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Frida E Lundberg,1 Anna LV Johansson,1 Jonas F Ludvigsson1,21Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden; 2Department of Pediatrics, Orebro University Hospital, Orebro, SwedenBackground: Previous studies indicate a higher risk of comorbidity in men with infertility; however, research on mortality is scarce and the few studies that do exist have rarely differentiated between infertility and infertility-related diagnoses.Objective: To examine mortality in men with an infertility or infertility-related diagnosis.Design, setting, and participants: Population-based cohort study of men born in 1944–1992 in Sweden. We used Cox regression estimated hazard ratios (HRs) for infertility while adjusting for number of children, education, year of birth, country of birth, diabetes, hypertension, liver disease and end-stage renal disease. In all, 43,598 men with a diagnosis of infertility and 57,733 men with an infertility-related diagnosis were compared with 2,762,254 men (reference group) without such diagnoses.Outcome measures: All-cause and cause-specific mortality at age 20 to 69 years.Results and limitations: The 2,863,585 men in the study were followed for a median time of 22.0 years. During follow-up, 439 men with a diagnosis of infertility died, corresponding to a crude incidence rate of 1.56 deaths per 1,000 person-years. These figures can be compared with 1,400 deaths in men with an infertility-related diagnosis (1.96 deaths/1,000 person-years) and 99,463 deaths in reference individuals (2.17 deaths/1,000 person-years). Overall, men with a diagnosis of infertility did not have a higher risk of death (adjusted [a]HR=0.98; 95% confidence interval [95% CI]=0.89–1.08), but had a higher risk of death before age 30 (20–29 years) (aHR=3.26; 95% CI=2.42–4.41). This early excess mortality was largely explained by cancer diagnosed before infertility. Having an infertility-related diagnosis was associated with death (aHR=1.23; 95% CI=1.17–1.30). Limitations include the lack of general screening for infertility in Sweden and the lack of information on semen parameters.Conclusion: Men with a diagnosis of infertility are not at a higher risk of death than the general population, although having a diagnosis related to infertility may be linked to a higher risk of death.Patient summary: Men with a diagnosis of infertility do not seem to have a higher risk of death though an infertility-related diagnosis in men is associated with the risk of death.Keywords: cancer, death, infertility

Background: While immediate breast reconstruction rates in breast cancer are increasing, they remain low in women over 65 years old. The aim was to investigate surgical outcomes in women older than 65 years receiving implant-based immediate breast reconstruction., Method: The population-based Stockholm Breast Reconstruction Database includes all adult women with breast cancer receiving an implant-based immediate breast reconstruction in Stockholm, Sweden, 2005-2015. Primary outcomes within 30 days from immediate breast reconstruction were: infection requiring antibiotics and reoperation on. Implant removal was a secondary outcome. Women more than 65 years were compared with younger age groups. Chi-square tests and multivariable logistic regression were applied for the primary outcomes, and Kaplan-Meier analysis for the secondary outcome., Results: Among 1749 cases of immediate breast reconstruction, 140 (8.0%) were in women more than 65 years. Median follow-up was 74 months (1-198). Postoperative infection was not more common in women older than 65 years old (22 of 140, 15.7%) than in women under 65 years old (303 of 1609, 18.8%; P = 0.221). Reoperation on was more frequent in women older than 65 years than in other age groups (more than 65: 8.6%; 50-64: 6.5%; 40-49: 3.5%; less than 40: 1.6%; P < 0.001), however, age older than 65 years was not an independent risk factor in the multivariable analysis (OR 1.00, 95% c.i. 0.44 to 2.28). Overall, 6-year probability of implant removal was 11.4%, (8.1% due to complications and 3.3% due to patient preference). There was no statistically significant difference between age groups for either reason (P = 0.085 and P = 0.794 respectively)., Conclusion: Older age alone was not associated with worse surgical outcomes after implant-based immediate breast reconstruction in highly selected patients older than 65 years when compared with their younger counterparts., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Objective: To use machine learning methods to develop prediction models of pregnancy complications in women who conceived with assisted reproductive techniques (ART)., Design: A nation-wide register-based cohort study with prospectively collected data., Setting: Swedish national registers and nationwide quality IVF register., Patient(s): all nulliparous women who achieved birth within the first 3 ART treatment cycles between 2008 and 2016 in Sweden., Intervention(s): Characteristics before the use of ART, such as demographics and medical history, were considered potential predictors in the development of before treatment prediction models. ART treatment details were further included in after treatment prediction models., Main Outcome Measure(s): Potential diagnoses of preeclampsia, placental complications (previa, accreta, and abruption), and postpartum hemorrhage were identified using the International Classification of Diseases recorded in the Swedish Medical Birth and Patient registers, respectively. Multiple prediction model algorithms were performed and compared for each outcome and treatment cycle, including logistic regression, decision tree model, naïve Bayes classification, support vector machine, random forest, and gradient boosting. The performance of each model was assessed with C statistic, and nested cross-validation was used to aid model selection and hyperparameter tuning., Result(s): A total of 14,732 women gave birth after the first (N = 7,302), second (N = 4,688), or third (N = 2,742) ART cycle, representing birth rates of 24.1%, 23.8%, and 22.0%. Overall prediction performance did not vary much across the different methods used. In the first cycle, the before treatment prediction performance was at best 66%, 66%, and 60% for preeclampsia, placental complications, and postpartum hemorrhage, respectively. Inclusion of after treatment characteristics conferred slight improvement (approximately 1%-5%), as did prediction in later cycles (approximately 1%-5%). The top influential and consistent predictors included age, region of residence, infertility diagnosis, and type of embryo transfer (fresh or frozen) in the later (2 nd and 3 rd ) cycles. Body mass index was a top predictor of preeclampsia and was also influential for placental complications but not for postpartum hemorrhage., Conclusion(s): The combined use of demographics, medical history, and ART treatment information was not enough to confidently predict serious pregnancy complications in women who conceived with ART. Future studies are needed to assess if additional longitudinal follow-up during pregnancy can improve the prediction to allow clinical protocol development., Competing Interests: Declaration of Interests C.W. reports funding from Forte grant number 2016-01202 and the National Institutes of Health (NIH) grant number R01HD088393 for the submitted work; employed as data analyst in Thermo Fisher Scientific, PPD, Evidera after the manuscript completion. A.L.V.J. has nothing to disclose. C.N. is employed as consulting specialist and chief medical manager at the fertility clinic Livio Kungsholmen Stockholm since 2016. A.P. is a medical associate at Cerebriu, a medical artificial intelligence company for radiology. C.A has nothing to disclose. S.H-D. reports funding from NIH grant R01HD088393 for the submitted work; funding from Takeda; consulting fees from JNJ, Moderna, and BWH-MGH outside the submitted work. A.S.O. received personal fees from Abbot for serving on a Scientific and Medical Advisory Council, unrelated to the current work and reports funding from Forte junior research grant no: 2016-01202 for the submitted work; funding from Forte research grant no: 2020-00753, NIH R01 HD088393, Swedish Research council no: 2018-02679, NIH R01 DA048042-01, and NIH R01 HD088393 outside the submitted work., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Study Question: What are the obstetric and perinatal outcomes in births to breast cancer survivors compared to women without previous breast cancer?, Summary Answer: Women who conceived during the first 2 years following a breast cancer diagnosis had a higher risk for preterm birth, induced delivery, and cesarean section, while no increased risks were observed in births conceived later than 2 years after a breast cancer diagnosis., What Is Known Already: A recent meta-analysis found higher risks of cesarean section, preterm birth, low birthweight, and small for gestational age in pregnancies among breast cancer survivors. Less is known about rarer outcomes such as pre-eclampsia or congenital malformations., Study Design Size Duration: We conducted a population-based matched cohort study including all breast cancer survivors who gave birth to singletons 1973-2017 in Sweden, identified through linkage between the Swedish Cancer Register, the Medical Birth Register, and the National Quality Register for Breast Cancer., Participants/materials Settings Methods: Each birth following breast cancer (n = 926) was matched by maternal age at delivery, parity, and calendar year at delivery to 100 births in a comparator cohort of women (n = 92 490). Conditional logistic and multinomial regression models estimated relative risks (RR) with 95% CI. Subgroup analyses by time since diagnosis and type of treatment were performed., Main Results and the Role of Chance: Previous breast cancer was associated with higher risks of induced delivery (RR; 1.3, 1.0-1.6), very preterm birth (RR; 1.8, 1.1-3.0), and planned preterm birth (RR; 1.6, 1.0-2.4). Women who conceived within 1 year after breast cancer diagnosis had higher risks of cesarean section (RR; 1.7, 1.0-2.7), very preterm birth (RR; 5.3, 1.9-14.8), and low birthweight (RR; 2.7, 1.4-5.2), while the risks of induced delivery (RR; 1.8, 1.1-2.9), moderately preterm birth (RR; 2.1, 1.2-3.7), and planned preterm birth (RR; 2.5, 1.1-5.7) were higher in women who conceived during the second year after diagnosis. Women who conceived later than 2 years after breast cancer diagnosis had similar obstetric risks to their comparators., Limitations Reasons for Caution: As information on the end date of treatment was unavailable, the time between the date of diagnosis and conception was used as a proxy, which does not fully capture the effect of time since end of treatment. In addition, treatments and clinical recommendations have changed over the long study period, which may impact childbearing patterns in breast cancer survivors., Wider Implications of the Findings: Risks of adverse obstetric outcomes in breast cancer survivors were confined to births conceived within 2 years of diagnosis. As family building holds significance for numerous young breast cancer patients, these findings are particularly important to inform both breast cancer survivors and clinicians about future reproductive outcomes., Study Funding/competing Interests: This work was supported by the Swedish Cancer Society (grant number 22-2044 Pj A.L.V.J.), Karolinska Institutet Foundations (grant number: 2022-01696 F.E.L., 2022-01559 A.L.V.J.), and the Swedish Research Council (grant number: 2021-01657 A.L.V.J.). K.A.R.-W. is supported by grants from the Swedish Cancer Society (20 0170 F) and the Radiumhemmets Research Foundations for clinical researchers 2020-2026. The authors declare that they have no conflicts of interest., Trial Registration Number: N/A., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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: 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.

Introduction: For women presenting with breast cancer during pregnancy, treatment guidelines were historically restricted to only surgical treatment. Over the past decades, chemotherapy administered during pregnancy has been gradually introduced. Although breast cancer treatments during ongoing pregnancy have been deemed safe, detailed information on potential obstetric risks is lacking. We aimed to assess the risk of adverse obstetric and perinatal outcomes of breast cancer in pregnancy and within 1 year postpartum and in relation to trimester at breast cancer diagnosis, tumor stage, and cancer treatment during pregnancy., Material and Methods: Population-based matched study. Women diagnosed with breast cancer during pregnancy in 1973-2017 were identified in the Swedish Cancer Register and the Medical Birth Register, with additional information from the National Quality Register for Breast Cancer. Each birth with maternal breast cancer (n = 208 pregnant, n = 672 postpartum) was matched by age, calendar year, and birth order to 10 unexposed births from cancer-free women in the population (n = 2080 and n = 6720). Adjusted conditional logistic and multinomial regression models were used to estimate odds ratios and relative risk ratios, commonly denoted relative risks (RR) with 95% confidence intervals (CI), of adverse obstetric and perinatal outcomes., Results: Breast cancer during pregnancy was associated with higher risks of preterm birth, both planned (RR 67.1, 95% CI 33.2-135.6) and spontaneous preterm birth (RR 3.8, 95% CI 2.0-7.5), and low birthweight (<2500 g: RR 7.5, 95% CI 4.9-11.3). The associated risks were higher if the breast cancer was diagnosed in the second trimester, and of similar magnitude irrespective of stage and treatment groups. There was a higher risk of low birthweight for gestational age (<25th centile) if breast cancer was diagnosed in the first trimester (RR 2.8, 95% CI 1.1-7.3). Risks of other pregnancy complications were similar to those of unexposed women, as were risks of neonatal mortality and malformations. Postpartum breast cancer was only associated with bleeding during pregnancy (RR 1.6, 95% CI 1.0-2.8)., Conclusions: Preterm birth and related adverse outcomes were more common in women diagnosed with breast cancer during pregnancy. Reassuringly, breast cancer was not associated with other maternal pregnancy complications or adverse outcomes in children., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Evidence suggests that women with breast cancer diagnosed during pregnancy (PrBC) and within 2 years of delivery (PPBC) have similar survival compared to women diagnosed not near pregnancy if adjusted for stage and subtype. To investigate whether this is true for all subtypes and for both pregnancy and post-delivery periods, we examined clinicopathologic features and survival in women with breast cancer by trimesters and 6-month post-delivery intervals., Materials and Methods: Women diagnosed with invasive breast cancer during 1992-2018 at ages 18-44 years were identified in the Swedish Cancer Register, with information on childbirths from the Swedish Multi-Generation Register and clinical data from Breast Cancer Quality Registers. Each woman with PrBC or PPBC was matched 1 : 2 by age and year to comparators diagnosed with breast cancer not near pregnancy. Distributions of stage, grade, and surrogate subtypes were compared. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer mortality were estimated using Cox regression., Results: We identified 1430 women with PrBC and PPBC (181 during pregnancy, 499 during the first and 750 during the second year after delivery). Compared to 2860 comparators, women with PrBC and PPBC in the first year after delivery had a significantly higher proportion of luminal human epidermal growth factor receptor 2 (HER2)-positive, HER2-positive and triple-negative tumours, and more advanced stage at diagnosis. After adjustment for age, year, parity, country of birth, hospital region, subtype, and stage, women diagnosed during the second trimester had a worse prognosis than matched comparators (HR 1.8, 95% CI: 1.0-3.2)., Conclusions: Women diagnosed during pregnancy or within the first year after delivery have a worse prognosis than women diagnosed not near pregnancy due to adverse tumour biology and advanced stage at diagnosis. A worse prognosis for women diagnosed during the second trimester remained after multivariable adjustment, possibly reflecting difficulties to provide optimal treatment during ongoing pregnancy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: The incidence of cancer during pregnancy and within first year post-delivery, ie pregnancy-associated cancer (PAC), is increasing in many countries, but little is known about risk factors for these trends. This study quantified incidence of PAC by trimesters and post-delivery periods, and assessed the role of maternal age, parity, immigrant status, education, smoking and body mass index for the risk and incidence trends of PAC., Material and Methods: We used data from the national birth and cancer registers in Sweden during 1973-2017 to define a register-based cohort of women aged 15-44 years. Incidence rates of PAC during pregnancy and up to 1 year post-delivery were calculated per 100 000 deliveries per year. Poisson regression with multiple imputation estimated incidence rate ratios with 95% confidence intervals adjusted by year, age, previous parity, immigrant status, education, smoking and BMI during 1990-2017, when information on risk factors was available., Results: Among 4 557 284 deliveries, a total of 1274 (during pregnancy) and 3355 (within 1 year post-delivery) cases of PAC were diagnosed, with around 50 cases/year diagnosed during pregnancy and 110 cases/year during the first year post-delivery in the latest period 2015-2017. The most common cancer types during pregnancy were malignant melanoma, breast and cervical cancer, together accounting for 57% of cases during pregnancy and 53% during the first year post-delivery. The numbers of PAC were lower during pregnancy than during post-delivery for all tumor types with lowest numbers during first trimester. The PAC incidence rates increased over calendar time. High maternal age at diagnosis, smoking, nulliparity and non-immigrant background were associated with significantly higher risks of PAC. The increasing PAC incidence was in part explained by higher maternal age over time, but not by the other factors., Conclusions: High maternal age is the strongest risk factor for PAC. We show for the first time that smoking, nulliparity and non-immigrant background are also contributing risk factors for PAC. However, only high maternal age contributed significantly to the increasing incidence. Further studies on other potential risk factors for PAC are warranted, since our results indicate that age on its own does not fully explain the increase., (© 2023 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Undertreatment of otherwise healthy men in their seventies with prostate cancer has been reported previously., Material and Methods: Using information in a Swedish prostate cancer research database, patterns of management and cancer-specific mortality were compared across age groups in over 70,000 men diagnosed with intermediate- or high-risk nonmetastatic prostate cancer between 2008 and 2020. Crude probabilities of death were estimated non-parametrically. Staging procedures, primary treatment, and cancer death were compared using regression models, adjusting for patient and tumor characteristics., Results: During the study period, the proportion of men treated with curative intent increased in ages 70-74 (intermediate-risk from 45% to 72% and high-risk from 49% to 84%), 75-79 (intermediate-risk from 11% to 52% and high-risk from 12% to 70%), and 80-84 years (intermediate-risk from < 1% to 14% and high-risk from < 1% to 30%). Older age was associated with lower likelihoods of staging investigations and curative treatment, also after adjustment for tumor characteristics and comorbidity. Men treated with curative intent and those initially managed conservatively had lower crude risks of prostate cancer death than men receiving androgen deprivation treatment (ADT). In adjusted analyses, ADT was associated with higher prostate cancer mortality than curative treatment across ages and risk groups. Among men managed conservatively, prostate cancer mortality was higher in ages 70 and above., Interpretation: Use of curative treatment increased substantially in older men with prostate cancer between 2008 and 2020. Our findings suggest reduced age-bias and under-treatment, likely reflecting improved individualized decision-making and adherence to guidelines recommending more active management of older men.

Background: Estrogen receptor-low (ER-low) HER2-negative breast cancer has similar pathological and molecular characteristics as triple-negative breast cancer (TNBC), and it is questionable whether it should be considered a separate entity. When the international guidelines lowered the cutoff for ER positivity to ≥1% in 2010, the ≥10% threshold was kept in Sweden. ER-low breast cancer (ER 1-9%) is thus in Sweden treated as TNBC. We aimed to describe patient and tumor characteristics, treatment patterns and overall survival in a Swedish population-based cohort of patients with ER-zero and ER-low HER2-negative breast cancer treated as TNBC., Methods: All TNBC cases diagnosed in Sweden 2008-2020 were included in a population-based cohort study. Patient, tumor and treatment characteristics were analyzed by ER-status (ER 0% vs 1-9%), and associations between subgroups compared using χ 2 test. Survival endpoint was overall survival (OS), and Kaplan-Meier curves were estimated. Cox proportional hazards models were used to estimate adjusted hazard ratios comparing ER-low to ER-zero., Findings: Of the 5655 tumors, 90.1% had an ER expression of 0%, while 9.9% were ER-low. ER-low tumors were grade III in 69.4% (80.8% in ER-zero tumors, p-value = 0.001), with a median Ki67 of 60% (63% in ER-zero tumors, p-value = 0.005). There were no significant differences in given chemotherapy (p = 0.546). A pathological complete response (pCR) was achieved in 28.1% of ER-low tumors (25.1% in ER-zero tumors). In the unadjusted analysis of OS, women with ER-low disease had a borderline but not significantly better OS than those with ER-zero disease (HR 0.84 (95% CI 0.71-1.00), p = 0.052). ER-status 1-9% vs 0% was not associated with OS in the multivariable analysis (HR 1.11 (0.90-1.36)). Distant disease-free survival did not differ by ER-status 0% vs 1-9% (HR 0.97 for ER-zero vs ER-low (0.62-1.53), p = 0.905). After preoperative treatment, the impact of pCR for OS did not significantly differ between ER-zero or ER-low disease., Interpretation: ER-low HER2-negative breast cancer has characteristics and prognosis similar to TNBC, when treated in the same way. Therefore, it seems reasonable to use a ≥10% threshold for ER positivity. This would provide patients with ER-low tumors the same treatment opportunities as patients with TNBC, within studies and within clinical routine., Funding: This work was financially supported by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in accordance with terms and conditions of a Master Collaboration Agreement between the company and Karolinska Institutet., Competing Interests: B.A is supported by The Swedish Society for Medical Research (Svenska Sällskapet för Medicinsk Forskning) postdoctoral grant. J.H has obtained speaker's honoraria or advisory board remunerations from Roche, Novartis, AstraZeneca, Pfizer, Eli Lilly, MSD and Gilead and has received institutional research support from Novartis, Pfizer, MSD, AstraZeneca outside the current work. J.H is scientific advisor to the National Board of Health and Welfare (Socialstyrelsen). J.H. is a co-founder and shareholder of Stratipath AB. J.H has two pending patent applications through Stratipath on AI-software medical device (filed 2021 and 2023). D.S. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and owns stocks and/or stock options in Merck & Co., Inc., Rahway, NJ, USA. H.L. reports personal fees from Novartis, AstraZeneca, Daiichi Sankyo, Pierre Fabre, MSD outside the current work. H.L. is scientific advisor to Lilly, MSD, Daiichi Sankyo, Pierre Fabre, Seagen, Astra Zeneca, Gilead. A.L.V.J. has no disclosures to declare. I.F. has received an institutional research support from MSD for this project in accordance with terms and conditions of a Master Collaboration Agreement between the company and Karolinska Institutet, as well as research grants from the Swedish Breast cancer Association and the Swedish Cancer Association unrelated to the current work., (© 2024 The Authors.)

The management of breast cancer during pregnancy (PrBC) is a relatively rare indication and an area where no or little evidence is available since randomized controlled trials cannot be conducted. In general, advances related to breast cancer (BC) treatment outside pregnancy cannot always be translated to PrBC, because both the interests of the mother and of the unborn should be considered. Evidence remains limited and/or conflicting in some specific areas where the optimal approach remains controversial. In 2022, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process on this topic to gain insights from a multidisciplinary group of experts and develop statements on controversial topics that cannot be adequately addressed in the current evidence-based ESMO Clinical Practice Guideline. The aim of this consensus-building process was to discuss controversial issues relating to the management of patients with PrBC. The virtual meeting included a multidisciplinary panel of 24 leading experts from 13 countries and was chaired by S. Loibl and F. Amant. All experts were allocated to one of four different working groups. Each working group covered a specific subject area with two chairs appointed: Planning, preparation and execution of the consensus process was conducted according to the ESMO standard operating procedures., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Routine reporting of cancer patient survival is important, both to monitor the effectiveness of health care and to inform about prognosis following a cancer diagnosis. A range of different survival measures exist, each serving different purposes and targeting different audiences. It is important that routine publications expand on current practice and provide estimates on a wider range of survival measures. We examine the feasibility of automated production of such statistics., Methods: We used data on 23 cancer sites obtained from the Cancer Registry of Norway (CRN). We propose an automated way of estimating flexible parametric relative survival models and calculating estimates of net survival, crude probabilities, and loss in life expectancy across many cancer sites and subgroups of patients., Results: For 21 of 23 cancer sites, we were able to estimate survival models without assuming proportional hazards. Reliable estimates of all desired measures were obtained for all cancer sites., Discussion: It may be challenging to implement new survival measures in routine publications as it can require the application of modeling techniques. We propose a way of automating the production of such statistics and show that we can obtain reliable estimates across a range of measures and subgroups of patients., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In a population-based setting, we investigated the risks of testing positive for SARS-CoV-2 and developing severe COVID-19 outcomes among cancer patients compared with the general population., Methods: In nationwide cohorts, we identified all individuals in Norway, Denmark and Iceland who tested positive for SARS-CoV-2 or had a severe COVID-19 outcome (hospitalisation, intensive care, and death) from March until December 2020, using data from national health registries. We estimated standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) comparing cancer patients with the general population., Findings: During the first wave of the pandemic, cancer patients in Norway and Denmark had higher risks of testing SARS-CoV-2 positive compared to the general population. Throughout 2020, recently treated cancer patients were more likely to test SARS-CoV-2 positive. In Iceland, cancer patients experienced no increased risk of testing positive. The risk of COVID-19-related hospitalisation was higher among cancer patients diagnosed within one year of hospitalisation (Norway: SIR = 2.43, 95% CI 1.89-3.09; Denmark: 2.23, 1.96-2.54) and within five years (Norway: 1.58, 1.35-1.83; Denmark: 1.54, 1.42-1.66). Risks were higher in recently treated cancer patients and in those diagnosed with haematologic malignancies, colorectal or lung cancer. Risks of COVID-19-related intensive care and death were higher among cancer patients., Interpretation: Cancer patients were at increased risk of testing positive for SARS-CoV-2 during the first pandemic wave when testing availability was limited, while relative risks of severe COVID-19 outcomes remained increased in cancer patients throughout 2020. Recent cancer treatment and haematologic malignancy were the strongest risk factors., Funding: Nordic Cancer Union., Competing Interests: ML declares stock or stock options in Astra Zeneca and Pfizer Inc. The other authors declare no competing interests., (© 2023 The Author(s).)

Background: The stage at diagnosis is one of the most important predictors for cancer survival. TNM stage is constructed from T (tumor size), N (nodal spread), and M (distant metastasis) components. In many notifications to cancer registries, TNM information is incomplete with unknown N and/or M. We aimed to evaluate the influence of various assumptions for recoding missing N (NX) and M (MX) as N0 and M0 on the proportion with available TNM stage, stage-distribution, and stage-specific relative survival., Material and Methods: We identified 140,201 patients diagnosed with incident cancer of the colon, rectum, lung, breast, or kidney during 2014-2016 in Denmark, Norway, Sweden, or Iceland. Information on TNM were obtained from cancer registry records used for an update of the Nordic cancer statistics database NORDCAN. Patients were followed for death or emigration through 2017. We calculated proportions of available TNM stage, stage distribution, and stage-specific relative survival under different approaches for each cancer site and country., Results: Application of the assumptions yielded higher numbers of cases with available TNM stage for stages 0-I, II, and III. We observed only minor differences in stage-specific one-year relative survival when applying N0M0 for missing N and M, especially for high completeness of TNM registrations, whereas relative survival for remaining cases with missing TNM stage declined substantially., Conclusion: We found no major changes in stage-specific one-year relative survival applying N0M0 for NXMX. We conclude that complete TNM information is preferable to making assumptions, but it seems reasonable to consider assuming N0M0 for missing N and M in future studies based on the Nordic cancer registries. An automatic algorithm, though, is not recommended without considering potential area-specific reasons for frequent use of NX and MX. Clinicians should be urged to report complete TNM information to improve surveillance of the TNM stage.

Background: Mastectomy rates in breast cancer are higher in older patients. The aim was to compare postoperative complication rates after breast-conserving surgery (BCS) to mastectomy in women aged 70-79 and older than 80 years versus those aged 50-69 years, and to evaluate survival effects., Methods: This population-based cohort included women aged 50 years and older with invasive breast cancer T1-3 N0-3 M0 operated on in Sweden 2008-2017. Major surgical and medical 30-day postoperative complications were assessed in adjusted logistic regression models. Overall survival was assessed in Cox models adjusted for clinical confounders, socio-economics, and comorbidity., Results: Of 34 139 women, 8372 (24.5 per cent) were aged 70-79 years, 3928 (11.5 per cent) were 80 years of age or older, and 21 839 (64.0 per cent) were aged 50-69 years. Major surgical postoperative complications did not differ between age groups receiving equivalent surgery (BCS: 2.1 per cent and 2.0 per cent versus 2.1 per cent (P = 0.90); mastectomy: 4.6 per cent and 5.1 per cent versus 4.6 per cent (P = 0.49)). Major medical postoperative complications were higher in women aged >70 years than in women aged 50-69 years (BCS: 1.0 per cent and 2.3 per cent versus 0.4 per cent (P < 0.001); mastectomy: 3.1 per cent and 6.2 per cent versus 1.1 per cent (P < 0.001)), which persisted after adjustments. In women treated by mastectomy, major medical and surgical postoperative complications were associated with worse overall survival in all but the middle age group., Conclusion: Mastectomy has higher medical and surgical postoperative complication rates than BCS. Major medical postoperative complications increase significantly with age. Major postoperative complications are associated with worse survival after mastectomy, which should be used with caution in older women., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Several metals act as endocrine disruptors, but there are few large longitudinal studies about associations with puberty onset., Objectives: We evaluated whether early life cadmium, lead, and arsenic exposure was associated with timing of menarche., Methods: In a mother-child cohort in rural Bangladesh ( n = 935 ), the exposure was assessed by concentrations in maternal erythrocytes in early pregnancy and in girls' urine at 5 and 10 years of age using inductively coupled plasma mass spectrometry. The girls were interviewed twice, at average ages 13.3 [standard deviation ( SD ) = 0.43 ] and 13.8 ( SD = 0.43 ) y, and the date of menarche, if present, was recorded. Associations were assessed using Kaplan-Meier analysis and multivariable-adjusted Cox regression., Results: In total, 77% of the girls ( n = 717 ) had reached menarche by the second follow-up. The median age of menarche among all girls was 13.0 y (25th-75th percentiles: 12.4-13.7 y). At 10 years of age, median urinary cadmium was 0.25 μ g / L (5th-95th percentiles: 0.087 - 0.72 μ g / L ), lead 1.6 μ g / L ( 0.70 - 4.2 μ g / L ), and arsenic 54 μ g / L ( 19 - 395 μ g / L ). Given the same age, girls in the highest quartile of urinary cadmium at 5 and 10 years of age had a lower rate of menarche than girls in the lowest quartile, with an adjusted hazard ratio of (HR) 0.80 (95% CI: 0.62, 1.01) at 5 years of age, and 0.77 (95% CI: 0.60, 0.98) at 10 years of age. This implies that girls in the highest cadmium exposure quartile during childhood had a higher age at menarche. Comparing girls in the highest to the lowest quartile of urinary lead at 10 years of age, the former had a higher rate of menarche [adjusted HR = 1.23 (95% CI: 0.97, 1.56)], implying lower age at menarche, whereas there was no association with urinary lead at 5 years of age. Girls born to mothers in the highest quartile of erythrocyte arsenic during pregnancy were less likely to have attained menarche than girls born to mothers in the lowest quartile [adjusted HR = 0.79 (95% CI: 0.62, 0.99)]. No association was found with girls' urinary arsenic exposure., Discussion: Long-term childhood cadmium exposure was associated with later menarche, whereas the associations with child lead exposure were inconclusive. Maternal exposure to arsenic, but not cadmium or lead, was associated with later menarche. https://doi.org/10.1289/EHP11121.

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: Radiotherapy (RT) is a risk factor for impaired outcomes after implant-based immediate breast reconstruction (IBR). Large studies including long-term follow-up are relatively scarce. The purpose of this analysis was to assess long-term effects of RT in implant-based IBR, distinguishing between implant removal because of postoperative complications versus patient preference., Methods: This population-based cohort study included all patients with breast cancer who underwent implant-based IBR in Stockholm between 2005 and 2015. Data were collected through national registers and medical charts. The main endpoint was implant removal owing to postoperative complications (wound breakdown, infection, bleeding) or patient preference (dissatisfaction, pain, capsular contracture), with or without conversion to autologous reconstruction., Results: Some 1749 implant-based IBRs in 1687 women were included. Median follow-up was 72 (range 1-198) months. Reconstructions were divided according to receipt of RT: No RT (n = 856, 48.9 per cent), adjuvant RT (n = 749, 42.8 per cent), and previous RT (n = 144, 8.2 per cent). Implant removal occurred after 266 reconstructions (15.2 per cent); 68 (7.9 per cent) in the no RT, 158 (21.1 per cent) in the adjuvant RT, and 40 (27.8 per cent) in the previous RT group. Implant removal was because of postoperative complications in 152 instances (57.1 per cent) and was most common in the first 3 years. This was especially observed in the previous RT group, where 15 of 23 implant removals occurred during the first 6 months. Implant removal owing to patient preference (114 of 266, 42.9 per cent) became more common with increasing follow-up., Conclusion: Implant removal after implant-based IBR is significantly associated with RT. The reason for implant removal shifts over time from postoperative complications to patient preference., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

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).)

Background: Postoperative complications may activate prometastatic systemic pathways through tissue damage, wound healing, infection, and inflammation. Postoperative complications are associated with inferior survival in several types of cancer. The aim was to determine the association between postoperative complications and survival in breast cancer., Methods: This population-based cohort included women operated for T1-3 N0-3 M0 invasive breast cancer in Sweden from 2008 to 2017. Only major surgical postoperative complications leading to readmission and/or reoperation within 30 days were considered. Main outcomes were overall survival (OS) and breast cancer-specific survival (BCSS). Prospectively collected nationwide register data were used. Multivariable Cox models were adjusted for clinical and socioeconomic confounders and co-morbidity., Results: Among 57 152 women, major surgical postoperative complications were registered for 1854 patients. Median follow-up was 6.22 (0.09-11.70) years. Overall, 9163 patients died, and 3472 died from breast cancer. Major surgical postoperative complications were more common after mastectomy with or without immediate reconstruction (7.3 and 4.3 per cent respectively) than after breast-conserving surgery (2.3 per cent). Unadjusted 5-year OS and BCSS rates were 82.6 (95 per cent c.i. 80.8 to 84.5) and 92.1 (90.8 to 93.5) per cent respectively for women with a major surgical postoperative complication, and 88.8 (88.6 to 89.1) and 95.0 (94.8 to 95.2) per cent for those without a complication (P < 0.001). After adjustment, all-cause and breast cancer mortality rates remained higher after a major surgical postoperative complication (OS: HR 1.32, 95 per cent c.i. 1.15 to 1.51; BCSS: HR 1.31, 1.04 to 1.65). After stratification for type of breast surgery, this association remained significant only for women who had mastectomy without reconstruction (OS: HR 1.41, 1.20 to 1.66; BCSS: HR 1.36, 1.03 to 1.79)., Conclusion: Major surgical postoperative complications are associated with inferior survival, especially after mastectomy. These results underline the importance of surgical de-escalation., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

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.)

The severity of the COVID-19 pandemic and subsequent mitigation strategies have varied across the Nordic countries. In a joint Nordic population-based effort, we compared patterns of new cancer cases and notifications between the Nordic countries during 2020. We used pathology notifications to cancer registries in Denmark, the Faroe Islands, Finland, Iceland, Norway and Sweden to determine monthly numbers of pathology notifications of malignant and in situ tumours from January to December 2020 compared to 2019 (2017-2019 for Iceland and the Faroe Islands). We compared new cancer cases per month based on unique individuals with pathology notifications. In April and May 2020, the numbers of new malignant cases declined in all Nordic countries, except the Faroe Islands, compared to previous year(s). The largest reduction was observed in Sweden (May: -31.2%, 95% CI -33.9, -28.3), followed by significant declines in Finland, Denmark and Norway, and a nonsignificant decline in Iceland. In Denmark, Norway, Sweden and Finland the reporting rates during the second half of 2020 rose to almost the same level as in 2019. However, in Sweden and Finland, the increase did not compensate for the spring decline (annual reduction -6.2% and -3.6%, respectively). Overall, similar patterns were observed for in situ tumours. The COVID-19 pandemic led to a decline in rates of new cancer cases in Sweden, Finland, Denmark and Norway, with the most pronounced reduction in Sweden. Possible explanations include the severity of the pandemic, temporary halting of screening activities and changes in healthcare seeking behaviour., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Overall, women have better cancer-specific survival than men following haematological malignancies. The effect of reproductive factors on prognosis in women remains unknown and population-based studies are needed., Material and Methods: A nationwide cohort of 21,237 Swedish women with a recorded haematological malignancy at ages 18-69 years was identified in the Swedish Cancer Register 1970-2018. Pre-diagnosis childbirths for each woman were linked to the Swedish Multigeneration Register. Net survival and excess hazard ratios for parity, age at first birth, time since the latest birth, and sex of offspring were estimated using flexible parametric models adjusted for age, year, and educational level., Results: In unadjusted analyses, parity ( p  = 0.0012) and high age at first birth ( p  < 0.0001) were associated with better survival. After co-adjustments for reproductive factors and confounders, the associations were attenuated. The adjusted association with parity was mainly observed among women aged above 40 years at diagnosis ( p  = 0.0033). The associations with reproductive factors were non-significant across subtypes of haematological malignancy. There was a tendency of higher excess mortality for an increasing number of boys compared to girls, although only significant for women with three or more children ( p  = 0.0126)., Conclusion: Reproductive factors were in part associated with survival following diagnosis of a haematological malignancy. However, the effect sizes were small with inconsistent association patterns, and thus reproductive factors may only partly contribute to the survival advantage of women over men.

Importance: Individuals conceived with assisted reproductive techniques (ARTs) could be at elevated risk of psychiatric disorders owing to potential adverse effects of the procedures themselves, or because such traits or their risk factors may be more common in couples with infertility., Objective: To investigate the risk of psychiatric disorders in adolescents and young adults conceived with ARTs and to evaluate the role of treatment-related parental characteristics., Design, Setting, and Participants: This prospective follow-up of a nationwide birth cohort used linkage of Swedish population registers with coverage through 2018. All children born in Sweden from January 1, 1994, to December 31, 2006, were included in the analysis. Follow-up was completed on December 31, 2018, when participants were 12 to 25 years of age, and data was analyzed from March 17, 2020, to September 10, 2021., Exposures: In vitro fertilization with or without intracytoplasmic sperm injection and transfer of fresh or frozen-thawed embryos., Main Outcomes and Measures: Clinical diagnoses of mood disorder, including major depression, anxiety, obsessive-compulsive disorder (OCD), or suicidal behavior, were identified from hospital records and outpatient specialist care. Suicide was additionally identified from death certificates. Antidepressant use was identified from dispensations of prescribed medications., Results: A total of 1 221 812 children (48.6% female, 51.4% male) born between 1994 and 2006 were followed up to a median age of 18 (IQR, 15-21) years. Among these participants, 31 565 (2.6%) were conceived with ART. Compared with all others, adolescents conceived with ART had an elevated risk of OCD (hazard ratio [HR], 1.35 [95% CI, 1.20-1.51]), but the association was attenuated and no longer statistically significant after adjustment for parental characteristics (adjusted HR [aHR], 1.10 [95% CI, 0.98-1.24]) and was no longer present when restricted to individuals born to couples with known infertility (aHR, 1.02 [95% CI, 0.89-1.17]). Adolescents conceived with ARTs were not at elevated risk of depression or suicidal behavior compared with other adolescents (irrespective of parental infertility). Type of fertilization (standard in vitro fertilization or intracytoplasmic sperm injection) had no association with outcomes. Compared with non-ART-conceived children of couples with infertility, fresh, but not frozen, embryo transfer was associated with a lower risk of mood disorders (aHR, 0.90 [95% CI, 0.83-0.97]), making frozen embryo transfer appear less advantageous when directly contrasted with fresh embryo transfer., Conclusions and Relevance: These findings suggest that adolescents conceived with ARTs around the millennium are not at risk of poor psychiatric health compared with the general population, except for an elevated risk of OCD that may be explained by differences in parental characteristics.

Background: Breast cancer incidence differs between non-immigrants and immigrants from low- and middle-income countries. This study investigates whether immigrants also have different subtype-specific incidences., Methods: We used national health registries in Norway and calculated subtype-specific incidence rate ratios (IRRs) for invasive breast cancer among women aged 20-75 and 20-49 years between 2005 and 2015. Immigrant groups were classified by country of birth broadly defined based on WHO regional groupings. Subtype was defined using estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2) status as luminal A-like (ER+ PR+ HER2-), luminal B-like/HER2- (ER+ PR- HER2-), luminal B-like/HER2+ (ER+ PR any HER2+), HER2+ (ER-PR-HER2+) and triple-negative breast cancer (TNBC) (ER-PR-HER2-)., Results: Compared to non-immigrants, incidence of the luminal A-like subtype was lower in immigrants from Sub-Saharan Africa (IRR 0.43 95% CI 0.28-0.66), South East Asia (IRR 0.63 95% CI 0.51-0.79), South Asia (IRR 0.67 95% CI 0.52-0.86) and Eastern Europe (IRR 0.86 95% CI 0.76-0.99). Immigrants from South Asia had higher rates of HER2 + tumors (IRR 2.02 95% CI 1.26-3.23). The rates of TNBC tended to be similar regardless of region of birth, except that women from South East Asia had an IRR of 0.54 (95% CI 0.32-0.91)., Conclusions: Women from Eastern Europe, Sub-Saharan Africa and Asia had different subtype-specific incidences compared to women from high-income countries (including non-immigrants). These differences in tumor characteristics between immigrant groups should be taken into consideration when planning preventive or screening strategies., (© 2022. The Author(s).)

Background: Due to recent changes in the legal framework, access to fertility preservation (FP) for transgender individuals has opened up in several countries. In Sweden and the Nordic countries, fertility preservation for medical reasons is fully reimbursed as part of the established tax-funded healthcare services. As this issue is relatively new, procedures for FP have seldom been reported in the transgender patient population. The very limited literature has indicated that transgender women may have poorer sperm quality than cisgender men when assessing samples aimed at semen banking., Objectives: To assess sperm quality parameters of semen samples provided for FP by transgender women before or after gender affirming hormone therapy (GAHT), and to compare sperm quality with a reference population of unscreened men defined by the World Health Organization (WHO). Additionally, we aimed to describe referral patterns over calendar time and estimate time from referral to semen cryopreservation., Material and Methods: Prospective cohort study of 212 transgender women referred for FP to the Reproductive Medicine Clinic of Karolinska University Hospital, Sweden, between 2013 and 2018. Among 177 individuals that provided semen samples for cryopreservation, 16 had previously received GAHT., Results: Individuals with previous GAHT presented with significantly lower total sperm count than individuals without GAHT (p = 0.002). However, higher proportions of sperm abnormalities were also noted among individuals who had not undergone previous GAHT, compared to the WHO reference population (p < 0.001). Referrals of transgender women for FP increased over time. The median time from referral to semen cryopreservation was 27 days., Conclusions: A high occurrence of sperm abnormalities was found in transgender women, especially among individuals who had previously received GAHT. The results underline the importance of thoroughly discussing parenthood options and FP with patients early after diagnosis and referring the patients for semen banking preferably before starting GAHT., (© 2021 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Pregnancy-associated cancer (PAC) is increasing over time in many countries. We provide a comprehensive, population-based overview of cancer survival in women with PAC across five decades., Methods: We performed a nationwide cohort study of 121,382 women diagnosed with cancer at age 15-49 between 1970 and 2018 using birth and cancer registers in Sweden. Pregnancy-associated cancer was defined as diagnosed during pregnancy and within one year of delivery, while non-PAC was outside this window. Cox regression estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing cancer mortality for PAC versus non-PAC., Results: In total, 5079 women had a diagnosis of PAC. Cutaneous malignant melanoma, breast, cervical, thyroid and central nervous system (CNS) were the most common sites of PAC. A higher cancer mortality was observed in PAC versus non-PAC for breast (HR = 1.72, 95% CI 1.54-1.93) and uterine cancer (myometrium/unspecified) (8.62, 2.80-26.53), in which all PAC deaths were uterine sarcomas. Increased mortality was also observed in upper digestive tract cancer diagnosed during pregnancy and colon cancer diagnosed during first year after delivery. Contrary, the HR for CNS tumours was significantly decreased (0.71, 0.55-0.91). Survival after PAC improved for most sites over time, with survival after breast cancer during pregnancy in recent years being similar to that of non-pregnancy associated breast cancer., Conclusion: For the majority of sites, PAC was not associated with poorer prognosis compared to non-PAC, a finding which was stable over time. The main exceptions were breast cancer and rarer cancers, such as uterine sarcoma., 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 © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Cohort studies show better survival after breast-conserving surgery (BCS) with postoperative radiotherapy (RT) than after mastectomy (Mx) without RT. It remains unclear whether this is an independent effect or a consequence of selection bias., Objective: To determine whether the reported survival benefit of breast conservation is eliminated by adjustment for 2 pivotal confounders, comorbidity and socioeconomic status., Design, Setting, and Participants: Cohort study using prospectively collected national data. Swedish public health care; nationwide clinical data from the National Breast Cancer Quality Register, comorbidity data from Patient Registers at the National Board of Health and Welfare, and individual-level education and income data from Statistics Sweden. The cohort included all women diagnosed as having primary invasive T1-2 N0-2 breast cancer and undergoing breast surgery in Sweden from 2008 to 2017. Data were analyzed between August 19, 2020, and November 12, 2020., Exposures: Locoregional treatment comparing 3 groups: breast-conserving surgery with radiotherapy (BCS+RT), mastectomy without radiotherapy (Mx-RT), and mastectomy with radiotherapy (Mx+RT)., Main Outcomes and Measures: Overall survival (OS) and breast cancer-specific survival (BCSS). Main outcomes were determined before initiation of data retrieval., Results: Among 48 986 women, 29 367 (59.9%) had BCS+RT, 12413 (25.3%) had Mx-RT, and 7206 (14.7%) had Mx+RT. Median follow-up was 6.28 years (range, 0.01-11.70). All-cause death occurred in 6573 cases, with death caused by breast cancer in 2313 cases; 5-year OS was 91.1% (95% CI, 90.8-91.3) and BCSS was 96.3% (95% CI, 96.1-96.4). Apart from expected differences in clinical parameters, women receiving Mx-RT were older, had a lower level of education, and lower income. Both Mx groups had a higher comorbidity burden irrespective of RT. After stepwise adjustment for all covariates, OS and BCSS were significantly worse after Mx-RT (hazard ratio [HR], 1.79; 95% CI, 1.66-1.92 and HR, 1.66; 95% CI, 1.45-1.90, respectively) and Mx+RT (HR, 1.24; 95% CI, 1.13-1.37 and HR, 1.26; 95% CI, 1.08-1.46, respectively) than after BCS+RT., Conclusions and Relevance: Despite adjustment for previously unmeasured confounders, BCS+RT yielded better survival than Mx irrespective of RT. If both interventions are valid options, mastectomy should not be regarded as equal to breast conservation.

Objectives: To examine the long-term impact of assisted reproductive techniques (ART) on offspring neurodevelopment, accounting for parental factors and the role of infertility., Methods: Linkage of national registers allowed follow-up of >2.4 million children born in Sweden 1986-2012. Information on ART was retrieved from fertility clinics, medical records, and maternal self-report. Attention-deficit/hyperactivity disorder (ADHD) was identified from specialist diagnosis and/or use of medication through 2018. School performance was assessed from records of ninth year final grade averages (0-20) and eligibility for upper secondary school through 2017., Results: Children conceived with ART had lower risk of ADHD (hazard ratio 0.83; 95% confidence interval [CI]: 0.80 to 0.87) and did better in school (grade mean difference 1.15; 95% CI: 1.09 to 1.21 and eligibility odds ratio 1.53; 95% CI: 1.45 to 1.63) compared with all other children. Differences in parental characteristics explained and even reversed associations, whereas no disadvantage was seen when the comparison was restricted to children of couples with known infertility (adjusted hazard ratio 0.95; 95% CI: 0.90 to 1.00, adjusted mean difference 0.05; 95% CI: -0.01 to 0.11, and adjusted odds ratio 1.03; 95% CI: 0.96 to 1.10). Among children conceived with ART, there was furthermore no indication that intracytoplasmic sperm injection (compared with standard in vitro fertilization) or frozen (compared with fresh) embryo transfer had any adverse influence., Conclusions: With this nationwide, long-term follow-up, we provide additional reassurance concerning offspring neurodevelopment after use of ART, finding no indication for concern about risk of ADHD or school performance in adolescence., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Background: In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death., Methods: We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up., Results: Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2- status. Among node-negative ER+HER2- tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR-HER2- tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes., Conclusions: There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

Background: Oncoplastic techniques in breast-conserving surgery (BCS) are used increasingly for larger tumours. This large cohort study aimed to assess oncological outcomes after oncoplastic BCS (OPS) versus standard BCS., Methods: Data for all women who had BCS in three centres in Stockholm during 2010-2016 were extracted from the Swedish National Breast Cancer Register. All patients with T2-3 tumours, all those receiving neoadjuvant treatment, and an additional random sample of women with T1 tumours were selected. Medical charts were reviewed for local recurrences and surgical technique according to the Hoffman-Wallwiener classification. Date and cause of death were retrieved from the Swedish Cause of Death Register., Results: The final cohort of 4178 breast cancers in 4135 patients was categorized into three groups according to surgical technique: 3720 for standard BCS, 243 simple OPS, and 215 complex OPS. Median duration of follow up was 64 (range 24-110) months. Node-positive and large tumours were more common in OPS than in standard BCS (P < 0.001). There were 61 local recurrences: 57 (1.5 per cent), 1 (0.4 per cent) and 3 (1.4 per cent) in the standard BCS, simple OPS and complex OPS groups respectively (P = 0.368). Overall, 297 patients died, with an unadjusted 5-year overall survival rate of 94.7, 93.1 and 92.6 per cent respectively (P = 0.350). Some 102 deaths were from breast cancer, with unadjusted 5-year cancer-specific survival rates of 97.9, 98.3 and 95.0 per cent respectively (P = 0.056)., Discussion: Oncoplastic BCS is a safe surgical option, even for larger node-positive tumours, with low recurrence and excellent survival rates., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

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: The natural history of breast cancer among BRCA2 carriers has not been clearly established. In a previous study from Iceland, positive ER status was a negative prognostic factor. We sought to identify factors that predicted survival after invasive breast cancer in an expanded cohort of BRCA2 carriers., Methods: We studied 608 women with invasive breast cancer and a pathogenic BRCA2 mutation (variant) from four Nordic countries. Information on prognostic factors and treatment was retrieved from health records and by analysis of archived tissue specimens. Hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression., Results: About 77% of cancers were ER-positive, with the highest proportion (83%) in patients under 40 years. ER-positive breast cancers were more likely to be node-positive (59%) than ER-negative cancers (34%) (P < 0.001). The survival analysis included 584 patients. Positive ER status was protective in the first 5 years from diagnosis (multivariate HR = 0.49; 95% CI 0.26-0.93, P = 0.03); thereafter, the effect was adverse (HR = 1.91; 95% CI 1.07-3.39, P = 0.03). The adverse effect of positive ER status was limited to women who did not undergo endocrine treatment (HR = 2.36; 95% CI 1.26-4.44, P = 0.01) and patients with intact ovaries (HR = 1.99; 95% CI 1.11-3.59, P = 0.02)., Conclusions: The adverse effect of a positive ER status in BRCA2 carriers with breast cancer may be contingent on exposure to ovarian hormones.

Background: Women with high socioeconomic status (SES) have the highest incidence rates of breast cancer. We wanted to determine if high SES women only have higher rates of localized disease, or whether they also have higher rates of non-localized disease. To study this, we used data on a young population with universal health care, but not offered screening., Material and Methods: Using individually linked registry data, we compared stage-specific breast cancer incidence, by education level and income quintile, in a Norwegian cohort of 1,106,863 women aged 30-48 years during 2000-2015 ( N  = 7531 breast cancer cases). We calculated stage-specific age-standardized rates and incidence rate ratios and rate differences using Poisson models adjusted for age, period and immigration history., Results: Incidence of localized and regional disease increased significantly with increasing education and income level. Incidence of distant stage disease did not vary significantly by education level but was significantly reduced in the four highest compared to the lowest income quintile. The age-standardized rates for tertiary versus compulsory educated women were: localized 28.2 vs 19.8, regional 50.8 vs 40.4 and distant 2.3 vs 2.6 per 100,000 person-years. The adjusted incidence rate ratios (tertiary versus compulsory) were: localized 1.40 (95% CI 1.25-1.56), regional 1.25 (1.15-1.35), distant 0.90 (0.64-1.26). The age-standardized rates for women in the highest versus lowest income quintile were: localized 28.9 vs 17.7, regional 52.8 vs 41.5 and distant 2.3 vs 3.2 per 100,000 person-years. The adjusted incidence rate ratios (highest versus lowest quintile) were: localized 1.63 (1.42-1.87), regional 1.27 (1.09-1.32), distant 0.64 (0.43-0.94)., Conclusion: Increased breast cancer rates among young high SES women is not just increased detection of small localized tumors, but also increased incidence of tumors with regional spread. The higher incidence of young high SES women is therefore real and not only because of excessive screening.

Purpose: To examine the influence of type of oncological treatment on sick leave in women of working age with early-stage breast cancer., Methods: We identified 8870 women aged 30-64 diagnosed with stage I-II breast cancer between 2005 and 2012 in the Breast Cancer Data Base Sweden. Associations between type of oncological treatment (radiotherapy, endocrine therapy, and chemotherapy) and sick leave were estimated by hazard ratios, probabilities, and length of sick leave using multi-state survival analysis., Results: During the first 5 years after diagnosis, women aged 50-54 years at diagnosis receiving chemotherapy spent on average 182 (95% CI 151-218) additional days on sick leave compared with women not receiving chemotherapy, but with otherwise similar characteristics. Correspondingly, women initiating endocrine therapy spent 30 (95% CI 18-44) additional days on sick leave and women receiving post-mastectomy radiotherapy 53 (95% CI 37-69) additional days. At year five, the rate of sick leave was increased in women who had received chemotherapy (HR 1.19, 95% CI 1.11-1.28) or endocrine therapy (HR 1.15, 95% CI 1.05-1.26). Chemotherapy and endocrine therapy were associated with increased rates of sick leave due to depression or anxiety., Conclusion: Our findings of increased long-term risks of sick leave after oncological treatment for breast cancer warrant attention from caregivers taking part in cancer rehabilitation. In light of the ongoing debate about overtreatment of early-stage breast cancer, our findings point to the importance of properly selecting patients for chemotherapy not only for the medical toxicity but also the possible impact on their livelihood.

Purpose: The stage-specific survival of young breast cancer patients has improved, likely due to diagnostic and treatment advances. We addressed whether survival improvements have reached all socioeconomic groups in a country with universal health care and national treatment guidelines., Methods: Using Norwegian registry data, we assessed stage-specific breast cancer survival by education and income level of 7501 patients (2317 localized, 4457 regional, 233 distant and 494 unknown stage) aged 30-48 years at diagnosis during 2000-2015. Using flexible parametric models and national life tables, we compared excess mortality up to 12 years from diagnosis and 5-year relative survival trends, by education and income as measures of socioeconomic status (SES)., Results: Throughout 2000-2015, regional and distant stage 5-year relative survival improved steadily for patients with high education and high income (high SES), but not for patients with low education and low income (low SES). Regional stage 5-year relative survival improved from 85 to 94% for high SES patients (9% change; 95% confidence interval: 6, 13%), but remained at 84% for low SES patients (0% change; - 12, 12%). Distant stage 5-year relative survival improved from 22 to 58% for high SES patients (36% change; 24, 49%), but remained at 11% for low SES patients (0% change; - 19, 19%)., Conclusions: Regional and distant stage breast cancer survival has improved markedly for high SES patients, but there has been little survival gain for low SES patients. Socioeconomic status matters for the stage-specific survival of young breast cancer patients, even with universal health care.

Background: Data on pregnancy outcomes in women with psoriasis are conflicting., Objective: We examined whether maternal psoriasis affects the risk of adverse maternal and pregnancy outcomes., Methods: We used population-based data to compare reproductive patterns in women with and without psoriasis. Odds ratios (ORs) with 95% confidence intervals (CIs) for adverse outcomes were estimated with adjustments for maternal age, period of childbirth, smoking, and prepregnancy body mass index., Results: Compared with women without psoriasis, women with psoriasis were younger at first birth and had longer interpregnancy intervals but did not differ in final parity. Risk estimates in women with psoriasis were elevated for pregnancy hypertension (OR, 1.37; 95% CI, 1.19-1.58), premature rupture of membranes (OR, 1.15; 95% CI, 1.04-1.27), large for gestational age (OR, 1.11; 95% CI, 1.01-1.21), cleft palate (OR, 1.69; 95% CI, 1.07-2.66), and unspecified malformations (OR, 1.08; 95% CI, 1.01-1.16)., Limitations: No information was available on lifestyle, disease severity, or type and duration of treatment. Small numbers hampered the assessment of rare outcomes., Conclusion: Although there was no evidence that fertility is negatively affected, women with psoriasis were at an increased risk of several adverse maternal and pregnancy outcomes. Our findings add to a growing body of evidence that pregnancies in women with psoriasis need special monitoring., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To assess infant (<1 year) and childhood (1-18 years) mortality in singletons conceived through assisted reproductive techniques (ART) versus naturally conceived singletons., Design: Nationwide prospective study., Setting: Sweden., Patient(s): All singleton liveborn infants born from 1983 to 2012 in Sweden identified using the Medical Birth Register (N = 2,847,108), of whom 43,506 were conceived through ART treatments including in vitro fertilization with and without intracytoplasmic sperm injection., Intervention(s): None., Main Outcome Measures(s): Infant (<1 year) and childhood (1-18 years) mortality., Result(s): Data on ART treatment and covariates were retrieved from population-based registers using the unique personal identity number assigned to all permanent residents in Sweden. Cox proportional hazards models estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) as measures of association between ART treatments and death. The analyses were adjusted for maternal characteristics, infertility, child sex, and birth cohort and were restricted to individuals with complete information on covariates for fully adjusted analysis. Compared with naturally conceived singletons, higher infant mortality risks were seen in infants conceived through ART (adjusted HR 1.45; 95% CI, 1.19-1.77), especially after transfer of cryopreserved embryos (adjusted HR 2.30; 95% CI, 1.46-3.64). Early neonatal mortality risk (deaths during the first week) was increased in children born after transfer of blastocysts (HR 2.40; 95% CI, 1.05-5.48). No increased mortality risk was observed between the ages of 1 and 18 years., Conclusion(s): Singletons conceived through ART had an increased risk of infant mortality from birth up to 1 year of life, predominantly in the early neonatal period and in pregnancies after transfer of frozen and thawed embryos., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While urinary bladder cancer is consistently more common in men worldwide, women have poorer prognosis. The aim of this study was to outline sex differences in prognostic factors and clinical management and to explore whether these can explain the poorer urinary bladder cancer outcome in women., Patients and Methods: We performed a population-based cohort study including all patients diagnosed with urothelial bladder cancer between 1997 and 2014 at age 18 to 89 who had data recorded in the Swedish Urinary Bladder Cancer Register (n = 36,344). Female-to-male odds ratios for clinical management parameters were estimated by logistic regression. To quantify sex differences in bladder cancer-specific survival, we estimated empirical survival proportions and mortality rates as well as applied flexible parametric models to estimate female-to-male hazard ratios and survival proportions over follow-up. Adjusted models included age, year, World Health Organization grade, stage, marital status, education, health care region, birth country, and comorbidity., Results: Except for an adverse stage distribution in women, we found no evidence of unequal clinical management. Among those diagnosed with bladder cancer, women had a higher bladder cancer mortality (adjusted hazard ratio, 1.15; 95% confidence interval, 1.08-1.23) driven by muscle-invasive tumors (adjusted hazard ratio, 1.24; 95% confidence interval, 1.14-1.34). The female survival disadvantage was confined to the first 2 years after diagnosis., Conclusion: The excess bladder cancer mortality in women is limited to those diagnosed with muscle-invasive tumors and cannot be explained by the examined clinicopathologic factors. Further investigations of sex differences in therapeutic procedures and outcomes, including complications, of muscle-invasive bladder cancer, must be performed., (Copyright © 2019 Elsevier Inc. All rights reserved.)