Surgical decisions in older women with early breast cancer: patient and disease factors.

BACKGROUND: Studies reporting lower rates of surgery for older women with early invasive breast cancer have focused on women with oestrogen receptor (ER)-positive tumours. This study examined the factors that influence receipt of breast surgery in older women with ER-positive and ER-negative early invasive breast cancer . METHODS: Women aged 50 years or above with unilateral stage 1-3A early invasive breast cancer diagnosed in 2014-2017 were identified from linked English and Welsh cancer registration and routine hospital data sets. Logistic regression analysis was used to evaluate the influence of tumour and patient factors on receipt of surgery. RESULTS: Among 83 188 women, 86.8 per cent had ER-positive and 13.2 per cent had ER-negative early invasive breast cancer. These proportions were unaffected by age at diagnosis. Compared with women with ER-negative breast cancer, a higher proportion of women with ER-positive breast cancer presented with low risk tumour characteristics: G1 (20.0 versus 1.5 per cent), T1 (60.8 versus 44.2 per cent) and N0 (73.9 versus 68.8 per cent). The proportions of women with any recorded co-morbidity (13.7 versus 14.3 per cent) or degree of frailty (25 versus 25.8 per cent) were similar among women with ER-positive and ER-negative disease respectively. In women with ER-positive early invasive breast cancer aged 70-74, 75-79 and 80 years or above, the rate of no surgery was 5.6, 11.0 and 41.9 per cent respectively. Among women with ER-negative early invasive breast cancer, the corresponding rates were 3.8, 3.7 and 12.3 per cent. The relatively lower rate of surgery for ER-positive breast cancer persisted in women with good fitness. CONCLUSION: The reasons for the observer differences should be further explored to ensure consistency in treatment decisions.

Breast Angiosarcoma Surveillance Study: UK national audit of management and outcomes of angiosarcoma of the breast and chest wall.

BACKGROUND: Breast angiosarcomas are rare tumours of vascular origin. Secondary angiosarcoma occurs following radiotherapy for breast cancer. Angiosarcomas have high recurrence and poor survival rates. This is concerning owing to the increasing use of adjuvant radiotherapy for the treatment of invasive breast cancer and ductal cancer in situ (DCIS), which could explain the rising incidence of angiosarcoma. Outcome data are limited and provide a poor evidence base for treatment. This paper presents a national, trainee-led, retrospective, multicentre study of a large angiosarcoma cohort. METHODS: Data for patients with a diagnosis of breast/chest wall angiosarcoma between 2000 and 2015 were collected retrospectively from 15 centres. RESULTS: The cohort included 183 patients with 34 primary and 149 secondary angiosarcomas. Median latency from breast cancer to secondary angiosarcoma was 6 years. Only 78.9 per cent of patients were discussed at a sarcoma multidisciplinary team meeting. Rates of recurrence were high with 14 of 28 (50 per cent ) recurrences in patients with primary and 80 of 124 (64.5 per cent ) in those with secondary angiosarcoma at 5 years. Many patients had multiple recurrences: total of 94 recurrences in 162 patients (58.0 per cent). Median survival was 5 (range 0-16) years for patients with primary and 5 (0-15) years for those with secondary angiosarcoma. Development of secondary angiosarcoma had a negative impact on predicted breast cancer survival, with a median 10-year PREDICT prognostic rate of 69.6 per cent, compared with 54.0 per cent in the observed cohort. CONCLUSION: A detrimental impact of secondary angiosarcoma on breast cancer survival has been demonstrated. Although not statistically significant, almost all excess deaths were attributable to angiosarcoma. The increased use of adjuvant radiotherapy to treat low-risk breast cancer and DCIS is a cause for concern and warrants further study.

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).

The need for triple assessment and predictors for diagnosis of breast cancer in patients <40 years of age.

AIM: To assess the safety of selective use of triple assessment with omission of radiological assessment proposed in patients <40-years old. MATERIALS AND METHODS: Data were collected retrospectively for all patients seen in the one-stop breast clinic between January 2014 and August 2015. Demographics, symptoms, diagnostics, and treatment details were recorded. Subgroup and logistic regression analysis was performed to identify predictors for breast cancer. RESULTS: Of the 3,305 patients included, 95.6% (n=3,161) were first-time referrals. 57.6% (n=1,903) had a breast lump, and 4% (n=133) had a high-risk family history; 75.6% (n=2,499) underwent imaging and 16.7% (n=552) underwent a biopsy. The median age was 29 years (interquartile range [IQR]=25-34). Breast cancer was diagnosed in 29 cases (0.88%) and 3.2% (n=105) had surgery. Median referral-to-diagnosis time was 13 days (IQR=9-14) and referral-to-surgery time was 44 days (IQR=34-95). Patients with breast cancer were significantly older (33 versus 28 years, p=0.016). All patients were first-time referrals. Most patients had a breast lump with low suspicion on clinical examination and breast cancer identified on imaging. Time-to-diagnosis (12 versus 14 days, p=0.017) and time-to-surgery (37 versus 67 days, p=0.012) was significantly shorter in the breast cancer group. Comparative older age (odds ratio [OR]=1.08, 95% confidence interval [CI]: 1.01-1.15) and breast lump (OR=11.43,95% CI: 2.72-48.07) were the only significant predictors of cancer on uni/multivariate regression. CONCLUSIONS: Triple assessment is also the best practice for all patients in the younger age group. This cohort should not be treated any differently regarding one-stop clinic infrastructure as the cancers detected were not clinically malignant. Missed cancers in this age group would have significant personal, clinical, and legal consequences.

Neoadjuvant chemotherapy with MRI monitoring for breast cancer.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly being offered to patients with breast cancer. No survival benefit has been demonstrated for NACT, but it may serve to reduce tumour size and improve prognosis through the attainment of a pathological complete response (pCR). The role and mode of MRI monitoring during NACT remain unclear. METHODS: Patients managed with NACT at a UK centre over 7 years were studied using a prospectively maintained database, which also included details of MRI. Clinicopathological and radiological predictors of NACT response were analysed in a univariable setting and survival analysis was undertaken using the Kaplan-Meier method. RESULTS: A total of 278 patients underwent surgery following NACT, of whom 200 (71·9 per cent) had residual invasive disease and 78 (28·1 per cent) achieved a pCR. Attaining a pCR improved survival significantly compared with that of patients with residual invasive disease (mean 77·1 versus 66·0 months; P = 0·004) and resulted in significantly fewer recurrences (6·0 versus 24·3 per cent; P = 0·001). The pCR rate varied significantly among molecular subgroups of breast cancer (P < 0·001): luminal A, 6 per cent; luminal B/human epidermal growth factor 2 receptor (Her2)-negative, 21 per cent; luminal B/Her2-positive, 35 per cent, Her2-positive/non-luminal, 72 per cent; and triple-negative breast cancer (TNBC), 32 per cent. High-grade disease (G3) correlated with an increased rate of pCR. A radiological response seen on the mid-treatment MRI was predictive of pCR (sensitivity 77·6 per cent, but specificity only 53·3 per cent), as was complete radiological response at final MRI (specificity 97·6 per cent, but sensitivity only 32·2 per cent). CONCLUSION: NACT allows identification of patient subgroups within TNBC and Her2-positive cohorts with a good prognosis. MRI can be used to identify patients who are responding to treatment.

Contralateral breast cancer: incidence according to ductal or lobular phenotype of the primary.

AIM: To identify differences in the incidence of contralateral breast cancer between patients with a primary tumour diagnosis of invasive ductal carcinoma (IDC) and those with a diagnosis of invasive lobular carcinoma (ILC). MATERIALS AND METHODS: Data from two large cancer registries (registry A & B) the Northern and Yorkshire Cancer Registry Information Service (NYCRIS) and the West Midlands Cancer Intelligence Unit (WMCIU) from 1998-2003 for all cases of invasive breast cancer of either pure ductal or pure lobular reported histology were obtained. The invasive status of the contralateral tumour diagnosis and tumour morphology was collected. Chi-square tests were undertaken to examine the differences in contralateral rates for both registries and univariate analysis to ascertain which predictors affected contralateral breast cancer risk for registry A the WMCIU cases. RESULTS: A total of 38,132 patients were studied, 32,735 patients with IDC and 5397 (14.2%) patients with ILC over the 6-year period. There was no significant difference between the occurrence and time to occurrence of contralateral breast cancer according to original cancer histology, 901 (2.8%) patients with IDC versus 166 (3.1%) patients with ILC (p=0.169). The analysis of registry A cases showed no association between original histology (ductal versus lobular), age at diagnosis, tumour grade, use of radiotherapy for the primary cancer or use of systemic therapy (chemotherapy and/or endocrine therapy), and development of a contralateral breast cancer. CONCLUSION: There is no apparent increase in risk of developing a contralateral breast cancer according to the primary cancer histology either IDC or ILC. Standard mammographic follow-up does not need to take account of original tumour pathology. Increased intervention or post-treatment surveillance for the contralateral breast is not indicated in the context of ILC. The role of MRI should be restricted to those patients with ILC who are planning breast-conservation surgery, but not for assessing the contralateral breast.

Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer. Currently, no consensus exists on the optimal site of injection of the radioactive tracer or blue dye. METHODS: A systematic review and meta-analysis of studies comparing superficial and deep injections of radioactive tracer or blue dye for lymphatic mapping and SLNB was performed. The axillary and extra-axillary sentinel lymph node (SLN) identification rates obtained by lymphoscintigraphy and intraoperative SLNB were evaluated. Pooled odds ratios (ORs) and 95 per cent c.i. were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (P < 0·050). RESULTS: Thirteen studies were included in the meta-analysis. There was no significant difference between superficial and deep injections of radioactive tracer for axillary SLN identification on lymphoscintigraphy (OR 1·59, 95 per cent c.i. 0·79 to 3·17), during surgery (OR 1·27, 0·60 to 2·68) and for SLN identification using blue dye (OR 1·40, 0·83 to 2·35). The rate of extra-axillary SLN identification was significantly greater when deep rather than superficial injection was used (OR 3·00, 1·92 to 4·67). The discordance rate between superficial and deep injections ranged from 4 to 73 per cent for axillary and from 0 to 61 per cent for internal mammary node mapping. CONCLUSION: Both superficial and deep injections of radioactive tracer and blue dye are effective for axillary SLN identification. Clinical consequences of discordance rates between the two injection techniques are unclear. Deep injections are associated with significantly greater extra-axillary SLN identification; however, this may not have a significant impact on clinical management.

Systematic review and meta-analysis of cytokeratin 19-based one-step nucleic acid amplification versus histopathology for sentinel lymph node assessment in breast cancer.

BACKGROUND: One-step nucleic acid amplification (OSNA) is a new rapid assay for detecting breast cancer metastases during surgery, saving a second procedure for patients requiring an axillary clearance. Many centres in the UK and abroad have adopted OSNA in place of routine histopathology, despite no published meta-analysis. The aim of this systematic review and meta-analysis was to determine whether intraoperative OSNA for lymph node assessment is comparable to routine histopathology in the detection of clinically relevant metastases. METHODS: PubMed, Embase, Web of Knowledge and regional databases were searched for relevant studies published before December 2012. Included studies compared OSNA and standard histology using fresh lymph nodes that were assessed in a clearly defined systematic manner in accordance with the index study. RESULTS: Twelve eligible studies were identified that included 5057 lymph nodes from 2192 patients. Although meta-analysis using a random-effects model showed a similar overall proportion of macrometastases detected (429 of 3234 versus 432 of 3234; odds ratio 0·99, 95 per cent confidence interval 0·86 to 1·15), analysis of concordance showed that the pooled positive predictive value for detecting macrometastases was 0·79. This suggests that up to 21 per cent of patients found to have macrometastases using OSNA would have an axillary clearance when histology would have classified the deposits as non-macrometastases. Furthermore, analysis of data from the index publication showed that the range of cytokeratin 19 titres for tumours of a given volume is too wide to predict tumour size. CONCLUSION: OSNA has an unacceptably low positive predictive value, leading to axillary clearances that would not be recommended if standard histology had been used to assess the sentinel node.

Results of a national training programme in sentinel lymph node biopsy for breast cancer.

BACKGROUND: New Start, a structured, validated, multidisciplinary training programme in sentinel lymph node biopsy (SLNB), was established to allow the introduction and rapid transfer of appropriate knowledge and technical skills to ensure safe and competent practice across the UK. METHODS: Multidisciplinary teams attended a theory/skills laboratory course, following which they performed 30 consecutive SLNBs, either concurrently with their standard axillary staging procedure (training model A) or as stand-alone SLNB (training model B). SLNB was performed according to a standard protocol using the combined technique of isotope ((99m) Tc-labelled albumin colloid) and blue dye. An accredited New Start trainer mentored the first five procedures in the participant's hospital, or all 30 if stand-alone. Validation standards for model A and B were a localization rate of at least 90 per cent. In addition, for model A only, in which a minimum of ten patients were required to be node-positive, a false-negative rate (FNR) of 10 per cent or less was required. RESULTS: From October 2004 to December 2008, 210 SLNB-naive surgeons, in 103 centres, performed 6685 SLNB procedures. The overall sentinel lymph node (SLN) localization rate was 98·9 (95 per cent confidence interval 98·6 to 99·1) per cent (6610 of 6685) and the FNR 9·1 (7·9 to 10·5) per cent (160 of 1757). The FNR was related to nodal yield, ranging from 14·8 per cent for one node and declining to 9·7, 6·6, 4·7 and 4·1 per cent for two, three, four and more than four SLNs respectively. No learning curve was identified for localization or FNR. CONCLUSION: The programme successfully trained a wide range of UK breast teams to perform safe SLNB and suggested that a standard injection protocol and structured multidisciplinary training can abolish learning curves.

The Association Between Survival and Receipt of Post-mastectomy Radiotherapy According to Age at Diagnosis Among Women With Early Invasive Breast Cancer: A Population-Based Cohort Study.

AIMS: Clinical trials of post-mastectomy radiotherapy (PMRT) for early invasive breast cancer (EIBC) have included few older women. This study examined whether the association between overall survival or breast cancer-specific survival (BCSS) and receipt of PMRT for EIBC altered with age. MATERIALS AND METHODS: The study used patient-level linked cancer registration, routine hospital and radiotherapy data for England and Wales. It included 31 243 women aged ≥50 years diagnosed between 2014 and 2018 with low- (T1-2N0), intermediate- (T3N0/T1-2N1) or high-risk (T1-2N2/T3N1-2) EIBC who received a mastectomy within 12 months from diagnosis. Patterns of survival were analysed using a landmark approach. Associations between overall survival/BCSS and PMRT in each risk group were analysed with flexible parametric survival models, which included patient and tumour factors; whether the association between PMRT and overall survival/BCSS varied by age was assessed using interaction terms. RESULTS: Among 4711 women with high-risk EIBC, 86% had PMRT. Five-year overall survival was 70.5% and BCSS was 79.3%. Receipt of PMRT was associated with improved overall survival [adjusted hazard ratio (aHR) 0.75, 95% confidence interval 0.64-0.87] and BCSS (aHR 0.78, 95% confidence interval 0.65-0.95) compared with women who did not have PMRT; associations did not vary by age (overall survival, P-value for interaction term = 0.141; BCSS, P = 0.077). Among 10 814 women with intermediate-risk EIBC, 59% had PMRT; 5-year overall survival was 78.4% and BCSS was 88.0%. No association was found between overall survival (aHR 1.01, 95% confidence interval 0.92-1.11) or BCSS (aHR 1.16, 95% confidence interval 1.01-1.32) and PMRT. There was statistical evidence of a small change in the association with age for overall survival (P = 0.007), although differences in relative survival were minimal, but not for BCSS (P = 0.362). CONCLUSIONS: The association between PMRT and overall survival/BCSS does not appear to be modified by age among women with high- or intermediate-risk EIBC and, thus, treatment recommendations should not be modified on the basis of age alone.

Variation in Rates of Post-Mastectomy Radiotherapy Among Women with Early Invasive Breast Cancer in England and Wales: A Population-Based Cohort Study.

AIMS: This study examined whether patterns of post-mastectomy radiotherapy (PMRT) among women with early invasive breast cancer (EIBC) varied within England and Wales and explored the role of different patient factors in explaining any variation. MATERIALS AND METHODS: The study used national cancer data on women aged ≥50 years diagnosed with EIBC (stage I-IIIa) in England and Wales between January 2014 and December 2018 who had a mastectomy within 12 months of diagnosis. A multilevel mixed-effects logistic regression model was used to calculate risk-adjusted rates of PMRT for geographical regions and National Health Service acute care organisations. The study examined the variation in these rates within subgroups of women with different risks of recurrence (low: T1-2N0; intermediate: T3N0/T1-2N1; high: T1-2N2/T3N1-2) and investigated whether the variation was linked to patient case-mix within regions and organisations. RESULTS: Among 26 228 women, use of PMRT increased with greater recurrence risk (low: 15.0%; intermediate: 59.4%; high: 85.1%). In all risk groups, use of PMRT was more common among women who had received chemotherapy and decreased among women aged ≥80 years. There was weak or no evidence of an association between use of PMRT and comorbidity or frailty, for each risk group. In women with an intermediate risk, unadjusted rates of PMRT varied substantially between geographical regions (range 40.3-77.3%), but varied less for the high-risk (range 77.1-91.6%) and low-risk groups (range 4.1-32.9%). Adjusting for patient case-mix reduced the variation in regional and organisational PMRT rates to a small degree. CONCLUSIONS: Rates of PMRT are consistently high across England and Wales among women with high-risk EIBC, but variation exists across regions and organisations for women with intermediate-risk EIBC. Effort is required to reduce unwarranted variation in practice for intermediate-risk EIBC.

Effect of dietary prebiotic (mannan oligosaccharide) supplementation on the caecal bacterial community structure of turkeys.

The identification of specific bacterial species influenced by mannan oligosaccharide (MOS) supplementation may assist in the formulation of new and improved diets that promote intestinal health and improve bird performance, offering suitable alternatives to antimicrobials in feed for sustainable poultry production. This study has been conducted to evaluate the use of a MOS compound derived from the yeast cell wall of Saccharomyces cerevisiae on turkey performance, bacterial community structure and their phylogenetic associations. A 42-day turkey trial was carried out on birds fed control and MOS-supplemented diets. Bird performance data (weight gains, feed consumption and feed efficiency ratios) were collected, and caecal contents were extracted from randomly caught poults on days 28, 35 and 42 posthatch. Bird performance data showed no improvements as a result of dietary supplementation. Automated ribosomal intergenic spacer analysis (ARISA) revealed the bacterial community structure to be significantly altered on days 28 and 35 posthatch but not day 42 as a result of dietary supplementation. This technique was coupled with 16S rRNA gene sequence analysis to elucidate phylogenetic identities of bacteria. The dominant bacteria of the caecum on all days in both treatment groups were members of phylum Firmicutes, followed by the Bacteroidetes and Proteobacteria phyla, respectively. Statistical analysis of the 16S rRNA gene libraries showed that the composition of the MOS clone library differed significantly to the control on day 35 posthatch. It can be concluded that MOS alters the bacterial community structure in the turkey caecum.

Change in the Use of Fractionation in Radiotherapy Used for Early Breast Cancer at the Start of the COVID-19 Pandemic: A Population-Based Cohort Study of Older Women in England and Wales.

AIMS: Adjuvant radiotherapy is recommended for most patients with early breast cancer (EBC) receiving breast-conserving surgery and those at moderate/high risk of recurrence treated by mastectomy. During the first wave of COVID-19 in England and Wales, there was rapid dissemination of randomised controlled trial-based evidence showing non-inferiority for five-fraction ultra-hypofractionated radiotherapy (HFRT) regimens compared with standard moderate-HFRT, with guidance recommending the use of five-fraction HFRT for eligible patients. We evaluated the uptake of this recommendation in clinical practice as part of the National Audit of Breast Cancer in Older Patients (NABCOP). MATERIALS AND METHODS: Women aged ≥50 years who underwent surgery for EBC from January 2019 to July 2020 were identified from the Rapid Cancer Registration Dataset for England and from Wales Cancer Network data. Radiotherapy details were from linked national Radiotherapy Datasets. Multivariate mixed-effects logistic regression models were used to assess characteristics influential in the use of ultra-HFRT. RESULTS: Among 35 561 women having surgery for EBC, 71% received postoperative radiotherapy. Receipt of 26 Gy in five fractions (26Gy5F) increased from <1% in February 2020 to 70% in April 2020. Regional variation in the use of 26Gy5F during April to July 2020 was similar by age, ranging from 49 to 87% among women aged ≥70 years. Use of 26Gy5F was characterised by no known nodal involvement, no comorbidities and initial breast-conserving surgery. Of those patients receiving radiotherapy to the breast/chest wall, 85% had 26Gy5F; 23% had 26Gy5F if radiotherapy included regional nodes. Among 5139 women receiving postoperative radiotherapy from April to July 2020, nodal involvement, overall stage, type of surgery, time from diagnosis to start of radiotherapy were independently associated with fractionation choice. CONCLUSIONS: There was a striking increase in the use of 26Gy5F dose fractionation regimens for EBC, among women aged ≥50 years, within a month of guidance published at the start of the COVID-19 pandemic in England and Wales.

Effect of dietary supplementation with a Saccharomyces cerevisiae mannan oligosaccharide on the bacterial community structure of broiler cecal contents.

This study investigated the effects of dietary supplementation with a prebiotic mannan oligosaccharide (MOS) on broiler performance, bacterial community structure, and phylogenetic populations of cecal contents. Bird performance data were collected, and cecal samples were extracted from randomly caught poults from each treatment group every 7 days from hatching to the age of 42 days. Weight gain, feed consumption, and feed efficiency ratios did not differ significantly between groups. Automated ribosomal intergenic spacer analysis (ARISA) of the bacterial communities in birds receiving MOS-supplemented diets indicated that dietary supplementation with MOS at either of 2 levels significantly altered the bacterial community structure from that of the control group on all sample days. The phylogenetic identities of bacteria contained within the cecum were determined by constructing a 16S rRNA gene clone library. A total of 594 partial 16S rRNA gene sequences from the cecal contents were analyzed and compared for the three dietary treatments. The dominant bacteria of the cecum belonged to three phyla, Firmicutes, Bacteroidetes, and Proteobacteria; of these, Firmicutes were the most dominant in all treatment groups. Statistical analysis of the bacterial 16S rRNA gene clone libraries showed that the compositions of the clone libraries from broilers receiving MOS-supplemented diets were, in most cases, significantly different from that of the control group. It can be concluded that in this trial MOS supplementation significantly altered the cecal bacterial community structure.

Crosslinking of the T cell-specific accessory molecules CD7 and CD28 modulates T cell adhesion.

Regulated adhesion enables T cells to migrate through tissue and transiently interact with an endless succession of cells. Monoclonal antibody (mAb) engagement of the CD3/T cell receptor (TCR) complex results in a rapid and transient augmentation of the adhesion function of LFA-1 and VLA integrin molecules on human T cells. We show in this study that mAb crosslinking of the T cell-specific accessory molecules CD7 and CD28, or treatment with the Ca2+ ionophore A23187, results in the rapid induction of integrin-mediated adhesion to three distinct ligands: the extracellular matrix protein fibronectin, and the cell surface molecules ICAM-1 and VCAM-1. Like CD3 crosslinking, increased adhesion via CD7 and CD28 crosslinking appears to involve both protein kinase C (PKC) and cAMP-dependent protein kinases. In contrast, A23187 induction of adhesion is unaffected by PKC inhibitors. CD7 is preferentially expressed on naive T cells and is unique in being a potent inducer of naive T cell adhesion. Enhanced expression/function of adhesion-inducing molecules thus overcomes relative deficits in adhesion receptor expression.

Analysis of T cell stimulation by superantigen plus major histocompatibility complex class II molecules or by CD3 monoclonal antibody: costimulation by purified adhesion ligands VCAM-1, ICAM-1, but not ELAM-1.

Many ligands of adhesion molecules mediate costimulation of T cell activation. The generality of this emerging concept is best determined by using model systems which exploit physiologically relevant ligands. We developed such an "antigen-specific" model system for stimulation of resting CD4+ human T cells using the following purified ligands: (a) major histocompatibility complex class II plus the superantigen Staphylococcus enterotoxin A, to engage the T cell receptor (TCR); (b) adhesion proteins vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and endothelial leukocyte adhesion molecule 1 (ELAM-1), to provide potential cell surface costimulatory signals; and (c) recombinant interleukin 1 beta (rIL-1 beta)/rIL-6 as costimulatory cytokines. In this biochemically defined system, we find that resting CD4+ T cells require costimulation in order to respond to TCR engagement. This costimulation can be provided by VCAM-1 or ICAM-1; however adhesion alone is not sufficient since ELAM-1 mediates adhesion but not costimulation. The cytokines IL-1 beta and IL-6 by themselves cannot mediate costimulation, but augment the adhesion ligand-mediated costimulation. Direct comparison with the model of TCR/CD3 engagement by CD3 monoclonal antibody demonstrated comparable costimulatory requirements in both systems, thereby authenticating the commonly used CD3 model. The costimulation mediated by the activation-dependent interaction of the VLA-4 and LFA-1 integrins with their respective ligands VCAM-1 and ICAM-1 leads to increased IL-2R alpha (CD25) expression and proliferation in both CD45RA+ CD4+ and CD45RO+ CD4+ T cells. The integrins also regulate the secretion of IL-2, IL-4, and granulocyte/macrophage colony-stimulating factor. In contrast the activation-independent adhesion of CD4+ T cell to ELAM-1 molecules does not lead to T cell stimulation as measured by proliferation, IL-2R alpha expression, or cytokine release. These findings imply that adhesion per se is not sufficient for costimulation, but rather that the costimulation conferred by the VLA-4/VCAM-1 and LFA-1/ICAM-1 interactions reflects specialized accessory functions of these integrin pathways. The new finding that VLA-4/VCAM-1 mediates costimulation adds significance to observations that VCAM-1 is expressed on a unique set of potential antigen-presenting cells in vivo.

CD31 expressed on distinctive T cell subsets is a preferential amplifier of beta 1 integrin-mediated adhesion.

The CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]/endothelial cell adhesion molecule [endoCAM]) molecule expressed on leukocytes, platelets, and endothelial cells is postulated to mediate adhesion to endothelial cells and thereby function in immunity, inflammation, and wound healing. We report the following novel features of CD31 which suggests a role for it in adhesion amplification of unique T cell subsets: (a) engagement of CD31 induces the adhesive function of beta 1 and beta 2 integrins; (b) adhesion induction by CD31 immunoglobulin G (IgG) monoclonal antibodies (mAbs) is sensitive, requiring only bivalent mAb; (c) CD31 mAb induces adhesion rapidly, but it is transient; (d) unique subsets of CD4+ and CD8+ T cells express CD31, including all naive (CD45RA+) CD8 T cells; and (e) CD31 induction is selective, inducing adhesive function of beta 1 integrins, particularly very late antigen-4, more efficiently than the beta 2 integrin lymphocyte function-associated antigen-1. Conversely, CD3 is more effective in inducing beta 2-mediated adhesion. Taken together, these findings indicate that unique T cell subsets express CD31, and CD31 has the capacity to induce integrin-mediated adhesion of T cells in a sensitive and selective fashion. We propose that, in collaboration with other receptors/ligands, CD31 functions in an "adhesion cascade" by amplifying integrin-mediated adhesion of CD31+ T cells to other cells, particularly endothelial cells.

Expression of COX-2, NF-kappaB-p65, NF-kappaB-p50 and IKKalpha in malignant and adjacent normal human colorectal tissue.

BACKGROUND: Cyclooxygenase-2 (COX-2) is selectively over-expressed in colorectal tumours. The mechanism of COX-2 induction in these tumours is not fully understood, although evidence suggests a possible link between nuclear factor (NF)-kappaB and COX-2. We hypothesised an association between COX-2 expression and NF-kappaB-p65, NF-kappaB-p50 and IkappaB-kinase-alpha (IKKalpha) in both epithelial and stromal cells in human colorectal cancer. METHODS: Using immunohistochemistry, we measured COX-2, NF-kappaB-p65, NF-kappaB-p65 nuclear localisation sequence (NLS), NF-kappaB-p50, NF-kappaB-p50 NLS and IKKalpha protein expression in matched colorectal biopsy samples comprising both non-tumour and adjacent tumour tissue from 32 patients with colorectal cancer. RESULTS: We have shown that stromal cells of malignant and surrounding normal colorectal tissue express COX-2. In all cell types of malignant tissue, and in vascular endothelial cells (VECs) of neighbouring normal tissue, COX-2 expression was strongly associated with NF-kappaB-p65 expression (Pearson's correlation, P=0.019 for macrophages, P=0.001 for VECs, P=0.002 for fibroblasts (malignant tissue), and P=0.011 for VECs (non-malignant tissue)) but not NF-kappaB-p50 or IKKalpha. CONCLUSIONS: These data suggest that in these cells COX-2 induction may be mediated through activation of the canonical NF-kappaB pathway. Finally, the lack of association between COX-2, NF-kappaB-p65 or IKKalpha in stromal cells with the clinical severity of colorectal cancer as determined by Duke's stage, suggests that COX-2, NF-kappaB-p65 and IKKalpha expression are possibly early post-initiation events, which could be involved in tumour progression.

Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.

T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM-X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1-transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell.