PubMed Health⌕ Search

Biomedical subjects

J Mackay

Publications and source records attributed to J Mackay.

At least 19 recordsLinked to original sources
PubMed2006

Surgery for local recurrence of rectal cancer.

OBJECTIVE: Despite improvement in management of primary rectal cancer, 2.6-32% of patients develop local recurrence. A proportion of these patients can be amenable to salvage surgery. The present article reviews the evidence for and against the surgical management for local recurrence of rectal cancer, the role of adjuvant and intraoperative radiotherapy (IORT), and evaluates short and long-term outcomes. METHOD: A literature search was performed using Medline, Embase, Ovid and Cochrane database for studies between 1980 and 2005 assessing surgical management of local recurrence of rectal cancer and the evidence was critically evaluated. RESULTS: Nearly 50% of rectal cancer recurrences are local and are therefore potentially amenable to curative resection. Preoperative imaging is important for appropriate selection of patients for surgery and preoperative adjuvant therapy is essential. Five-year survival following resection ranges from 18% to 58% with 5-year survival following complete resection of over 35% though morbidity ranges from 21% to 82%. Neoadjuvant radiotherapy is beneficial and IORT may have a contributory role in treatment. Aggressive surgical treatment favourably affects quality of life and is cost effective. Surgery for local recurrence can result in significant long-term survival with acceptable morbidity and improved quality of life in appropriately selected patients. Assessment in a specialist centre familiar with these techniques is essential.

Combined Modality Therapy↗
PubMed2005

UK guidance for non-heart-beating donation.

This guidance offers consensus opinion on the optimum management of non-heart-beating organ donation in adult critical care units. The guidance is not meant to dictate practice but rather to offer suggestions as to what might be considered reasonable practice. The following sections mainly relate to the medical aspects of non-heart-beating organ donation. Fuller guidance on other aspects of organ and tissue donation is available on the Society's website (www.ics.ac.uk). There are a number of parallel areas of work, such as the law on consent, the definition of death and revision of the original Code of Practice describing brainstem testing, which means that many aspects of organ donation are changing rapidly. This guidance is designed to help critical care practitioners while these issues are resolved.

Adult↗
PubMed2005

A robust neural networks approach for spatial and intensity-dependent normalization of cDNA microarray data.

MOTIVATION: Microarray experiments are affected by numerous sources of non-biological variation that contribute systematic bias to the resulting data. In a dual-label (two-color) cDNA or long-oligonucleotide microarray, these systematic biases are often manifested as an imbalance of measured fluorescent intensities corresponding to Sample A versus those corresponding to Sample B. Systematic biases also affect between-slide comparisons. Making effective corrections for these systematic biases is a requisite for detecting the underlying biological variation between samples. Effective data normalization is therefore an essential step in the confident identification of biologically relevant differences in gene expression profiles. Several normalization methods for the correction of systemic bias have been described. While many of these methods have addressed intensity-dependent bias, few have addressed both intensity-dependent and spatiality-dependent bias. RESULTS: We present a neural network-based normalization method for correcting the intensity- and spatiality-dependent bias in cDNA microarray datasets. In this normalization method, the dependence of the log-intensity ratio (M) on the average log-intensity (A) as well as on the spatial coordinates (X,Y) of spots is approximated with a feed-forward neural network function. Resistance to outliers is provided by assigning weights to each spot based on how distant their M values is from the median over the spots whose A values are similar, as well as by using pseudospatial coordinates instead of spot row and column indices. A comparison of the robust neural network method with other published methods demonstrates its potential in reducing both intensity-dependent bias and spatial-dependent bias, which translates to more reliable identification of truly regulated genes.

Algorithms↗
PubMed2005

Oxaliplatin combined with infusional 5-fluorouracil and concomitant radiotherapy in inoperable and metastatic rectal cancer: a phase I trial.

The aim of this study was to define the recommended dose of oxaliplatin when combined with infusional 5-fluorouracil (5-FU) and concurrent pelvic radiotherapy. Eligible patients had inoperable rectal cancer, or symptomatic primary rectal cancer with metastasis. Oxaliplatin was given on day 1 of weeks 1, 3 and 5 of radiotherapy. Dose level 1 was oxaliplatin 70 mg m(-2) with 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1). On dose level 2, the oxaliplatin dose was increased to 85 mg m(-2). On dose level 3, the duration of the 5-FU was increased to 168 h per week. Pelvic radiotherapy was 45 Gray (Gy) in 25 fractions over 5 weeks with a boost of 5.4 Gy. Fluorine-18 fluoro deoxyglucose and Fluorine-18 fluoro misonidazole positron emission tomography (FDG-PET and FMISO-PET) were used to assess metabolic tumour response and hypoxia. In all, 16 patients were accrued. Dose-limiting toxicities occurred in one patient at level 2 (grade 3 chest infection), and two patients at level 3 (grade 3 diarrhoea). Dose level 2 was declared the recommended dose level. FDG-PET imaging showed metabolic responses in 11 of the 12 primary tumours assessed. Four of six tumours had detectable hypoxia on FMISO-PET scans. The addition of oxaliplatin to infusional 5-FU chemoradiotherapy was feasible and generally well tolerated. For future trials, oxaliplatin 85 mg m(-2) and 5-FU 200 mg m(-2) day(-1) continuous infusion 96 h week(-1) is the recommended dose when combined with 50.4 Gy of pelvic radiotherapy.

Adult↗
PubMed2005

Security and confidentiality approach for the Clinical E-Science Framework (CLEF).

OBJECTIVES: CLEF is an MRC sponsored project in the E-Science programme that aims to establish methodologies and a technical infrastructure for the next generation of integrated clinical and bioscience research. METHODS: The heart of the CLEF approach to this challenge is to design and develop a pseudonymised repository of histories of cancer patients that can be accessed by researchers. Robust mechanisms and policies have been developed to ensure that patient privacy and confidentiality are preserved while delivering a repository of such medically rich information for the purposes of scientific research. RESULTS: This paper summarises the overall approach adopted by CLEF to meet data protection requirements, including the data flows, pseudonymisation measures and additional monitoring policies that are currently being developed. CONCLUSION: Once evaluated, it is hoped that the CLEF approach can serve as a model for other distributed electronic health record repositories to be accessed for research.

Access to Information↗
PubMed2004

Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort.

This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 91 gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at any time point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41 yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.

Adult↗
PubMed2004

A cross-sectional survey to estimate the prevalence of family history of colorectal, breast and ovarian cancer in a Scottish general practice population.

A cross-sectional survey of all patients aged 30-65 in four general practices within one Local Health Care Co-operative in Fife, Scotland was undertaken to measure the prevalence of family history of colorectal, breast and ovarian cancer. A total of 7619 patients aged 30-65 responded to a postal questionnaire (response rate 59%). In all, 17% of respondents (1324, 95% Cl 16-18%) reported a relative affected by colorectal, breast or ovarian cancer. Of those, 6% (78, 95% CI 5-7%) met the Scottish guidelines for referral for genetics counselling. In all, 2% (24, 95% CI 1-3%) of all individuals with an affected relative had received genetic counselling and risk assessment. Of these, 25% (6, 95% CI 8-42%) met the moderate- or high-risk criteria for developing a cancer. In conclusion, the number of patients who are at a significantly increased risk of cancer on the basis of a family history is small (approximately 10 per General Practitioner (GP) list). It is therefore unrealistic to expect GPs to develop expertise in genetic risk estimation. A simple family history chart or pedigree is one way that a GP can, within the constraints of a GP consultation, determine which patients should be reassured and which referred to the local cancer genetic clinic.

Adult↗
PubMed2004

A phase I trial of preoperative radiotherapy and capecitabine for locally advanced, potentially resectable rectal cancer.

The purpose of the study was to determine the maximum-tolerated dose (MTD) of oral capecitabine, combined with concurrent, standard preoperative pelvic radiotherapy, when given twice daily, from Monday to Friday throughout the course of radiotherapy, for locally advanced potentially resectable rectal cancer. Maximum-tolerated dose was defined as the total (given in two equally divided doses) oral dose of capecitabine that caused treatment-related grade 3 or 4 toxicity in one-third or more of the patients treated. Radiotherapy involved 50.4 Gy given in 28 fractions in 5 weeks and 3 days. Eligible patients had a newly diagnosed clinical stage T3-4 N0-2 M0 rectal adenocarcinoma located within 12 cm of the anal verge suitable for curative resection. Surgery was performed 4-6 weeks from completion of preoperative chemoradiotherapy. In all, 28 patients were enrolled in the study at predefined dose levels: 850 mg m(-2) day(-1) (n=3), 1000 mg m(-2) day(-1) (n=6), 1250 mg m(-2) day(-1) (n=3), 1650 mg m(-2) day(-1) (n=3), 1800 mg m(-2) day(-1) (n=8) and 2000 mg m(-2) day(-1) (n=5). The mean age was 62.3 years (range: 33-80 years). Five patients were female and 23 male. The median distance of tumour from the anal verge was 6 cm (range: 1-11 cm). Endorectal ultrasound was performed in 93% of patients. A total of 26 patients (93%) had T3 disease and two patients had resectable T4 disease. Dose-limiting toxicity (DLT) developed in one patient at dose level 1000 mg m(-2) day(-1) (RTOG grade 3 cystitis). Two of the five patients at dose level 2000 mg m(-2) day(-1) had a total of three DLT (grade 3 perineal skin reaction, grade 3 diarrhoea and grade 3 dehydration). Dose escalation of capecitabine was ceased at 2000 mg m(-2) day(-1) after reaching MTD. None of the eight patients at dose level 1800 mg m(-2) day(-1) developed DLT. All except one patient underwent surgery. A total of 15 patients had the clinical T stage reduced by at least one stage in pathologic specimens. Five patients (19%) achieved a pathologic complete response. We conclude that the MTD of capecitabine was reached at a dose level of 2000 mg m(-2) day(-1), given as 1000 mg m(-2) twice daily, from Monday to Friday throughout the course of preoperative pelvic irradiation of 50.4 Gy. For patients with resectable rectal cancer receiving concurrent, full dose radiotherapy, the recommended dose of capecitabine for further study is 1800 mg m(-2) day(-1) when given in this schedule.

Adenocarcinoma↗
PubMed2004

Non-uptake of predictive genetic testing for BRCA1/2 among relatives of known carriers: attributes, cancer worry, and barriers to testing in a multicenter clinical cohort.

BRCA1/2 test decliners/deferrers have received almost no attention in the literature and this is the first study of this population in the United Kingdom. The aim of this multicenter study is to examine the attributes of a group of individuals offered predictive genetic testing for breast/ovarian cancer predisposition who did not wish to proceed with testing at the time of entry into this study. This forms part of a larger study involving 9 U.K. centers investigating the psychosocial impact of predictive genetic testing for BRCA1/2. Cancer worry and reasons for declining or deferring BRCA1/2 predictive genetic testing were evaluated by questionnaire following genetic counseling. A total of 34 individuals declined the offer of predictive genetic testing. Compared to the national cohort of test acceptors, test decliners are significantly younger. Female test decliners have lower levels of cancer worry than female test acceptors. Barriers to testing include apprehension about the result, traveling to the genetics clinic, and taking time away from work/family. Women are more likely than men to worry about receiving less screening if found not to be a carrier. The findings do not indicate that healthy BRCA1/2 test decliners are a more vulnerable group in terms of cancer worry. However, barriers to testing need to be discussed in genetic counseling.

Adult↗
PubMed2003

Issues of consent and feedback in a genetic epidemiological study of women with breast cancer.

Women (N=21) who had had breast cancer and had been enrolled in a large genetic breast cancer epidemiological study were interviewed about their experience of participation in the study, their attitudes to the confidentiality of data, and the feedback of personal and general research results. Collection of family history information seemed more salient in indicating the genetic nature of the study than the enrolment information sheet. There were no concerns about confidentiality. While participants would have welcomed general feedback about the results of the study and were critical that this had not been provided, the feedback of personal information proved complicated and, sometimes, difficult. It is suggested that individual feedback of genetic test information in epidemiological studies should be undertaken only when there are specific reasons.

Adult↗
PubMed2002

Predictive testing for BRCA1/2: attributes, risk perception and management in a multi-centre clinical cohort.

The aim of this multi-centre UK study is to examine the attributes of a cohort offered predictive genetic testing for breast/ovarian cancer predisposition. Participants are adults unaffected with cancer from families with a known BRCA1/2 mutation. This is the first large multi-centre study of this population in the UK. The study evaluates mental health, perceived risk of developing cancer, preferred risk management options, and motivation for genetic testing. Participants were assessed when coming forward for genetic counselling prior to proceeding to genetic testing. Three hundred and twelve individuals, 76% of whom are female, from nine UK centres participated in the study. There are no gender differences in rates of psychiatric morbidity. Younger women (<50 years) are more worried about developing cancer than older women. Few women provide accurate figures for the population risk of breast (37%) or ovarian (6%) cancer but most think that they are at higher risk of developing breast (88%) and ovarian (69%) cancer than the average woman. Cancer related worry is not associated with perceived risk or uptake of risk management options except breast self-examination. The findings indicate that younger women may be particularly vulnerable at the time of the offer of a predictive genetic test.

Adult↗
PubMed2002

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS).

The UK national study of magnetic resonance imaging as a method of screening for breast cancer (MARIBS) is in progress. The study design, accrual to date, and related research projects are described. Revised accrual rates and expected recruitment are given. 15 cancers have been detected to date, from a total of 1236 screening measurements. This event rate and the tumour grades reported are compared with recent reports from other studies in women at high risk of breast cancer.

Adult↗
PubMed2001

The N-terminal zinc finger of the erythroid transcription factor GATA-1 binds GATC motifs in DNA.

The mammalian transcription factor GATA-1 is required for normal erythroid and megakaryocytic development. GATA-1 contains two zinc fingers, the C-terminal finger, which is known to bind (A/T)GATA(A/G) motifs in DNA and the N-finger, which is important for interacting with co-regulatory proteins such as Friend of GATA (FOG). We now show that, like the C-finger, the N-finger of GATA-1 is also capable of binding DNA but recognizes distinct sequences with the core GATC. We demonstrate that the GATA-1 N-finger can bind these sequences in vitro and that in cellular assays, GATA-1 can activate promoters containing GATC motifs. Experiments with mutant GATA-1 proteins confirm the importance of the N-finger, as the C-finger is not required for transactivation from GATC sites. Recently four naturally occurring mutations in GATA-1 have been shown to be associated with familial blood disorders. These mutations all map to the N-finger domain. We have investigated the effect of these mutations on the recognition of GATC sites by the N-finger and show that one mutation R216Q abolishes DNA binding, whereas the others have only minor effects.

Amino Acid Sequence↗