Estimating micro area behavioural risk factor prevalence from large population-based surveys: a full Bayesian approach.

BACKGROUND: An important public health goal is to decrease the prevalence of key behavioural risk factors, such as tobacco use and obesity. Survey information is often available at the regional level, but heterogeneity within large geographic regions cannot be assessed. Advanced spatial analysis techniques are demonstrated to produce sensible micro area estimates of behavioural risk factors that enable identification of areas with high prevalence. METHODS: A spatial Bayesian hierarchical model was used to estimate the micro area prevalence of current smoking and excess bodyweight for the Erie-St. Clair region in southwestern Ontario. Estimates were mapped for male and female respondents of five cycles of the Canadian Community Health Survey (CCHS). The micro areas were 2006 Census Dissemination Areas, with an average population of 400-700 people. Two individual-level models were specified: one controlled for survey cycle and age group (model 1), and one controlled for survey cycle, age group and micro area median household income (model 2). Post-stratification was used to derive micro area behavioural risk factor estimates weighted to the population structure. SaTScan analyses were conducted on the granular, postal-code level CCHS data to corroborate findings of elevated prevalence. RESULTS: Current smoking was elevated in two urban areas for both sexes (Sarnia and Windsor), and an additional small community (Chatham) for males only. Areas of excess bodyweight were prevalent in an urban core (Windsor) among males, but not females. Precision of the posterior post-stratified current smoking estimates was improved in model 2, as indicated by narrower credible intervals and a lower coefficient of variation. For excess bodyweight, both models had similar precision. Aggregation of the micro area estimates to CCHS design-based estimates validated the findings. CONCLUSIONS: This is among the first studies to apply a full Bayesian model to complex sample survey data to identify micro areas with variation in risk factor prevalence, accounting for spatial correlation and other covariates. Application of micro area analysis techniques helps define areas for public health planning, and may be informative to surveillance and research modeling of relevant chronic disease outcomes.

Influence of pre-diagnostic cigarette smoking on colorectal cancer survival: overall and by tumour molecular phenotype.

BACKGROUND: Smoking is a risk factor for incident colorectal cancer (CRC); however, it is unclear about its influence on survival after CRC diagnosis. METHODS: A cohort of 706 CRC patients diagnosed from 1999 to 2003 in Newfoundland and Labrador, Canada, was followed for mortality and recurrence until April 2010. Smoking and other relevant data were collected by questionnaire after cancer diagnosis, using a referent period of '2 years before diagnosis' to capture pre-diagnosis information. Molecular analyses of microsatellite instability (MSI) status and BRAF V600E mutation status were performed in tumour tissue using standard techniques. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards regression, controlling for major prognostic factors. RESULTS: Compared with never smokers, all-cause mortality (overall survival, OS) was higher for current (HR: 1.78; 95% CI: 1.04-3.06), but not for former (HR: 1.06; 95% CI: 0.71-1.59) smokers. The associations of cigarette smoking with the study outcomes were higher among patients with ≥40 pack-years of smoking (OS: HR: 1.72; 95% CI: 1.03-2.85; disease-free survival (DFS: HR: 1.99; 95% CI: 1.25-3.19), those who smoked ≥30 cigarettes per day (DFS: HR: 1.80; 95% CI: 1.22-2.67), and those with microsatellite stable (MSS) or MSI-low tumours (OS: HR: 1.38; 95% CI: 1.04-1.82 and DFS: HR: 1.32; 95% CI: 1.01-1.72). Potential heterogeneity was noted for sex (DFS HR: 1.68 for men and 1.01 for women: P for heterogeneity=0.04), and age at diagnosis (OS: HR: 1.11 for patients aged <60 and 1.69 for patients aged ≥60: P for heterogeneity=0.03). CONCLUSIONS: Pre-diagnosis cigarette smoking is associated with worsened prognosis among patients with CRC.

Preventing ovarian cancer through genetic testing: a population-based study.

Genetic testing for BRCA1 and BRCA2 gene mutations, in conjunction with preventive salpingo-oophorectomy for mutation carriers, may be used to prevent a proportion of invasive ovarian cancers ('personalized medicine'). We evaluated the potential utility of this approach at a population level by reviewing the pedigree information and genetic test results from 1342 ovarian cancer patients in Ontario. Of the 1342 patients tested, 176 patients had a BRCA1 or BRCA2 mutation; of these, 48 women would have qualified for testing prior to the development of cancer based on the eligibility criteria in place for the province of Ontario. In summary, 48 of 1342 unselected cases of ovarian cancer (3.6%) might have been prevented if genetic testing criteria were universally applied to all women in Ontario at risk for ovarian cancer.

Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO).

BACKGROUND: The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated. METHODS: We performed a pooled analysis of six case-control studies (1961 cases and 2609 controls) contributing to the International Lung Cancer Consortium. Potential associations were investigated with multivariable unconditional logistic regression and meta-analytic models. Multinomial logistic regressions were performed to investigate lung cancer risk across histologic types. RESULTS: A reduced lung cancer risk was found for OC (odds ratio (OR)=0.81; 95% confidence interval (CI): 0.68-0.97) and HRT ever users (OR=0.77; 95% CI: 0.66-0.90). Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk (OR=0.76; 95% CI: 0.61-0.94, and OR=0.66; 95% CI: 0.49-0.88, respectively). No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma (OR=0.53; 95% CI: 0.37-0.76) in OC users and in both adenocarcinoma (OR=0.79; 95% CI: 0.66-0.95) and small cell carcinoma (OR=0.37; 95% CI: 0.19-0.71) in HRT users. No interaction with smoking status or BMI was observed. CONCLUSION: Our findings suggest that exogenous hormones can play a protective role in lung cancer aetiology. However, given inconsistencies with epidemiological evidence from cohort studies, further and larger investigations are needed for a more comprehensive view of lung cancer development in women.

Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph).

BACKGROUND: The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes. PATIENTS AND METHODS: Through the InterLymph Consortium, 12 case-control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein-Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls. RESULTS: Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01-1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29-1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27-2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90-1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72-1.44) was not increased. CONCLUSION: These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.

Estimating survival rates after ovarian cancer among women tested for BRCA1 and BRCA2 mutations.

Several studies have reported that women with ovarian cancer and a BRCA1 or BRCA2 mutations have better survival than women with ovarian cancer and no mutation. Potential reasons for this include possible differences in histologic subtype, stage, grade and response to chemotherapy, but some of the difference in survival may be due to systematic bias, i.e. a difference in survival rates for women who do and who do not undergo genetic testing. We estimated the survival rate in 1423 ovarian cancer patients from Ontario who had genetic testing and compared this with the survival rate for all 3367 ovarian cancer patients from the province from whom the tested sample was derived. Tested women had a 10-year survival of 54.5%, compared to 35.8% for all patients in the province. We evaluated the extent to which three different methods of adjustment eliminated the observed difference. The adjusted rates for the tested cohort were closer to the provincial average, but each adjustment method resulted in a modest over-estimate of 10-year survival, ranging from 6.1% to 10.0%. The mortality advantage for tested women was due, in part, to a lower than expected mortality rate of tested women in the period following genetic testing.

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients.

BACKGROUND: In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs. METHODS: Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival. RESULTS: In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4-7.4, P<10(-6)) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9-21.7, P<10(-17)), but was not associated with patient survival. Concordant results were obtained in Newfoundland. CONCLUSION: Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.

Very high incidence of familial colorectal cancer in Newfoundland: a comparison with Ontario and 13 other population-based studies.

Newfoundland has the highest rate of colorectal cancer (CRC) of any Canadian province. In order to investigate the factors, especially genetic components, responsible for CRC we established the Newfoundland Colorectal Cancer Registry. In a 5-year period we examined every case of CRC diagnosed under the age of 75 years and obtained consent from 730 cases. Careful analysis of family history was used to assign a familial cancer risk, based on established criteria. We observed that 3.7% of CRC cases came from families meeting the Amsterdam II criteria and a further 0.9% of cases involved familial adenomatous polyposis (FAP). An additional 43% of cases met one or more of the revised Bethesda criteria and 31% of all cases had a first-degree relative affected with CRC. We compared the Newfoundland data with data from the province of Ontario, where the same recruitment and risk-assessment criteria were used. In all categories, the indicators of familial risk were significantly higher in Newfoundland. These data were also compared to results published from 13 other population-based studies worldwide. In every category the proportion of Newfoundland cases meeting the criteria was higher than in any other population. The mean differences were: 3.5-fold greater for FAP, 2.8-fold higher for Amsterdam criteria, 2.0-fold higher for Bethesda criteria and 1.9-fold higher for the number of affected first-degree relatives. We conclude that the high incidence of CRC in Newfoundland may be attributable to genetic, or at least familial, factors. In the high-risk families we provide evidence for the involvement of founder mutations in the APC and MSH2 genes.

The outcome of total hip replacement in obese and non-obese patients at 10- to 18-years.

We studied a consecutive series of 285 uncemented total hip replacements in 260 patients using the Taperloc femoral component and the T-Tap acetabular component. The outcome of every hip was determined in both living and deceased patients. A complete clinical and radiological follow-up was obtained for 209 hips in 188 living patients, followed for a mean of 14.5 years (10 to 18.9). They were divided into two groups, obese and non-obese, as determined by their body mass index. There were 100 total hip replacements in 89 patients in the obese cohort (body mass index > or = 30 kg/m(2)), and 109 in 99 non-obese (body mass index < 30 kg/m(2)) patients. A subgroup analysis of 31 patients of normal weight (body mass index 20 kg/m(2) to 25 kg/m(2)) (33 hips) and 26 morbidly obese patients (body mass index > or = 35 kg/m(2)) (30 hips) was also carried out. In the obese group five femoral components (5%) were revised and one (1%) was loose by radiological criteria. Femoral cortical osteolysis was seen in eight hips (8%). The acetabular component was revised in 57 hips (57%) and a further 17 (17%) were loose. The mean Harris hip score improved from 52 (30 to 66) pre-operatively to 89 (49 to 100) at final follow-up. Peri-operative complications occurred in seven patients (7%). In the non-obese group six (6%) femoral components were revised and one (1%) was loose. Femoral cortical osteolysis occurred in six hips (6%). The acetabular component was revised in 72 hips (66%) and a further 18 (17%) were loose. The mean Harris hip score increased from 53 (25 to 73) prior to surgery to 89 (53 to 100) at the time of each patient's final follow-up radiograph. No statistically significant difference was identified between the obese and non-obese patients with regards to clinical and radiological outcome or complications. The subgroup analysis of patients of normal weight and those who were morbidly obese showed no statistically significant difference in the rate of revision of either component. Our findings suggest there is no evidence to support withholding total hip replacement from obese patients with arthritic hips on the grounds that their outcome will be less satisfactory than those who are not obese.

Long-term results of uncemented total hip arthroplasty with the Taperloc femoral component in patients with Dorr type C proximal femoral morphology.

AIMS: To investigate the longevity of uncemented fixation of a femoral component in total hip arthroplasty (THA) in patients with Dorr type C proximal femoral morphology. PATIENTS AND METHODS: A total of 350 consecutive uncemented THA in 320 patients were performed between 1983 and 1987, by a single surgeon using the Taperloc femoral component. The 63 patients (68 hips) with Dorr type C proximal femoral morphology were the focus of this review. The mean age of the patients was 69 years (24 to 88) and mean follow-up was 16.6 years (ten to 29). Survival analysis included eight patients (eight hips) who died without undergoing revision surgery prior to obtaining ten years follow-up. All 55 surviving patients (60 hips) were available for clinical assessment and radiographic review. As a comparator group, the survival and implant fixation in the remaining 282 THAs (257 patients) with Dorr type A and B morphology were evaluated. The mean age of these patients was 52 years (20 to 82). RESULTS: In the Dorr C patient group the mean Harris hip score improved from 51 points (21 to 69 points) pre-operatively to 89 (74 to 100) at final follow-up. No femoral component was loose by radiological criteria and osteolysis was only identified around two stems (3.3%). There was one revision (1.6%) of a well-fixed femoral component for sepsis at 11 years. The survival of the Taperloc femoral component at 20 years with revision for any reason as the endpoint was 98% (95% confidence interval; 87 to 99). A total of ten (3.5%) of the Dorr A and B patient group of 282 THAs required revision surgery. Only one (0.4%) for aseptic loosening. A total of two hips (1%) were loose by radiographic criteria and osteolysis occurred around 12 hips (4%). CONCLUSION: This study demonstrates that excellent fixation can be achieved using the Taperloc stem in patients with Dorr type A and B, and Dorr type C bone. TAKE HOME MESSAGE: The Taperloc stem demonstrated equivalent results in Dorr type A and B and Dorr type C bone. Cite this article: Bone Joint J 2016;98-B:595-600.

SISE matters: the sum of information on seventy-yr-old equivalents measures pedigree information content when assessing the risk of HNPCC in a family.

Hereditary non-polyposis colon cancer (HNPCC) is a significant cause of colorectal and other malignancies. Due to the lack of features that reliably differentiate between a sporadic case and an inherited case of colon cancer, it is likely that HNPCC is under reported. The diagnosis of HNPCC relies heavily on finding multiple cases of colorectal or other specific cancers within a family. In the absence of a significant family history, a diagnosis of HNPCC is seldom considered. We postulate that small kinships--or, more specifically, kinships with a low information content--are more likely to be designated as having a low risk of an inherited cancer predisposition than are large kinships. This has the potential to exacerbate the under-diagnosis of HNPCC in small families, leading to inadequate treatment, follow-up and family counselling. We have developed an objective measure of the information content of individual pedigrees called the Sum of Information on Seventy-yr-old Equivalents (SISE) coefficient. The SISE coefficient is a function of the number of relatives in a kinship and their relationship to the proband, of their ages and of the age-dependent penetrance of HNPCC mutations. A population-based series of colorectal cancer cases was assessed, by currently accepted methods, for the likelihood of there being an HNPCC mutation segregating in each family. We observed that families with a low SISE coefficient were significantly more likely to be designated at low risk of HNPCC (P< or =0.001). Using a cumulative binomial distribution function, we estimated the likelihood of observing multiple cancers in families of different SISE coefficients.

Calbindin d28k overexpression protects striatal neurons from transient focal cerebral ischemia.

BACKGROUND AND PURPOSE: Increased intracellular calcium accumulation is known to potentiate ischemic injury. Whether endogenous calcium-binding proteins can attenuate this injury has not been clearly established, and existing data are conflicting. Calbindin D28K (CaBP) is one such intracellular calcium buffer. We investigated whether CaBP overexpression is neuroprotective against transient focal cerebral ischemia. METHODS: Bipromoter, replication-incompetent herpes simplex virus vectors that encoded the genes for cabp and, as a reporter gene, lacZ were used. Sprague-Dawley rats received bilateral striatal injections of viral vector 12 to 15 hours before ischemia onset. With the use of an intraluminal occluding suture, animals were subjected to 1 hour of middle cerebral artery occlusion followed by 47 hours of reperfusion. Brains were harvested and stained with X-gal (to visualize beta-galactosidase, the gene product of lacZ). The number of remaining virally transfected, X-gal-stained neurons in both the ischemic and contralateral striata were counted and expressed as the percentage of surviving neurons in the ischemic striatum relative to the contralateral nonischemic striatum. RESULTS: Striatal neuron survivorship among cabp-injected animals was 53.5+/-4.1% (n=10) versus 26.8+/-5.4% among those receiving lacZ (n=9) (mean+/-SEM; P<0.001). CONCLUSIONS: We conclude that viral vector-mediated overexpression of CaBP leads to neuroprotection in this model of central nervous system injury. This is the first demonstration that CaBP overexpression protects neurons in a focal stroke model.

Herpes simplex viral vectors expressing Bcl-2 are neuroprotective when delivered after a stroke.

Considerable interest has focused on the possibility of using viral vectors to deliver genes to the central nervous system for the purpose of decreasing necrotic neuronal injury. To that end, we have previously shown that a herpes simplex virus (HSV) vector expressing Bcl-2 could protect neurons from ischemia. In that study, vector was delivered before the ischemia. However, for such gene therapy to be of clinical use, vectors must be protective even if delivered after the onset of the insult. In the present study, we show that an HSV vector expressing Bcl-2 protects striatal neurons when delivered after focal ischemia. Rats were exposed to middle cerebral artery occlusion for 1 hour, followed by reperfusion, and damage was assessed 48 hours later. Delivery of the Bcl-2 vector 30 minutes after reperfusion (i.e., 1.5 hours after ischemia onset) prevented any significant loss of virally-targeted neurons in the striatum. In contrast, in rats microinfused with a vector only expressing a reporter gene, a highly significant loss of neurons occurred. By 4 hours into the reperfusion period (5 hours after ischemia onset), delivery of the Bcl-2 vector was no longer protective. These data show the efficacy of postinsult gene therapy strategies for the brain, underline the finite length of this temporal therapeutic window, and support the growing evidence attesting to the neuroprotective potential of Bcl-2.

Recombination following transformation of Escherichia coli by heteroduplex plasmid DNA molecules.

Circular heteroduplex DNA molecules introduced into Escherichia coli-competent cells are converted to new recombinant plasmids as a result of enzymatic actions in vivo. A pair of plasmids with partial sequence homology were each linearized at a different position with restriction enzymes, and the termini were made flush with the single-strand-specific S1 nuclease. Duplex molecules were then formed by melting and annealing these plasmid DNAs together. In contrast to linear homoduplex molecules, heteroduplexes circularize and therefore transform E. coli efficiently. Unique DNA sequences on each of the parental strands in the transforming heteroduplexes can be selectively incorporated or deleted as a result of in vivo enzymatic activities in transformed cells. This method permits the generation of new recombinant sequences in vivo without relying solely on the presence of convenient restriction sites for manipulation of DNA fragments in vitro.

Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers.

p53 alterations are the most common genetic lesions observed in lung cancers. Because of the limited size of individual studies, the distributions of p53 alterations by clinicopathological features have not been well characterized. Here, we present meta-analyses describing the occurrence of p53 alterations by patient/tumor characteristics in resected lung cancer. The association between p53 alterations (gene and/or protein) and a variety of variables were evaluated by calculating pooled odds ratios (ORs) and confidence intervals (CIs). p53 alterations were detected in 46.8% of 4684 non-small cell lung cancers. p53 alterations occurred more frequently in the more strongly smoking-associated histotypes: squamous cell (51.2%) and large cell (53.7%) carcinomas versus adenocarcinomas [38.8%; OR (squamous versus adenocarcinoma) = 1.81, 95% CI = 1.55-2.11]. p53 alterations were found to be associated with T1-4, N0-3, stage I-III, differentiation, and sex: OR (T3 versus T1) = 1.62 (95% CI = 0.99-2.65), OR (N1-3 versus N0) = 1.65 (95% CI = 1.27-2.15), OR (stage III versus stage I) = 1.98 (95% CI = 1.35-2.89), OR (poorly and moderately versus well-differentiated) = 3.04 (95% CI = 1.56-5.94), and OR (male versus female) = 1.39 (95% CI = 1.10-1.75). No strong associations between p53 and ras or aneuploidy were observed. Lung cancer studies of p53 and smoking need to consider the effect of histotype, and prognostic studies of p53 should adjust for the effects of T and N or stage and histotype. The apparent association between p53 and sex may be confounded by histotype and must be evaluated by multivariate studies.

Non-Hodgkin's lymphoma and specific pesticide exposures in men: cross-Canada study of pesticides and health.

Our objective in the study was to investigate the putative associations of specific pesticides with non-Hodgkin's Lymphoma [NHL; International Classification of Diseases, version 9 (ICD-9) 200, 202]. We conducted a Canadian multicenter population-based incident, case (n = 517)-control (n = 1506) study among men in a diversity of occupations using an initial postal questionnaire followed by a telephone interview for those reporting pesticide exposure of 10 h/year or more, and a 15% random sample of the remainder. Adjusted odds ratios (ORs) were computed using conditional logistic regression stratified by the matching variables of age and province of residence, and subsequently adjusted for statistically significant medical variables (history of measles, mumps, cancer, allergy desensitization treatment, and a positive history of cancer in first-degree relatives). We found that among major chemical classes of herbicides, the risk of NHL was statistically significantly increased by exposure to phenoxyherbicides [OR, 1.38; 95% confidence interval (CI), 1.06-1.81] and to dicamba (OR, 1.88; 95% CI, 1.32-2.68). Exposure to carbamate (OR, 1.92; 95% CI, 1.22-3.04) and to organophosphorus insecticides (OR, 1.73; 95% CI, 1.27-2.36), amide fungicides, and the fumigant carbon tetrachloride (OR, 2.42; 95% CI, 1.19-5.14) statistically significantly increased risk. Among individual compounds, in multivariate analyses, the risk of NHL was statistically significantly increased by exposure to the herbicides 2,4-dichlorophenoxyacetic acid (2,4-D; OR, 1.32; 95% CI, 1.01-1.73), mecoprop (OR, 2.33; 95% CI, 1.58-3.44), and dicamba (OR, 1.68; 95% CI, 1.00-2.81); to the insecticides malathion (OR, 1.83; 95% CI, 1.31-2.55), 1,1,1-trichloro-2,2-bis (4-chlorophenyl) ethane (DDT), carbaryl (OR, 2.11; 95% CI, 1.21-3.69), aldrin, and lindane; and to the fungicides captan and sulfur compounds. In additional multivariate models, which included exposure to other major chemical classes or individual pesticides, personal antecedent cancer, a history of cancer among first-degree relatives, and exposure to mixtures containing dicamba (OR, 1.96; 95% CI, 1.40-2.75) or to mecoprop (OR, 2.22; 95% CI, 1.49-3.29) and to aldrin (OR, 3.42; 95% CI, 1.18-9.95) were significant independent predictors of an increased risk for NHL, whereas a personal history of measles and of allergy desensitization treatments lowered the risk. We concluded that NHL was associated with specific pesticides after adjustment for other independent predictors.

Cancer incidence registration and trends in Ontario.

The Ontario Cancer Registry (OCR) contains information on the incidence, mortality and survival of cancer in Ontario. The OCR refers to the population of Ontario, which is currently more than 9 million people. Cancer registration is accomplished by the computerised linkage of records collected routinely for other purposes. Incidence data are available from the OCR beginning in 1964. Incidence rates, age-standardised to the World Standard Population, are presented for Ontario in two recent 5-year periods (1979-1983 and 1984-1988). Age-specific rates are also presented for selected sites. The most common cancer sites, in terms of Ontario incidence rates, were similar to those reported from other registries. In males, these were cancers of the lung, prostate, colon, bladder and rectum. In females, these were cancers of the breast, lung, colon, body of the uterus and ovary. The potential effects of changes in medical services, screening practices and risk factor prevalence on the incidence rates and trends are discussed.

A study of smoking, p53 tumor suppressor gene alterations and non-small cell lung cancer.

PURPOSE: The purpose of this study was to investigate the relationship between smoking and p53 tumor suppressor gene alterations, and their association with clinicopathologic features and prognosis in non-small cell lung cancer (NSCLC). METHODS: For 111 of 119 stage I-III NSCLC patients that had been followed prospectively, tumor p53 protein accumulation was measured immunohistochemically (IHC). Staining was evaluated as a score (p53IHCS) combining intensity and percent distribution. RESULTS: Forty-eight of 111 (43%) tumors had p53IHCS > 1. p53 IHC was associated with increasing tumor size (T) (p = 0.035), nodal status (N) (p = 0.091), stage (p = 0.054), and histology: squamous cell carcinoma (70%) and adenocarcinoma (27%) (p = 0.0002). In logistic regression analysis, p53 IHC was associated with squamous cell histology versus other histotypes [adjusted odds ratio (OR)5.90, 95% confidence interval (CI) 2.34-14.90]. p53 IHC was not associated with smoking variables. In multivariate proportional hazards analysis, p53IHCS and pack-years smoked (PY), both as continuous variables, were negative prognostic factors. The adjusted hazard ratios (HR) for the survival outcome recurrence for p53IHCS and PY were 1.20 (95% CI 1.02-1.40) and 1.03 (95% CI 1.01-1.04), and for death due to recurrent disease (DRD) were 1.35 (95% CI 1.11-1.64) and 1.03 (95% CI 1.01-1.04), respectively. Comparing the 75th percentile to the baseline 0, the adjusted HR for p53IHCS (5 vs. 0) was 4.5 and for PY (55 vs. 0) was 5.1 for the outcome DRD. Both variables demonstrated a dose-response relationship with survival. CONCLUSIONS: PY and p53IHCS are significant, independent and important predictors of recurrence and DRD in stage I-III NSCLC.

Inducible gene expression from defective herpes simplex virus vectors using the tetracycline-responsive promoter system.

Herpes simplex virus-based amplicon vectors have been used for gene transfer into cultured neurons and the adult CNS. Since constitutive expression of a foreign gene or overexpression of an endogenous gene may have deleterious effects, the ability to control temporal expression would be advantageous. To achieve inducible gene expression, we have incorporated the tetracycline-responsive promoter system into amplicon vectors and showed, both in vitro and in vivo, that expression can be modulated by tetracycline. Using the firefly luciferase as the reporter gene, maximal repression by tetracycline in hippocampal cultures was about 50-fold. Withdrawal of tetracycline derepressed gene expression, reaching maximal levels within 10-12 h. In contrast, addition of tetracycline to cultures without prior tetracycline exposure inhibited gene expression rapidly; luciferase activity was reduced to less than 8% within 24 h. In adult rat hippocampus, vectors expressing luciferase or the Escherichia coli lacZ were repressed by tetracycline 9- and 60-fold, respectively. Maximum gene expression from the vectors occurred 2-3 days post-infection and declined thereafter. Such decline impeded further induction of expression by withdrawing tetracycline. This study demonstrates the feasibility of incorporating a powerful inducible promoter system into HSV vectors. The development of such an inducible viral vector system for gene transfer into the adult CNS might prove to be of experimental and therapeutic value.

An historical cohort study of cardiac catheterization during childhood and the risk of cancer.

This study aimed to determine whether cancer risk was elevated among patients exposed to radiation from diagnostic cardiac catheterization during childhood. The study cohort included 3915 children who underwent at least one cardiac catheterization at a major children's hospital in Toronto, Canada, between 1950 and 1965, were < or = 18 years at the time of the procedure, and were residents of Ontario. Follow-up of the cohort was done by linkage to the Ontario Cancer Registry up to 1986. A total of seven cancer deaths were observed (O), compared with 5.7 expected (E) based on provincial cancer rates (mortality ratio [O/E] = 1.2; 90% confidence interval [CI] : 0.6-2.3). In the analysis of cancer incidence, 13 cancers were detected, compared with 17.3 expected (O/E = 0.75; 90% CI : 0.4-1.2). These mortality and incidence ratios were not statistically significantly elevated. Detailed analyses were conducted according to age at exposure, age at diagnosis, sex, number of procedures, year of first catheterization, and latent period. Detected deviations in risk were confined to an early period of exposure, indicating that later practices of cardiac catheterization were not associated with increased risk. In general, there was no statistically significant excess risk of cancer among the cohort.