15.15 bcn to btc
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Requests to access the datasets should be directed to ten. This retrospective cohort study evaluated whether metformin use in patients with type 2 diabetes mellitus might reduce the risk of biliary tract cancer BTC ; and explored whether metformin use might affect the overall survival in patients who developed BTC. A total of , ever users and 16, never users were identified unmatched original cohort and a matched pairs of 16, ever users and 16, never users based on propensity score PS were created matched cohort.
Hazard ratios were estimated by three Cox regression models: 1 adjusted for PS; 2 incorporated with the inverse probability of treatment weighting using PS; and 3 all covariates treated as independent variables.
Overall survival was compared between ever users and never users of metformin who developed BTC. In the unmatched cohort, 73 never users and ever users developed BTC, with respective incidence of Findings in the matched cohort were consistent with those observed in the unmatched cohort. The overall survival did not differ significantly between ever and never users of metformin among patients who developed BTC.
A dose-response effect is observed and users of approximately 2 years show significantly reduced risk. However, metformin does not affect the overall survival in patients with BTC.
Biliary tract cancer BTC arises from the epithelium of the biliary tree and can be classified as intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer according to its anatomical location. Metabolism reprogramming with a shift from oxidative phosphorylation to glycolysis Warburg effect or aerobic glycolysis is a major feature of BTC 3. Although the risk factors of BTC are not well characterized 3 , patients with type 2 diabetes mellitus may have an increased risk of various types of cancer including BTC 4 — 7.
Metformin is now considered the first-line therapy for type 2 diabetes mellitus because it exerts multiple beneficial effects beyond glycemic control, such as anti-inflammation, anti-atherosclerosis, anti-cancer and anti-aging 4.
Because of the highly malignant nature of BTC, metformin does not provide a useful therapeutic benefit or improve the survival of the patients once BTC is diagnosed 10 — However, in in vitro studies, metformin does inhibit the proliferation and viability of BTC and promote the apoptosis of BTC through various mechanisms.
A recent in vitro study by Tang et al. Furthermore, metformin may sensitize the anticancer effect of cisplatin on BTC through activating the oxidative stress-mediated mitochondrial cell death pathway Therefore, even though metformin may not be useful as a therapeutic agent for BTC, its beneficial effect to prevent the early development of such a highly malignant cancer is worthy of investigation.
The beneficial effect observed by Chaiteerakij et al. The present study aimed at investigating whether metformin use might reduce the risk of BTC in Taiwanese patients with type 2 diabetes mellitus. Furthermore, we also explored whether the use of metformin might affect the overall survival in patients who developed BTC during follow-up. All disease diagnoses, prescribed medications and performed procedures are recorded as computerized database.
The database can be used for academic research after approval by an ethics review board. The present study was approved with a number of Diabetes was coded XX and BTC included Figure 1 shows the procedures followed in creating the unmatched original cohort used in the study.
Among them, , patients had ever been prescribed metformin and 16, had never been treated with metformin the unmatched original cohort. These methods have also been used in our previous papers 19 , The PS was created by logistic regression with all the characteristics collected until the end of follow-up listed in Table 1 and the date of entry treated as independent variables. The procedures in creating the unmatched original cohort of ever and never users of metformin by using the reimbursement database of the National Health Insurance of Taiwan.
Characteristics in metformin never users and ever users in the unmatched original cohort and in the propensity score matched cohort. The specific drugs in the class of sulfonylurea include chlorpropamide, glibenclamide, glipizide, gliclazide, glimepiride and gliquidone. Cumulative duration of metformin therapy months was calculated and its tertiles were used to evaluate the dose-response relationship. The living region and occupation were classified as detailed elsewhere Occupation was classified as class I civil servants, teachers, employees of governmental or private businesses, professionals and technicians , class II people without a specific employer, self-employed people or seamen , class III farmers or fishermen , and class IV low-income families supported by social welfare, or veterans.
The ICDCM codes for the related diagnoses are provided below: hypertension — , dyslipidemia Analyses were conducted in both the unmatched original cohort and the matched cohort. Incidence densities for never users, ever users and each tertile of cumulative duration of metformin therapy were calculated.
The numerator was the case number of new-onset BTC identified during follow-up. The denominator was the person-years of follow-up, which ended at the time of BTC diagnosis or on the date of death, the last reimbursement record or December 31, Kaplan-Meier curves for BTC-free probability for ever versus never users of metformin in the unmatched cohort and the matched cohort were plotted.
Log-rank test was used to test the difference between ever and never users. The following two sensitivity analyses were then conducted in the unmatched cohort. First, patients who happened to be treated with incretin-based therapies during follow-up were excluded. Incretin-based therapies including the dipeptidyl peptidase 4 inhibitors and the glucagon-like peptide 1 receptor agonists were introduced into Taiwan after the enrollment of the patients.
On March 1, sitagliptin was the first incretin-based therapy approved for reimbursement by the NHI and it has been shown to reduce the risk of breast cancer in our population Second, patients who developed cancers other than BTC during follow-up were excluded.
These patients were excluded because the occurrence of other cancers might have shortened the lifespan of the patients leading to biased estimates of follow-up time.
Furthermore, patients who developed other cancers might have different propensity for the risk of developing BTC. To investigate whether the prognosis among incident cases of BTC might be different between ever and never users of metformin, the overall survival curves comparing ever versus never users were plotted for the unmatched cohort and the matched cohort, respectively.
Log-rank test was used to test whether overall survivals could be significantly different between ever and never users. SAS statistical software version 9. Table 1 compares the characteristics between never and ever users of metformin. In the unmatched original cohort, age and sex differed significantly. The mean age was older All other variables, except hypertension, pioglitazone, Epstein-Barr virus-related diagnoses and hepatitis B virus infection, also differed significantly in the unmatched original cohort.
However, in the matched cohort, except for age, obesity, eye disease, insulin and sulfonylurea, all other variables were not different significantly. The Kaplan-Meier curves for BTC-free probability comparing ever versus never users of metformin are shown in Figure 2. Kaplan-Meier curves for biliary tract cancer-free probability in never and ever users of metformin in the unmatched cohort A and matched cohort B. HR, hazard ratio; CI, confidence interval. The incidence of BTC and the hazard ratios by metformin exposure in the main analyses are shown in Table 2.
In the tertile analyses, the risk was neutral when metformin was used within a short period of approximately 2 years in the first tertile in all models. However, a significantly lower risk of BTC could be seen in the second and third tertiles in all models when metformin had been used for approximately 2 or more years. There was a trend of decreasing risk of BTC with increasing cumulative duration of metformin therapy. Incidence rates of biliary tract cancer and hazard ratios by metformin exposure in the main analyses.
Table 3 shows the incidence rates and hazard ratios in the sensitivity analyses after excluding patients who happened to be treated with incretin-based therapies and patients who developed other cancers during follow-up, respectively. The findings were consistent with the main analyses shown in Table 2 , suggesting a significantly lower risk of BTC associated with metformin use in a dose-response pattern.
Subgroup analyses and the P values of interaction are shown in Table 4. Except for Helicobacter pylori infection, no significant interaction between metformin use and any of the other variables was observed. For patients with a history of Helicobacter pylori infection, the protective effect of metformin was attenuated and not significant.
Subgroup analyses and P -values for the interactions between metformin and each of the variables. Figure 3 shows the overall survival in ever versus never users among those who had incident BTC in the unmatched cohort Figure 3A and the matched cohort Figure 3B , respectively. The findings suggested that metformin did not affect the overall survival in patients with BTC after the diagnosis of the cancer. Overall survival in patients with incident biliary tract cancer in ever users and never users of metformin in the unmatched cohort A and the matched cohort B.
The findings supported that metformin use in patients with type 2 diabetes mellitus was associated with a significantly lower risk of BTC in a dose-response pattern, which could be demonstrated in different regression models in either the main analyses Table 2 or the sensitivity analyses Table 3.
Except for Helicobacter pylori infection, no significant interaction was observed for any of the other potential confounders Table 4. Although metformin use was associated with a lower risk of BTC Figure 2 , Tables 2 — 4 , the prognosis did not differ significantly between ever and never users once the patients developed BTC Figure 3.
In our previous studies, metformin use was also associated with a lower risk of other types of cancer and the overall hazard ratios in well-matched cohorts were 0. Here the lowest overall hazard ratio of 0.
Although metformin provided the most effective prevention on BTC, it might not be a useful therapeutic agent because its use was not associated with a better prognosis among incident cases of BTC Figure 3. This is compatible with most previous studies that consistently showed a null effect when metformin was used for the treatment of BTC 10 — Because BTC is highly malignant 1 , 2 , the more remarkable effect of metformin on the prevention of BTC renders a chance to reduce a greater burden of this life-threatening cancer if metformin is used for early prevention.
A confirmation of such a chemopreventive effect of metformin on BTC by clinical trials, especially in high risk people, is urgently needed. The protective effect of metformin on BTC was well demonstrated in the matched cohort Table 2. The difference in age was small and slightly older in ever users in the matched cohort Table 1.
This might only have underestimated the beneficial effect of metformin because older age can be a risk factor of BTC. The slightly higher prevalence of obesity 2. The mechanisms explaining a reduced risk of BTC associated with metformin use may be multifactorial. The development and proliferation of BTC is favored by an alteration of cellular metabolism from oxidative phosphorylation to glycolysis the Warburg effect 3. The in vitro study by Tang et al.
Metformin may also reduce inflammation, another feature of BTC 28 , through the improvement of metabolic disturbances such as hyperglycemia, insulin resistance and dyslipidemia 29 , Transforming growth factor beta 1 plays an important role in the initiation and growth of BTC 31 and metformin has been identified as a suppressor of this growth factor in an in vitro study Inactivation of tumor suppression function of FoxO3 is related to human development of BTC 33 and metformin activates the AMPK-FoxO3 pathway resulting in a reduction of intracellular reactive oxygen species Lysophosphatidylcholine may cause cholangiocyte senescence which is potentially related to the development of BTC
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This is dangerously misleading. Rather than give another high-level argument, I decided to run the numbers on the actual risk. The answer is around five hours, rather than his answer of " days". As is apparent from the data, one way to mitigate this risk is to make the signalling threshold for the tax much higher. Alternatively, if BCN removed the automated checkpoints and unparking PoW penalty, the risk would also be minimal in normal conditions. Again, this analysis is in the absence of an intentional attack. The risk only increases with the presence of any malicious actors. However, I wanted to see exactly who's benefiting, so I graphed the average difficulty per solved block per pool for each day over the past few weeks.
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BAR to ZEC Exchange
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