Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors

BackgroundProton pump inhibitors (PPIs) are widely prescribed drugs for the treatment of gastroesophageal reflux disease (GERD). Several meta-analysis studies have reported associations between prolonged use of PPIs and major adverse cardiovascular events. However, interaction of PPIs with biological molecules involved in cardiovascular health is incompletely characterized. Dimethylarginine dimethylaminohydrolase (DDAH) is a cardiovascular enzyme expressed in cardiomyocytes, and other somatic cell types in one of two isotypes (DDAH1 and DDAH2) to metabolize asymmetric dimethylarginine (ADMA); a cardiovascular risk factor and competitive inhibitor of nitric oxide synthases (NOSs).MethodsWe performed high throughput drug screening of over 130,000 small molecules to discover human DDAH1 inhibitors and found that PPIs directly inhibit DDAH1. We expressed and purified the enzyme for structural and mass spectrometry proteomics studies to understand how a prototype PPI, esomeprazole, interacts with DDAH1. We also performed molecular docking studies to model the interaction of DDAH1 with esomeprazole. X-ray crystallography was used to determine the structure of DDAH1 alone and bound to esomeprazole at resolutions ranging from 1.6 to 2.9 Å.ResultsAnalysis of the enzyme active site shows that esomeprazole interacts with the active site cysteine (Cys273) of DDAH1. The structural studies were corroborated by mass spectrometry which indicated that cysteine was targeted by esomeprazole to inactivate DDAH1.ConclusionsThe inhibition of this important cardiovascular enzyme by a PPI may help explain the reported association of PPI use and increased cardiovascular risk in patients and the general population.General significanceOur study calls for pharmacovigilance studies to monitor adverse cardiovascular events in chronic PPI users.     

Proton pump inhibitors on pancreatic cancer risk and survival

BackgroundHypergastrinemia may promote the development and progression of pancreatic cancer. Proton pump inhibitor (PPI) therapy is known to cause hypergastrinemia. We sought to determine the association between PPI therapy and the risk of developing pancreatic cancer as well as survival following pancreatic cancer diagnosis.MethodsWe conducted a nested case-control study and a retrospective cohort study in The Health Improvement Network (THIN), a medical records database representative of the UK population. In the case-control study, each patient with incident pancreatic cancer was matched with up to four controls based on age, sex, practice site and both duration and calendar time of follow-up using incidence density sampling. The odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer risk associated with PPI use were estimated using multivariable conditional logistic regression. The retrospective cohort study compared the survival of pancreatic cancer patients according to their PPI exposure at the time of diagnosis. The effect of PPI use on pancreatic cancer survival was assessed using a multivariable Cox regression analysis.ResultsThe case-control study included 4113 cases and 16,072 matched controls. PPI use was more prevalent in cases than controls (53% vs. 26% active users). Adjusting for diabetes, smoking, alcohol use and BMI, PPI users including both former users and active users with longer cumulative PPI use had a higher risk of pancreatic cancer compared to non-users. When assessing survival following pancreatic cancer diagnosis, only short-term, active users had a modest decrease in survival.ConclusionsLong-term PPI therapy may be associated with pancreatic cancer risk. While PPI users recently started on treatment had a slightly worse survival, this result likely is from reverse causation.     

Incidence trends in oesophageal cancer by histological type: An updated analysis in Sweden

BackgroundWe aimed to update incidence trends of oesophageal cancer by histological type in Sweden.MethodsUsing data from the Swedish Cancer Registry, we examined incidence trends of oesophageal cancer by histological types in individuals aged ≥50 years in 1970–2014 using log-linear joinpoint regressions.ResultsThe age-standardised incidence rate of oesophageal adenocarcinoma in men increased on average by 3.0% per year in 1970–1994, followed by a more rapid increase of 13.7% per year in 1994–2000, and a slower increase of 2.6% per year in 2010–2014. The rate of oesophageal adenocarcinoma in women increased on average by 4.2% per year during the entire period. The rate of squamous cell carcinoma generally decreased over the past 2–3 decades in both sexes.ConclusionsThe incidence of oesophageal adenocarcinoma continues to rise in Sweden, although the increase seems to have slowed down in men since 2000. The incidence of oesophageal squamous cell carcinoma is decreasing.     

Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population

Background and Aims

Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches.

Methods

Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population.

Results

In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H₂ blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000.

Conclusions

Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.     

Effects of Clopidogrel and Proton Pump Inhibitors on Cardiovascular Events in Patients with Type 2 Diabetes Mellitus after Drug-Eluting Stent Implantation: A Nationwide Cohort Study

Objective

To investigate whether there is an increased risk of cardiac events in diabetic patients with a combined therapy of clopidogrel (CLO) and proton pump inhibitors (PPIs) after drug-eluting stent (DES) deployment.

Methods

By using National Health Insurance Research Database, all patients who received CLO with or without PPI therapy within 90 days after undergoing DES (limus-eluting or paclitaxel-eluting stents) deployment were enrolled. Endpoints were acute coronary syndrome (ACS) and readmission for revascularization (percutaneous coronary intervention or coronary artery bypass graft surgery) after 3, 6, and 12 months.

Results

A total of 6,603 diabetic patients received LESs (5,933 in the CLO subgroup and 670 in the CLO plus PPIs subgroup), and 3,202 patients received PESs (2,923 in the CLO subgroup and 279 in the CLO plus PPIs subgroup). The patients who received CLO plus PPIs were at higher risk of ACS than those receiving CLO within 1 year after DES deployment (LESs: 6-month hazard ratio [HR] = 1.63, and 1-year HR = 1.37; PESs: 3-month HR = 1.72). Patients with a history of ACS who received CLO plus PPIs were at higher risk of ACS after LES implantation (HR = 1.55) than those in the CLO group.

Conclusion

In “real-world” diabetic patients with LES deployment, the combination of PPIs and CLO is associated with higher rates of ACS after 6 months and 1 year. Even after correction for confounding factors, concomitant PPI use remained an independent predictor of cardiac events, emphasizing the clinical importance of this drug—drug interaction.     

Assessment of surveillance versus etiologic factors in the reciprocal association between papillary thyroid cancer and breast cancer

BackgroundMutually increased risks for thyroid and breast cancer have been reported, but the contribution of etiologic factors versus increased medical surveillance to these associations is unknown.MethodsLeveraging large-scale US population-based cancer registry data, we used standardized incidence ratios (SIRs) to investigate the reciprocal risks of thyroid and breast cancers among adult females diagnosed with a first primary invasive, non-metastatic breast cancer (N = 652,627) or papillary thyroid cancer (PTC) (N = 92,318) during 2000–2017 who survived ≥1-year.ResultsPTC risk was increased 1.3-fold [N = 1434; SIR = 1.32; 95 % confidence interval (CI) = 1.25–1.39] after breast cancer compared to the general population. PTC risk declined significantly with time since breast cancer (Poisson regression = P_trend <0.001) and was evident only for tumors ≤2 cm in size. The SIRs for PTC were higher after hormone-receptor (HR)+ (versus HR-) and stage II or III (versus stage 0-I) breast tumors. Breast cancer risk was increased 1.2-fold (N = 2038; SIR = 1.21; CI = 1.16–1.26) after PTC and was constant over time since PTC but was only increased for stage 0-II and HR + breast cancers.ConclusionAlthough some of the patterns by latency, stage and size are consistent with heightened surveillance contributing to the breast-thyroid association, we cannot exclude a role of shared etiology or treatment effects.     

Cancer Incidence following Expansion of HIV Treatment in Botswana

BackgroundThe expansion of combination antiretroviral treatment (ART) in southern Africa has dramatically reduced mortality due to AIDS-related infections, but the impact of ART on cancer incidence in the region is unknown. We sought to describe trends in cancer incidence in Botswana during implementation of the first public ART program in Africa.MethodsWe included 8479 incident cases from the Botswana National Cancer Registry during a period of significant ART expansion in Botswana, 2003–2008, when ART coverage increased from 7.3% to 82.3%. We fit Poisson models of age-adjusted cancer incidence and counts in the total population, and in an inverse probability weighted population with known HIV status, over time and estimated ART coverage.FindingsDuring this period 61.6% of cancers were diagnosed in HIV-infected individuals and 45.4% of all cancers in men and 36.4% of all cancers in women were attributable to HIV. Age-adjusted cancer incidence decreased in the HIV infected population by 8.3% per year (95% CI -14.1 to -2.1%). However, with a progressively larger and older HIV population the annual number of cancers diagnosed remained constant (0.0% annually, 95% CI -4.3 to +4.6%). In the overall population, incidence of Kaposi’s sarcoma decreased (4.6% annually, 95% CI -6.9 to -2.2), but incidence of non-Hodgkin lymphoma (+11.5% annually, 95% CI +6.3 to +17.0%) and HPV-associated cancers increased (+3.9% annually, 95% CI +1.4 to +6.5%). Age-adjusted cancer incidence among individuals without HIV increased 7.5% per year (95% CI +1.4 to +15.2%).InterpretationExpansion of ART in Botswana was associated with decreased age-specific cancer risk. However, an expanding and aging population contributed to continued high numbers of incident cancers in the HIV population. Increased capacity for early detection and treatment of HIV-associated cancer needs to be a new priority for programs in Africa.     

Risk of prostate cancer among cancer survivors in the Netherlands

BackgroundIn parallel with increasing numbers of cancer patients and improving cancer survival, the occurrence of second primary cancers becomes a relevant issue. The aim of our study was to evaluate risk of prostate cancer as second primary cancer in a population-based setting.MethodsData from the Netherlands Cancer Registry were used to estimate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for prostate cancer as second primary cancer. The effect of time since first cancer diagnosis, specific first cancer sites, age, and pelvic radiotherapy was taken into account.ResultsOut of 551,553 male patients diagnosed with a first primary cancer between 1989 and 2008, 9243 patients were subsequently diagnosed with prostate cancer. Overall, cancer survivors showed an increased risk (SIR 1.3, 95% CI 1.2–1.3) of prostate cancer. The increased prostate cancer risk was limited to the first year of follow-up for the majority of the specific first cancer sites. More than 10 years after the first cancer diagnosis, only melanoma patients were at increased risk (SIR 1.5, 95% CI 1.2–1.9), while patients with head or neck cancers were at decreased risk (SIR 0.7, 95% CI 0.5–0.9) of being diagnosed with prostate cancer. Patients who underwent primary pelvic radiotherapy for their first cancer had a decreased risk of prostate cancer in the long term (SIR 0.5, 95% CI 0.4–0.6).ConclusionsOur data showed that cancer survivors have an increased prostate cancer risk in the first year following a first cancer diagnosis, which is most likely the result of active screening or incidental detection.     

Epidemiological trends of neuroendocrine tumours over three decades in Queensland,Australia

IntroductionWhile neuroendocrine tumours (NETs) account for only a small proportion of cancer diagnoses, incidence has been rising over time. We examined incidence, mortality and survival over three decades in a large population-based registry study.MethodsThis retrospective study included all cases (n = 4580) of NETs diagnosed from 1986 to 2015 in Queensland, Australia. We examined directly age-standardised incidence and mortality rates. The impact on overall survival according to demographic factors and primary site was modelled using multivariable Cox proportional hazards regression (HR). Cause-specific and relative survival were estimated using the Kaplan-Meier survival function.ResultsAnnual incidence increased from 2.0 in 1986 to 6.3 per 100,000 in 2015, while mortality remained stable. The most common primary site was appendix followed by lung, small intestine and rectum. Rectal, stomach, appendiceal and pancreatic NETs had the greatest rate increase, while lung NETs decreased over the same period. Five-year cause-specific survival improved from 69.4% during 1986–1995 to 92.6% from 2006 to 2015. Survival was highest for appendiceal and rectal NETs and lowest for pancreas and unknown primary sites. The risk of dying within five years of diagnosis was about 40% higher for males (HR = 1.41, 95%CI 1.20–1.65) and significantly higher for patients aged over 40 years compared to younger patients (p < 0.001).ConclusionThis study, including 30 years of data, found significantly increasing rates of NETs and confirms results from elsewhere. Increasing survival over time in this study, likely reflects increased awareness, improvements in diagnostic imaging, greater use of endoscopy and colonoscopy, and the development of new therapies.     

Effect of Proton Pump Inhibitors on Serum Thyroid-Stimulating Hormone Level in Euthyroid Patients Treated with Levothyroxine for Hypothyroidism

ObjectiveTo examine retrospectively the effect of proton pump inhibitors (PPIs) on thyrotropin (thyroid-stimulating hormone or TSH) values in patients with hypothyroidism and normal TSH levels receiving levothyroxine (LT₄) replacement therapy.MethodsThe data collection was done by retrospective review of electronic medical records from the period of December 2002 to August 2005 from patients with hypothyroidism who were receiving at least 25 μg of LT₄ replacement daily at Queens Hospital Center. The first 92 patients meeting all inclusion and exclusion criteria were included in the study. The study group (N = 37) patient data were collected by selecting euthyroid patients who had received stable LT₄ replacement for at least 6 months and in whom PPI therapy (lansoprazole) was later initiated. TSH levels were collected before and at least 2 months after the PPI treatment was started. The control group (N = 55) patient data were collected by reviewing TSH levels among euthyroid patients with a history of hypothyroidism receiving stable LT₄ therapy and not receiving a PPI during the period of data collection. The statistical analysis was done by comparing the mean change in TSH level in each group with use of the Student t test.ResultsIn the study group, the mean change in the TSH level from before to at least 2 months after initiation of PPI therapy, 0.69 ± 1.9 μIU/mL, was statistically significant (P = 0.035). In the control group, the mean change in the TSH level during the study period, 0.11 ± 1.06 μIU/mL, was not statistically significant (P = 0.45).ConclusionTo our best knowledge, this is the first study in humans with hypothyroidism demonstrating the effect of PPIs on serum TSH levels. PPIs should be added to the list of medications affecting the level of thyroid hormone in patients with hypothyroidism treated with LT₄ replacement. Patients with hypothyroidism and normal TSH values during LT₄ replacement therapy may need additional thyroid function testing after treatment with PPIs and may need adjustment of their LT₄ dose. (Endocr Pract. 2007;13:345-349)     

Risk of Community-Acquired Pneumonia with Outpatient Proton-Pump Inhibitor Therapy: A Systematic Review and Meta-Analysis

Background

Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults.

Methods

We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy.

Results

Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31).

Discussion

Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.     

Changing temporal trends in non-AIDS cancer mortality among people diagnosed with AIDS: San Francisco,California, 1996–2013

BackgroundAntiretroviral therapy (ART) has reduced AIDS-defining cancer (ADC) mortality, but its effect on non-AIDS-defining cancer (NADC) mortality is unclear. To help inform cancer prevention and screening, we evaluated trends in NADC mortality among people with AIDS (PWA) in the ART era.MethodsThis retrospective cohort study analyzed AIDS surveillance data, including causes of death from death certificates, for PWA in San Francisco who died in 1996–2013. Proportional mortality ratios (PMRs), and year, age, race, sex-adjusted standardized mortality ratios (SMRs) were calculated for 1996–1999, 2000–2005, and 2006–2013, corresponding to advances in ART.ResultsThe study included 5822 deceased PWA of whom 90% were male and 68% were aged 35–54 at time of death. Over time, the PMRs significantly decreased for ADCs (2.6%, 1.4%, 1.2%) and increased for NADCs (4.3%, 7.0%, 12.3%). For all years combined (1996–2013) and compared to the California population, significantly elevated SMRs were observed for these cancers: all NADCs combined (2.1), anal (58.4), Hodgkin lymphoma (10.5), liver (5.2), lung/larynx (3.0), rectal (5.2), and tongue (4.7). Over time, the SMRs for liver cancer (SMR 19.8, 11.2, 5.0) significantly decreased while the SMRs remained significantly elevated over population levels for anal (SMR 123, 48.2, 45.5), liver (SMR 19.8, 11.2, 5.0), and lung/larynx cancer (SMR 5.3, 4.7, 3.6).ConclusionA decline in ADC PMRs and increase in NADC PMRs represent a shift in the cancer burden, likely due to ART use. Moreover, given their elevated SMRs, anal, liver, and lung/larynx cancer remain targets for improved cancer prevention, screening, and treatment.     

Beyond gastric acid reduction: proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidant defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection.     

Helicobacter pylori, proton pump inhibitors and gastroesophageal reflux disease

Proton pump inhibitors have become of pivotal importance for the treatment of GERD. The purpose of this paper is to review the interaction between Helicobacter pylori and PPIs in the treatment of GERD. H. pylori exaggerates the acid suppressive effects of PPIs. During treatment with these drugs, H. pylori-positive subjects thus have a higher intragastric pH than H. pylori-negative subjects. The mechanism for this phenomenon remains to be elucidated. We hypothesize that it is related to H. pylori-induced corpus gastritis, which impairs parietal cell function. The available evidence suggests that this phenomenon has no clinical relevance for the treatment of GERD. The 24-hr esophageal pH during PPI treatment does not depend on the H. pylori status, nor does the medication dose needed for maintenance therapy or the number of clinical relapses during such therapy depend on the H. pylori status. PPIs, on the other hand, also affect H. pylori. During treatment with these drugs, the pattern of bacterial colonization and associated gastritis shifts proximally. The increased gastritis of the body mucosa is associated with a more rapid development of atrophic gastritis, a condition characterized by a loss of gastric glands and associated with an increased cancer risk. For these reasons, one has to consider H. pylori eradication in infected GERD patients in need of PPI maintenance therapy.     

Association of LINC00673 rs11655237 polymorphism with cancer susceptibility: A meta-analysis based on 23,478 subjects

BackgroundSome studies on the relationship between LINC00673 polymorphism and cancer susceptibility have been inconsistent. To perform a more comprehensively quantitative assessment of LINC00673 rs11655237 and risk of overall cancer, we operated this meta-analysis for the first time.MethodsA comprehensive search was conducted to obtain relevant literature up to November 20, 2019. Pooled odds ratios and 95% confidence intervals were utilized to assess rs11655237 and cancer susceptibility under five different genetic models.ResultsEventually, 11 case-control studies from 9 articles were included. We found that LINC00673 rs11655237 polymorphism increased the susceptibility to overall cancer under all genetic models in the overall population. By dividing ethnicity and cancer type into subgroups, we also obtained similar positive results in subgroups of Chinese population, pancreatic cancer, cervical cancer, neuroblastoma, hepatoblastoma and gastric cancer.ConclusionOverall, this meta-analysis has demonstrated for the first time that LINC00673 rs11655237 could increase susceptibility to cancer.     

Effect of body-mass index on the risk of gastric cancer: A population-based cohort study in A Japanese population

BackgroundBody fatness and weight gain are considered probable causes of gastric cancer, specifically in the cardia region. However, limited evidence is available in Asia, where the burden of gastric cancer is high. The objective of this study was to determine an association between body-mass index (BMI) and gastric cancer risk using a large population prospective cohort.Methods92,056 subjects enrolled in the Japan Public Health Center-based prospective Study who reported their height and weight were followed up until the end of 2013. A Cox proportional hazards model was used to estimate the risk for gastric cancer and its subsite based on baseline BMI. A subgroup analysis was conducted taking account of Helicobacter pylori (H. pylori) infection and atrophic gastritis status.Results2,860 gastric cancer cases (2,047 men, 813 women), 307 proximal gastric cancer cases (244 men, 63 women), and 1967 distal gastric cancer cases (1,405 men, 562 women) were found during the follow-up period. Among men, baseline BMI ≥ 27 kg/m² increased the risk of overall gastric cancer (hazards ratio (HR) 1.23, 95% confidence interval (CI) 1.00–1.53). For both sexes, U-shaped increase in the risk was observed for proximal gastric cancer. Subgroup analysis showed a statistically significant association between the risk of proximal gastric cancer and BMI ≥ 27 kg/m² among those who were atrophic gastritis positive, H. pylori antibody positive, and those who tested positive to either or both atrophic gastritis and H. pylori antibody.ConclusionOur result suggests that gastric cancer risk increases for men with BMI ≥ 27 kg/m².     

Risk of primary haematologic cancers following incident non-metastatic breast cancer: A Danish population-based cohort study

BackgroundBreast cancer survivors may have increased risk of subsequent haematologic cancer. We compared their risk of haematologic cancers with the general population during 38 years of follow-up.MethodsUsing population-based Danish medical registries, we assembled a nationwide cohort of women diagnosed with incident non-metastatic breast cancer during 1980–2017, with follow-up through 2018. We compared breast cancer survivors with the general population by computing standardised incidence ratios (SIR) and 95% confidence intervals (CI).ResultsAmong 101,117 breast cancer survivors, we observed 815 incident haematologic cancers (median follow-up: 7.9 years). We observed excess risk of acute myeloid leukaemia (AML) (SIR: 1.65, 95%CI: 1.33–2.01), particularly in women who received chemotherapy (SIR: 3.33, 95%CI: 2.24–4.75) and premenopausal women (SIR: 3.23, 95%CI: 2.41–4.25). The risk of acute lymphoid leukaemia (ALL) was increased (SIR: 2.25, 95%CI: 1.29–3.66), whereas the risk of chronic lymphoid leukaemia (CLL) was decreased (SIR: 0.66, 95%CI: 0.53–0.82). An additional analysis showed elevated risk of CLL 0–6 months after breast cancer diagnosis (SIR: 3.00 95%CI: 1.75–4.80).ConclusionCompared to the general population, breast cancer survivors had elevated risk of AML, particularly when treated with chemotherapy. The risk of ALL was elevated, whereas the risk of CLL was lower. The higher risk of CLL in the first six months after diagnosis likely reflects surveillance bias—due to intensified diagnostic efforts at breast cancer diagnosis and treatment—prompting earlier detection. This has likely reduced the long-term risk of CLL in breast cancer survivors.     

Risk of Cancer in Patients with Iron Deficiency Anemia: A Nationwide Population-Based Study

ObjectiveThis study evaluated the risk of cancer among patients with iron deficiency anemia (IDA) by using a nationwide population-based data set.MethodPatients newly diagnosed with IDA and without antecedent cancer between 2000 and 2010 were recruited from the Taiwan National Health Insurance Research Database. The standardized incidence ratios (SIRs) of cancer types among patients with IDA were calculated.ResultsPatients with IDA exhibited an increased overall cancer risk (SIR: 2.15). Subgroup analysis showed that patients of both sexes and in all age groups had an increased SIR. After we excluded patients diagnosed with cancer within the first and first 5 years of IDA diagnosis, the SIRs remained significantly elevated at 1.43 and 1.30, respectively. In addition, the risks of pancreatic (SIR: 2.31), kidney (SIR: 2.23), liver (SIR: 1.94), and bladder cancers (SIR: 1.74) remained significantly increased after exclusion of patients diagnosed with cancer within 5 years after IDA diagnosis.ConclusionThe overall cancer risk was significantly elevated among patients with IDA. After we excluded patients diagnosed with IDA and cancer within 1 and 5 years, the SIRs remained significantly elevated compared with those of the general population. The increased risk of cancer was not confined to gastrointestinal cancer when the SIRs of pancreatic, kidney, liver, and bladder cancers significantly increased after exclusion of patients diagnosed with IDA and cancer within the first 5 years. This finding may be caused by immune activities altered by IDA. Further study is necessary to determine the association between IDA and cancer risk.