Marialena Trivella

Reoperation rates after breast conserving surgery for breast cancer among women in England: retrospective study of hospital episode statistics

Objectives To examine whether rate of reoperation after breast conserving surgery is associated with patients’ characteristics and investigate whether reoperation rates vary among English NHS trusts. Design Cohort study using patient level data from hospital episode statistics. Setting English NHS trusts. Participants Adult women who had breast conserving surgery between 1 April 2005 and 31 March 2008. Main outcome measure Reoperation rates after primary breast conserving surgery within 3 months, adjusted using logistic regression for tumour type, age, comorbidity, and socioeconomic deprivation. Tumours were grouped by whether a carcinoma in situ component was coded at the time of the primary breast conserving surgery. Results 55 297 women had primary breast conserving surgery in 156 NHS trusts during the three year period. 11 032 (20.0%, 95% confidence interval 19.6% to 20.3%) women had at least one reoperation. 10 212 (18.5%, 18.2% to 18.8%) had one reoperation only; of these, 5943 (10.7%, 10.5% to 11.0%) had another breast conserving procedure and 4269 (7.7%, 7.5% to 7.9%) had a mastectomy. Of the 45 793 women with isolated invasive disease, 8229 (18.0%) had at least one reoperation. In comparison, 2803 (29.5%) of the 9504 women with carcinoma in situ had at least one reoperation (adjusted odds ratio 1.9, 95% confidence interval 1.8 to 2.0). Substantial differences were found in the adjusted reoperation rates among the NHS trusts (10th and 90th centiles 12.2% and 30.2%). Conclusion: One in five women who had breast conserving surgery in England had a reoperation. Reoperation was nearly twice as likely when the tumour had a carcinoma in situ component coded. Women should be informed of this reoperation risk when deciding on the type of surgical treatment of their breast cancer.

Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas.

We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing αVβ3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and αVβ3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0–60%) expressed LH39, while αVβ3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5–90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed.

Timing of Allergenic Food Introduction to the Infant Diet and Risk of Allergic or Autoimmune Disease: A Systematic Review and Meta-analysis

Importance Timing of introduction of allergenic foods to the infant diet may influence the risk of allergic or autoimmune disease, but the evidence for this has not been comprehensively synthesized. Objective To systematically review and meta-analyze evidence that timing of allergenic food introduction during infancy influences risk of allergic or autoimmune disease. Data Sources MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS databases were searched between January 1946 and March 2016. Study Selection Intervention trials and observational studies that evaluated timing of allergenic food introduction during the first year of life and reported allergic or autoimmune disease or allergic sensitization were included. Data Extraction and Synthesis Data were extracted in duplicate and synthesized for meta-analysis using generic inverse variance or Mantel-Haenszel methods with a random-effects model. GRADE was used to assess the certainty of evidence. Main Outcomes and Measures Wheeze, eczema, allergic rhinitis, food allergy, allergic sensitization, type 1 diabetes mellitus, celiac disease, inflammatory bowel disease, autoimmune thyroid disease, and juvenile rheumatoid arthritis. Results Of 16 289 original titles screened, data were extracted from 204 titles reporting 146 studies. There was moderate-certainty evidence from 5 trials (1915 participants) that early egg introduction at 4 to 6 months was associated with reduced egg allergy (risk ratio [RR], 0.56; 95% CI, 0.36-0.87; I2 = 36%; P = .009). Absolute risk reduction for a population with 5.4% incidence of egg allergy was 24 cases (95% CI, 7-35 cases) per 1000 population. There was moderate-certainty evidence from 2 trials (1550 participants) that early peanut introduction at 4 to 11 months was associated with reduced peanut allergy (RR, 0.29; 95% CI, 0.11-0.74; I2 = 66%; P = .009). Absolute risk reduction for a population with 2.5% incidence of peanut allergy was 18 cases (95% CI, 6-22 cases) per 1000 population. Certainty of evidence was downgraded because of imprecision of effect estimates and indirectness of the populations and interventions studied. Timing of egg or peanut introduction was not associated with risk of allergy to other foods. There was low- to very low-certainty evidence that early fish introduction was associated with reduced allergic sensitization and rhinitis. There was high-certainty evidence that timing of gluten introduction was not associated with celiac disease risk, and timing of allergenic food introduction was not associated with other outcomes. Conclusions and Relevance In this systematic review, early egg or peanut introduction to the infant diet was associated with lower risk of developing egg or peanut allergy. These findings must be considered in the context of limitations in the primary studies.

Demand for and supply of out of hours care from general practitioners in England and Scotland: observational study based on routinely collected data.

Abstract Objectives: To determine the level of demand and supply of out of hours care from a nationally representative sample of general practice cooperatives. Design: Observational study based on routinely collected data on telephone calls, patient population data from general practices, and information about cooperatives from interviews with managers. Setting: 20 cooperatives in England and Scotland selected after stratification by region and by size. Subjects: 899 657 out of hours telephone calls over 12 months. Main outcome measures: Numbers and age and sex specific rates of calls; variation in demand and activity in relation to characteristics of the population; timing of calls; proportion of patients consulting at home, at a primary care centre, or on the telephone; response times; hospital admission rates. Results: The out of hours call rate (excluding bank holidays) was 159 calls per 1000 patients/year, with rates in children aged under 5 years four times higher than for adults. Little variation occurred by day of the week or seasonally. Cooperatives in Scotland experienced higher demand than those in England. Patients living in deprived areas made 70% more calls than those in non-deprived areas, but this had little effect on the overall variation in demand. 45.4% (408 407) of calls were handled by telephone advice, 23.6% (212 550) by a home visit, and 29.8% (267 663) at a centre. Cooperatives responded to 60% of calls within 30 minutes and to 83% within one hour. Hospital admission followed 5.5% (30 743/554 179) of out of hours calls (8 admissions per 1000 patients/year). Conclusions: This project provides national baseline data for the planning of services and the analysis of future changes.

Controlled ovarian hyperstimulation for IVF: impact on ovarian, endometrial and cervical cancer—a systematic review and meta-analysis

BACKGROUND In response to the ongoing debate on the long-term effects of assisted reproduction technologies, such as IVF, we systematically reviewed and meta-analyzed available evidence on the association between controlled ovarian hyperstimulation for IVF and risk of ovarian, endometrial and cervical cancer. METHODS Eligible studies were identified and pooled effect estimates for relative risk (RR) were calculated by cancer type among two reference groups (general population or infertile women), through fixed- or random-effects models as appropriate. RESULTS Nine cohort studies were synthesized, corresponding to a total size of 109 969 women exposed to IVF, among whom 76 incident cases of ovarian, 18 of endometrial and 207 cases of cervical cancer were studied. The synthesis of studies with general population as the reference group pointed to a statistically significant positive association between IVF and increased risk for ovarian (RR = 1.50, 95% confidence interval (CI): 1.17-1.92) and endometrial (RR = 2.04, 95% CI: 1.22-3.43), but not cervical (RR = 0.86, 95% CI: 0.49-1.49) cancers. On the contrary, when infertile women were used as the reference group, no significant associations with ovarian, endometrial or cervical cancer types were noted (RR = 1.26, 95% CI: 0.62-2.55 RR = 0.45, 95% CI: 0.18-1.14 and RR = 5.70, 95% CI: 0.28-117.20, respectively). CONCLUSIONS IVF does not seem to be associated with elevated cervical cancer risk, nor with ovarian or endometrial cancer when the confounding effect of infertility was neutralized in studies allowing such comparisons. Of note, only one study provided follow-up longer than 10 years for the group exposed to IVF. Future cohort studies should preferably use infertile women as the reference group, rely on IVF-registered valid exposure data, adjust for a variety of meaningful confounders and adopt relatively longer follow-up periods before sound conclusions are drawn.

Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis

Objective To determine whether feeding infants with hydrolysed formula reduces their risk of allergic or autoimmune disease. Design Systematic review and meta-analysis, as part of a series of systematic reviews commissioned by the UK Food Standards Agency to inform guidelines on infant feeding. Two authors selected studies by consensus, independently extracted data, and assessed the quality of included studies using the Cochrane risk of bias tool. Data sources Medline, Embase, Web of Science, CENTRAL, and LILACS searched between January 1946 and April 2015. Eligibility criteria for selecting studies Prospective intervention trials of hydrolysed cows’ milk formula compared with another hydrolysed formula, human breast milk, or a standard cows’ milk formula, which reported on allergic or autoimmune disease or allergic sensitisation. Results 37 eligible intervention trials of hydrolysed formula were identified, including over 19 000 participants. There was evidence of conflict of interest and high or unclear risk of bias in most studies of allergic outcomes and evidence of publication bias for studies of eczema and wheeze. Overall there was no consistent evidence that partially or extensively hydrolysed formulas reduce risk of allergic or autoimmune outcomes in infants at high pre-existing risk of these outcomes. Odds ratios for eczema at age 0-4, compared with standard cows’ milk formula, were 0.84 (95% confidence interval 0.67 to 1.07; I2=30%) for partially hydrolysed formula; 0.55 (0.28 to 1.09; I2=74%) for extensively hydrolysed casein based formula; and 1.12 (0.88 to 1.42; I2=0%) for extensively hydrolysed whey based formula. There was no evidence to support the health claim approved by the US Food and Drug Administration that a partially hydrolysed formula could reduce the risk of eczema nor the conclusion of the Cochrane review that hydrolysed formula could prevent allergy to cows’ milk. Conclusion These findings do not support current guidelines that recommend the use of hydrolysed formula to prevent allergic disease in high risk infants. Review registration PROSPERO CRD42013004252.

Microvessel density as a prognostic factor in non-small-cell lung carcinoma: a meta-analysis of individual patient data

BACKGROUND Angiogenesis is a potential prognostic factor that has been investigated in patients with non-small-cell lung carcinoma. However, published studies of the role of angiogenesis as a prognostic factor are inconclusive. We aimed to collect individual patient data to assess microvessel-density counts (ie, a measure of angiogenesis) as a prognostic factor in non-small-cell lung carcinoma. METHODS We obtained published and unpublished datasets and extracted appropriate data, taking particular care to ensure data quality. Detailed information was obtained for the laboratory methods used by every research centre that generated the data. The outcome of interest was overall survival. We did a meta-analysis to estimate the prognostic role of microvessel density by combining separately estimated hazard ratios (HR) from every study, which were adjusted for tumour stage and age. Analyses were done separately for studies that used the Chalkley method or for those that counted all microvessels. FINDINGS 17 centres provided data for 3200 patients, 2719 of which were included in the analysis. All but three centres (datasets 9, 10, and 13-367 cases) had already published their findings, and six had updated follow-up information (datasets 1, 2, 3, 6, 7, and 8-1273 cases). For all but three centres (datasets 4, 11, and 13) some data corrections were necessary. For microvessel density counts obtained by the Chalkley method, the HR for death per extra microvessel was 1.05 (95% CI 1.01-1.09, p=0.03) when analysed as a continuous variable. For microvessel density counts obtained by the all vessels method, the HR for death per ten extra microvessels was 1.03 (0.97-1.09, p=0.3) when analysed as a continuous variable. INTERPRETATION Microvessel density does not seem to be a prognostic factor in patients with non-metastatic surgically treated non-small-cell lung carcinoma. This conclusion contradicts the results of a meta-analysis of published data only. Therefore, the methodology used to assess prognostic factors should be assessed carefully.

When and how to update systematic reviews: consensus and checklist.

Updating of systematic reviews is generally more efficient than starting all over again when new evidence emerges, but to date there has been no clear guidance on how to do this. This guidance helps authors of systematic reviews, commissioners, and editors decide when to update a systematic review, and then how to go about updating the review.

Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma

The few studies published on angiogenesis in lymphoma have raised the question of whether or not microvessel density (MVD) is associated with more aggressive disease and have reported the observation that in follicular lymphomas, vessels are mature rather than immature. We investigated MVD and the vascular phenotype within follicular or diffuse large B-cell lymphomas, reactive nodes and tonsils. Vascular phenotype was defined by the expression or loss of reactivity to the antibody LH39 (detecting the LH39 laminin epitope of the basement membrane in mature vessels) and by detection of αVβ3 (expressed on immature vessels). In reactive nodes and in follicular lymphomas, MVD was higher in the paracortex than in germinal centres or in neoplastic follicles. However, in neoplastic follicles an increase in αVβ3-positive endothelium suggested the activation of an angiogenic pathway different from that present in the reactive follicles. In large B-cell lymphomas, MVD was higher than in reactive and neoplastic follicles but lower than in the reactive paracortex. The number of immature vessels (LH39 negative) and of αVβ3-positive vessels was higher than in reactive lymph nodes and follicular lymphoma suggesting that a switch to a different angiogenic pathway has occurred. Finally, we have demonstrated that within reactive and neoplastic follicles vascular regression is occurring, perhaps constraining the growth of reactive follicles alongside other phenomena such as apoptosis. Vascular regression was previously believed to occur in adults only in ovarian and endometrial tissue. We conclude that different types of angiogenesis are present in follicular lymphomas and large B-cell lymphomas. This has implications for possible future therapies.

Systematic review of multiple studies of prognosis: The feasibility of obtaining individual patient data

Studies of prognosis have received rather little attention by those carrying out systematic reviews. Such reviews are increasingly being attempted but the poor quality of published ‘primary’ studies leads to serious difficulties. Thus there have been calls for such reviews to be based on individual patient data (IPD) but such studies are as yet rare.