IL-1-cytokines are strongly involved in carcinogenesis and tumor genesis. In this systematic review we will describe the role of IL-1 RA within the cytokine network and its predictive and prognostic value in cancer.

To conduct a systematic review of the effects of genetic counselling and testing for familial breast cancer on women's perception of risk and psychological morbidity.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewing's sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFT's were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.

Familial adenomatous polyposis (FAP) is a well-known hereditary colorectal cancer-predisposing syndrome. Genetic testing for colorectal cancer risk is now part of standard medical practice, but very little is known about the economic impact of this technology. The aim of this study was to assess, from a healthcare system perspective, the direct costs of two strategies for screening at-risk relatives of FAP patients: clinical screening versus genetic testing for FAP.

Exposure to cadmium fumes or dusts has been associated with an increased risk of lung cancer and the characterisation of the genotoxic potential of cadmium compounds is, among other possible mechanisms, an important element in the assessment of the carcinogenic hazard of the element. While there is some evidence that in experimental systems, cadmium compounds may exert genotoxic effects, the results of the epidemiological studies having examined cytogenetic endpoints in humans exposed to cadmium appear conflicting. Therefore, a systematic review was undertaken to assess whether a cytogenetic effect of cadmium exposure is supported by the studies with the strongest design.

The literature relating to human leucocyte antigens (HLA) and nasopharyngeal carcinoma (NPC) identifies conflicting ranges of possible allelic associations. We aimed to clarify this by conducting a systematic review to identify and quantify associations present across all of the available studies. A literature search was performed and, subsequently, a meta-analysis was performed on 13 published studies using both fixed-effects and random-effects models when appropriate. Evidence for positive associations between NPC and the HLA alleles A2, B14 and B46 (P = 1.57 x 10-5, 1.13 x 10-3 and 6.38 x 10-5 respectively) were found, and negative associations were identified for the alleles A11, B13 and B22 (P = 5.42 x 10-3, 0.017 and 0.009). Whereas an association between HLA-B13 or B22 and NPC has not been noted previously, the results for HLA-A2, A11, B14 and B46 are in accordance with published studies. There is evidence that specific allele subtypes or combinations of alleles may carry particular risk for NPC.

The role of p53, as a prognostic factor for survival in lung cancer, is controversial and the purpose of the present systematic review of the literature is to determine this effect. Published studies were identified with the objective to aggregate the available survival results after a methodological assessment using a scale specifically designed by the European Lung Cancer Working Party (ELCWP). To be eligible, a study had to deal with p53 assessment in lung cancer (primary site) only, and to provide a survival comparison according to the p53 status. Among the 74 eligible papers, 30 identified p53 abnormalities as a univariate statistically significant poor prognostic factor and 56 provided sufficient data to allow survival results aggregation. There was no significant difference between the trials that either showed or did not show a prognostic effect of p53 according to the methodological score or to the laboratory technique used. The studies were categorized by histology, disease stage, treatment and laboratory technique. Combined hazard ratios suggested that an abnormal p53 status had an unfavourable impact on survival: in any stage nonsmall cell lung cancer (NSCLC) the mean (95% confidence interval) was 1.44 (1.20-1.72) (number of studies included in the subgroup was 11), 1.50 (1.32-1.70) in stages I-II NSCLC (n=19), 1.68 (1.23-2.29) in stages I-IIIB NSCLC (n=5), 1.68 (1.30-2.18) in stages III-IV NSCLC (n=9), 1.48 (1.29-1.70) in surgically resected NSCLC (n=20), 1.37 (1.02-1.85) in squamous cell carcinoma (n=9), 2.24 (1.70-2.95) in adenocarcinoma (n=9), 1.57 (1.28-1.91) for a positive immunohistochemistry with antibody 1801 (n=8), 1.25 (1.09-1.43) for a positive immunohistochemistry with antibody DO-7 (n=16), and 1.65 (1.35-2.00) for an abnormal molecular biology test (n=13). Data were insufficient to determine the prognostic value of p53 in small cell lung cancer. In each subgroup of nonsmall cell lung cancer, p53 abnormal status was shown to be associated with a poorer survival prognosis.

The aim of this study was to identify published studies quantifying familial colorectal cancer (CRC) risks in first-degree relatives of CRC and colorectal adenoma (CRA) cases and, through a meta-analysis, obtain more precise estimates of familial risk according to the nature of the family history and type of neoplasm.

Increasingly, studies of the relationship between common genetic variants and colorectal tumor risk are being proposed. To assess the evidence that any of these confers a risk, a systematic review and meta-analysis of published studies was undertaken.

The results of individual studies examining the role of p53 as a predictive and prognostic factor in lymphoid malignancies have varied considerably. In order to summarize the available data on the overexpression or mutation of p53 in Hodgkin's and non-Hodgkin's lymphoma, a systematic literature review was performed. Twenty-four studies met the eligibility criteria. With respect to non-Hodgkin's lymphoma, most studies seem to support the hypothesis that patients whose tumors contain wild-type p53 respond better to treatment and have increased survival rates. If true, the implication may be that patients with p53 mutated tumors could be selected for non-standard treatment. With respect to Hodgkin's lymphoma, comparable associations were rarely reported. However, techniques for assessing the inactivation of p53 varied widely. Furthermore, in most instances, the study design and/or statistical methods did not allow sufficient analyses of the influence of confounding factors such as histologic type, stage, first-line and salvage treatment, etc. Therefore, it remains unclear whether the apparent influence of p53 status on outcome in non-Hodgkin's lymphoma is independent of established parameters such as stage, performance status, etc. Further studies involving large numbers of specimens derived from patients treated in clinical trials with identical regimens, follow-up and salvage strategies are needed. These studies should also be stratified according to histologic subtypes.

To obtain refined knowledge regarding trilateral retinoblastoma (TRb), which is a syndrome that consists of hereditary retinoblastoma associated with an intracranial neuroblastic tumor.

Studies investigating the relationship between common genetic variants and cancer risk are being reported with rapidly increasing frequency. We have identified 46 published case-control studies that have examined the effect of common alleles of 18 different genes on breast cancer risk. Of these, 12 report statistically significant associations, none of which were reported by more than one study. However, many of the studies were small: 10 of the 46 had 80% power or greater to detect a rare allele homozygote relative risk <2.5. We therefore combined the results of individual studies to obtain more precise estimates of risk. Statistically significant differences in genotype frequencies were found in three case-control comparisons of unselected cases. These were for CYP19 (TTTA)n polymorphism [(TTTA)10 carrier odds ratio (OR) = 2.33; P = 0.002], the GSTP1 Ile105Val polymorphism (Val carrier OR = 1.60; P = 0.02), and the TP53 Arg72Pro polymorphism (Pro carrier OR = 1.27; P = 0.03). In addition, the GSTM1 gene deletion was found to be significantly associated with postmenopausal breast cancer (null homozygote OR = 1.33; P = 0.04). There was also some evidence that homozygotes for the PR PROGINS allele are protected against breast cancer, although this result was of borderline statistical significance. For polymorphisms in BRCA1, COMT, CYP17, CYP1A1, NAT1, and NAT2, the best estimate of risk either from the individual studies or the meta-analyses was sufficiently precise to exclude a relative risk of 1.5 or greater. For the polymorphisms in EDH17B2, ER, CYP2D6, CYP2E1, GSTT1, HSP70, and TNFalpha, the risk estimates, although nonsignificant, were insufficiently precise to exclude a moderate risk (>1.5). Precise estimation of the risks associated with these and other as yet untested genes, as well as investigation of more complex risks arising from gene-gene and gene-environment interactions, will require much larger studies.

Meta-analysis, though increasingly popular in clinical medicine, has not found acceptance in anatomic pathology. This paper argues that, in combination with a systematic review of the literature, meta-analysis may be usefully applied to pathological research and two examples drawn from gynaecological pathology (the value of nuclear DNA quantitation in predicting progression in low grade cervical intraepithelial neoplasia and the difference in prognosis between squamous cell carcinoma and adenocarcinoma of the cervix) are included to illustrate the methods used and to demonstrate some of the difficulties associated with these techniques.

To estimate the relative risk and lifetime risk of ovarian cancer in women with various categories of family history.

An increased risk of breast cancer in women with a family history of breast cancer has been demonstrated by many studies using a variety of study designs. However, the extent of this risk varies according to the nature of the family history (type of relative affected, age at which relative developed breast cancer and number of relatives affected) and may also vary according to age of the individual. The aim of our study was to identify all the published studies which have quantified the risk of breast cancer associated with a family history of the disease, and to summarise the evidence from these studies, with particular emphasis on age-specific risks according to subject and relative age. Seventy-four published studies were identified. The pooled estimate of relative risk (RR) associated with various family histories was as follows: any relative, RR = 1.9 (95% CI, 1.7-2.0); a first-degree relative, RR = 2.1 (CI = 2.0, 2.2); mother, RR = 2.0 (CI = 1.8, 2.1); sister, RR = 2.3 (CI = 2.1, 2.4); daughter, RR = 1.8 (CI = 1.6, 2.0); mother and sister, RR = 3.6 (CI = 2.5, 5.0); and a second-degree relative, RR = 1.5 (CI = 1.4, 1.6). Risks were increased in subjects under age 50 and when the relative had been diagnosed before age 50.

The molecular epidemiology of p53 mutations allows the possibility of correlating particular mutations with specific environmental carcinogens and establishing one step in the causal pathway between exposure to carcinogens and the development of cancer. A striking example is the G > T transversion at the third base pair of codon 249 observed in liver cancer patients possibly exposed to high levels of aflatoxins in their agricultural products. In this paper, we describe a systematic review of the literature and access the quality of the available data. We found methodologic limitations in the studies. In particular, the key independent variable, aflatoxin exposure, was not assessed in these studies, with the exception of one study that measured a marker of exposure. Instead, nationality, geographic residence, or geographic site of hospital were used as surrogate markers for exposure. Patients from areas with high aflatoxin levels were more likely to have p53 mutations than were patients from areas with low aflatoxin levels. In the group with p53 mutations, patients from areas with high aflatoxin levels had higher proportions of mutations with codon 249 G > T transversions. The differences in proportions with p53 mutations were significant, as were the differences in proportions of codon 249 G > T transversions among patients with p53 mutations. Aflatoxin may increase the proportion of p53 mutations by causing a single mutation, the codon 249 G > T transversion, thus explaining some of the excess liver cancer associated with aflatoxin exposure. However, it is premature to conclude that p53 mutations are established markers for environmental carcinogens.

The concurrent finding of neurofibromatosis type 1 (NF), juvenile chronic myelogenous leukemia (JCML), and juvenile xanthogranuloma (JXG) has been repeatedly reported. Juvenile chronic myelogenous leukemia has been found more frequently in patients with NF and may present with various cutaneous manifestations, including JXG. To our knowledge, the relationship among these three entities has never been explored. The purpose of the present study is to explore this relationship by using a systematic review of the literature. We present five demonstrative cases of various associations among NF, JCML, and JXG.

A systematic review of the more than 2,000 genetic loci of man cataloged by McKusick indicated that approximately 7% may play a role in modulating the rates of development of various aspects of the senescent phenotype. Assuming an upper limit of about 100,000 loci in man, numerous alleles at approximately 7,000 loci could be contributing to characteristic patterns of aging in individual human beings. Point mutations or chromosomal aberrations involving such loci may result in various progeroid syndromes. These have been classified into two categories: segmental progeroid syndromes, which involve multiple aspects of the senescent phenotype, and unimodal progeroid syndromes, in which predominantly one aspect of the phenotype is involved. Two different examples of segmental progeroid syndromes were discussed: the Werner syndrome (an autosomal recessive) and the Down syndrome (trisomy 21). Examples of unimodal progeroid syndromes included familial hypercholesterolemia (accelerated atherogenesis), xeroderma pigmentosum (acceleration of skin aging, including age-related neoplasms), and certain forms of intestinal polyposis (acceleration of adenocarcinoma of the colon). It is remarkable and encouraging that the biochemical genetic basis of many progeroid syndromes, including all of those mentioned above, may be amenable to investigation with cultured mesenchymal somatic cells from individual subjects. For example, cells from patients with the Werner's syndrome have a striking limitation of their in vitro replicative life-spans and undergo extensive chromosomal rearrangements. These abnormalities are presumably related to an enzyme deficiency which, in principle, could be identified by biochemical studies of cultured cells.