these surgical wounds healing by secondary intention (SWHSI), resulting in uncertainty regarding effective treatments and difficulty in planning care and research. Objectives: To derive a better understanding of the nature, extent, costs, impact and outcomes of SWHSI, effective treatments and the value and nature of further research. Design: Cross-sectional survey; inception cohort; cost-effectiveness and value of implementation analyses; qualitative interviews; and a pilot, feasibility randomised controlled trial (RCT). Setting: Acute and community care settings in Leeds and Hull, Yorkshire, UK. Participants: Adults with (or for qualitative interviews, patients or practitioners with previous experience of) a SWHSI. Inclusion criteria varied between the individual Workstreams. Interventions: The pilot, feasibility RCT compared negative pressure wound therapy (NPWT) – a device applying a controlled vacuum to a wound via a dressing - with Usual Care (no NPWT). Results: Survey data estimated that treated SWHSI have a point prevalence of 4.1 per 10,000 population (95% CI: 3.5 to 4.7). SWHSI most frequently occurred following colorectal surgery (n=80, 42.8% - Cross-sectional survey, n=136, 39.7% - Inception cohort), and were often planned before surgery (n=89, 47.6% - Survey, n=236, 60.1% - Cohort). Wound care was frequently delivered in community settings (n=109, 58.3%) and most patients (n=184, 98.4%) received active wound treatment. Cohort data identified hydrofibre dressings (n=259, 65.9%) as the most common treatment, although 29.3% (n=115) participants used NPWT at some time during the study. SWHSI healing occurred in 81.4% (n=320) of participants at a median of 86 days (95% CI: 75 to 103). Baseline wound area (p=<0.01), surgical wound contamination (determined during surgery) (p=0.04) and wound infection at any time (p=<0.01) (i.e. at baseline or post-operatively) were found to be predictors of prolonged healing. Econometric models, using observational, cohort study data, identified that with little uncertainty, that NPWT treatment is more costly and less effective than standard dressing treatment for the healing of open surgical wounds: Model A (ordinary least squares with imputation): Effectiveness: 73 days longer than those who did not receive NPWT (95% Credible Interval (CrI): 33.8 to 112.8); Cost Effectiveness (Associated incremental quality adjusted life years): -0.012 (SE 0.005) (Observables); -0.008 (SE 0.011) (Unobservables) , Model B (Two Stage Model – Logistic and linear regression): Effectiveness: 46 days longer the those who did not receive NPWT (95% CrI: 19.6 to 72.5); Cost Effectiveness (Associated incremental quality adjusted life years): -0.007 (Observables) and -0.027 (Unobservables) (SE 0.017). Patient interviews (n=20) identified initial reactions to SWHSI of shock and disbelief. Impaired quality of life characterised the long healing process, with particular impact on daily living for patients with families or in paid employment. Patients were willing to try any treatment promising wound healing. Health professionals (n=12) had variable knowledge of SWHSI treatments, and frequently favoured NPWT despite the lack of robust evidence, The pilot, feasibility RCT screened 248 patients for eligibility and subsequently recruited and randomised 40 participants to receive NPWT or Usual Care (no NPWT). Data indicated that it was feasible to complete a full RCT to provide definitive evidence for the effectiveness of NPWT as a treatment for SWHSI. Key elements and recommendations for a larger RCT were identified. Limitations: This research programme was conducted in a single geographical area (Yorkshire and the Humber, UK) and local guidelines and practices may have affected treatment availability and so may not represent UK wide treatment choices. A wide range of wound types were included, however, some wound types may be underrepresented meaning this research may not represent the overall SWHSI population. The lack of RCT data on the relative effects of NPWT in SWHSI resulted in much of the economic modelling being based on observational data. Observational data, even with adjustment, does not negate the potential for unresolved confounding to affect the results. This may reduce confidence in the conclusions drawn and may lead to calls for definitive evidence from an RCT. Conclusions: This research has provided new information regarding the nature, extent, costs, impacts and outcomes of SWHSI, treatment effectiveness and the value and nature of future research; addressing previous uncertainties regarding the problem of SWHSI. Aspects of our research indicate that NPWT is more costly and less effective than standard dressing for the healing of open surgical wounds. However, because this conclusion is based solely on observational data it may be affected by unresolved confounding. Should a future RCT be considered necessary, its design should reflect careful consideration of the findings of this programme of research