K-ras and p16(INK4A)alterations in sputum of NSCLC patients and in heavy asymptomatic chronic smokers

NSCLC rates among the most frequent and lethal neoplasm world-wide and a significant decrease in morbidity and mortality relies only upon effective early diagnostic strategies. We investigated K-ras mutations and p16(INK4A) hypermethylation in tumor tissue and sputum of 50 patients with NSCLC and correlated them with sputum cytology and with tumor staging, grading and location, to ascertain, in sputum, their potential diagnostic impact. The same genetic/epigenetic abnormalities and cytological features were also evaluated in sputum from 100 chronic heavy smokers. Genetic analysis identified molecular abnormalities in 64% tumors (14/50 K-ras mutations and 24/50 p16(INK4A) hypermethylation) and in 48% sputum (11/50 K-ras mutations and 16/50 p16(INK4A) hypermethylation). In tumors K-ras mutations and p16(INK4A) hypermethylation were mostly mutually exclusive, being found in the same patients in 3 cases only. Genetic abnormalities in sputum were detected only in molecular abnormal tumors. Molecular changes in sputum had rates of detection similar to cytology (42%) but the cyto-molecular combination increased the diagnostic yield up to 60%. Interestingly, the rate of detection of genetic changes in sputum of tumors at early stage (T1) was not significantly different from that of tumors at more advanced stage (T2-T4). In fact K-ras point mutations were frequently recognised in tumors at early stage while p16(INK4A) inactivation prevailed in tumors at advanced stage ( P=0.0063). As expected, diagnostic cytological findings were more frequently found in tumors at advanced stage (P=0.004). No correlation was found between tumor grading and location (central versus peripheral) and molecular changes. p16(INK4A) hypermethylation, but not K-ras mutations, was documented in sporadic cases of asymptomatic heavy smokers (4%) where it was uncoupled from cytological abnormalities. In conclusion the cyto-molecular diagnostic strategy adopted in this study was able to detect the majority of tumors but in order to be proposed as effective and early diagnostic tool, this molecular panel needs to be tested in prospective studies with adequate follow-up.     

Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial

The efficacy and cost-effectiveness of low-dose spiral computed tomography (LDCT) screening in heavy smokers is currently under evaluation worldwide. Our screening program started with a pilot study on 1035 volunteers in Milan in 2000 and was followed up in 2005 by a randomized trial comparing annual or biennial LDCT with observation, named Multicentric Italian Lung Detection. This included 4099 participants, 1723 randomized to the control group, 1186 to biennial LDCT screening, and 1190 to annual LDCT screening. Follow-up was stopped in November 2011, with 9901 person-years for the pilot study and 17 621 person-years for Multicentric Italian Lung Detection. Forty-nine lung cancers were detected by LDCT (20 in biennial and 29 in the annual arm), of which 17 were identified at baseline examination; 63% were of stage I and 84% were surgically resectable. Stage distribution and resection rates were similar in the two LDCT arms. The cumulative 5-year lung cancer incidence rate was 311/100 000 in the control group, 457 in the biennial, and 620 in the annual LDCT group (P=0.036); lung cancer mortality rates were 109, 109, and 216/100 000 (P=0.21), and total mortality rates were 310, 363, and 558/100 000, respectively (P=0.13). Total mortality in the pilot study was similar to that observed in the annual LDCT arm at 5 years. There was no evidence of a protective effect of annual or biennial LDCT screening. Furthermore, a meta-analysis of the four published randomized trials showed similar overall mortality in the LDCT arms compared with the control arm.     

Characteristics of female smokers attending a lung cancer screening program: a pilot study with implications for program development

Anticipating the development of lung cancer early detection programs, we examined the: (1) feasibility of a lung cancer early detection program; (2) characteristics of enrollees (e.g. motivation to quit smoking); (3) correlates of enrollee motivation to quit smoking; and (4) rates of smoking cessation following screening. Brief surveys were completed before and after screening, which involved sputum cytology, chest X-ray, bronchoscopy, spiral CT, and a meeting with an oncologist to discuss smoking cessation. Of the 168 eligible women who were heavy smokers recruited via newspaper and cancer center advertisements, 55 agreed to undergo screening. Enrollees showed low-to-moderate levels of quit motivation and high levels of nicotine addiction; enrollees were interested in a range of smoking cessation treatments; 20% of enrollees exhibited clinical-levels of emotional distress; 64% of enrollees reported low levels of self-efficacy (i.e. self-confidence) to quit; 24% of enrollees reported low levels of quitting pros and 25% reported high levels of quitting cons; 31% of enrollees showed high levels of fatalistic beliefs about cancer; and all enrollees recognized their elevated lung cancer risk. Greater motivation to quit smoking was related to: greater age, lower nicotine addiction, fewer health symptoms, and higher quitting self-efficacy and quitting pros. Finally, 16% of enrollees quit smoking after screening. Overall, many women eligible for screening refused to undergo comprehensive screening that included bronchoscopy and spiral CT. Screening may represent an opportunity for quitting smoking, although more intensive smoking cessation interventions that target nicotine addiction and self-efficacy may be needed to maximize the health benefits of an early detection program.     

Effectiveness of an organized cervical cancer screening program in Korea: results from a cohort study

Although the value of cervical cancer screening is widely acknowledged, the effectiveness of an organized cervical cancer screening program in Korea has never been evaluated. We investigated the associations of the frequency of cervical cancer screening with cervical cancer incidence using data from a large prospective cohort study. In this analysis, 253,472 women without a hysterectomy or previous cancer diagnosis were included. Follow-up was between 1995 and 2002. Frequency of Pap smear testing was determined by searching the National Health Examination Database. Using the Korean Central Cancer Registry, 248 cases of invasive cervical cancer and 346 cases of carcinoma in situ (CIS) of the cervix were identified. Subjects screened 2 or more times showed a 71% (corrected reduction 60%) and a 66% (corrected reduction 53%) reduced risk of invasive cervical cancer and CIS of the cervix, respectively, as compared with unscreened subjects [relative risk (RR) = 0.29; 95% confidence interval (CI) = 0.20-0.45; RR = 0.34; 95% CI = 0.25-0.46, respectively]. Women with a normal or benign pap smear had a statistically significantly lower risk of invasive cervical cancer and CIS of cervix compared with those never screened. In age-stratified analyses, there was a significant reduction in cervical cancer incidence among women aged 30 and over who were screened 2 or more times compared with women never screened. The results of this prospective cohort study show that regular screening of cervical cancer reduces invasive cervical cancer incidence and CIS of the cervix among Korean women.     

Beta-carotene supplementation in smokers reduces the frequency of micronuclei in sputum.

beta-carotene has been hypothesised to reduce lung cancer risk. We studied the effect of 14 weeks of beta-carotene supplementation (20 mg d-1) on the frequency of micronuclei in sputum in 114 heavy smokers in a double-blind trial. Micronuclei reflect DNA damage in exfoliated cells and may thus provide a marker of early-stage carcinogenesis. Pre-treatment blood levels of cotinine, beta-carotene, retinol and vitamins C and E were similar in the placebo group (n = 61) and the treatment group (n = 53). Plasma beta-carotene levels increased 13-fold in the treatment group during intervention. Initial micronuclei counts (per 3,000 cells) were higher in the treatment group than in the placebo group (5.0 vs 4.0, P < 0.05). During intervention, the treatment group showed a 47% decrease, whereas the placebo group showed a non-significant decrease (16%). After adjustment for the initial levels, the treatment group had 27% lower micronuclei counts than the placebo group at the end of the trial (95% CI: 9-41%). These results indicate that beta-carotene may reduce lung cancer risk in man by preventing DNA damage in early-stage carcinogenesis.     

The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomised trial.

Laboratory studies, and one previous uncontrolled trial, have suggested that retinoids may reverse bronchial atypia, a putatively premalignant condition. Sputum sampling is a simple, non-invasive method of assessing atypia. Smokers with at least a 15 pack-year history were screened for sputum atypia. One hundred and fifty subjects' were randomised to receive the synthetic retinoid etretinate 25 mg orally or identical placebo daily for 6 months. Compliance was measured by performing pill counts and serum sampling every 2 months for etretinate levels. The outcomes assessed were, improvements in sputum atypia and toxicity. At baseline there was no significant difference between the two groups with respect to gender, smoking history or extent of atypia. Four of 75 subjects on etretinate and six of 75 on placebo dropped out before 6 months. Compliance as measured by pill counts and etretinate levels was high. Eighty-six per cent of subjects on etretinate took 90% or more of their prescribed medication and etretinate was detected in 245 of 264 samples. By contrast etretinate was detected in only six of 266 samples in the control group and probably did not represent true contamination. After 6 months on etretinate there was no difference in the degree of atypia between the two treatment arms. Toxicity was mild in both groups with considerable placebo effect noted. Etretinate, at the dose used in this study, had no impact on sputum atypia as detected by sputum sampling.     

Molecular alterations in a patient with Turcot's syndrome.

Cells of a patient with Turcot''s syndrome and of her parents were evaluated for the presence of molecular alterations in the p53 and the Ki-ras gene. Deletions on chromosome 17p, overexpression and point mutations of the p53 gene as well as mutations of the Ki-ras gene were detected in primary and metastatic tumour but not in the germline of the patient nor in her parents.     

Participation in a sigmoidoscopic colorectal cancer screening program: a pilot study.

At present, very little is known about the determinants of endoscopic screening participation. This study presents an analysis of the psychosocial associations of participation and nonparticipation in a sigmoidoscopic colorectal cancer screening program. The present pilot study was executed among members of a Dutch target group, ages 50-60 years, who visited an internal medicine outpatient clinic. Individuals who were asked to participate in the program (n = 200) received general information with regard to the screening procedure. The participation rate was 45%. Persons who participated in the screening program as well as those who wanted to participate in the study but did not want to participate in the screening program were asked to fill out a questionnaire. Self-efficacy, i.e., the individual's perception of the difficulty of participating in the screening program, appeared to be the most important association of participation. Furthermore, response efficacy, i.e., the individual's beliefs about the outcome of participation, and social support proved to be concepts that were associated with participation.     

Predictors of participation in a smoking cessation program among young adult smokers.

This study investigated the predictors of participation in a smoking cessation trial for young adults ages 18 to 30 years old. Eligible smokers (n = 164) completed a telephone survey that measured demographic, smoking history, and psychosocial variables before the initiation of smoking cessation treatment. Young adult smokers who attended at least one smoking cessation session were compared with those who did not attend any sessions. Logistic regression analysis indicated that race and age were statistically significant multivariate predictors of participation. Caucasians were over six times (odds ratio, 6.03; 95% confidence interval, 2.41-15.05) more likely to participate in the smoking cessation program compared with non-Caucasians (61% versus 19%). For every SD increase in age (SD, 2.45), there was about a 2-fold increase in the likelihood that a young adult smoker participated in the smoking cessation program (odds ratio, 1.82; 95% confidence interval, 1.23-2.71). Future research should investigate how to promote participation in smoking cessation programs among smokers in emerging adulthood and among non-Caucasian young adult smokers to prevent a lifelong habit associated with disproportionate morbidity and mortality.     

Detection of mononucleotide repeat sequence alterations in a large background of normal DNA for screening high-frequency microsatellite instability cancers.

PURPOSE: Mutations in mononucleotide repeat sequence (MRS) are good indicators of high-frequency microsatellite instability (MSI-H) cancers, but it has been a challenge to detect such mutations in a large background of wild-type DNA; as in this setting, PCR errors often generate false positive mutant alleles. In this study, we developed a general strategy, referred to as probe clamping primer extension-PCR (PCPE-PCR), to detect MRS alterations in a large background of wild-type DNA. EXPERIMENTAL DESIGN: In PCPE-PCR, genomic DNA is first subjected to PCPE, in which mutant single-strand DNA molecules are preferentially produced. Next, genomic DNA is removed to enrich for the mutant DNA fraction. Thereafter, PCR is carried out using the remaining single-strand DNA molecules as templates. Finally, the PCR products are analyzed to reveal the MSI-H status. In this study, the sensitivity of this new method was first examined by spiking mutant DNA into wild-type DNA at specific ratios followed by studying whether this method is applicable to fecal DNA testing. RESULTS: We showed that PCPE-PCR could detect both mutated BAT26 and transforming growth factor-beta-RII (A)10 markers in the presence of 500-fold excess of normal DNA and that as few as three copies of mutated DNA could be detected. In addition, we showed that this technology could detect MSI-H colorectal cancer by fecal DNA analysis. CONCLUSION: PCPE-PCR is sensitive. In addition, PCPE-PCR is simple and amendable to a cost-effective and high-throughput screening operation. This technology may be applicable to noninvasive screening of MSI-H cancer.     

2014—2017年广西城市癌症早诊早治项目癌症风险评估及筛查结果分析

目的 分析 2014—2017 年广西城市癌症早诊早治项目中癌症高危评估和临床筛查结果。 方法 采用整群抽样的方法选取2014年11月至2017年8月广西南宁市西乡塘区和青秀区的40~74岁常住户籍人口为调查对象,以《防癌风险评估问卷》对其进行调查,评估出五大癌症（肺癌、上消化道癌、肝癌、结直肠癌和乳腺癌）高危人群并进行临床筛查,分析各癌种的高风险率、筛查参与率和检出率。结果 共152 630人完成问卷调查和风险评估,癌症高危72 376人（47.62%）,其中肺癌、食管癌、胃癌、肝癌、结直肠癌和女性乳腺癌评估的高风险率分别为25.66%、17.39%、26.11%、28.95%、22.19%、32.76%;男性肺癌高风险率高于女性,女性食管癌、胃癌、肝癌、结直肠癌高风险率高于男性。肺癌、乳腺癌、肝癌、结直肠癌、上消化道癌的临床筛查参与率依次为26.42%、25.18%、25.03%、11.31%、7.68%。临床筛查结果显示,疑似肺癌、疑似肝癌、乳腺BI-RADS 4～5级、结直肠癌和上消化道癌的检出率分别为0.58%、0.05%、2.79%、0.13%和0.12%。结论 2014—2017年广西城市癌症早诊早治项目癌症筛查参与率及各癌种阳性病变检出率均不高,需提高区域人群防癌意识和体检筛查参与度,进一步识别癌症高危人群,提高筛查效果。     

Micronuclei in bronchial biopsy specimens from heavy smokers: characterization of an intermediate marker of lung carcinogenesis.

Bronchial micronuclei, small fragments of extra-nuclear DNA formed during cell division, provide a non-specific but quantifiable marker of DNA damage. Micronuclei have been used to assess carcinogen exposure and as an intermediate endpoint in chemoprevention trials. As part of an ongoing chemoprevention trial, heavy smokers underwent screening bronchoscopy, with biopsies taken at 6 standardized sites. Micronuclei counts were obtained for each site in each of the 40 volunteers found to have squamous metaplasia. Unlike squamous metaplasia, the average micronuclei counts among these heavy smokers were not associated with smoking history. Micronuclei counts were also not associated with the presence or extent of metaplasia. A striking degree of intra-individual variability was observed by comparing the micronuclei counts from different biopsy sites within individuals. The findings suggest that use of micronuclei from single sites may be misleading as a marker of carcinogen exposure or as an estimate of cancer risk. Serial measurements in individuals may provide the most useful information concerning carcinogenic exposure and the impact of chemopreventive agents.     

Effects of a 6-month vitamin intervention on DNA damage in heavy smokers.

Because their formation is associated with tumor development in specific tissues, DNA adducts have potential usefulness as intermediate end points in chemoprevention studies. To determine the efficacy of a combination of antioxidant vitamins (vitamins C and E and beta-carotene), a randomized clinical trial was conducted among heavy smokers using DNA damage as the end point. Immunological methods were used to measure polycyclic aromatic hydrocarbon-DNA adducts and oxidative DNA damage (8-oxo or hydroxydeoxyguanosine) in mononuclear and oral cells. A total of 121 subjects were randomized to the 6-month intervention and received either vitamins or placebo. Dropout rates were higher in the placebo than in the vitamin group; 65% of subjects in the vitamin group, but only 47% in the placebo group, provided specimens at 6 months. Plasma levels of all three antioxidants rose significantly in the vitamin group but not in the placebo group. All four measures of DNA damage decreased in both groups; the between-group differences were not statistically significant. These data do not provide clear evidence that antioxidant vitamin intake prevents DNA damage. However, the study demonstrates that DNA damage is a useful end point in chemoprevention trials.     

Mammography screening in Norway: results from the first screening round in four counties and cost-effectiveness of a modeled nationwide screening

Objective: To evaluate whether the results of the first screening round in the Norwegian Breast Cancer Screening Program predict future mortality reduction and to explore the cost-effectiveness of the program. Methods: The results of surrogate measures were calculated and compared with the targets. A cost-effectiveness analysis was performed assuming a nationwide program starting in 1996 with an attendance rate of 80% and a mortality reduction of 30%. Results: The attendance rate was 79.5% and the detection rate was 0.67%. The proportion of invasive tumors smaller than 15 mm was 53.1%, and 21.7% of the patients who underwent axillary surgery had lymphatic metastasis. The C/E ratios were found to be 3750 US dollars (USD) per year of life saved and 86,045 USD per life saved. Conclusion: The results of the first screening round will lead to a mortality reduction of at least 30%. The cost-effectiveness analysis shows that it is possible to run a highly cost-efficient screening program in Norway.     

The South Australian Breast X-Ray Service: results from a statewide mammographic screening programme.

The South Australian Breast X-Ray Service is a centralised breast cancer screening programme in the State of South Australia. In its first 5 years of operation nearly 100 000 screens were performed. This study reports the clinical performance of the programme and compares it with other published series. Women aged 40 years and over were screened with two-view mammography every 2 years. Radiologists double-read the screening films and multidisciplinary teams assessed the recalled women at a single centre. In the prevalent round 76 106 women were screened, and subsequently 21 506 of them were rescreened. The recall rate for further investigation was 4.9% in the prevalent round and 2.4% in the incident rounds. The cancer detection rate per 1000 women was 7.0 in the prevalent screening round and 3.4 in the incident rounds. Forty-two per cent of invasive carcinomas measured < or = 10 mm in the prevalent screening round and the median tumour size was 12 mm. The benign to malignant biopsy ratio was 1:1.4 in the prevalent round and 1:2.8 in the incident rounds. In the prevalent round 77% of invasive tumours were lymph node negative and this proportion increased to 86% in the incident rounds.     

Participation in mass screening for colorectal cancer: results of screening and rescreening from the Burgundy study.

A controlled study was made in Burgundy (France) to assess the acceptability and efficiency of colorectal cancer screening using the Hemoccult test. A total of 91,000 people aged 45 to 74 years were included. The first screening campaign was made from January to July 1988 or 1989, and rescreening occurred from January to July 1990. During the first 4 months of the campaign, the General Practitioners (GPs) offered the test to their patients. It was then mailed to all subjects who had not completed it with a recall letter, if necessary, one month later. The overall compliance rate was 54.0% in the first campaign and 55.5% in the second campaign. A total of 63.7% subjects had completed at least one screening test over the two screening campaigns. Compliance was lower among men than women; compliance rate was also lower in the youngest and oldest age group than in the intermediate age groups. During the second screening campaign, the participation rate was 83.6% among participants in the first screening campaign and 20.9% among non-participants. Compliance during the medical offer phase was higher (81.4% during the first campaign, 82.9% during the second campaign) than during the postal offer phase (respectively, 33.8% and 28.5%). It was easier for GPs to propose the test when they had to offer it than when they had to prescribe it. These results suggest that a satisfactory participation rate can be obtained in France if GPs are actively involved in the screening programme. The final objective is to find a 25% difference in 5-year mortality by large bowel cancer between the screened and the test population.     

The impact of new technologies in cervical cancer screening: results of the recruitment phase of a large randomised controlled trial from a public health perspective

The decision to introduce liquid-based cytology (LBC) and HPV as screening tests involves criteria based on resource consumption. We used cross-sectional data at recruitment from the NTCC trial [ISRCTN81678807] on 28,000 women aged 35-60, randomised to receive a conventional Pap test or LBC plus HPV. We computed the resources employed to detect a CIN2+ with different screening strategies. In order to result in the same overall cost per CIN2+ detected as screening by conventional cytology, the unit cost of LBC used alone should be less than that of a conventional Pap while its unit cost may be up to 20% higher if HPV-triage for Atypical Squamous Cells of Undetermined Significance is applied together. With the same criterion the unit cost of HPV used alone may be about 20% higher than that of a Pap-test using a 1 pg/ml cut-off and over 40% higher using a 10 pg/ml cut-off. If HPV testing is applied with cytology-triage, a single HPV test may cost 20-30% more than a conventional Pap to result in the same overall cost per CIN2+ detected.