Abstract
Study Question
Is hormone replacement therapy (HRT) associated with an increased risk of melanoma skin cancer or prognostic outcomes amongst post-menopausal women?
SUMMARY ANSWER
Whilst we ...found evidence of an association with melanoma risk, the lack of dose-response and associations observed with recent use, localised disease and intravaginal oestrogens suggests this is a non-causal association.
WHAT IS KNOWN ALREADY
Evidence on HRT and melanoma risk remains inconclusive, with studies providing conflicting results. Furthermore, evidence on melanoma survival is sparse, with only one previous study reporting protective associations with HRT use, likely attributable to immortal time bias.
STUDY DESIGN, SIZE, DURATION
We conducted a nation-wide population-based case-control study and a retrospective cohort study utilising the Danish healthcare registries. Case-control analyses included 8279 women aged 45–85 with a first-ever diagnosis of malignant melanoma between 2000 and 2015, matched by age and calendar time to 165 580 population controls. A cohort of 6575 patients with a diagnosis of primary malignant melanoma between 2000 and 2013 and followed through 2015 was examined to determine if HRT use had an impact on melanoma survival outcomes.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Based on prescriptions dispensed since 1995, ever-use of HRT was defined as having filled at least one prescription for HRT prior to the index date. In total, 2629 cases (31.8%) and 47 026 controls (28.4%) used HRT. Conditional logistic regression was used to calculate odds ratios (ORs) for melanoma risk according to HRT use, compared with non-use, adjusting for potential confounders. For cohort analyses, Cox proportional hazards models was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for second melanoma incidence and all-cause mortality associated with HRT.
MAIN RESULTS AND THE ROLE OF CHANCE
High use of HRT was associated with an OR of 1.21 (95% CI 1.13–1.29) for melanoma risk, with no evidence of a dose-response pattern. Results were most pronounced amongst recent high users (OR, 1.28; 95% CI 1.17–1.41), for localised disease (OR, 1.25; 95% CI 1.15–1.36) and for intravaginal oestrogen therapy (OR, 1.38; 95% CI 1.13–1.68). Compared with non-use, there was no evidence of an association for secondary melanoma for post-diagnostic new-use (fully adjusted HR, 1.56; 95% CI 0.64–3.80) or continuous HRT use (fully adjusted HR, 1.26; 95% CI 0.89–1.78). Similar associations were observed for all-cause mortality.
LIMITATIONS, REASONS FOR CAUTION
Despite the large sample size and the use of robust population-based registries with almost complete coverage, we lacked information on some important confounders including sun exposure.
WIDER IMPLICATIONS OF THE FINDINGS
Whilst we cannot rule out an association between HRT use and melanoma risk, the associations observed are also compatible with increased healthcare utilisation and thus increased melanoma detection amongst HRT users. No association between HRT use and melanoma survival outcomes was observed. This should provide some reassurance to patients and clinicians, particularly concerning the use of HRT in patients with a history of melanoma.
STUDY FUNDING/COMPETING INTEREST(S)
B.M.H. is funded by a Cancer Research UK Population Research Postdoctoral Fellowship. The funding source had no influence on the design or conduct of this study. A.P. reports participation in research projects funded by Alcon, Almirall, Astellas, Astra-Zeneca, Boehringer-Ingelheim, Servier, Novo Nordisk and LEO Pharma, all with funds paid to the institution where he was employed (no personal fees) and with no relation to the work reported in this article. The other authors have no competing interests to declare.
TRIAL REGISTRATION NUMBER
N/A.
The treatment of traumatic tympanic membrane perforations varies in different investigations, ranging from observation to early surgical repair. The present study aimed to focus on the closure rate ...and the closure time in a group of patients treated with a watchful waiting policy.
The study comprised 133 consecutive patients with a total of 137 perforations. Data were evaluated in terms of aetiology, location and size of perforation, audiometric findings, closure rate, and closure time.
The overall closure rate was 97 per cent. For patients with a known closure time within three months, the median closure time was between three and four weeks. The probability of spontaneous closure over time was further analysed with Kaplan-Meier plots, for those perforations with known closure times and for all perforations including those with unknown closure times. Perforation size was the only significant determining factor for closure time.
Small perforations had a high probability of spontaneous closure within three to four weeks, justifying a watchful waiting policy. Larger uncomplicated perforations might warrant early surgical repair, depending on the patient's needs and the availability of surgery.
The aim of this investigation was to identify pathogenic variants of the ryanodine receptor 2 (
RYR2
) gene in a cohort of persons aged 0–40 years who died of sudden unexpected death syndrome (SUD), ...including a cohort of infants who died of sudden infant death syndrome (SIDS). We genetically screened 29 of the 105 exons of the
RYR2
gene associated with catecholaminergic polymorphic ventricular tachycardia (CPVT) in 74 cases of SUD without reported structural abnormalities of the heart. Cases were selected from the case database at the Institute of Forensic Medicine, and subsequent mutational screening by DNA sequencing was performed to detect variants in DNA samples extracted from blood samples of deceased persons. A total of 7 of the examined 74 cases were heterozygous for a rare sequence variant in the
RYR2
gene. We identified five novel missense variants (p.Q486H, p.D1872N, p.G2367R, p.E4213D, and p.H4579Y), one synonymous variant (p.L4767L), and one previously reported missense variant (p.G4315E). Follow-up studies were possible in family members of three probands (p.Q486H, p.D1872N, and p.H4579Y), and clinical examinations were conducted in family members of two of these probands (p.Q486H and p.H4579Y). In conclusion, we identified a higher prevalence of variants in the CPVT-associated gene
RYR2
than in a previously reported cohort of SIDS (9.4% vs. 1–2%). Segregation studies show that one variant (p.H4579Y) co-segregates with CPVT and is presumed to be pathogenic.
Colorectal cancer management may require an ostomy formation; however, a stoma may negatively impact health-related quality of life (HRQoL). This study aimed to compare generic and stoma-specific ...HRQoL in patients with a permanent colostomy after rectal cancer across different countries.
A cross-sectional cohorts of patients with a colostomy after rectal cancer in Denmark, Sweden, Spain, the Netherlands, China, Portugal, Australia, Lithuania, Egypt, and Israel were invited to complete questionnaires regarding demographic and socioeconomic factors along with the Colostomy Impact (CI) score, European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and five anchor questions assessing colostomy impact on HRQoL. The background characteristics of the cohorts from each country were compared and generic HRQoL was measured with the EORTC QLQ-C30 presented for the total cohort. Results were compared with normative data of reference European populations. The predictors of reduced HRQoL were investigated by multivariable logistic regression, including demographic and socioeconomic factors and stoma-related problems.
A total of 2557 patients were included. Response rates varied between 51-93 per cent. Mean time from stoma creation was 2.5-6.2 (range 1.1-39.2) years. A total of 25.8 per cent of patients reported that their colostomy impairs their HRQoL 'some'/'a lot'. This group had significantly unfavourable scores across all EORTC subscales compared with patients reporting 'no'/'a little' impaired HRQoL. Generic HRQoL differed significantly between countries, but resembled the HRQoL of reference populations. Multivariable logistic regression showed that stoma dysfunction, including high CI score (OR 3.32), financial burden from the stoma (OR 1.98), unemployment (OR 2.74), being single/widowed (OR 1.35) and young age (OR 1.01 per year) predicted reduced stoma-related HRQoL.
Overall HRQoL is preserved in patients with a colostomy after rectal cancer, but a quarter of the patients interviewed reported impaired HRQoL. Differences among several countries were reported and socioeconomic factors correlated with reduced quality of life.
Purpose
Current response assessment systems for cancer patients receiving immunotherapy are limited. This is due to the associated inflammatory response that may confound the conventional ...morphological response evaluation criteria in solid tumors and metabolic positron emission tomography (PET) response criteria in solid. Recently, novel PET imaging techniques using radiolabeled antibodies and fragments have emerged as a particularly sensitive and specific modality for quantitative tracking of immune cell dynamics. Therefore, we sought to investigate the utility of Cu-64 labeled F(ab)′2 fragments for
in vivo
detection of CD8a
+
T cells as a prognostic imaging biomarker of response to immunotherapy in an immunocompetent mouse model of colorectal cancer.
Procedures
64
CuNOTA-CD8a was produced by enzymatic digestion of rat-anti-mouse CD8a antibody (clone YTS169.4), purified yielding isolated CD8a-F(ab)′2 fragments and randomly conjugated with the 2-
S
-(isothiocyanatbenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (
p
-SCN-Bn-NOTA) chelator. NOTA-CD8a was radiolabeled with Cu-64 and injected into CT26 tumor-bearing mice for longitudinal assessment. To investigate the value of
64
CuNOTA-CD8a PET imaging for assessment of treatment response, CT26 tumor-bearing mice were subjected to external radiation therapy (XRT) in combination with anti-CTLA-4 therapy. Imaging data was supported by flow cytometry and immunohistochemistry (IHC).
Results
Combination treatment with XRT and anti-CTLA-4 effectively inhibited tumor growth until day 22 post-therapy initiation (
p
= 0.0025) and increased the overall survival of mice compared to control (
p
= 0.0017). The
64
CuNOTA-CD8a tumor-to-heart ratio was increased in XRT + anti-CTLA-4-treated mice on day 8 after initiation of therapy (
p
= 0.0246). Flow cytometry and IHC confirmed the increase in tumor-infiltrating CD8a
+
cells in XRT + anti-CTLA-4-treated mice. Furthermore,
64
CuNOTA-CD8a PET imaging distinguished responders and non-responders prior to treatment-induced changes in tumor volume among mice.
Conclusion
In the present study, we demonstrated that
64
CuNOTA-CD8a was able to detect treatment-induced changes in CD8a
+
infiltration in murine CT26 colon tumors following a common preclinical combination treatment protocol. Overall,
64
CuNOTA-CD8a exhibited good prognostic and predictive value. We suggest that
64
CuNOTA-CD8a PET imaging can be used as an early biomarker of response to therapy in preclinical models.
Humic-like substances (HULIS) comprise a significant fraction of the organic compounds in aerosol particles. In the present study we report the chemical properties of HULIS samples originating from ...urban (Copenhagen, Denmark), rural (Melpitz, Germany) and remote (Storm Peak Laboratory, CO, USA) environments. Suwannee River Fulvic Acid Standard (SRFA) was included in the study as a reference. Raman, Fourier transform infrared (FTIR) and ultraviolet-visible (UV-Vis) spectroscopy were used together with high performance liquid chromatography-mass spectrometry (HPLC-MS) for characterisation of the samples. The same main functional groups were present in all samples, but the relative abundance of functional groups varied among the studied samples, which was mainly evident from the FTIR spectra. The urban and rural samples were found to be very similar with respect to the relative abundance of functional groups. The remote sample contained relatively more C=O and COOH groups, which may be due to the remote environment. Organonitrates appeared to be present in the three atmospheric samples, while it did not appear to be present in the SRFA. The SRFA sample comprised significantly larger amounts of aromatic groups relative to the atmospheric samples in line with previous findings. All the obtained mass spectra showed clear periods of 14-16 Da in line with previous studies. The estimated average molecular weight (AMW) was comparable for the atmospheric samples within the errors - while the AMW of SRFA was higher. In general the atmospheric HULIS samples from different environments were rather similar with respect to the properties investigated.
The influence of organic and conventional farming practices on the content of single nutrients in plants is disputed in the scientific literature. Here, large-scale untargeted LC-MS-based ...metabolomics was used to compare the composition of white cabbage from organic and conventional agriculture, measuring 1,600 compounds. Cabbage was sampled in 2 years from one conventional and two organic farming systems in a rigidly controlled long-term field trial in Denmark. Using Orthogonal Projection to Latent Structures–Discriminant Analysis (OPLS-DA), we found that the production system leaves a significant (
p
= 0.013) imprint in the white cabbage metabolome that is retained between production years. We externally validated this finding by predicting the production system of samples from one year using a classification model built on samples from the other year, with a correct classification in 83 % of cases. Thus, it was concluded that the investigated conventional and organic management practices have a systematic impact on the metabolome of white cabbage. This emphasizes the potential of untargeted metabolomics for authenticity testing of organic plant products.
Partitioning of electron acceptors and macrofaunal bioirrigation were assessed in sediments from 4 stations along a Skagerrak–Kattegat–Belt Sea depth transect. Sediment was examined for benthic fauna ...composition and abundance, sediment–water fluxes (O₂, dissolved inorganic carbon DIC, NH₄⁺, and NO₃⁻), anaerobic reactions (carbon oxidation Cox, sulfate reduction SR, manganese reduction MnR, iron reduction FeR, and ammonification Nmin), porewater profiles (O₂, DIC, SO₄2− and NH₄⁺), and solid phase profiles (organic content, Fe and Mn). Deep stations had less than half the abundance of benthic fauna than shallow stations, while the Belt Sea station was azoic due to bottom-water hypoxia. Solute fluxes and anaerobic reactions showed order-of-magnitude lower rates in sediment from deep than from shallow water. In general, anaerobic Cox in sediments along the Skagerrak−Kattegat−Belt Sea transect is dominated by SR (>50%) in shallow water and decreases gradually when moving into deeper water and reaches 0 at ~700 m depth. FeR increases from 0 in shallow water to ~50% at ~600 m, but rapidly reaches 0 again at 700 m. MnR is close to 0 down to at least 500 m and increases to complete dominance at 700 m. The contribution of denitrification is generally below 10% at all depths. Bioirrigation—quantified as non-local exchange through diagenetic modelling—is proportional to fauna biomass and functional traits. The Br⁻ tracer approach to determine bioirrigation on newly extracted sediment onboard a ship is not recommended. It is concluded that enhanced downward translocation of O₂ into anoxic sediment through bioirrigation is the major mechanism reoxidizing subsurface metals in the deep Skagerrak and Kattegat.
PDF
