Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China

Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A... Bo X, et al. Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China. Annals of Global Health. 2019; 85(1): 103, 1–9. DOI: https://doi.org/10.5334/aogh.2463 ORIGINAL RESEARCH Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China * †,‡ * § § § ‡,‖,¶ Xiaojie Bo , Jianwei Shi , Rui Liu , Shasha Geng , Qingqing Li , Yang Li , Hua Jin , ‡,‖,¶ § *,† Sen Yang , Hua Jiang and Zhaoxin Wang Background: The incidence of pancreatic cancer has increased annually, but the risk factors and their interactions are still unknown. Objective: The aim of this study was to identify risk factors and the effects of their interactions on pancreatic cancer occurrence among patients in Shanghai, China. Methods: We conducted a hospital-based case-control study. The case group consisted of pathologically diagnosed pancreatic cancer patients, and the control group consisted of a healthy population. The Pearson Chi-square test was used to compare the distribution frequencies of data between groups. Multivariate analysis and interaction analysis were conducted to explore possible risk factors and interac- tions between various variables. Findings: Among the 4,821 recruited participants, 1,392 were pancreatic cancer patients and 3,429 were controls. Multivariate logistic analysis suggested that age (>50 years old) (AOR: 16.20 [95% CI 6.78; 38.69]), diabetes (AOR: 5.40 [95% CI 2.70; 10.80]), chronic pancreatitis (AOR: 27.43 [95% CI 2.14; 351.77]), smoking (AOR: 8.86 [95% CI 3.07; 25.58]), and family cancer history (AOR: 2.10 [95% CI 1.09; 8.56]) were the primary risk factors for pancreatic cancer. Interestingly, synergistic interactions between risk factors were found, especially between age and chronic pancreatitis (RERI = 447.93, API = 96.74%, SI = 32.78), age and smoking (RERI = 187.42, API = 94.97%, SI = 21.99), and diabetes and smoking (RERI = 14.39, API = 48.06%, SI = 1.99). Conclusions: Age, diabetes, chronic pancreatitis, smoking, and family cancer history have been verified as the primary risk factors for pancreatic cancer in this study. Moreover, the interaction effects between old age, diabetes, chronic pancreatitis, and smoking substantially increase the probability of the development of pancreatic cancer. Cancer screening should be conducted extensively among people with these multiple factors to improve the efficiency. Strengths and limitations of this study are as vention and screening of pancreatic cancer. follows 4. As a hospital-based case-control study, selection bias 1. This study confirmed the significance of previously was inevitable. established risk factors for pancreatic cancer. 5. The study period was limited by relevant informa- 2. This study found significant synergistic interactions tion on body mass index and diet, and detailed in- between some risk factors for pancreatic cancer. formation on the amount of smoking and alcohol 3. The results of this study contribute to the early pre- consumption was not available. Introduction * Department of Pediatrics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, CN Pancreatic cancer is a highly lethal disease, with a mortality School of Public Health, Shanghai Jiaotong University School rate that is very close to its incidence rate [1]. With no of Medicine, Shanghai, CN specific observable symptoms until in its advanced and Department of General Practice, Yangpu Hospital, Tongji incurable stage, pancreatic cancer develops insidiously [2] University School of Medicine, Shanghai, CN Due to the late diagnosis, patients with pancreatic cancer Shanghai East Hospital, Tongji University School of Medicine, have one of the worst five-year survival rates of all cancers Shanghai, CN (6% in the US) [1]. Currently, the number of deaths from Academic Department of General Practice, Tongji University pancreatic cancer is increasing, and it is predicted to be School of Medicine, Shanghai, CN the second-leading cause of cancer-related death in the Shanghai General Practice and Community Health Development US by 2030 [3]. Similarly, an increase in pancreatic cancer Research Center, Shanghai, CN mortality has been reported in European populations [4]. Corresponding authors: Dr. Hua Jiang (east_hua_ jiang@163.com); Dr. Zhaoxin Wang (supercell002@sina.com) In China, the incidence and mortality rates of pancreatic Art. 103, page 2 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Study participants cancer increased steadily from 2000 to 2011. In 2015, the In this study, a total of 1,903 pancreatic cancer cases were number of male and female pancreatic cancer patients in selected through the hospital registry system once they China reached 52,200 and 37,900, respectively, and the were diagnosed with pancreatic cancer. For the controls, numbers of deaths were 45,600 and 33,800, respectively 4,848 were chosen when they received a health examina- [5]. tion. Then, each participant was asked to provide informed Similar to most malignancies, pancreatic cancer results consent to participate in a structured questionnaire. Some from the combination of environmental factors and of the questionnaires were finished when the participants genetic factors [6]. Although studies have reached a con- were in the hospitals, and the rest were finished over the sensus on the etiology of pancreatic cancer, the epidemio- telephone. All the questionnaires were administered by logical causes of pancreatic cancer identified in different our trained investigators. Finally, we checked the informa- studies have varied, and the influence of these factors tion pertaining to medical history on the questionnaire on pancreatic cancer is still under debate [7]. At present, by comparing it with the participant’s medical file and smoking has been identified as the most well-established then excluded the participants with inconsistent informa- risk factor for pancreatic cancer on a global scale [8, 9, 10]. tion. In total, the participation rates of patients in the case Other factors, such as age, diabetes and chronic pancrea- group and the control group were 73.15% (1392/1903) titis, have also been associated with pancreatic cancer in and 70.73% (3429/4848), respectively. The loss was due most recent studies [11, 12]. Possible interactions between to the following reasons: inconsistent information and the risk factors may exist due to the multifactorial nature refusal to answer the questionnaire. A total of 4,821 of pancreatic carcinogenesis. However, few studies have (1,392 cases, 3,429 controls) participants were enrolled, examined the possible interactions, and no large case- and there were no significant differences between the control studies have been conducted on the interactions case group and the control group in terms of the charac- among the risk factors for pancreatic cancer. teristics of gender, race, marital status, and so on. Considering that there are few studies on the interactions between various risk factors for pancreatic Questionnaire data cancer in China, we conducted this study to identify these The questionnaire was designed by relevant experts from risk factors and their interactions, aiming to contribute the hospital and university who have abundant experience to the early prevention of and screening for pancreatic in clinical diagnosis or screening for pancreatic cancer. cancer. The hospital staff members were available for assistance if participants had enquiries regarding the questions. The Methods questionnaire was divided into three sections: section 1 Study design contained questions on demographic characteristics, such A hospital-based case-control study was conducted to as age, gender, race and marital status; section 2 contained identify the risk factors for pancreatic cancer and their questions on smoking status and alcohol consumption; interactions based on data from pancreatic cancer patients and section 3 was about the participant’s medical history from 14 tertiary hospitals in Shanghai, China. A total of and family cancer history. All information was collected by 4,821 participants were recruited, including 1,392 with self-report. All questionnaires were cross-checked daily by pathologically verified cancer and 3,429 healthy controls. the investigators. All participants were selected from fourteen tertiary hos- pitals in Shanghai. Data analysis All of the primary pancreatic cancer patients were diag- All analyses were performed with SPSS software (version nosed in the oncology departments of the above fourteen 21.0; SPSS, Inc., Chicago, IL, USA). Chi-square tests were tertiary hospitals between January 1, 2012, and December used to assess the differences between the case and con- 12, 2017. The inclusion criteria for the case group were as trol groups. First, univariate analysis was conducted for follows: pathologically diagnosed pancreatic ductal ade- each relevant risk factor. Based on univariate analysis of nocarcinoma and literate. The exclusion criteria were as the relevant risk factors combined with literature reports follows: patients diagnosed with other types of pancreatic and clinical experience, all the risk factors with screening disease, such as neuroendocrine tumor, adenomas, cysts, value were then included in multiple logistic regression or other unknown primary tumors; concurrent cancer at models to evaluate their independent effects. Multivariate another organ site; and a history of other cancers. analysis was adjusted for potential confounders, such as Participants in the control group were recruited from sex, race, and marital status, to evaluate the association the physical examination center of the same hospitals; of exposure risk factors with the risk of pancreatic can- their physical medical examination results indicated that cer. The adjusted odds ratios (AORs) and 95% confidence they were healthy. According to the ages recorded on the intervals (CIs) of the associations between the risk factors physical examination form, we chose the control group and pancreatic cancer risk were calculated by multivariate such that their age composition matched that of the total logistic analysis. population of Shanghai. Moreover, controls and cases Moreover, we used multiple logistic regression mod- were matched according to sex and race. The eligibility els to investigate possible interactions between the risk criteria for the controls were the same as those for the factors. We chose to use an additive model rather than patients, except for the cancer diagnosis. a multiplicative model because the former has a more Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 3 of 9 appropriate scale for addressing biologic interactions interference from potential confounding factors, we con- and public health concerns. To assess deviation from the ducted a multivariate analysis using a logistic regression additive model (which assumes there is no interaction model. Based on the results of the univariate analysis, we between variables), the relative excess rate due to inter- divided the participants into two age groups, with the cut- action (RERI = OR – OR – OR + 1), the attributable off value of 50 years old. We incorporated all the potential 11 01 10 proportion due to interaction (API = (RERI/OR ) and the confounding factors and the risk factors into a multiple synergism index (SI = [OR − 1]/([OR + OR ] − 2) were regression model, and the final model equation contained 11 01 10 calculated, where OR = the OR of the joint effect of two a total of five variables (Table 2). The results showed that risk factors, and OR and OR = the OR of each risk factor people with diabetes (AOR = 5.40, 95% CI [2.70–10.80]), 10 01 in the absence of the other [13]. chronic pancreatitis (AOR = 27.43, 95% CI [2.14–351.77]), old age (AOR = 16.20, 95% CI [6.78–38.69]), smoking Results (AOR = 8.86, 95% CI [3.07–25.58]), and a family cancer Participant demographics history (AOR = 2.1, 95% CI [1.09–8.56]) had a higher risk. This hospital-based case-control study included 1,392 All of the results were obtained after adjusting for sex, cases of pancreatic cancer patients and 3,429 healthy race, marital status, and other risk factors. cases. Table 1 summarizes the demographic characteris- tics of our sample in both the case and control groups. Interaction analysis The ratio of male to female was slightly higher than 1:1, For the above four primary risk factors that were statis- and there was no significant difference in the sex ratio tically significant in the multivariate logistic regression between the case and control groups. All patients in the model with an AOR value larger than 1, an interaction case group and the vast majority in the control group analysis was further performed with the logistic regres- (97.75%) were of Han ethnicity. There was no significant sion model and the additive model. difference in the sex ratio or the race ratio between the Table 3 shows the independent and interactive effects cases and controls. Concerning marital status, most of of age, diabetes, chronic pancreatitis, and smoking on the participants in the case (99.43%) and control groups pancreatic cancer incidence. The results indicated additiv- (82.62%) were married, but there was still a significant ity and synergism between age and chronic pancreatitis, difference between the two groups (P < 0.001). We chose age and smoking, and diabetes and smoking, after adjust- to adjust for all demographic factors in the multivariate ing for the effects of other significant risk factors. logistic regression models. The RERIs were 447.93, 187.42, and 14.39 for the age/chronic pancreatitis, age/smoking, and dia- Univariate analysis betes/smoking interactions, respectively. Using the RERIs, Table 1 shows the results of the univariate analysis by we estimated that the attributable proportion due to Chi-square tests. According to the preliminary results, interaction (API %) values explained by age/chronic pan- we found that there were no significant differences in creatitis, age/smoking, and diabetes/smoking interac- the risk of pancreatic cancer among people aged 18–29 tion were 96.74%, 94.97%, and 48.06%, respectively. The years old, 30–39 years old, and 40–49 years old; hence, estimated SI values were 32.78, 21.99, and 1.99, respec- they were combined in one group under 50 years old. tively. This may indicate that the interaction effect of The results show that increasing age can increase the risk the above three groups of pancreatic cancer risk factors of pancreatic cancer; with less than 50 years old as the is super additive. Additionally, the results revealed that reference, the odds ratios are as follows: from 50 to 59 there was a negative interaction between age and diabetes years old (OR = 25.00, 95% CI [3.41–200.00]), 60 to 69 (RERI = –31.43, API = –26.38%, SI = 0.79). No other sig- years old (OR = 76.92, 95% CI [10.20–500.00]), 70 to 79 nificant interaction was observed between groups, such as years old (OR = 111.11, 95% CI [1.52–1000.00]), and 80 diabetes and chronic pancreatitis and chronic pancreatitis years old or older (OR = 142.86, 95% CI [19.23–1000.00]). and smoking. The risk of pancreatic cancer increases gradually as age increases. The results also suggest that other possible Discussion risk factors include hypertension (OR = 2.08, 95% CI Studies have suggested that the development of pancre- [1.39–3.11]), diabetes (OR = 4.94, 95% CI [3.03–8.05]), atic cancer is a complex and multistep process with a mul- chronic pancreatitis (OR = 6.85, 95% CI [3.70–12.68]), tifactorial etiology, as many factors (genetic susceptibility, biliary disease (OR = 1.77, 95% CI [1.12–2.80]), a history environmental factors, lifestyles, and physical conditions) of surgery or trauma (OR = 2.04, 95% CI [1.37–3.04]), may contribute to its occurrence [14, 15, 16]. In our study, smoking (OR = 5.92, 95% CI [4.68–7.49]), and family can- we found that pancreatic cancer is more common among cer history (OR = 1.93, 95% CI [1.47–2.54]). In contrast, older adults, and there was a significantly higher risk asso- hyperlipidemia (OR = 0.06, 95% CI [0.02–0.25]), is a pro- ciated with older age. Consistent with our results, Qi Dong tective factor. However, alcohol consumption (P = 0.721) et al. retrospectively analyzed the clinical data of 207 was not statistically significant in the univariate analysis. patients with pancreatic cancer, and their study showed that age is an independent risk factor for the incidence Multivariate analysis of pancreatic cancer. The relative risk of pancreatic can- To assess the independent effects of different risk factors cer increased approximately 1.78 times in the older group on the incidence of pancreatic cancer and to control for compared with the younger group [17]. One possible Art. 103, page 4 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Table 1: Characteristics of the study participants. Study Variables Patients Controls χ P OR(95% CI) (N = 1,392) (N = 3,429) n % n % Sex Male 830 59.63 1,981 57.77 / 0.16 0.689 Female 562 40.37 1,448 42.23 Race Han ethnicity 1,392 100.00 3,352 97.75 / 3.29 0.069 Others 0 0.00 77 2.25 Marital status Married 1,384 99.43 2,833 82.62 / 25.18 0.000 Unmarried 8 0.57 596 17.38 Age (years) <50 71 5.10 1,507 43.95 1.00 50–59 249 17.89 721 21.03 21.87 0.000 25.00 (3.41–200.00) 60–69 501 35.99 452 13.18 63.18 0.000 76.92 (10.20–500.00) 70–79 313 22.49 228 6.65 91.48 0.000 111.11 (1.52–1000.00) ≥80 258 18.53 521 15.19 108.51 0.000 142.86 (19.23–1000.00) Hypertension Yes 660 47.41 1,038 30.27 2.08 (1.39–3.11) 12.76 0.000 No 732 52.59 2,391 69.73 1.00 Hyperlipidemia Yes 23 1.65 671 19.57 0.06 (0.02–0.25) 26.41 0.000 No 1.369 98.35 2,758 80.43 1.00 Diabetes Yes 511 36.71 359 10.47 4.94 (3.03–8.05) 45.89 0.000 No 881 63.29 3,070 89.53 1.00 Chronic pancreatitis Yes 38 2.73 14 0.41 6.85 (3.70–12.68) 50.01 0.001 No 1,354 97.27 3,415 99.59 1.00 Biliary disease Yes 391 28.09 622 18.14 1.77 (1.12–2.80) 5.95 0.015 No 1.001 71.91 2,807 81.86 1.00 History of surgical trauma Yes 803 57.69 1,371 39.98 2.04 (1.37–3.04) 12.39 0.000 No 589 42.31 2,058 60.02 1.00 Smoking Yes 232 16.67 112 3.27 5.92 (4.68–7.49) 268.31 0.000 No 1,160 83.33 3,317 96.73 1.00 Family cancer history Yes 94 6.75 124 3.62 1.93 (1.47–2.54) 22.56 0.000 No 1,298 93.25 3,305 96.38 1.00 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 5 of 9 Table 2: Risk factors for pancreatic cancer in multivariable logistic regression analysis. Variables SE (β) Wald (χ ) AOR (95% CI) P Diabetes Yes 1.69 0.35 22.73 5.40 (2.70–10.80) 0.000 No 1.00 Chronic pancreatitis Yes 3.31 1.3 6.47 27.43 (2.14–351.77) 0.011 No 1.00 Smoking Yes 2.18 0.54 16.24 8.86 (3.07–25.58) 0.000 No 1.00 Family cancer history Yes 1.14 0.23 20.21 2.1 (1.09–8.56) 0.000 No 1.00 Age, years <50 2.79 0.44 39.3 16.20 (6.78–38.69) 0.000 ≥50 1.00 Adjusted for gender, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, and drinking. reason may be that aging causes the body to accumulate hereditary, and tropical pancreatitis, are associated with more carcinogens and changes some of the body’s defense pancreatic cancer to some extent [21]. A significant associ- mechanisms [18]. This can be one of the pathophysiologi- ation between chronic pancreatitis and pancreatic cancer cal mechanisms underlying the development of pancre- risk was found in our study. The results of our multivari- atic cancer. It is predicted that the incidence of pancreatic ate logistic analysis showed that the risk for pancreatic cancer will continue to rise as the aging of the population cancer was 20-fold higher among patients affected by continues to accelerate. chronic pancreatitis after adjusting for potential con- Diabetes can be a cause and a complication of pancreatic founders. In previous studies, most authors had drawn cancer, although reports are not consistent. Our results similar conclusions, and the relative risks for pancreatic indicated that diabetes is an important risk factor for pan- cancer in chronic pancreatitis patients varied from 2.3 to creatic cancer. This is in accordance with the results of the 18.5 [22]. Furthermore, a recent meta-analysis conducted meta-analysis conducted by Huxley et al., which analyzed by Raimondi et al. of 22 studies that found that the risk 19 cohort studies and 17 case-control studies between of developing pancreatic cancer in patients with chronic 1966 and 2005 [18]. Zhan et al. conducted a retrospective pancreatitis was 20 times higher than among those with- study of 2,405 patients with malignant tumors and found out chronic pancreatitis [23]. In addition, chromosomal that 28% of the patients had been diagnosed with diabetes instability in patients with chronic pancreatitis is also con- before developing cancer. Among them, the percentage of ducive to the occurrence of pancreatic cancer. Therefore, pancreatic cancer patients (57.1%) was the highest, which we believe that patients with chronic pancreatitis should suggested that diabetes may be a risk factor for pancreatic be considered at high risk for pancreatic cancer, and they cancer, and it is advisable to perform conventional screen- would benefit from preventive measures and early detec- ing of diabetic patients for the early diagnosis of pancre- tion programs. atic cancer [19]. However, according to Liao et al.’s 10-year According to other studies, smoking has been defini- population-based cohort study (49,803 vs. 199,212) based tively identified as the most important environmental risk on the Taiwan National Health Insurance Database, diabe- factor for pancreatic cancer [24]. To date, at least 30 epide- tes with <2 years’ duration was associated with pancreatic miological studies have confirmed this view [8, 9, 25–28]. cancer and could be an early manifestation of pancreatic The results of our multivariate analysis also revealed that cancer, but long-standing diabetes was not found to be smoking was associated with an increased risk of pancre- a risk factor for pancreatic cancer [20]. However, we did atic cancer. Consistent with our results, a nested case-con- not obtain information on the duration of diabetes in this trol study conducted by Lynch S.M. et al., including 1,481 study. Therefore, the association of diabetes with pancre- cases and 1,539 controls, found that the ORs of pancre- atic cancer warrants further investigation. atic cancer were 1.1 (95% CI, 0.9–1.3) for former smokers Some studies have concluded that various types of and 1.8 (95% CI, 1.4–2.3) for current smokers compared chronic pancreatitis, including alcoholic, non-alcoholic, to nonsmokers [29]. Similar findings were obtained in a Art. 103, page 6 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Table 3: Synergistic interactions among age, diabetes, chronic pancreatitis and smoking. Interaction Variables AOR (95% CI) RERI API SI Variable 1 Variable 2 1 1 Age Diabetes ≤50 years No 1 –31.43 –26.38% 0.79 ≤50 years Yes 123.06 (10.22–1482.18) >50 years No 28.50 (9.38–86.62) >50 years Yes 119.14 (33.91–418.55) 2 2 Age Chronic pancreatitis ≤50 years No 1 447.93 96.74% 32.78 ≤50 years Yes / >50 years No 16.10 (6.73–38.48) >50 years Yes 463.03 (29.54–7258.03) 3 3 Age Smoking ≤50 years No 1 187.42 94.97% 21.99 ≤50 years Yes / >50 years No 10.93 (4.66–25.64) >50 years Yes 197.35 (40.49–962.03) 4 4 Diabetes Chronic pancreatitis No No 1 / / / No Yes 23.25 (1.58–342.12) Yes No 5.35 (2.67–10.71) Yes Yes / 5 5 Diabetes Smoking No No 1 14.39 48.06% 1.99 No Yes 10.48 (3.38–32.52) Yes No 6.07 (2.85–12.91) Yes Yes 29.94 (5.36–167.33) Chronic Smoking pancreatitis No No 1 / / / No Yes 8.83(3.05–25.55) Yes No 26.21 (1.76–389.40) Yes Yes / Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, chronic pancreatitis, and smoking. Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, diabetes, and smoking. Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, diabetes, and chronic pancreatitis. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and smoking. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and chronic pancreatitis. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and diabetes. /: P > 0.05. large hospital-based case-control study (808 vs. 808) and Consistent with our results, Schulte’s study, which a 40-year follow-up cohort study [30, 31]. According to included 591 pancreatic cancer patients and 646 con- pathological studies, the effect mechanism may result trols, reported that a family history of pancreatic cancer from the carcinogens in tobacco acting on the pancreas (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, through the blood or duodenal fluid and bile reflux [32]. 95% CI 1.03–2.95) were risk factors for pancreatic cancer Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 7 of 9 [30]. Hassan’s case-control study showed that family his- Conclusion tories of cancer in general and of pancreatic cancer in The results of this study show that age, diabetes, chronic particular were associated with a significantly elevated pancreatitis, smoking, and family cancer history are risk risk for pancreatic cancer. The effect of a positive fam- factors for pancreatic cancer. Moreover, the interactions ily history of pancreatic cancer was significant in women of the risk factors increase the probability of developing and men. The pattern was consistent with the familial pancreatic cancer. This study provides important clues predisposition reported for pancreatic cancer and with for the prevention of pancreatic cancer. We believe that the array of tumors associated with hereditary nonpoly- identifying individuals with the highest risk of pancreatic posis colon cancer. In our analysis, hyperlipidemia had a cancer can contribute greatly to the development of pre- negative association with pancreatic cancer. The results vention programs and the early detection of pancreatic are inconsistent with other studies showing that high cancer. More large-scale epidemiological studies with dif- blood lipid levels increase the risk of pancreatic cancer ferent populations on the interactions among risk factors [33], and possible reasons were related to the use of are warranted, with stratification by sex. statins for treating hyperlipidemia. Regular statin use before the diagnosis of pancreatic cancer was associ- Abbreviations ated with modest increases in survival times in two large AOR: Adjusted Odd Ratio prospective cohort studies [34]. In our study, it is pos- CI: Confidence Interval sible that the patients did not take statins to treat hyper- RERI: Relative Excess Rate due to Interaction lipidemia. However, we did not obtain this information API: Attributable Proportion due to Interaction from the questionnaires, and the association needs to be SI: Synergism Index explored in future analyses. The most noteworthy finding of our study was the Ethics and Consent interactions between certain risk factors. Our results Ethics approval was given by the medical ethics showed that there were significant positive synergistic committees of all participating hospitals. All participants interactions between age and chronic pancreatitis, age gave informed consent before being enrolled in the study. and smoking, and diabetes and smoking after adjusting for the effects of other significant risk factors. This sup- Acknowledgements ports the hypothesis that people with a combination of We are grateful to Shanghai East Hospital for allowing us two or more risk factors are more vulnerable to pancreatic to perform this study and helping us collect data. cancer. Similar to our research design, a large case-con- trol study (808 vs. 808) conducted by Hassan et al. found Funding Information that synergistic interactions did exist between cigarette The design of this study involving some previous inves- smoking and a family history of pancreatic cancer (AOR tigations was supported by the Key Developing Disci- = 12.8, 95% CI 1.6–108.9) and between smoking and dia- plines of Shanghai Municipal Commission of Health betes (AOR = 9.3, 95% CI 2.0–44.1) in women. Moreover, and Family Planning (2015ZB0602). Data extraction was a recent study in Italy in 2014 found that important syn- financially funded by the Natural Science Foundation of ergistic interactions existed between smoking and alcohol China (71774116). The analysis and interpretation of the consumption (SI = 17.61) and alcohol consumption and data guided by statisticians were funded by the Soft Pro- diabetes (SI = 17.77) [35]. However, in our study, similar to jects of Shanghai Municipal Commission of Science and in other studies, we did not find a significant interaction Technology (17692105200), and the writing and revi- between chronic pancreatitis and smoking, and a possible sion, including the language editing, were supported mechanism still needs to be explored. To a certain extent, by the Surface Project of Shanghai Municipal Commis- this study provided insight into whether the performance sion of Health and Family Planning (201740202) and of pancreatic cancer screening among people with mul- the Shanghai Excellent Young Talents Project in Health tiple risk factors, such as old age, diabetes, and smok- System (2018YQ52), National Natural Science Foundation ing, would substantially improve the efficiency of cancer of China (71603182), National Natural Science Founda- screening. tion of China (71804128). The limitations of the study should be taken into account. First, our study is a case-control study that Competing Interests applies an analytical epidemiological research method The authors have no competing interests to declare. that has inherent limitations and disadvantages. The selection bias and recall bias cannot be eliminated com- Author Contributions pletely. To address the selection bias problem, we adopted XJB and JWS participated in the epidemiological investiga- a multicenter design in which the cases and controls were tion and drafted the manuscript; HJ and ZXW participated recruited from the same hospitals. We selected newly in the overall design, study coordination, data analysis and diagnosed cases and avoided using proxy respondents, final draft of the manuscript. SSG and SY were responsi- minimizing recall bias. Second, we did not obtain relevant ble for the data collection; QQL and YL participated in the information on body mass index, diet, details regarding epidemiological investigation; JWS, HJ and RL carried out smoking and alcohol consumption, or the duration of the data analysis; HJ interpreted the results and refined diabetes. Therefore, further investigations into pancreatic the manuscript. All of the authors read and approved the cancer risk factors are warranted. final manuscript. Art. 103, page 8 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Author Information a cohort study. BMJ Open. 2018; 8: e020827. DOI: Xiaojie Bo and Jianwei Shi are co-first authors in this https://doi.org/10.1136/bmjopen-2017-020827 article. 13. Hedström A, Katsoulis M, Alfredsson L, et al. The interaction between smoking and HLA genes in References multiple sclerosis: Replication and refinement. Eur J 1. Terumi K, Wood L, Takaori K, et al. Pancreatic Epidemiol. 2017; 32(10): 909–919. DOI: https://doi. cancer. Lancet. July 2, 2016; 388(10039): 73–85. DOI: org/10.1007/s10654-017-0250-2 https://doi.org/10.1016/S0140-6736(16)00141-0 14. Zheng Z, Zheng R, Chen W, et al. Risk factors for 2. Buha A, Wallace D, Djordjevic V, et al. Cadmium pancreatic cancer in China: A multicenter case- exposure as a putative risk factor for the development control study. J Epidemiol. 2016; 26(2): 64–70. DOI: of pancreatic cancer: Three different lines of evidence. https://doi.org/10.2188/jea.JE20140148 Biomed Research International. 2017; 1981837. DOI: 15. Keane MG, Horsfall L, Rait G, et al. A case- https://doi.org/10.1155/2017/1981837 control study comparing the incidence of early 3. Rahib L, Smith BD, Aizenberg R, et al. Projecting symptoms in pancreatic and biliary tract cancer. cancer incidence and deaths to 2030: The unexpected BMJ Open. 2014; 4: e005720. DOI: https://doi. burden of thyroid, liver, and pancreas cancers in the org/10.1136/bmjopen-2014-005720 United States. Cancer Res. 2014; 74: 2913–21. DOI: 16. Klein A. Identifying people at a high risk of devel- https://doi.org/10.1158/0008-5472.CAN-14-0155 oping pancreatic cancer. Nature Reviews Cancer. 4. Malvezzi M, Bertuccio P, Levi F, et al. European 2013; 13(1): 66–74. DOI: https://doi.org/10.1038/ cancer mortality predictions for the year 2014. nrc3420 Ann Oncol. 2014; 25: 1650–56. DOI: https://doi. 17. Yan D, Wang XY, Xu XJ, et al. Analyses of partial org/10.1093/annonc/mdu138 risk factors for pancreatic cancer. Journal of Xinjiang 5. Chen W, Zheng R, He J, et al. Cancer statistics Medical University. 2010; 33(08): 928–930. in China, 2015. CA: A Cancer Journal For Clini- 18. Huxley R, Ansary-Moghaddam A, Berrington de cians. 2016; 66(2): 115–132. DOI: https://doi. Gonzalez A, et al. Type-II diabetes and pancreatic org/10.3322/caac.21338 cancer: A meta-analysis of 36 studies. Br J Cancer. 6. Edderkaoui M and Eibl G. Risk factors for pan- 2005; 92: 2076–83. DOI: https://doi.org/10.1038/ creatic cancer: Underlying mechanisms and poten- sj.bjc.6602619 tial targets. Frontiers In Physiology. December 19. Zhan YS, Feng L, Tang SH, et al. Glucose metabo- 10, 2014; 5: 490. DOI: https://doi.org/10.3389/ lism disorders in cancer patients in a Chinese popu- fphys.2014.00490 lation. Medical Oncology. 2010; 27(2): 177–184. 7. López Serrano A. Risk factors and early diagnosis of DOI: https://doi.org/10.1007/s12032-009-9189-9 pancreatic cancer. Gastroenterologia Y Hepatologia. 20. Liao K, Lai S, Li C and Chen W. Diabetes mellitus May 2010; 33(5): 382–390. DOI: https://doi. correlates with increased risk of pancreatic can- org/10.1016/j.gastrohep.2009.10.004 cer: A population-based cohort study in Taiwan. 8. Silverman DT, Dunn JA, Hoover RN, et al. Cigarette Journal of Gastroenterology and Hepatology. smoking and pancreas cancer: A case-control study 2012; 27(4): 709–713. DOI: https://doi. based on direct interviews. J Natl Cancer Inst. org/10.1111/j.1440-1746.2011.06938.x 1994; 86: 1510–6. DOI: https://doi.org/10.1093/ 21. Li BR, Hu LH and Li ZS. Chronic pancreatitis jnci/86.20.1510 and pancreatic cancer. Gastroenterology. 2014; 9. Bonelli L, Aste H, Pugliese V, et al. Exocrine pan- 147: 541–542. DOI: https://doi.org/10.1053/j. creatic cancer, cigarette smoking, and diabetes gastro.2014.03.054 mellitus: A case-control study in northern Italy. Pan- 22. Apple SK, Hecht JR, Lewin DN, et al. Immunohis- creas. August 2003; 27(2): 143–149. DOI: https:// tochemical evaluation of K-ras, p53, and HER-2/ doi.org/10.1097/00006676-200308000-00007 neu expression in hyperplastic, dysplastic, and 10. Anderson L, Cotterchio M and Gallinger S. carcinomatous lesions of the pancreas: Evidence Lifestyle, dietary, and medical history factors asso- for multistep carcinogenesis. Human Pathol. 1999; ciated with pancreatic cancer risk in Ontario, 30(2): 123–129. DOI: https://doi.org/10.1016/ Canada. Cancer Causes & Control: CCC. August 2009; S0046-8177(99)90265-4 20(6): 825–834. DOI: https://doi.org/10.1007/ 23. Raimondi S, Lowenfels AB and Morselli-Labate s10552-009-9303-5 AM, et al. Pancreatic cancer in chronic pancreatitis, 11. Midha S, Sreenivas V, Kabra M, et al. Genetically aetiology, incidence, and early detection. Best Pract determined chronic pancreatitis but not alcoholic Res Clin Gastroenterol. 2010; 24(3): 349–358. DOI: pancreatitis is a strong risk factor for pancreatic https://doi.org/10.1016/j.bpg.2010.02.007 cancer. Pancreas. 2016; 45(10): 1478–1484. DOI: 24. Parkin DM. The fraction of cancer attributable to https://doi.org/10.1097/MPA.0000000000000684 lifestyle and environmental factors in the UK in 12. Williams R, van Staa T, Gallagher AM, et al. Cancer 2010. Br J Cancer. 2011; 105 Suppl 2: S2–5. DOI: recording in patients with and without type 2 dia- https://doi.org/10.1038/bjc.2011.474 betes in the Clinical Practice Research Datalink pri- 25. Brand R, Lerch M, Canto M, et al. Advances in mary care data and linked hospital admission data: counselling and surveillance of patients at risk for Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 9 of 9 pancreatic cancer. Gut. 2007; 56(10): 1460–1469. 31. Doll R and Hill AB. Mortality in relation to smoking: DOI: https://doi.org/10.1136/gut.2006.108456 Ten years’ observations of British doctors. Br Med J. 26. Iodice S, Gandini S, Maisonneuve P and 1964; i: 1399–1410. DOI: https://doi.org/10.1136/ Lowenfels AB. Tobacco and the risk of pancreatic bmj.1.5395.1399 cancer: a review and meta-analysis. Langenbecks 32. Hao J, Li G and Pang B. Evidence for cigarette Arch Surg. 2008; 393(4): 535–45. DOI: https://doi. smoke-induced oxidative stress in the rat org/10.1007/s00423-007-0266-2 pancreas. Inhalation Toxicology. 2009; 27. Bosetti C, Lucenteforte E, Silverman DT, 21(12): 1007–1012. DOI: https://doi. Petersen G, Bracci PM, Ji BT, et al. Cigarette smok- org/10.1080/08958370802665937 ing and pancreatic cancer: an analysis from the 33. Thiebaut AC, Jiao L, Silverman DT, et al. Dietary International Pancreatic Cancer Case-Control Con- fatty acids and pancreatic cancer in the NIH-AARP sortium (Panc4). Ann Oncol. 2012; 23(7): 1880–8. diet and health study. J Natl Cancer Inst. 2009; DOI: https://doi.org/10.1093/annonc/mdr541 101(14): 1001–1011. DOI: https://doi.org/10.1093/ 28. Kuzmickiene I, Everatt R, Milinaviciene E, et al. jnci/djp168 Smoking and other risk factors for pancreatic can- 34. Hamada T, Khalaf N, Yuan C, et al. Pre-diagno- cer: A cohort study in men in Lithuania. Cancer Epi- sis use of statins associates with increased sur- demiology. 2013; 37(2): 133–139. DOI: https://doi. vival times of patients with pancreatic cancer. org/10.1016/j.canep.2012.10.001 Clinical Gastroenterology and Hepatology. 2018; 29. Lynch SM, Vrieling A, Lubin JH, et al. Cigarette S1542356518301678. smoking and pancreatic cancer: A pooled analysis 35. La Torre G, Sferrazza A, Ricciardi W, et al. from the pancreatic cancer cohort consortium. Am Investigating the synergistic interaction of J Epidemiol. 2009; 170: 403–13. DOI: https://doi. diabetes, tobacco smoking, alcohol consump- org/10.1093/aje/kwp134 tion, and hypercholesterolemia on the risk of 30. Hassan M, Bondy M, Li D, et al. Risk factors for pancre- pancreatic cancer: A case-control study in Italy. atic cancer: Case-control study. The American Journal Biomed Research International. 2014; 2014: of Gastroenterology. 2007; 102(12): 2696–2707. DOI: 481019. DOI: https://doi.org/10.1155/2014/48 https://doi.org/10.1111/j.1572-0241.2007.01510.x 1019 How to cite this article: Bo X, Shi J, Liu R, Geng S, Li Q, Li Y, Jin H, Yang S, Jiang H and Wang Z. Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China. Annals of Global Health. 2019; 85(1): 103, 1–9. DOI: https://doi.org/10.5334/aogh.2463 Published: 11 July 2019 Copyright: © 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/. Annals of Global Health is a peer-reviewed open access journal published by Ubiquity Press. OPEN ACCESS http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Global Health Pubmed Central

Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China

Bo, Xiaojie; Shi, Jianwei; Liu, Rui; Geng, Shasha; Li, Qingqing; Li, Yang; Jin, Hua; Yang, Sen; Jiang, Hua; Wang, Zhaoxin
Annals of Global Health , Volume 85 (1) – Jul 11, 2019
Download PDF
9 pages

Loading next page...
 
/lp/pubmed-central/using-the-risk-factors-of-pancreatic-cancer-and-their-interactions-in-PWtTBXVCGb

References (76)

Publisher
Pubmed Central
Copyright
Copyright: © 2019 The Author(s)
ISSN
2214-9996
eISSN
2214-9996
DOI
10.5334/aogh.2463
Publisher site
See Article on Publisher Site

Abstract

Bo X, et al. Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China. Annals of Global Health. 2019; 85(1): 103, 1–9. DOI: https://doi.org/10.5334/aogh.2463 ORIGINAL RESEARCH Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China * †,‡ * § § § ‡,‖,¶ Xiaojie Bo , Jianwei Shi , Rui Liu , Shasha Geng , Qingqing Li , Yang Li , Hua Jin , ‡,‖,¶ § *,† Sen Yang , Hua Jiang and Zhaoxin Wang Background: The incidence of pancreatic cancer has increased annually, but the risk factors and their interactions are still unknown. Objective: The aim of this study was to identify risk factors and the effects of their interactions on pancreatic cancer occurrence among patients in Shanghai, China. Methods: We conducted a hospital-based case-control study. The case group consisted of pathologically diagnosed pancreatic cancer patients, and the control group consisted of a healthy population. The Pearson Chi-square test was used to compare the distribution frequencies of data between groups. Multivariate analysis and interaction analysis were conducted to explore possible risk factors and interac- tions between various variables. Findings: Among the 4,821 recruited participants, 1,392 were pancreatic cancer patients and 3,429 were controls. Multivariate logistic analysis suggested that age (>50 years old) (AOR: 16.20 [95% CI 6.78; 38.69]), diabetes (AOR: 5.40 [95% CI 2.70; 10.80]), chronic pancreatitis (AOR: 27.43 [95% CI 2.14; 351.77]), smoking (AOR: 8.86 [95% CI 3.07; 25.58]), and family cancer history (AOR: 2.10 [95% CI 1.09; 8.56]) were the primary risk factors for pancreatic cancer. Interestingly, synergistic interactions between risk factors were found, especially between age and chronic pancreatitis (RERI = 447.93, API = 96.74%, SI = 32.78), age and smoking (RERI = 187.42, API = 94.97%, SI = 21.99), and diabetes and smoking (RERI = 14.39, API = 48.06%, SI = 1.99). Conclusions: Age, diabetes, chronic pancreatitis, smoking, and family cancer history have been verified as the primary risk factors for pancreatic cancer in this study. Moreover, the interaction effects between old age, diabetes, chronic pancreatitis, and smoking substantially increase the probability of the development of pancreatic cancer. Cancer screening should be conducted extensively among people with these multiple factors to improve the efficiency. Strengths and limitations of this study are as vention and screening of pancreatic cancer. follows 4. As a hospital-based case-control study, selection bias 1. This study confirmed the significance of previously was inevitable. established risk factors for pancreatic cancer. 5. The study period was limited by relevant informa- 2. This study found significant synergistic interactions tion on body mass index and diet, and detailed in- between some risk factors for pancreatic cancer. formation on the amount of smoking and alcohol 3. The results of this study contribute to the early pre- consumption was not available. Introduction * Department of Pediatrics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, CN Pancreatic cancer is a highly lethal disease, with a mortality School of Public Health, Shanghai Jiaotong University School rate that is very close to its incidence rate [1]. With no of Medicine, Shanghai, CN specific observable symptoms until in its advanced and Department of General Practice, Yangpu Hospital, Tongji incurable stage, pancreatic cancer develops insidiously [2] University School of Medicine, Shanghai, CN Due to the late diagnosis, patients with pancreatic cancer Shanghai East Hospital, Tongji University School of Medicine, have one of the worst five-year survival rates of all cancers Shanghai, CN (6% in the US) [1]. Currently, the number of deaths from Academic Department of General Practice, Tongji University pancreatic cancer is increasing, and it is predicted to be School of Medicine, Shanghai, CN the second-leading cause of cancer-related death in the Shanghai General Practice and Community Health Development US by 2030 [3]. Similarly, an increase in pancreatic cancer Research Center, Shanghai, CN mortality has been reported in European populations [4]. Corresponding authors: Dr. Hua Jiang (east_hua_ jiang@163.com); Dr. Zhaoxin Wang (supercell002@sina.com) In China, the incidence and mortality rates of pancreatic Art. 103, page 2 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Study participants cancer increased steadily from 2000 to 2011. In 2015, the In this study, a total of 1,903 pancreatic cancer cases were number of male and female pancreatic cancer patients in selected through the hospital registry system once they China reached 52,200 and 37,900, respectively, and the were diagnosed with pancreatic cancer. For the controls, numbers of deaths were 45,600 and 33,800, respectively 4,848 were chosen when they received a health examina- [5]. tion. Then, each participant was asked to provide informed Similar to most malignancies, pancreatic cancer results consent to participate in a structured questionnaire. Some from the combination of environmental factors and of the questionnaires were finished when the participants genetic factors [6]. Although studies have reached a con- were in the hospitals, and the rest were finished over the sensus on the etiology of pancreatic cancer, the epidemio- telephone. All the questionnaires were administered by logical causes of pancreatic cancer identified in different our trained investigators. Finally, we checked the informa- studies have varied, and the influence of these factors tion pertaining to medical history on the questionnaire on pancreatic cancer is still under debate [7]. At present, by comparing it with the participant’s medical file and smoking has been identified as the most well-established then excluded the participants with inconsistent informa- risk factor for pancreatic cancer on a global scale [8, 9, 10]. tion. In total, the participation rates of patients in the case Other factors, such as age, diabetes and chronic pancrea- group and the control group were 73.15% (1392/1903) titis, have also been associated with pancreatic cancer in and 70.73% (3429/4848), respectively. The loss was due most recent studies [11, 12]. Possible interactions between to the following reasons: inconsistent information and the risk factors may exist due to the multifactorial nature refusal to answer the questionnaire. A total of 4,821 of pancreatic carcinogenesis. However, few studies have (1,392 cases, 3,429 controls) participants were enrolled, examined the possible interactions, and no large case- and there were no significant differences between the control studies have been conducted on the interactions case group and the control group in terms of the charac- among the risk factors for pancreatic cancer. teristics of gender, race, marital status, and so on. Considering that there are few studies on the interactions between various risk factors for pancreatic Questionnaire data cancer in China, we conducted this study to identify these The questionnaire was designed by relevant experts from risk factors and their interactions, aiming to contribute the hospital and university who have abundant experience to the early prevention of and screening for pancreatic in clinical diagnosis or screening for pancreatic cancer. cancer. The hospital staff members were available for assistance if participants had enquiries regarding the questions. The Methods questionnaire was divided into three sections: section 1 Study design contained questions on demographic characteristics, such A hospital-based case-control study was conducted to as age, gender, race and marital status; section 2 contained identify the risk factors for pancreatic cancer and their questions on smoking status and alcohol consumption; interactions based on data from pancreatic cancer patients and section 3 was about the participant’s medical history from 14 tertiary hospitals in Shanghai, China. A total of and family cancer history. All information was collected by 4,821 participants were recruited, including 1,392 with self-report. All questionnaires were cross-checked daily by pathologically verified cancer and 3,429 healthy controls. the investigators. All participants were selected from fourteen tertiary hos- pitals in Shanghai. Data analysis All of the primary pancreatic cancer patients were diag- All analyses were performed with SPSS software (version nosed in the oncology departments of the above fourteen 21.0; SPSS, Inc., Chicago, IL, USA). Chi-square tests were tertiary hospitals between January 1, 2012, and December used to assess the differences between the case and con- 12, 2017. The inclusion criteria for the case group were as trol groups. First, univariate analysis was conducted for follows: pathologically diagnosed pancreatic ductal ade- each relevant risk factor. Based on univariate analysis of nocarcinoma and literate. The exclusion criteria were as the relevant risk factors combined with literature reports follows: patients diagnosed with other types of pancreatic and clinical experience, all the risk factors with screening disease, such as neuroendocrine tumor, adenomas, cysts, value were then included in multiple logistic regression or other unknown primary tumors; concurrent cancer at models to evaluate their independent effects. Multivariate another organ site; and a history of other cancers. analysis was adjusted for potential confounders, such as Participants in the control group were recruited from sex, race, and marital status, to evaluate the association the physical examination center of the same hospitals; of exposure risk factors with the risk of pancreatic can- their physical medical examination results indicated that cer. The adjusted odds ratios (AORs) and 95% confidence they were healthy. According to the ages recorded on the intervals (CIs) of the associations between the risk factors physical examination form, we chose the control group and pancreatic cancer risk were calculated by multivariate such that their age composition matched that of the total logistic analysis. population of Shanghai. Moreover, controls and cases Moreover, we used multiple logistic regression mod- were matched according to sex and race. The eligibility els to investigate possible interactions between the risk criteria for the controls were the same as those for the factors. We chose to use an additive model rather than patients, except for the cancer diagnosis. a multiplicative model because the former has a more Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 3 of 9 appropriate scale for addressing biologic interactions interference from potential confounding factors, we con- and public health concerns. To assess deviation from the ducted a multivariate analysis using a logistic regression additive model (which assumes there is no interaction model. Based on the results of the univariate analysis, we between variables), the relative excess rate due to inter- divided the participants into two age groups, with the cut- action (RERI = OR – OR – OR + 1), the attributable off value of 50 years old. We incorporated all the potential 11 01 10 proportion due to interaction (API = (RERI/OR ) and the confounding factors and the risk factors into a multiple synergism index (SI = [OR − 1]/([OR + OR ] − 2) were regression model, and the final model equation contained 11 01 10 calculated, where OR = the OR of the joint effect of two a total of five variables (Table 2). The results showed that risk factors, and OR and OR = the OR of each risk factor people with diabetes (AOR = 5.40, 95% CI [2.70–10.80]), 10 01 in the absence of the other [13]. chronic pancreatitis (AOR = 27.43, 95% CI [2.14–351.77]), old age (AOR = 16.20, 95% CI [6.78–38.69]), smoking Results (AOR = 8.86, 95% CI [3.07–25.58]), and a family cancer Participant demographics history (AOR = 2.1, 95% CI [1.09–8.56]) had a higher risk. This hospital-based case-control study included 1,392 All of the results were obtained after adjusting for sex, cases of pancreatic cancer patients and 3,429 healthy race, marital status, and other risk factors. cases. Table 1 summarizes the demographic characteris- tics of our sample in both the case and control groups. Interaction analysis The ratio of male to female was slightly higher than 1:1, For the above four primary risk factors that were statis- and there was no significant difference in the sex ratio tically significant in the multivariate logistic regression between the case and control groups. All patients in the model with an AOR value larger than 1, an interaction case group and the vast majority in the control group analysis was further performed with the logistic regres- (97.75%) were of Han ethnicity. There was no significant sion model and the additive model. difference in the sex ratio or the race ratio between the Table 3 shows the independent and interactive effects cases and controls. Concerning marital status, most of of age, diabetes, chronic pancreatitis, and smoking on the participants in the case (99.43%) and control groups pancreatic cancer incidence. The results indicated additiv- (82.62%) were married, but there was still a significant ity and synergism between age and chronic pancreatitis, difference between the two groups (P < 0.001). We chose age and smoking, and diabetes and smoking, after adjust- to adjust for all demographic factors in the multivariate ing for the effects of other significant risk factors. logistic regression models. The RERIs were 447.93, 187.42, and 14.39 for the age/chronic pancreatitis, age/smoking, and dia- Univariate analysis betes/smoking interactions, respectively. Using the RERIs, Table 1 shows the results of the univariate analysis by we estimated that the attributable proportion due to Chi-square tests. According to the preliminary results, interaction (API %) values explained by age/chronic pan- we found that there were no significant differences in creatitis, age/smoking, and diabetes/smoking interac- the risk of pancreatic cancer among people aged 18–29 tion were 96.74%, 94.97%, and 48.06%, respectively. The years old, 30–39 years old, and 40–49 years old; hence, estimated SI values were 32.78, 21.99, and 1.99, respec- they were combined in one group under 50 years old. tively. This may indicate that the interaction effect of The results show that increasing age can increase the risk the above three groups of pancreatic cancer risk factors of pancreatic cancer; with less than 50 years old as the is super additive. Additionally, the results revealed that reference, the odds ratios are as follows: from 50 to 59 there was a negative interaction between age and diabetes years old (OR = 25.00, 95% CI [3.41–200.00]), 60 to 69 (RERI = –31.43, API = –26.38%, SI = 0.79). No other sig- years old (OR = 76.92, 95% CI [10.20–500.00]), 70 to 79 nificant interaction was observed between groups, such as years old (OR = 111.11, 95% CI [1.52–1000.00]), and 80 diabetes and chronic pancreatitis and chronic pancreatitis years old or older (OR = 142.86, 95% CI [19.23–1000.00]). and smoking. The risk of pancreatic cancer increases gradually as age increases. The results also suggest that other possible Discussion risk factors include hypertension (OR = 2.08, 95% CI Studies have suggested that the development of pancre- [1.39–3.11]), diabetes (OR = 4.94, 95% CI [3.03–8.05]), atic cancer is a complex and multistep process with a mul- chronic pancreatitis (OR = 6.85, 95% CI [3.70–12.68]), tifactorial etiology, as many factors (genetic susceptibility, biliary disease (OR = 1.77, 95% CI [1.12–2.80]), a history environmental factors, lifestyles, and physical conditions) of surgery or trauma (OR = 2.04, 95% CI [1.37–3.04]), may contribute to its occurrence [14, 15, 16]. In our study, smoking (OR = 5.92, 95% CI [4.68–7.49]), and family can- we found that pancreatic cancer is more common among cer history (OR = 1.93, 95% CI [1.47–2.54]). In contrast, older adults, and there was a significantly higher risk asso- hyperlipidemia (OR = 0.06, 95% CI [0.02–0.25]), is a pro- ciated with older age. Consistent with our results, Qi Dong tective factor. However, alcohol consumption (P = 0.721) et al. retrospectively analyzed the clinical data of 207 was not statistically significant in the univariate analysis. patients with pancreatic cancer, and their study showed that age is an independent risk factor for the incidence Multivariate analysis of pancreatic cancer. The relative risk of pancreatic can- To assess the independent effects of different risk factors cer increased approximately 1.78 times in the older group on the incidence of pancreatic cancer and to control for compared with the younger group [17]. One possible Art. 103, page 4 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Table 1: Characteristics of the study participants. Study Variables Patients Controls χ P OR(95% CI) (N = 1,392) (N = 3,429) n % n % Sex Male 830 59.63 1,981 57.77 / 0.16 0.689 Female 562 40.37 1,448 42.23 Race Han ethnicity 1,392 100.00 3,352 97.75 / 3.29 0.069 Others 0 0.00 77 2.25 Marital status Married 1,384 99.43 2,833 82.62 / 25.18 0.000 Unmarried 8 0.57 596 17.38 Age (years) <50 71 5.10 1,507 43.95 1.00 50–59 249 17.89 721 21.03 21.87 0.000 25.00 (3.41–200.00) 60–69 501 35.99 452 13.18 63.18 0.000 76.92 (10.20–500.00) 70–79 313 22.49 228 6.65 91.48 0.000 111.11 (1.52–1000.00) ≥80 258 18.53 521 15.19 108.51 0.000 142.86 (19.23–1000.00) Hypertension Yes 660 47.41 1,038 30.27 2.08 (1.39–3.11) 12.76 0.000 No 732 52.59 2,391 69.73 1.00 Hyperlipidemia Yes 23 1.65 671 19.57 0.06 (0.02–0.25) 26.41 0.000 No 1.369 98.35 2,758 80.43 1.00 Diabetes Yes 511 36.71 359 10.47 4.94 (3.03–8.05) 45.89 0.000 No 881 63.29 3,070 89.53 1.00 Chronic pancreatitis Yes 38 2.73 14 0.41 6.85 (3.70–12.68) 50.01 0.001 No 1,354 97.27 3,415 99.59 1.00 Biliary disease Yes 391 28.09 622 18.14 1.77 (1.12–2.80) 5.95 0.015 No 1.001 71.91 2,807 81.86 1.00 History of surgical trauma Yes 803 57.69 1,371 39.98 2.04 (1.37–3.04) 12.39 0.000 No 589 42.31 2,058 60.02 1.00 Smoking Yes 232 16.67 112 3.27 5.92 (4.68–7.49) 268.31 0.000 No 1,160 83.33 3,317 96.73 1.00 Family cancer history Yes 94 6.75 124 3.62 1.93 (1.47–2.54) 22.56 0.000 No 1,298 93.25 3,305 96.38 1.00 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 5 of 9 Table 2: Risk factors for pancreatic cancer in multivariable logistic regression analysis. Variables SE (β) Wald (χ ) AOR (95% CI) P Diabetes Yes 1.69 0.35 22.73 5.40 (2.70–10.80) 0.000 No 1.00 Chronic pancreatitis Yes 3.31 1.3 6.47 27.43 (2.14–351.77) 0.011 No 1.00 Smoking Yes 2.18 0.54 16.24 8.86 (3.07–25.58) 0.000 No 1.00 Family cancer history Yes 1.14 0.23 20.21 2.1 (1.09–8.56) 0.000 No 1.00 Age, years <50 2.79 0.44 39.3 16.20 (6.78–38.69) 0.000 ≥50 1.00 Adjusted for gender, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, and drinking. reason may be that aging causes the body to accumulate hereditary, and tropical pancreatitis, are associated with more carcinogens and changes some of the body’s defense pancreatic cancer to some extent [21]. A significant associ- mechanisms [18]. This can be one of the pathophysiologi- ation between chronic pancreatitis and pancreatic cancer cal mechanisms underlying the development of pancre- risk was found in our study. The results of our multivari- atic cancer. It is predicted that the incidence of pancreatic ate logistic analysis showed that the risk for pancreatic cancer will continue to rise as the aging of the population cancer was 20-fold higher among patients affected by continues to accelerate. chronic pancreatitis after adjusting for potential con- Diabetes can be a cause and a complication of pancreatic founders. In previous studies, most authors had drawn cancer, although reports are not consistent. Our results similar conclusions, and the relative risks for pancreatic indicated that diabetes is an important risk factor for pan- cancer in chronic pancreatitis patients varied from 2.3 to creatic cancer. This is in accordance with the results of the 18.5 [22]. Furthermore, a recent meta-analysis conducted meta-analysis conducted by Huxley et al., which analyzed by Raimondi et al. of 22 studies that found that the risk 19 cohort studies and 17 case-control studies between of developing pancreatic cancer in patients with chronic 1966 and 2005 [18]. Zhan et al. conducted a retrospective pancreatitis was 20 times higher than among those with- study of 2,405 patients with malignant tumors and found out chronic pancreatitis [23]. In addition, chromosomal that 28% of the patients had been diagnosed with diabetes instability in patients with chronic pancreatitis is also con- before developing cancer. Among them, the percentage of ducive to the occurrence of pancreatic cancer. Therefore, pancreatic cancer patients (57.1%) was the highest, which we believe that patients with chronic pancreatitis should suggested that diabetes may be a risk factor for pancreatic be considered at high risk for pancreatic cancer, and they cancer, and it is advisable to perform conventional screen- would benefit from preventive measures and early detec- ing of diabetic patients for the early diagnosis of pancre- tion programs. atic cancer [19]. However, according to Liao et al.’s 10-year According to other studies, smoking has been defini- population-based cohort study (49,803 vs. 199,212) based tively identified as the most important environmental risk on the Taiwan National Health Insurance Database, diabe- factor for pancreatic cancer [24]. To date, at least 30 epide- tes with <2 years’ duration was associated with pancreatic miological studies have confirmed this view [8, 9, 25–28]. cancer and could be an early manifestation of pancreatic The results of our multivariate analysis also revealed that cancer, but long-standing diabetes was not found to be smoking was associated with an increased risk of pancre- a risk factor for pancreatic cancer [20]. However, we did atic cancer. Consistent with our results, a nested case-con- not obtain information on the duration of diabetes in this trol study conducted by Lynch S.M. et al., including 1,481 study. Therefore, the association of diabetes with pancre- cases and 1,539 controls, found that the ORs of pancre- atic cancer warrants further investigation. atic cancer were 1.1 (95% CI, 0.9–1.3) for former smokers Some studies have concluded that various types of and 1.8 (95% CI, 1.4–2.3) for current smokers compared chronic pancreatitis, including alcoholic, non-alcoholic, to nonsmokers [29]. Similar findings were obtained in a Art. 103, page 6 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Table 3: Synergistic interactions among age, diabetes, chronic pancreatitis and smoking. Interaction Variables AOR (95% CI) RERI API SI Variable 1 Variable 2 1 1 Age Diabetes ≤50 years No 1 –31.43 –26.38% 0.79 ≤50 years Yes 123.06 (10.22–1482.18) >50 years No 28.50 (9.38–86.62) >50 years Yes 119.14 (33.91–418.55) 2 2 Age Chronic pancreatitis ≤50 years No 1 447.93 96.74% 32.78 ≤50 years Yes / >50 years No 16.10 (6.73–38.48) >50 years Yes 463.03 (29.54–7258.03) 3 3 Age Smoking ≤50 years No 1 187.42 94.97% 21.99 ≤50 years Yes / >50 years No 10.93 (4.66–25.64) >50 years Yes 197.35 (40.49–962.03) 4 4 Diabetes Chronic pancreatitis No No 1 / / / No Yes 23.25 (1.58–342.12) Yes No 5.35 (2.67–10.71) Yes Yes / 5 5 Diabetes Smoking No No 1 14.39 48.06% 1.99 No Yes 10.48 (3.38–32.52) Yes No 6.07 (2.85–12.91) Yes Yes 29.94 (5.36–167.33) Chronic Smoking pancreatitis No No 1 / / / No Yes 8.83(3.05–25.55) Yes No 26.21 (1.76–389.40) Yes Yes / Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, chronic pancreatitis, and smoking. Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, diabetes, and smoking. Adjusted for sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, diabetes, and chronic pancreatitis. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and smoking. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and chronic pancreatitis. Adjusted for age, sex, race, marital status, hypertension, hyperlipidemia, biliary disease, history of surgical trauma, alcohol consumption, and diabetes. /: P > 0.05. large hospital-based case-control study (808 vs. 808) and Consistent with our results, Schulte’s study, which a 40-year follow-up cohort study [30, 31]. According to included 591 pancreatic cancer patients and 646 con- pathological studies, the effect mechanism may result trols, reported that a family history of pancreatic cancer from the carcinogens in tobacco acting on the pancreas (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, through the blood or duodenal fluid and bile reflux [32]. 95% CI 1.03–2.95) were risk factors for pancreatic cancer Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 7 of 9 [30]. Hassan’s case-control study showed that family his- Conclusion tories of cancer in general and of pancreatic cancer in The results of this study show that age, diabetes, chronic particular were associated with a significantly elevated pancreatitis, smoking, and family cancer history are risk risk for pancreatic cancer. The effect of a positive fam- factors for pancreatic cancer. Moreover, the interactions ily history of pancreatic cancer was significant in women of the risk factors increase the probability of developing and men. The pattern was consistent with the familial pancreatic cancer. This study provides important clues predisposition reported for pancreatic cancer and with for the prevention of pancreatic cancer. We believe that the array of tumors associated with hereditary nonpoly- identifying individuals with the highest risk of pancreatic posis colon cancer. In our analysis, hyperlipidemia had a cancer can contribute greatly to the development of pre- negative association with pancreatic cancer. The results vention programs and the early detection of pancreatic are inconsistent with other studies showing that high cancer. More large-scale epidemiological studies with dif- blood lipid levels increase the risk of pancreatic cancer ferent populations on the interactions among risk factors [33], and possible reasons were related to the use of are warranted, with stratification by sex. statins for treating hyperlipidemia. Regular statin use before the diagnosis of pancreatic cancer was associ- Abbreviations ated with modest increases in survival times in two large AOR: Adjusted Odd Ratio prospective cohort studies [34]. In our study, it is pos- CI: Confidence Interval sible that the patients did not take statins to treat hyper- RERI: Relative Excess Rate due to Interaction lipidemia. However, we did not obtain this information API: Attributable Proportion due to Interaction from the questionnaires, and the association needs to be SI: Synergism Index explored in future analyses. The most noteworthy finding of our study was the Ethics and Consent interactions between certain risk factors. Our results Ethics approval was given by the medical ethics showed that there were significant positive synergistic committees of all participating hospitals. All participants interactions between age and chronic pancreatitis, age gave informed consent before being enrolled in the study. and smoking, and diabetes and smoking after adjusting for the effects of other significant risk factors. This sup- Acknowledgements ports the hypothesis that people with a combination of We are grateful to Shanghai East Hospital for allowing us two or more risk factors are more vulnerable to pancreatic to perform this study and helping us collect data. cancer. Similar to our research design, a large case-con- trol study (808 vs. 808) conducted by Hassan et al. found Funding Information that synergistic interactions did exist between cigarette The design of this study involving some previous inves- smoking and a family history of pancreatic cancer (AOR tigations was supported by the Key Developing Disci- = 12.8, 95% CI 1.6–108.9) and between smoking and dia- plines of Shanghai Municipal Commission of Health betes (AOR = 9.3, 95% CI 2.0–44.1) in women. Moreover, and Family Planning (2015ZB0602). Data extraction was a recent study in Italy in 2014 found that important syn- financially funded by the Natural Science Foundation of ergistic interactions existed between smoking and alcohol China (71774116). The analysis and interpretation of the consumption (SI = 17.61) and alcohol consumption and data guided by statisticians were funded by the Soft Pro- diabetes (SI = 17.77) [35]. However, in our study, similar to jects of Shanghai Municipal Commission of Science and in other studies, we did not find a significant interaction Technology (17692105200), and the writing and revi- between chronic pancreatitis and smoking, and a possible sion, including the language editing, were supported mechanism still needs to be explored. To a certain extent, by the Surface Project of Shanghai Municipal Commis- this study provided insight into whether the performance sion of Health and Family Planning (201740202) and of pancreatic cancer screening among people with mul- the Shanghai Excellent Young Talents Project in Health tiple risk factors, such as old age, diabetes, and smok- System (2018YQ52), National Natural Science Foundation ing, would substantially improve the efficiency of cancer of China (71603182), National Natural Science Founda- screening. tion of China (71804128). The limitations of the study should be taken into account. First, our study is a case-control study that Competing Interests applies an analytical epidemiological research method The authors have no competing interests to declare. that has inherent limitations and disadvantages. The selection bias and recall bias cannot be eliminated com- Author Contributions pletely. To address the selection bias problem, we adopted XJB and JWS participated in the epidemiological investiga- a multicenter design in which the cases and controls were tion and drafted the manuscript; HJ and ZXW participated recruited from the same hospitals. We selected newly in the overall design, study coordination, data analysis and diagnosed cases and avoided using proxy respondents, final draft of the manuscript. SSG and SY were responsi- minimizing recall bias. Second, we did not obtain relevant ble for the data collection; QQL and YL participated in the information on body mass index, diet, details regarding epidemiological investigation; JWS, HJ and RL carried out smoking and alcohol consumption, or the duration of the data analysis; HJ interpreted the results and refined diabetes. Therefore, further investigations into pancreatic the manuscript. All of the authors read and approved the cancer risk factors are warranted. final manuscript. Art. 103, page 8 of 9 Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Author Information a cohort study. BMJ Open. 2018; 8: e020827. DOI: Xiaojie Bo and Jianwei Shi are co-first authors in this https://doi.org/10.1136/bmjopen-2017-020827 article. 13. Hedström A, Katsoulis M, Alfredsson L, et al. The interaction between smoking and HLA genes in References multiple sclerosis: Replication and refinement. Eur J 1. Terumi K, Wood L, Takaori K, et al. Pancreatic Epidemiol. 2017; 32(10): 909–919. DOI: https://doi. cancer. Lancet. July 2, 2016; 388(10039): 73–85. DOI: org/10.1007/s10654-017-0250-2 https://doi.org/10.1016/S0140-6736(16)00141-0 14. Zheng Z, Zheng R, Chen W, et al. Risk factors for 2. Buha A, Wallace D, Djordjevic V, et al. Cadmium pancreatic cancer in China: A multicenter case- exposure as a putative risk factor for the development control study. J Epidemiol. 2016; 26(2): 64–70. DOI: of pancreatic cancer: Three different lines of evidence. https://doi.org/10.2188/jea.JE20140148 Biomed Research International. 2017; 1981837. DOI: 15. Keane MG, Horsfall L, Rait G, et al. A case- https://doi.org/10.1155/2017/1981837 control study comparing the incidence of early 3. Rahib L, Smith BD, Aizenberg R, et al. Projecting symptoms in pancreatic and biliary tract cancer. cancer incidence and deaths to 2030: The unexpected BMJ Open. 2014; 4: e005720. DOI: https://doi. burden of thyroid, liver, and pancreas cancers in the org/10.1136/bmjopen-2014-005720 United States. Cancer Res. 2014; 74: 2913–21. DOI: 16. Klein A. Identifying people at a high risk of devel- https://doi.org/10.1158/0008-5472.CAN-14-0155 oping pancreatic cancer. Nature Reviews Cancer. 4. Malvezzi M, Bertuccio P, Levi F, et al. European 2013; 13(1): 66–74. DOI: https://doi.org/10.1038/ cancer mortality predictions for the year 2014. nrc3420 Ann Oncol. 2014; 25: 1650–56. DOI: https://doi. 17. Yan D, Wang XY, Xu XJ, et al. Analyses of partial org/10.1093/annonc/mdu138 risk factors for pancreatic cancer. Journal of Xinjiang 5. Chen W, Zheng R, He J, et al. Cancer statistics Medical University. 2010; 33(08): 928–930. in China, 2015. CA: A Cancer Journal For Clini- 18. Huxley R, Ansary-Moghaddam A, Berrington de cians. 2016; 66(2): 115–132. DOI: https://doi. Gonzalez A, et al. Type-II diabetes and pancreatic org/10.3322/caac.21338 cancer: A meta-analysis of 36 studies. Br J Cancer. 6. Edderkaoui M and Eibl G. Risk factors for pan- 2005; 92: 2076–83. DOI: https://doi.org/10.1038/ creatic cancer: Underlying mechanisms and poten- sj.bjc.6602619 tial targets. Frontiers In Physiology. December 19. Zhan YS, Feng L, Tang SH, et al. Glucose metabo- 10, 2014; 5: 490. DOI: https://doi.org/10.3389/ lism disorders in cancer patients in a Chinese popu- fphys.2014.00490 lation. Medical Oncology. 2010; 27(2): 177–184. 7. López Serrano A. Risk factors and early diagnosis of DOI: https://doi.org/10.1007/s12032-009-9189-9 pancreatic cancer. Gastroenterologia Y Hepatologia. 20. Liao K, Lai S, Li C and Chen W. Diabetes mellitus May 2010; 33(5): 382–390. DOI: https://doi. correlates with increased risk of pancreatic can- org/10.1016/j.gastrohep.2009.10.004 cer: A population-based cohort study in Taiwan. 8. Silverman DT, Dunn JA, Hoover RN, et al. Cigarette Journal of Gastroenterology and Hepatology. smoking and pancreas cancer: A case-control study 2012; 27(4): 709–713. DOI: https://doi. based on direct interviews. J Natl Cancer Inst. org/10.1111/j.1440-1746.2011.06938.x 1994; 86: 1510–6. DOI: https://doi.org/10.1093/ 21. Li BR, Hu LH and Li ZS. Chronic pancreatitis jnci/86.20.1510 and pancreatic cancer. Gastroenterology. 2014; 9. Bonelli L, Aste H, Pugliese V, et al. Exocrine pan- 147: 541–542. DOI: https://doi.org/10.1053/j. creatic cancer, cigarette smoking, and diabetes gastro.2014.03.054 mellitus: A case-control study in northern Italy. Pan- 22. Apple SK, Hecht JR, Lewin DN, et al. Immunohis- creas. August 2003; 27(2): 143–149. DOI: https:// tochemical evaluation of K-ras, p53, and HER-2/ doi.org/10.1097/00006676-200308000-00007 neu expression in hyperplastic, dysplastic, and 10. Anderson L, Cotterchio M and Gallinger S. carcinomatous lesions of the pancreas: Evidence Lifestyle, dietary, and medical history factors asso- for multistep carcinogenesis. Human Pathol. 1999; ciated with pancreatic cancer risk in Ontario, 30(2): 123–129. DOI: https://doi.org/10.1016/ Canada. Cancer Causes & Control: CCC. August 2009; S0046-8177(99)90265-4 20(6): 825–834. DOI: https://doi.org/10.1007/ 23. Raimondi S, Lowenfels AB and Morselli-Labate s10552-009-9303-5 AM, et al. Pancreatic cancer in chronic pancreatitis, 11. Midha S, Sreenivas V, Kabra M, et al. Genetically aetiology, incidence, and early detection. Best Pract determined chronic pancreatitis but not alcoholic Res Clin Gastroenterol. 2010; 24(3): 349–358. DOI: pancreatitis is a strong risk factor for pancreatic https://doi.org/10.1016/j.bpg.2010.02.007 cancer. Pancreas. 2016; 45(10): 1478–1484. DOI: 24. Parkin DM. The fraction of cancer attributable to https://doi.org/10.1097/MPA.0000000000000684 lifestyle and environmental factors in the UK in 12. Williams R, van Staa T, Gallagher AM, et al. Cancer 2010. Br J Cancer. 2011; 105 Suppl 2: S2–5. DOI: recording in patients with and without type 2 dia- https://doi.org/10.1038/bjc.2011.474 betes in the Clinical Practice Research Datalink pri- 25. Brand R, Lerch M, Canto M, et al. Advances in mary care data and linked hospital admission data: counselling and surveillance of patients at risk for Bo et al: Risk Factors and Their Interaction on Pancreatic Cancer Art. 103, page 9 of 9 pancreatic cancer. Gut. 2007; 56(10): 1460–1469. 31. Doll R and Hill AB. Mortality in relation to smoking: DOI: https://doi.org/10.1136/gut.2006.108456 Ten years’ observations of British doctors. Br Med J. 26. Iodice S, Gandini S, Maisonneuve P and 1964; i: 1399–1410. DOI: https://doi.org/10.1136/ Lowenfels AB. Tobacco and the risk of pancreatic bmj.1.5395.1399 cancer: a review and meta-analysis. Langenbecks 32. Hao J, Li G and Pang B. Evidence for cigarette Arch Surg. 2008; 393(4): 535–45. DOI: https://doi. smoke-induced oxidative stress in the rat org/10.1007/s00423-007-0266-2 pancreas. Inhalation Toxicology. 2009; 27. Bosetti C, Lucenteforte E, Silverman DT, 21(12): 1007–1012. DOI: https://doi. Petersen G, Bracci PM, Ji BT, et al. Cigarette smok- org/10.1080/08958370802665937 ing and pancreatic cancer: an analysis from the 33. Thiebaut AC, Jiao L, Silverman DT, et al. Dietary International Pancreatic Cancer Case-Control Con- fatty acids and pancreatic cancer in the NIH-AARP sortium (Panc4). Ann Oncol. 2012; 23(7): 1880–8. diet and health study. J Natl Cancer Inst. 2009; DOI: https://doi.org/10.1093/annonc/mdr541 101(14): 1001–1011. DOI: https://doi.org/10.1093/ 28. Kuzmickiene I, Everatt R, Milinaviciene E, et al. jnci/djp168 Smoking and other risk factors for pancreatic can- 34. Hamada T, Khalaf N, Yuan C, et al. Pre-diagno- cer: A cohort study in men in Lithuania. Cancer Epi- sis use of statins associates with increased sur- demiology. 2013; 37(2): 133–139. DOI: https://doi. vival times of patients with pancreatic cancer. org/10.1016/j.canep.2012.10.001 Clinical Gastroenterology and Hepatology. 2018; 29. Lynch SM, Vrieling A, Lubin JH, et al. Cigarette S1542356518301678. smoking and pancreatic cancer: A pooled analysis 35. La Torre G, Sferrazza A, Ricciardi W, et al. from the pancreatic cancer cohort consortium. Am Investigating the synergistic interaction of J Epidemiol. 2009; 170: 403–13. DOI: https://doi. diabetes, tobacco smoking, alcohol consump- org/10.1093/aje/kwp134 tion, and hypercholesterolemia on the risk of 30. Hassan M, Bondy M, Li D, et al. Risk factors for pancre- pancreatic cancer: A case-control study in Italy. atic cancer: Case-control study. The American Journal Biomed Research International. 2014; 2014: of Gastroenterology. 2007; 102(12): 2696–2707. DOI: 481019. DOI: https://doi.org/10.1155/2014/48 https://doi.org/10.1111/j.1572-0241.2007.01510.x 1019 How to cite this article: Bo X, Shi J, Liu R, Geng S, Li Q, Li Y, Jin H, Yang S, Jiang H and Wang Z. Using the Risk Factors of Pancreatic Cancer and Their Interactions in Cancer Screening: A Case-Control Study in Shanghai, China. Annals of Global Health. 2019; 85(1): 103, 1–9. DOI: https://doi.org/10.5334/aogh.2463 Published: 11 July 2019 Copyright: © 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/. Annals of Global Health is a peer-reviewed open access journal published by Ubiquity Press. OPEN ACCESS

Journal

Annals of Global Health – Pubmed Central

Published: Jul 11, 2019

There are no references for this article.