Melissa Wright

Impact of media reporting of cervical cancer in a UK celebrity on a population-based cervical screening programme

Objectives To determine the impact of media reporting of cervical cancer in a UK celebrity on cervical screening uptake, response time and colposcopy referral and attendance. Setting Population-based national cervical screening programme for women in Wales, UK. Methods A time series regression analysis of the Welsh national cervical screening and colposcopy databases was used to examine the number of smear tests carried out between 2000 and 2010, stratified by age group and deprivation indicators. Logistic regression was used to analyse colposcopy attendance. Results Over 33,000 more cervical screening tests than expected were carried out in the year of media reporting (2008/9), 11,539 (35%) of which were in the month of Jade Goodys death. The largest increase was evident in women aged 35–39 years (475 additional tests per month, 95% CI 331–619). Impacts were similar across deprivation quintiles. Colposcopy referrals increased by 18% during the year of media reporting. Increases were observed for all smear test results in 2008/9, particularly among younger women, and further rises were evident in 2009/10 for smear tests showing borderline changes and mild dyskaryosis. The proportion of women attending colposcopy appointments rose in the year of media reporting (χ 2 = 45.8, P < 0.001). Conclusions Mass media reporting of cervical cancer in a UK celebrity was associated with a significant, but transient, increase in screening uptake and colposcopy referral and attendance. Mass media reporting can play a role in enhanced detection of abnormalities, but public health messages must be communicated effectively to minimize anxiety whilst maximizing case-finding and uptake among non-responders.

Interobserver agreement in the reporting of colorectal polyp pathology among bowel cancer screening pathologists in Wales

To assess the interobserver agreement in the reporting of colorectal polyps among histopathologists participating in the Welsh Bowel Cancer Screening (BCS) programme.

A prospective study of the accuracy and concordance between in-situ and postfixation measurements of colorectal polyp size and their potential impact upon surveillance

Objectives To determine the differences between in-situ, prefixation and postfixation colorectal polyp measurements, their clinical impact upon determining adenoma surveillance intervals, and to compare postfixation measurements using three different devices. Patients and methods A prospective study of 107 colorectal polyps resected from 65 consecutive patients (45 men, 20 women) undergoing colonoscopy as part of the Bowel Cancer Screening Programme was undertaken. The polyps were measured in situ, prefixation (study gold standard) and using three measurement devices (ruler, callipers and magnifying lens) postfixation in formalin. Results Prefixation ruler measurements were significantly higher than in-situ (P=0.02) and postfixation ruler measurements (P=0.04). No significant difference was observed between in-situ and postfixation ruler measurements (P=0.36), although in-situ measurements were more variable. In-situ measurements also generated more variation in surveillance intervals than postfixation measurements (9.3 vs. 5.6%). No significant difference was seen between measurements obtained by the three different devices postfixation (P=0.89). Conclusion This study provides evidence supporting the use of postfixation polyp size measurements as advised by recent European pathology colorectal cancer screening recommendations. In the absence of a clinically significant difference between measurement devices, we advise the ruler to be used as a standard for postfixation measurements because of its widespread availability.

Effect of Modified Vaccinia Ankara–5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer: A Randomized Clinical Trial

Importance The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara–5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. Objective To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. Design, Setting, and Participants In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Interventions Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. Main Outcomes and Measures The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Results Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data. Trial Registration isrctn.org Identifier: ISRCTN54669986

Prevalence of defined ultrasound findings of unknown significance at the second trimester fetal anomaly scan and their association with adverse pregnancy outcomes: the Welsh study of mothers and babies population-based cohort.

The aim of this article was to estimate the population prevalence of seven defined ultrasound findings of uncertain significance (‘markers’) in the second trimester and the associated risk of adverse pregnancy outcomes.

No evidence that CD33 splicing SNP impacts the response to GO in younger adults with AML treated on UK MRC/NCRI trials

TO THE EDITOR: Addition of the CD33-targeted immunoconjugate gemtuzumab ozogamicin (GO; Pfizer) has been shown to improve the response to standard-induction chemotherapy and results in better long-term survival in adult patients with acute myeloid leukemia (AML).[1][1] The greatest impact was

Variable outcome and methylation status according to CEBPA mutant type in double-mutated acute myeloid leukemia patients and the possible implications for treatment

Although CEBPA double-mutated (CEBPADM) acute myeloid leukemia is considered to be a favorable-risk disease, relapse remains a major cause of treatment failure. Most CEBPADM patients have a classic biallelic mutant combination with an N-terminal mutation leading to production of p30 protein plus a C-terminal loss-of-function in-frame indel mutation (CEBPAClassic-DM), but approximately one-third of cases have one or more non-classic mutations, with diverse combinations reported, and there is little information on the consequences of such mutants. We evaluated outcome in a cohort of 104 CEBPADM patients, 79 CEBPAClassic-DM and 25 with non-classic mutants, and found that the latter may have poorer survival (5-year overall survival 64% vs. 46%; P=0.05), particularly post relapse (41% vs. 0%; P=0.02). However, for this analysis, all non-classic cases were grouped together, irrespective of mutant combination. As CEBPADM cases have been reported to be hypermethylated, we used methylation profiling to assess whether this could segregate the different mutants. We developed a CEBPAClassic-DM methylation signature from a preliminary cohort of 10 CEBPADM (including 8 CEBPAClassic-DM) and 30 CEBPA wild-type (CEBPAWT) samples, and independently validated the signature in 17 CEBPAClassic-DM cases. Assessment of the signature in 16 CEBPADM cases with different non-classic mutant combinations showed that only 31% had a methylation profile equivalent to CEBPAClassic-DM whereas for 69% the profile was either intermediate between CEBPAClassic-DM and CEBPAWT or equivalent to CEBPAWT. These results suggest that CEBPADM cases with non-classic mutants may be functionally different from those with CEBPAClassic-DM mutants, and should not automatically be included in the same prognostic group. (AML12 is registered under ISRCTN17833622 and AML15 under ISRCTN17161961).