Low-Dose Aspirin and Prevention of Colorectal Cancer: Evidence From a Nationwide Registry-Based Cohort in Norway.

INTRODUCTION: To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC). METHODS: In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use. RESULTS: We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period. DISCUSSION: In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

Beta-blockade enhances anthracycline control of metastasis in triple-negative breast cancer.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Low-dose aspirin and risk of breast cancer: a Norwegian population-based cohort study of one million women.

Several studies evaluated the association between aspirin use and risk of breast cancer (BC), with inconsistent results. We identified women aged ≥ 50 years residing in Norway between 2004 and 2018, and linked data from nationwide registries; including the Cancer Registry of Norway, the Norwegian Prescription Database, and national health surveys. We used Cox regression models to estimate the association between low-dose aspirin use and BC risk, overall and by BC characteristics, women's age and body mass index (BMI), adjusting for sociodemographic factors and use of other medications. We included 1,083,629 women. During a median follow-up of 11.6 years, 257,442 (24%) women used aspirin, and 29,533 (3%) BCs occurred. For current use of aspirin, compared to never use, we found an indication of a reduced risk of oestrogen receptor-positive (ER +) BC (hazard ratio [HR] = 0.96, 95% confidence interval [CI]: 0.92-1.00), but not ER-negative BC (HR = 1.01, 95%CI: 0.90-1.13). The association with ER + BC was only found in women aged ≥ 65 years (HR = 0.95, 95%CI: 0.90-0.99), and became stronger as the duration of use increased (use of ≥ 4 years HR = 0.91, 95%CI: 0.85-0.98). BMI was available for 450,080 (42%) women. Current use of aspirin was associated with a reduced risk of ER + BC in women with BMI ≥ 25 (HR = 0.91, 95%CI: 0.83-0.99; HR = 0.86, 95%CI: 0.75-0.97 for use of ≥ 4 years), but not in women with BMI < 25.Use of low-dose aspirin was associated with reduced risk of ER + BC, in particular in women aged ≥ 65 years and overweight women.

Antimicrobial use in Sweden during the COVID-19 pandemic: prescription fill and inpatient care requisition patterns.

BACKGROUND: Increased and inappropriate antimicrobial use are the key drivers of the emergence of antimicrobial resistance, and there have been widespread concerns around potential antimicrobial misuse, overuse and their consequences during the COVID-19 pandemic. To better understand the impact of the pandemic on antimicrobial use, particularly in light of the resurgence of COVID-19 cases since the summer of 2020, we assessed trends in antimicrobial prescription fills and hospital requisitions in Sweden during 2020 against those of preceding years. METHODS: We performed a descriptive study using population-based data from the Swedish Prescribed Drug Register and the Swedish e-Health Agency. The weekly number of prescriptions filled and the total volume sold to inpatient care institutions in defined daily doses (DDDs) per 1000 inhabitants for systemic antibacterials (Anatomical Therapeutic Chemical therapeutic subgroup J01 excluding J01XX), antimycotics (J02), antivirals (J05) and antiprotozoals (P01) were computed and evaluated from time series graphs. A time series linear regression with ordinary least squares (OLS) estimation was used to model 2015-2019 data and predict the expected number of prescriptions filled and volumes sold in DDDs per 1000 inhabitants during 2020 with 95% confidence limits. RESULTS: From mid-March 2020, the weekly rate of antibiotic and antiprotozoal prescriptions filled plummeted to unprecedentedly low levels for the rest of the year; while unprecedentedly high numbers of antiviral prescriptions were filled weekly between mid-February and mid-March 2020. There was a net reduction in annual dispensing of antibiotics by 17%; of antiprotozoals by 21%; and of antivirals by 0.3% during 2020 compared to 2019. Inpatient care requisitions of antiprotozoals and antibiotics surged to 6-year highs during March 2020, resulting in a 127% increase in DDDs of antiprotozoals sold from 2019. The volume of antibiotics and antivirals sold to inpatient care institutions in 2020 decreased by 3% and 13% compared to 2019, respectively. CONCLUSIONS: The overall decline in antimicrobial prescriptions filled in Sweden during 2020 were in part, collateral dividends of the COVID-19 pandemic.

Temporal trends in lung cancer survival: a population-based study.

BACKGROUND: Lung cancer is the number one cancer-related cause of death in Sweden and worldwide. In most countries, five-year survival estimates vary between 10% and 20% with evidence of improved survival over time. Over the last decades, the management of lung cancer has changed including the introduction of national guidelines, new diagnostic procedures and treatments. This study aimed to investigate temporal trends in lung cancer survival both overall and in subgroups defined by established prognostic factors (i.e., sex, stage, histopathology and smoking history). MATERIALS AND METHODS: We estimated one-, two-, and five-year relative survival, and excess mortality, in patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016 in Sweden. We used population-based information available in a national lung cancer research database (LCBaSe) generated by cross-linkage between the Swedish National Lung Cancer Register and several Swedish health and sociodemographic registers. RESULTS: We included 36,935 patients diagnosed with squamous cell carcinoma or adenocarcinoma of the lung between 1995 and 2016. The overall one-, two- and five-year survival estimates increased between 1995 and 2016, from 38% to 53%, 21% to 37%, and 14% to 24%, respectively. Over the study period, we also found improved survival in subgroups, for example in patients with stages III-IV disease, patients with adenocarcinoma, and never-smokers. The excess mortality decreased over the study period, both overall and in all subgroups. CONCLUSION: Lung cancer survival increased over time in the overall lung cancer population. Of special note was evidence of improved survival in patients with stage IV disease. Our results corroborate a previously observed global trend of improved survival in patients with lung cancer.

Patterns of prescription dispensation and over-the-counter medication sales in Sweden during the COVID-19 pandemic.

INTRODUCTION: On February 26th 2020, a high alert was issued in Sweden in response to the diagnosis of the first few coronavirus disease 2019 (COVID-19) cases in the country. Subsequently, a decreased supply of essential goods, including medical products, was anticipated. We aimed to explore the weekly patterns of prescription dispensing and over-the-counter (OTC) medication sales in Sweden in 2020 compared with previous years, to assess the influence of the government restrictions on medication sales, and to assess whether there is evidence of medication stockpiling in the population. METHODS: Aggregated data on the weekly volume of defined daily doses (DDDs) of prescription medication dispensed and OTC sales from 2015 to 2020 were examined. From 2015-2019 data, the predicted weekly volume of DDDs for 2020 was estimated and compared to the observed volume for each ATC anatomical main group and therapeutic subgroup. RESULTS: From mid-February to mid-March 2020, there were increases in the weekly volumes of dispensed medication, peaking in the second week of March with a 46% increase in the observed versus predicted number of DDDs dispensed (16,440 vs 11,260 DDDs per 1000 inhabitants). A similar pattern was found in all age groups, in both sexes, and across metropolitan and non-metropolitan regions. In the same week in March, there was a 96% increase in the volume of OTC sold (2,504 vs 1,277 DDDs per 1000 inhabitants), specifically in ATC therapeutic subgroups including vitamins, antipyretics, painkillers, and nasal, throat, cough and cold preparations. CONCLUSION: Beginning in mid-February 2020, there were significant changes in the volume of prescription medication dispensed and OTC drugs sold. The weekly volume of DDDs quickly decreased following recommendations from public authorities. Overall, our findings suggest stockpiling behavior over a surge in new users of medication.

Antibiotic use prior to a lung cancer diagnosis: a population-based study.

AIM: To examine patterns of recent pre-diagnostic fillings of antibiotics as an indicator of early symptoms of lung cancer. METHODS: Individuals diagnosed with lung cancer (cases) in 2009-2016 were identified in the Swedish National Lung Cancer Register, a population-based register, and randomly matched with up to five individuals free of lung cancer (controls) from the general population. Conditional logistic models were used to estimate odds ratios for the association between lung cancer and a recent history of filled antibiotic prescriptions. RESULTS: The study included 27,017 cases and 129,355 controls. The likelihood of recent exposure was approximately two times higher in cases compared to controls. The magnitude of the effect size became more pronounced with proximity to the diagnosis of lung cancer and an increasing number of filled prescriptions. While the magnitude of the effect size did not differ by sex or educational level, it became attenuated with increasing age. There was no evidence supporting a trend in the magnitude of the effect size for the association between lung cancer and a history of repeated fillings by cancer stage. CONCLUSION: Lung cancer was associated with an increased likelihood of a recent history of filled antibiotic prescriptions. However, there was no evidence of an association between repeated fillings and a diagnostic delay, as reflected by stage. Our findings underscore the importance of clinical reassessment to rule out lung cancer following pneumonia treatment, especially for patients with multiple treatment cycles.

Outcomes in patients with lung cancer treated with crizotinib and erlotinib in routine clinical practice: A post-authorization safety cohort study conducted in Europe and in the United States.

PURPOSE: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice. METHODS: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately. RESULTS: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US. CONCLUSIONS: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases.

Clinical characteristics and survival in non-small cell lung cancer patients by smoking history: a population-based cohort study.

Introduction: Approximately, 10-15% of lung cancer patients have never smoked. Previous epidemiological studies on non-tobacco associated lung cancer have been hampered by selected data from a small number of hospitals or limited numbers of patients. By use of data from large population-based registers with national coverage, this study aims to compare characteristics and survival of patients with non-small cell lung cancer (NSCLC) with different smoking histories.Methods: Swedish national population-based registers were used to retrieve data on patients diagnosed with primary NSCLC between 2002 and 2016. The Kaplan-Meier method and Cox proportional hazard models were used to estimate overall survival and lung cancer-specific survival by smoking history.Results: In total, 41,262 patients with NSCLC were included. Of those, 4624 (11%) had never smoked. Never-smokers were more often women and older compared to ever smokers (current and former). Adenocarcinoma was proportionally more common in never-smokers (77%) compared to current (52%) and former smokers (57%). Stage IV disease was more common in never-smokers (57%) than in current (48%) and former smokers (48%). Epidermal growth factor receptor mutation was observed more in never-smokers (37%) compared to current (5%) and former smokers (9%). Both lung cancer-specific and overall survival were higher for never-smokers compared to current smokers.Conclusions: The observed differences in characteristics between never-smokers and smokers, and the higher survival in never-smokers compared to smokers from this large population-based study provide further evidence that lung cancer in never-smokers is clinically different to tobacco-associated lung cancer. The findings from this study emphasise the need for an improved understanding of genetics, pathogenesis, mechanisms and progression of non-tobacco associated lung cancer that may help prevent lung cancer or identify individually targeted treatments.

Exposure to antimuscarinic medications for treatment of overactive bladder and risk of lung cancer and colon cancer.

INTRODUCTION: One out of six adults has symptoms of overactive bladder (OAB). Antimuscarinic medication is the main pharmacological group used in the treatment of OAB. In preclinical studies, antimuscarinic compounds have been found to inhibit cell proliferation in lung cancer and colon cancer. OBJECTIVE: The aim of this study was to investigate the association between exposure to anti-muscarinic medication and the risk of lung cancer and colon cancer. METHODS: Individuals in Sweden who first filled a prescription for an antimuscarinic medication used to treat OAB (ie, oxybutynin, solifenacin, darifenacin, fesoterodine, or tolterodine) between July 1, 2006, and December 31, 2012, were identified and classified as exposed. Each exposed individual was individually matched with up to ten unexposed individuals from the Swedish general population, based on year of birth, sex, and county of residence. Cox proportional hazard models with follow-up time as the underlying time scale were used to estimate HRs with 95% CIs. RESULTS: In total, 164,000 exposed and 1,446,472 unexposed individuals were included in this study. The estimated HRs for lung cancer, in follow-up time intervals of <1 year, 1-4 years, and ≥4 years, were as follows: 0.86 (95% CI: 0.75-0.98), 0.63 (95% CI: 0.56-0.70), and 0.43 (0.34-0.55), respectively. The corresponding estimates for colon cancer were as follows: 0.91 (95% CI: 0.80-1.03), 0.81 (95% CI: 0.74-0.88), and 0.61 (95% CI: 0.51-0.73), respectively. CONCLUSION: There was an inverse association between exposure to antimuscarinic medications, used in the treatment of OAB, and a diagnosis of colon cancer or lung cancer, which is in line with the findings in preclinical studies.

Pharmacological agents preceding a diagnosis of immune thrombocytopenia in adult patients developing the chronic form: A Swedish national register study.

Patients with primary chronic immune thrombocytopenia (cITP) have been reported to use more anti-infective medications, even before diagnosis of immune thrombocytopenia (ITP). The more common use of anti-infective medications may be due to general health problems, requiring medication in the early stages of cITP and before the diagnosis is set, rather than infections preceding the disease. Accordingly, cITP may not only be associated with use of anti-infective medications but also with medications for more general symptoms. OBJECTIVE: To investigate use of medications for general symptoms, such as analgesics and vitamin supplements in patients with ITP developing the chronic form, the year preceding their first primary diagnosis in comparison with such use in the general population. METHOD: Swedish Health Registers were used to identify adult patients (n=1087) with primary cITP during 2006-2012 and data on medications. Standardized Incidence Ratios (SIRs) and 95% confidence intervals (CI), were estimated as a measure of relative risk. RESULTS: The association for overall studied medications was SIR=1.36 (95% CI 1.32-1.41). A majority of the point estimates were above unity. CONCLUSION: In patients with cITP, prescription fills for medications used to treat pain conditions and vitamin deficiencies are more common in the year preceding their first diagnosis as compared with prescription fills in the general population. Our results suggest that patients later diagnosed with cITP receive treatment due to symptoms that could be signs of an early ITP. Accordingly, in investigations for unspecific pain symptoms and vitamin deficiencies, cITP should be considered as a differential diagnosis.

Maternal and infant characteristics: differences and similarities between the Nordic countries and the US.

BACKGROUND: Data from the Nordic health care registers have been of great value in perinatal epidemiological research. It has been assumed that findings from the Nordic population (Denmark, Finland, Iceland, Norway, and Sweden) are applicable to other populations as well, including the population of the US. OBJECTIVE: To describe and compare maternal and infant characteristics between the Nordic and the American populations as recorded in the official statistics. MATERIALS AND METHODS: This population-based study included data on all females who gave birth and their infants in the Nordic countries and the US. The data were obtained from the US National Center for Health Statistics and the official statistics data for the Nordic countries. The data from all six countries included births from 2006 to 2010. RESULTS: The mean maternal age at delivery was lower in the US than in the Nordic countries (27.5 vs 30.3 years). Cesarean sections (32.2% vs 17.9%), low birth weight (8.2% vs 4.8%), and preterm birth (12.3% vs 5.9%) were more common in the US than in the Nordic countries. Smoking during early pregnancy was slightly less common in the US compared with Nordic countries (9.8% vs 11.2%). Restricting the data from the US to females with a university degree, characteristics such as age at delivery, birth weight, and preterm deliveries were more in alignment with the Nordic data. CONCLUSION: There are differences in some key maternal and neonatal characteristics between the Nordic countries and the US. However, some characteristics are related to socioeconomic status, suggesting that the Nordic data seem to be applicable to the part of the population in the US with a higher socioeconomic status.