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Despite advances in cancer treatment and surgery, cancer-related mortality remains the leading cause of death globally, harvesting over ten million lives annually. While the risk factors are both hormonal and non-hormonal, common prescription drugs’ long-term effects are understudied and likely even underestimated. Particularly drugs including oestrogens or those altering the metabolism of oestrogens may promote carcinogenesis of oestrogen receptor sensitive cancers and possibly even lower the risk of sex hormone-associated cancers. Two common examples of such prescription drugs are systemic menopausal hormone therapy (MHT) and oral antibiotic treatment. Historically, preventive measures have been the key factor in our unending battle against cancer’s burden. This doctoral thesis within clinical epidemiology was conducted to evaluate the association between exposure to contemporary MHT use and cancer risk (Studies I and II); and colorectal cancer mortality (Study IV). These associations were investigated on a population level, longitudinally, based on nationwide and population-based cohort studies, taking advantage of the unique Swedish prescription feature, including various MHT treatment options. Notably, these large-scale cohort studies are feasible to conduct only in a few other countries than Sweden, underscoring the importance of valid evidence from methodologically well-grounded studies with complete and reliable data sources. Furthermore, Study III aimed to clarify the posed association between exposure to oral antibiotic treatment and colorectal cancer risk based on a systematic review and dose-response meta-analysis. For Studies I, II, and IV, data were retrieved from the Swedish Prescribed Drug Registry, Swedish Cancer Registry, Causes of Death Registry, Patient Registry, and the Total Population Registry (Study I only). Study I evaluated the net effect of systemic MHT use on cancer risk; and 16 different cancer types. The findings suggested an associatio

BACKGROUND: Menopausal hormone therapy (MHT) reduces the risk of developing colorectal cancer (CRC), yet it is largely unclear whether it could also influence survival in women with CRC. Therefore, we aimed to investigate the influence of prediagnostic MHT use on CRC-specific and all-cause mortality in women with CRC. METHODS: This nationwide nested cohort study, within a large population-based matched cohort, included all women diagnosed with incident CRC between January 2006 and December 2012 (N = 7814). A total of 1529 women had received at least one dispensed prescription of systemic MHT before CRC diagnosis, and 6285 CRC women with CRC did not receive MHT during the study period, as ascertained from the Swedish Prescribed Drug Registry. Multivariable Cox regression models provided adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for CRC-specific mortality and all-cause mortality. RESULTS: Past use of prediagnostic estrogen-only therapy (E-MHT) was associated with lower CRC-specific (HR = 0.67, 95%CI 0.44-0.99) and all-cause mortality (HR = 0.68, 95%CI 0.59-0.93). However, all-cause mortality (HR = 1.23, 95%CI 1.02-1.48) was elevated among current prediagnostic E-MHT users who were 70+ years at diagnosis. Current estrogen combined progestin therapy (EP-MHT) was associated with higher CRC-specific mortality (HR = 1.61, 95%CI 1.06-2.44) in older women, but no association was shown for all-cause mortality. CONCLUSIONS: Our findings suggest that E-MHT, but not EP-MHT use, might be associated with improved CRC survival, indicating a potential role of estrogens in sex hormone-related cancers. However, association of MHT use with grade of cancer remains unclear., Funding Agency:China Scholarship Council 201700260302

BACKGROUND: Menopausal hormone therapy (MHT) has been associated with various malignancies. AIMS: To investigate the association of various MHT regimens with the risk of colorectal cancer (CRC). METHODS: All MHT ever-users (n = 290 186) were included through the Swedish Prescribed Drug Registry, with a 1:3 group-level matching to non-users. Ever-users were defined as women who received ≥1 dispensed prescription of systemic MHT during 2005-2012 in Sweden. All CRC cases after drug initiation were extracted from the Swedish Cancer Registry. The association was assessed by multivariable conditional logistic and Cox regression models, presented as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) considering different regimens, duration and age at treatment initiation. RESULTS: Compared with non-users, MHT users had an overall reduced odds for colon (OR = 0.67, 95% CI 0.63-0.72) and rectal adenocarcinoma (OR = 0.66, 95% CI 0.60-0.73), especially among women aged 40-60 years. Current users of oestrogen-only preparations (E-MHT) showed a reduced odds (colon OR = 0.73, 95% CI 0.65-0.82; rectal OR = 0.76, 95% CI 0.64-0.90) compared to non-users, particularly with oestradiol and oestriol. Past E-MHT use showed stronger odds reductions (colon OR = 0.49, 95% CI 0.43-0.56; rectal OR = 0.36, 95% CI 0.28-0.45). Current use of oestrogen combined progestin therapy (EP-MHT) indicated a less prominent odds reduction (colon adenocarcinoma OR 0.62, 95% CI 0.54-0.72; rectal adenocarcinoma OR = 0.60, 95% CI 0.49-0.74) than past users. Tibolone showed an increased risk of left-sided colorectal adenocarcinoma. Oral and cutaneous MHT usage showed similar patterns. CONCLUSIONS: MHT use may decrease colorectal adenocarcinoma risk, for both E-MHT and EP-MHT, and especially in past users.

Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta-analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co-infected, compared to HBV mono-infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross-sectional studies. Random-effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta-regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co-infected and 57,620 chronic HBV mono-infected patients were analysed. The overall pooled ES showed that HBV/HDV co-infected patients were at 2-fold increased risk of HCC compared to HBV mono-infected patients (ES = 2.12, 95% CI 1.14-3.95, I2 = 72%, N = 12). A six-fold significant increased risk of HCC was noted among HIV/HBV/HDV triple-infected, compared to HIV/HBV co-infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow-up duration in univariable meta-regression analysis. This systematic review and meta-analysis shows that infection with HDV is associated with a 2-fold higher risk of HCC development compared to HBV mono-infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted., Funding agencies:Foundation of ALFFoundation of Becas-Chile, (ANID, National Agency of Investigation and Research, Chile)Center for innovative medicine CIMED 20180889 AbbVieGilead Sciences