TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

Quality of life in participants of a CRC screening program.

BACKGROUND: Little is known about the effect of participating in a colorectal cancer (CRC) screening programme on quality of life (QOL), neither for participants with a negative nor for those with a positive test result. These findings, however, are important to evaluate the impact of CRC screening. METHODS: Participants from CRC screening trials were sent a questionnaire, which included validated measures on generic health-related QOL, generic anxiety and screen-specific anxiety. Both faecal immunochemical test (FIT) and flexible sigmoidoscopy (FS) participants, either with negative or positive test results, were addressed. RESULTS: The response rate was 73% (1289 out of 1772) for FIT and 78% (536 out of 689) for FS participants, with mean ages varying from 63-66 years. Positive FIT participants had worse physical (PCS-12, 47.1 vs 48.3, P=0.02), but equal mental QOL scores (MCS-12, 51.1 vs 51.6, P=0.26). Positive and negative FS participants had similar QOL scores. Both FIT and FS participants with a positive test result reported more screen-specific anxiety than negative FIT and FS participants. Positive and negative FS participants had similar generic anxiety scores. CONCLUSION: Our findings indicate that the burden of participating in CRC screening may be limited. Conducting a prospective study to confirm these results is recommended.

The NordICC Study: rationale and design of a randomized trial on colonoscopy screening for colorectal cancer.

BACKGROUND AND STUDY AIM: While colonoscopy screening is widely used in several European countries and the United States, there are no randomized trials to quantify its benefits. The Nordic-European Initiative on Colorectal Cancer (NordICC) is a multinational, randomized controlled trial aiming at investigating the effect of colonoscopy screening on colorectal cancer (CRC) incidence and mortality. This paper describes the rationale and design of the NordICC trial. STUDY DESIGN: Men and women aged 55 to 64 years are drawn from the population registries in the participating countries and randomly assigned to either once-only colonoscopy screening with removal of all detected lesions, or no screening (standard of care in the trial regions). All individuals are followed for 15 years after inclusion using dedicated national registries. The primary end points of the trial are cumulative CRC-specific death and CRC incidence during 15 years of follow-up. POWER ANALYSIS: We hypothesize a 50 % CRC mortality-reducing efficacy of the colonoscopy intervention and predict 50 % compliance, yielding a 25 % mortality reduction among those invited to screening. For 90 % power and a two-sided alpha level of 0.05, using a 2:1 randomization, 45 600 individuals will be randomized to control, and 22 800 individuals to the colonoscopy group. Interim analyses of the effect of colonoscopy on CRC incidence and mortality will be performed at 10-year follow-up. CONCLUSIONS: The aim of the NordICC trial is to quantify the effectiveness of population-based colonoscopy screening. This will allow development of evidence-based guidelines for CRC screening in the general population.

A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and tumor growth in the rodent colon. We assessed NSAID use in relation to risk of human large-bowel cancer in a hospital-based, case-control study of 1326 patients with colorectal cancer and 4891 control patients. For regular NSAID use that continued into the year before interview, the multivariate relative risk estimate was 0.5 (95% confidence interval, 0.4 to 0.8); the estimate decreased as the duration of use increased, but the trend was not statistically significant. Similar results were obtained whether cancer or non-cancer controls were used, and the inverse association was apparent for both colon cancer and rectal cancer in men and women and in subjects younger and older than 60 years. Regular NSAID use that had been discontinued at least 1 year previously and non-regular use were not associated with risk. Almost all regular NSAID use was of aspirin-containing drugs. The present data suggest that the sustained use of NSAIDs reduces the incidence of human large-bowel cancer.

Incidence of second cancers in patients treated for Hodgkin's disease.

BACKGROUND: Numerous studies of treatment for Hodgkin's disease have demonstrated large increases in the incidence of leukemia in the early years following chemotherapy, although the duration of effect and the specific agents involved are not well understood. Also, some, but not all, studies have indicated that the incidence of certain solid tumors increases following treatment for Hodgkin's disease. PURPOSE: We studied the association between treatment for Hodgkin's disease and the incidence of second cancers. METHODS: We conducted a study within a cohort that included 10,472 patients from 14 cancer centers in the United States and Canada who were first diagnosed as having Hodgkin's disease at some point from 1940 through 1987. Discounting the 1st year after diagnosis, the average length of follow-up was 7.1 years per subject. RESULTS: We observed 122 leukemias and 438 solid tumors. The relative risk (RR) of leukemia following chemotherapy, compared with no chemotherapy, was 14 (95% confidence interval [CI] = 5.6-35). Increased risks of leukemia were observed after treatment with chlorambucil (RR = 2.0; 95% CI = 1.1-3.6), procarbazine (RR = 4.9; 95% CI = 2.6-9.1), vinblastine (RR = 1.7; 95% CI = 1.1-2.8), and a group of rarely used drugs that included methotrexate, vindesine, etoposide, and 22 others (RR = 3.8; 95% CI = 1.9-7.4). RRs were also estimated for various combinations of drugs, including MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) (RR = 5.9; 95% CI = 2.9-12) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (RR = 1.5; 95% CI = 0.7-3.4). The RR of leukemia associated with splenectomy was 1.6 (95% CI = 1.0-2.5). The RR of solid tumors following chemotherapy was 1.4 (95% CI = 1.1-1.8). For the group of rarely used drugs, the RR of solid tumors was 3.1 (95% CI = 1.7-5.8). Chemotherapy was associated with an increased risk of cancers of the bones, joints, articular cartilage, and soft tissues (RR = 6.0; 95% CI = 1.7-20), and cancers of the female genital system (RR = 1.8; 95% CI = 1.1-3.2). In patients followed for 10 or more years after radiotherapy, increased risks were found for cancers of the respiratory system and intrathoracic organs (RR = 2.7; 95% CI = 1.1-6.8) and for cancers of the female genital system (RR = 2.4; 95% CI = 1.1-5.4). CONCLUSIONS: Procarbazine, chlorambucil, and vinblastine are associated with increased leukemia risk. Combination drug regimens have leukemogenic effects estimated as the product of RRs for individual drugs. Chemotherapy and radiotherapy increase the risk of selected solid tumors, and the effect of chemotherapy on solid tumor risk is weaker than the leukemogenic effect. IMPLICATIONS: Without doubt, the benefits of treatment of Hodgkin's disease outweigh the risk of a subsequent malignancy, but data on the carcinogenic effects of radiation and drugs beyond 10 years after treatment continue to be sparse, and future analyses should be directed at long-term survivors.

A case-control study of analgesic use and ovarian cancer.

A recent case-control study raised the hypothesis that acetaminophen use 1 day or more per week for at least 6 months reduces the risk of epithelial ovarian cancer. We assessed analgesic use in relation to epithelial ovarian cancer risk using data from our case-control surveillance study of medication use and cancer. Patients were interviewed in hospitals in Baltimore, Boston, New York, and Philadelphia during 1976-1998. We compared 780 women with epithelial ovarian cancer to 2053 cancer controls and 2570 noncancer controls. For acetaminophen use 1 day or more per week for at least 6 months, the odds ratio estimate was 0.9 (95% confidence interval, 0.6-1.4) derived with cancer controls and 1.0 (0.6-1.5) with noncancer controls. Estimates for more frequent and longer term use were also compatible with 1.0. The odds ratios among patients with metastatic ovarian cancer were reduced but not statistically significant. The odds ratio for use of nonsteroidal anti-inflammatory drugs 4 or more days per week for at least 5 years, 0.5, was statistically significant. The present results provide only weak support for a reduction in the risk of epithelial ovarian cancer among acetaminophen users. They raise the possibility of an inverse association with long-term nonsteroidal anti-inflammatory drug use.

Nonsteroidal anti-inflammatory drugs and risk of digestive cancers at sites other than the large bowel.

Regular continuing nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a reduction in risk of large bowel cancer in many studies, including our Case-Control Surveillance Study of medication use and cancer risk. We assessed the relation of NSAID use to the risk of digestive cancers at sites other than the large bowel in this database. Nurse-interviewers administered questionnaires to patients admitted to hospitals in four centers from 1977 to 1998. Cases comprised 1149 patients with cancers of the pancreas (n = 504), stomach (n = 254), esophagus (n = 215), gallbladder (n = 125), or liver (n = 51). Controls were 5952 patients admitted for trauma or acute infection. History of NSAID use was elicited by questions about indications for use. Multiple logistic regression models were used to calculate odds ratios (ORs) for categories of regular NSAID use (at least 4 days/week for at least 3 months) relative to never use. The OR for regular use initiated at least 1 year before admission and continuing into that year was reduced for stomach cancer (OR = 0.3; 95% confidence interval, 0.1-0.6) and was compatible with 1.0 for other sites. The ORs for regular continuing use of at least 5 years duration were < 1.0 for cancers of the stomach, pancreas, esophagus, and gallbladder but were statistically significant only for stomach cancer. These data suggest that regular continuing NSAID use may be associated with reduced risk of stomach cancer. For the other sites, the data are consistent with no effect of NSAID use.

Geographically-based cancer control: methods for targeting and evaluating the impact of screening interventions on defined populations.

Successful implementation of cancer control programs depends on efficient targeting to those at highest risk of developing and dying from the disease. This study presents a methodology for targeting cancer screening on the basis of population and disease variation among small geographic areas. Techniques for quantifying the impact of targeting on the predictive value of a positive test are demonstrated, using 329 New York City health areas. Age-truncated crude incidence, late-stage incidence and mortality rates for breast, cervix, and colorectal cancer are used, using site-specific truncation points relevant to the age groups appropriate for screening. Coefficient alpha was used to determine rate stability with 2, 3, 5 and 7 years of data. The stability of most small area rates was found to reach acceptable levels only with 5 and 7 years of data. Targeting into areas where breast cancer prevalence was high increased the expected predictive value of a positive test by as much as 50% when compared with areas of average prevalence. Geographic targeting will be most useful where between-area variability in prevalence is large and within-area variability is small. The implications of these results are discussed and future studies are suggested.

Comparative molecular pathology of sporadic hyperplastic polyps and neoplastic lesions from the same individual.

AIM: The biology of colorectal hyperplastic polyps is of considerable relevance, because recent evidence suggests that under certain circumstances hyperplastic polyps may be precursors of neoplasms. The aim of this study was to assess and compare the clinical and molecular characteristics of hyperplastic polyps and neoplastic lesions removed from patients without the hyperplastic polyposis syndrome. METHODS: One hundred and twenty six patients were identified through a series of genetic epidemiological studies. Each patient had at least one neoplastic lesion and one hyperplastic polyp; there was a total of 147 hyperplastic polyps. All lesions were evaluated for K-ras mutations, loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene, and microsatellite instability. RESULTS: K-ras mutation was detected in 15 (10%) hyperplastic polyps, all from the rectosigmoid colon. No hyperplastic polyp had APC LOH or microsatellite instability. Patients with adenomas or carcinomas showing K-ras mutations were not more likely to have hyperplastic polyps with K-ras mutations. The average number of adenomas did not differ between those patients with hyperplastic polyps with K-ras mutations and those without K-ras mutations. There was no association between the hyperplastic polyp and the adenoma regarding the colon segments from which the two lesions were removed. CONCLUSIONS: The sporadic hyperplastic polyp is a lesion with limited molecular change and no relation to patients' neoplastic lesions.

Hematologic data of healthy very old people.

Hematologic values were analyzed for 44 people who were 84 years of age or older. Individuals were selected based on extensive long-term records confirming their excellent health. Mean hemoglobin values were 14.8 +/- 1.1 g/dL (148 +/- 11 g/L) for men and 13.6 +/- 1.0 g/dL (136 +/- 10 g/L) for women. Mean values were also computed for red blood cell indexes, red and white blood cell counts, sedimentation rate, and serum iron, and all values were compared with those of a concurrent control group of healthy young adults. Results are discussed in the context of previous reports on hematologic data of the elderly.

Initial management and follow-up surveillance of patients with colorectal adenomas.

The clinical management of patients with adenomas is interesting because of the adenomas' malignant potential, the availability of effective intervention by colonoscopy, and the increasing number of patients having adenomas detected and removed. The current literature on follow-up surveillance is reviewed, and surveillance intervals are suggested based on data from the National Polyp Study. Patients newly diagnosed with three or more adenomas, an adenoma of more than 0.5 cm, or with a family history of colorectal cancer should have surveillance colonoscopy at 3 years following the polypectomy. Surveillance of patients with single, small tubular adenomas can be extended to 5 or more years. Patients with large sessile or malignant adenomas need to have follow-up earlier. Identification and removal of adenomatous polyps have been shown to reduce colorectal cancer incidence.

Clinical characteristics of patients with epidermoid carcinoma of the upper aerodigestive tract who develop second malignant tumors.

A total of 1294 patients with primary head and neck (H&N) cancer of a single site was diagnosed during the years 1970 to 1979 at the Memorial Sloan-Kettering Cancer Center, 163 subsequently developed a second malignant tumor (SMT). In 50% of the cases, the second tumor was in the H&N, and in 30% in the lung and esophagus; 41 patients developed a third tumor. Again, in 50% of these cases, the tumor was in the H&N and in 17% in the lung and esophagus. The stage of disease of all the second primary tumors was more advanced at diagnosis, mainly as a result of the large number of patients with lung and esophagus cancer. Patients who had a second tumor in the H&N were diagnosed in an earlier stage of disease than patients with a single H&N tumor. The survival of patients with localized second H&N cancer was worse than for those with a primary, localized single tumor.

Second malignancies after childhood Hodgkin's disease. The Memorial Sloan-Kettering Cancer Center experience.

A review of the Memorial Sloan-Kettering Cancer Center experience with second malignancies (SM) after childhood Hodgkin's Disease (HD) identified 17 SM in 320 patients who survived more than 1 year from, and were 15 years old or younger at the time of, HD diagnosis (1949 to 1983). Of 254 previously untreated patients, 12 SM were noticed as compared with 0.606 expected on the basis of rates in the general pediatric population (relative risk, 19.8; 95% confidence interval, 10.2 to 34.6). For patients who received multi-agent chemotherapy, the cumulative probability of developing acute nonlymphocytic leukemia (ANLL) or bone sarcoma was 6.2% and 5.5%, respectively, at 10 years from the initiation of therapy; the cumulative risk of all SM in this group reached 18.7% at 15 years. For patients who received radiation alone or with single-agent chemotherapy, the cumulative risk of SM rose from 0% at 10 years and 2% at 15 years, to 10.7% at 25 years from the initiation of treatment. The risk of ANLL after childhood HD was highest in the first 5 to 10 years after combined modality treatment, and aggressive forms of NHL were associated with excessive immunosuppression. Bone sarcomas predominated in solid SM in the first decade after HD treatment, whereas "adult-type" cancers, for example, breast and colon carcinomas, were more delayed. Our findings, supported by a literature review, point to a therapy-related enhanced risk of approximately age-appropriate solid SM. This possibility mandates careful surveillance of long-term survivors of childhood HD.

Determinants of late stage diagnosis of breast and cervical cancer: the impact of age, race, social class, and hospital type.

Previous studies of the relationship between cancer stage, age, and race have not controlled for social class and health care setting. Logistic regression analyses, using information from the New York State Tumor Registry and area-level social class indicators, demonstrated that, in New York City, older Black, lower class women in public hospitals were 3.75 and 2.54 times more likely to have late stage breast or cervical cancer, respectively, than were younger White, high social class women in non-public hospitals.

The natural history of colorectal cancer. Opportunities for intervention.

There is now a better understanding of the natural history of colorectal cancer, which has provided a basis for intervention to influence outcome. The possible interventions include earlier detection of colorectal cancer, removal of premalignant adenomas, demonstration of the mucosal field defect that precedes neoplasia to evaluate baseline risk and its change with dietary modification, and identification of inherited and dietary risk factors. Five controlled trials evaluating early detection of colorectal cancer with fecal occult blood testing have enrolled more than 309,000 patients. Early stage cancers with improved survival has been observed, but data on mortality reduction have not as yet been reported. Studies of patients with adenomas have demonstrated high synchronous and metachronous rates as a basis for complete colon evaluation initially and a surveillance follow-up program. Hyperproliferation and lack of normal differentiation have been observed as a field defect in the colon preceding neoplasia. Inherited factors have recently been shown to be important in a larger proportion of individuals destined to develop colorectal adenomas and cancer. These observations of the natural history of colorectal cancer have provided new opportunities for the application of radiologic and endoscopic techniques in diagnosis and surveillance; each examination has its merit. Further research is needed to answer many critical questions that have been raised regarding the impact of these interventions.

Predictors of smoking prevalence among New York Latino youth.

BACKGROUND: We examined prevalence rates and risk factors for smoking among Latino adolescents, using a multiethnic sample of sixth- and seventh-grade students (n = 3129) in 47 New York City public and parochial schools. METHODS: The students completed questionnaires; self-reported smoking data were collected by means of the "bogus pipeline" technique. The largest group of Latino students (43%) was Puerto Rican; 20% were of Dominican background, 7% were Colombian, and 7% were Ecuadorian. "Current smoking" was defined as smoking at least once per month. RESULTS: A series of logistic regression analyses indicated that peer influence was the strongest predictor of smoking. Family influence was important as well. CONCLUSIONS: The results are discussed in terms of their implications for prevention.