Dawn Everington

Randomised controlled trial of conservation therapy for breast cancer: 6-year analysis of the Scottish trial

Summary Background To determine whether, when primary breast cancer is treated by local excision supported by systemic therapy appropriate to the oestrogen receptor status (ER) of the tumour, local radiotherapy can be avoided. Methods We carried out a randomised controlled trial in 585 patients aged less than 70 years with primary breast cancers of 4 cm or less in size in four specialist units and seven other hospitals in Scotland. After local excision of the tumour (1 cm margin) and an axillary lymph-node clearance or sample, all patients received systemic therapy with oral tamoxifen 20 mg daily or six 3-weekly intravenous bolus injections of cyclophosphamide 600 mg, methotrexate 50 mg, and fluorouracil 600 mg per m 2 , depending upon the ER concentration in the primary tumour. Patients were then randomly allocated to postoperative radical radiotherapy (50 Gy to breast with boost to the tumour bed) or to no further local treatment. The median follow-up of living patients was 5·7 years. The primary analysis was by intention to treat but since some patients did not receive systemic therapy appropriate to their ER status, a subsidiary analysis was restricted to 464 patients in whom all details of the protocol had been observed. Findings In the primary analysis survival was equal in the radiotherapy and non-radiotherapy groups (hazard ratio [HR] 0·98, 95% CI 0 67–1·44). Event-free survival showed an advantage in the irradiated patients (HR 0·54, 95% CI 0·39–0·74), largely due to fewer loco-regional relapses (HR 0·20, 95% CI 0·12–0·33). The relapse rate in the ipsilateral breast was 24·5% in the non-irradiated group and 5·8% following breast irradiation. The subsidiary analysis confirmed these findings and indicated the advantage of radiotherapy irrespective of ER concentration. There was a non-significant trend towards fewer distant metastases in the irradiated group. Interpretation After local excision of a primary breast cancer, we conclude that radiotherapy to the residual breast tissue is advisable even when selective adjuvant systemic therapy is given.

Risk factors for variant Creutzfeldt-Jakob disease: A case-control study

To investigate the potential risk factors for variant Creutzfeldt‐Jakob disease (VCJD) in the United Kingdom.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt–Jakob disease in the UK: a 10-year review

Background It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt–Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. Methods CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997–2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. Results and discussion CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3-3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD.

PRNP contains both intronic and upstream regulatory regions that may influence susceptibility to Creutzfeldt-Jakob Disease

The Prion protein (PrP) plays a central role in Creutzfeldt-Jakob Disease (CJD) and other transmissible spongiform encephalopathies (TSEs). Mutations in the protein coding region of the human PrP gene (PRNP), which have been proposed to alter the stability of the PrP protein, have been linked to a number of forms of TSE. However, the majority of CJD cases are not associated with mutations in the PRNP coding region and alternative mechanisms must therefore underlie susceptibility to these forms of CJD. Transgenic mice, that over- or under-express PrP genes, have shown a correlation between the level of PrP gene expression and the incubation time of disease. Polymorphisms that lead to alterations in human PRNP gene expression, could therefore be candidates for influencing susceptibility of an individual to CJD. In order to investigate this hypothesis, we have defined an upstream and intronic regulatory region of the PRNP gene. Sequencing of these regions in controls, sporadic CJD (sCJD) and variant CJD (vCJD) patients has identified three polymorphisms, all of which are more common in sCJD patients than controls. Our data suggests that polymorphisms in the regulatory region of the PRNP gene may be a risk factor for CJD.

Risk factors for sporadic Creutzfeldt–Jakob disease

Although surgical transmission of Creutzfeldt–Jakob disease (CJD) has been demonstrated, these iatrogenic cases account for only a small proportion of all CJD cases. The majority are sporadic CJD (sCJD) cases of unknown cause. This study investigated whether some cases classified as sCJD might have an unrecognized iatrogenic basis through surgical or other medical procedures

Raised CSF phospho-tau concentrations in variant Creutzfeldt–Jakob disease: diagnostic and pathological implications

Objective: To investigate whether phosphorylated tau protein (tau-pT181) is increased in variant Creutzfeldt–Jakob disease (vCJD) and if the tau-pT181/tau protein ratio is useful for distinguishing between patients with and without CJD. Methods: CSF tau protein and tau-pT181 were measured in 50 patients with sporadic CJD (sCJD), 51 patients with vCJD, 46 sCJD controls, and 37 vCJD controls, using Innotest hTau and Innotest P-Thr181, Innogenetics. Results: Concentrations of CSF tau protein were increased in sCJD (5120 v 367 pg/ml in controls, p<0.001) and vCJD (952 v 106 pg/ml, p<0.001); tau-pT181 was also raised in sCJD (61 v 35 pg/ml in controls, p = 0.002) and vCJD (114 v 33 pg/ml, p<0.001). Median concentrations of tau-pT181 were higher in vCJD than in sCJD (p<0.001). The tau-pT181/tau protein ratio was lower than in controls in both sCJD (12 v 128 (p<0.001)) and vCJD (119 v 279 (p<0.001)). Mean tau-pT181/tau protein ratio was 10-fold higher in vCJD than in sCJD. Raised CSF tau protein had the highest efficiency for distinguishing sCJD and vCJD from controls. Conclusions: CSF tau-pT181 concentrations are raised in vCJD and are higher than in sCJD. Measurement of CSF tau-pT181/tau protein ratio does not improve the diagnostic efficiency of CSF tau protein alone for either vCJD or sCJD. The higher concentration of CSF tau-pT181 found in vCJD suggests that unexplained pathogenic factors influence the phosphorylation of tau protein in vCJD patients.

Sporadic Creutzfeldt-Jakob disease and risk of blood transfusion in the United Kingdom.

An article in TRANSFUSION has recently implicated blood transfusion as a possible risk factor for sporadic Creutzfeldt-Jakob disease (sCJD) in Italy. In this study of patients notified to the Italian National Registry for CJD, Puopolo and colleagues compared blood transfusion histories in patients with a final diagnosis of sCJD with those of noncases, concluding that patients exposed to blood transfusion more than 10 years before clinical onset had a significantly greater risk of subsequently developing sCJD than patients who had been exposed earlier or not at all. In contrast, analysis of similar data from the UK National CJD Surveillance system provides no evidence that blood transfusion is a risk factor for sCJD. In the UK study, we considered all patients referred to the UK national surveillance program with suspected CJD from May 1990 until December 2010 and included in our analysis cases with a final diagnosis of definite or probable sCJD and noncases (patients who definitely did not have CJD or in whom a CJD diagnosis was considered unlikely), in which the history of blood transfusion before clinical onset of symptoms was known, based on information provided by the patients’ families at interview. Patients with sCJD were compared to noncases with respect to 1) having ever received a blood transfusion before onset and 2) the interval between the year of first transfusion and year of clinical onset. Patients transfused in the same year or after onset of illness were considered as not having been transfused before onset. The risks of sCJD by blood transfusion history and interval were evaluated by calculating the odds ratios (ORs, with 95% confidence interval [CI]) for sCJD in exposed compared to unexposed patients, adjusted for potential confounders such as age at onset, sex, year of notification (which might mask changes in transfusion rates and referral practice over time), and history of surgery (which may be associated with blood transfusion as well as a potential risk factor for sCJD), using a multivariable logistic regression model. All analyses were conducted with computer software (STATA/IC 11.1, StataCorp LP, College Station, TX). Between 1990 and 2010, a total of 1206 patients with a final diagnosis of sCJD and 585 noncases were notified in the United Kingdom. Of these, the preonset blood transfusion history was known for 987 (81.8%) patients with sCJD and 159 (27.2%) of noncases. The characteristics of patients with sCJD and noncases are presented in terms of their preonset blood transfusion history and interval and associated adjusted ORs in Table 1. Having received a blood transfusion before onset was not identified as a risk factor for sCJD, either overall or accounting for the interval between first transfusion and clinical onset. There are of course limitations to analyses such as this, including the quality of information on blood transfusion history for both sCJD cases and noncases, which may be recalled inaccurately by family members, and the potential bias that might arise if a noncomparable control group was selected. Preonset hospital medical records, where one might expect blood transfusions to be accurately recorded, are not routinely examined in CJD suspects or cases in the United Kingdom. As in the Italian study we have tried to minimize recall and other bias, by selecting a control group (noncases) that is comparable to patients with sCJD in terms of demographic and referral characteristics, all of whom had been notified and interviewed as CJD suspects before a more definitive later diagnosis. While data are more complete for patients with sCJD than for noncases, the age and sex distribution of both sCJD cases and noncases with known blood transfusion histories was no different from those with unknown histories who were excluded from

The geographical distribution of variant Creutzfeldt-Jakob disease cases in the UK: what can we learn from it?

The causative agents of variant Creutzfeldt-Jakob disease (vCJD) and of bovine spongiform encephalopathy (BSE) are currently indistinguishable. However, the route(s) by which humans became infected remain unknown. The path by which humans were infected with the BSE agent might impact on the geographical distribution of cases and we therefore sought evidence of regional variation and local clustering of vCJD cases. With the notable exception of a group of five cases in Leicestershire, the absence of local clustering of vCJD cases is compatible with most human exposure to the vCJD agent arising through routes that result in the risk of infection being similar over wide geographical areas, rather than through small-scale local events. Infection through the consumption of mechanically recovered meat (MRM) contaminated with the BSE agent was a potential route for such widespread exposure. An ecological analysis relating the regional incidence of vCJD to historical dietary data does not provide a clear evidence that humans became infected through consumption of MRM.