Germline Elongator mutations in Sonic Hedgehog medulloblastoma.

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.

Cumulative incidence of second primary cancers in a large nationwide cohort of Danish cancer survivors: a population-based retrospective cohort study.

BACKGROUND: A new primary cancer is a serious late effect of a pre-existing cancer diagnosis, and can be attributed to hereditary cancer syndromes, immune or hormonal factors, cancer treatment, or modifiable lifestyle or environmental factors. We investigated the absolute and relative incidence of second primary cancers in a large cohort of Danish cancer survivors. Furthermore, we examined the association between alcohol-related, smoking-related, virus-related, and hormone-related first and second primary cancers. METHODS: In this retrospective cohort study, we identified a cohort of Danish adults (aged ≥40 years) diagnosed with cancer from Jan 1, 1997, to Dec 31, 2014 and alive 1 year after diagnosis. Follow-up was from date of first cancer diagnosis and lasted up to 24 years, ending on Dec 31, 2020. Cohort identification and information on second primary cancers was obtained from the Danish Cancer Registry, and comorbidity and sociodemographic information was obtained from Danish population-based registries. Overall, and for 27 cancer types, cumulative incidence functions and Cox proportional hazard regression models were used to estimate the incidence of second primary cancer and death, and hazard ratios (HRs) and 95% CIs of second primary cancer adjusted for sex, age and year of diagnosis, cohabitation status, income, and comorbidity. FINDINGS: 457 334 Danish adults were included in our study (230 150 [50·3%] male individuals and 227 184 [49·7%] female individuals; median age at diagnosis 68·3 years, IQR 59·7-76·6; median follow-up 3·6 years, IQR 0·6-9·3). The cumulative incidence of second primary cancer increased over time from 6·3% (95% CI 6·2-6·4) 5 years after diagnosis to 10·5% (10·4-10·6) 10 years after diagnosis and to 13·5% (13·4-13·7) 15 years after diagnosis. The highest cumulative incidence of second primary cancer 10 years after diagnosis was observed in survivors of cancers in the larynx (21·8%, 20·5-23·1), oropharynx and oral cavity (19·5%, 18·7-20·3), and bladder and urinary tract (18·5%, 18·0-19·0). Survivors of cancers related to alcohol (HR 1·09, 95% CI 1·06-1·13), smoking (1·73, 1·68-1·78), diet high in red or processed meat (1·32, 1·24-1·39), or virus (1·23, 1·13-1·35) were at increased risk of developing a second cancer with the same aetiology, whereas having had a hormone-related first cancer was associated with lower risk of a second hormone-related cancer (0·77, 0·73-0·81). INTERPRETATION: Our results could help optimise prevention efforts targeting modifiable risk factors to reduce risk of developing a second primary cancer. FUNDING: Nordic Cancer Union and The Health Foundation (Helsefonden).

Regression calibration of self-reported mobile phone use to optimize quantitative risk estimation in the COSMOS study.

The Cohort Study of Mobile Phone Use and Health (COSMOS) has repeatedly collected self-reported and operator-recorded data on mobile phone use. Assessing health effects using self-reported information is prone to measurement error, but operator data were available prospectively for only part of the study population and did not cover past mobile phone use. To optimize the available data and reduce bias, we evaluated different statistical approaches for constructing mobile phone exposure histories within COSMOS. We evaluated and compared the performance of 4 regression calibration (RC) methods (simple, direct, inverse, and generalized additive model for location, shape, and scale), complete-case analysis, and multiple imputation in a simulation study with a binary health outcome. We used self-reported and operator-recorded mobile phone call data collected at baseline (2007-2012) from participants in Denmark, Finland, the Netherlands, Sweden, and the United Kingdom. Parameter estimates obtained using simple, direct, and inverse RC methods were associated with less bias and lower mean squared error than those obtained with complete-case analysis or multiple imputation. We showed that RC methods resulted in more accurate estimation of the relationship between mobile phone use and health outcomes by combining self-reported data with objective operator-recorded data available for a subset of participants.

Changes in experienced quality of oncological cancer care during the COVID-19 pandemic based on patient reported outcomes - a cross-sectional study.

AIM: The study aims to investigate the impact of the COVID-19 pandemic on cancer patients' perceptions of the quality of their oncological treatment and care. BACKGROUND: The COVID-19 pandemic disrupted healthcare delivery and oncological resources were repurposed, potentially leading to prolonged treatment and reduced access to innovative therapies and clinical trials. Still, little is known about how patients perceived the quality of their treatment. METHODS: A cross-sectional study was conducted in the spring of 2020 among cancer patients at the Department of Oncology, Aarhus University Hospital and Rigshospitalet, Denmark. Patients were invited to complete an online questionnaire on clinical, socioeconomic, emotional, behavioural, and quality-related aspects of oncological cancer care. Patients who experienced reduced treatment quality and those who reported no or slight reductions were compared using multiple logistic regression, exploring the associations with patient characteristics, behaviours, and fear of cancer progression or recurrence. RESULTS: A total of 2,040/5,372 patients experienced changes in their treatment plans during the pandemic, and 1,570/5,372 patients experienced reduced treatment quality, with 236 reporting a high degree of reduction. Patients with breast, head and neck, and upper gastrointestinal cancers were more likely to experience reduced treatment quality. Altered interactions with healthcare providers, along with isolation, lack of social support, and heightened fear of cancer progression, were significant risk factors for experiencing reduced cancer care quality. INTERPRETATION: We identified subgroups of cancer patients needing targeted communication and care during health crises affecting cancer treatment. The findings underscore the importance of safeguarding the needs of vulnerable patient populations in future healthcare emergencies.

Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study.

BACKGROUND: The European EPI-CT study aims to quantify cancer risks from CT examinations of children and young adults. Here, we assess the risk of brain cancer. METHODS: We pooled data from nine European countries for this cohort study. Eligible participants had at least one CT examination before age 22 years documented between 1977 and 2014, had no previous diagnosis of cancer or benign brain tumour, and were alive and cancer-free at least 5 years after the first CT. Participants were identified through the Radiology Information System in 276 hospitals. Participants were linked with national or regional registries of cancer and vital status, and eligible cases were patients with brain cancers according to WHO International Classification of Diseases for Oncology. Gliomas were analysed separately to all brain cancers. Organ doses were reconstructed using historical machine settings and a large sample of CT images. Excess relative risks (ERRs) of brain cancer per 100 mGy of cumulative brain dose were calculated with linear dose-response modelling. The outcome was the first reported diagnosis of brain cancer after an exclusion period of 5 years after the first electronically recorded CT examination. FINDINGS: We identified 948 174 individuals, of whom 658 752 (69%) were eligible for our study. 368 721 (56%) of 658 752 participants were male and 290 031 (44%) were female. During a median follow-up of 5·6 years (IQR 2·4-10·1), 165 brain cancers occurred, including 121 (73%) gliomas. Mean cumulative brain dose, lagged by 5 years, was 47·4 mGy (SD 60·9) among all individuals and 76·0 mGy (100·1) among people with brain cancer. A significant linear dose-response relationship was observed for all brain cancers (ERR per 100 mGy 1·27 [95% CI 0·51-2·69]) and for gliomas separately (ERR per 100 mGy 1·11 [0·36-2·59]). Results were robust when the start of follow-up was delayed beyond 5 years and when participants with possibly previously unreported cancers were excluded. INTERPRETATION: The observed significant dose-response relationship between CT-related radiation exposure and brain cancer in this large, multicentre study with individual dose evaluation emphasises careful justification of paediatric CTs and use of doses as low as reasonably possible. FUNDING: EU FP7; Belgian Cancer Registry; La Ligue contre le Cancer, L'Institut National du Cancer, France; Ministry of Health, Labour and Welfare of Japan; German Federal Ministry of Education and Research; Worldwide Cancer Research; Dutch Cancer Society; Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat de Catalunya, Spain; US National Cancer Institute; UK National Institute for Health Research; Public Health England.

Earlier Recurrence Detection Using Routine FDG PET-CT Scans in Surveillance of Stage IIB to IIID Melanoma: A National Cohort Study of 1480 Patients.

BACKGROUND: The effect of routine imaging in melanoma surveillance is unknown. In 2016, Denmark was the first country in the world to implement routine imaging with positron emission tomography-computed tomography with fluorodeoxyglucose (FDG PET-CT) in a nationwide, population-based surveillance program. This study aimed to determine the impact of surveillance with routine FDG PET-CT on hazard, cumulative incidence, and absolute risk of overall, locoregional, and distant recurrence detection in patients with stage IIB to IIID cutaneous melanoma. METHODS: This retrospective, population-based, nationwide cohort study used prospectively collected data from five national health registries to compare hazard, cumulative incidence, and absolute risk of recurrence in patients with cutaneous melanoma diagnosed in 2008-2010 (cohort 1, followed with clinical examinations) and patients with cutaneous melanoma diagnosed in 2016-2017 (cohort 2, followed with clinical examinations and routine FDG PET-CT at 6, 12, 24, and 36 months). RESULTS: The study included 1480 patients with stage IIB to IIID cutaneous melanoma. Cumulative incidences of overall and distant recurrence were higher in cohort 2, with a peak difference at three years (32.3 % vs 27.5 % and 25.8 % vs. 18.5 %, respectively). The hazard of recurrence was higher in cohort 2 during the first two years, with hazard rates for overall and distant recurrence of 1.16 (95 % confidence interval [CI], 0.93-1.44) and 1.51 (95 % CI, 1.16-1.96), respectively. The patterns persisted in absolute risk estimates. CONCLUSIONS: Patients with stage IIB to IIID melanoma followed with routine FDG PET-CT had a 51 % increased hazard of distant recurrence detection within the first two years of surveillance. Future studies must determine whether this earlier recurrence detection translates into improved survival.

ConquerFear-Group: A randomized controlled trial of an online-delivered group-based psychological intervention for fear of cancer recurrence in breast cancer survivors.

OBJECTIVE: Fear of cancer recurrence (FCR) is a distressing concern among cancer survivors. Interventions to address FCR need to be effective but also accessible and low cost. This randomized controlled trial evaluated the efficacy of an online group-based psychological intervention for FCR (ConquerFear-Group). METHODS: Eligible breast cancer (BC) survivors had completed primary treatment 3 months-5 years previously, were ≥18 years, and scored ≥22 on the Fear of Cancer Recurrence Inventory-Short Form (FCRI-SF). Participants were randomized to online ConquerFear-Group (focusing on metacognitive strategies, values-clarification, and education about follow-up behavior) or online group-based relaxation training (active control). Questionnaires were completed at baseline (T1), 1 week post-intervention (T2), three (T3) and six (T4) months later. The primary outcome was FCR (FCRI total). A number of secondary and process outcomes were also collected. Treatment effects were evaluated with mixed linear models. RESULTS: Of 866 eligible BC survivors, 475 (55%) completed the FCR screening, and 85 (18%) were randomized to ConquerFear-Group or relaxation training (2 × 6 groups). Compared with control participants, ConquerFear-Group participants experienced larger reductions in FCR (Cohen's d = 0.47, p = 0.001) and FCR severity (d = 0.57, p < 0.001), as well as mindfulness and decentering from baseline through follow-up, and improvements in emotion regulation (T2), worry (T2, T3) and rumination (T2) at some time points. CONCLUSIONS: The results demonstrated statistically significant and stable effects of ConquerFear-Group on FCR that were maintained over a 6-month period. It is suggested to investigate the program in a real-life setting, where a pragmatic trial can further demonstrate feasibility and effectiveness.

The long-term burden of a symptom cluster and association with longitudinal physical and emotional functioning in breast cancer survivors.

BACKGROUND: Fatigue, insomnia and pain are some of the most common and distressing symptoms experienced during breast cancer (BC) treatment and survivorship. The symptoms have been found to impact one another and to form a symptom cluster, and greater severity of the symptoms may be negatively associated with physical and emotional functioning in survivorship. In exploratory analyses from a randomized controlled trial examining the effect of progressive resistance training on the development of lymphedema after BC, we aimed to examine the burden of the symptom cluster fatigue-pain-insomnia, and its prognostic value for long-term symptom severity as well as emotional and physical functioning. MATERIAL AND METHODS: Latent profile analysis was used to identify groups with similar severity of pain, fatigue and insomnia among 158 patients with BC two weeks after surgery. Mixed effects Tobit regression models were used to estimate fatigue, pain, insomnia, and physical and emotional functioning 20 weeks, 1 year and 3.5 years after surgery. RESULTS: Two symptom burden groups were identified: 80% of women had a low severity while 20% of women had a high severity of the three symptoms after BC surgery. 3.5 years later, the women with high symptom burden post-surgery still had higher pain, insomnia and fatigue scores than women with low symptom burden. High symptom burden post-surgery was associated with worse physical functioning 3.5 years later, while emotional functioning was only negatively impacted during the first year. DISCUSSION: These findings warrant larger studies investigating if symptom burden early in BC trajectory can be used for risk stratification for persistent symptoms and diminished physical functioning with the purpose of developing and implementing targeted interventions.

Effects on long-term survival of psychosocial group intervention in early-stage breast cancer: follow-up of a randomized controlled trial.

BACKGROUND: The promise of prolonged survival after psychosocial interventions has long been studied, but not convincingly demonstrated. This study aims to investigate whether a psychosocial group intervention improved long-term survival in women with early-stage breast cancer and investigate differences in baseline characteristics and survival between study participants and non-participants. METHODS: A total of 201 patients were randomized to two six-hour psychoeducation sessions and eight weekly sessions of group psychotherapy or care as usual. Additionally, 151 eligible patients declined to participate. Eligible patients were diagnosed and treated at Herlev Hospital, Denmark, and followed for vital status up to 18 years after their primary surgical treatment. Cox's proportional hazard regressions were used to estimate hazard ratios (HRs) for survival. RESULTS: The intervention did not significantly improve survival in the intervention group compared with the control group (HR, 0.68; 95% confidence interval (CI), 0.41-1.14). Participants and non-participants differed significantly in age, cancer stage, adjuvant chemotherapy, and crude survival. When adjusted, no significant survival difference between participants and non-participants remained (HR, 0.77; 95% CI, 0.53-1.11). CONCLUSIONS: We could not show improved long-term survival after the psychosocial intervention. Participants survived longer than nonparticipants, but clinical and demographic characteristics, rather than study participation, seem accountable for this difference.

Are education and cohabitation associated with health-related quality of life and self-management during breast cancer follow-up? A longitudinal study.

BACKGROUND: Oncologist-led follow-up after breast cancer (BC) is increasingly replaced with less intensive follow-up based on higher self-management, which may overburden the less resourceful patients. We examined whether socioeconomic factors measured recently after the implementation of a new follow-up program for BC patients were associated with health-related quality of life (HRQoL) and self-management 12 months later. METHODOLOGY: Between January and August 2017, we invited 1773 patients in Region Zealand, Denmark, to participate in baseline and 12 months follow-up questionnaires. The patients had surgery for low- and intermediate risk BC 1-10 years prior to the survey, and they had recently been allocated to the new follow-up program of either patient-initiated follow-up, or in-person or telephone follow-up with a nurse, based on patients' preferences. We examined associations between socioeconomic factors (education and cohabitation) at baseline and two outcomes: HRQoL (EORTC QLQ-C30 and QLQ-BR23) and self-management factors (health care provider, confidence in follow-up, contact at symptoms of concern, and self-efficacy) at 12 months follow-up. Sensitivity analyses were performed according to time since diagnosis (≤ 5 > 5 years). Furthermore, we investigated whether treatment and self-management factors modified the associations. RESULTS: A total of 987 patients were included in the analyses. We found no statistically significant associations between socioeconomic factors and HRQoL, except in patients ≤ 5 years from diagnosis. For self-management patients with short education were more likely to report that they had not experience relevant symptoms of concern compared to those with medium/long education (OR 1.75 95% CI: 1.04; 2.95). We found no clear patterns indicating that treatment or self-management factors modified the associations between socioeconomics' and HRQoL. CONCLUSION: Overall socioeconomic factors did not influence HRQoL and self-management factors except for experiencing and reporting relevant symptoms of concern. Socioeconomic factors may, however, influence HRQoL in patients within five years of diagnosis.

Sarcopenia and loss of muscle mass in patients with lung cancer undergoing chemotherapy treatment: a systematic review and meta-analysis.

BACKGROUND: In patients with cancer, sarcopenia is associated with treatment related complications, treatment cessation, poor quality of life and reduced overall survival. Despite this, there is limited knowledge about changes in skeletal muscle mass during chemotherapy. The aim of this systematic review and meta-analysis was to investigate the change of skeletal muscle mass and sarcopenia during chemotherapy treatment among patients with lung cancer. METHODS: A systematic literature search was conducted in three databases, PubMed, EMBASE and Web of Science. Observational studies with patients with lung cancer were eligible for inclusion if skeletal muscle mass was measured before and after receiving chemotherapy treatment. RESULTS: Ten cohort studies with a total of 867 participants met the inclusion criteria. During 5.2 ± 2.9 months of chemotherapy treatment, patients with lung cancer experienced a significant loss of skeletal muscle mass with a standardized mean difference (SMD) of: -0.25 (95% CI -0.47 to -0.03). The pretreatment prevalence of sarcopenia varied across studies from 35% to 74%. Only one study reported prevalence of sarcopenia both before and after chemotherapy treatment with an increase from 35% to 59%. CONCLUSION: The present data demonstrate a marked loss of skeletal muscle mass in patients with lung cancer undergoing chemotherapy treatment, as well as a high prevalence of sarcopenia. As sarcopenia is associated with poor clinical outcomes, it seems important to include and use assessments of skeletal muscle mass in clinical practice to identify patients in need for interventions. Moreover, interventional studies to hinder development of sarcopenia are needed.

Impact of multimorbidity and polypharmacy on mortality after cancer: a nationwide registry-based cohort study in Denmark 2005-2017.

BACKGROUND: Concurrent chronic diseases and treatment hereof in patients with cancer may increase mortality. In this population-based study we examined the individual and combined impact of multimorbidity and polypharmacy on mortality, across 20 cancers and with 13-years follow-up in Denmark. MATERIALS AND METHODS: This nationwide study included all Danish residents with a first primary cancer diagnosed between 1 January 2005 and 31 December 2015, and followed until the end of 2017. We defined multimorbidity as having one or more of 20 chronic conditions in addition to cancer, registered in the five years preceding diagnosis, and polypharmacy as five or more redeemed medications 2-12 months prior to cancer diagnosis. Cox regression analyses were used to estimate the effects of multimorbidity and polypharmacy, as well as the combined effect on mortality. RESULTS: A total of 261,745 cancer patients were included. We found that patients diagnosed with breast, prostate, colon, rectal, oropharynx, bladder, uterine and cervical cancer, malignant melanoma, Non-Hodgkin lymphoma, and leukemia had higher mortality when the cancer diagnosis was accompanied by multimorbidity and polypharmacy, while in patients with cancer of the lung, esophagus, stomach, liver, pancreas, kidney, ovarian and brain & central nervous system, these factors had less impact on mortality. CONCLUSION: We found that multimorbidity and polypharmacy was associated with higher mortality in patients diagnosed with cancer types that typically have a favorable prognosis compared with patients without multimorbidity and polypharmacy. Multimorbidity and polypharmacy had less impact on mortality in cancers that typically have a poor prognosis.

Impact of previous depression on the risk of suicide among prostate cancer patients.

BACKGROUND: Prior studies of suicide risk among prostate cancer patients are conflicting. We compared the risk of suicide in prostate cancer patients to cancer-free men including adjustment for clinical stage, socioeconomic position, somatic comorbidity, and previous depression. MATERIALS AND METHODS: A cohort of 37,527 men diagnosed with prostate cancer in Denmark during 1998-2011 was identified in the Danish Prostate Cancer Registry (DaPCaR) and compared with 357,384 cancer-free men matched by age at the time of diagnosis. The primary outcome was death from suicide. Data were analyzed using cumulative incidence functions and multivariable Cox regression models. RESULTS: Among prostate cancer patients, 3813 had a previous depression, defined as filed antidepressant prescription within three years before diagnosis. In the study period, 108 prostate cancer patients were registered with suicide as the cause of death, hereof 26 with previous depression. There was no difference in the cumulative incidence of suicide between prostate cancer patients and cancer-free men. There was no effect modification of previous depression on the risk of suicide (p = .12). The hazard ratio (HR) for suicide varied with time since diagnosis. A sensitivity analysis showed that the risk of suicide was highest within the first year of diagnosis where prostate cancer patients had a 1.70-fold increased hazard compared with cancer-free men (95% CI, 1.11-2.59). Men with prostate cancer and previous depression had a three-fold increased hazard for suicide compared with prostate cancer patients without a history of depression (HR 2.84, 95% CI, 1.82-4.45). CONCLUSION: The absolute risk of suicide is low following a prostate cancer diagnosis. Time since diagnosis and a history of depression was associated with the highest risk of suicide. Healthcare professionals should be aware of an increased risk of suicide among men with previous depression, especially in the immediate aftermath of the diagnosis.

The association between education and fear of recurrence among breast cancer patients in follow-up - and the mediating effect of self-efficacy.

BACKGROUND: Major restructuring of surveillance after breast cancer treatment with less follow-up consultations may result in insecurity and fear of recurrence (FCR) among the less resourceful breast cancer patients. We investigate the association between breast cancer patients' education and FCR and if self-efficacy mediates the associations between education and FCR. MATERIAL AND METHODS: A questionnaire survey was conducted from 2017 to 2019, among 1773 breast cancer patients shortly after having their follow-up switched from regular outpatient visits with an oncologist to either nurse-led or patient-initiated follow-up, with a subsequent questionnaire after 12 months. Data on disease and treatment characteristics were extracted from medical records and the Danish Breast Cancer Group Database. Logistic regression analyses were used to examine the association between education and FCR. Separate analyses were conducted for patients ≤ and >5 years since diagnosis and all models were adjusted for age and cohabitation status. To explore potential mediation by self-efficacy, we conducted regression analyses on education and FCR further adjusting for self-efficacy. RESULTS: The participation rate was 57%, and after the exclusion of patients due to missing data, 917 were included in analyses. Patients with long education had significantly less FCR compared to patients with short education (OR (95% CI) 0.71 (0.51;0,99)). When separated by time since diagnosis, there was no association among patients >5 years since diagnosis while the OR was 0.51 (95% CI, 0.30;0.85) for patients ≤5 years since diagnosis. Further adjusting for self-efficacy among patients <5 years since diagnosis resulted in an OR of 0.56 (95% CI, 0.33;0.95) among patients with long compared to short education. CONCLUSION: Up to 5 years after diagnosis, breast cancer patients with long education are less likely to experience FCR than patients with short education. Self-efficacy mediated only a very small part of this association, indicating that other factors play a role in socioeconomic differences in FCR among breast cancer patients.

Effects of home-based specialized palliative care and dyadic psychological intervention on caregiver burden: results from a randomized controlled trial.

Background The Domus study, a randomized controlled trial (RCT), evaluated the effect of home-based specialized palliative care (SPC) reinforced with a psychological intervention for the patient-caregiver dyad on increasing advanced cancer patients' time spent at home, as opposed to hospitalized, and the number of home deaths. As palliative care extends to include support for patients' families and may thus assist caregivers and decrease demands on them, in this study we evaluated a secondary outcome, caregiver burden.Material and Methods Patients with incurable cancer and their caregivers were randomized (1:1) to care as usual or home-based SPC. Caregiver burden was assessed using the Zarit Burden Interview (ZBI) at baseline and 2, 4, 8 weeks and 6 months after randomization. Intervention effects were assessed in mixed effects models.Results A total of 258 caregivers were enrolled. Eleven per cent of informal caregivers experienced severe caregiver burden at baseline. Caregiver burden increased significantly over time in both groups (p = 0.0003), but no significant effect of the intervention was seen on overall caregiver burden (p = 0.5046) or burden subscales measuring role and personal strain.Conclusion In line with the majority of previous RCTs, the Domus intervention was not able to significantly reduce caregiver burden. Future interventions should consider targeting only caregivers reporting the greatest caregiver burden.

Cardiovascular events after elective colorectal cancer surgery in patients with stage I-III disease with no previous cardiovascular disease.

BACKGROUND: The risk of cardiovascular events in patients treated for colorectal cancer is debated due to diverging results in previous studies. Colorectal cancer and cardiovascular disease share several risk factors such as physical inactivity, obesity, and smoking. Information about confounding covariates and follow-up time are therefore essential to address the issue. This study aims to investigate the risk of new-onset cardiovascular events for patients with stage I-III colorectal cancer receiving elective surgery compared to a matched population. MATERIAL AND METHODS: Using a prospective cohort, we compared cardiovascular events among 876 patients treated with elective surgery for incident stage I-III colorectal cancer diagnosed between January 1st, 2001 and December 31st, 2016 to a cancer-free cohort matched by age, sex, and time since enrollment (N = 3504). Regression analyses were adjusted for lifestyle, cardiovascular risk factors, and comorbidity. Multivariable analyses were used to identify risk factors associated with cardiovascular events in the postoperative (<90 days of elective surgery) and long-term phase (>90 days after elective surgery). RESULTS: After a median follow-up of 3.9 years, the hazard ratio (HR) for incident heart failure was 1.53 (95% CI 1.02-2.28) among patients operated for colorectal cancer. The postoperative risk of myocardial infarction or angina pectoris was associated with the use of lipid-lowering drugs. Long-term risks of cardiovascular events were ASA-score of III+IV and lipid-lowering drugs with HRs ranging from 2.20 to 15.8. Further, the use of antihypertensive drugs was associated with an HR of 2.09 (95% CI 1.06-4.13) for angina pectoris or acute myocardial infarction. Heart failure was associated with being overweight, diabetes, and anastomosis leakage. CONCLUSION: We observed an increased hazard of heart failure in patients operated on for stage I-III colorectal cancer compared to cancer-free comparisons. We identified several potential risk factors for cardiovascular events within and beyond 90 days of elective surgery.

Quality of life and mental health in real-world patients with resected stage III/IV melanoma receiving adjuvant immunotherapy.

INTRODUCTION: Treatment with immune checkpoint inhibitors (ICI) has expanded into the adjuvant setting enhancing the importance of knowledge on the immune-related toxicities and their impact on health-related quality of life (HRQoL). Large phase 3 trials of patients with resected Stage III/IV melanoma found no effect on HRQoL during adjuvant immunotherapy. This study investigates how HRQoL was affected during and after adjuvant immunotherapy in a real-world setting. METHODS: Patients with resected melanoma treated with adjuvant nivolumab from 2018 to 2021 in Denmark were identified using the Danish Metastatic Melanoma Database (DAMMED). The study was performed as a nationwide cross-sectional analysis as a questionnaire consisting of six different validated questionnaires on HRQoL, cognitive function, fatigue, depression, fear of recurrence, and decision regret was sent to all patients in March 2021. To evaluate HRQoL during and after adjuvant treatment, patients were divided into groups depending on their treatment status when answering the questionnaire; patients in active treatment for 0-6 months, patients in active treatment for >6 months, patients who ended treatment 0-6 months ago, and patients who ended treatment >6 months ago. RESULTS: A total of 271/412 (66%) patients completed the questionnaire. Patients who ended therapy 0-6 months ago had the lowest HRQoL and had more fatigue. Patients in active treatment for >6 months had lower HRQoL and more fatigue than patients who started treatment 0-6 months ago. Patients ending therapy >6 months ago had higher HRQoL and less fatigue compared to patients who ended therapy 0-6 months ago. Multivariable analysis showed an association between HRQoL and treatment status, comorbidity, civil status, and employment status. CONCLUSIONS: Adjuvant nivolumab may affect some aspects of QoL, but the influence seems temporary. Patient characteristics, such as civil status, employment status, and comorbidity were associated with HRQoL.

Effects of an early intervention with Hyperbaric Oxygen Treatment on arm lymphedema and quality of life after breast cancer-an explorative clinical trial.

PURPOSE: Lymphedema (LE) is a common complication after breast cancer treatment, which negatively affects the quality of life (QOL). Hyperbaric Oxygen Treatment (HBOT) is an established treatment for radiation-induced tissue injury, but evidence of effect on breast cancer-related LE is inconclusive. We aimed to explore effects of HBOT on early breast cancer-related LE and the implications for QOL. METHODS: We invited women with breast cancer treated with surgery, axillary dissection and radiotherapy, who had participated in a randomized controlled trial and who presented with LE 1 year after surgery. In a prospective observational study design, change in LE was assessed with perometry, dual-energy X-ray absorptiometry (DXA) and lymphoscintigraphy, and QOL by validated self-report scales. Participants were offered 40 sessions of HBOT on every weekday for 8 weeks and were followed for 6 months. RESULTS: Out of 50 eligible participants, 20 women accepted participation. Nineteen women initiated and completed treatment and follow-up. None of the objective measures of LE severity showed consistent changes during the study period, but participants reported significant improvements in QOL (physical functioning, fatigue, insomnia and breast and arm symptoms), with improvements peaking at 6-month follow-up. CONCLUSION: Participants receiving HBOT experienced improved QOL without consistently significant changes in arm mass, volume or lymphatic drainage. These results call for studies into differential effect in patient sub-groups, and a large-scale, randomized placebo-controlled trial with long-term follow-up to assess the effect of HBOT in patients with soft tissue radiation injuries after breast cancer seems warranted. TRIAL REGISTRATION: Danish Health and Medicines Authority, EUDRACT no. 2015-000,604-25 Ethical committee of the Capitol Region, No. R96-A6604-14-S22.

Effects on Pediatric Cancer Survivors: The FAMily-Oriented Support (FAMOS) Randomized Controlled Trial.

OBJECTIVE: To examine as secondary analyses the effect the FAMily-Oriented Support (FAMOS) family therapy program on reducing parent-reported medical traumatic stress in the sub-sample of pediatric cancer survivors, age 2-5 years. METHODS: The FAMOS study was a national multicenter randomized controlled trial with all four pediatric oncology departments in Denmark (Clinicaltrials.gov [NCT02200731]). Families were randomized in parallel design (1:1) to intervention or usual care. The FAMOS program includes seven home-based psychotherapeutic sessions and is based on family systems therapy to address the individuals in the family system using cognitive behavioral, problem-solving and goal-setting techniques. Questionnaires were completed by parents at baseline, 6, and 12 months. In linear mixed-effects models, the effect of FAMOS on reducing children's trauma-related behavior after 6 and 12 months was examined in 62 children (31 in the intervention and 29 in the control group, respectively). It was also examined if a trauma-related behavior effect was mediated through reduced symptoms of depression in mothers and fathers, respectively. RESULTS: On average, children in the intervention group experienced significantly larger decreases in trauma-related behaviors at 6 and 12 months than the control group (predicted mean difference -3.89, p = .02 and -6.24, p = .003, respectively). The effect on trauma-related behavior was partly mediated through reduced symptoms of depression in mothers, but not fathers. CONCLUSIONS: Adding to previously reported positive effects of the FAMOS intervention on parents' symptoms of post-traumatic stress and depression, significant improvements were found in young children's trauma related-behavior. Further research is needed to develop therapy for children with cancer.

Pregnancy outcomes in women with neurofibromatosis 1: a Danish population-based cohort study.

BACKGROUND: The probability of a pregnancy, live birth, stillbirth and abortion has never been assessed in women with neurofibromatosis 1 (NF1) in a large population-based study. METHODS: We included 1006 women (15-49 years) registered with NF1 in the Danish National Patient Registry or followed in two national Centers for Rare Diseases and 10 020 women from the Danish population. Information on pregnancy outcomes was ascertained from health registries. Cumulative incidence, mean cumulative count, hazard ratios (HRs) and proportion ratios (PRs) with 95% CIs were calculated. RESULTS: The cumulative incidence of a first pregnancy at age 50 years was slightly lower in women with NF1 (74%; 95% CI 70 to 77) than in population comparisons (78%; 95% CI 77 to 79). When all pregnancies were included, two pregnancies were expected per woman at age of 50 years, irrespective of a NF1 diagnosis. The hazard of a pregnancy did not differ between women with NF1 (HR 1.03; 95% CI 0.95 to 1.11) and the comparisons after adjustment for somatic and psychiatric disease. The proportion of pregnancies that resulted in a live birth was 63% (783/1252) among women NF1 and 68% (8432/12 465) among the comparisons, yielding a PR of 0.95 (95% CI 0.90 to 1.00). The proportions of stillbirths (PR 2.83; 95% CI 1.63 to 4.93) and spontaneous abortions (PR 1.40; 95% CI 1.09 to 1.79) were increased in women with NF1. CONCLUSIONS: A similar hazard for pregnancy was observed for women with NF1 and population comparisons after adjustment for potential medical consequences of NF1. However, women with NF1 experienced more spontaneous abortions and stillbirths.