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Biomedical subjects

V Blair

Publications and source records attributed to V Blair.

At least 19 recordsLinked to original sources
PubMed2005

Chromoendoscopic surveillance in hereditary diffuse gastric cancer: an alternative to prophylactic gastrectomy?

BACKGROUND: Hereditary diffuse gastric cancer (HDGC) is defined by germline mutations in the E-cadherin gene, CDH-1. The first family in which CDH-1 mutations were identified was a large Maori kindred, where lifetime penetrance is 70%. Prophylactic gastrectomy is an unacceptable option for many mutation carriers. The results of annual chromoendoscopic surveillance using the methylene blue/congo red technique in 33 mutation carriers over a five year period are described. PATIENTS AND METHODS: Thirty three confirmed CDH-1 mutation carriers (18 males, 15 females), median age 32 years (range 14-69), were enrolled in 1999-2003. Medical records, endoscopy, and pathology were reviewed retrospectively. RESULTS: Over five years, 99 surveillance endoscopies were performed, of which 93 were chromo-dye enhanced. Sixty nine chromoendoscopies were normal. In 24 procedures, 1-6 pale areas/stomach (size 2-10 mm) were detected post chromo-dye application (totalling 56 pale lesions). One biopsy was taken from each pale lesion: 23 lesions (41%) showed signet ring cell carcinoma (10 patients), 10 lesions (18%) gastritis (four patients), and 23 (41%) normal mucosa (10 patients). No chromo-dyes were used in six procedures with macroscopic lesions (two HDGC, four ulceration). Total gastrectomies from patients with carcinoma were macroscopically normal but pathological mapping showed multiple microscopic foci of early signet ring cell carcinoma. Correlation of chromoendoscopic and gastrectomy findings showed that congo red/methylene blue detected carcinoma foci 4-10 mm in size but not foci <4 mm. CONCLUSIONS: The use of chromoendoscopy following normal white light gastroscopy facilitated detection of early gastric carcinoma foci not visible with white light gastroscopy. If these findings are validated in other HDGC kindred, chromogastroscopy represents an improved surveillance technique that can be safely considered alongside prophylactic gastrectomy.

Adolescent↗
PubMed2004

Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone.

BACKGROUND AND AIMS: Germline mutations in the CDH-1/E-cadherin gene are, to date, the only known cause of hereditary diffuse gastric cancer (HDGC). While two recent series of prophylactic gastrectomy described microscopic foci of signet ring cell carcinoma in sample sections from 10 macroscopically normal stomachs, whole stomach phenotype has not been mapped. We aimed to describe the size and distribution of foci in relation to mucosal zones and anatomical location. METHODS: Six patients (from three HDGC kindred) were referred for total gastrectomy via three different referral pathways. Following fixation, five stomachs were completely blocked and one extensively sampled. Histopathology was mapped to a mucosal photograph of each stomach, enabling precise localisation of carcinoma foci, benign pathology, and mucosal zones. RESULTS: There were 4-318 microscopic foci of intramucosal signet ring cell adenocarcinoma in the six macroscopically normal stomachs (foci size 0.1-10 mm in diameter). The distal third of the stomach contained 48% of total foci (range 29-75%). The body-antral transitional zone occupied 7.7% of mucosal area (range 3.6-11.8) but had 37% of foci (range 10%-75%). The largest foci were found in the transitional zone and foci density was five times greater in the transitional zone than in body or antral type mucosa. CONCLUSIONS: In germline CDH-1 mutation carriers, multiple microscopic foci of intramucosal signet ring cell carcinoma show a predilection for the distal stomach and the body-antral transitional zone. Targeting the transitional zone would maximise the likelihood of finding foci in macroscopically normal gastrectomies, and particular attention should be paid to this area during endoscopy.

Adolescent↗
PubMed2000

Space-time clustering patterns in childhood leukaemia support a role for infection.

Previous studies of space-time clustering in childhood leukaemia have produced equivocal and inconsistent results. To address this issue we have used Manchester Children's Tumour Registry leukaemia data in space-time clustering analyses. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km and close in time <1 year apart. Addresses at birth as well as diagnosis were utilized. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. All methods showed highly significant evidence of space-time clustering based on place of birth and time of diagnosis, particularly for all leukaemias aged 0-14 and 0-4 years, and acute lymphoblastic leukaemia (ALL) 0-4 years. Some results based on location at diagnosis were significant but mainly gave larger P-values. The results are consistent with an infectious hypothesis. Furthermore, we found an excess of male cases over females involved in space-time pairs. We suggest this may be related to genetic differences in susceptibility to infection between males and females. These findings provide the basis for future studies to identify possible infectious agents.

Adolescent↗
PubMed1999

Relationship with Family of Origin Scale (REFAMOS). Interrater reliability and associations with childhood experiences.

BACKGROUND: Family relationships in the transition from childhood to adult life may be important mediators of risk and resilience for adult psychopathology. AIMS: To develop a reliable and valid measure of the quality of relationships with each parent in young adults. METHOD: Interrater reliability of the Relationship with Family of Origin Scale (REFAMOS) was assessed from audio-taped interviews with 59 subjects. Age-related trends and associations with recalled childhood relationships were examined in survivors of childhood cancer and their controls (n = 178). RESULTS: Intraclass correlation coefficients were in the range 0.69-0.95, and kappa values 0.80-0.82. Indices of current closeness to mothers were negatively correlated with age of subject and positively correlated with recalled maternal care in childhood. Negative qualities in current relationships were correlated with recalled overprotection. CONCLUSIONS: The REFAMOS has good interrater reliability, and shows the predicted age-related trends in scores and associations with recalled childhood relationships.

Adolescent↗
PubMed1998

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Adolescent↗
PubMed1998

Seasonal variations in the onset of childhood leukaemia and lymphoma.

Infection has long been suspected as a possible factor in the aetiology of leukaemia and lymphoma. If seasonal variation in the onset of disease could be shown in any of the diagnostic subgroups of leukaemia or lymphoma, this would provide supportive evidence of an aetiology linked to exposure to infection. All cases in the Manchester Children's Tumour Registry (aged 0-14 years at diagnosis) with acute lymphoblastic leukaemia (ALL), acute non-lymphocytic leukaemia (ANLL), Hodgkin's disease (HD) or non-Hodgkin lymphoma (NHL) between 1 January 1954 and 31 December 1996 were included in an analysis of seasonal variation in the month of first symptom and the month of diagnosis. Cases of common acute lymphoblastic leukaemia (c-ALL) diagnosed from 1979 onwards were also analysed separately. The groups considered for analysis were: all cases of ALL (n = 1070), ALL diagnosed between 18 and 95 months of age (n = 730), ALL diagnosed over 95 months of age (n = 266), c-ALL (n = 309), ANLL (n = 244), all infant acute leukaemias (ALL and ANLL under 18 months; n = 107), HD (n = 166) and NHL (n = 189). Using the Edwards method, both c-ALL and HD demonstrated significant seasonal variation (P = 0.037 and 0.001 respectively) in date of first symptom, with peaks occurring in November and December respectively. Using this method, no indication of seasonal variation was found in the other diagnostic groups for date of first symptom or in any of the diagnostic groups for date of diagnosis. For comparison with a previous study, a further analysis based on date of diagnosis for all ALL cases, using summer-winter ratios, showed a significant summer excess. These results provide supportive evidence for an infectious aetiology for c-ALL and HD, and possibly for all ALL, which warrants further investigation.

Adolescent↗
PubMed1998

Evidence that an HLA-DQA1-DQB1 haplotype influences susceptibility to childhood common acute lymphoblastic leukaemia in boys provides further support for an infection-related aetiology.

Comparison of DQA1 and DQB1 alleles in 60 children with common acute lymphoblastic leukaemia (c-ALL) and 78 newborn infant control subjects revealed that male but not female patients had a higher frequency of DQA1*0101/*0104 and DQB1*0501 than appropriate control subjects. The results suggest a male-associated susceptibility haplotype in c-ALL and supports an infectious aetiology.

Alleles↗
PubMed1995

Radiotherapy in the treatment of low-grade astrocytomas. I. A survival analysis.

Between 1954 and 1986 inclusive, 160 children in the North West Region of England were registered with histologically proven lowgrade astrocytomas (grade 1 or 2). Ten died before receiving any treatment, and a further seven died within 28 days of surgery, leaving 143 children whose survival in relation to treatment modality is the subject of this paper. Low-grade astrocytomas are responsive to radiation therapy. This treatment has no clear benefit to offer children with superficial tumours that can be resected completely or nearly so, but significantly improves survival rates when tumours are deep-seated and not amenable to excision.

Adolescent↗
PubMed1995

Variation of expression of the gene for type 2 neurofibromatosis: absence of a gender effect on vestibular schwannomas, but confirmation of a preponderance of meningiomas in females.

Type 2 neurofibromatosis is a dominantly inherited disorder in which the great majority of sufferers develop bilateral vestibular schwannomas. In a UK study of 183 individuals from 112 families we have previously shown a fairly similar disease course within families, but quite marked inter-familial variation. We have confirmed an increase in severity when the gene is inherited from an affected mother, but evidence that women are more severely affected than men is lacking. Age at onset of symptoms, of deafness and at diagnosis are identical for the entire dataset and for a comparison of 10 male/female sibling pairs. Only three out of 42 pregnancies in symptomatic women were accompanied by a reversible worsening in symptoms due to vestibular schwannomas. Of 328 consecutive cases of unilateral vestibular schwannoma, there was no significant difference in the sex ratio or size. There now appears to be little evidence for a female hormonal effect on vestibular schwannomas. However, females with type 2 neurofibromatosis have significantly more meningiomas.

Adolescent↗
PubMed1995

Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene.

Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as "Gardner syndrome." Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dentoosseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort of FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5' of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3' of codon 1444, none of whom expressed CHRPE. Families with mutations 3' of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that the severity of some of the features of Gardner syndrome may correlate with genotype in FAP.

DNA↗
PubMed1994

Leukemia, lymphoma, and related disorders in families of children diagnosed with Wilms' tumor.

Leukemias and lymphomas occurring in a series of families with Wilms' tumor (WT) are described. One surviving case developed a large cell anaplastic Ki-1 lymphoma at age 20 years, and 23 second- and higher degree relatives were affected. In two instances leukemia/lymphoma occurred in the context of Li-Fraumeni syndrome (LFS) and two other families showed striking clusters of unusual and early-onset malignancies. In several cases, children had genitourinary abnormalities of the type associated with the WT1 gene on chromosome 11p13. Some of these families may provide important subjects for study of WT genes in hematologic disease and lymphomas and for investigation of interaction between different tumor-suppressor genes, e.g., WT1 and other candidate WT genes, and p53.

Adolescent↗
PubMed1994

Foetal loss and infant deaths in families of children with soft-tissue sarcoma.

Distribution of miscarriages, stillbirths and infant deaths in the families of a population-based series of children with soft-tissue sarcoma was examined in relation to index case histology (rhabdomyosarcoma or other soft-tissue sarcoma) and to the possible presence of genetic predisposition to cancer in the families (Li-Fraumeni syndrome or neurofibromatosis). Reproductive loss was not related to index histology (miscarriages, p = 0.3; all losses, p = 0.6) but was significantly higher in "genetic" rather than "sporadic" families (miscarriages, p = 0.02; all losses, p = 0.01). However, excess reproductive loss was not a feature of families with the Li-Fraumeni syndrome, but appeared to be concentrated in the families affected by neurofibromatosis.

Abortion, Spontaneous↗
PubMed1994

Second primary neoplasms in a population-based series of patients diagnosed with renal tumours in childhood.

Eight second malignant tumours developed in a population-based series of 218 patients diagnosed with renal tumours in childhood: renal cell carcinoma of the contralateral kidney, hepatocellular carcinoma, Hodgkin's disease, and 4 basal cell and 1 squamous cell carcinomas of skin. Excess risk of developing a second malignancy (excluding skin carcinomas but including a registrable spinal neurofibroma) was 14.7 (95% CI 4.0-37.7, P = 0.0003) for Wilms' tumour patients. Cumulative incidence of second malignant neoplasms (excluding skin carcinoma) was zero at 10 years, 5.0% at 20 years, and 10.2% at 30 years. The most common second neoplasms seen were benign osseous/chondromatous tumours and 4 of the 7 Wilms' tumour patients with malignant tumours had previous or synchronous tumours of this kind. Development of bony exostoses may be a marker for those patients at particularly high risk of subsequent malignancy.

Adolescent↗
PubMed1994

Genitourinary tumors in the families of children with renal tumors.

The occurrence of genitourinary tumors in the relatives of a population-based series of 218 children diagnosed with renal tumors was investigated. Family data on 92% (176 of 192) of Wilms' tumor (WT) patients and 77% (20 of 26) of other renal tumor patients were obtained. In all, 21 genitourinary tumors in first-degree relatives in 19 families were ascertained, together with 30 such tumors in second-degree relatives. Ten families were diagnosed with multiple genitourinary tumors, although none of these manifested familial WT. It is proposed that a small proportion of families of children with renal tumors has a genetic predisposition to develop genitourinary tumors and that these tumors may represent further manifestations of the pleiotropic effects of the WT1 gene or of other genes involved in WT predisposition.

Adult↗
PubMed1994

Patterns and temporal trends in the incidence of malignant disease in children: I. Leukaemia and lymphoma.

Patterns and trends in incidence of leukaemia and lymphoma in children aged under 15 years and resident in the North Western Regional Health Authority area of England at diagnosis, over the 35-year time period 1954-1988, were analysed. The study included 1407 cases registered with the Manchester Children's Tumour Registry, 100% of which had a histologically or cytologically verified diagnosis. Log-linear modelling identified significant linear increases in acute lymphocytic leukaemia (ALL) (average quinquennial increase 4%) and Hodgkin's disease (HD) (10%), but not in acute non-lymphocytic leukaemia nor non-Hodgkin's lymphoma. Additionally, the chi 2 test for trend identified a significant increase in the incidence of chronic myeloid leukaemia. The possibility that the increases seen in ALL and HD are linked to increases in prevalence of unknown infectious agents is discussed.

Adolescent↗
PubMed1994

Patterns and temporal trends in the incidence of malignant disease in children: II. Solid tumours of childhood.

Incidence patterns and trends, in children, of individual types of non-reticulo-endothelial solid tumours and of all cancers combined (including leukaemia and lymphoma) were analysed. The study included 3360 cases diagnosed in residents under 15 years of age of the North Western Regional Health Authority area of England during 1954-1988. Log-linear modelling identified significant increases of juvenile astrocytoma (average quinquennial increase 15%) in males, of medulloblastoma (19%) and neuroblastoma (17%) in females, and of non-skin epithelial tumours (18%) overall, and a significant decrease of unspecified malignant neoplasms around 1974 by approximately 80%. The chi 2 trend test identified significant increases in gonadal germ cell tumours and skin cancers, and borderline significant increases in craniopharyngioma and hepatoblastoma. The incidence of all cancers combined increased significantly in those aged under 1 year (8%), 1-4 years (5%) and 10-14 years (8%). Age-sex patterns were similar to those in other Caucasian populations. Studies of incidence trends can provide the basis for investigations of the aetiology of childhood cancers.

Adolescent↗