Cancer Research UK

About: Cancer Research UK is a nonprofit organization based out in London, United Kingdom. It is known for research contribution in the topics: Cancer & Gene. The organization has 1025 authors who have published 777 publications receiving 148154 citations. The organization is also known as: CRUK.

Portal vein chemotherapy for colorectal cancer: A meta-analysis of 4000 patients in 10 studies

Abstract: BACKGROUND Systemic delivery of cytotoxic drugs yields relatively low doses in the liver, a major site of recurrence for colorectal cancer. Giving chemotherapy by means of continuous portal vein infusion (PVI) into the liver during the immediate postoperative period may improve therapeutic efficacy. PURPOSE We undertook a meta-analysis to assess the effects on recurrence and survival of administering fluorouracil (5-FU)-based chemotherapy by PVI after colorectal cancer surgery. METHODS Data on mortality and recurrence were sought for all patients enrolled in randomized trials initiated before 1987 in which a few days (range, 5-7 days) of continuous postoperative PVI of cytotoxic drugs was compared with no further treatment. Data from 10 trials (a promising initial study and nine hypothesis-testing trials) involving about 4000 patients were available for analysis. The main cytotoxic drug in each trial was 5-FU (given with heparin); however, mitomycin C was co-administered in two of the trials. Four trials included an additional control group of patients treated with continuous noncytotoxic PVI of either heparin or urokinase alone; one trial included a second control group of patients treated with continuous systemic infusion of 5-FU. Reported P values are two-sided. RESULTS Among the 3499 patients randomly assigned to receive either cytotoxic PVI or no further treatment, 1557 deaths are known to have occurred. Survival with and without PVI appeared to be the same for the first 2 years; thereafter, it diverged significantly, with the absolute survival difference (i.e., improvement) associated with PVI at 5 years being 4.7 % (standard deviation [SD] = 1.2 %) (P = .006). When just the nine hypothesis-testing trials were considered, the absolute survival difference was 3.6% (SD = 1.2%) (P = .04). If, ignoring any potential for bias in stage assignment, attention was restricted to patients with Dukes' stage A, B, or C disease (88.3% of the total), the absolute effect on 5-year survival for all 10 trials increased to 6.0% (SD = 1.8%) (P = .001); this estimate remained statistically significant when the initial study was excluded (absolute survival difference = 4.8%; SD = 1.8%; P = .01). In contrast to the highly significant reduction in liver metastases seen in the initial study (79% reduction; SD = 15%; P = .00000007), the reduction found in the nine hypothesis-testing trials was not significant (14% reduction; SD = 10%; P = .2). In the trials with additional control groups, survival appeared to be better with cytotoxic PVI than with noncytotoxic PVI or with systemic cytotoxic drug infusion. CONCLUSIONS PVI of 5-FU (with or without other cytotoxic drugs) for about 1 week after surgery in patients with colorectal cancer may produce an absolute improvement in 5-year survival of a few percent. Although encouraging, this finding is not statistically secure, and additional evidence from randomized trials involving several thousand more patients is needed.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

Abstract: BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

Abstract: Dyskeratosis congenita (DC) is a heterogeneous inherited bone marrow failure and cancer predisposition syndrome in which germline mutations in telomere biology genes account for approximately one-half of known families. Hoyeraal Hreidarsson syndrome (HH) is a clinically severe variant of DC in which patients also have cerebellar hypoplasia and may present with severe immunodeficiency and enteropathy. We discovered a germline autosomal recessive mutation in RTEL1, a helicase with critical telomeric functions, in two unrelated families of Ashkenazi Jewish (AJ) ancestry. The affected individuals in these families are homozygous for the same mutation, R1264H, which affects three isoforms of RTEL1. Each parent was a heterozygous carrier of one mutant allele. Patient-derived cell lines revealed evidence of telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C. The molecular data and the patterns of inheritance are consistent with a hypomorphic mutation in RTEL1 as the underlying basis of the clinical and cellular phenotypes. This study further implicates RTEL1 in the etiology of DC/HH and immunodeficiency, and identifies the first known homozygous autosomal recessive disease-associated mutation in RTEL1.

Nomenclature for Factors of the HLA System, 1987

Abstract: The HLA Nomenclature Committee met after the Tenth International Histocompatibility Testing Workshop to consider revisions and additions to the nomenclature of specificities identified by serologic and cellular typing, and the naming of genes based on molecular techniques following the principles established in previous reports (1-7). Only nomenclature for HLA “class I” and “class II” products was considered. Special attention was given to the naming of genes and alleles in the HLA-D region.