Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

Sample size determination in bioequivalence studies using statistical assurance.

AIMS: Bioequivalence (BE) trials aim to demonstrate that the 90% confidence interval of the T/R-ratio of the pharmacokinetic metrics between two formulations (test [T] and reference [R]) of a drug is fully included in the acceptance interval [0.80, 1.25]. Traditionally, the sample size of BE trials is based on a power calculation based on the intrasubject variability coefficient of variation (CV) and the T/R-ratio of the metrics. Since the exact value of the T/R-ratio is not known prior to the trial, it is often assumed that the difference between the treatments does not exceed 5%. Hence, uncertainty about the T/R-ratio is expressed by using a fixed value for the sample size calculation. We propose to characterise the uncertainty about the T/R-ratio by a (normal) distribution for the log(T/R-ratio), with an assumed mean of  log Î¸ = 0.00 (i.e. θ = 1.00) and a standard deviation σu , which quantifies the uncertainty. Evaluating this distribution leads to the statistical assurance of the BE trial. METHODS: The assurance of a clinical trial can be derived by integrating the power over the distribution of the input parameters, in this case, the assumed distribution of the log(T/R)-ratio. Because it is an average power, the assurance can be interpreted as a measure of the probability of success that does not depend on a specific assumed value for the log(T/R)-ratio. The relationship between power and assurance will be analysed by comparing the numerical outcomes. RESULTS: Using the assurance concept, values of the standard deviation for the distribution of potential log(T/R)-ratios can be chosen to reflect the magnitude of uncertainty. For most practical cases (i.e. when 0.95 ≤ Î¸ ≤ 1.05), the sample size is not, or only slightly, changed when σ = |log(θ)|. CONCLUSION: The advantage of deriving the assurance for BE trials is that uncertainty is directly expressed as a parameter of variability.

Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer.

Background: Selection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer. Patients and methods: Eighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI. Results: Of the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival. Conclusions: Cancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

Sternal Reconstruction with the Omental Flap-Acute and Late Complications, Predictors of Mortality, and Quality of Life.

BACKGROUND: The omental flap is a reliable flap for the coverage of sternal defects. However, little is known about the predictors of mortality and the long-term outcome in such patients. METHODS: We, therefore, performed a retrospective study from 2002 to 2013, including all patients who underwent sternal reconstruction with the omental flap. RESULTS: A total of 50 patients were identified and mean follow-up was 3.8 years. Patient data was collected from the charts and 14 patients were available for telephone interviews. The majority of patients suffered from deep sternal wound infections. There was no complete flap loss and an overall success rate was 96%. In-hospital mortality was 14% and overall survival over follow-up was 50%. Significant predictors of mortality were age > 65, American Society of Anesthesiologists' status, defect size, prolonged ventilation, and the need for tracheotomy. Postoperative quality of life was reduced compared with other cohorts, especially with regard to bodily function. Pain was also a major problem for most patients along with herniation. CONCLUSION: The omental flap is a safe option even in patients with severe comorbidities. However, based on the data in this study, we would recommend the omental flap as a reserve option rather than first-line treatment for sternal defects.

Comprehensive geriatric assessment in 326 older women with early breast cancer.

BACKGROUND: One-third of new early breast cancer diagnoses occur in women over 70 years old. However, older women are less likely to receive radical curative treatments. This study prospectively evaluated a cohort of older women using a Comprehensive Geriatric Assessment (CGA) to determine whether fitness explained the apparent under-treatment in this patient group. METHODS: In this multi-centre prospective study, patients aged ⩾70 years with Stages I-III breast cancer underwent a pretreatment baseline CGA consisting of eight assessment tools. Patients were defined as 'fit' if they had normal score in seven out of eight of the assessment tools. 'High risk' patients were defined as those with grade 3, ER negative, HER2 positive, or node positive breast cancer. RESULTS: Data on 326 patients were available for full analysis. The median age was 77 years. In all, 182 (56%) of the total population were defined as high risk, with 49%, 61% and 53% of those in the 70-74, 75-84 and ⩾85 years age groups respectively having high risk tumours. A total of 301 patients had sufficient CGA records of whom 131 (44%) were reported as fit, with 34%, 54% and 12% of them in the 70-74, 75-84 and ⩾85 years age groups respectively. More fit than unfit patients underwent primary breast surgery (100% vs 91%, P=0.0002), axillary surgery (92% vs 84%, P=0.0340), and adjuvant chemotherapy for high-risk disease (51% vs 20%, P=0.0001). Rates of adjuvant radiotherapy after wide local excision were not significantly different (88% vs 90% respectively, P=0.8195). CONCLUSIONS: In this study, all women ⩾70 years deemed fit by CGA underwent primary surgery. Nearly 50% of fit women with high-risk disease did not receive adjuvant chemotherapy suggesting under treatment in this group.

Phase I trial outcomes in older patients with advanced solid tumours.

BACKGROUND: This study had two aims: (a) to test the hypothesis that advanced age is associated with lower levels of tolerability and clinical benefit to experimental Phase I trial agents; (b) to assess the validity of the Royal Marsden Hospital (RMH) prognostic score as a patient selection tool in older patients. METHODS: Clinico-pathological characteristics and treatment outcomes of all patients treated consecutively from 2005 to 2009 in phase I trials at the RMH were recorded. All toxicity and clinical outcome data were compared between patients aged below and above 65 years of age. RESULTS: One thousand and four patients were treated in 30 Phase I trials, with 315 (31%) patients aged 65 years and older. Grade 3-5 toxicities (22.8% vs 24.8% (P=0.52)), trial discontinuation (6% vs 4%; P=0.33), and dose interruptions (8.0% vs 8.0% (P=0.96)) were observed at similar rates in patients below and above 65 years of age, respectively. The overall response rate 5.2% vs 4.1%, progression-free survival (PFS) 1.9 vs 3.5 months and clinical benefit rate (CBR) at 6 months 15.2% vs 14.3% were comparable in both groups. To avoid bias due to the potential therapeutic benefit of abiraterone, comparisons were repeated excluding prostate cancer patients with similar results (ORR 4.6% vs 4%, PFS 1.8 vs 3.0 months, CBR at 6 months 13.5% vs 9.5%). Multivariate analysis indicated that the previously identified RMH score (including albumin and lactate dehydrogenase levels) was an accurate predictor of outcome. CONCLUSIONS: Phase I clinical trials should be considered in patients with advanced cancers regardless of age, as older patients who enter these have similar safety and efficacy outcomes as their younger counterparts. The RMH prognostic score can assist in the selection of suitable older patients.

[Options for reconstructive surgery of the thoracic wall]. / Plastisch-chirurgische Möglichkeiten der Thoraxwandrekonstruktion.

The integrity of the thoracic wall and therefore the protection of the thoracic organs is paramount for survival. This integrity can be compromised by various factors, be it tumours, wound-healing disorders or injuries. An adequate surgical therapy for these entities often requires (partial) resections of the thoracic wall resulting in a loss of its protective function. A safe and timely reconstruction of the thoracic wall is therefore mandatory and can be achieved by means of reconstructive procedures. This article therefore aims to illustrate such reconstructive procedures utilising our own clinical cases while also giving a review of the literature in order to construct an algorithm for the reconstruction procedure.

[Plastic reconstructive options for chronic pilonidal disease]. / Plastische Rekonstruktionsmöglichkeiten beim chronischen Sinus pilonidalis.

INTRODUCTION: Chronic pilonidal disease represents an infectious disease of the gluteal cleft that often requires surgical resection. AIM: In this article, several plastic-surgical reconstructions are presented. METHODS AND RESULTS: Based on our experience and the current literature, different plastic surgical reconstructive methods are presented and discussed. Thorough debridement including sinus tracts and follicles represents an important step in the treatment algorithm. Subsequently, wide defects may remain that can require reconstructive surgery with local flaps. These may include a Karydakis procedure, Limberg transposition flap, V-Y advancement or rotation flap. CONCLUSION: After thorough debridement and adherence to plastic surgical principles, sufficient reconstructions can be obtained with the presented methods.

[Reconstruction options for pelvic defects after abdominal exenteration]. / Defektdeckungsoptionen nach Eviszeration.

Soft tissue defects after oncological pelvic exenteration still represent a significant problem. Because of the anatomic and functional peculiarities, the reconstruction of defects in the pelvic region is challenging and requires a differentiated approach. In this paper, current strategies and options for reconstructive procedures are presented considering preoperative conditions and factors related to surgical planning. The relevance of interdisciplinary collaboration and the resulting benefits are set out. The inclusion of the plastic surgeon already in the preoperative planning of tumour resection is recommended.

Indirect bioequivalence assessment using network meta-analyses.

AIMS: For market approval, new drug formulations (test) must demonstrate bioequivalence (BE) to at least one approved formulation (reference). If several formulations of a drug are already on the market, one might have to show BE to more than one reference formulation. Similarly, if several test formulations have shown BE to a reference formulation, it will be of interest whether the test formulations are bioequivalent to each other. METHODS: An enhanced statistical model to assess BE indirectly through a network meta-analysis is provided. Statistical properties of a parallel and a bridging approach are derived, in particular the relative statistical efficiency of the two approaches. The analysis is illustrated using individual subject data from two 3×3 crossover trials of metformin formulations, which have one of the formulations in common. RESULTS: The parallel estimate of relative bioavailability is confounded with between-trial differences, while the bridging estimate is not. The standard errors of the formulation differences using the bridging approach are smaller than the standard errors using the parallel approach if the within-subject correlation in each trial of the network is larger than 0.5. This is the condition for a crossover trial to be more efficient than a parallel trial, and thus is usually fulfilled in pharmacokinetic crossover trials. CONCLUSIONS: Indirect BE assessment offers the opportunity to efficiently determine the relative bioavailability of drug formulations that have not been studied in the same randomized BE trial. The methodology developed here allows estimating formulation differences across a larger network.

[Surgical treatment of extravasation injuries]. / Chirurgische Behandlung von Paravasaten.

OBJECTIVE: Extravasations account for most iatrogenic injuries. The aim of the study was to analyse the results of surgery in patients with extravasations and to draw conclusions for future treatment. MATERIALS AND METHODS: 24 patients with soft-tissue defects after extravasations were treated between 1999 and 2009 in our hospital. The cases were analysed retrospectively. We looked at the drugs causing tissue necrosis and the localisation in relation to the number of interventions and reconstruction complexity. RESULTS: In 83 % (n = 20) of cases tissue necrosis was caused by chemotherapeutic agents, in 8 % (n = 2) by contrast mediums and in 4 % (n = 1) by antibiotics and insulin. 70 % of the cases involved the upper extremity, in 30 % the thoracic wall was affected. 38 % of the extravasations occurred over venous access ports. In mean 2 ±â€Š1.5 interventions were necessary for defect coverage. Two patients died as a direct result of the extravasations, one due to sepsis originating from an infected necrosis area and one due to right-heart failure with prior pulmonary damage. CONCLUSION: Most extravasations can be treated without surgery. In cases of toxic extravasations or pressure-caused ischaemia rapid surgical intervention is necessary to prevent the necrosis progressing to deeper tissue layers.

Association of post-operative ctDNA detection with outcomes of patients with early breast cancers.

BACKGROUND: In early breast cancer (EBC) patients, we aimed to determine whether circulating tumor DNA (ctDNA) analysis following primary surgery, before systemic therapy, identified molecular residual disease and was associated with risk of relapse and relapse-free survival (RFS). METHODS: Plasma was collected, retrospectively, before surgery, 1-14 weeks post-operatively, and before adjuvant therapy, and in a subset of patients after adjuvant therapy. A personalized, tumor-informed, multiplex PCR next generation sequencing assay (Signatera™) was used for ctDNA detection and quantification. The primary objective was to compare RFS and distant recurrence-free survival (DRFS) in patients with detected versus non-detected ctDNA. RESULTS: A total of 48 patients with EBC (median age 50.5 years) [34 hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), 5 HER2+, 9 triple-negative breast cancer) were included. ctDNA was detected in 64.5% (20/31) of patients before surgery, and 35.4% (17/48) after surgery. ctDNA detection before surgery was associated with tumor grade (P = 0.019), ctDNA detection after surgery was associated with receptor subtype (P = 0.01). Patients with ctDNA detected after surgery had worse DRFS [hazard ratio = 5.5, 95% confidence interval (CI) 1.1-28.5, P = 0.04]. RFS in patients with ctDNA detected after surgery was worse than in those with lack of ctDNA detection, although not statistically significant (hazard ratio = 3.7, 95% CI 0.9-15.7, P = 0.073). Patients with ctDNA detected preoperatively or post-operatively had a trend towards worse RFS (hazard ratio = 7.8, 95% CI 0.9-63.7, P = 0.05) and DRFS (hazard ratio = 6.8, 95% CI 0.8-57, P = 0.07) compared with those with ctDNA undetected at both timepoints. ctDNA detection anticipated clinical relapse with a median lead time of 16 months. CONCLUSIONS: In patients with treatment-naive EBC, ctDNA is detectable after surgery. The absence of ctDNA at a single post-surgical timepoint is associated with improved DRFS, supporting the development of future trials studying de-escalation of systemic therapy.

Adjuvant chemotherapy in elderly women with breast cancer (AChEW): an observational study identifying MDT perceptions and barriers to decision making.

BACKGROUND: As few older women with breast cancer receive adjuvant chemotherapy, we examined the barriers and perceptions of 24 UK NHS multidisciplinary breast cancer teams to offering this treatment to women ≥70 years. PATIENTS AND METHODS: Questionnaires regarding 803 patients with newly diagnosed breast cancer were completed by specialist teams following discussion or outpatient consultation. RESULTS: Of 803 patients, 116 (14%), all <85 years, were offered chemotherapy and 66 (8%) received it. Only 94 of 309 (30%) of women with high-risk disease were offered chemotherapy, and 53 (17%) received it. The most common reasons for not offering chemotherapy were 'other treatments more appropriate' (usually patients with ER-positive tumours) or 'benefits too small' (63% and 54% of patients, respectively). Co-morbidities and frailty were less common reasons but became more frequent with increasing age. Recommendations regarding chemotherapy were made in the absence of documented HER2 and performance status in 29% and 33%, respectively. Treatment offered varied considerably between cancer centres. CONCLUSIONS: National guidelines need development describing the minimally acceptable data for decision making, incorporating objective fitness measures and specific treatment recommendations. Such guidelines will require educational support for implementation but should standardise care and improve chemotherapy uptake in this increasing population of older patients.

Breast cancer in older patients: national cancer registry data.

BACKGROUND: The population in developed countries is ageing. Cancer is a disease of ageing, and this is likely to lead to an increase in the number of older patients diagnosed with cancer with significant implications for resource allocation and research priorities. Breast Cancer in older women presents a number of challenges. AIMS: This paper describes the trends in number of new breast cancer registrations in older patients over the last 38 years. MATERIALS AND METHODS: Data were extracted from the Office for National Statistics describing new registrations of breast cancer for patients aged 65 or over, from 1971 to 2009. RESULTS: The number of diagnoses of breast cancer across all age groups increased from 17,694 in 1971 to 40,260 in 2009. The proportion of diagnoses of breast cancer made in women aged 65 and over increased from 42% in 1971 to 45% in 2009. The proportion of diagnoses of breast cancer made in women aged 70 and over increased from 30% in 1971 to 33% in 2009. The number of cases of breast cancer registered in patients aged 65 and over has increased from 7376 in 1971 to 17,934 in 2009. DISCUSSION: The reasons for the large increases in the number of older women diagnosed with breast cancer, and older women represent an increasing proportion of those diagnosed are multi-factorial. These include the ageing of the population, obesity, alcohol consumption, use of hormone replacement therapy and reproductive factors, improved breast cancer awareness and the UK National Screening Programme. Clinician attitudes and behaviours and also cancer registries striving to increase their levels are other causes. The effective management of these women will present constraints to service delivery and should therefore influence research priorities. CONCLUSION: This short communication reports on the increasing registration of breast cancer in the older age group which will present a number of challenges for the future.

Handley's Thread Lymphangioplasty Vs. BioBridgetm Collagen Matrix for Lymphedema Therapy - Old Wine in New Bottles?

Lymphangioplasty is a technique of reconstructive lymphatic surgery where subcutaneous lymphatic neocollectors are created, using surgical threads, nanofibrillar collagen threads, plastic tubes or autologous tissue flaps. The history and success rates of these techniques are outlined and a classification for lymphangioplasty techniques is proposed. The use of absorbable surgical threads is suggested for modern attempts of thread lymphangioplasties. The results of such a thread lymphangioplasty should be compared with that of implanted nanofibrillar collagen threads or plastic tubes in order to evaluate whether the technique itself or the material used is responsible for the therapeutic success.

The Fate of Implanted BioBridgetm Collagen Matrix - Findings in Histology, Scanning, and Transmission Electron Microscopy.

The technique of lymphangioplasty or capillary thread drainage was historically performed with subcutaneously implanted surgical threads. It has recently been revived by introducing a thread-like aligned nanofibrillar collagen matrix (BioBridgetm). These collagen threads consitute subcutaneous neocollectors along which guided lymphangiogenesis is said to occur secondarily. We present for the first time a tissue examination of a 10-month implanted BioBridgetm sample with surrounding tissue from a human subject by histology, scanning and transmission electron microscopy.

Geographical Variation in Underlying Social Deprivation, Cardiovascular and Other Comorbidities in Patients with Potentially Curable Cancers in England: Results from a National Registry Dataset Analysis.

AIMS: To describe the prevalence of cardiovascular disease (CVD), multiple comorbidities and social deprivation in patients with a potentially curable cancer in 20 English Cancer Alliances. MATERIALS AND METHODS: This National Registry Dataset Analysis used national cancer registry data and CVD databases to describe rates of CVD, comorbidities and social deprivation in patients diagnosed with a potentially curable malignancy (stage I-III breast cancer, stage I-III colon cancer, stage I-III rectal cancer, stage I-III prostate cancer, stage I-IIIA non-small cell lung cancer, stage I-IV diffuse large B-cell lymphoma, stage I-IV Hodgkin lymphoma) between 2013 and 2018. Outcome measures included observation of CVD prevalence, other comorbidities (evaluated by the Charlson Comorbidity Index) and deprivation (using the Index of Multiple Deprivation) according to tumour site and allocation to Cancer Alliance. Patients were allocated to CVD prevalence tertiles (minimum: <33.3rd percentile; middle: 33.3rd to 66.6th percentile; maximum: >66.6th percentile). RESULTS: In total, 634 240 patients with a potentially curable malignancy were eligible. The total CVD prevalence for all cancer sites varied between 13.4% (CVD n = 2058; 95% confidence interval 12.8, 13.9) and 19.6% (CVD n = 7818; 95% confidence interval 19.2, 20.0) between Cancer Alliances. CVD prevalence showed regional variation both for male (16-26%) and female patients (8-16%) towards higher CVD prevalence in northern Cancer Alliances. Similar variation was observed for social deprivation, with the proportion of cancer patients being identified as most deprived varying between 3.3% and 32.2%, depending on Cancer Alliance. The variation between Cancer Alliance for total comorbidities was much smaller. CONCLUSION: Social deprivation, CVD and other comorbidities in patients with a potentially curable malignancy in England show significant regional variations, which may partly contribute to differences observed in treatments and outcomes.

Imprints from genetic drift and mutation imply relative divergence times across marine transition zones in a pan-European small pelagic fish (Sprattus sprattus).

Geographic distributions of most temperate marine fishes are affected by postglacial recolonisation events, which have left complex genetic imprints on populations of marine species. This study investigated population structure and demographic history of European sprat (Sprattus sprattus L.) by combining inference from both mtDNA and microsatellite genetic markers throughout the species' distribution. We compared effects from genetic drift and mutation for both genetic markers in shaping genetic differentiation across four transition zones. Microsatellite markers revealed significant isolation by distance and a complex population structure across the species' distribution (overall θ(ST)=0.038, P<0.01). Across transition zones markers indicated larger effects of genetic drift over mutations in the northern distribution of sprat contrasting a stronger relative impact of mutation in the species' southern distribution in the Mediterranean region. These results were interpreted to reflect more recent divergence times between northern populations in accordance with previous findings. This study demonstrates the usefulness of comparing inference from different markers and estimators of divergence for phylogeographic and population genetic studies in species with weak genetic structure, as is the case in many marine species.

System resilience and neighbourhood action on social determinants of health inequalities: an English Case Study.

AIMS: This article seeks to make the case for a new approach to understanding and nurturing resilience as a foundation for effective place-based co-produced local action on social and health inequalities. METHODS: A narrative review of literature on community resilience from a public health perspective was conducted and a new concept of neighbourhood system resilience was developed. This then shaped the development of a practical programme of action research implemented in nine socio-economically disadvantaged neighbourhoods in North West England between 2014 and 2019. This Neighbourhood Resilience Programme (NRP) was evaluated using a mixed-method design comprising: (1) a longitudinal household survey, conducted in each of the Neighbourhoods For Learning (NFLs) and in nine comparator areas in two waves (2015/2016 and 2018/2019) and completed in each phase by approximately 3000 households; (2) reflexive journals kept by the academic team; and (3) semi-structured interviews on perceptions about the impacts of the programme with 41 participants in 2019. RESULTS: A difference-in-difference analysis of household survey data showed a statistically significant increase of 7.5% (95% confidence interval (CI), 1.6 to 13.5) in the percentage of residents reporting that they felt able to influence local decision-making in the NFLs relative to the residents in comparator areas, but no effect attributable to the NRP in other evaluative measures. The analysis of participant interviews identified beneficial impacts of the NRP in five resilience domains: social connectivity, cultural coherence, local decision-making, economic activity, and the local environment. CONCLUSION: Our findings support the need for a shift away from interventions that seek solely to enhance the resilience of lay communities to interventions that recognise resilience as a whole systems phenomenon. Systemic approaches to resilience can provide the underpinning foundation for effective co-produced local action on social and health inequalities, but they require intensive relational work by all participating system players.