Cigarette smoking is a well-established risk factor for bladder cancer. The effects of smoking duration, intensity (cigarettes per day), and total exposure (pack-years); smoking cessation; exposure to environmental tobacco smoke; and changes in the composition of tobacco and cigarette design over time on risk of bladder cancer are unclear.
We examined bladder cancer risk in relation to smoking practices based on interview data from a large, population-based case–control study conducted in Maine, New Hampshire, and Vermont from 2001 to 2004 (N = 1170 urothelial carcinoma case patients and 1413 control subjects). We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. To examine changes in smoking-induced bladder cancer risk over time, we compared odds ratios from New Hampshire residents in this study (305 case patients and 335 control subjects) with those from two case–control studies conducted in New Hampshire in 1994–1998 and in 1998–2001 (843 case patients and 1183 control subjects).
Regular and current cigarette smokers had higher risks of bladder cancer than never-smokers (for regular smokers, OR = 3.0, 95% CI = 2.4 to 3.6; for current smokers, OR = 5.2, 95% CI = 4.0 to 6.6). In New Hampshire, there was a statistically significant increasing trend in smoking-related bladder cancer risk over three consecutive periods (1994–1998, 1998–2001, and 2002–2004) among former smokers (OR = 1.4, 95% CI = 1.0 to 2.0; OR = 2.0, 95% CI = 1.4 to 2.9; and OR = 2.6, 95% CI = 1.7 to 4.0, respectively) and current smokers (OR = 2.9, 95% CI = 2.0 to 4.2; OR = 4.2, 95% CI = 2.8 to 6.3; OR = 5.5, 95% CI = 3.5 to 8.9, respectively) (P for homogeneity of trends over time periods = .04). We also observed that within categories of intensity, odds ratios increased approximately linearly with increasing pack-years smoked, but the slope of the increasing trend declined with increasing intensity.
Smoking-related risks of bladder cancer appear to have increased in New Hampshire since the mid-1990s. Based on our modeling of pack-years and intensity, smoking fewer cigarettes over a long time appears more harmful than smoking more cigarettes over a shorter time, for equal total pack-years of cigarettes smoked.
Restoring p53 function by antagonizing its interaction with the negative regulator MDM2 is an appealing nongenotoxic approach to treating tumors with wild-type p53. Mutational inactivation of p53 is rare in neuroblastoma tumors at diagnosis and occurs in only a subset of multidrug-resistant neuroblastomas.
The antiproliferative and cytotoxic effect of nutlin-3, a small-molecule MDM2 antagonist, was examined in chemosensitive (UKF-NB-3) and matched chemoresistant neuroblastoma cells with wild-type p53 (UKF-NB-3rDOX20) or with mutant p53 (UKF-NB-3rVCR10). Activation of the p53 pathway was assessed by expression analysis of p53 target genes, flow cytometric cell cycle analysis, and apoptosis assays. Mice with established chemoresistant tumor xenografts were treated orally with nutlin-3 or vehicle control (n = 5–10 mice per group) and were used to evaluate effects on tumor growth, p53 pathway activity, and metastatic tumor burden. All statistical tests were two-sided.
Nutlin-3 induced a similar activation of the p53 pathway in UKF-NB-3 and UKF-NB-3rDOX20 cells, as evidenced by increased expression of p53 target genes, G1 cell cycle arrest, and induction of apoptosis. No such response was observed in UKF-NB-3rVCR10 cells with mutant p53. Oral administration of nutlin-3 to UKF-NB-3rDOX20 xenograft–bearing mice led to inhibition of primary tumor growth (mean tumor volume after 3 weeks of treatment, nutlin-3– vs vehicle-treated mice: 772 vs 1661 mm3, difference = 890 mm3, 95% confidence interval = 469 to 1311 mm3, P < .001), p53 pathway activation, and reduction in the extent of metastatic disease. The growth of UKF-NB-3rVCR10 xenografts was unaffected by nutlin-3.
Nutlin-3 activates the p53 pathway and suppresses tumor growth in this model system of chemoresistant neuroblastoma, provided that wild-type p53 is present.
The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area.
In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASRw) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASRw. All statistical tests were two-sided.
In 2002–2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASRw = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASRw = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, ≤10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASRw = 31.7, 95% CI = 29.1 to 34.3; and among men, ASRw = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASRw = 14.1, 95% CI = 13.2 to 15.0; and among men, ASRw = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily (P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily.
Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.
Since the 1980s, Spain experienced two decades of sharply increasing breast cancer incidence. Declines in breast cancer incidence have recently been reported in many developed countries. We examined whether a similar downturn might have taken place in Spain in recent years.
Cases of invasive female breast cancer were drawn from all population-based Spanish cancer registries that had at least 10 years of uninterrupted registration over the period 1980–2004. Overall and age-specific changes in incidence rates were evaluated using change-point Poisson models, which allow for accurate detection and estimation of trend changes. All statistical tests were two-sided.
A total of 80 453 incident cases of invasive breast cancer were identified. Overall age- and registry-adjusted incidence rates rose by 2.9% (95% confidence interval [CI] = 2.7% to 3.1%) annually during the 1980s and 1990s; there was a statistically significant change in this trend in 2001 (95% CI = 1998 to 2004; P value for the existence of a change point <.001), after which incidence declined annually by 3.0% (95% CI = 1.8% to 4.1%). This trend differed by age group: There was a steady increase in incidence for women younger than 45 years, an abrupt downturn in 2001 for women aged 45–64 years, and a gradual leveling off in 1995 for women aged 65 years or older. Separate analyses for registries that had at least 15 years of uninterrupted registration detected a statistically significant interruption of the previous upward trend in breast cancer incidence in provinces that had aggressive breast cancer screening programs and high screening participation rates, including Navarra (change point = 1991, P < .001), Granada (change point = 2002, P = .003), Bizkaia (change point = 1998, P < .001), Gipuzkoa (change point = 1998, P = .001), and Araba (change point = 1997, P = .002).
The recent downturn in breast cancer incidence among Spanish women older than 45 years is best explained by a period effect linked to screening saturation.
Israeli Jews of European origin have high incidence rates of all cancers, and many of them were exposed to severe famine and stress during World War II. We assessed cancer incidence in Israeli Jewish survivors of World War II.
Cancer rates were compared in a cohort of 315 544 Israeli Jews who were born in Europe and immigrated to Israel before or during World War II (nonexposed group, n = 57 496) or after World War II and up to 1989 (the exposed group, ie, those potentially exposed to the Holocaust, n = 258 048). Because no individual data were available on actual Holocaust exposure, we based exposure on the immigration date for European-born Israeli Jews and decided against use of the term "Holocaust survivors," implying a known, direct individual Holocaust exposure. Cancer incidences were obtained from the Israel National Cancer Registry. Relative risk (RR) estimates and 95% confidence intervals (95% CIs) were calculated for all cancer sites and for specific cancer sites, stratified by sex and birth cohort, and adjusted for time period.
The nonexposed group contributed 908 436 person-years of follow-up, with 13 237 cancer diagnoses (crude rate per 100 000 person-years = 1457.1). The exposed group contributed 4 011 264 person-years of follow-up, with 56 060 cancer diagnoses (crude rate per 100 000 person-years = 1397.6). Exposure, compared with nonexposure, was associated with a statistically significantly increased risk for all-site cancer for all birth cohorts and for both sexes. The strongest associations between exposure and all-site cancer risk were observed in the youngest birth cohort of 1940–1945 (for men, RR = 3.50, 95% CI = 2.17 to 5.65; for women, RR = 2.33, 95% CI = 1.69 to 3.21). Excess risk was pronounced for breast cancer in the 1940–1945 birth cohort (RR = 2.44, 95% CI = 1.46 to 4.06) and for colorectal cancer in the 1935–1939 cohort (for men, RR = 1.75, 95% CI = 1.19 to 2.59; for women, RR = 1.93, 95% CI = 1.25 to 3.00).
Incidence of all cancers, particularly breast and colorectal cancer, was higher among Israeli Jews who were potentially exposed to the Holocaust than among those who were not.
Müllerian inhibiting substance (MIS) is a member of the transforming growth factor β family of growth and differentiation factors that inhibits elongation and branching of mammary ducts and has been shown to inhibit mammary tumor growth in vitro and in animal models. The objective of this study was to determine whether serum MIS levels are associated with breast cancer risk.
We conducted a prospective case–control study of 309 participants who were registered in the Columbia, Missouri Serum Bank. Each of 105 in situ or invasive breast cancer case patients with prediagnostic serum collected before menopause was matched to two control subjects by age, date, menstrual cycle day, and time of day of blood collection. MIS was measured in serum by using an enzyme-linked immunosorbent assay, and estradiol and testosterone concentrations were quantified by using specific radioimmunoassays. Data were analyzed using conditional logistic regression. All tests of statistical significance were two-sided.
The relative odds ratio of breast cancer for women in increasing MIS quartiles were 1, 2.8 (95% confidence interval [CI] = 1.0 to 7.4), 5.9 (95% CI = 2.4 to 14.6), and 9.8 (95% CI = 3.3 to 28.9, Ptrend < .001). The association of MIS with breast cancer was weaker in women who were not taking oral contraceptives at the time of blood collection, but adjustment for estradiol and testosterone levels did not materially alter results for these women. The association of MIS with breast cancer did not vary by age at blood collection but was stronger among women who were diagnosed with breast cancer at an older age than among those who were diagnosed at a younger age.
MIS may be a novel biomarker of increased breast cancer risk. Additional research including confirmatory epidemiological studies and mechanistic studies is needed.
Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma.
Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain–specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162.
We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval [CI] = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162.
Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma.
The Hutchinson Study of High School Smoking randomized trial was designed to rigorously evaluate a proactive, personalized telephone counseling intervention for adolescent smoking cessation.
Fifty randomly selected Washington State high schools were randomized to the experimental or control condition. High school junior smokers were proactively identified (N = 2151). Trained counselors delivered the motivational interviewing plus cognitive behavioral skills training telephone intervention to smokers in experimental schools during their senior year of high school. Participants were followed up, with 88.8% participation, to outcome ascertainment more than 1 year after random assignment. The main outcome was 6-months prolonged abstinence from smoking. All statistical tests were two-sided.
The intervention increased the percentage who achieved 6-month prolonged smoking abstinence among all smokers (21.8% in the experimental condition vs 17.7% in the control condition, difference = 4.0%, 95% confidence interval [CI] = –0.2 to 8.1, P = .06) and in particular among daily smokers (10.1% vs 5.9%, difference = 4.1%, 95% CI = 0.8 to 7.1, P = .02). There was also generally strong evidence of intervention impact for 3-month, 1-month, and 7-day abstinence and duration since last cigarette (P = .09, .015, .01, and .03, respectively). The intervention effect was strongest among male daily smokers and among female less-than-daily smokers.
Proactive identification and recruitment of adolescents via public high schools can produce a high level of intervention reach; a personalized motivational interviewing plus cognitive behavioral skills training counseling intervention delivered by counselor-initiated telephone calls is effective in increasing teen smoking cessation; and both daily and less-than-daily teen smokers participate in and benefit from telephone-based smoking cessation intervention.
Effective smoking cessation for youth is urgently needed, but the literature guiding such efforts is nascent. We evaluated the implementation of a proactive intervention for adolescent smoking cessation that incorporated motivational interviewing (MI) and cognitive behavioral skills training (CBST).
We proactively identified 1058 smokers via classroom survey of enrolled juniors in 25 experimental high schools. After parental consent was obtained, trained counselors telephoned participants to invite their participation and deliver personalized smoking cessation counseling that combined MI and CBST. Implementation quality was assessed via weekly supervision of counselors, monitoring of counselor adherence to protocol via review of 5% of each counselor’s calls, and formal evaluation of counselor fidelity to MI via review of a random sample of 19.8% of counseling calls using the Motivational Interviewing Treatment Integrity Code.
Among identified smokers, 948 (89.6%) were eligible for intervention by age (≥18 years) or parental consent, 736 (70%) agreed to participate in telephone counseling, 691 (65%) completed one or more counseling calls, and 499 (47%) completed all planned calls. Telephone delivery of the personalized MI and CBST counseling intervention to a general population of adolescents was done with greater than 90% adherence to the intervention protocol. Review of the random sample of counselors’ calls demonstrated that more than 85% of counselors’ calls met or exceeded benchmark scores for four of six evaluated behaviors: MI spirit (99.1%), empathy (96.2%), ratio of reflections to questions (97.2%), and MI adherent (85.7%).
An effective proactive telephone counseling intervention consisting of MI and CBST can be successfully implemented with reach and fidelity in a general population of adolescent smokers.
A recent nested case–control study found that the presence of antibodies against Trichomonas vaginalis, a common nonviral sexually transmitted infection, was positively associated with subsequent incidence of prostate cancer. We confirmed these findings in an independent population and related serostatus for antibodies against T vaginalis to prostate cancer incidence and mortality.
We conducted a case–control study nested within the Physicians’ Health Study that included 673 case subjects with prostate cancer and 673 individually matched control subjects who had available plasma samples. Plasma from blood samples collected at baseline was assayed for antibodies against T vaginalis with an enzyme-linked immunosorbent assay. We used conditional logistic regression to estimate the odds ratios (ORs) of incident prostate cancer, extraprostatic prostate cancer, and cancer that would ultimately progress to bony metastases or prostate cancer–specific death.
Although not statistically significant, the magnitude of the association between T vaginalis–seropositive status and overall prostate cancer risk (OR = 1.23, 95% confidence interval [CI] = 0.94 to 1.61) was similar to that reported previously. Furthermore, a seropositive status was associated with statistically significantly increased risks of extraprostatic prostate cancer (OR = 2.17, 95% CI = 1.08 to 4.37) and of cancer that would ultimately progress to bony metastases or prostate cancer–specific death (OR = 2.69, 95% CI = 1.37 to 5.28).
This large prospective case–control study obtained further support for an association between a seropositive status for antibodies against T vaginalis and the risk of prostate cancer, with statistically significant associations identified for the risk of extraprostatic prostate cancer and for clinically relevant, potentially lethal prostate cancer.
Although colorectal cancer screening is cost-effective, it requires a considerable net investment by governments or insurance companies. If screening was cost saving, governments and insurance companies might be more inclined to invest in colorectal cancer screening programs. We examined whether colorectal cancer screening would become cost saving with the widespread use of the newer, more expensive chemotherapies.
We used the MISCAN-Colon microsimulation model to assess whether widespread use of new chemotherapies would affect the treatment savings of colorectal cancer screening in the general population. We considered three scenarios for chemotherapy use: the past, the present, and the near future. We assumed that survival improved and treatment costs for patients diagnosed with advanced stages of colorectal cancer increased over the scenarios. Screening strategies considered were annual guaiac fecal occult blood testing (FOBT), annual immunochemical FOBT, sigmoidoscopy every 5 years, colonoscopy every 10 years, and the combination of sigmoidoscopy every 5 years and annual guaiac FOBT. Analyses were conducted from the perspective of the health-care system for a cohort of 50-year-old individuals who were at average risk of colorectal cancer and were screened with 100% adherence from age 50 years to age 80 years and followed up until death.
Compared with no screening, the treatment savings from preventing advanced colorectal cancer and colorectal cancer deaths by screening more than doubled with the widespread use of new chemotherapies. The lifetime average treatment savings were larger than the lifetime average screening costs for screening with Hemoccult II, immunochemical FOBT, sigmoidoscopy, and the combination of sigmoidoscopy and Hemoccult II (average savings vs costs per individual in the population: Hemoccult II, $1398 vs $859; immunochemical FOBT, $1756 vs $1565; sigmoidoscopy, $1706 vs $1575; sigmoidoscopy and Hemoccult II $1931 vs $1878). Colonoscopy did not become cost saving, but the total net costs of this strategy decreased from $1317 to $296 per individual in the population.
With the increase in chemotherapy costs for advanced colorectal cancer, most colorectal cancer screening strategies have become cost saving. As a consequence, screening is a desirable approach not only to reduce colorectal cancer incidence and mortality but also to control the costs of colorectal cancer treatment.