Association of Diabetes Mellitus and Pancreatic Adenocarcinoma: A Meta-Analysis of 88 Studies

Ann Surg Oncol DOI 10.1245/s10434-014-3625-6

ORIGINAL ARTICLE – PANCREATIC TUMORS

Association of Diabetes Mellitus and Pancreatic Adenocarcinoma: A Meta-Analysis of 88 Studies Pikli Batabyal, MBBS1, Stephen Vander Hoorn, MSc, BSc2, Christopher Christophi, MD, FACS, FRACS1, and Mehrdad Nikfarjam, MD, PhD, FRACS1 Department of Surgery, University of Melbourne, Melbourne, VIC, Australia; 2Statistical Consulting Centre, Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia

1

ABSTRACT Background. Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced, incurable stage. Previous epidemiological data suggests that diabetes mellitus (DM) is a risk factor for PDAC, which may be important in early detection. However, the strength of this association needs to be determined, taking into account a number of recently published studies. Methods. A systematic review of the association between DM and PDAC was undertaken by searching electronic databases and journal references from 1973 to 2013. Summary estimates were obtained separately for case– control and cohort studies by means of a ‘random effects’ approach. Data pertaining to the DM was recorded and plotted at both an individual and study level, with the relative risks (RR) pooled separately to determine the relationship of DM duration and PDAC. Results. A total of 88 independent studies, including 50 cohort and 39 case–control studies were examined. The overall summary-combined RR was 1.97 (95 % CI 1.78–2.18) with marked heterogeneity that could not be clearly attributed to any subgroup analyses. The risk of PDAC was greatest early after the diagnosis of DM but remained elevated long after the diagnosis. The individuallevel RR ranged from 6.69 at less than 1 year to 1.36 at 10 years.

Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3625-6) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 24 December 2013 M. Nikfarjam, MD, PhD, FRACS e-mail: [email protected]

Conclusion. The results demonstrate a strong association between PDAC and recently diagnosed DM, which may be attributed to a paraneoplastic effect. However, the presence of diabetes also remains a modest risk factor for the development of PDAC long-term. Selective screening of patients with new-onset DM for PDAC needs to be considered. Pancreatic ductal adenocarcinoma (PDAC) results in an estimated 266,000 deaths worldwide each year.1 The overall 5-year survival for patients diagnosed with PDAC is less than 1 %, and few patients with metastatic disease survive beyond 4–6 months.2 This poor prognosis is largely attributed to the advanced stage of disease at presentation, with a small number of cases amenable to curative resection at the time of diagnosis. Earlier detection of PDAC by identification of possible biomarkers may increase the number of cases that can be offered potentially curative treatment. The link between DM and PDAC may be an important key to early detection and screening. It remains uncertain whether DM is a predisposing risk factor for the development of PDAC or a consequence of disease onset. Approximately 50–80 % of PDAC patients have some form of impaired glucose tolerance or DM.2 Of these, 85 % occur within 2 years of PDAC diagnosis.3 In patients with recent-onset diabetes, PDAC develops in 1–2 % over the first 3 years.4 It is hypothesized that early in the development of PDAC, it may produce factors such as islet amyloid polypeptide (IAPP) that leads to impaired glucose tolerance and DM, which improves upon subsequent tumor removal.5,6 In patients with long-term DM, the PDAC risk is considered to be increased by 40–100 %.4 The potential mechanisms involved in the interaction between DM and PDAC that may promote the

P. Batabyal et al. TABLE 1 Summary of systematic reviews examining the association between diabetes mellitus and pancreatic cancer Author

Year

Cohort

Case–control

Total independent studies

Overall relative risk

Confidence interval

1995

9

11

20

2.10

1.60–2.80

Huxley et al.

2005

19

17

36

1.82

1.66–1.89

Ben et al.10

2011

35

0

35

1.94

1.66–2.27

Batabyal

2013

50

39

88

1.97

1.78–2.18

9

Everhart and Wright 8

FIG. 1 Search strategy. MeSH terms were used for pancreatic adenocarcinoma (pancreas, neoplasm, tumor) and type 2 diabetes mellitus (NIDDM, diabetes mellitus) in MEDLINE, PubMed and EMBASE up to May 2013. MeSH medical subject headings, NIDDM non-insulindependent diabetes mellitus

Potentially relevant studies identified and screened for retrieval n = 2418 Studies excluded n = 2127 Duplicate articles n = 172 Irrelevant by reading title n = 1955 Studies retrieved for more detailed evaluation n = 291 Studies excluded n = 107 Incorrect study type n = 95 Type 1 DM n = 12 Potentially appropriate studies to be included in the meta-analysis n = 184

Studies included in meta-analysis n = 90

Studies excluded from meta-analysis n = 94 RR not included n = 62 Overlapping patient cohorts n = 13 Neuroendocrine pancreatic tumours n = 6 Recent-onset diabetes n = 4 Other/irrelevant n = 9

Studies withdrawn, by outcome, n = 2 Studies with usable information, by outcome, n = 88

progression of PDAC include hyperglycemia, hyperinsulinemia, cytokine alterations and genotype changes.7 Previously published literature demonstrates an overall approximate twofold increased risk of PDAC in patients with DM.8–10 The reported risk varies according to the study type but few clearly demonstrate a relationship between the duration of DM and PDAC. A meta-analysis of 36 studies by Huxley et al. in 2005 provided a detailed analysis of the relationship between DM and PDAC, with an overall 1.8-fold increased risk of PDAC in the diabetic population.8 It also suggested that the risk of PDAC may be higher after the initial diagnosis of DM. Since this report, the number of studies on this topic have more than doubled (Table 1). Our study aims to further clarify the association between PDAC and DM by incorporating recent studies and, in particular, determine the relationship between the duration of DM and the risk of PDAC.

METHODS Literature Search The search strategy is outlined Fig. 1. The searches were carried out in PubMed and EMBASE up to October 2013. Text word and Medical Subject Heading (MeSH) terms were used for PDAC (pancreas, neoplasm and tumor) and type 2 DM [non-insulin-dependent diabetes mellitus (NIDDM) and DM]. Articles were limited to the English language. Journal references were further assessed to identify relevant articles that may have not been captured using the search strategy. Selection Criteria Case–control or cohort studies were selected if they contained quantitative estimates and standard errors, or

Association of Diabetes and Pancreatic Cancer

confidence limits of the degree of risk or association between type 2 DM and PDAC [usually expressed as relative risk (RR)]. Studies were excluded if they provided only an estimate of effect, with no means by which to calculate the standard error, or if the estimates were not adjusted by age. Mortality ratios were not included. Eligible articles included 95 % confidence intervals (CI). Those studies (and a study with a 99 % CI), were adjusted for in the summary of effect sizes. In the case of pooled analyses or multiple studies published of the same cohort, overlapping populations were excluded and the most recent publication was used. Data pertaining to the duration of DM was recorded to determine the relation of DM duration and PDAC. ‘Newlydiagnosed’ DM for the purposes of subgroup analysis was considered to be cases documenting DM duration of less than 1 year.

Data Analysis The variance of the effect size from each study was calculated by converting the 95 % CI to its natural logarithm by taking the width of the CI and dividing by 3.92. If this was not possible, p values were used to estimate the CI. Odds ratios were extracted from results obtained for case– control studies and assumed to be approximately the same as the RR, as pancreatic cancer is relatively uncommon in the general population. Summary estimates were obtained separately for case–control and cohort studies by means of a ‘random effects’ approach,11 and studies were weighted according to an estimate of its ‘statistical size’, defined as the inverse of the variance of the effect size on the log scale. An I2 test for heterogeneity was conducted for case– control and cohort studies respectively. Possible sources of heterogeneity were further investigated by comparing effect sizes for studies with respect to different patient characteristics in a sensitivity analysis. Only study results reporting specific categories of the duration of diabetes underwent two separate analyses in order to examine how the strength of the association varied with duration of diabetes. This subset of studies used for both duration analyses were found to be broadly similar to the overall sample. First, effect sizes were plotted at the ‘study level’ against the midpoint of the duration of diabetes for each category and then informally investigated in a meta-regression analysis. The clinical relevance of this analysis pertains to presenting risk across study populations or cohorts as a whole by comparing risk for subgroups of patients with longer average duration of diabetes against those with shorter average duration. Second, effects size were pooled according to one of four mutually exclusive categories (\1, 1–4, 5–9, and C10 years). This second

analysis provided an ‘individual level’ risk assessment across the duration of diabetes category. All analyses were performed using R version 3.0.1.12,13

RESULTS This meta-analysis included 88 independent studies. These consisted of 50 cohort14–63 (Supplementary Table 1) and 39 case–control studies33,64–101 (Supplementary Table 2) carried out over the last 40 years (1973–2013). One article contained both a case–control and cohort component.33 Including separate summary estimates for gender, as indicated in Fig. 2a, b, an overall total of 106 estimates of the association between diabetes and PDAC were examined. The overall summary estimate for the relationship between type 2 DM and PDAC was 1.97 (95 % CI 1.78–2.18). The pooled OR for case–control studies was 2.08 (95 % CI 1.87–2.32) (Fig. 2a). The pooled effect size from the cohort (Fig. 2b) was smaller than the case–control studies at 1.88 (95 % CI 1.71–2.07). There was marked heterogeneity within both sets of meta-analyses (I2 of 91 and 65 % with p \ 0.0001 for cohort and case–control studies, respectively). This could not be clearly attributed to any single factor, as shown by the relatively small differences in pooled estimates across subgroup results in the sensitivity analyses (Fig. 2c). Alternative explanations for this heterogeneity are the inclusion of all studies in this section, regardless of whether data based on recent-onset diabetes had been reported. Other contributing factors could be the inclusion of more recent large-scale studies with varying effect sizes, or lifestyle factors such as body mass index (BMI) or alcohol, which were not encompassed by Fig. 2c. Figure 3a presents an exploratory meta-regression, which was based on 122 estimates from 51 studies reporting data on the duration of diabetes at the study level. The effect size for each subgroup was plotted against the midpoint for the duration of diabetes corresponding to the participants included as part of each subgroup. The association between PDAC and DM was presented as the best-fitting curve to the study-level aggregate data. This suggests that PDAC is associated with DM in a non-linear manner, with increased studylevel risk for those with the shortest history of DM. However, the analysis also reveals a persistently increased RR [1.5 with DM of midpoint duration beyond 10 years, supporting a positive association between long-term diabetes and PDAC. The individual-level RRs were extracted from 75 estimates from 31 studies and were significant (p \ 0.001) at less than 1, 1–4, 5–9 and 10 years or greater (Fig. 3b).

P. Batabyal et al. FIG. 2 a Meta-analysis and pooled OR of case-control studies (n = 39). Heterogeneity statistic also included. b Metaanalysis and pooled RR of cohort studies (n = 50). Heterogeneity statistic also included. c Sensitivity analysis incorporating study design, gender, smoking, diabetes diagnosis method, statistical size, publication year, and recent-onset diabetes subgroups. OR odds ratios, RR relative risk, CI confidence interval, MR medical records, OGTT oral glucose tolerance test, RD registry data

(a) First author and year

Level of adjustment

Relative risk [95% Cl]

* Norell, 1986 *** Farrow, 1990 * Cuzick, 1989 * Wynder, 1973 **** Kuriki (F), 2007 * Sciallero, 1993 ** Bueno de Mesquita (M), 1992 **** Yeh, 2012 ** Jain, 1991 **** Rosseau, 2006 * Frye, 2000 * Mizuno, 1992 *** Ekoe, 1992 **** Lo, 2007 ** Wu, 2012 * Kuang, 2009 * Kalopthaki, 1993 *** Henry, 2013 * Magliano, 2012 * Mack, 1986 *** Bonelli, 2003 **** Kuriki (M), 2007 ** Bueno de Mesquita (F), 1992 *** Rosato, 2011 **** Bosetti, 2012 **** Grote, 2011 **** Attner (F), 2012 * Anderson, 2009 * Lee, 1996 * Attner, 2012 *** Maissoneuve (F), 2010 *** Maissoneuve (M), 2010 * Gong, 2012 *** Hassan, 2007 ** Gullo, 1994 ** Ben, 2011 * O’ Mara (F), 1985 * La Vecchia, 1994 **** Lipworth, 2011 ** Matsubayashi, 2011 **** Attner (M), 2012 * Stapley, 2012 **** Li, 2011 **** Jamal, 2009

2.40 [0.60, 9.70] 6.70 [1.80, 24.9] 4.10 [1.44, 14.8] 1.00 [0.31, 3.12] 1.68 [0.58, 4.82] 1.82 [0.66, 5.02] 0.73 [0.27, 1.99] 2.67 [1.02, 6.97] 2.48 [0.98, 6.26] 1.15 [0.46, 2.84] 2.25 [0.93, 5.63] 1.50 [0.61, 3.67] 2.52 [1.04, 6.11] 7.40 [3.10, 17.6] 2.42 [1.07, 5.46] 0.83 [0.39, 1.76] 3.60 [1.80, 7.10] 2.78 [1.49, 5.18] 2.26 [1.20, 4.10] 1.30 [0.70, 2.20] 2.80 [1.63, 4.76] 2.26 [1.33, 3.84] 0.93 [0.35, 0.98] 2.36 [1.43, 3.90] 3.32 [2.02, 5.44] 1.45 [0.89, 2.37] 2.66 [1.63, 4.34] 1.21 [0.75, 1.94] 2.84 [1.80, 4.52] 1.76 [1.11, 2.77] 2.07 [1.31, 3.26] 2.18 [1.47, 3.25] 2.87 [1.97, 4.19] 2.40 [1.70, 3.40] 1.77 [1.26, 2.49] 2.11 [1.51, 2.94] 2.40 [1.80, 3.50] 2.10 [1.50, 2.90] 2.35 [1.70, 3.26] 1.62 [1.18, 2.21] 1.51 [1.21, 1.89] 2.10 [1.70, 2.50] 1.60 [1.30, 1.90] 3.22 [3.03, 3.42]

Pooled estimate

2.08 [1.87, 2.32]

0.50

1.00

2.00

4.00

8.00

16.00

Odds Ratio % Heterogeneity (95% CI) = 65% (44 – 85%) P-value for heterogeneity < .0001

DISCUSSION The results indicate an overall 1.97-fold risk of PDAC among diabetic patients, which is consistent with previous systematic reviews.8,9,14 The addition of more recent studies and inclusion of all patients, regardless of when diabetes was diagnosed, adds power to this meta-analysis and more clearly demonstrates the association between the duration of diabetes and PDAC. The study-level duration analyses indicate an inverse relationship in the first 7.5 years, whereby new-onset diabetic patients have the

greatest RR of PDAC, presumably due to PDAC inducing a ‘diabetogenic’ state. However, the persistently elevated RR above baseline for durations beyond this time also supports a moderate increased risk between long-term diabetes and PDAC. DM as a paraneoplastic effect of PDAC may be a unique feature as there is a higher DM prevalence in this population compared with patients with other cancer types or non-cancer controls.102 Chronological analyses show that for 40–74 % of PDAC patients, hyperglycemia was recentonset (less than 24–36 months).102–104 In addition, diabetes

Association of Diabetes and Pancreatic Cancer FIG. 2 continued

(b) First author

Level of adjustment

and year Hjalgrim, 1997 Whittemore, 1985 Rulyak, 2003 Martin (F), 2009 Balkau (M), 1993 Batty (NM), 2009 Lund-Nilsen (F), 2000 Lund-Nilsen (M), 2000 Hiatt, 1988 Ragozzonio, 1982 Zhou (M), 2010 Luo (F), 2007 Ogunleye, 2009 Mills, 1998 Shibata, 1994 Lin (F), 2002 Ansary-Moghaddam, 2006 Gapstur (M), 2000 Zhou (F), 2010 Luo (M), 2007 Elena, 2012 Lin (M), 2002 Stolzenberg-Solomon (M), 2002 Larsson, 2005 Luo (F), 2012 Chodick (M), 2010 Chodick (F), 2010 Friedman, 1993 Eijgenraam, 2013 Ulcickas-Yood, 2009 Henry (F), 2013 Lam, 2011 Hense, 2011 Johnson, 2011 Arnold (B), 2009 Jee (F), 2005 Wotton (ORLS2), 2011 Stevens (F), 2009 Hwang, 2012 Chiou, 2011 Hippisley-Cox (F), 2012 Seshashi, 2011 Wotton (ORLS1), 2011 Yun, 2006 Jee (M), 2005 Walker (F), 2013 Hippisley-Cox (M), 2012 Walker (M), 2013 Adami, 1991 Brodovicz, 2012 Gupta, 2006 Wideroff (F), 1997 Lai, 2013 Wideroff (M), 1997 Campbell (F), 2012 Campbell (M), 2012 Arnold (W), 2009 Chen, 2011 Hemminiki, 2010 Chow, 1995 Atchison (M), 2010 Jiao, 2010

Relative risk [95% Cl] 2.02 [0.07, 55.3] 6.10 [1.00, 36.5] 2.10 [0.40, 10.9] 4.70 [1.00, 22.2] 3.30 [0.98, 12.0] 2.47 [0.79, 7.75] 0.80 [0.30, 2.70] 1.10 [0.40, 3.00] 2.10 [0.80, 5.70] 2.60 [0.90, 6.10] 3.13 [1.21, 8.08] 1.80 [0.70, 4.60] 2.85 [1.27, 6.43] 3.76 [1.70, 8.31] 2.37 [1.13, 4.99] 1.50 [0.73, 3.12] 1.75 [0.87, 3.55] 2.48 [1.20, 4.49] 2.34 [1.27, 4.32] 2.40 [1.30, 4.20] 1.36 [0.79, 2.36] 2.10 [1.20, 3.60] 2.02 [1.17, 3.50] 1.88 [1.09, 3.26] 1.69 [1.02, 2.78] 1.47 [0.90, 2.41] 1.89 [1.16, 3.07] 2.37 [1.46, 3.85] 1.79 [1.12, 2.87] 3.31 [2.12, 5.15] 1.86 [1.23, 2.83] 1.78 [1.20, 2.65] 1.45 [0.97, 2.06] 2.02 [1.42, 2.90] 0.97 [0.68, 1.38] 1.71 [1.25, 2.34] 4.00 [2.92, 5.40] 1.51 [1.13, 2.03] 1.13 [0.85, 1.50] 3.46 [2.72, 4.40] 2.07 [1.66, 2.58] 1.51 [1.24, 1.83] 2.21 [1.81, 2.67] 1.80 [1.50, 2.20] 1.73 [1.42, 2.07] 3.64 [3.03, 4.38] 2.11 [1.76, 2.52] 2.85 [2.39, 3.41] 1.40 [1.20, 1.70] 1.80 [1.52, 2.14] 2.17 [1.84, 2.56] 1.60 [1.40, 1.90] 1.37 [1.18, 1.59] 1.70 [1.50, 2.00] 1.31 [1.14, 1.51] 1.40 [1.23, 1.59] 1.36 [1.22, 1.51] 1.54 [1.39, 1.71] 3.57 [3.28, 3.88] 1.93 [1.78, 2.08] 1.50 [1.42, 1.59] 1.05 [1.01, 1.11]

* * * * ** * *** *** * * **** **** ** * ** ** **** * **** **** **** ** *** **** **** **** **** * **** ** **** * **** ** **** ** ** **** * * ** **** ** **** **** ** ** ** * ** * **** **** **** **** **** **** *** **** * **** **

Pooled estimate

1.88 [1.71, 2.07]

0.50

1.00

2.00

4.00

8.00

16.00

Relative risk % Heterogeneity (95% CI) = 91% (84 – 93%) P-value for heterogeneity < .0001

often improves after tumor resection.6,104,105 These studies, in addition to our results, support the notion of tumorsecreted products causing a secondary, new-onset hyperglycemia. Several potential factors have been identified, such as vanin-1/matrix metalloproteinase 9106 S-100 calcium-binding protein107 and IAPP,7 with the suggestion that some may be useful biomarkers for early disease. Our findings of increased risk between PDAC and longstanding diabetes is a continuation of previous reviews.8,9 Chronic insulin resistance is hypothesized to upregulate circulating insulin-like growth factors,2,3 which accelerates

mitotic proliferation of pancreatic cells, promotes angiogenesis, and decreases cellular apoptosis.3,108 This has been supported by hyperinsulinemia and higher circulating levels of C-peptide in PDAC patients.109 Another competing theory relates to the metabolic syndrome triggering pro-inflammatory pathways and free radical production, which causes cellular damage, reduces immunity, and promotes angiogenesis.3,110 Established risk factors for PDAC include age, smoking and family history.111–113 Obesity has also been shown to increase risk by 10 % for every 5-unit increment in BMI,11

P. Batabyal et al. FIG. 2 continued

(c) Subgroup

Number of subgroups/studies

Relative risk [95% Cl]

P-value*

Study design Cohort

62

1.88 [1.71, 2.07]

Case-control

44

2.08 [1.87, 2.32]

Males

31

1.77 [1.61, 1.95]

Females

31

1.68 [1.49, 1.90]

No

33

2.05 [1.79, 2.35]

Yes

73

1.92 [1.76, 2.09]

MR/OGTT/RD

38

2.14 [1.90, 2.40]

Self-report/proxy

68

1.81 [1.66, 1.98]

20

45

1.88 [1.71, 2.08]

1980-1999

28

1.95 [1.79, 2.12]

2000-2012

78

1.92 [1.68, 2.19]

Pooled estimate

106

1.97 [1.78, 2.18]

0.16

Sex

0.5

Adjusted for smoking

0.43

Method of diagnosis

0.03

Statistical size

0.21

Publication year

1.00

2.00

0.87

4.00

Relative risk

and, to a lesser extent, alcohol has been associated with PDAC.114 Subanalyses adjusting for gender and smoking in this study continued to identify DM as a risk factor for PDAC. Other risk factors were not assessed due to lack of consistent reporting by the studies examined. However, due to the large number of studies included and overall patient numbers, the association of DM and PDAC appears to be a real finding. Whether oral hypoglycemic use itself can alter the development of PDAC was not addressed by this metaanalysis. Studies have shown conflicting changes in PDAC risk with oral hypoglycemic use. Sulphonylureas have been associated with increased PDAC risk, whereas there has been a reduction (RR 0.48), or no change, in risk in patients on metformin.115,116 As only one study in our review specifically adjusted for metformin, and many diabetic patients in this analysis are likely to be using these medications, the true strength of the association may be lower than anticipated. Other limitations of the study include differentiation between types I and II DM. Type I DM has been linked to a twofold risk of PDAC;117 however, this is based on a very small number of cases, with the majority (80–90 %) of patients in reported series predicted to have type II DM.2 While specific studies on patients with neuroendocrine tumors were excluded, not every paper defined pancreatic

cancer as representing PDAC, and may include some heterogonous tumor types. Although rare, DM potentially increases the risk of neuroendocrine tumors by 1.5-fold,118 which may serve to confound our results. Finally, although all included studies were age-adjusted for pancreatic cancer diagnosis, none adjusted for the age of patients at formal diabetes diagnosis. Incorporation of onset age of diabetes into future study designs is important as preliminary studies have shown a higher proportion of PDAC in those with diabetes of late onset ([55 years).103 Additional risk factors for PDAC also differ for early-onset diabetic patients (family history of PDAC and insulin use) compared with late-onset diabetes (onset age of DM and multiple diabetic family members).103 For the purposes of this paper, new-onset DM was defined as DM within 1 year prior to PDAC diagnosis. A consensus has not been reached as to what constitutes ‘new-onset’ in the literature, with cutoffs ranging from less than 1–3 years.119,120 Although we demonstrated a persistently increased risk of PDAC in patients with a duration of diabetes exceeding 10 years, we clearly showed in our analysis a stronger association between DM and PDAC early after the diagnosis of DM. In papers that reported a duration of diabetes of less than 1 year, this association was greatest, albeit based upon a small number of studies.

Association of Diabetes and Pancreatic Cancer

(a) 16

Relative risk

8

4

2

1

0.5 0 1

10

5

15

20

25

Diabetes duration (years)

(b)

Duration Diabetes

< 1 year

Number of subgroups/studies

Relative risk [95% Cl]

limitations and patient volumes place priority on screening those with new-onset diabetes first, although programs may later be expanded to long-standing diabetic patients. Given that age itself is a risk factor for PDAC and that new-onset diabetes is more prevalent in those with later diabetes onset ([55 years),103 one option is to recommend a screening cutoff of 50–55 years in new-onset diabetic patients. Secondary screening filters such as family history or diabetes in the absence of other metabolic risk factors may also be considered.123 There is little literature available on the screening of asymptomatic new-onset diabetic patients with PDAC; however, a clinical trial evaluating performance characteristics and cost effectiveness of both endoscopic ultrasound and computed tomography/magnetic resonance imaging for detecting PDAC in this population is currently being conducted.123 Further research is thus required before specific serological, radiological, or endoscopic screening modalities are selected for screening programs.

6.69 [3.80, 11.78]

3

CONCLUSIONS 1-4 years

21

1.86 [1.56, 2.21]

5-9 years

23

1.72 [1.47, 2.00]

>= 10 years 28

1.36 [1.19, 1.55]

1.00

2.00

4.00

8.00

16.00

There is a time-dependent association between diabetes and PDAC, which is primarily new-onset in nature. Until sensitive biomarkers are available to quantify this relationship, screening older patients with hyperglycemia of less than 1 year in the absence of other metabolic risk factors for PDAC may be recommended.121,124 To a lesser degree, primary prevention of DM may also alleviate longterm pancreatic cancer burden.

Relative risk

FIG. 3 a Study-level risk of pancreatic cancer by midpoint for the range of duration of diabetes reported in each study. Effect sizes reported based on patients not restricted to a particular duration are not included. Size of symbols are proportional to the precision of estimated effect size. Circles represent the effect size from cohort studies and triangles represent the effect size from case-control studies. Several studies reported multiple effect sizes based on varying cutoffs for the duration of diabetes, all of which are presented here. An upper limit of 30 years for duration of diabetes was assumed for those studies where it was not specified. The blue curve is estimated using a loess smoother weighted by precision of estimated effect size. b Individual-level relative risk of PDAC by duration of diabetes. CI confidence interval

A recent retrospective case–control study shows that PDAC-associated DM and recent-onset DM in healthy controls could be distinguished with 80.8 % sensitivity and 67.6 % specificity.121 Individual studies indicate that at the time of diabetes onset, PDAC is often resectable122 and preoperative DM is an important determinant for surgical outcomes and disease-free survival.15,123 Due to the relatively low population prevalence of pancreatic cancer, the success of screening programs relies upon targeting specific patient subsets.123 Resource

ACKNOWLEDGMENT Pikli Batabyal, Stephen Vander Hoorn, Christopher Christophi, and Mehrdad Nikfarjam declare no competing source of financial or material support or commercial interest in the subject of the study.

REFERENCES 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. 2. Wang F, Herrington M, Larsson J, Permert J. The relationship between diabetes and pancreatic cancer. Mol Cancer. 2003;2:4. 3. Li D. Diabetes and pancreatic cancer. Mol Carcinog. 2012;51(1):64–74. 4. Magruder JT, Elahi D, Andersen DK. Diabetes and pancreatic cancer: chicken or egg? Pancreas. 2011;40(3):339–51. 5. Permert J, Larsson J, Westermark GT, et al. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med. 1994;330(5):313–8. 6. Permert J, Ihse I, Jorfeldt L, Von Schenck H, Arnquist HJ, Larsson J. Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg. 1993;80(8):1047–50. 7. Li J, Cao G, Ma Q, Liu H, Li W, Han L. The bidirectional interation between pancreatic cancer and diabetes. World J Surg Oncol. 2012;10(171):1477–7819. 8. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M. Type-II diabetes and pancreatic cancer:

P. Batabyal et al.

9. 10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

a meta-analysis of 36 studies. Br J Cancer. 2005;92(11): 2076–83. Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer: a meta-analysis. JAMA. 1995;273(20):1605–9. Ben Q, Xu M, Ning X, et al. Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies. Eur J Cancer. 2011;47(13):1928–37. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for meta-analysis in medical research. Chichester: Wiley; 2000. A language and environment for statistical computing [computer program]. Vienna: R Foundation for Statistical Computing; 2008. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1–48. Eijgenraam P, Heinen MM, Verhage BAJ, Keulemans YC, Schouten LJ, van den Brandt PA. Diabetes type II, other medical conditions and pancreatic cancer risk: a prospective study in The Netherlands. Br J Cancer. 2013;109(11):2924–32. Walker JJ, Brewster DH, Colhoun HM, et al. Type 2 diabetes, socioeconomic status and risk of cancer in Scotland 2001–2007. Diabetologia. 2013;56(8):1712–1715. Adami H-O, McLaughlin J, Ekbom A, et al. Cancer risk in patients with diabetes mellitus. Cancer Causes Control. 1991;2(5): 307–14. Ansary-Moghaddam A, Huxley R, Barzi F, et al. The effect of modifiable risk factors on pancreatic cancer mortality in populations of the Asia-Pacific region. Cancer Epidemiol Biomarkers Prev. 2006;15(12):2435–40. Arnold LD, Patel AV, Yan Y, et al. Are racial disparities in pancreatic cancer explained by smoking and overweight/obesity? Cancer Epidemiol Biomarkers Prev. 2009;18(9):2397–405. Atchison EA, Gridley G, Carreon JD, Leitzmann MF, McGlynn KA. Risk of cancer in a large cohort of U.S. veterans with diabetes. Int J Cancer. 2011;128(3):635–43. Balkau B, Barrett-Connor E, Eschwege E, Richard JL, Claude JR, Ducimetiere P. Diabetes and pancreatic carcinoma. Diabete Metab. 1993;19(5):458–62. Batty GD, Kivimaki M, Morrison D, et al. Risk factors for pancreatic cancer mortality: extended follow-up of the original whitehall study. Cancer Epidemiol Biomarkers Prev. 2009;18(2):673–5. Brodovicz KG, Kou TD, Alexander CM, Engel S, Girman CJ. Synergistic effect of type 2 diabetes (T2D) and history of pancreatitis on pancreatic cancer risk: a retrospective cohort study from the general practice research database (GPRD). Pharmacoepidemiol Drug Saf. 2011;20:S283. Campbell PT, Jacobs EJ, Newton CC, Gapstur SM, Patel AV. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care. 2012;35(9):1835–44. Chen HF, Chen P, Li CY. Risk of malignant neoplasm of the pancreas in relation to diabetes: a population-based study in Taiwan. Diabetes Care. 2011;34(5):1177–9. Chiou WK, Huang BY, Chou WY, Weng HF, Lin JD. Incidences of cancers in diabetic and non-diabetic hospitalized adult patients in Taiwan. Asian Pac J Cancer Prev. 2011;12(6):1577–81. Chodick G, Heymann AD, Rosenmann L, et al. Diabetes and risk of incident cancer: a large population-based cohort study in Israel. Cancer Causes Control. 2010;21(6):879–87. Chow WH, Gridley G, Nyren O, et al. Risk of pancreatic cancer following diabetes mellitus: a nationwide cohort study in Sweden. J Natl Cancer Inst. 1995;87(12):930–1. Elena JW, Steplowski E, Yu K, et al. Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control. 2013;24(1):13–25. Friedman GD, van den Eeden SK. Risk factors for pancreatic cancer: an exploratory study. Int J Epidemiol. 1993;22(1):30–7.

30. Gapstur SM, Gann PH, Lowe W, Liu L, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA. 2000;283(19):2552–8. 31. Gupta S, Vittinghoff E, Bertenthal D, et al. New-onset diabetes and pancreatic cancer. Clin Gastroenterol Hepatol. 2006;4(11):1366–72. 32. Hemminki K, Li X, Sundquist J, Sundquist K. Risk of cancer following hospitalization for type 2 diabetes. Oncologist. 2010;15(6):548–55. 33. Henry SA, Prizment AE, Anderson KE. Duration of diabetes and pancreatic cancer in a case-control study in the midwest and the Iowa Women’s Health Study (IWHS) cohort. Jop. 2013; 14(3):243–9. 34. Hense HW, Kajuter H, Wellmann J, Batzler WU. Cancer incidence in type 2 diabetes patients: first results from a feasibility study of the D2C cohort. Diabetol Metab Syndr. 2011;3(1):15. 35. Hiatt RA, Klatsky AL, Armstrong MA. Pancreatic cancer, blood glucose and beverage consumption. Int J Cancer. 1988;41(6):794–7. 36. Hippisley-Cox J, Coupland C. Identifying patients with suspected pancreatic cancer in primary care: derivation and validation of an algorithm. Br J Gen Pract. 2012;62(594): e38–45. 37. Hjalgrim H, Frisch M, Ekbom A, Kyvik KO, Melbye M, Green A. Cancer and diabetes: a follow-up study of two populationbased cohorts of diabetic patients. J Intern Med. 1997;241(6): 471–5. 38. Hwang A, Narayan V, Yang Y-X. Type 2 diabetes mellitus and survival in pancreatic adenocarcinoma: a retrospective cohort study. Cancer. 2013;119(2):404–10. 39. Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA. 2005;293(2):194–202. 40. Jiao L, Berrington De Gonzalez A, Hartge P, et al. Body mass index, effect modifiers, and risk of pancreatic cancer: a pooled study of seven prospective cohorts. Cancer Causes Control. 2010;21(8):1305–14. 41. Johnson JA, Bowker SL, Richardson K, Marra CA. Timevarying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia. 2011;54(9): 2263–71. 42. Lai GY, Park Y, Hartge P, Hollenbeck AR, Freedman ND. The association between self-reported diabetes and cancer incidence in the NIH-AARP Diet and Health Study. J Clin Endocrinol Metab. 2013;98(3):2012–3335. 43. Lam EKK, Batty GD, Huxley RR, et al. Associations of diabetes mellitus with site-specific cancer mortality in the Asia-Pacific region. Ann Oncol. 2011;22(3):730–8. 44. Larsson SC, Permert J, Hakansson N, Naslund I, Bergkvist L, Wolk A. Overall obesity, abdominal adiposity, diabetes and cigarette smoking in relation to the risk of pancreatic cancer in two Swedish population-based cohorts. Br J Cancer. 2005;93(11):1310–5. 45. Lin Y, Tamakoshi A, Kawamura T, et al. Risk of pancreatic cancer in relation to alcohol drinking, coffee consumption and medical history: findings from the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. Int J Cancer. 2002;99(5):742–6. 46. Lund Nilsen TI, Johnsen R, Vatten LJ. Socio-economic and lifestyle factors associated with the risk of prostate cancer. Br J Cancer. 2000;82(7):1358–63. 47. Luo J, Chlebowski R, Liu S, et al. Diabetes mellitus as a risk factor for gastrointestinal cancers among postmenopausal women. Cancer Causes Control. 2012;24:24. 48. Luo J, Iwasaki M, Inoue M, et al. Body mass index, physical activity and the risk of pancreatic cancer in relation to smoking status and history of diabetes: a large-scale population-based cohort study in Japan—The JPHC study. Cancer Causes Control. 2007;18(6):603–12.

Association of Diabetes and Pancreatic Cancer 49. Martin JH, Coory MD, Valery PC, Green AC. Association of diabetes with survival among cohorts of indigenous and nonIndigenous Australians with cancer. Cancer Causes Control. 2009;20(3):355–60. 50. Mills PK, Beeson WL, Abbey DE, Fraser GE, Phillips RL. Dietary habits and past medical history as related to fatal pancreas cancer risk among Adventists. Cancer. 1988;61(12):2578–85. 51. Ogunleye AA, Ogston SA, Morris AD, Evans JMM. A cohort study of the risk of cancer associated with type 2 diabetes. Br J Cancer. 2009;101(7):1199–1201. 52. Ragozzino M, Melton LJ 3rd, Chu CP, Palumbo PJ. Subsequent cancer risk in the incidence cohort of Rochester, Minnesota, residents with diabetes mellitus. J Chronic Dis. 1982;35(1):13–19. 53. Rulyak SJ, Lowenfels AB, Maisonneuve P, Brentnall TA. Risk factors for the development of pancreatic cancer in familial pancreatic cancer kindreds. Gastroenterology. 2003;124(5):1292–9. 54. Seshasai SRK, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829–41. 55. Shibata A, Mack TM, Paganini-Hill A, Ross RK, Henderson BE. A prospective study of pancreatic cancer in the elderly. Int J Cancer. 1994;58(1):46–9. 56. Stevens RJ, Roddam AW, Spencer EA, et al. Factors associated with incident and fatal pancreatic cancer in a cohort of middleaged women. Int J Cancer. 2009;124(10):2400–05. 57. Stolzenberg-Solomon RZ, Pietinen P, Taylor PR, Virtamo J, Albanes D. A prospective study of medical conditions, anthropometry, physical activity, and pancreatic cancer in male smokers (Finland). Cancer Causes Control. 2002;13(5):417–26. 58. Ulcickas Yood M, Oliveria SA, Campbell UB, Koro CE. Incidence of cancer in a population-based cohort of patients with type 2 diabetes. Diabetes Metab Syndr. 2009;3(1):12–6. 59. Whittemore AS, Paffenbarger RS Jr, Anderson K, Lee JE. Early precursors of site-specific cancers in college men and women. J Natl Cancer Inst. 1985;74(1):43–51. 60. Wideroff L, Gridley G, Mellemkjaer L, et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst. 1997;89(18): 1360–5. 61. Wotton CJ, Yeates DG, Goldacre MJ. Cancer in patients admitted to hospital with diabetes mellitus aged 30 years and over: record linkage studies. Diabetologia. 2011;54(3):527–534. 62. Yun JE, Jo I, Park J, et al. Cigarette smoking, elevated fasting serum glucose, and risk of pancreatic cancer in Korean men. Int J Cancer. 2006;119(1):208–12. 63. Zhou XH, Qiao Q, Zethelius B, et al. Diabetes, prediabetes and cancer mortality. Diabetologia. 2010;53(9):1867–76. 64. Anderson LN, Cotterchio M, Gallinger S. Lifestyle, dietary, and medical history factors associated with pancreatic cancer risk in Ontario, Canada. Cancer Causes Control. 2009;20(6):825–34. 65. Attner B, Landin-Olsson M, Lithman T, Noreen D, Olsson H. Cancer among patients with diabetes, obesity and abnormal blood lipids: a population-based register study in Sweden. Cancer Causes Control. 2012;23(5):769–77. 66. Ben Q, Cai Q, Li Z, et al. The relationship between new-onset diabetes mellitus and pancreatic cancer risk: a case-control study. Eur J Cancer. 2011;47(2):248–54. 67. Bonelli L, Aste H, Bovo P, et al. Exocrine pancreatic cancer, cigarette smoking, and diabetes mellitus: a case-control study in Northern Italy: Pancreas. 2003;27(2):143–9. 68. Bosetti C, Rosato V, Polesel J, et al. Diabetes mellitus and cancer risk in a network of case-control studies. Nutr Cancer. 2012;64(5):643–51. 69. Bueno De Mesquita HB, Maisonneuve P, Moerman CJ, Walker AM. Aspects of medical history and exocrine carcinoma of the

70.

71.

72.

73.

74.

75.

76. 77.

78.

79.

80.

81.

82.

83. 84. 85.

86.

87.

88.

89.

pancreas: a population-based case-control study in The Netherlands. Int J Cancer. 1992;52(1):17–23. Cuzick J, Babiker AG. Pancreatic cancer, alcohol, diabetes mellitus and gall-bladder disease. Int J Cancer. 1989;43(3): 415–21. Ekoe JM, Ghadirian P, Simard A, Baillargeon J, Perret C. Diabetes mellitus and pancreatic cancer: a case-control study in greater Montreal, Quebec, Canada (in French). Rev Epidemiol Sante Publique. 1992;40(6):447–53. Farrow DC, Davis S. Risk of pancreatic cancer in relation to medical history and the use of tobacco, alcohol and coffee. Int J Cancer. 1990;45(5):816–20. Frye JN, Inder WJ, Dobbs BR, Frizelle FA. Pancreatic cancer and diabetes: is there a relationship? A case-controlled study. Aust N Z J Surg. 2000;70(10):722–4. Gong Y, Yang YS, Zhang XM, et al. ABO blood type, diabetes and risk of gastrointestinal cancer in northern China. World J Gastroenterol. 2012;18(6):563. Grote VA, Rohrmann S, Nieters A, et al. Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: s study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia. 2011;54(12):3037–46. Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. N Engl J Med. 1994;331(2):81–4. Hassan MM, Bondy ML, Wolff RA, et al. Risk factors for pancreatic cancer: case-control study. Am J Gastroenterol. 2007;102(12):2696–707. Jain M, Howe GR, St Louis P, Miller AB. Coffee and alcohol as determinants of risk of pancreas cancer: a case-control study from Toronto. Int J Cancer. 1991;47(3):384–9. Jamal MM, Yoon EJ, Vega KJ, Hashemzadeh M, Chang KJ. Diabetes mellitus as a risk factor for gastrointestinal cancer among American veterans. World J Gastroenterol. 2009;15(42): 5274–8. Kalapothaki V, Tzonou A, Hsieh CC, Toupadaki N, Karakatsani A, Trichopoulos D. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control. 1993;4(4):375–82. Kuang TT, Jin DY, Wang DS, et al. Clinical epidemiological analysis of the relationship between pancreatic cancer and diabetes mellitus: data from a single institution in China. J Dig Dis. 2009;10(1):26–9. Kuriki K, Hirose K, Tajima K. Diabetes and cancer risk for all and specific sites among Japanese men and women. Eur J Cancer Prev. 2007;16(1):83–9. La Vecchia C, Negri E, D’Avanzo B, et al. Medical history, diet and pancreatic cancer. Oncology. 1990;47(6):463–6. Lee CTE, Chang FY, Lee SD. Risk factors for pancreatic cancer in orientals. J Gastroenterol Hepatol. 1996;11(5):491–5. Li D, Tang H, Hassan MM, Holly EA, Bracci PM, Silverman DT. Diabetes and risk of pancreatic cancer: a pooled analysis of three large case-control studies. Cancer Causes Control. 2011;22(2): 189–97. Lipworth L, Zucchetto A, Bosetti C, et al. Diabetes mellitus, other medical conditions and pancreatic cancer: a case-control study. Diabetes Metab Res Rev. 2011;27(3):255–61. Lo AC, Soliman AS, El-Ghawalby N, et al. Lifestyle, occupational, and reproductive factors in relation to pancreatic cancer risk. Pancreas. 2007;35(2):120–9. Mack TM, Yu MC, Hanisch R, Henderson BE. Pancreas cancer and smoking, beverage consumption, and past medical history. J Natl Cancer Inst. 1986;76(1):49–60. Magliano DJ, Davis WA, Shaw JE, Bruce DG, Davis TME. Incidence and predictors of all-cause and site-specific cancer in

P. Batabyal et al.

90.

91.

92.

93. 94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105. 106.

type 2 diabetes: the Fremantle Diabetes Study. Eur J Endocrinol. 2012;167(4):589–99. Maisonneuve P, Lowenfels AB, Bueno-de-Mesquita HB, et al. Past medical history and pancreatic cancer risk: results from a multicenter case-control study. Ann Epidemiol. 2010;20(2):92–8. Matsubayashi H, Maeda A, Kanemoto H, et al. Risk factors of familial pancreatic cancer in Japan: current smoking and recent onset of diabetes. Pancreas. 2011;40(6):974–8. Mizuno S, Watanabe S, Nakamura K, et al. A multi-institute case-control study on the risk factors of developing pancreatic cancer. Jpn J Clin Oncol. 1992;22(4):286–91. Norell S, Ahlbom A, Erwald R, et al. Diabetes, gall stone disease, and pancreatic cancer. Br J Cancer. 1986;54(2):377–8. O’Mara BA, Byers T, Schoenfeld E. Diabetes mellitus and cancer risk: a multisite case-control study. J Chronic Dis. 1985;38(5):435–41. Rosato V, Tavani A, Bosetti C, et al. Metabolic syndrome and pancreatic cancer risk: a case-control study in Italy and metaanalysis. Metabolism. 2011;60(10):1372–8. Rousseau MC, Parent ME, Pollak MN, Siemiatycki J. Diabetes mellitus and cancer risk in a population-based case-control study among men from Montreal, Canada. Int J Cancer. 2006;118(8): 2105–9. Sciallero S, Bonelli L, Saccomanno S, Conio M, Bruzzi P, Pugliese V. Socioeconomic characteristics, life style, diabetes, family history of cancer and risk of pancreatic cancer. Eur J Gastroenterol Hepatol. 1993;5(5):367–71. Stapley S, Peters TJ, Neal RD, Rose PW, Walter FM, Hamilton W. The risk of pancreatic cancer in symptomatic patients in primary care: a large case-control study using electronic records. Br J Cancer. 2012;106(12):1940–4. Wu Q, Chen G, Wu WM, et al. Metabolic syndrome components and risk factors for pancreatic adenocarcinoma: a case-control study in China. Digestion. 2012;86(4):294–301. Wynder EL, Mabuchi K, Maruchi N, Fortner JG. Epidemiology of cancer of the pancreas. J Natl Cancer Inst. 1973;50(3): 645–67. Yeh HC, Platz EA, Wang NY, Visvanathan K, Helzlsouer KJ, Brancati FL. A prospective study of the associations between treated diabetes and cancer outcomes. Diabetes Care. 2012;35(1): 113–8. Aggarwal G, Kamada P, Chari ST. Prevalence of diabetes mellitus in pancreatic cancer compared to common cancers. Pancreas. 2013;42(2):198–201. Mizuno S, Nakai Y, Isayama H, et al. Risk factors and early signs of pancreatic cancer in diabetes: screening strategy based on diabetes onset age. J Gastroenterol. 2013;48(2):238–46. Pannala R, Leirness JB, Bamlet WR, Basu A, Petersen GM, Chari ST. Prevalence and clinical profile of pancreatic cancer-associated diabetes mellitus. Gastroenterology. 2008;134(4):981–7. Fogar P, Pasquali C, Basso D, et al. Diabetes mellitus in pancreatic cancer follow-up. Anticancer Res. 1994;14(6B):2827–30. Huang H, Dong X, Kang MX, et al. Novel blood biomarkers of pancreatic cancer-associated diabetes mellitus identified by peripheral blood-based gene expression profiles. Am J Gastroenterol. 2010;105(7):1661–9.

107. Basso D, Greco E, Fogar P, et al. Pancreatic cancer-associated diabetes mellitus: an open field for proteomic applications. Clin Chim Acta. 2005;357(2):184–9. 108. Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev. 2000;21(3):215–44. 109. Pisani P. Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem. 2008;114(1):63–70. 110. Arcidiacono B, Iiritano S, Nocera A, et al. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res. 2012;2012:789174. 111. Iodice S, Gandini S, Maisonneuve P, Lowenfels AB. Tobacco and the risk of pancreatic cancer: a review and meta-analysis. Langenbecks Arch Surg. 2008;393(4):535–45. 112. Tersmette AC, Petersen GM, Offerhaus GJ, et al. Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer. Clin Cancer Res. 2001;7(3):738–44. 113. Lynch HT, Smyrk T, Kern SE, et al. Familial pancreatic cancer: a review. Semin Oncol. 1996;23(2):251–75. 114. Tramacere I, Scotti L, Jenab M, et al. Alcohol drinking and pancreatic cancer risk: a meta-analysis of the dose-risk relation. Int J Cancer. 2010;126(6):1474–86. 115. Noto H, Goto A, Tsujimoto T, Noda M. Cancer risk in diabetic patients treated with metformin: a systematic review and metaanalysis. PloS One. 2012;7(3):e33411. 116. Singh S, Singh PP, Singh AG, Murad MH, McWilliams RR, Chari ST. Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):510–19. 117. Stevens RJ, Roddam AW, Beral V. Pancreatic cancer in type 1 and young-onset diabetes: systematic review and meta-analysis. Br J Cancer. 2007;96(3):507–9. 118. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: a U.S.-based case–control study. Int J Cancer. 2008;123(4):867–73. 119. Chari ST, Leibson CL, Rabe KG, Ransom J, De Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology. 2005;129(2):504–11. 120. Trna J, Dı´te˘, Adamcova´ A, et al. Diabetes mellitus in pancreatic cancer patients in the Czech Republic: sex differences. Exp Diabetes Res. 2012;2012:414893. 121. Lee JH, Kim SA, Park HY, et al. New-onset diabetes patients need pancreatic cancer screening? J Clin Gastroenterol. 2012;46(7):e58–61. 122. Pelaez-Luna M, Takahashi N, Fletcher JG, Chari ST. Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: a retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol. 2007;102(10):2157–63. 123. Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10(1):88–95. 124. Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST. New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol. 2013;10(7):423–33.