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Mohammadhossein Hajiebrahimi,1,2 Ci Song,3 David Hägg,1 Therese M-L Andersson,4 Reginald Villacorta,5 Marie Linder1 1Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Statistics and Epidemiology, Public Health Faculty, Golestan University of Medical Sciences, Gorgan, Iran; 3Janssen GCSO, Stockholm, Sweden; 4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 5Market Access Department, Janssen Pharmaceuticals, Horsham, PA, USACorrespondence: Mohammadhossein Hajiebrahimi Email mohammadhossein.hajiebrahimi@synergusrwe.comPurpose: To assess the relative risk of metabolic risk factors in patients stratified by psoriasis severity compared with population controls.Patients and Methods: A retrospective cohort study was conducted using national Swedish registers. Adult patients with psoriasis were selected if they had a dispensing of anti-psoriasis prescription (2007– 2013) and at least one diagnosis within five years before the dispensing date. The patients with psoriasis were matched 1:10 to controls from the general population on birth year, sex, and county. The cohort was further divided into three disease severity groups (mild, moderate, or severe) based on their dispensed anti-psoriasis medication. Subjects were followed from the index date until censoring. We applied flexible parametric modeling to understand the risks of the incident comorbidities hypertension, hypercholesterolemia, and diabetes mellitus among patients with psoriasis from 6 months through 10 years. Hazard ratios and predicted risk (ie, 1 minus the survival probability) of comorbidities were reported.Results: The hazard of hypertension, hypercholesterolemia, and diabetes mellitus is higher among psoriasis patients compared with population controls, and the hazard ratio increases with psoriasis severity. For example, HRs of hypertension for patients with mild, moderate, and severe psoriasis are 1.29 (95% CI: 1.27– 1.32), 1.35 (95% CI: 1.32– 1.38), and 1.73 (95% CI: 1.64– 1.82), respectively. The predicted risk of hypertension, hypercholesterolemia, and diabetes mellitus among patients with severe psoriasis at year ten was 0.58 (95% CI: 0.56, 0.59), 0.33 (95% CI: 0.32, 0.35), and 0.21 (95% CI: 0.20, 0.23), respectively, while it was 0.42 (0.41, 0.43), 0.23 (0.22, 0.23), 0.11 (0.10, 0.11) among controls, respectively. The predicted risk at year ten was similar among patients with mild or moderate psoriasis.Conclusion: The HRs and predicted risks of metabolic risk factors are higher among patients with psoriasis compared with matched controls and are more prominent among the severe psoriasis group.Keywords: psoriasis severity, predicted risk, survival probability, population-based, metabolic risk factors

Qianwei Liu,1 Therese ML Andersson,2 Anna Jöud,3,4 Qing Shen,2 Maria EC Schelin,3,5 Patrik KE Magnusson,2 Karin E Smedby,6 Fang Fang1 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 3Lund University, Department of Clinical Sciences Lund, Orthopaedics, Lund, Sweden; 4Lund University, Department of Laboratory Medicine, Occupational and Environmental Medicine, Lund, Sweden; 5Institute for Palliative Care, IKVL, Lund University and Region Skåne, Lund, Sweden; 6Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, SwedenCorrespondence: Fang FangInstitute of Environmental Medicine, Karolinska Institutet, Box 23109, 104 35, Stockholm, SwedenTel +46 8 52486131Email fang.fang@ki.seBackground: Little attention has been given to the risk of cardiovascular and psychiatric comorbidities during the clinical evaluation of a suspected hematological malignancy.Methods: Based on Skåne Healthcare Register, we performed a population-based cohort study of 1,527,449 individuals residing during 2005–2014 in Skåne, Sweden. We calculated the incidence rate ratios (IRRs) of cardiovascular diseases or psychiatric disorders during the diagnostic workup of 5495 patients with hematological malignancy and 18,906 individuals that underwent a bone marrow aspiration or biopsy or lymph node biopsy without receiving a diagnosis of any malignancy (“biopsied individuals”), compared to individuals without such experience (i.e., reference).Results: There was a higher rate of cardiovascular diseases during the diagnostic workup of patients with hematological malignancy (overall IRR, 3.3; 95% CI, 2.9 to 3.8; greatest IRR for embolism and thrombosis, 8.1; 95% CI, 5.2 to 12.8) and biopsied individuals (overall IRR, 4.9; 95% CI, 4.6 to 5.3; greatest IRR for stroke, 37.5; 95% CI, 34.1 to 41.2), compared to reference. Similarly, there was a higher rate of psychiatric disorders during the diagnostic workup of patients with hematological malignancy (IRR, 2.1; 95% CI, 1.5 to 2.8) and biopsied individuals (IRR, 3.1; 95% CI, 2.9 to 3.4). The rate increases were greater around the time of diagnosis or biopsy, compared to thereafter, for both outcomes.Conclusion: There were higher rates of cardiovascular diseases and psychiatric disorders during the diagnostic workup of a suspected hematological malignancy, regardless of the final diagnosis.Keywords: hematological malignancy, cardiovascular diseases, psychiatric disorders, diagnostic workup

Objective: The Nordic Nutrition Recommendations (NNR) aim at preventing diet-associated diseases such as cancer in the Nordic countries. We evaluated adherence to the NNR in relation to prostate cancer (PC) in Swedish men, including potential interaction with a genetic risk score and with lifestyle factors.Design: Population-based case-control study (Cancer of the Prostate in Sweden (CAPS), 2001-2002). Using data from a semi-quantitative FFQ, we created an NNR adherence score and estimated relative risks of PC by unconditional logistic regression. Individual score components were modelled separately and potential modifying effects were assessed on the multiplicative scale.Setting: Four regions in the central and northern parts of Sweden.Subjects: Incident PC patients (n 1386) and population controls (n 940), frequency-matched on age and region.Results: No overall association with PC was found, possibly due to the generally high adherence to the NNR score and its narrow distribution in the study population. Among individual NNR score components, high compared with low intakes of polyunsaturated fat were associated with an increased relative risk of localized PC. No formal interaction with genetic or lifestyle factors was observed, although in stratified analysis a positive association between the NNR and PC was suggested among men with a high genetic risk score but not among men with a medium or low genetic risk score.Conclusions: Our findings do not support an association between NNR adherence and PC. The suggestive interaction with the genetic risk score deserves further investigations in other study populations. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate if the previously reported improvements in lung cancer survival were consistent across age at diagnosis and by lung cancer subtypes., Materials and Methods: Data on lung cancers diagnosed between 1990 and 2016 in Denmark, Finland, Iceland, Norway and Sweden were obtained from the NORDCAN database. Flexible parametric models were used to estimate age-standardized and age-specific relative survival by sex, as well as reference-adjusted crude probabilities of death and life-years lost. Age-standardised survival was also estimated by the three major subtypes; adenocarcincoma, squamous cell and small-cell carcinoma., Results: Both 1- and 5-year relative survival improved continuously in all countries. The pattern of improvement was similar across age groups and by subtype. The largest improvements in survival were seen in Denmark, while improvements were comparatively smaller in Finland. In the most recent period, age-standardised estimates of 5-year relative survival ranged from 13% to 26% and the 5-year crude probability of death due to lung cancer ranged from 73% to 85%. Across all Nordic countries, survival decreased with age, and was lower in men and for small-cell carcinoma., Conclusion: Lung cancer survival has improved substantially since 1990, in both women and men and across age. The improvements were seen in all major subtypes. However, lung cancer survival remains poor, with three out of four patients dying from their lung cancer within five years of diagnosis., Competing Interests: Declaration of competing interest PCL received support from the Swedish Cancer Society and the Swedish Research Council for the submitted work. ML received support from the Swedish Cancer Society for the submitted work. ML owns stock in Pfizer and Astra Zeneca. The authors have no other relationships of activities that could appear to have influenced the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Differences in the prognosis after colorectal cancer (CRC) by socioeconomic position (SEP) have been reported previously; however, most studies focused on survival differences at a particular time since diagnosis. We quantified the lifetime impact of CRC and its variation by SEP, using individualised income to conceptualise SEP., Methods: Data included all adults with a first-time diagnosis of colon or rectal cancers in Sweden between 2008 and 2021. The analysis was done separately for colon and rectal cancers using flexible parametric models. For each cancer and income group, we estimated the life expectancy in the absence of cancer, the life expectancy in the presence of cancer and the loss in life expectancy (LLE)., Results: We found large income disparities in life expectancy after a cancer diagnosis, with larger differences among the youngest patients. Higher income resulted in more years lost following a cancer diagnosis. For example, 40-year-old females with colon cancer lost 17.64 years if in the highest-income group and 13.68 years if in the lowest-income group. Rectal cancer resulted in higher LLE compared with colon cancer. Males lost a larger proportion of their lives. All patients, including the oldest, lost more than 30% of their remaining life expectancy. Based on the number of colon and rectal cancer diagnoses in 2021, colon cancer results in almost double the number of years lost compared with rectal cancer (24 669 and 12 105 years, respectively)., Conclusion: While our results should be interpreted in line with what individualised income represents, they highlight the need to address inequalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The survival in patients diagnosed with cutaneous malignant melanoma (CMM) has improved in the Nordic countries in the last decades. It is of interest to know if these improvements are observed in all ages and for both women and men., Methods: Patients diagnosed with CMM in the Nordic countries in 1990-2016 were identified in the NORDCAN database. Flexible parametric relative survival models were fitted, except for Iceland where a non-parametric Pohar-Perme approach was used. A range of survival metrics were estimated by sex, both age-standardised and age-specific., Results: The 5-year relative survival improved in all countries, in both women and men and across age. While the improvement was more pronounced in men, women still had a higher survival at the end of the study period. The survival was generally high, with age-standardised estimates of 5-year relative survival towards the end of the study period ranging from 85% in Icelandic men to 95% in Danish women. The age-standardised and reference-adjusted 5-year crude probability of death due to CMM ranged from 5% in Danish and Swedish women to 13% in Icelandic men., Conclusion: Although survival following CMM was relatively high in the Nordic countries in 1990, continued improvements in survival were observed throughout the study period in both women and men and across age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could appear to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Myeloproliferative neoplasms (MPN) are associated with inferior pregnancy outcome, however, little is known about fertility and childbearing potential in women with MPN. In this study we aimed to describe reproductive patterns, as well as to quantify risk of miscarriage and stillbirth. Women aged 15-44 years with an MPN diagnosis 1973-2018, were identified in Swedish health care registers, and age-matched 1:4 to population controls. We identified 1141 women with MPN and 4564 controls. Women with MPN had a lower rate of childbirth (hazard ratio [HR] with 95% confidence interval was 0.78 (0.68-0.90)). Subgroup analysis showed that the rate was not significantly reduced in essential thrombocythemia, HR 1.02 (0.86-1.22) while the HR was 0.50 (0.33-0.76) in PV and 0.45 (0.28-0.74) in PMF. The risk of miscarriage was not significantly increased before MPN diagnosis, the HR during follow-up after diagnosis was 1.25 (0.89-1.76). Women with MPN were more likely to have had a previous stillbirth. Women with MPN had fewer children at diagnosis, and fewer children in total. In conclusion, the childbirth rate was lower among women with MPN than controls, but not among women with essential thrombocythemia., (© 2024. The Author(s).)

Background: Survival in cutaneous melanoma (CM) is heterogeneous. Loss in life expectancy (LLE) measures impact of CM on remaining lifespan compared to general population., Objectives: Investigating LLE in operated stage II-III CM patients., Methods: Data from 8061 patients (aged 40-80 years) with stage II-III CM in Sweden, diagnosed between 2005 and 2018, were analyzed (Swedish Melanoma Registry). A flexible parametric survival model estimated life expectancy and LLE., Results: Based on 2018 diagnoses, stage II and III CM patients lost 2209 and 1902 life years, respectively. LLE was higher in stage III: 5.2 versus 10.9 years (stage II vs III 60-year-old females). Younger patients had higher LLE: 10.7 versus 3.9 years (stage II CM in 40 vs 70-year-old males). In stage II, females had lower LLE than males; 50-year-old females and males stage II CM had LLE equal to 7.3 and 8.3 years, respectively. LLE increased with higher substages, stage IIB resembling IIIB and IIC resembling IIIC-D., Limitations: Extrapolation was used to estimate LLE. Varying stage group sizes require caution., Conclusions: Our results are both clinically relevant and easy-to-interpret measures of the impact of CM on survival, but the results also summarize the prognosis over the lifetime of a CM patient., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Most Western countries have increasing number of new cancer cases per year. Cancer incidence is primarily influenced by basically avoidable risk factors and an aging population. Through hypothetical elimination scenarios of multiple major risk factors for cancer, we estimated the number of new cancer cases that are non-preventable in 2050. We compare numbers of new postmenopausal breast, prostate, lung, and colorectal cancer cases in 2021 to projected numbers of new cases in 2050 under prevention scenarios regarding smoking, overweight and obesity, and alcohol consumption: no intervention, 50%, and 100% instant reduction. Cancer incidence data were derived from NORDCAN, and risk factor prevalence data from the Danish National Health Survey. Cancer projections were calculated with the Prevent program. Hypothetical 100% instant elimination of major risk factors for cancer in Denmark in 2022 will result in unchanged numbers of new breast and colorectal cancers in 2050. The number of new prostate cancers will increase by 25% compared to 2021. Unchanged risk factor levels will result in noticeable increase in cancer burden. Increase in life expectancy and age will entail an increase in cancer incidence, despite maximum effect of preventive actions in the population. Our results are important when planning future health care., (© 2024. The Author(s).)

Background: Since the early 2000s, overall and site-specific cancer survival have improved substantially in the Nordic countries. We evaluated whether the improvements have been similar across countries, major cancer types, and age groups., Material and Methods: Using population-based data from the five Nordic cancer registries recorded in the NORDCAN database, we included a cohort of 1,525,854 men and 1,378,470 women diagnosed with cancer (except non-melanoma skin cancer) during 2002-2021, and followed for death until 2021. We estimated 5-year relative survival (RS) in 5-year calendar periods, and percentage points (pp) differences in 5-year RS from 2002-2006 until 2017-2021. Separate analyses were performed for eight cancer sites (i.e. colorectum, pancreas, lung, breast, cervix uteri, kidney, prostate, and melanoma of skin)., Results: Five-year RS improved across nearly all cancer sites in all countries (except Iceland), with absolute differences across age groups ranging from 1 to 21 pp (all cancer sites), 2 to 20 pp (colorectum), -1 to 36 pp (pancreas), 2 to 28 pp (lung), 0 to 9 pp (breast), -11 to 26 pp (cervix uteri), 2 to 44 pp (kidney), -2 to 23 pp (prostate) and -3 to 30 pp (skin melanoma). The oldest patients (80-89 years) exhibited lower survival across all countries and sites, although with varying improvements over time., Interpretation: Nordic cancer patients have generally experienced substantial improvements in cancer survival during the last two decades, including major cancer sites and age groups. Although survival has improved over time, older patients remain at a lower cancer survival compared to younger patients.

Background: The introduction of national guidelines should eliminate previously observed associations between socioeconomic status (SES) and colorectal cancer treatment. The aim of the study was to investigate whether inequalities remain., Methods: CRCBaSe, a register-linkage originating from the Swedish Colorectal Cancer Registry, was used to identify information on patient and tumour characteristics, for 83,460 patients with stage I-III disease diagnosed 2008-2021. SES was measured as disposable income (quartiles) and the highest level of education. Outcomes of interest were emergency surgery, multidisciplinary team (MDT) conference discussion, and oncological treatment. Differences in treatment between SES groups were explored using multivariable logistic regression adjusted for year of diagnosis, age at diagnosis, sex, civil status, comorbidities, tumour location and stage., Results: Patients in the highest income quartile had a lower risk of emergency surgery (OR 0.73 95%CI 0.68-0.80), a higher chance of being discussed at the preoperative (OR 1.39 95%CI 1.28-1.51) and postoperative MDT (OR 1.41 95%CI 1.30-1.53), receiving neoadjuvant (OR 1.15 95%CI 1.06-1.25) and adjuvant treatment (OR 2.04 95%CI 1.88-2.20). Higher education level increased the odds of MDT discussion but was not associated with oncological treatment. The proportion of patients discussed at the MDT increased, with almost all patients discussed since 2016. Despite this, treatment differences remained when patients diagnosed since 2016 were analysed separately., Conclusion: There were significant differences in how patients with different SES were treated for colorectal cancer. Further action is required to investigate the drivers of these differences as well as their impact on mortality and, ultimately, eliminate the inequalities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study introduces a novel method for estimating the variance of life expectancy since diagnosis (LE C ) and loss in life expectancy (LLE) for cancer patients within a relative survival framework in situations where life tables based on the entire general population are not accessible. LE C and LLE are useful summary measures of survival in population-based cancer studies, but require information on the mortality in the general population. Our method addresses the challenge of incorporating the uncertainty of expected mortality rates when using a sample from the general population., Methods: To illustrate the approach, we estimated LE C and LLE for patients diagnosed with colon and breast cancer in Sweden. General population mortality rates were based on a random sample drawn from comparators of a matched cohort. Flexible parametric survival models were used to model the mortality among cancer patients and the mortality in the random sample from the general population. Based on the models, LE C and LLE together with their variances were estimated. The results were compared with those obtained using fixed expected mortality rates., Results: By accounting for the uncertainty of expected mortality rates, the proposed method ensures more accurate estimates of variances and, therefore, confidence intervals of LE C and LLE for cancer patients. This is particularly valuable for older patients and some cancer types, where underestimation of the variance can be substantial when the entire general population data are not accessible., Conclusion: The method can be implemented using existing software, making it accessible for use in various cancer studies. The provided example of Stata code further facilitates its adoption., (© 2023. The Author(s).)

Incidence and mortality are default measures to describe cancer trends. Mortality compounds incidence and survival but not age at death. We calculated years of life lost (YLL) due to 1 of the 10 solid tumors causing most deaths (lung, colorectal, prostate, pancreatic, breast, hepatobiliary, urinary, central nervous system, gastric, melanoma) using Swedish National Cancer and Cause of Death Registers. Comparing YLL with mortality in 2019, lung (43 152 YLL) and colorectal (32 340 YLL) cancer remained at the top, pancreatic cancer was upranked fourth to third (22 592 YLL) and breast cancer fifth to fourth (21 810 YLL), while prostate cancer was downranked third to fifth (17 380 YLL). Assessing YLL over 2010-2019, women lost consistently more life years because of lung and pancreatic cancer. A downward colorectal cancer mortality trend was reflected as a YLL decline only in women. YLL is simple to calculate, is intuitive to interpret, and expands the understanding of the cancer burden on society., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Multi-state models are used to study several clinically meaningful research questions. Depending on the research question of interest and the information contained in the data, different multi-state structures and modelling choices can be applied. We aim to explore different research questions using a series of multi-state models of increasing complexity when studying repeated prescriptions data, while also evaluating different modelling choices., Methods: We develop a series of research questions regarding the probability of being under antidepressant medication across time using multi-state models, among Swedish women diagnosed with breast cancer (n = 18,313) and an age-matched population comparison group of cancer-free women (n = 92,454) using a register-based database (Breast Cancer Data Base Sweden 2.0). Research questions were formulated ranging from simple to more composite ones. Depending on the research question, multi-state models were built with structures ranging from simpler ones, like single-event survival analysis and competing risks, up to complex bidirectional and recurrent multi-state structures that take into account the recurring start and stop of medication. We also investigate modelling choices, such as choosing a time-scale for the transition rates and borrowing information across transitions., Results: Each structure has its own utility and answers a specific research question. However, the more complex structures (bidirectional, recurrent) enable accounting for the intermittent nature of prescribed medication data. These structures deliver estimates of the probability of being under medication and total time spent under medication over the follow-up period. Sensitivity analyses over different definitions of the medication cycle and different choices of timescale when modelling the transition intensity rates show that the estimates of total probabilities of being in a medication cycle over follow-up derived from the complex structures are quite stable., Conclusions: Each research question requires the definition of an appropriate multi-state structure, with more composite ones requiring such an increase in the complexity of the multi-state structure. When a research question is related with an outcome of interest that repeatedly changes over time, such as the medication status based on prescribed medication, the use of novel multi-state models of adequate complexity coupled with sensible modelling choices can successfully address composite, more realistic research questions., (© 2023. The Author(s).)

Background: It is unknown if the reduction in the expected number of cancer cases diagnosed during Swedish holidays are due to diagnostic delays, how different cancers are affected, and if the season of diagnosis influences long-term cancer survival. We aimed to quantify seasonal trends in incidence and excess mortality for a wide range of malignancies, requiring more or less urgent clinical management., Material and Methods: This nationwide cohort study included all Swedish residents aged 20-84 in 1990-2019. Incidence and relative survival in pancreatic, colorectal, lung, urothelial, breast, and prostate cancer, together with malignant melanoma, non-Hodgkin lymphoma, and acute leukemia diagnosed during holiday and post-holiday were compared to working (reference) season. Incidence rate ratios (IRR) were estimated using Poisson regression and excess (cancer) mortality rate ratios using flexible parametric models., Results: We identified 882,980 cancer cases. Incidence declined during holiday season for all malignancies and the IRR ranged from 0.58 (95% CI 0.57-0.59 in breast to 0.92 (95% CI 0.89-0.94) in pancreatic cancer. A post-holiday increase was noted for acute leukemia, pancreatic, and lung cancer. For all malignancies except lung cancer, non-Hodgkin lymphoma, and acute leukemia, the excess mortality at 2 years from diagnosis was higher among those diagnosed during the holiday season. A tendency toward elevated short-term (0.5 years) excess mortality was noted in the post-holiday group, but long-term effects only persisted in breast cancer., Conclusion: This study demonstrates lower holiday detection rates and higher mortality rates in various cancer types diagnosed during holiday season. Healthcare systems should offer a uniform level of cancer care independent of calendar season.

Background: A recent overview of cancer survival trends 1990-2016 in the Nordic countries reported continued improvements in age-standardized breast cancer survival among women. The aim was to estimate age-specific survival trends over calendar time, including life-years lost, to evaluate if improvements have benefited patients across all ages in the Nordic countries., Methods: Data on breast cancers diagnosed 1990-2016 in Denmark, Finland, Iceland, Norway, and Sweden were obtained from the NORDCAN database. Age-standardized and age-specific relative survival (RS) was estimated using flexible parametric models, as was reference-adjusted crude probabilities of death and life-years lost., Results: Age-standardized period estimates of 5-year RS in women diagnosed with breast cancer ranged from 87% to 90% and 10-year RS from 74% to 85%. Ten-year RS increased with 15-18 percentage points from 1990 to 2016, except in Sweden (+9 percentage points) which had the highest survival in 1990. The largest improvements were observed in Denmark, where a previous survival disadvantage diminished. Most recent 5-year crude probabilities of cancer death ranged from 9% (Finland, Sweden) to 12% (Denmark, Iceland), and life-years lost from 3.3 years (Finland) to 4.6 years (Denmark). Although survival improvements were consistent across different ages, women aged ≥70 years had the lowest RS in all countries. Period estimates of 5-year RS were 94-95% in age 55 years and 84-89% in age 75 years, while 10-year RS were 88-91% in age 55 years and 69-84% in age 75 years. Women aged 40 years lost on average 11.0-13.8 years, while women lost 3.8-6.0 years if aged 55 and 1.9-3.5 years if aged 75 years., Conclusions: Survival for Nordic women with breast cancer improved from 1990 to 2016 in all age groups, albeit with larger country variation among older women where survival was also lower. Women over 70 years of age have not had the same survival improvement as women of younger age.

Background: There are situations when we need to model multiple time-scales in survival analysis. A usual approach in this setting would involve fitting Cox or Poisson models to a time-split dataset. However, this leads to large datasets and can be computationally intensive when model fitting, especially if interest lies in displaying how the estimated hazard rate or survival change along multiple time-scales continuously., Methods: We propose to use flexible parametric survival models on the log hazard scale as an alternative method when modelling data with multiple time-scales. By choosing one of the time-scales as reference, and rewriting other time-scales as a function of this reference time-scale, users can avoid time-splitting of the data., Result: Through case-studies we demonstrate the usefulness of this method and provide examples of graphical representations of estimated hazard rates and survival proportions. The model gives nearly identical results to using a Poisson model, without requiring time-splitting., Conclusion: Flexible parametric survival models are a powerful tool for modelling multiple time-scales. This method does not require splitting the data into small time-intervals, and therefore saves time, helps avoid technological limitations and reduces room for error., (© 2022. The Author(s).)

Background: Descriptive data on late effects associated with castrate-resistant prostate cancer (CRPC) are sparse. We aimed to define the timing and incidence of cardiovascular disease (CVD), fractures, and diabetes in a patient population with CRPC., Methods: In the population-based STHLM0 cohort 1464 men with CRPC were identified and matched with three men free from prostate cancer (PC) in the Stockholm region of Sweden. Kaplan-Meier estimates of net survival were used to describe time to CVD, fracture, and diabetes. Cox regression was used to compare incidence rates (IRRs) for the respective late effects. Cumulative incidence analyses of late effects in the presence of the competing risk of death were performed to estimate absolute risks., Results: The Kaplan Meier estimates demonstrated a higher net probability for CVD, fracture, and diabetes among men diagnosed with CRPC compared to the matched comparators. The IRRs were 1.94 (95% CI: 1.79-2.12) for CVD, 2.08 (95% CI: 1.70-2.53) for fracture, and 2.00 (95% CI: 1.31-3.05) for diabetes, respectively, comparing men diagnosed with CRPC to men free from PC. The cumulative incidence of CVD at 12 months of follow-up was higher in men diagnosed with CRPC compared to healthy controls regardless of age with a difference in cumulative incidence being 0.20 for men aged <65 and 0.11 for men aged >84., Conclusions: In this cohort, the incidence of CVD was significantly higher among men with CRPC compared to healthy controls. Despite having this end-stage disease this finding proves that clinicians must recognize this late effect in men diagnosed with CRPC to improve preventive actions. These men did not have a higher absolute risk of fractures and diabetes after accounting for deaths due to any cause compared to healthy controls.

Background: When interested in studying the effect of a treatment (or other exposure) on a time-to-event outcome, the most popular approach is to estimate survival probabilities using the Kaplan-Meier estimator. In the presence of confounding, regression models are fitted, and results are often summarised as hazard ratios. However, despite their broad use, hazard ratios are frequently misinterpreted as relative risks instead of relative rates., Methods: We discuss measures for summarising the analysis from a regression model that overcome some of the limitations associated with hazard ratios. Such measures are the standardised survival probabilities for treated and untreated: survival probabilities if everyone in the population received treatment and if everyone did not. The difference between treatment arms can be calculated to provide a measure for the treatment effect., Results: Using publicly available data on breast cancer, we demonstrated the usefulness of standardised survival probabilities for comparing the experience between treated and untreated after adjusting for confounding. We also showed that additional important research questions can be addressed by standardising among subgroups of the total population., Discussion: Standardised survival probabilities are a useful way to report the treatment effect while adjusting for confounding and have an informative interpretation in terms of risk., (© 2022. The Author(s).)

Pregnancy and childbirth in women with myeloproliferative neoplasms (MPN) are reported to be associated with maternal thrombosis, hemorrhage, and placental dysfunction. To assess the risks of adverse events in pregnancy in women with MPN, we performed a large population-based study using Swedish health care registers, and included all pregnancies that had reached gestational week 22 (prior to 2008, week 28) during the years 1973-2017 in women with MPN. Control pregnancies were matched 1:1 for age, calendar year, and parity. We identified 342 pregnancies in 229 women with MPN. Preterm birth was significantly increased in pregnancies in MPN, 14% compared to 4% of pregnancies in controls (p < 0.001). Correspondingly, low birth weight (<2500 g) was also significantly increased in MPN pregnancies (p = 0.042). Stillbirth was rare, with two events (0.6%) in MPN, none in controls. Maternal thrombotic complications occurred in three (1%) of the pregnancies in MPN patients, compared to none in controls. Pregnancy-related bleeding affected 14% of pregnancies in MPN and 9% in controls (p < 0.110). Cesarean section was significantly more common in pregnancies in MPN. Incidence was 12.2 per 100.000 pregnancies. In summary, preterm birth was an important complication in MPN pregnancies, while maternal complications were less common than previously reported., (© 2022. The Author(s).)

In competing risks settings where the events are death due to cancer and death due to other causes, it is common practice to use time since diagnosis as the timescale for all competing events. However, attained age has been proposed as a more natural choice of timescale for modeling other cause mortality. We examine the choice of using time since diagnosis versus attained age as the timescale when modeling other cause mortality, assuming that the hazard rate is a function of attained age, and how this choice can influence the cumulative incidence functions ( INLINEMATH ), provided that the effect of age at diagnosis is included in the model with sufficient flexibility, with higher bias under scenarios where a covariate has a time-varying effect on the hazard rate for other cause mortality on the attained age scale., (© 2022 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Background: Completeness of recording for cancer stage at diagnosis is often historically poor in cancer registries, making it challenging to provide long-term stage-specific survival estimates. Stage-specific survival differences are driven by differences in short-term prognosis, meaning estimated survival metrics using period analysis are unlikely to be sensitive to imputed historical stage data., Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER) Program for lung, colon and breast cancer. To represent missing data patterns in less complete registry data, we artificially inflated the proportion of missing stage information conditional on stage at diagnosis and calendar year of diagnosis. Period analysis was applied and missing stage at diagnosis information was imputed under four different conditions to emulate extreme imputed stage distributions., Results: We fit a flexible parametric model for each cancer stage on the excess hazard scale and the differences in stage-specific marginal relative survival were assessed. Estimates were also obtained from non-parametric approaches for validation. There was little difference between the 10-year stage-specific marginal relative survival estimates, regardless of the assumed historical stage distribution., Conclusions: When conducting a period analysis, multiple imputation can be used to obtain stage-specific long-term estimates of relative survival, even when the historical stage information is largely incomplete., (© 2022. The Author(s).)

Background: The loss in life expectancy, LLE, is defined as the difference in life expectancy between patients with cancer and that of the general population. It is a useful measure for summarizing the impact of a cancer diagnosis on an individual's life expectancy. However, it is less useful for making comparisons of cancer survival across groups or over time, because the LLE is influenced by both mortality due to cancer and other causes and the life expectancy in the general population., Methods: We present an approach for making LLE estimates comparable across groups and over time by using reference expected mortality rates with flexible parametric relative survival models. The approach is illustrated by estimating temporal trends in LLE of patients with colon cancer in Sweden., Results: The life expectancy of Swedish patients with colon cancer has improved, but the LLE has not decreased to the same extent because the life expectancy in the general population has also increased. When using a fixed population and other-cause mortality, that is, a reference-adjusted approach, the LLE decreases over time. For example, using 2010 mortality rates as the reference, the LLE for females diagnosed at age 65 decreased from 11.3 if diagnosed in 1976 to 7.2 if diagnosed in 2010, and from 3.9 to 1.9 years for women 85 years old at diagnosis., Conclusions: The reference-adjusted LLE is useful for making comparisons across calendar time, or groups, because differences in other-cause mortality are removed., Impact: The reference-adjusted approach enhances the use of LLE as a comparative measure., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Survival of patients with colon and rectal cancer has improved in all Nordic countries during the past decades. The aim of this study was to further assess survival trends in patients with colon and rectal cancer in the Nordic countries by age at diagnosis and to present additional survival measures., Methods: Data on colon and rectal cancer cases diagnosed in the Nordic countries between 1990 and 2016 were obtained from the NORDCAN database. Relative survival was estimated using flexible parametric models. Both age-standardized and age-specific measures for women and men were estimated from the models, as well as reference-adjusted crude probabilities of death and life-years lost., Results: The five-year age-standardized relative survival of colon and rectal cancer patients continued to improve for women and men in all Nordic countries, from around 50% in 1990 to about 70% at the end of the study period. In general, survival was similar across age and sex. The largest improvement was seen for Danish men and women with rectal cancer, from 41% to 69% and from 43% to 71%, respectively. The age-standardized and reference-adjusted five-year crude probability of death in colon cancer ranged from 30% to 36% across countries, and for rectal cancer from 20% to 33%. The average number of age-standardized and reference-adjusted life-years lost ranged between six and nine years., Conclusion: There were substantial improvements in colon and rectal cancer survival in all Nordic countries 1990-2016. Of special note is that the previously observed survival disadvantage in Denmark is no longer present., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This study quantified differences in remaining life expectancy (RLE) among Aboriginal and Torres Strait Islander and other Australian patients with cancer. We assessed how much of this disparity was due to differences in cancer and noncancer mortality and calculated the population gain in life years for Aboriginal and Torres Strait Islanders cancer diagnoses if the cancer survival disparities were removed., Methods: Flexible parametric relative survival models were used to estimate RLE by Aboriginal and Torres Strait Islander status for a population-based cohort of 709,239 persons (12,830 Aboriginal and Torres Strait Islanders), 2005 to 2016., Results: For all cancers combined, the average disparity in RLE was 8.0 years between Aboriginal and Torres Strait Islanders (12.0 years) and other Australians (20.0 years). The magnitude of this disparity varied by cancer type, being >10 years for cervical cancer versus <2 years for lung and pancreatic cancers. For all cancers combined, around 26% of this disparity was due to differences in cancer mortality and 74% due to noncancer mortality. Among 1,342 Aboriginal and Torres Strait Islanders diagnosed with cancer in 2015 an estimated 2,818 life years would be gained if cancer survival disparities were removed., Conclusions: A cancer diagnosis exacerbates the existing disparities in RLE among Aboriginal and Torres Strait Islanders. Addressing them will require consideration of both cancer-related factors and those contributing to noncancer mortality., Impact: Reported survival-based measures provided additional insights into the overall impact of cancer over a lifetime horizon among Aboriginal and Torres Strait Islander peoples., (©2022 American Association for Cancer Research.)

Differentiated thyroid cancer (DTC) has a good prognosis; however, patients often need lifelong follow up, and they face potential side effects. The aim of this study was to investigate health anxiety among DTC patients and its relationship to TSH suppression. In 2020, patients from a previous cohort who were from Stockholm completed the 14-item Short Health Anxiety Inventory (SHAI-14; 0−42; 18 being the threshold for clinical significance) and a study-specific questionnaire. Clinical information was also retrieved from medical records. Linear regression was used to investigate the relationship between the TSH levels and the SHAI-14, while adjusting for potential confounders. In total, 146 (73%) patients were included. A total of 24 respondents (16%) scored 18 or more on the SHAI-14, and the mean score was 11.3. Patients with TSH levels of 0.1−0.5 (mE/L) scored, on average, 3.28 points more (p-value 0.01) on the SHAI-14 compared to patients with TSH levels > 0.5. There was no statistically significant difference between patients with TSH levels < 0.1 and TSH levels > 0.5. Thus, we found no linear relationship between the TSH values and health anxiety. Clinically significant levels of health anxiety are slightly higher than those in the general population, but do not appear to be a major psychiatric comorbidity among patients with DTC.

Background: A relative survival approach is often used in population-based cancer studies, where other cause (or expected) mortality is assumed to be the same as the mortality in the general population, given a specific covariate pattern. The population mortality is assumed to be known (fixed), i.e. measured without uncertainty. This could have implications for the estimated standard errors (SE) of any measures obtained within a relative survival framework, such as relative survival (RS) ratios and the loss in life expectancy (LLE). We evaluated the existing approach to estimate SE of RS and the LLE in comparison to if uncertainty in the population mortality was taken into account., Methods: The uncertainty from the population mortality was incorporated using parametric bootstrap approach. The analysis was performed with different levels of stratification and sizes of the general population used for creating expected mortality rates. Using these expected mortality rates, SEs of 5-year RS and the LLE for colon cancer patients in Sweden were estimated., Results: Ignoring uncertainty in the general population mortality rates had negligible (less than 1%) impact on the SEs of 5-year RS and LLE, when the expected mortality rates were based on the whole general population, i.e. all people living in a country or region. However, the smaller population used for creating the expected mortality rates, the larger impact. For a general population reduced to 0.05% of the original size and stratified by age, sex, year and region, the relative precision for 5-year RS was 41% for males diagnosed at age 85. For the LLE the impact was more substantial with a relative precision of 1286%. The relative precision for marginal estimates of 5-year RS was 3% and 30% and for the LLE 22% and 313% when the general population was reduced to 0.5% and 0.05% of the original size, respectively., Conclusions: When the general population mortality rates are based on the whole population, the uncertainty in the estimates of the expected measures can be ignored. However, when based on a smaller population, this uncertainty should be taken into account, otherwise SEs may be too small, particularly for marginal values, and, therefore, confidence intervals too narrow., (© 2022. The Author(s).)

Background: Comparisons of population-based cancer survival between countries are important to benchmark the overall effectiveness of cancer management. The International Cancer Benchmarking Partnership (ICBP) Survmark-2 study aims to compare survival in seven high-income countries across eight cancer sites and explore reasons for the observed differences. A critical aspect in ensuring comparability in the reported survival estimates are similarities in practice across cancer registries. While ICBP Survmark-2 has shown these differences are unlikely to explain the observed differences in cancer-specific survival between countries, it is important to keep in mind potential biases linked to registry practice and understand their likely impact., Methods: Based on experiences gained within ICBP Survmark-2, we have developed a set of recommendations that seek to optimally harmonise cancer registry datasets to improve future benchmarking exercises., Results: Our recommendations stem from considering the impact on cancer survival estimates in five key areas: (1) the completeness of the registry and the availability of registration sources; (2) the inclusion of death certification as a source of identifying cases; (3) the specification of the date of incidence; (4) the approach to handling multiple primary tumours and (5) the quality of linkage of cases to the deaths register., Conclusion: These recommendations seek to improve comparability whilst maintaining the opportunity to understand and act upon international variations in outcomes among cancer patients., (© 2022. The Author(s).)

Background: An increasingly popular measure for summarising cancer prognosis is the loss in life expectancy (LLE), i.e. the reduction in life expectancy following a cancer diagnosis. The proportion of life lost (PLL) can also be derived, improving comparability across age groups as LLE is highly age-dependent. LLE and PLL are often used to assess the impact of cancer over the remaining lifespan and across groups (e.g. socioeconomic groups). However, in the presence of screening, it is unclear whether part of the differences across population groups could be attributed to lead time bias. Lead time is the extra time added due to early diagnosis, that is, the time from tumour detection through screening to the time that cancer would have been diagnosed symptomatically. It leads to artificially inflated survival estimates even when there are no real survival improvements., Methods: In this paper, we used a simulation-based approach to assess the impact of lead time due to mammography screening on the estimation of LLE and PLL in breast cancer patients. A natural history model developed in a Swedish setting was used to simulate the growth of breast cancer tumours and age at symptomatic detection. Then, a screening programme similar to current guidelines in Sweden was imposed, with individuals aged 40-74 invited to participate every second year; different scenarios were considered for screening sensitivity and attendance. To isolate the lead time bias of screening, we assumed that screening does not affect the actual time of death. Finally, estimates of LLE and PLL were obtained in the absence and presence of screening, and their difference was used to derive the lead time bias., Results: The largest absolute bias for LLE was 0.61 years for a high screening sensitivity scenario and assuming perfect screening attendance. The absolute bias was reduced to 0.46 years when the perfect attendance assumption was relaxed to allow for imperfect attendance across screening visits. Bias was also present for the PLL estimates., Conclusions: The results of the analysis suggested that lead time bias influences LLE and PLL metrics, thus requiring special consideration when interpreting comparisons across calendar time or population groups., (© 2022. The Author(s).)

Background: Accurately recorded vital status of individuals is essential when estimating cancer patient survival. When deaths are ascertained by linkage with vital statistics registers, some may be missed, and such individuals will wrongly appear to be long-term survivors, and survival will be overestimated. Interval-specific relative survival that levels off above one indicates that the survival among the cancer patients is better than expected, which could be due to the presence of immortals., Methods: We included colon cancer cases diagnosed in 1995-1999 within the 19 jurisdictions in seven countries participating in ICBP SURVMARK-2, with follow-up information available until end-2015. Interval-specific relative survival was estimated for each year following diagnosis, by country and age group at diagnosis., Results: The interval-specific relative survival levels off at 1 for all countries and age groups, with two exceptions: for the age group diagnosed at age 75 years and above in Ireland, and, to a lesser extent, in New Zealand., Conclusion: Overall, a subset of immortals are not apparent in the early years within the ICBP SURVMARK-2 study, except for possibly in Ireland. We suggest this approach as one strategy of exploring the existence of immortals, and to be part of routine checks of cancer registry data., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Background: Ensuring fair comparisons of cancer survival statistics across population groups requires careful consideration of differential competing mortality due to other causes, and adjusting for imbalances over groups in other prognostic covariates (e.g. age). This has typically been achieved using comparisons of age-standardised net survival, with age standardisation addressing covariate imbalance, and the net estimates removing differences in competing mortality from other causes. However, these estimates lack ease of interpretability. In this paper, we motivate an alternative non-parametric approach that uses a common rate of other cause mortality across groups to give reference-adjusted estimates of the all-cause and cause-specific crude probability of death in contrast to solely reporting net survival estimates., Methods: We develop the methodology for a non-parametric equivalent of standardised and reference adjusted crude probabilities of death, building on the estimation of non-parametric crude probabilities of death. We illustrate the approach using regional comparisons of survival following a diagnosis of rectal cancer for men in England. We standardise to the covariate distribution and other cause mortality of England as a whole to offer comparability, but with close approximation to the observed all-cause region-specific mortality., Results: The approach gives comparable estimates to observed crude probabilities of death, but allows direct comparison across population groups with different covariate profiles and competing mortality patterns. In our illustrative example, we show that regional variations in survival following a diagnosis of rectal cancer persist even after accounting for the variation in deprivation, age at diagnosis and other cause mortality., Conclusions: The methodological approach of using standardised and reference adjusted metrics offers an appealing approach for future cancer survival comparison studies and routinely published cancer statistics. Our non-parametric estimation approach through the use of weighting offers the ability to estimate comparable survival estimates without the need for statistical modelling., (© 2022. The Author(s).)

Background: Multi-state models are used in complex disease pathways to describe a process where an individual moves from one state to the next, taking into account competing states during each transition. In a multi-state setting, there are various measures to be estimated that are of great epidemiological importance. However, increased complexity of the multi-state setting and predictions over time for individuals with different covariate patterns may lead to increased difficulty in communicating the estimated measures. The need for easy and meaningful communication of the analysis results motivated the development of a web tool to address these issues., Results: MSMplus is a publicly available web tool, developed via the Shiny R package, with the aim of enhancing the understanding of multi-state model analyses results. The results from any multi-state model analysis are uploaded to the application in a pre-specified format. Through a variety of user-tailored interactive graphs, the application contributes to an improvement in communication, reporting and interpretation of multi-state analysis results as well as comparison between different approaches. The predicted measures that can be supported by MSMplus include, among others, the transition probabilities, the transition intensity rates, the length of stay in each state, the probability of ever visiting a state and user defined measures. Representation of differences, ratios and confidence intervals of the aforementioned measures are also supported. MSMplus is a useful tool that enhances communication and understanding of multi-state model analyses results., Conclusions: Further use and development of web tools should be encouraged in the future as a means to communicate scientific research., (© 2021. The Author(s).)

Background: Arm and shoulder problems (ASP), including lymphedema, were common among women with breast cancer in high-income countries before sentinel lymph node biopsy became the standard of care. Although ASP impair quality of life, as they affect daily life activities, their frequency and determinants in Sub-Saharan Africa remain unclear., Methods: All women newly diagnosed with breast cancer at the Namibian, Ugandan, Nigerian, and Zambian sites of the African Breast Cancer-Disparities in Outcomes (ABC-DO) cohort study were included. At each 3-month follow-up interview, women answered the EORTC-QLQ-Br23 questionnaire, including three ASP items: shoulder/arm pain, arm stiffness, and arm/hand swelling. We estimated the cumulative incidence of first self-reported ASP, overall and stratified by study and treatment status, with deaths treated as competing events. To identify determinants of ASP, we estimated cause-specific hazard ratios using Cox models stratified by study site., Results: Among 1476 women, up to 4 years after diagnosis, 43% (95% CI 40-46), 36% (33-38) and 23% (20-25), respectively, self-reported having experienced arm/shoulder pain, stiffness and arm/hand swelling at least once. Although risks of self-reported ASP differed between sites, a more advanced breast cancer stage at diagnosis, having a lower socioeconomic position and receiving treatment increased the risk of reporting an ASP., Conclusion: ASP are very common in breast cancer survivors in Sub-Saharan Africa. They are influenced by different factors than those observed in high-income countries. There is a need to raise awareness and improve management of ASP within the African setting., (© 2021. The Author(s).)

The risk of suicide is elevated among patients with treatment-resistant depression (TRD). Risk factors for suicide and suicide attempts among cases and controls with TRD were investigated using data from nationwide Swedish registers. Among 119,407 antidepressant initiators with a diagnosis of depression, 15,631 patients who started a third sequential treatment trial during the same depressive episode were classified with TRD. A nested case-control study compared cases with suicide and suicide attempts with up to three closely matched controls. Sociodemographic and clinical risk factors were assessed using conditional logistic regression analyses. In all, 178 patients died by suicide and 1,242 experienced a suicide attempt during follow-up. History of suicide attempts, especially if <1 year after the attempt, was a significant independent risk factor for suicide (adjusted odds ratio [aOR], 8.9; 95% confidence interval [CI], 5.1-15.7) as were 10 to 12 years of education compared to lower education (aOR, 1.69; 95% CI, 1.02-2.81). For attempted suicide, the strongest independent risk factors were history of suicide attempts (<1 year aOR, 5.1; 95% CI, 4.0-6.5), substance abuse (aOR, 2.6; 95% CI, 2.2-3.1), personality disorders (aOR, 1.9; 95% CI, 1.5-2.3), and somatic comorbidity (aOR, 2.0; 95% CI, 1.04-3.9). Suicide attempts, especially if recent, are strong risk factors for completed suicide among patients with TRD. Established risk factors for suicide attempts were confirmed for patients with TRD.

Background: Cure proportion represents the proportion of patients who experience the same mortality rate as the general population and can be estimated together with the survival of the proportion experiencing excess mortality (the uncured). The aim was to estimate the cure proportions and survival among uncured stage II-III cutaneous melanoma (CM) patients., Methods: 1- and 5-year relative survival ratios, cure proportions and the median survival times of uncured stage II-III CM patients in Sweden ( n = 6466) were calculated based on data from the nationwide population-based Swedish Melanoma Register 2005-2013 with a follow-up through 2018., Results: Stages IIB and IIC showed significant differences in standardized cure proportions vs. stage IIA CM (0.80 (95% CI 0.77-0.83) stage IIA; 0.62 (95% CI 0.59-0.66) stage IIB; 0.42 (95% CI 0.37-0.46) for stage IIC). Significant differences in standardized cure proportions were found for stages IIIB and IIIC-D CM vs. stage IIIA (0.76 (95% CI 0.68-0.84) stage IIIA; 0.52 (95% CI 0.45-0.59) stage IIIB; 0.35 (95% CI 0.30-0.39) for stage IIIC-D)., Conclusions: The results are emphasizing the poor prognosis with low proportions cured by surgery only for sub-groups of stage II-III CM, specifically within stages IIB-C CM.

Background: Patients with treatment-resistant depression (TRD) have an increased mortality risk compared with other patients with depression, but it is not known how this translates into absolute numbers of excess deaths., Methods: Swedish national registers were used to identify a cohort of 118,774 antidepressant initiators 18-69 years old with a depression diagnosis. Patients who initiated a third consecutive treatment trial were classified as having TRD. Flexible parametric survival models were used to estimate the mortality risk due to all causes and external causes (suicides and accidents), comparing TRD patients with patients with other depression while adjusting for clinical and sociodemographic covariates and including interactions with TRD, age, and Charlson comorbidity index (CCI) for a number of somatic comorbidities. Standardized survival was estimated, as were numbers of excess deaths among TRD patients within each age and comorbidity category., Results: Compared with the mortality risk of other depressed patients, patients with TRD experienced excess deaths in most age and comorbidity categories in the range of 7-16 deaths per 1000 patients during 5 years. Highest numbers for all-cause excess deaths were found among patients 18-29 years old with CCI 1, where 16 [95% confidence interval 5-28] of the expected 37 [25-48] deaths per 1000 patients were excess deaths. The majority of the excess deaths were due to external causes., Conclusion: Patients with TRD experience significant numbers of excess deaths compared with other patients with depression., Competing Interests: Conflict of interest statement: PB and JR are affiliated with/employed at the Centre for Pharmacoepidemiology at Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities, contract research organizations) for the performance of drug safety and drug utilization studies. MN is an employee and stockholder of Janssen Inc. and contributed to conceptualization of the study and manuscript writing., (© The Author(s), 2021.)

Background: Population-based cancer registries strive to cover all cancer cases diagnosed within the population, but some cases will always be missed and no register is 100 % complete. Many cancer registries use death certificates to identify additional cases not captured through other routine sources, to hopefully add a large proportion of the missed cases. Cases notified through this route, who would not have been captured without death certificate information, are referred to as Death Certificate Initiated (DCI) cases. Inclusion of DCI cases in cancer registries increases completeness and is important for estimating cancer incidence. However, inclusion of DCI cases will generally lead to biased estimates of cancer survival, but the same is often also true if excluding DCI cases. Missed cases are probably not a random sample of all cancer cases, but rather cases with poor prognosis. Further, DCI cases have poorer prognosis than missed cases in general, since they have all died with cancer mentioned on the death certificates., Methods: We performed a simulation study to estimate the impact of including or excluding DCI cases on cancer survival estimates, under different scenarios., Results: We demonstrated that including DCI cases underestimates survival. The exclusion of DCI cases gives unbiased survival estimates if missed cases are a random sample of all cancer cases, while survival is overestimated if these have poorer prognosis., Conclusion: In our most extreme scenarios, with 25 % of cases initially missed, the usual practice of including DCI cases underestimated 5-year survival by at most 3 percentage points., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Background: Data from population-based cancer registries are often used to compare cancer survival between countries or regions. The ICBP SURVMARK-2 study is an international partnership aiming to quantify and explore the reasons behind survival differences across high-income countries. However, the magnitude and relevance of differences in cancer survival between countries have been questioned, as it is argued that observed survival variations may be explained, at least in part, by differences in cancer registration practice, completeness and the availability and quality of the respective data sources., Methods: As part of the ICBP SURVMARK-2 study, we used a simulation approach to better understand how differences in completeness, the characteristics of those missed and inclusion of cases found from death certificates can impact on cancer survival estimates., Results: Bias in 1- and 5-year net survival estimates for 216 simulated scenarios is presented. Out of the investigated factors, the proportion of cases not registered through sources other than death certificates, had the largest impact on survival estimates., Conclusion: Our results show that the differences in registration practice between participating countries could in our most extreme scenarios explain only a part of the largest observed differences in cancer survival.

Infections are a common complication in patients with many hematologic malignancies, however, whether patients with myeloproliferative neoplasms (MPN) also are at an increased risk of infections is largely unknown. To assess the risk of serious infections, we performed a large population-based matched cohort study in Sweden including 8 363 MPN patients and 32,405 controls using high-quality registers between the years 1992-2013 with follow-up until 2015. The hazard ratio (HR) of any infection was 2.0 (95% confidence interval 1.9-2.0), of bacterial infections 1.9 (1.8-2.0), and of viral infections 2.1 (1.9-2.3). One of the largest risk increases was that of sepsis, HR 2.6 (2.4-2.9). The HR of any infection was highest in primary myelofibrosis 3.7 (3.2-4.1), and significantly elevated in all MPN subtypes; 1.7 (1.6-1.8) in polycythemia vera and 1.7 (1.5-1.8) in essential thrombocythemia. There was no significant difference in risk of infections between untreated patients and patients treated with hydroxyurea or interferon-α during the years 2006-2013. These novel findings of an overall increased risk of infections in MPN patients, irrespective of common cytoreductive treatments, suggest the increased risk of infection is inherent to the MPN.

Monitoring survival of cancer patients using data collected by population-based cancer registries is an important component of cancer control. In this setting, patient survival is often summarized using net survival, that is survival from cancer if there were no other possible causes of death. Although net survival is the gold standard for comparing survival between groups or over time, it is less relevant for understanding the anticipated real-world prognosis of patients. In this review, we explain statistical concepts targeted towards patients, clinicians and healthcare professionals that summarize cancer patient survival under the assumption that other causes of death exist. Specifically, we explain the appropriate use, interpretation and assumptions behind statistical methods for competing risks, loss in life expectancy due to cancer and conditional survival. These concepts are relevant when producing statistics for risk communication between physicians and patients, planning for use of healthcare resources, or other applications when consideration of both cancer outcomes and the competing risks of death is required. To reinforce the concepts, we use Swedish population-based data of patients diagnosed with cancer of the breast, prostate, colon and chronic myeloid leukaemia. We conclude that when choosing between summary measures of survival it is critical to characterize the purpose of the study and to determine the nature of the hypothesis under investigation. The choice of terminology and style of reporting should be carefully adapted to the target audience and may range from summaries for specialist readers of scientific publications to interactive online tools aimed towards lay persons., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Many infectious diseases are well prevented by proper vaccination. However, when a vaccine is not completely efficacious, there is great interest in determining how the vaccine effect differs in subgroups conditional on measured immune responses postvaccination and also according to the type of infecting agent (eg, strain of a virus). The former is often called correlate of protection (CoP) analysis, while the latter has been called sieve analysis. We propose a unified framework for simultaneously assessing CoP and sieve effects of a vaccine in a large Phase III randomized trial. We use flexible parametric models treating times to infection from different agents as competing risks and estimated maximum likelihood to fit the models. The parametric models under competing risks allow for estimation of both cumulative incidence-based contrasts and instantaneous rates. We outline the assumptions with which we can link the observable data to the causal contrasts of interest, propose hypothesis testing procedures, and evaluate our proposed methods in an extensive simulation study., (© 2019 The International Biometric Society.)

Introduction: International differences in cancer incidence and survival may partly reflect differences in cancer registration practices. As opposed to most other National Cancer Registries, Death Certificate Initiated (DCI) cases are not included in the Swedish Cancer Register. We characterized cases not reported to the Swedish Cancer Register and assessed the impact of inclusion of DCI cases on the completeness and estimates of one-year lung and pancreatic cancer survival., Methods: We used information in the Swedish Cause of Death Register to identify individuals in two Health Care Regions (West and Uppsala Örebro) with lung or pancreatic cancer as cause of death in 2013. These records were cross-linked to the Cancer Register to identify individuals without a corresponding cancer registration, i.e. Death Certificate Notified (DCN) cases. DCN cases were cross-linked to the Patient Register to retrieve hospital discharge information to confirm the diagnosis. In a separate step, trace-back of DCN cases was performed to access medical records to validate the diagnosis., Results: Following validity checks, an estimated 16% and 34% of individuals with a diagnosis of lung or pancreatic cancer, respectively, had not been reported to the SCR. Non-reported patients were older and had a considerable poorer survival than those included in the SCR. Inclusion of DCI cases decreased one-year lung cancer overall survival from 45% to 41%. The corresponding decrease for pancreatic cancer was five percentage points, from 29% to 24%., Conclusions: Lung and pancreatic cancers are underreported to the SCR yielding too low incidence rates and upward biased survival estimates. We conclude that implementation of systematic death certificate processing with trace-back is feasible also within the Swedish system with regionalized cancer reporting. Verifying registrability by use of information in the Patient Register provided a good approximation of "corrected" survival estimates based on chart review.

Background: Differences in cancer survival between the Nordic countries have previously been reported. The aim of this study was to examine whether these differences in outcome remain, based on updated information from five national cancer registers., Materials and Methods: The data used for the analysis was from the NORDCAN database focusing on nine common cancers diagnosed 1990-2016 in Denmark, Finland, Iceland, Norway and Sweden with maximum follow-up through 2017. Relative survival (RS) was estimated at 1 and 5 years using flexible parametric RS models, and percentage point differences between the earliest and latest years available were calculated., Results: A consistent improvement in both 1- and 5-year RS was found for most studied sites across all countries. Previously observed differences between the countries have been attenuated. The improvements were particularly pronounced in Denmark that now has cancer survival similar to the other Nordic countries., Conclusion: The reasons for the observed improvements in cancer survival are likely multifactorial, including earlier diagnosis, improved treatment options, implementation of national cancer plans, uniform national cancer care guidelines and standardized patient pathways. The previous survival disadvantage in Denmark is no longer present for most sites. Continuous monitoring of cancer survival is of importance to assess the impact of changes in policies and the effectiveness of health care systems.

Background: In population-based cancer survival studies, the most common measure to compare population groups is age-standardized marginal relative survival, which under assumptions can be interpreted as marginal net survival; the probability of surviving if it was not possible to die of causes other than the cancer under study (if the age distribution was that of a common reference population). The hypothetical nature of this definition has led to confusion and incorrect interpretation. For any measure to be fair in terms of comparing cancer survival, then differences between population groups should depend only on differences in excess mortality rates due to the cancer and not differences in other-cause mortality rates or differences in the age distribution., Methods: We propose using crude probabilities of death and all-cause survival which incorporate reference expected mortality rates. This makes it possible to obtain marginal crude probabilities and all-cause probability of death that only differ between population groups due to excess mortality rate differences. Choices have to be made regarding what reference mortality rates to use and what age distribution to standardize to., Results: We illustrate the method and some potential choices using data from England for men diagnosed with melanoma. Various marginal measures are presented and compared., Conclusions: The new measures help enhance understanding of cancer survival and are a complement to the more commonly used measures., (© The Author(s) 2020; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Psychiatric disorders and infections are both common comorbidities among patients with cancer. However, little is known about the role of precancer psychiatric disorders on the subsequent risk of sepsis as a complication of infections among patients with cancer. We conducted a cohort study of 362,500 patients with newly diagnosed cancer during 2006-2014 in Sweden. We used flexible parametric models to calculate the HRs of sepsis after cancer diagnosis in relation to precancer psychiatric disorders and the analyses were performed in two models. In model 1, analyses were adjusted for sex, age at cancer diagnosis, calendar period, region of residence, and type of cancer. In model 2, further adjustments were made for marital status, educational level, cancer stage, infection history, and Charlson Comorbidity Index score. During a median follow-up of 2.6 years, we identified 872 cases of sepsis among patients with cancer with precancer psychiatric disorders (incidence rate, IR, 14.8 per 1,000 person-years) and 12,133 cases among patients with cancer without such disorders (IR, 11.6 per 1000 person-years), leading to a statistically significant association between precancer psychiatric disorders and sepsis in both the simplified (HR, 1.31; 95% CI, 1.22-1.40) and full (HR, 1.26; 95% CI, 1.18-1.35) models. The positive association was consistently noted among patients with different demographic factors or cancer characteristics, for most cancer types, and during the entire follow-up after cancer diagnosis. Collectively, preexisting psychiatric disorders were associated with an increased risk of sepsis after cancer diagnosis, suggesting a need of heightened clinical awareness in this patient group. SIGNIFICANCE: These results call for extended prevention and surveillance of sepsis among patients with cancer with psychiatric comorbidities., (©2020 American Association for Cancer Research.)

Patients with diffuse large B-cell lymphoma (DLBCL) who fail to complete planned treatment with R-CHOP due to toxicity are sparsely described. We investigated the extent of failure to complete treatment (six cycles or more, or three cycles + RT for patients with stage I disease) with R-CHOP for reasons unrelated to non-response, the determinants of such failure and the outcome among these patients. Three thousand one hundred and forty nine adult DLBCL patients who started primary treatment with R-CHOP were identified through the Swedish lymphoma register 2007-2014. Of these, 147 (5%) stopped prematurely after 1-3 cycles of R-CHOP for reasons unrelated to non-response, 168 (5%) after 4-5 cycles and 2639 patients (84%) completed planned treatment. Additionally, 195 (6%) patients did not complete treatment due to non-response or death before treatment end. In a multivariable logistic regression model, age > 75 years, poor performance status, extranodal disease and Charlson Comorbidity Index ≥1 were significantly associated with failure to complete planned R-CHOP treatment for other reasons than non-response. Non-completion of treatment strongly correlated with survival. Five-year overall survival for patients who received 1-3 cycles was 26% (95% CI: 19%-33%), 49% (95% CI: 41%-57%) for 4-5 cycles and 76% (74%-77%) for patients who completed treatment. Failure to complete planned R-CHOP treatment is an important clinical issue associated with inferior survival. Old age and poor performance status most strongly predict such failure. These results indicate a need for improved treatment tailoring for patients with certain baseline demographics to improve tolerability and chance for treatment completion., (© 2020 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)