Abstract
Objective: To estimate the possible association between periodontal disease (PD) clinical indices, and number of missing teeth and the risk of developing gallbladder carcinoma (GBC) in Greek adults using data from a population based case-control study.
Material and Method: The study sample comprised 80 males and 67 females, aged 45 to 79 years. 49 individuals suffered from GBC- cases and 98 were healthy individuals - controls. All clinical indices examined were obtained via a modified standardized questionnaire and an oral and dental clinical examination. Periodontal status included the following clinical parameters, probing pocket depth (PPD), gingival index (GI), plaque index (PlI), clinical attachment loss (CAL), and bleeding on probing (BOP), and the number of missing teeth. The questionnaire included data regarding the dependent and independent risk factors for GBC development. Univariate and logistic regression models adjusted for possible confounders were carried out for data analysis.
Results: Statistical analysis showed that chronic GB inflammation (p=0.00, OR=2.74, 95% CI=1.28-5.86), smoking (p=0.05, OR=1.63, 95% CI=1.26-2.72), GI (p=0.05, OR=1.56, 95% CI=1.20-2.62), and missing teeth more than four teeth (p=0.03, OR=1.74,95% CI=1.30-3.75, p=0.02, OR= 2.03, 95% CI=1.67-4.11) were statistically significantly associated with the risk of developing GBC.
Conclusions: The current research suggested positive associations of chronic inflammation of the gallbladder, smoking, gingival inflammation, and missing teeth more than four with GBC development.
Keywords
Gallbladder cancer, Periodontal disease, Loss of dentition, Dental disease
Introduction
Primary GBC is the most common biliary tract malignancy and the sixth most common cancer affecting the gastrointestinal tract [1,2]. The majority of cases are diagnosed in advanced stages, resulting in extremely poor prognosis [3]. This late diagnosis may be attributed to the absence of symptoms/clinical signs at initial stages. This leads to lack of early treatment [3]. The prognosis is mainly dependent on histological subtype, grade, and the stage of the tumor at the presentation time. The overall mean survival rate for GBC patients is six months, with a 5-year survival rate of 5% [1]. GBC is a rare malignant tumor in western countries but is much more frequent in some other regions worldwide. The occurrence of GBC is less than 2/100,000 individuals worldwide; however, this has been recorded with extensive variance [4]. Its extensive incidence variation in ethnicity, geography, and cultural differences suggests the possible roles of genetic and environmental factors associated with its appearance and progression [5,6].
PD, gingivitis and periodontitis, is a multifactorial, and chronic immunological disease [7,8]. Gingivitis concerns the soft tissue surrounding the teeth and is a reversible inflammation. On the contrary, periodontitis is characterized by irreversible loss of periodontal tissue support and leads to tooth loss [9]. Gingivitis may progress to periodontitis in those susceptible individuals with compromised immune system [7,8]. PD global prevalence has been estimated to be 20-50% whereas a rate of 10% of the population globally is affected by severe periodontitis [9-11], and its prevalence varies in different countries [10]. In the United States 42.2% of dentate adults aged 30 years or older suffer from periodontitis, whereas 7.8% suffer from severe periodontitis [12].
GBC appearance has been associated with diverse genetic and environmental factors. To be more specific, main independent etiological factors concern female gender [13], advanced age [13], gallstones family history [14,15], increased BMI [16] and obesity [17], cholelithiasis [13,18], chronic inflammation-cholecystitis and porcelain gallbladder[19], chronic infection by Salmonella species, S. paratyphi or S.typhican [13,20-22], H. pylori [23], gallbladder polyp [24], abnormal pancreatobiliary duct junction [25], and high parity (females having had five or more births) [26,27]. Associated risk factors such as Mirizzi’s syndrome and bile reflux have also been played an essential role as predisposing GBC factors [28]. Other, dependent etiological factors concern environmental exposure to specific chemicals and heavy metals such as nickel, cadmium, etc. [29], mustard oil [30], argemone oil and butter yellow [31], occupational exposure to benzene [32], free radical oxidation products [33], and smoking [34]. In addition, use of oral contraceptives [27,34], an early age at first pregnancy [26], red chili pepper [35], xanthogranulomatous cholecystitis [36], secondary bile acids [15,37], and genetic factors [38] have also been incriminated in GBC development.
A number of studies have recorded associations between PD, and periodontitis mainly and diverse systemic diseases and disorders, including cancer [39-46]. Especially, prospective studies reported increases in the overall cancer risk associated with PD of 14% to 24%, whereas the association was not attenuated even after adjustment for known risk factors, such as smoking, socio-economic status, and other confounders [44,46,47]. It is possible that the conflicting and controversial associations in specific cancer types could be attributed to differences in study designs, cohort sizes, study populations, the use of diverse clinical indices to define PD, and the effects of known and unknown confounders. Although the methodology to determine PD was not consistent across studies, those that were based on large samples showed a consistent association between PD and cancer risk, and that risk seemed to increase significantly depending on PD severity [47].
The mechanisms through which cancer may appear among individuals who have PD are not entirely clear. A number of plausible mechanisms have been suggested and inflammation seems to play a significant role in many of those supposed mechanisms. Inflammatory responses are able to produce free radicals and active intermediates (ROS and RNI) causing oxidative/nitrosative stress, that may result in DNA mutations in cells, or they may interfere with DNA repair mechanisms [48]. The inflammatory cells themselves may contribute to the damage by producing ROS and RNI, cytokines, chemokines, and metabolites of arachidonic acid, etc. Those products, in turn, demonstrate a strong affinity for more inflammatory cells, enhancing the vicious cycle [48]. It has also been recorded that periodontal treatment can substantially decrease biomarkers of systemic inflammation [49,50] and that certain anti?inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) may help to prevent or decrease the risk of certain site?specific cancers, such as colorectum, stomach, esophagus, breast, and biliary tract [51,52].
Another possible mechanism is the role of oral microbiota dysbiosis that appears to be involved in the pathogenesis of both periodontitis and systemic diseases, including cancer [53,54]. Previous reports suggested that periodontal tissues or oral mucosa microbiota is implicated in cancer pathogenesis and modify the responses to cancer treatment [55,56]. Oral cavity microbiota is connected to the respiratory tract as is able to enter the respiratory and gastrointestinal tract. Therefore, oral microbiota dysbiosis, mainly in periodontitis, can contribute to carcinogenesis of the gastrointestinal and respiratory tract, such as head-neck squamous cell carcinoma (HNSCC), gastric, lung, pancreatic, and colorectal cancer [57-61]. Ten cancer hallmarks have been described in an effort to explain the complex multistage alterations occurring during cancer pathogenesis and progress [62,63]. The microbiota plays an essential role in the homeostasis of the tumor-micro-environment and modifies almost all cancer hallmarks [64]. Therefore, epidemiologic studies must investigate the role of oral microbiome and/or specific established periodontal pathogens in relation to PD and cancer risk.
No previous prospective or retrospective epidemiological research have been carried out for assessing the possible association between PD and risk of GBC in Greece. The purpose of the current case-control study was to assess the possible association between PD indices and tooth loss and risk of developing GBC in a sample of adults in Greece.
Material and Method
The present survey was based on a case-control design and was carried out between December 2020 and August 2023.
Study size assessment was based on GBC prevalence [65] and the EPITOOLS guidelines (https://epitools.ausvet.com.au) determined with 95% Confidence Interval (CI) and desired power 0.8. The World Health Organization (WHO) recommendations for evaluating periodontal status incidence were used for assessing age group [66]. That procedure led to a study sample of 49 individuals suffering from GBC as case studies and 98 healthy participants as controls. All participants ages ranged from 45 to 79 years. Participants were selected from one dental and two medical private practices and were out-patients of the mentioned practices in the city of Athens.
Cases and controls eligibility Criteria
Inclusion criteria was as follows: Participants should not have been treated by a conservative or a surgical process in their oral cavity in the last 6 months, or prescribed systemic antibiotic regimens, or systematic glucocorticoids, or immune-suppression agents within the previous 6 months. They should also have more than 15 teeth and periodontitis from stage I to IV [67].
Participants that suffered from cardiovascular disease (CVD), diabetes mellitus (DM), rheumatoid arthritis, acute pulmonary diseases or any type of malignancies were excluded from the study protocol as those diseases could potentially affect oral and periodontal tissues [68] and lead to biased secondary associations.
All participants were recruited from the same city and were presented to routine health follow-up at the mentioned practices. Moreover, they were matched for gender, age, and smoking status, as gender [69], age [70], and smoking history [71] are the principal risk factors for periodontitis development as covariates according to epidemiological studies [72].
Advanced GBC patients under medical treatment/metastatic disease, patients with GB metastases of a primary focus at a different location, and hospital patients were excluded from the study. The case group consisted of individuals whose GBC primary diagnosis was based on patients’ medical files and CT findings, however the definitive diagnosis was confirmed by percutaneous fine needle aspiration (FNA) or core biopsy, most frequently under ultrasound (US) guidance, and occasionally under CT guidance [73].
The current report was not an experimental one and was not approved by authorized committees (Health Ministry, etc.). All participants were informed about the aims/methods and significance of the present survey and gave their written consent to enroll in the study protocol.
Data collection and intra-oral examination
The interview questionnaire was a modified Medical Questionnaire [74] by Minnesota Dental School. A well-trained and calibrated dental surgeon was responsible for completing the questionnaire and the intra-oral examination. The collected data included the medical/dental history of the participants, and epidemiological variables, such as age, gender, smoking status, educational and socio-economic status, etc. Participants’ age was classified as 45-50, 51-60, 61-70,71+, educational status as elementary level and graduated from University/College, socio-economic status as ≤ 1,000 and >1,000 €/month, and cigarette smoking status was categorized as never (individuals who smoked <100 cigarettes during their lifetime), and former (individuals who smoked at least 100 cigarettes in their lifetime and reported that they now smoke “not at all”)/current smokers (individuals who smoked at least 100 cigarettes in their life-time and reported they now smoke “every day” or “some days”).
The intra-examiner variance was assessed by a sample of 30 (20%) individuals that was chosen randomly and re-examined clinically by the same dentist after three weeks, and no significant differences were recorded between the 1st and the 2nd clinical examination (Cohen's Kappa = 0.95). During the mentioned time period no oral hygiene instructions were given to the participants.
The mentioned dental surgeon completed all periodontal examinations in a dental clinic using a Williams (with a controlled force of 0.2N DB764R, Aesculap AG &Co. KG,) periodontal probe, mouth mirror, dental light source, and tissue forceps. Third molars and remaining roots were excluded from scoring.
The oral and dental examination focused on periodontal health condition and included assessment of PPD, CAL, PlI, GI, and BOP as a measure of PD status. All PD indices were assessed at four sites per tooth (mesio-lingual, mesio-buccal, disto-lingual, and disto-buccal) in all four quadrants and the worst values of the indices recorded to the nearest 1.0 mm and coded as dichotomous variables.
PPD was classified as 0-3.00 mm (absence of disease/mild disease) and ≥ 4.0 mm (moderate and severe disease) for mean PPD [75], CAL severity was classified as mild, 1-2.0 mm of attachment loss and moderate/severe, ≥ 3.0 mm of attachment loss [76], and the number of missing teeth as none, 1-4, 5-10, >10 missing teeth [77]. Gingival inflammation was determined by the examination of four sites per tooth, and its severity was coded as follows:-score 0: healthy gingival tissue and/or mild gingival inflammation, that corresponds to Löe and Silness [78] classification as score 0 and 1, respectively, and -score 1: moderate/severe gingival inflammation that corresponds to the mentioned classification as score 2 and 3, respectively.
PlI, by Löe and Silness [79] was assessed by the same probe at the mentioned sites. The presence of dental plaque was determined whether it was visualized with naked eye or existed in abundance of soft matter within the gingival pocket and/or on the tooth and gingival margin (score 2 and 3, respectively, according to PlI) and considered as present if at least one site showed the characteristic sign.The presence/absence of BOP were recorded and coded as dichotomous variables.
Body Mass Index (BMI) is an obesity index and was classified as normal (<30 Kg/m2) and high (≥ 30 Kg/m2), and is considered as a risk factor for GBC development [80].
Statistical analysis
The univariate analysis model was carried out to assess the association between the independent indices examined and the GBC risk, separately. Categorical data were shown as frequencies and percentages. Cohort-related variables, including socio-demographic factors (age, income, education), comorbidities (GBC family history, increased BMI, chronic GB inflammation), self-reported questionnaire (smoking status, exposure to environmental pollutants, etc.), were analyzed using the univariate model. Multivariate logistic regression analysis was carried out to assess the associations between the dependent variable, GBC, and independent ones using the Enter method, whereas the Stepwise method was applied to assess the significant associations among the variables examined. Unadjusted and Adjusted Odds Ratios (OR's) and 95% (Confidence Interval) CI were also recorded.
Statistical analysis was performed by SPSS statistical package (SPSS PC20.0, SPSS, Inc., Chicago, IL, USA), and a p value less than 5% (p< 0.05) was considered to be statistically significant.
Results
The mean age of the sample was 59.6 ± 3.4 years. The univariate analysis is presented in Table 1 regarding the examined variables. Previous GB chronic inflammation (p=0.01) and dental plaque accumulation (PlI) (p=0.00) were found to be statistically significantly associated with the risk of developing GBC. Table 1 also presents the unadjusted OR’s and 95% CIs. According to the step 1a of the logistic regression model, the main findings were that previous GB chronic inflammation (p= 0.04), smoking (p= 0.05), and missing teeth more than four (p= 0.04, OR= 1.62,95% CI=1.19-3.36, p= 0.03, OR= 1,81, 95% CI= 1,31-3,95) were statistically significantly associated with the risk for GBC development.
|
Variables |
Cases No (%) |
Controls No (%) |
p-value |
Odds Ratio and 95% Confidence Interval |
|
Gender Males Females |
22 (44.9) 27 (55.1) |
58 (59.2) 40 (40.8) |
0.10
|
0.56 (0.28-1.12)
|
|
Age (years) 45-49 50-59 60-69 70+ |
8 (16.3) 12 (24.5) 21 (42.9) 8 (16.3) |
21 (21.4) 30 (30.6) 34 (34.7) 13 (13.3) |
0.65 |
______ |
|
Socio-economic status Low High |
27 (55.1) 22 (44.9) |
44 (44.9) 54 (55.1) |
0.24 |
1.51 (0.76-3.00) |
|
Education level Low High |
21 (42.9) 28 (57.1) |
40 (40.8) 58 (59.2) |
0.81 |
1.09 (0.54-2.18) |
|
Previous GB chronic inflammation Absence Presence |
19 (38.8) 30 (61.2) |
59 (60.2) 39 (39.8) |
0.01* |
0.42 (0.21-0.84)
|
|
Body Mass Index <30 kg/m2 ≥ 30 kg/m2 |
18 (36.7) 31 (63.3) |
52 (53.1) 46 (46.9) |
0.06 |
1.95 (0.96-3.93) |
|
GB family history Absence Presence |
20 (40.8) 29 (59.2) |
44 (44.9) 54 (55.1) |
0.64 |
1.18 (0.59-2.37) |
|
Smoking Never Previous/Current |
22 (44.9) 27 (55.1) |
51 (52.0) 47 (48.0) |
0.41 |
0.75 (0.38-1.50)
|
|
Occupational exposure (Mustard Oil, argemon oil) Yes (Butter yellow, heavy metals) No |
12 (24.5) 37 (75.5) |
19 (19.4) 79 (80.6) |
0.48 |
1.35 (0.59-3.07) |
|
Probing pocket depth 0-3.00 mm ≥ 4.0 mm |
20 (40.8) 29 (59.2) |
50 (51.0) 48 (49.0) |
0.24 |
0.66 (0.33-1.33) |
|
Clinical Attachment Loss Absence/Mild: 1.00-2.00 mm Moderate/Severe: ≥ 3.0 mm |
18 (36.7) 31 (63.3) |
47 (48.0) 51 (52.0) |
0.20 |
0.63 (0.31-1.27)
|
|
Gingival Index Absence/Mild Inflammation Moderate/Severe Inflammation |
16 (32.7) 33 (67.3) |
46 (46.9) 52 (53.1) |
0.10 |
0.55 (0.27-1.12) |
|
Plaque Index Absence Presence |
12 (24.5) 37 (75.5) |
48 (49.0) 50 (51.0) |
0.00* |
0.34 (0.16-0.72) |
|
Bleeding on probing Absence Presence |
20 (40.8) 29 (59.2) |
45 (45.9) 53 (54.1) |
0.56 |
1.23 (0.62-2.47) |
|
Tooth Loss None 1-4 Teeth 5-10 Teeth > 10 Teeth |
5 (10.2) 7 (14.3) 22 (44.9) 15 (30.6) |
8 (8.22) 21 (21.4) 42 (42.8) 27 (27.6) |
0.76 |
______ |
|
* p-value : statistically significant |
||||
Table 2 also presents adjusted ORs with 95% CIs and the final step 12a in which previous GB chronic inflammation (p=0.00), smoking (p= 0.05), gingival inflammation (p=0.05) and missing teeth more than four (p=0.03, OR=1.74,95% CI=1.30-3.75, p= 0.02, OR=2,03, 95% CI=1,67-4,11) were statistically significantly associated with the risk of developing GBC after adjusting for known confounders, smoking and socioeconomic status.
|
Variables in the Equation |
|||||||||
|
|
B |
S.E. |
Wald |
df |
Sig. |
Exp(B) |
95% C.I.for EXP(B) |
||
|
Lower |
Upper |
||||||||
|
Step 1a |
gender |
,351 |
,432 |
,662 |
1 |
,42 |
,70 |
,30 |
1,64 |
|
age.groups |
,112 |
,221 |
,079 |
1 |
,79 |
1,12 |
,49 |
2,15 |
|
|
socio.econ.st |
-,456 |
,425 |
1,154 |
1 |
,28 |
,63 |
,27 |
1,46 |
|
|
educ.level |
-,401 |
,429 |
,875 |
1 |
,35 |
,67 |
,29 |
1,55 |
|
|
chron.inflamm |
,853 |
,423 |
4,072 |
1 |
,04* |
2,35 |
1,03 |
5,37 |
|
|
body.mass.ind |
,270 |
,447 |
,364 |
1 |
,55 |
1,31 |
,55 |
3,15 |
|
|
family.history |
,168 |
,498 |
,135 |
1 |
,71 |
,85 |
,35 |
2,07 |
|
|
smok.status |
,634 |
,417 |
3,279 |
1 |
,05* |
1,40 |
1,21 |
2,53 |
|
|
occup.expos |
,580 |
,423 |
1,874 |
1 |
,17 |
1,80 |
,78 |
4,09 |
|
|
clin.att.loss |
,299 |
,417 |
,513 |
1 |
,47 |
1,35 |
,60 |
3,05 |
|
|
prob.pock.depth |
,222 |
,446 |
,248 |
1 |
,62 |
1,25 |
,52 |
2,99 |
|
|
plaque. index |
,288 |
,552 |
,272 |
1 |
,60 |
,75 |
,25 |
2,21 |
|
|
gingival.index |
1,302 |
,548 |
3,141 |
1 |
,07 |
1,22 |
1,11 |
2,57 |
|
|
bleed.on.prob |
,105 |
,553 |
,036 |
1 |
,850 |
1,11 |
,38 |
3,28 |
|
|
tooth.loss (none) |
|
|
3,581 |
3 |
,06* |
|
|
|
|
|
tooth loss (1-4) |
-,435 |
,298 |
4,882 |
1 |
,05* |
1,53 |
1,17 |
2,78 |
|
|
tooth loss (5-10) |
,502 |
,221 |
5,112 |
1 |
,04* |
1,62 |
1,19 |
3,36 |
|
|
tooth loss (>10) |
,544 |
,244 |
5,448 |
1 |
,03* |
1,81 |
1,31 |
3,95 |
|
|
Constant |
3,454 |
1,087 |
10,109 |
1 |
,00 |
,03 |
|
|
|
|
Step 12a |
smok.status |
,655 |
,502 |
3,502 |
1 |
,05* |
1,63 |
1,26 |
2,72 |
|
chron.inflamm |
1,237 |
,388 |
6,743 |
1 |
,00* |
2,74 |
1,28 |
5,86 |
|
|
gingival.index |
1,271 |
,426 |
4,891 |
1 |
,05* |
1,57 |
1,20 |
2,62 |
|
|
tooth.loss (none) |
|
|
4,992 |
3 |
,04* |
|
|
|
|
|
tooth.loss (1-4) |
-,481 |
,309 |
5,109 |
1 |
,03* |
1,68 |
1,27 |
3,02 |
|
|
tooth.loss (5-10) |
,513 |
,257 |
5,330 |
1 |
,03* |
1,74 |
1,30 |
3,75 |
|
|
tooth.loss (>10) |
,581 |
,258 |
5,731 |
1 |
,02* |
2,03 |
1,67 |
4,11 |
|
|
Constant |
3,732 |
,839 |
19,807 |
1 |
,00 |
,024 |
|
|
|
|
a. Variable(s) entered on step 1: gender, age.groups, socio.econ.st, educ.level, chron.infect, body.mass.ind, family.history, smok.status, occup.expos, clin.att.loss, prob.pock.depth, ging.index, plaque.index, bleed.on.prob, tooth.loss. |
|||||||||
Discussion
PD as a chronic infectious disease has been associated with diverse systemic diseases and disorders [81-84]. Epidemiological studies have suggested an association between periodontitis, tooth loss and the risk of cancers in diverse organs such as head and neck region, upper gastrointestinal system, pancreas, lungs, etc. [58,59,85-96]. However, those associations have little practical significance as prevention indices [85], even though useful aspects have been provided on the role of PD treatment in decreasing the risk of different types of cancers [97].
The outcomes of the current research showed that GB chronic inflammation, smoking, gingival inflammation, and missing teeth more than four were statistically significantly associated with the risk for developing GBC.
GBC appearance, as already mentioned, has been associated with diverse genetic and environmental factors.
Gender is a known cancer risk factor; however it is considered as a confounder. The results revealed no association between gender and GBC risk, finding that was not in accordance with those from previous reports [13,98]. It is also known that older individuals are in a higher risk for total cancer [13,99], PD initiation and progression [100], however age is also considered as a confounder. No association was recorded between age and GBC risk in the current study.
Other crucial confounders are socio-economic status and educational level; however, it has been proven that their possible role in other types of cancer. Socioeconomic patterns in all-cancer, and cancer mortality have been changed dramatically over time. Individuals with lower education and income status showed higher mortality and incidence rates than the more well-off ones, with a high risk being particularly significant for gastric, lung, cervical, liver, and colorectal cancer [101]. In the present research no associations were recorded between those variables and GBC risk.
GBC family history was not found to be significantly associated with the GBC risk, finding that was not in accordance with those from previous reports [102,103].
Obesity and increased BMI have been linked with many types of cancer including breast, colorectal, prostate, GBC, etc. [16,17,104]. The present research did not confirm such an association.
Chronic inflammation-cholecystitis and porcelain gallbladder is an essential independent etiological factor for GBC development [26], finding that was in accordance with the current study.
Smoking is a causal risk factor of total cancer [105]. Several carcinogenic compounds in tobacco such as polycyclic aromatic hydrocarbons (PAH), arylamines and nitrosamines, are factors responsible for carcinogenesis. In addition, exposure to tobacco smoke has been linked with mutational or epigenetic alterations in cellular signaling pathways, which are involved in GBC pathogenesis [34]. The current study confirmed its role as a causal risk factor.
Other dependent etiological factors concern environmental exposure to specific chemicals and heavy metals [29-33]. No associations were found in the current survey between those etiological factors and the risk for GBC development.
Among the PD indices examined, GI was found to be statistically significantly associated with the risk for GBC development. GI expresses the gingival inflammation severity, however that index is not frequently used in epidemiological studies despite the fact that assesses the gingival tissue inflammatory load. Previous reports suggested a special role for gingival inflammation as a risk factor for diverse types of cancer [106,107], whereas similar studies recorded no associations [108-110].
PPD assesses PD severity [111], and the outcomes showed that was not statistically significantly associated with the risk for GBC development. In the literature, only one study has investigated the examined association, and revealed a significantly greater risk of GBC diagnosis among individuals who self?reported a history of PD compared with those with no PD history (HR=1.73, 95% CI=1.01?2.95). However, in never?smokers, the association was significantly reduced (HR= 1.26, 95% CI= 0.59?2.68) [44].
CAL is a crucial index of cumulative tissue destruction, including previous PD, whereas PPD is an indicator of current disease status inflammation [112]. The outcomes showed no association between CAL and the risk for GBC development. Previous studies recorded associations between CAL and other types of cancers [113,114]. PPD and CAL concern the chronic inflammation long-term stages including destructive processes signs of a chronic inflammatory response [115].
BOP is an essential index of periodontal examination and diagnosis, and the most valid PD activity indicator [116]. It expresses the host’s vascular response in relation to hyperemia, the capillaries’ dilation and enhanced blood flow in the inflammation region, and it is a widely used criterion to diagnose gingival inflammation [116]. No statistically significantly association was observed concerning BOP between cases and controls, finding that was in accordance with a similar previous research [114].
PlI assesses dental plaque accumulation. In a previous study it was found that poor oral hygiene, as reflected in the amount of dental plaque, was associated with increased cancer mortality, as based on the findings, the high bacterial load on tooth surfaces and in gingival pockets over a prolonged time could play a role in carcinogenesis [117]. No association between PlI and risk for GBC was recorded in the current study. Similar results were observed in previous reports [118,119], whereas Zhang et al. [120] suggested that poor oral health was associated with higher risks of total cancer incidence and diverse site-specific cancers except for GBC.
Tooth loss is the final result of advanced periodontitis. A number of prospective reports have recorded an association between the number of missing teeth and the risk of cancer in various locations [42,110,121]. Similarly, case-control studies have revealed strong associations for tooth loss and oral [122,123], esophageal [124], upper gastro-intestinal [125], gastric [126], pancreatic [127] and lung [41,106,122] cancers.
The mechanisms that are responsible for cancer development among PD patients are not entirely clear. A number of plausible mechanisms have been suggested and inflammation appears to play a significant role in many of those. Moreover, inflammation is a crucial cancer hallmark as is necessary for malignant transformation [62].
PD is a prototype inflammation process that induces chronic low?grade inflammation if left untreated, and a persistent low?grade inflammation has been associated with cancer [127-130]. Persistent chronic periodontitis leads to alterations in the mononuclear cell?cytokine system resulting in a much stronger inflammatory response than common exposure to bacterial stimuli such as lipopolysaccharide (LPS) [130,131]. Genetic polymorphisms of inflammatory cytokines may contribute to susceptibility to [128] carcinogenesis. Chronic periodontitis patients have an inherent defect in their immune system, particularly in relation to bacterial clearance and tumor immune surveillance [132], that may increase their susceptibility to cancer.
On the other hand, GBC is a critical model for understanding inflammation-associated carcinogenesis, since gallstones can result in GB inflammation [133]. Another suggested GBC risk factor, infection caused by Salmonella enterica serovariant Typhi, has also an inflammatory component [134], as circulating inflammatory biomarkers, cytokines and chemokines have been associated with GBC development [135-138], however that association requires further investigation [138].
The human flora appears to play an essential role in normal physiological functions [139], and in carcinogenesis [140]. In the normal oral cavity, more than 700 types of bacteria live, among which red complex is responsible for PD [141]. The red complex consists of P. gingivalis, T. forsythia, and T. denticola [141]. Those Gram-negative anaerobic bacteria are able to release virulence factors to interfere in the host’s defense system and destroy periodontal tissue and host’s immune system [141]. The subgingival biofilms in periodontitis act as gram?negative anaerobic bacteria reservoirs of P. gingivalis and A. actinomycetemcomitans [142], that release enzymes and invade to gingival epithelial cells [143]. Those enzymes and other bacterial components such as endotoxins, and metabolic by?products that are toxic to tissues, may cause direct damage to DNA of the surrounding epithelial cells, or are able to induce mutations in proto?oncogenes and tumor suppressor genes, or interfere with the molecular signaling pathways involved in cell survival and/or proliferation [144]. P. gingivalisis a periopathogenic bacterium that mediates the local inflammatory response of periodontitis [145], interferes with physiological metabolism, invades gingival epithelial cells, and inhibits apoptosis [146], that is a cancer hallmark [147]. Previous reports have recorded an association between P. gingivalis and digestive tract cancer [148,149].
A large amount of gram?negative anaerobic bacteria in individuals with periodontitis has been revealed in the periodontal pockets [149] and may become detached and be micro?aspirated or ingested. Although the release into the blood circulation of those oral bacteria is not permanent, periodontal pathogens such as P. gingivalis can evade their destruction by phagocytes via protease release [150]. The bacterium can further evade their destruction by regulating Th2?cell?mediated, anti?inflammatory responses to favor M2 macrophage phenotype production, that are less capable of destroying them [151]. Dendritic cells cannot destroy P. gingivalis, therefore allowing those to reach distant organs [152]. It is evident that P. gingivalis could survive within the systemic blood circulation and remain viable enough to reach remote regions and cause deleterious effects. That theory has been supported by the observation that periodontal pathogens have been revealed in many body locations except the oral cavity such as blood vessels, atheromatous plaques [153], lung aspirates [154], lymph nodes [155], pericardial fluid [156], liver [157], tonsils [158], spinal infections [159] and the appendix [160]. Periodontal pathogens have also been detected in gastric precancerous lesions [161], in colorectal adenomas [162] and certain cancers such as colorectal [162,163], oral [164], esophageal, and gastric cancers [165,166].
Periodontitis has been linked to a number of immune-inflammatory diseases, some of which are independently associated with increased risk of malignancies [167]. Pro-inflammatory cytokines, such as IL-1, IL-6, IL-8, IL-13 and TNF-α, are up-regulated in periodontitis, stimulate cellular proliferation, remodel the extracellular matrix, and activate immune cells [168]. The protumorigenic function of TNF-α and IL-6 mediated through the transcription nuclear factor NF-κB leading to stimulation of cell proliferation and survival . NF-κB also controls the expression of many genes associated with inflammation and therefore is involved in a feed-forward loop by driving inflammation that results in further NF-κB activation. It is a critical mediator in any chronic inflammation, including periodontitis, and carcinogenesis [169].
PD is also often accompanied by increasing levels of inflammatory biomarkers in blood circulation, as already mentioned [170], such as Il-6, TNF-α, and prostaglandin E2 (PGE2), in response to periodontal inflammation and are responsible for systemic effects at remote body locations [171]. The local immune mediators activated as a consequence of periodontal infection, in blood circulation, may lead to the production of large amounts of acute?phase proteins such as serum C?reactive protein (C-rp), a systemic inflammation biomarker and other systemic inflammatory mediators, such as histamine and serotonin, bradykinin, eicosanoids such as thromboxanes, leukotrienes, and PGs [171]. Increased levels of C-rp have been associated with PD [171-174], and periodontal pathogens [173?176], whereas increased serum C?rp levels have been also associated with increased risk of precursor lesions [177] and diverse types of cancers [178,179]. In addition, pathogenic bacteria can enter the blood circulation [180], and they are associated with diverse systemic diseases, disorders and cancers [181]. In the blood circulation periodontal bacteria may cause damage via their LPS component, by inducing either a systemic [182] or a local inflammatory response at the site where they colonize.
Reactive oxygen species (ROS) and reactive nitrogen species (RNI) are free radicals, produced by normal cellular metabolism, and act as a protective mechanism against bacterial pathogens by direct effects and through recruitment of innate immune response cells [183]. In high concentration, free radicals induce tissue destruction through DNA damage and lipid and protein peroxidation [184]. Abnormal host responses to the microbial infection observed in periodontitis lead to excess ROS and RNI production in periodontal tissues [184], and this is partly mediated by pro-inflammatory cytokines. As free radical concentration increases in the periodontal tissues, ROS and RNI diffuse into the blood circulation, leading to increased oxidative and nitrosative stress and eventually distant tissue/organ damage [184]. ROS and RNI production results in a signaling cascade that triggers the pro-inflammatory cytokines and chemokines production thereby up-regulating systemic inflammation [185]. Oxidative stress from other inflammation causes, including smoking, toxins, diabetes, and obesity, also impact on the periodontitis progression. Free radicals contribute to carcinogenesis by the up-regulation of systemic inflammation or by direct DNA damage, which can lead to events associated with carcinogenesis such as genomic instability, transcriptional arrest, and replication errors. Eventually, ROS at very low and impermanent levels seem to increase cell proliferation, survival and migration and may therefore impact on tumor progression [186].
Epigenetic alterations leading to hypermethylation of E?cadherin and cyclooxygenase?2 have been associated with chronic periodontitis and may be associated with increased cancer risk [187]. Epigenetic mechanisms are implicated in normal development; however, epigenetic process disruption has been observed to play a crucial role in oncogenesis. Epigenetic alterations in cancer concern DNA methylation, histone modifications, non-coding RNAs, and nucleosome positioning [188]. Epigenetics has not been extensively investigated in periodontitis, however, there is some evidence that epigenetic alterations play a role in the development of periodontitis [189]. An increase in E-cadherin and cyclooxygenase-2 gene hypermethylation is implicated in tumor growth and metastasis [190]. Similarly, it has been found that P. gingivalis can induce DNA methylation in normal gingival epithelial cells, finding confirmed in mice infected with P. gingivalis and in human periodontal tissues obtained from individuals with periodontitis [191]. Periodontal bacteria involved in metabolic processes, produce several chemical products that can influence tumorigenesis and tumor progression. Nitrosamines have been involved in the development of human cancers for over 40 years and this is considered to be mediated through direct damage to DNA [192]. Nitrosamines dietary sources such as preserved and cured aliments have been involved in nasopharyngeal, esophageal, gastric, pancreatic and colorectal cancers although the data supporting that association remains inconclusive and controversial [193].
Acetaldehyde is the main oxidation product of ethanol. In vitro and in vivo studies have shown that has mutagenic and carcinogenic effects through genetic events, such as inducing point mutations and chromosomal aberrations and interfering with DNA repair. Those effects are mediated directly by covalent binding to DNA and indirectly through folate catabolisation, with reduced folate levels resulting in DNA hypomethylation, an event that has been observed in many human cancers [194]. It has been suggested that acetaldehyde is a local carcinogen in humans, and oral bacteria such as Neisseria, Streptococcus and Prevotellaspecies are capable of metabolizing ethanol to acetaldehyde [195].
Some interfering factors should be taken into account in interpretation of the observed outcomes regarding the relation between PD and cancer, in general. Those studies have used different criteria in the definition and measurement of PD. Some used the common PD indices, such as PPD, GI, CAL, tooth loss and others based on patient history, self-questionnaires, clinical, and radiographic findings as criteria for PD patients [196]. It must also be taken into account that teeth can be lost due to trauma, caries, or PD. Therefore, it is difficult to eliminate trauma and caries as possible confounders [123].
Strengths of the current research are the follow-up completeness, the well-characterized cohort that it was possible to examine both confounding and interaction by known risk factors, in order to avoid referring secondary biased associations. Another essential aspect is PD definition by oral clinical examination and not by self-reported questionnaires, therefore no possible misclassification of exposure to PD exists that may result in the underestimation of the association investigated.
A potential limitation is the possibility of confounding in estimates of risk caused by additional unknown confounders. Moreover, some environmental factors also seem to be confounders among those studies [197]. Those variables are age, gender, genetic, educational, and socioeconomic status as are considered as risk factors for both diseases. Actually, research studies which are adjusted for those variables can be used for the estimation of PD as an independent risk factor of cancer [90].
Conclusions
In conclusion, smokers and individuals with chronic GB inflammation, gingival inflammation and with missing teeth more than four were at significantly higher risk for GBC development. Those associations remained after controlling for certain confounders such as smoking status and SES.
Conflict of Interest
The authors declare that they have no conflict of interests.
Funding
The study was self-funded by the author and co-authors.
References
2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA: a Cancer Journal for Clinicians. 2007 Jan;57(1):43-66.
3. Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clinical Epidemiology. 2014 Mar 7:99-109.
4. Shaffer EA. Gallbladder cancer: the basics. Gastroenterology & Hepatology. 2008 Oct;4(10):737-41.
5. Andia ME, Hsing AW, Andreotti G, Ferreccio C. Geographic variation of gallbladder cancer mortality and risk factors in Chile: a population-based ecologic study. International Journal of Cancer. 2008 Sep 15;123(6):1411-6.
6. Sharma A, Sharma KL, Gupta A, Yadav A, Kumar A. Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update. World Journal of Gastroenterology. 2017 Jun 6;23(22):3978-98.
7. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nature Reviews Disease Primers. 2017 Jun 22;3(1):1-4.
8. Highfield J. Diagnosis and classification of periodontal disease. Australian Dental Journal. 2009 Sep;54:S11-26.
9. Peres MA, Macpherson LM, Weyant RJ, Daly B, Venturelli R, Mathur MR, et al. Oral diseases: a global public health challenge. The Lancet. 2019 Jul 20;394(10194):249-60.
10. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990-2010: a systematic review and meta-regression. Journal of Dental Research. 2014 Nov;93(11):1045-53.
11. GBD 2017 Oral Disorders Collaborators, Bernabe E, Marcenes W, Hernandez CR, Bailey J, Abreu LG, et al. Global, regional, and national levels and trends in burden of oral conditions from 1990 to 2017: a systematic analysis for the global burden of disease 2017 study. Journal of Dental Research. 2020 Apr;99(4):362-73.
12. Eke PI, Thornton-Evans GO, Wei L, Borgnakke WS, Dye BA, Genco RJ. Periodontitis in US adults: national health and nutrition examination survey 2009-2014. The Journal of the American Dental Association. 2018 Jul 1;149(7):576-88.
13. Lazcano‐Ponce EC, Miquel JF, Muñoz N, Herrero R, Ferrecio C, Wistuba II, et al. Epidemiology and molecular pathology of gallbladder cancer. CA: A Cancer Journal for Clinicians. 2001 Nov;51(6):349-64.
14. Hsing AW, Bai Y, Andreotti G, Rashid A, Deng J, Chen J, et al. Family history of gallstones and the risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. International Journal of Cancer. 2007 Aug 15;121(4):832-8.
15. Jain K, Sreenivas V, Velpandian T, Kapil U, Garg PK. Risk factors for gallbladder cancer: a case–control study. International Journal of Cancer. 2013 Apr 1;132(7):1660-6.
16. Park M, Je Y, Lee JE. Body mass index and biliary tract disease: a systematic review and meta-analysis of prospective studies. Preventive Medicine. 2014 Aug 1;65:13-22.
17. Larsson SC, Wolk A. Obesity and the risk of gallbladder cancer: a meta-analysis. British Journal of Cancer. 2007 May;96(9):1457-61.
18. Kimura W, Miyata R, Takahashi T, Yamashiro M. Simultaneous development of gallbladder and bile duct carcinomas with atypical epithelium intervention: a case report. Japanese Journal of Clinical Oncology. 1989 Sep 1;19(3):287-93.
19. Stephen AE, Berger DL. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery. 2001 Jun 1;129(6):699-703.
20. Iyer P, Barreto SG, Sahoo B, Chandrani P, Ramadwar MR, Shrikhande SV, et al. Non-typhoidal Salmonella DNA traces in gallbladder cancer. Infectious Agents and Cancer. 2016 Dec;11:12.
21. Nath G, Gulati AK, Shukla VK. Role of bacteria in carcinogenesis, with special reference to carcinoma of the gallbladder. World Journal of Gastroenterology: WJG. 2010 Nov 11;16(43):5395-404.
22. Scanu T, Spaapen RM, Bakker JM, Pratap CB, Wu LE, Hofland I, et al. Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma. Cell Host & Microbe. 2015 Jun 10;17(6):763-74.
23. Hassan EH, Gerges SS, El-Atrebi KA, El-Bassyouni HT. The role of H. pylori infection in gall bladder cancer: clinicopathological study. Tumor Biology. 2015 Sep;36:7093-8.
24. Wiles R, Varadpande M, Muly S, Webb J. Growth rate and malignant potential of small gallbladder polyps-systematic review of evidence. The Surgeon. 2014 Aug 1;12(4):221-6.
25. Tanaka K, Ikoma A, Hamada N, Nishida S, Kadono J, Taira A. Biliary tract cancer accompanied by anomalous junction of pancreaticobiliary ductal system in adults. The American Journal of Surgery. 1998 Mar 1;175(3):218-20.
26. Moerman CJ, Berns MP, de Messqita HB, Runia S. Reproductive history and cancer of the biliary tract in women. International Journal of Cancer. 1994 Apr 15;57(2):146-53.
27. Dhiman RK, Chawla YK. Is there a link between oestrogen therapy and gallbladder disease?. Expert Opinion on Drug Safety. 2006 Jan 1;5(1):117-29.
28. Pilgrim CH, Groeschl RT, Christians KK, Gamblin TC. Modern perspectives on factors predisposing to the development of gallbladder cancer. Hpb. 2013 Nov 1;15(11):839-44.
29. Pandey M. Environmental pollutants in gallbladder carcinogenesis. Journal of Surgical Oncology. 2006 Jun 15;93(8):640-3.
30. Shukla VK, Rastogi AN, Adukia TK, Raizada RB, Reddy DC, Singh S. Organochlorine pesticides in carcinoma of the gallbladder: a case-control study. European Journal of Cancer Prevention. 2001 Apr 1;10(2):153-6.
31. Mishra V, Mishra M, Ansari KM, Chaudhari BP, Khanna R, Das M. Edible oil adulterants, argemone oil and butter yellow, as aetiological factors for gall bladder cancer. European Journal of Cancer. 2012 Sep 1;48(13):2075-85.
32. Shim KY, Cha SW, Um WH, Chun CG, Jeong SW, Jang JY, et al. Simultaneous occurrence of gallbladder cancer in a laundry couple: association between gallbladder cancer and benzene. The Korean Journal of Gastroenterology. 2013 Feb 1;61(2):107-9.
33. Shukla VK, Shukla PK, Pandey M, Rao BR, Roy SK. Lipid peroxidation product in bile from patients with carcinoma of the gallbladder: a preliminary study. Journal of Surgical Oncology. 1994 Aug;56(4):258-62.
34. Yen S, Hsieh CC, Macmahon B. Extrahepatic bile duct cancer and smoking, beverage consumption, past medical history, and oral-contraceptive use. Cancer. 1987 Jun 15;59(12):2112-6.
35. Serra I, Yamamoto M, Calvo A, Cavada G, Báez S, Endoh K, et al. Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population. International Journal of Cancer. 2002 Dec 1;102(4):407-11.
36. Benbow EW. Xanthogranulomatous cholecystitis. Br J Surg. 1990 Mar;77(3):255-6.
37. Gowda GN. Human bile as a rich source of biomarkers for hepatopancreatobiliary cancers. Biomarkers in Medicine. 2010 Apr;4(2):299-314.
38. Srivastava K, Srivastava A, Sharma KL, Mittal B. Candidate gene studies in gallbladder cancer: a systematic review and meta-analysis. Mutation Research/Reviews in Mutation Research. 2011 Jul 1;728(1-2):67-79.
39. Herrera D, Molina A, Buhlin K, Klinge B. Periodontal diseases and association with atherosclerotic disease. Periodontology 2000. 2020 Jun;83(1):66-89.
40. Bobetsis YA, Graziani F, Gürsoy M, Madianos PN. Periodontal disease and adverse pregnancy outcomes. Periodontology 2000. 2020 Jun;83(1):154-74.
41. Nwizu N, Wactawski‐Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontology 2000. 2020 Jun;83(1):213-33.
42. Michaud DS, Liu Y, Meyer M, Giovannucci E, Joshipura K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. The Lancet Oncology. 2008 Jun 1;9(6):550-8.
43. Arora M, Weuve J, Fall K, Pedersen NL, Mucci LA. An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study. American Journal of Epidemiology. 2010 Jan 15;171(2):253-9.
44. Nwizu NN, Marshall JR, Moysich K, Genco RJ, Hovey KM, Mai X, et al. Periodontal disease and incident cancer risk among postmenopausal women: results from the women's health initiative observational cohort. Cancer Epidemiology, Biomarkers & Prevention. 2017 Aug 1;26(8):1255-65.
45. Michaud DS, Kelsey KT, Papathanasiou E, Genco CA, Giovannucci E. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study. Annals of Oncology. 2016 May 1;27(5):941-7.
46. Michaud DS, Fu Z, Shi J, Chung M. Periodontal disease, tooth loss, and cancer risk. Epidemiologic Reviews. 2017 Jan 1;39(1):49-58.
47. Michaud DS, Lu J, Peacock-Villada AY, Barber JR, Joshu CE, Prizment AE, et al. Periodontal disease assessed using clinical dental measurements and cancer risk in the ARIC study. JNCI: Journal of the National Cancer Institute. 2018 Aug 1;110(8):843-54.
48. Federico A, Morgillo F, Tuccillo C, Ciardiello F, Loguercio C. Chronic inflammation and oxidative stress in human carcinogenesis. International Journal of Cancer. 2007 Dec 1;121(11):2381-6.
49. Vidal F, Figueredo CM, Cordovil I, Fischer RG. Periodontal therapy reduces plasma levels of interleukin‐6, C‐reactive protein, and fibrinogen in patients with severe periodontitis and refractory arterial hypertension. Journal of Periodontology. 2009 May;80(5):786-91.
50. Demmer RT, Trinquart L, Zuk A, Fu BC, Blomkvist J, Michalowicz BS, et al. The influence of anti-infective periodontal treatment on C-reactive protein: a systematic review and meta-analysis of randomized controlled trials. PloS One. 2013 Oct 14;8(10):e77441.
51. Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. The Lancet Oncology. 2012 May 1;13(5):518-27.
52. Flossmann E. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial: Effect of aspirin on long-term risk of colorectal cancer: Consistent evidence from randomised and observational studies. Lancet. 2007;369:1603-13.
53. Curtis MA, Diaz PI, Van Dyke TE. The role of the microbiota in periodontal disease. Periodontology 2000. 2020 Jun;83(1):14-25.
54. Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology. 2021 Jul;21(7):426-40.
55. Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nature Reviews Microbiology. 2014 Oct;12(10):661-72.
56. Helmink BA, Khan MW, Hermann A, Gopalakrishnan V, Wargo JA. The microbiome, cancer, and cancer therapy. Nature Medicine. 2019 Mar;25(3):377-88.
57. Eliot MN, Michaud DS, Langevin SM, McClean MD, Kelsey KT. Periodontal disease and mouthwash use are risk factors for head and neck squamous cell carcinoma. Cancer Causes & Control. 2013 Jul;24:1315-22.
58. Zeng XT, Xia LY, Zhang YG, Li S, Leng WD, Kwong JS. Periodontal disease and incident lung cancer risk: a meta-analysis of cohort studies. Journal of Periodontology. 2016 Oct;87(10):1158-64.
59. Maisonneuve P, Amar S, Lowenfels AB. Periodontal disease, edentulism, and pancreatic cancer: a meta-analysis. Annals of Oncology. 2017 May 1;28(5):985-95.
60. Sun J, Zhou M, Salazar CR, Hays R, Bedi S, Chen Y, et.al. Chronic periodontal disease, periodontal pathogen colonization, and increased risk of precancerous gastric lesions. Journal of Periodontology. 2017 Nov;88(11):1124-34.
61. Koliarakis I, Messaritakis I, Nikolouzakis TK, Hamilos G, Souglakos J, Tsiaoussis J. Oral bacteria and intestinal dysbiosis in colorectal cancer. International Journal of Molecular Sciences. 2019 Aug 25;20(17):4146.
62. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. cell. 2011 Mar 4;144(5):646-74.
63. Hanahan D, Weinberg RA. The hallmarks of cancer. cell. 2000 Jan 7;100(1):57-70.
64. Yamashita Y, Takeshita T. The oral microbiome and human health. Journal of Oral Science. 2017;59(2):201-6.
65. WHO International Agency for Research in Cancer, WHO: Globocan, 2020
66. World Health Organization. Oral health surveys: basic methods. World Health Organization; 2013.
67. Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classification and case definition. J Clin Periodontol. 2018 Jun;45:S149-S161.
68. Machuca G, Segura-Egea JJ, Jiménez-Beato G, Lacalle JR, Bullón P. Clinical indicators of periodontal disease in patients with coronary heart disease: A 10 years longitudinal study. Medicina oral, patologia oral y cirugia bucal. 2012 Jul;17(4):e569-74.
69. Reichert S, Stein J, Gautsch A, Schaller HG, Machulla HK. Gender differences in HLA phenotype frequencies found in German patients with generalized aggressive periodontitis and chronic periodontitis. Oral Microbiology and Immunology. 2002 Dec;17(6):360-8.
70. Lavstedt S, Bolin A, Henrikson CO. Proximal alveolar bone loss in a longitudinal radiographic investigation: II. A 10-year follow-up study of an epidemiologic material. Acta Odontologica Scandinavica. 1986 Jan 1;44(4):199-205.
71. Tonetti MS. Advances in the progression of periodontitis and proposal of definitions of a periodontal case and disease progression for use in risk factor research. Group C consensus report of the 5^< th> European workshop in periodontology. J Clin Periodontol. 2005;32(6):210-3.
72. Loos BG, John RP, Laine ML. Identification of genetic risk factors for periodontitis and possible mechanisms of action. Journal of Clinical Periodontology. 2005 Oct;32:159-79.
73. Ahmed O, Mathevosian S, Arslan B. Biliary interventions: tools and techniques of the trade, access, cholangiography, biopsy, cholangioscopy, cholangioplasty, stenting, stone extraction, and brachytherapy. InSeminars in interventional radiology. Thieme Medical Publishers. 2016 Dec; 33(04):283-90.
74. Molloy J, Wolff LF, Lopez‐Guzman A, Hodges JS. The association of periodontal disease parameters with systemic medical conditions and tobacco use. Journal of Clinical Periodontology. 2004 Aug;31(8):625-32.
75. Cutress TW, Ainamo J, Sardo-Infirri J. The community periodontal index of treatment needs (CPITN) procedure for population groups and individuals. International Dental Journal. 1987 Dec 1;37(4):222-33.
76. Wiebe CB, Putnins EE. The periodontal disease classification system of the American Academy of Periodontology-an update. Journal-Canadian Dental Association. 2000 Dec 1;66(11):594-7.
77. Yoon HS, Wen W, Long J, Zheng W, Blot WJ, Cai Q. Association of oral health with lung cancer risk in a low-income population of African Americans and European Americans in the Southeastern United States. Lung Cancer. 2019 Jan 1;127:90-5.
78. Löe H. The gingival index, the plaque index and the retention index systems. The Journal of Periodontology. 1967 Nov;38(6):610-6.
79. Silness J, Loe HA. Periodontal disease in pregnancy. Acta Odontol. Scand.. 1964;22:121-35.
80. Aurilio G, Piva F, Santoni M, Cimadamore A, Sorgentoni G, Lopez-Beltran A, et.al. The role of obesity in renal cell carcinoma patients: clinical-pathological implications. International Journal of Molecular Sciences. 2019 Nov 13;20(22):5683.
81. Blaizot A, Vergnes JN, Nuwwareh S, Amar J, Sixou M. Periodontal diseases and cardiovascular events: meta-analysis of observational studies. International Dental Journal. 2009 Aug 1;59(4):197-209.
82. de Oliveira Ferreira R, de Brito Silva R, Magno MB, Carvalho Almeida AP, Fagundes NC, Maia LC, Lima RR. Does periodontitis represent a risk factor for rheumatoid arthritis? A systematic review and meta-analysis. Therapeutic Advances in Musculoskeletal Disease. 2019 Jul;11:1759720X19858514.
83. Moghadam SA, Shirzaiy M, Risbaf S. The associations between periodontitis and respiratory disease. J Nepal Health Res Counc. 2017; 15(35): 1-6.
84. Helenius‐Hietala J, Suominen AL, Ruokonen H, Knuuttila M, Puukka P, Jula A, Meurman JH, et.al. Periodontitis is associated with incident chronic liver disease—a population‐based cohort study. Liver International. 2019 Mar;39(3):583-91.
85. Fitzpatrick SG, Katz J. The association between periodontal disease and cancer: a review of the literature. Journal of Dentistry. 2010 Feb 1;38(2):83-95.
86. Yin XH, Wang YD, Luo H, Zhao K, Huang GL, Luo SY, et.al. Association between tooth loss and gastric cancer: a meta-analysis of observational studies. PloS One. 2016 Mar 2;11(3):e0149653.
87. Zeng XT, Deng AP, Li C, Xia LY, Niu YM, Leng WD. Periodontal disease and risk of head and neck cancer: a meta-analysis of observational studies. PloS One. 2013 Oct 23;8(10):e79017.
88. Ahn J, Segers S, Hayes RB. Periodontal disease, Porphyromonas g ingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis. 2012 May 1;33(5):1055-8.
89. Linden GJ, Lyons A, Scannapieco FA. Periodontal systemic associations: review of the evidence. Journal of Periodontology. 2013 Apr;84:S8-19.
90. Hiraki A, Matsuo K, Suzuki T, Kawase T, Tajima K. Teeth loss and risk of cancer at 14 common sites in Japanese. Cancer Epidemiology Biomarkers & Prevention. 2008 May 1;17(5):1222-7.
91. Chen H, Nie S, Zhu Y, Lu M. Teeth loss, teeth brushing and esophageal carcinoma: a systematic review and meta-analysis. Scientific Reports. 2015 Oct 14;5(1):15203.
92. Corbella S, Veronesi P, Galimberti V, Weinstein R, Del Fabbro M, Francetti L. Is periodontitis a risk indicator for cancer? A meta-analysis. PloS One. 2018 Apr 17;13(4):e0195683.
93. Ma P, Dai S, Jin C, Yao Y, Zou C. Tooth loss and risk of colorectal cancer: a dose–response meta-analysis of prospective cohort studies. OncoTargets and Therapy. 2018 Mar 21:1617-23.
94. Yao QW, Zhou DS, Peng HJ, Ji P, Liu DS. Association of periodontal disease with oral cancer: a meta-analysis. Tumor Biology. 2014 Jul;35:7073-7.
95. Thistle JE, Yang B, Petrick JL, Fan JH, Qiao YL, Abnet CC, et.alS. Association of tooth loss with liver cancer incidence and chronic liver disease mortality in a rural Chinese population. PLoS One. 2018 Sep 17;13(9):e0203926.
96. Sakai H, Yamada SI, Gibo T, Yoshimura N, Nishimaki F, Kondo E, et.al. A retrospective analysis of the prevalence of dental diseases in patients with digestive system cancers. Medicine. 2019 Mar;98(13):e14771.
97. Hwang IM, Sun LM, Lin CL, Lee CF, Kao CH. Periodontal disease with treatment reduces subsequent cancer risks. QJM: An International Journal of Medicine. 2014 Oct 1;107(10):805-12.
98. Jackson SS, Adami HO, Andreotti G, Beane-Freeman LE, de Gonzalez AB, Buring JE, et.al. Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project. Journal of Hepatology. 2020 Oct 1;73(4):863-72.
99. Estape T. Cancer in the elderly: challenges and barriers. Asia-Pacific Journal of Oncology Nursing. 2018 Jan 1;5(1):40-2
100. Nazir MA. Prevalence of periodontal disease, its association with systemic diseases and prevention. International Journal of Health Sciences. 2017 Apr;11(2):72-80.
101. Singh GK, Jemal A. Socioeconomic and racial/ethnic disparities in cancer mortality, incidence, and survival in the United States, 1950-2014: over six decades of changing patterns and widening inequalities. Journal of Environmental and Public Health. 2017 Oct;2017:2819372.
102. Rawla P, Sunkara T, Thandra KC, Barsouk A. Epidemiology of gallbladder cancer. Clinical and Experimental Hepatology. 2019 May 23;5(2):93-102.
103. Chung SD, Tsai MC, Huang CC, Kao LT, Chen CH. A population-based study on the associations between chronic periodontitis and the risk of cancer. International Journal of Clinical Oncology. 2016 Apr;21:219-23.
104. Arnold M, Pandeya N, Byrnes G, Renehan AG, Stevens GA, Ezzati M, et al. Global burden of cancer attributable to high body-mass index in 2012: a population-based study. The lancet Oncology. 2015 Jan 1;16(1):36-46.
105. Dimou N, Yarmolinsky J, Bouras E, Tsilidis KK, Martin RM, Lewis SJ, et al. Causal effects of lifetime smoking on breast and colorectal cancer risk: Mendelian Eandomization Study. Cancer Epidemiology, Biomarkers & Prevention. 2021 May 1;30(5):953-64.
106. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the Periodontitis–Cancer Association. Annals of Epidemiology. 2003 May 1;13(5):312-6.
107. Beger-Luedde J, Loosen SH, Luedde T, Roderburg C, Kostev K. Association between Chronic Gingivitis and Cancer: A Retrospective Cohort Study of 19,782 Outpatients from the United Kingdom. Cancers. 2023 Mar 28;15(7):2007.
108. Meurman JH, Källmén H, Andersson LC, Yucel-Lindberg T, Söder B. Prevalence of cancer in relation to signs of periodontal inflammation. Plos one. 2022 Oct 21;17(10):e0276375.
109. Wen BW, Tsai CS, Lin CL, Chang YJ, Lee CF, Hsu CH, et al. Cancer risk among gingivitis and periodontitis patients: a nationwide cohort study. QJM: An International Journal of Medicine. 2014 Apr 1;107(4):283-90.
110. Virtanen E, Söder PÖ, Meurman JH, Andersson LC, Söder B. Chronic periodontal disease: a Proxy of Increased Cancer Risk. Int J Cancer Res. 2013 Apr;47(1):1127-33.
111. Papapanou PN. Periodontal diseases: epidemiology. Annals of Periodontology. 1996 Nov 1;1(1):1-36.
112. Burt B. Position paper: Epidemiology of Periodontal Diseases. Journal of Periodontology. 2005 Aug 1;76(8):1406-19.
113. Tezal M, Grossi SG, Genco RJ. Is periodontitis associated with oral neoplasms?. Journal of Periodontology. 2005 Mar;76(3):406-10.
114. Komlós G, Csurgay K, Horváth F, Pelyhe L, Németh Z. Periodontitis as a risk for oral cancer: a case–control study. BMC Oral Health. 2021 Dec 15;21(1):640.
115. Miskiewicz A, Szparecki G, Durlik M, Rydzewska G, Ziobrowski I, Górska R. The correlation between pancreatic dysfunction markers and selected indices of periodontitis. Advances in Clinical and Experimental Medicine. 2018;27(3):313-9.
116. Lang NP, Joss A, Orsanic T, Gusberti FA, Siegrist BE. Bleeding on probing. A predictor for the progression of periodontal disease?. Journal of Clinical Periodontology. 1986 Jul;13(6):590-6.
117. Söder B, Yakob M, Meurman JH, Andersson LC, Söder PÖ. The association of dental plaque with cancer mortality in Sweden. A longitudinal study. BMJ open. 2012;2(3):e001083.
118. Kim EH, Nam S, Park CH, Kim Y, Lee M, Ahn JB, et al. Periodontal disease and cancer risk: A nationwide population-based cohort study. Frontiers in Oncology. 2022 Aug 23;12:901098.
119. Chen SH, Chen JF, Hung YT, Hsu TJ, Chiu CC, Kuo SJ. Exploring the Relationship between Periodontitis, Anti-Periodontitis Therapy, and Extra-Oral Cancer Risk: Findings from a Nationwide Population-Based Study. Biomedicines. 2023 Jul 10;11(7):1949.
120. Zhang X, Liu B, Lynn HS, Chen K, Dai H. Poor oral health and risks of total and site-specific cancers in China: A prospective cohort study of 0.5 million adults. EClinicalMedicine. 2022 Mar 1;45:101330.
121. Michaud DS, Joshipura K, Giovannucci E, Fuchs CS. A prospective study of periodontal disease and pancreatic cancer in US male health professionals. Journal of the National Cancer Institute. 2007 Jan 17;99(2):171-5.
122. Shamami MS, Amini S. Periodontal disease and tooth loss as risks for cancer: a systematic review of the literature. Iranian Journal of Cancer Prevention. 2011;4(4):189-98.
123. Garrote LF, Herrero R, Reyes RM, Vaccarella S, Anta JL, Ferbeye L, et al. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. British Journal of Cancer. 2001 Jul;85(1):46-54.
124. Rosenquist K. Risk factors in oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Swedish Dental Journal. Supplement. 2005 Jan 1(179):1-66.
125. Abnet CC, Qiao YL, Dawsey SM, Dong ZW, Taylor PR, Mark SD. Tooth loss is associated with increased risk of total death and death from upper gastrointestinal cancer, heart disease, and stroke in a Chinese population-based cohort. International Journal of Epidemiology. 2005 Apr 1;34(2):467-74.
126. Abnet CC, Kamangar F, Dawsey SM, Stolzenberg-Solomon RZ, Albanes D, Pietinen P, et al. Tooth loss is associated with increased risk of gastric non-cardia adenocarcinoma in a cohort of Finnish smokers. Scandinavian Journal of Gastroenterology. 2005 Jun 1;40(6):681-7.
127. Stolzenberg-Solomon RZ, Dodd KW, Blaser MJ, Virtamo J, Taylor PR, Albanes D. Tooth loss, pancreatic cancer, and Helicobacter pylori. The American Journal of Clinical Nutrition. 2003 Jul 1;78(1):176-81.
128. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002 Dec 19;420(6917):860-7.
129. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-Related Inflammation. Nature. 2008 Jul 24;454(7203):436-44.
130. Meurman JH. Oral microbiota and cancer. Journal of oral microbiology. 2010 Jan 1;2(1):5195.
131. Hernichel-Gorbach E, Kornman KS, Holt SC, Nichols F, Meador H, Kung JT, et al. Host responses in patients with Generalized Refractory Periodontitis. Journal of Periodontology. 1994 Jan;65(1):8-16.
132. Meyer MS, Joshipura K, Giovannucci E, Michaud DS. A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer causes & control. 2008 Nov;19:895-907.
133. Espinoza JA, Bizama C, García P, Ferreccio C, Javle M, Miquel JF, et al. The inflammatory inception of gallbladder Cancer. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer. 2016 Apr 1;1865(2):245-54.
134. Izarzugaza MI, Fernández L, Forman D, Sierra MS. Burden of gallbladder cancer in Central and South America. Cancer Epidemiology. 2016 Sep 1;44:S82-9.
135. Koshiol J, Castro F, Kemp TJ, Gao YT, Roa JC, Wang B, et al. Association of inflammatory and other immune markers with gallbladder cancer: Results from two Independent case-control studies. Cytokine. 2016 Jul 1;83:217-25.
136. Koshiol J, Gao YT, Corbel A, Kemp TJ, Shen MC, Hildesheim A, et al. Circulating inflammatory proteins and gallbladder cancer: Potential for risk stratification to improve prioritization for cholecystectomy in high-risk regions. Cancer Epidemiology. 2018 Jun 1;54:25-30.
137. Liu Z, Kemp TJ, Gao YT, Corbel A, McGee EE, Roa JC, et al. Circulating levels of inflammatory proteins and survival in patients with gallbladder Cancer. Scientific reports. 2018 Apr 4;8(1):5671.
138. Nagaraja V, Eslick GD. Systematic review with meta‐analysis: the relationship between chronic S almonella typhi carrier status and gall‐bladder cancer. Alimentary Pharmacology & Therapeutics. 2014 Apr;39(8):745-50.
139. Kaczmarczyk MM, Miller MJ, Freund GG. The health benefits of dietary fiber: beyond the usual suspects of type 2 Diabetes mellitus, Cardiovascular Disease and Colon Cancer. Metabolism. 2012 Aug 1;61(8):1058-66.
140. Schwabe RF, Jobin C. The microbiome and cancer. Nature Reviews Cancer. 2013 Nov;13(11):800-12.
141. Bodet C, Chandad F, Grenier D. Pathogenic potential of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, the red bacterial complex associated with Periodontitis. Pathologie-Biologie. 2006 Oct 17;55(3-4):154-62.
142. Page RC. The pathobiology of periodontal diseases may affect systemic diseases: Inversion of a paradigm. Annals of Periodontology. 1998 Jul;3(1):108-20.
143. Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Laboratory investigation; a Journal of technical methods and Pathology. 1976 Mar 1;34(3):235-49.
144. Anil S, Varma SV, Preethanath RS, Anand PS, Aldosari AA. The emerging concepts on the impact of periodontitis on systemic health. Periodontal Disease–A Clinician’s Guide. 2012 Feb 3:131-64.
145. Rafiei M, Kiani F, Sayehmiri F, Sayehmiri K, Sheikhi A, Azodi MZ. Study of Porphyromonas gingivalis in periodontal diseases: A systematic review and meta-analysis. Medical Journal of the Islamic Republic of Iran. 2017;31:62.
146. Weinberg A, Belton CM, Park Y, Lamont RJ. Role of fimbriae in Porphyromonas gingivalis invasion of gingival epithelial cells. Infection and Immunity. 1997 Jan;65(1):313-6.
147. Sayehmiri F, Sayehmiri K, Asadollahi K, Soroush S, Bogdanovic L, Jalilian FA, et al. The prevalence rate of Porphyromonas gingivalis and its association with cancer: A systematic review and meta-analysis. International Journal of Immunopathology and Pharmacology. 2015 Jun;28(2):160-7.
148. Yuan X, Liu Y, Kong J, Gu B, Qi Y, Wang X, et al. Different frequencies of Porphyromonas gingivalis infection in cancers of the upper digestive tract. Cancer letters. 2017 Sep 28;404:1-7.
149. Darveau RP, Tanner A, Page RC. The microbial challenge in periodontitis. Periodontology 2000. 1997 Jun;14(1):12-32.
150. Cutler CW, Arnold RR, Schenkein HA. Inhibition of C3 and IgG proteolysis enhances phagocytosis of Porphyromonas gingivalis. Journal of Immunology (Baltimore, Md.: 1950). 1993 Dec 15;151(12):7016-29.
151. Mège JL, Mehraj V, Capo C. Macrophage polarization and bacterial infections. Current opinion in Infectious Diseases. 2011 Jun 1;24(3):230-4.
152. Carrion J, Scisci E, Miles B, Sabino GJ, Zeituni AE, Gu Y, et al. Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential. The Journal of Immunology. 2012 Sep 15;189(6):3178-87.
153. Gaetti-Jardim Jr E, Marcelino SL, Feitosa AC, Romito GA, Avila-Campos MJ. Quantitative detection of periodontopathic bacteria in atherosclerotic plaques from coronary arteries. Journal of Medical Microbiology. 2009 Dec;58(12):1568-75.
154. Bartlett JG, Gorbach SL, Finegold SM. The bacteriology of aspiration pneumonia. The American Journal of Medicine. 1974 Feb 1;56(2):202-7.
155. Amodini Rajakaruna G, Umeda M, Uchida K, Furukawa A, Yuan B, Suzuki Y, et al. Possible translocation of periodontal pathogens into the lymph nodes draining the oral cavity. Journal of Microbiology. 2012 Oct;50:827-36.
156. Truant AL, Menge S, Milliorn K, Lairscey R, Kelly MT. Fusobacterium nucleatum pericarditis. Journal of Clinical Microbiology. 1983 Feb;17(2):349-51.
157. Yoneda M, Naka S, Nakano K, Wada K, Endo H, Mawatari H, et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterology. 2012 Dec;12(1):16.
158. Le Moal G, Juhel L, Grollier G, Godet C, Azais I, Roblot F. Vertebral osteomyelitis due to Fusobacterium species: report of three cases and review of the literature. Journal of Infection. 2005 Aug 1;51(2):E5-9.
159. Brook I, de Leyva F. Microbiology of tonsillar surfaces in infectious mononucleosis. Archives of Pediatrics & Adolescent Medicine. 1994 Feb 1;148(2):171-3.
160. Swidsinski A, Dörffel Y, Loening-Baucke V, Theissig F, Rückert JC, Ismail M, et al. Acute appendicitis is characterized by local invasion with Fusobacterium nucleatum/necrophorum. Gut. 2011;60(1):34‐40
161. Salazar CR, Sun J, Li Y, Francois F, Corby P, Perez-Perez G, et al. Association between selected oral pathogens and gastric precancerous lesions. PloS one. 2013 Jan 7;8(1):e51604.
162. Kostic AD, Gevers D, Pedamallu CS, Michaud M, Duke F, Earl AM, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Research. 2012 Feb 1;22(2):292-8.
163. Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Research. 2012 Feb 1;22(2):299-306.
164. Sasaki M, Yamaura C, Ohara‐Nemoto Y, Tajika S, Kodama Y, Ohya T, et al. Streptococcus anginosus infection in oral cancer and its infection route. Oral Diseases. 2005 May;11(3):151-6.
165. Narikiyo M, Tanabe C, Yamada Y, Igaki H, Tachimori Y, Kato H, et al. Frequent and preferential infection of Treponema denticola, Streptococcus mitis, and Streptococcus anginosus in esophageal cancers. Cancer Science. 2004 Jul;95(7):569-74.
166. Sasaki H, Ishizuka T, Muto M, Nezu M, Nakanishi Y, Inagaki Y, et al. Presence of Streptococcus anginosus DNA in esophageal cancer, dysplasia of esophagus, and gastric cancer. Cancer Research. 1998 Jul 15;58(14):2991-5.
167. Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nature Reviews Immunology. 2021 Jul;21(7):426-40.
168. Ramadan DE, Hariyani N, Indrawati R, Ridwan RD, Diyatri I. Cytokines and chemokines in periodontitis. European Journal of Dentistry. 2020 Jun 23;14(03):483-95.
169. Park MH, Hong JT. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells. 2016 Mar 29;5(2):15.
170. de Araújo Nobre M, Maló P. Prevalence of periodontitis, dental caries, and peri-implant pathology and their relation with systemic status and smoking habits: Results of an open-cohort study with 22009 patients in a private rehabilitation center. Journal of Dentistry. 2017 Dec 1;67:36-42.
171. Loos BG, Craandijk J, Hoek FJ, Dillen PM, Van Der Velden U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. Journal of Periodontology. 2000 Oct;71(10):1528-34.
172. Slade GD, Ghezzi EM, Heiss G, Beck JD, Riche E, Offenbacher S. Relationship between periodontal disease and C-reactive protein among adults in the Atherosclerosis Risk in Communities study. Archives of Internal Medicine. 2003 May 26;163(10):1172-9.
173. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. Journal of Periodontology. 2001 Sep;72(9):1221-7.
174. Ioannidou E, Malekzadeh T, Dongari‐Bagtzoglou A. Effect of periodontal treatment on serum C‐reactive protein levels: A systematic review and meta‐analysis. Journal of Periodontology. 2006 Oct;77(10):1635-42.
175. Pejcic A, Kesic LJ, Milasin J. C-reactive protein as a systemic marker of inflammation in periodontitis. European journal of clinical microbiology & infectious diseases. 2011 Mar;30:407-14.
176. Straka M, Kazar J, Pijak MR, Gasparovic J, Wsolova L, Mongiellova V. The importance of the presence of aggregatibacter actinomycetemcomitans in sulcus gingivalis of patients with cardiovascular diseases. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2011;17(11):CR646.
177. Gunter MJ, Cross AJ, Huang WY, Stanczyk FZ, Purdue M, Xue X, et al. A prospective evaluation of C-reactive protein levels and colorectal adenoma development. Cancer epidemiology, biomarkers & prevention. 2011 Mar 1;20(3):537-44.
178. Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, Uitterlinden AG, et al. C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. Journal of Clinical Oncology. 2006 Nov 20;24(33):5216-22.
179. Trichopoulos D, Psaltopoulou T, Orfanos P, Trichopoulou A, Boffetta P. Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiology Biomarkers & Prevention. 2006 Feb 1;15(2):381-4.
180. Michaud DS. Role of bacterial infections in pancreatic cancer. Carcinogenesis. 2013 Oct 1;34(10):2193-7.
181. Plaza K, Kalinska M, Bochenska O, Meyer-Hoffert U, Wu Z, Fischer J, et al. Gingipains of Porphyromonas gingivalis affect the stability and function of serine protease inhibitor of Kazal-type 6 (SPINK6), a tissue inhibitor of human Kallikreins. Journal of Biological Chemistry. 2016 Sep 2;291(36):18753-64.
182. Pussinen PJ, Tuomisto K, Jousilahti P, Havulinna AS, Sundvall J, Salomaa V. Endotoxemia, immune response to periodontal pathogens, and systemic inflammation associate with incident cardiovascular disease events. Arteriosclerosis, thrombosis, and vascular biology. 2007 Jun 1;27(6):1433-9.
183. Andrés CM, Pérez de la Lastra JM, Juan CA, Plou FJ, Pérez-Lebeña E. The Role of Reactive Species on Innate Immunity. Vaccines. 2022 Oct 17;10(10):1735.
184. Juan CA, Pérez de la Lastra JM, Plou FJ, Pérez-Lebeña E. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. International Journal of Molecular Sciences. 2021 Apr 28;22(9):4642.
185. Liu C, Mo L, Niu Y, Li X, Zhou X, Xu X. The role of reactive oxygen species and autophagy in periodontitis and their potential linkage. Frontiers in Physiology. 2017 Jun 23;8:439.
186. Liou GY, Storz P. Reactive oxygen species in cancer. Free Radical Research. 2010 Jan 1;44(5):479-96.
187. Loo WT, Jin L, Cheung MN, Wang M, Chow LW. Epigenetic change in e-cardherin and COX-2 to predict chronic periodontitis. Journal of Translational Medicine. 2010 Dec;8(1):110.
188. Ilango S, Paital B, Jayachandran P, Padma PR, Nirmaladevi R. Epigenetic alterations in cancer. Frontiers in Bioscience-Landmark. 2020 Mar 1;25(6):1058-109.
189. Ari G, Cherukuri S, Namasivayam A. Epigenetics and periodontitis: a contemporary review. Journal of clinical and diagnostic research: JCDR. 2016 Nov;10(11):ZE07-09.
190. Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of cadherins in cancer—a review. International Journal of molecular Sciences. 2020 Oct 15;21(20):7624.
191. Jurdziński KT, Potempa J, Grabiec AM. Epigenetic regulation of inflammation in periodontitis: cellular mechanisms and therapeutic potential. Clinical Epigenetics. 2020 Dec;12(1):186.
192. Li Y, Hecht SS. Metabolic activation and DNA interactions of carcinogenic N-nitrosamines to which humans are commonly exposed. International Journal of Molecular Sciences. 2022 Apr 20;23(9):4559.
193. Jakszyn P, González CA. Nitrosamine and related food intake and gastric and oesophageal cancer risk: a systematic review of the epidemiological evidence. World Journal of Gastroenterology: WJG. 2006 Jul 7;12(27):4296-303.
194. Mizumoto A, Ohashi S, Hirohashi K, Amanuma Y, Matsuda T, Muto M. Molecular mechanisms of acetaldehyde-mediated carcinogenesis in squamous epithelium. International Journal of Molecular Sciences. 2017 Sep 10;18(9):1943.
195. Karpiński TM. Role of oral microbiota in cancer development. Microorganisms. 2019 Jan 13;7(1):20.
196. Marshall JR, Graham S, Haughey BP, Shedd D, O'Shea R, Brasure J, et al. Smoking, alcohol, dentition and diet in the epidemiology of oral cancer. European Journal of Cancer Part B: Oral Oncology. 1992 Jul 1;28(1):9-15.
197. Hujoel PP, Drangsholt M, Spiekerman C, Weiss NS. An exploration of the periodontitis-cancer association. Annals of Epidemiology. 2003 May 1;13(5):312-6.