The Cost of Metastatic Prostate Cancer in the United States.

INTRODUCTION: We sought to estimate per patient and annual aggregate health care costs related to metastatic prostate cancer. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified fee-for-service Medicare beneficiaries ages 66 and older diagnosed with metastatic prostate cancer or claims with diagnosis codes for metastatic disease (indicating tumor progression following diagnosis) between 2007 and 2017. We measured annual health care costs and compared costs between cases and a sample of beneficiaries without prostate cancer. RESULTS: We estimate that per-patient annual costs attributable to metastatic prostate cancer are $31,427 (95% CI: $31,219-$31,635; 2019 dollars). Annual attributable costs rose over time, from $28,311 (95% CI: $28,047-$28,575) in 2007-2013 to $37,055 (95% CI: $36,716-$37,394) in 2014-2017. In aggregate, health costs attributable to metastatic prostate cancer are $5.2 to $8.2 billion per year. CONCLUSIONS: The per patient annual health care costs attributable to metastatic prostate cancer are substantial and have increased over time, corresponding to the approval of new oral therapies used in treating metastatic prostate cancer.

Combination Immune Checkpoint Blockade Regimens for Previously Untreated Metastatic Renal Cell Carcinoma: The Winship Cancer Institute of Emory University Experience.

Introduction: There are three combination immune checkpoint inhibitor (ICI)-based regimens in the first-line setting for metastatic renal cell carcinoma (mRCC). Currently, there is limited real-world data for clinical outcomes and toxicity in mRCC patients treated with first-line ICI-based regimens. Methods: We performed a retrospective review of 49 mRCC patients treated with ICI-based combination regimens in the standard of care setting at the Winship Cancer Institute of Emory University from 2015-2020. We collected baseline data from the electronic medical record including demographic information and disease characteristics. Immune-related adverse events (irAEs) were collected from clinic notes and laboratory values. The primary clinical outcomes measured were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: The median age was 65 years, and most patients (80%) were males. The majority were White (86%) and had clear cell RCC (83%). Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 (43%) or 1 (45%). Approximately one-half (49%) had at least three sites of distant metastatic disease. Most patients (88%) received nivolumab and ipilimumab. More than one-half (53%) of patients experienced an irAE, with 13 (27%) patients having treatment delayed and 18% discontinuing treatment for toxicity. The median OS was not reached, and the median PFS was 8.0 months per a Kaplan-Meier estimation. More than half of patients (53%) had a PFS > 6 months, and 22% had PFS > 1 year. The ORR was 33% for the entire cohort, and 7% of patients had a complete response. Conclusion: We presented real-world efficacy and toxicity data for front-line ICI combination treatment regimens. The ORR and median PFS were lower in our cohort of patients compared to the available data in the clinical trial setting. This was likely because of more advanced disease in this study. Future studies should provide additional data that will allow comparisons between different ICI combination regimens for untreated mRCC.

Advances in Knowledge and Management of Immune-Related Adverse Events in Cancer Immunotherapy.

Immune-oncologic (IO) therapy has revolutionized the treatment and management of oncologic disease. Immunotherapy functions by enhancing the host immune-systems ability to endogenously clear malignant cells, however, this activation can also lead to immune-mediated damage to healthy native tissues. These side effects are known as immune-related adverse events or irAEs and can even present with phenotypes similar to autoimmune diseases. IrAEs are the major consequence of checkpoint inhibitors and can have a significant impact on a patient's cancer treatment and long-term quality of life. The management of these irAEs follows a similar approach to autoimmune diseases. More specifically, the management is akin to that of autoimmune disease exacerbations. While there is an array of immune-suppressing agents that can be used, steroids, immunomodulators and IO discontinuation are cornerstones of irAE management. The exact approach and dosing are based on the severity and subtype of irAE presented. Within recent years, there has been a push to better prevent and manage irAEs when they arise. There has been an additional effort to increase the number of steroid-sparing agents available for irAE treatment given the consequences of long-term steroid therapy as well as patient contraindications to steroids. The goals of this review are to summarize irAE management, highlight significant advances made in recent years and emphasize the future directions that will optimize the use of IO therapy in oncology.

Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study.

BACKGROUND: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. METHODS: UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator-assessed for patients with at least 1 post-baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. RESULTS: The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression-free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). CONCLUSIONS: In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. LAY SUMMARY: Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real-world setting, and support the use of this drug in broader patient populations.

Analysis of Toxicity and Clinical Outcomes in Full Versus Reduced Starting Dose Cabozantinib in Metastatic Renal Cell Carcinoma Patients.

BACKGROUND: Full dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60 mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full vs. reduced starting cabozantinib dose. METHODS: We performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016 to 2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis was also performed using Cox proportional hazard model. RESULTS: Most patients were men (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60 mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs. 58%) and ≥2 prior lines of systemic therapy (50% vs. 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, P = .095), PFS (HR: 1.50, P = .107), and lower chance of OR (HR:0.42, P = .149) among reduced dose patients. This trend did not hold in Multivariable analysis (OS HR: 1.20, P = .636; PFS HR: 1.23, P = .4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA. CONCLUSIONS: Although we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.

Who lives in care homes in Greenland? A nationwide survey of demographics, functional level, medication use and comorbidities.

BACKGROUND: Greenland is facing an ageing population, and little is known about the characteristics of the elderly population in Greenland. This study offers both a comparison and a description of the demographics, causes of admission, comorbidities and medication of the residents in care homes in the capital, major and minor towns in four of the five administrative regions of Greenland. METHODS: The study was conducted from 2010 to 2016 as a descriptive questionnaire-based cross-sectional study. Data from eligible residents from eight care homes were collected from the regular care staff. Data were categorised into three groups based on town size for analysis. RESULTS: 244 (100 %) of eligible residents participated in the study. Nearly 100 % were of Greenlandic ethnicity based on parents' place of birth, and 62 % were women. The median age at admission/study was 69/71 years for men and 77/79 years for women (both p = 0.001). The median Body Mass Index was 25.6 kg/m2, more than half of the population were previous- or never-smokers and less than ten per cent consumed more than ten drinks of alcohol per week. The most common causes of admission were dementia (25.4 %), stroke (19.3 %) and social causes (11.1 %), while stroke (30.7 %), dementia (29.5 %) and musculoskeletal diseases (25.8 %) were the most common diagnoses at the time of the study. The Barthel Index was used to estimate the residents' level of independence, and residents in smaller towns were found to have a higher level of independence than residents in the capital. The median number of prescribed medications was five, and more residents in the capital were prescribed more than ten medications than elsewhere in Greenland. CONCLUSIONS: This study is the first to describe care home residents in Greenland. We found a population younger than residents in comparable Danish care homes and that women were older than men at admission. In addition, care home residents in the capital had a lower level of independence and a higher number of prescribed medications, which could relate to differences in morbidity, access to health care services and differences in social circumstances influencing the threshold for care home admission.

Body Composition as an Independent Predictive and Prognostic Biomarker in Advanced Urothelial Carcinoma Patients Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Several immune checkpoint inhibitors (ICIs) are approved for the treatment of advanced urothelial carcinoma (UC). There are limited biomarkers for ICI-treated patients with UC. We investigated the association between body composition and clinical outcomes in ICI-treated UC patients. MATERIALS AND METHODS: We conducted a retrospective analysis of 70 ICI-treated patients with advanced UC at Winship Cancer Institute from 2015 to 2020. Baseline computed tomography images within 2 months of ICI initiation were collected at mid-L3 and muscle and fat compartments (subcutaneous, intermuscular, and visceral) were segmented using SliceOMatic v5.0 (TomoVision, Magog, Canada). A prognostic body composition risk score (high: 0-1, intermediate: 2-3, or low-risk: 4) was created based on the ß coefficient from the multivariate Cox model (MVA) following best-subset variable selection. Our body composition risk score was skeletal muscle index (SMI) + 2 × attenuated skeletal muscle (SM) mean + visceral fat index (VFI). Concordance statistics (C-statistics) were used to quantify the discriminatory magnitude of the predictive model. RESULTS: Most patients (70%) were men and the majority received ICIs in the second- (46%) or third-line (21%) setting. High-risk patients had significantly shorter overall survival (OS; hazard ratio [HR], 6.72; p < .001), progression-free survival (HR, 5.82; p < .001), and lower chance of clinical benefit (odds ratio [OR], 0.02; p = .003) compared with the low-risk group in MVA. The C-statistics for our body composition risk group and myosteatosis analyses were higher than body mass index for all clinical outcomes. CONCLUSION: Body composition variables such as SMI, SM mean, and VFI may be prognostic and predictive of clinical outcomes in ICI-treated patients with UC. Larger, prospective studies are warranted to validate this hypothesis-generating data. IMPLICATIONS FOR PRACTICE: This study developed a prognostic body composition risk scoring system using radiographic biomarkers for patients with bladder cancer treated with immunotherapy. The study found that the high-risk patients had significantly worse clinical outcomes. Notably, the study's model was better at predicting outcomes than body mass index. Importantly, these results suggest that radiographic measures of body composition should be considered for inclusion in updated prognostic models for patients with urothelial carcinoma treated with immunotherapy. These findings are useful for practicing oncologists in the academic or community setting, particularly given that baseline imaging is routine for patients starting on treatment with immunotherapy.

Racial Differences in Clinical Outcomes for Metastatic Renal Cell Carcinoma Patients Treated With Immune-Checkpoint Blockade.

BACKGROUND: Immune-checkpoint-inhibitors (ICIs) have become the cornerstone of metastatic renal-cell-carcinoma (mRCC) therapy. However, data are limited regarding clinical outcomes by race. In this study, we compared the real-world outcomes between African American (AA) and Caucasian mRCC patients treated with ICIs. METHODS: We performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015-2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) defined as a complete or partial response maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. Univariate and multivariable analyses were carried out for OS and PFS by Cox proportional-hazard model and ORR by logistical-regression model. Descriptive statistics compared rates of immune-related adverse events (irAEs) and non-clear-cell-RCC (nccRCC) histology were assessed using Chi-square test. RESULTS: Our cohort was comprised of 38 AA and 160 Caucasian patients. Most were diagnosed with clear-cell-RCC (ccRCC) (78%) and more than half received (57%) PD-1/PD-L1 monotherapy. Most patients were intermediate or poor-risk groups (83%). Comparing to Caucasians, our AA cohort contained more females and nccRCC cases. Kaplan-Meier method showed AAs had no statistically different median OS (17 vs 25 months, p=0.368) and PFS (3.1 vs 4.4 months, p=0.068) relative to Caucasian patients. On multivariable analysis, AA patients had significantly shorter PFS (HR=1.52, 95% CI: 1.01-2.3, p=0.045), similar ORR (OR=1.04, 95% CI: 0.42-2.57, p=0.936) and comparable OS (HR=1.09, 95% CI: 0.61-1.95, p=0.778) relative to Caucasians. CONCLUSIONS: Our real-world analysis of ICI-treated mRCC patients showed that AAs experienced shorter PFS but similar OS relative to Caucasians. This similarity in survival outcomes is reassuring for the use of ICI amongst real-world patient populations, however, the difference in treatment response is poorly represented in early outcomes data from clinical trials. Thus, the literature requires larger prospective studies to validate these findings.

Body Composition Variables as Radiographic Biomarkers of Clinical Outcomes in Metastatic Renal Cell Carcinoma Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC). Biomarkers for mRCC patients treated with ICI are limited, and body composition is underutilized in mRCC. We investigated the association between body composition and clinical outcomes in ICI-treated mRCC patients. METHODS: We performed a retrospective analysis of 79 ICI-treated mRCC patients at Winship Cancer Institute from 2015-2020. Baseline CT images were collected at mid-L3 and segmented using SliceOMatic v5.0 (TomoVision). Density of skeletal muscle (SM), subcutaneous fat, inter-muscular fat, and visceral fat were measured and converted to indices by dividing by height(m)2 (SMI, SFI, IFI, and VFI, respectively). Total fat index (TFI) was defined as the sum of SFI, IFI, and VFI. Patients were characterized as high versus low for each variable at gender-specific optimal cuts using overall survival (OS) as the primary outcome. A prognostic risk score was created based on the beta coefficient from the multivariable Cox model after best subset variable selection. Body composition risk score was calculated as IFI + 2*SM mean + SFI and patients were classified as poor (0-1), intermediate (2), or favorable risk (3-4). Kaplan-Meier method and Log-rank test were used to estimate OS and PFS and compare the risk groups. Concordance statistics (C-statistics) were used to measure the discriminatory magnitude of the model. RESULTS: Most patients were male (73%) and most received ICI as first (35%) or second-line (51%) therapy. The body composition poor-risk patients had significantly shorter OS (HR: 6.37, p<0.001), PFS (HR: 4.19, p<0.001), and lower chance of CB (OR: 0.23, p=0.044) compared to favorable risk patients in multivariable analysis. Patients with low TFI had significantly shorter OS (HR: 2.72, p=0.002), PFS (HR: 1.91, p=0.025), and lower chance of CB (OR: 0.25, p=0.008) compared to high TFI patients in multivariable analysis. The C-statistics were higher for body composition risk groups and TFI (all C-statistics ≥ 0.598) compared to IMDC and BMI. CONCLUSIONS: Risk stratification using the body composition variables IFI, SM mean, SFI, and TFI may be prognostic and predictive of clinical outcomes in mRCC patients treated with ICI. Larger, prospective studies are warranted to validate this hypothesis-generating data.

Immune-Related Adverse Events as Clinical Biomarkers in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important treatment for metastatic renal cell carcinoma (mRCC). These agents may cause immune-related adverse events (irAEs), and the relationship between irAEs and outcomes is poorly understood. We investigated the association between irAEs and clinical outcomes in patients with mRCC treated with ICIs. METHODS: We performed a retrospective study of 200 patients with mRCC treated with ICIs at Winship Cancer Institute from 2015 to 2020. Data on irAEs were collected from clinic notes and laboratory values and grades were determined using Common Terminology Criteria in Adverse Events version 5.0. The association with overall survival (OS) and progression-free survival (PFS) was modeled by Cox proportional hazards model. Logistic regression models were used to define odds ratios (ORs) for clinical benefit (CB). Landmark analysis and extended Cox models were used to mitigate lead-time bias by treating irAEs as a time-varying covariate. RESULTS: Most patients (71.0%) were male, and one-third of patients (33.0%) experienced at least one irAE, most commonly involving the endocrine glands (13.0%), gastrointestinal tract (10.5%), or skin (10.0%). Patients who experienced irAEs had significantly longer OS (hazard ratio [HR], 0.52; p = .013), higher chance of CB (OR, 2.10; p = .023) and showed a trend toward longer PFS (HR, 0.71; p = .065) in multivariate analysis. Patients who had endocrine irAEs, particularly thyroid irAEs, had significantly longer OS and PFS and higher chance of CB. In a 14-week landmark analysis, irAEs were significantly associated with prolonged OS (p = .045). Patients who experienced irAEs had significantly longer median OS (44.5 vs. 18.2 months, p = .005) and PFS (7.5 vs. 3.6 months, p = .003) without landmark compared with patients who did not. CONCLUSION: We found that patients with mRCC treated with ICIs who experienced irAEs, particularly thyroid irAEs, had significantly improved clinical outcomes compared with patients who did not have irAEs. This suggests that irAEs may be effective clinical biomarkers in patients with mRCC treated with ICIs. Future prospective studies are warranted to validate these findings. IMPLICATIONS FOR PRACTICE: This study found that early onset immune-related adverse events (irAEs) are associated with significantly improved clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). In this site-specific irAE analysis, endocrine irAEs, particularly thyroid irAEs, were significantly associated with improved clinical outcomes. These results have implications for practicing medical oncologists given the increasing use of ICIs for the treatment of mRCC. Importantly, these results suggest that early irAEs and thyroid irAEs at any time on treatment with ICIs may be clinical biomarkers of clinical outcomes in patients with mRCC treated with ICIs.

Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report.

BACKGROUND: Combination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet. CASE PRESENTATION: We report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved. CONCLUSIONS: Combination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.

Case Report: Exceptional Response to Nivolumab Plus Ipilimumab in a Young Woman With TFE3-SFPQ Fusion Translocation-Associated Renal Cell Carcinoma.

Translocation-associated renal cell carcinoma (tRCC) is a rare, aggressive malignancy that primarily affects children and young adults. There is no clear consensus on the most effective treatment for tRCC and there are no biomarkers of response to treatments in these patients. We present a case of a 23 year-old female with metastatic tRCC to the lungs who was started on treatment with nivolumab and ipilimumab. She had a complete radiographic response to treatment and has been progression-free for over 18 months. Immunofluorescence imaging performed on the baseline primary tumor sample showed significant intratumoral immune infiltration. Importantly, these cells are present in niches characterized by TCF1+ CD8+ T cells. Histopathologic investigation showed the presence of lymphocytes in the fibrovascular septae and foci of lymphovascular invasion. Furthermore, lymphovascular invasion and intratumor niches with TCF1+ CD8+ T cells may predict a favorable response to treatment with nivolumab and ipilimumab. These findings have significant clinical relevance given that immune checkpoint inhibitors are approved for several malignancies and predictive biomarkers for response to treatment are lacking. Importantly, the identification of these TCF1+ CD8+ T cells may guide treatment for patients with tRCC, which is a rare malignancy without a consensus first-line treatment option.

General medical conditions and mortality in women with postpartum psychiatric disorders.

BACKGROUND: Psychiatric patients have an increased risk of general medical conditions and mortality, but no study has systematically explored these outcomes among women with mental disorders following childbirth (postpartum psychiatric disorders: PPD). Therefore, we aimed to investigate the risk of subsequent general medical conditions and mortality in women with a broad spectrum of PPD. METHODS: This register-based cohort study followed all Danish women born after January 1, 1960, until January 1, 2016. The exposure of interest was (i) mild-moderate PPD: first-ever prescription of psychotropic medication (ATC codes: N03-N07) and (ii) severe PPD: first-ever in- or out-patient contact to a psychiatric facility, both within six months postpartum. Outcomes of interest were (i) hospital-registered chronic medical conditions and (ii) mortality from natural and unnatural causes. We included 1 841 949 women representing 22 615 310 person-years at risk. RESULTS: Among 15 852 women with mild-moderate PPD and 4266 women with severe PPD, we found a higher risk of any subsequent general medical condition (mild-moderate PPD: IRR 1.25; 95% CI 1.20-1.31 and severe PPD: IRR 1.35; 95% CI: 1.24-1.48) when compared to the female background population. Mortality from both natural and unnatural causes was higher in both groups: Mild-moderate PPD: natural causes MRR 1.37; 95% CI: 1.17-1.61; unnatural causes MRR 1.52; 95% CI: 1.10-2.11, and severe PPD: natural causes MRR 1.42; 95% CI 1.02-2.00, and unnatural causes MRR 5.05; 95% CI: 3.40-7.51. CONCLUSIONS: This first overview of general medical prognosis in PPD shows that women at either end of the spectrum are at increased risk of subsequent chronic medical conditions and overall mortality.

Postpartum psychiatric disorders and subsequent live birth: a population-based cohort study in Denmark.

STUDY QUESTION: Are women with a history of first-onset postpartum psychiatric disorders after their first liveborn delivery less likely to have a subsequent live birth? SUMMARY ANSWER: Women with incident postpartum psychiatric disorders are less likely to go on to have further children. WHAT IS KNOWN ALREADY: Women are particularly vulnerable to psychiatric disorders in the postpartum period. The potential effects of postpartum psychiatric disorders on the mother's future chances of live birth are so far under-researched. STUDY DESIGN, SIZE, DURATION: A population-based cohort study consisted of 414 571 women who had their first live birth during 1997-2015. We followed the women for a maximum of 19.5 years from the date of the first liveborn delivery until the next conception leading to a live birth, emigration, death, their 45th birthday or 30 June 2016, whichever occurred first. PARTICIPANTS/MATERIALS, SETTING, METHODS: Postpartum psychiatric disorders were defined as filling a prescription for psychotropic medications or hospital contact for psychiatric disorders for the first time within 6 months postpartum. The outcome of interest was time to the next conception leading to live birth after the first liveborn delivery. Records on the death of a child were obtained through the Danish Register of Causes of Death. Cox regression was used to estimate the hazard ratios (HRs), stratified by the survival status of the first child. MAIN RESULTS AND THE ROLE OF CHANCE: Altogether, 4327 (1.0%) women experienced postpartum psychiatric disorders after their first liveborn delivery. The probability of having a subsequent live birth was 69.1% (95% CI: 67.4-70.7%) among women with, and 82.3% (95% CI: 82.1-82.4%) among those without, postpartum psychiatric disorders. Women with postpartum psychiatric disorders had a 33% reduction in the rate of having second live birth (HR = 0.67, 95% CI: 0.64-0.69), compared to women without postpartum psychiatric disorders. The association disappeared if the first child died (HR = 1.01, 95% CI: 0.85-1.20). If postpartum psychiatric disorders required hospitalisations, this was associated with a more pronounced reduction in live birth rate, irrespective of the survival status of the first child (HR = 0.54, 95% CI: 0.47-0.61 if the first child survived, and HR = 0.49, 95% CI: 0.23-1.04 if the first child died). LIMITATIONS, REASONS FOR CAUTION: The use of population-based registers allows for the inclusion of a representative cohort with almost complete follow-up. The large sample size enables us to perform detailed analyses, accounting for the survival status of the child. However, we did not have accurate information on stillbirths and miscarriages, and only pregnancies that led to live birth were included. WIDE IMPLICATIONS OF THE FINDINGS: Our study is the first study to investigate subsequent live birth after postpartum psychiatric disorders in a large representative population. The current study indicates that postpartum psychiatric disorders have a significant impact on subsequent live birth, as women experiencing these disorders have a decreased likelihood of having more children. However, the variations in subsequent live birth rate are influenced by both the severity of the disorders and the survival status of the first-born child, indicating that both personal choices and decreased fertility may have a role in the reduced subsequent live birth rate among women with postpartum psychiatric disorders. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Danish Council for Independent Research (DFF-5053-00156B), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 837180, AUFF NOVA (AUFF-E 2016-9-25), iPSYCH, the Lundbeck Foundation Initiative for Integrative Psychiatric Research (R155-2014-1724), Niels Bohr Professorship Grant from the Danish National Research Foundation and the Stanley Medical Research Institute, the National Institute of Mental Health (NIMH) (R01MH104468) and Fabrikant Vilhelm Pedersen og Hustrus Legat. The authors do not declare any conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Incidence of medically treated depression in Denmark among individuals 15-44 years old: a comprehensive overview based on population registers.

OBJECTIVE: Examine the overall incidence of medically treated depression in Denmark among individuals 15-44 years old, and estimate the 5-year cumulative incidence of psychiatric hospital care among individuals treated first in non-hospital-based care. METHODS: We followed all individuals born in Denmark between 1969 and 1998 from age 15 or 2006 (whichever came first) until first depression treatment; death; emigration; or December 31, 2013. Incidence rates were estimated using Poisson regression. Cumulative incidence of hospital care following treatment in non-hospital care was estimated using Kaplan-Meier curves. RESULTS: In this sample of 2 014 760 individuals, incidence rates of depression in non-hospital and hospital-based care in 2012-2013 were 6.6 (95% Confidence Interval: 6.5-6.7) per 1000 person-years and 1.5 (95% CI: 1.5-1.6) per 1000 person-years, respectively. Overall, 85-90% of first medical treatment for depression took place outside of psychiatric hospitals, but a quarter (26.3%) of individuals treated for depression received hospital care initially or within 5 years. Incidence of hospital care was higher in women and younger individuals. CONCLUSIONS: Most medical treatment for depression in Denmark takes place in non-hospital settings. Women and younger individuals are more likely to receive hospital care both initially and within 5 years after first antidepressant treatment.

Impact of severe mental illness on cancer stage at diagnosis and subsequent mortality: A population-based register study.

BACKGROUND: Excess mortality in individuals with severe mental illness (SMI) is often explained by physical comorbidity and suboptimal healthcare. Cancer is a prevalent cause of death, and tumour stage at diagnosis is a strong predictor of mortality. We aimed to study cancer incidence, disease stage at diagnosis and subsequent mortality in individuals with SMI compared to individuals without SMI. METHODS: The entire Danish population was followed in 1978-2013 using nationwide registries. Cancer incidence and subsequent mortality stratified by disease stage were compared in individuals with and without SMI. Cox regression was used to estimate incidence rate ratios (IRR) and mortality rate ratios (MRR). Cancer was examined overall and grouped by major aetiological factors. RESULTS: The overall cancer incidence rate was lower in males with SMI than in males without SMI; IRR = 0.89 (95% CI: 0.85-0.94), but rates were similar in females with SMI and without SMI; IRR = 1.03 (95% CI: 0.99-1.07). The overall mortality rate was higher in individuals with SMI than those without; MRR = 1.56 (95% CI: 1.48-1.64) for males and MRR = 1.49 (95% CI: 1.43-1.56) for females. Incidence rates and mortality rates showed similar estimates when stratified by tumour stage and aetiology. CONCLUSIONS: We found lower cancer incidence in males with SMI compared to males without SMI and similar incidence in the two groups of women. Higher subsequent mortality was found in both sexes with SMI. The excess mortality was not explained by more advanced stages of cancer; future studies should evaluate the effect of cancer treatment and rehabilitation.

Stroke case-fatality and marital status.

OBJECTIVES: Most studies show that marriage conveys a survival advantage. Whether this is valid also for stroke patients is unclear. Results of studies have been inconsistent and conflicting. MATERIAL & METHODS: We studied 1-week and 1-month stroke case-fatality in relation to marital status (married, unmarried, divorced, and widowed) in all patients admitted to hospital for incident stroke in Denmark during 2003-2012. We used information from Danish registries on stroke merged to information on age, sex, marital status, stroke severity, stroke subtype, socioeconomic status, cardiovascular risk profile, and causes of death. We studied deaths due to the index stroke within the first week and month after stroke. Multivariate Cox regression models were applied to estimate cause-specific hazards and relative risks. RESULTS: We included 60507 patients with an incident stroke of which 51.19% were married, 9.47% were unmarried, 13.29% were divorced, and 26.05% were widowers. Death within the first week and first month was caused by stroke in 2110 (3.5%) and 3423 (5.7%) patients, respectively. Compared to married stroke patients, 1-week/1-month case-fatality (by stroke) was lower for the unmarried (HR (hazard ratio):0.69/0.74), divorced (HR:0.69/0.72), and widowed (HR:0.80/0.74) men and the unmarried (HR:0.84/0.86), divorced (HR:0.82/0.80), and widowed (HR:0.87/0.88) women with stroke. CONCLUSIONS: One-week and one-month case-fatality by stroke was lower among the unmarried, divorced, and widowed than among the married stroke patients. Selection by so-called mortality displacement linked to shorter life expectancy among divorced, widowed, and singles may explain our findings.

COMPLETE - a school-based intervention project to increase completion of upper secondary school in Norway: study protocol for a cluster randomized controlled trial.

BACKGROUND: Drop out from upper secondary school represents a risk for the future health and wellbeing of young people. Strengthening of psychosocial aspects of the learning environment may be an effective strategy to promote completion of upper secondary school. This paper is a study protocol of a school based cluster randomized controlled trial (RCT) evaluating two school-based interventions, namely the Dream School Program (DSP) and the Mental Health Support Team (MHST). The interventions aim to improve psychosocial learning environments and subsequently school achievements and decrease drop-out and absence. METHODS/DESIGN: The COMPLETE RCT is aimed at youth in upper secondary school, grade 1 (age 15-16 years), and examines the effect of the combination of the DSP and the MHST; and the DSP only, compared with a comparison group on the following primary outcomes: student completion, presence, average grade, and self-reported mental health. Seventeen upper secondary schools from four counties in Norway were randomized to one of the three arms: 1) DSP and MHST; 2) DSP; and 3) comparison (offered DSP intervention in 2018/2019). The study will evaluate the interventions based on information from two cohorts of students (cohort 1 (C1) and cohort 2 (C2)). For C1, data was collected at baseline (August 2016), and at first follow-up seven months later. Second follow-up will be collected 19 months after baseline. For C2, data was collected at baseline (August 2017), and first and second follow-up will be collected similarly to that of C2 seven and 19 months respectively after baseline. Process evaluations based on focus groups, interviews and observation will be conducted twice (first completed spring 2017). DISCUSSION: The COMPLETE trial is a large study that can provide useful knowledge about what interventions might effectively improve completion of upper secondary school. Its thorough process evaluation will provide critical information about barriers and points of improvement for optimizing intervention implementation. Findings can guide school development in the perspective of improving psychosocial learning environments and subsequent completion of upper secondary schooling. TRIAL REGISTRATION: The trial was retrospectively registered in the ClinicalTrials.gov register on December 22.2017: NCT03382080 .

Married, unmarried, divorced, and widowed and the risk of stroke.

OBJECTIVES: Most studies report that marriage carries a lower risk of stroke than single living. Whether the marriage advantage is applicable with respect to all other marital status categories (unmarried, divorced, widow) remains unclear. We studied marital status and its association with incident stroke. MATERIAL AND METHODS: We included all patients > 40 years of age admitted to hospital for stroke in Denmark during 2003-2012 and compared marital status to the general Danish population (5.5 millions). Relative risks (RR) for stroke were estimated in log-linear Poisson regression models adjusting for age, sex, calendar year, income, and length of education. RESULTS: A total of 58 847 patients with incident stroke were included. Crude incidence rates of stroke (per 1000 per year) among the four marital status categories were as follows: 1.96 (married), 1.52 (unmarried), 2.36 (divorced), and 5.43 (widowed). Compared to married persons, adjusted risk of stroke was significantly increased for divorced (RR 1.23; CI 1.19-1.27) and unmarried men (RR 1.07; CI 1.03-1.11) but not for widowed men (RR 1.02; CI 0.98-1.06); risk was slightly increased for divorced women (RR 1.10; CI 1.06-1.15) while not for widowed (RR 1.0; CI 0.97-1.03) and unmarried women (RR 0.97; CI 0.97-1.03). CONCLUSIONS: Divorce was associated with higher risk of stroke, especially in men. Living in marriage or as unmarried or widower had only little or no impact on the risk of stroke.

Comorbidity of autoimmune thyroid disorders and psychiatric disorders during the postpartum period: a Danish nationwide register-based cohort study.

BACKGROUND: The postpartum period is well-known risk period for the first onset of autoimmune thyroid disorders (AITDs) as well as first onset of psychiatric disorders. These two disorders are some of the most prevalent medical conditions postpartum, often misdiagnosed and disabling if left untreated. Our study was designed to explore the possible bidirectional association between AITDs and psychiatric disorders during the postpartum period. METHODS: A population-based cohort study through linkage of Danish national registers, which comprised 312 779 women who gave birth to their first child during 1997-2010. We conducted Poisson regression analysis to estimate the incidence rate ratio (IRR) of psychiatric disorders among women with first-onset AITDs, the IRR of AITDs among women with first-onset psychiatric disorders as well as the overlap between these disorders using a comorbidity index. RESULTS: Women with first-onset AITDs postpartum were more likely to have first-onset psychiatric disorders than women who did not have postpartum AITDs (IRR = 1.88, 95% confidence interval (CI): 1.25-2.81). Women with first-onset postpartum psychiatric disorders had a higher risk of AITDs than women with no psychiatric disorders (IRR = 2.16, 95% CI: 1.45-3.20). The comorbidity index 2 years after delivery was 2.26 (95% CI: 1.61-2.90), indicating a comorbidity between first-onset AITDs and psychiatric disorders. CONCLUSIONS: First-onset AITDs and psychiatric disorders co-occur in the postpartum period, which has relevance to further studies on the etiologies of these disorders and why childbirth in particular triggers the onset.