Background: To date, a number of pre-clinical and clinical studies have been conducted to investigate the potential therapeutic effect of nitrates or nitric oxide in cancer prevention and treatment. Since there is a lack of epidemiological studies investigating the relationships between nitrates and cancers, we conducted a study with the aim of investigating the relationship between nitrates and cancer using big data. Methods: A cross-sectional analysis of nitrate use and cancer diagnosis was performed using the HIRA-NPS data from 2010 to 2014.
Logistic regression analysis was used to evaluate multivariate associations between nitrate use and cancer diagnoses, while adjusting for confounding variables such as sex, age, type of insurance, obesity, smoking, and angina. However, due to several limitations of this study, findings need to be confirmed in further research investigating the links between nitrates and the cancers. One of the underlying causes of high medical costs comes from anti-cancer drugs.
Because of possible antitumor effects of nitrates, NTG, one of the nitrates, is proposed as a candidate drug for repurposing by the Repurposing Drugs in Oncology (ReDO) project supported by Harvard University researchers and clinicians and non- for-profit organizations [ 8, 10]. To date, a number of pre-clinical and clinical trials investigating the influence of nitrates or NO on cancer have been conducted, but the results are conflicting. Although several studies have been conducted to investigate the potential therapeutic effect of nitrates or NO in cancer treatment and prevention, the findings are still contradictory.
Our study was designed to evaluate cross-sectional association between nitrate prescriptions and diagnoses with the top five cancers in Korea, such as thyroid, gastric, colorectal, lung, and breast cancer using Korean national health claims sample data obtained from the Health Insurance Review and Assessment Service (HIRA) from 2010 to.
MATERIALS & METHODS
A patient record with one or more cancer diagnoses was defined as the patient with the specific cancer in the HIRA-NPS datasets between January 2010 and December 2014. Of the seven nitrate drugs, only the generic drugs available in Korea were included. study: NTG, ISMN and ISDN. The NTG ointments for hemorrhoids were excluded because they were not included in the NHI Formulary;
GNL_NM_CD_8” of table 30 of the HIRA data, which contains specific information on the health services provided [22]. From the KCD-6 codes for neoplasms (C00-D48), we extracted the codes for thyroid, stomach, colon and rectum, lung and breast. Each type of cancer was then categorized into malignant neoplasm, carcinoma in situ, benign neoplasm, and neoplasm of uncertain or unknown behavior.
For thyroid neoplasm, the codes used were malignant neoplasm (C73), carcinoma in situ (D09.3), benign neoplasm (D34), and neoplasm of uncertain or unknown behavior (D44.0). MSICK_CD” (main diagnosis) or “SSICK_CD” (secondary diagnosis) of Table 20 of the HIRA data, which contains general patient characteristics [22]. However, because smoking cessation or weight reduction medications were not included in the NHI formulary, they could not be used as proxy indicators of smoking status and obesity.
Instead, disease codes of obesity (E66, E66.X) and mental and behavioral disorders due to the use of tobacco (F17, F17.X) or the toxic effect of tobacco and nicotine (T65.2) were used (Table 3). . Angina was considered a confounding variable because it is a major approved indication for the nitrates and it was neither inclusion nor exclusion criterion of the study population of previous studies. The KCD-6 codes of unstable angina, prinzmetal angina, other forms of angina pectoris and unspecified angina pectoris (I20, I20.X, I20.XX) were used (Table 3).
All analyzes in the study were designed to obtain national-level estimates that reflect overall Korean insurance coverage using weighting procedures. Multivariate associations between nitrate use and cancer diagnoses were evaluated by performing logistic regression analysis while adjusting for confounding variables such as sex, age, type of insurance, obesity, smoking, and angina. Records of prescribed drugs or records of diagnosed diseases are not mutually exclusive, meaning that a patient may be prescribed more than one type of nitrate product or be diagnosed with one or more cancers in a year.
Thus, the number of patients with all nitrate prescriptions or top 5 cancer diagnoses may exceed the sum of each nitrate prescription or cancer diagnosis. This study was approved by the Seoul National University Institutional Review Board (IRB) (approval number: IRB No. E.
RESULTS
The total number of patients with at least one neoplasm diagnosis among the 5 most common types of cancer was from the entire study population). Among all nitrate users, the number of male patients with a prescription for nitrates was higher than that of female patients (n=. The prevalence of the 65 to 79-year-old patient group comprised the largest proportion and most nitrate users were insured by the NHI.
Among all nitrate users (of all nitrate users), patients had at least one neoplasm diagnosis among the top 5 cancers. Of these, benign neoplasm of the colon and rectum was the most common diagnosis, followed by malignant neoplasm of the colon and rectum, malignant neoplasm of the stomach, malignant neoplasm of the lungs, and malignant neoplasm of the stomach (Table 5). Other neoplasms, such as benign neoplasm of the lungs, neoplasm of uncertain or unknown behavior of colon and rectum, and malignant neoplasm of colon and rectum, were approximately two times more likely to be diagnosed in the nitrate users (Table 6).
DISCUSSION
Other protumorigenic effects such as angiogenesis and metastasis were also demonstrated in the in vitro studies. In the study of prostate cancer cells conducted by Polytarchou et al., exogenously added or endogenously produced NO led to the expression of pleiotrophin, a growth factor involved in angiogenesis and tumor growth, and cell migration [27]. Another finding from our study was that ISMN and ISDN users were less likely to be diagnosed with benign thyroid tumors.
Based on the current literature, clear explanations on the delineation of the relationship between tumor and nitrate products are lacking, except for a study that reported a negative correlation between nitrates and benign thyroid neoplasm, while malignant neoplasm showed a positive correlation. ARG2 was found to be downregulated in benign tumors, while overexpression was found in almost all follicular thyroid carcinomas. However, further studies are needed for the definitive mechanism of action of NO in thyroid tumor [28].
The main strength of the current study is a large sample size that reflects the entire national population. In addition, our study has a novelty due to the lack of information about nitrates and cancer research using big data. A representative example is studies of statins, HMG-CoA reductase inhibitors used to control hypercholesterolemia [30] and cancers.
Thus, several observational studies, such as cohort studies using big data, have been conducted to investigate the association between statins and cancers [33–37]. Unlike a number of studies on statins, we believe that our study, as an exploratory study on the effects of nitrates on cancer development, is innovative for its originality and scarcity, especially by using big data at the population level . Furthermore, although a plausible pharmacological mechanism is unknown, there was a novel finding that ISMN and ISDN users were less likely to be diagnosed with benign thyroid neoplasm.
As the fourth most common diagnosis in our study population, the association between benign thyroid neoplasm and ISMN or ISDN is worth investigating. In HIRA-NPS, patients' obesity and smoking status can only be verified if they were recoded with diagnostic codes for the treatments. There is, however, the possibility of missing the records, as some patients with overweight and
CONCLUSION
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