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Purpose: The purpose of this study was to evaluate the clinical benefits of nivolumab with/without ipilimumab combined with stereotactic body radiotherapy (SBRT) in patients with pretreated metastatic biliary tract cancer (mBTC)., Patients and Methods: The study was a phase 2 randomized trial with Simon's optimal two-stage design requiring 36 evaluable patients per group after second stage. Sixty-one patients were included from September 2018 to January 2022 and randomized (1:1) to receive SBRT (15 Gy × 1 on day 1 to a primary or metastatic lesion) and nivolumab (3 mg/kg intravenously on day 1 and every 2 weeks) with/without ipilimumab (1 mg/kg intravenously on day 1 and every 6 weeks). Primary endpoint was clinical benefit rate (CBR), defined as the percentage of patients with complete response, partial response, or stable disease. Decision to continue accrual into the second stage depended on the CBR from the first stage., Results: Forty-two patients received SBRT/nivolumab/ipilimumab with a CBR of 31.0% [95% confidence interval (CI), 17.6-47.1]. Five patients (11.9%) achieved partial response with median duration of 4.4 months (range, 1.1-21.5). Nineteen patients received SBRT/nivolumab. This group was closed after the initial stage based on a CBR of 10.5% (95% CI, 1.3-33.1). Adverse events were graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Grade ≥3 treatment-related adverse events occurred in 13 (31%) and 3 (16%) patients in the SBRT/nivolumab/ipilimumab and SBRT/nivolumab groups, respectively. One patient died from immune-related hepatitis in the SBRT/nivolumab/ipilimumab group., Conclusions: Combining SBRT, nivolumab, and ipilimumab is well tolerated, feasible, and shows response in a subgroup of patients with mBTC., (©2024 American Association for Cancer Research.)

Background: Individual placement and support (IPS) is an evidence-based practice that helps individuals with mental illness gain and retain employment. IPS was implemented for young adults at a municipality level through a cross-sectoral collaboration between specialist mental healthcare, primary mental healthcare, and the government funded employment service (NAV). We investigated whether IPS implementation had a causal effect on employment outcomes for all young adults in receipt of a temporary health-related rehabilitation (work assessment allowance, WAA) welfare benefit, measured at the societal level compared to municipalities that did not implement IPS., Method: We used a difference in differences design to estimate the effects of IPS implementation on the outcome of workdays per year using longitudinal registry data. We estimate the average effect of being exposed to IPS implementation during four-years of implementation compared to ten control municipalities without IPS for all WAA recipients., Results: We found a significant, positive, causal effect on societal level employment outcomes of 5.6 ( p = 0.001, 95% CI 2.7-8.4) increased workdays per year per individual, equivalent to 12.7 years of increased work in the municipality where IPS was implemented compared to municipalities without IPS. Three years after initial exposure to IPS implementation individuals worked, on average, 10.5 more days per year equating to 23.8 years of increased work., Conclusions: Implementing IPS as a cross sectoral collaboration at a municipality level has a significant, positive, causal, societal impact on employment outcomes for all young adults in receipt of a temporary health-related rehabilitation welfare benefit.

Background: Neoantigens can serve as targets for T cell-mediated antitumor immunity via personalized neopeptide vaccines. Interim data from our clinical study NCT03715985 showed that the personalized peptide-based neoantigen vaccine EVX-01, formulated in the liposomal adjuvant, CAF09b, was safe and able to elicit EVX-01-specific T cell responses in patients with metastatic melanoma. Here, we present results from the dose-escalation part of the study, evaluating the feasibility, safety, efficacy, and immunogenicity of EVX-01 in addition to anti-PD-1 therapy., Methods: Patients with metastatic melanoma on anti-PD-1 therapy were treated in three cohorts with increasing vaccine dosages (twofold and fourfold). Tumor-derived neoantigens were selected by the AI platform PIONEER and used in personalized therapeutic cancer peptide vaccines EVX-01. Vaccines were administered at 2-week intervals for a total of three intraperitoneal and three intramuscular injections. The study's primary endpoint was safety and tolerability. Additional endpoints were immunological responses, survival, and objective response rates., Results: Compared with the base dose level previously reported, no new vaccine-related serious adverse events were observed during dose escalation of EVX-01 in combination with an anti-PD-1 agent given according to local guidelines. Two patients at the third dose level (fourfold dose) developed grade 3 toxicity, most likely related to pembrolizumab. Overall, 8 out of the 12 patients had objective clinical responses (6 partial response (PR) and 2 CR), with all 4 patients at the highest dose level having a CR (1 CR, 3 PR). EVX-01 induced peptide-specific CD4+ and/or CD8+T cell responses in all treated patients, with CD4+T cells as the dominating responses. The magnitude of immune responses measured by IFN-γ ELISpot assay correlated with individual peptide doses. A significant correlation between the PIONEER quality score and induced T cell immunogenicity was detected, while better CRs correlated with both the number of immunogenic EVX-01 peptides and the PIONEER quality score., Conclusion: Immunization with EVX-01-CAF09b in addition to anti-PD-1 therapy was shown to be safe and well tolerated and elicit vaccine neoantigen-specific CD4+and CD8+ T cell responses at all dose levels. In addition, objective tumor responses were observed in 67% of patients. The results encourage further assessment of the antitumor efficacy of EVX-01 in combination with anti-PD-1 therapy., Competing Interests: Competing interests: MD has received honoraria for lectures from Roche and Novartis (past 2 years). IMS has received honoraria for lectures and consultancies from Novartis, Roche, MSD, BMS, and Pierre Fabre. KB has received honoraria (institutional) for lectures and advisory boards of MSD, Pierre Fabre, and BMS. CCIT-DK has been granted economic support for personal wages from Evaxion Biotech A/S, Denmark. SRH is a cofounder of PokeACell and coinventor of several licensed patents. ABS, DK-K, AJ, NVP, NT and JK are employees of Evaxion Biotech A/S and have a financial interest in the company. All other authors have declared that they have no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In this study we investigated the health-related rehabilitation trajectories of young Norwegian adults between 2004-2019. The study period is interesting because it overlaps with an extensive welfare system reform that occurred in Norway between 2006-2011. In parallel with the reform there was a substantial increase in health-related welfare dependency among young people due to mental health conditions. To better understand this group, we addressed three questions: 1) what were the most typical health-related rehabilitation trajectories for young Norwegians aged 23-27 between 2004-2019, 2) did the trajectories and composition of health-related benefit recipients change overtime and 3) in parallel with the welfare reform, do we see improved labour market outcomes in our study population?, Methods: Using high-quality Norwegian registry data, we established four cohorts of Norwegian health-related rehabilitation benefit recipients aged 23-27 in either 2004 (cohort 1), 2008 (cohort 2), 2011 (cohort 3) or 2014 (cohort 4). The follow-up period for each cohort was six years. We used sequence and cluster analyses to identify typical health-related rehabilitation trajectories. In addition, descriptive statistics and multinomial logistic regression were used to scrutinise the relationship between trajectory types, sociodemographic characteristics and cohort membership., Results: The majority follow trajectories consisting of welfare dependency, unemployment and unstable, low-income work. Both the trajectories and composition of the study population changed across cohorts. Over the observation period there was a 1) three-fold increase in the proportion following a trajectory ending in permanent disability benefits, 2) nine-fold increase in the proportion following trajectories characterised by long periods of health-related rehabilitation, 3) five-fold decrease in the share following unemployment occupational handicap trajectories 4) 6.9% increase in the proportion of early school leavers and 5) 8.9% decrease in the share with disabled parents., Conclusion: Our study population is a vulnerable group with suboptimal mental health, functioning and employment outcomes. In conjunction with the welfare reform, we witnessed a significant drop in use of work-related benefits, accompanied by a substantial increase in uptake of health-related rehabilitation- and disability benefits. Thus, it appears that rather than improving employment outcomes, welfare policy changes have created a new problem by steering a greater proportion into disability benefits., (© 2023. The Author(s).)

Purpose: Ablation is a valuable treatment alternative to surgery for colorectal liver metastases. This study reports the long-term clinical outcomes in patients treated with ablation for colorectal liver metastases with or without extrahepatic metastases., Methods: Patients with colorectal liver metastases treated with ultrasound-guided ablation at Herlev Hospital, Denmark were included in this retrospective study., Results: This study included 284 patients with 582 metastases. Complete ablation was obtained in 258 patients (91%) evaluated within 6 weeks. During follow-up, 94 patients (33%) developed local recurrence. The median survival for all patients was 31 months, with 1-, 3-, and 5-year survival rates of 82%, 45%, and 21%, respectively. The median survival for patients with extrahepatic metastases (n=49, 17%) was 24 months compared with 33 months for patients without (P=0.142). Propensity score-adjusted Cox regression showed that extrahepatic metastases were associated with increased mortality, with a hazard ratio (HR) of 1.45 (95% confidence interval [CI], 1.02 to 2.05; P=0.039). In multivariate Cox regression analysis for all patients, increased mortality risk was found for a diameter ≥2.6 cm (HR, 1.59; 95% CI, 1.23 to 2.05), >1 metastasis (HR, 1.66; 95% CI, 1.28 to 2.16), and extrahepatic metastases (HR, 1.45; 95% CI, 1.04 to 2.03). Male sex (HR, 0.75; 95% CI, 0.58 to 0.98) and receiving chemotherapy (HR, 0.69; 95% CI, 0.52 to 0.92) were associated with decreased mortality., Conclusion: Ablation for colorectal liver metastases offers acceptable survival rates, including for patients with extrahepatic metastases. In addition, chemotherapy was associated with improved survival for both patients with and without extrahepatic metastases.

Background: Interleukin-6 blockade and radiation combined with immunotherapy may modulate the tumour microenvironment to overcome immune resistance. We assessed the efficacy of ipilimumab, nivolumab, and tocilizumab combined with stereotactic body radiotherapy (SBRT) in patients with refractory pancreatic cancer (PC)., Methods: Patients with PC who had progressive disease (PD) or intolerance to gemcitabine- or fluorouracil-containing regimens were enrolled in Part A of the two-part, single-centre, phase 2 study (NCT04258150). SBRT with 15 Gy was administered on day one of the first cycle. Ipilimumab was administered (1 mg/kg every 6 weeks) for a maximum of two infusions. Nivolumab (6 mg/kg) and tocilizumab (8 mg/kg) were given every four weeks until the PD or unacceptable toxicity, or for up to one year. The primary end-point was the objective response rate, with a threshold of 15%., Results: Twenty-six patients were enrolled and treated between April 17, 2020, and January 25, 2021. The median follow-up time at the time of data cutoff (February 7, 2022) was 4.9 months (interquartile range 2.1-7.7). No responses were observed. Five patients (19%; 95% confidence intervals [CI], 7-39) achieved a stable disease. The median progression-free survival was 1.6 months (95% CI 1.4-1.7), and the median overall survival was 5.3 months (95% CI 2.3-8.0). Overall, 19 (73%) experienced adverse events related to the treatment including two (8%) with grade 3 or higher events., Conclusion: The combination of ipilimumab, nivolumab, tocilizumab, and SBRT in patients with PC did not meet the prespecified criteria for expansion for full accrual., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Immunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and hypofractionated stereotactic body radiotherapy (SBRT) may work synergistically, and recent trials have supported this. We hypothesise that adding SBRT to CPI treatment can improve response rates in patients with mCRPC., Methods and Analysis: The CheckPRO trial is an open-label, randomised, two-stage, phase II trial. We aim to enrol and randomise 80 evaluable patients with mCRPC who progressed following ≥2 lines of treatment. Enrolment started in November 2019 with 38 months expected enrolment period. The participants receive treatment for 52 weeks including four cycles of ipilimumab and nivolumab with or without concomitant SBRT (24 Gray in three fractions) to a single soft tissue or bone metastasis, followed by 10 cycles of nivolumab. Participants are followed until progression, death, or for 12 months after the end of treatment.Co-primary endpoints are the objective response rate and prostate-specific antigen (PSA) response rate. Secondary endpoints include safety, radiographic progression-free survival, clinical benefit rate, duration of response, PSA-progression-free survival beyond 12 weeks, quality of life and overall survival. Exploratory endpoints include translational analyses of tumour biopsies and consecutive blood samples. Biopsies from metastatic sites are collected at baseline, before the third treatment and at the end of treatment. Blood sampling for immune monitoring and circulating tumour DNA is performed consecutively at baseline and every radiographic assessment., Ethics and Dissemination: This study follows the Helsinki Declaration and is approved by the Danish Ethics Committee System (journal no. H-19016100). All participants must receive written and oral information and provide a signed informed consent document prior to inclusion. The study results will be published in an international peer-review journal., Trial Registration Number: EudraCT number: 2018-003461-34., Clinicaltrials: gov ID NCT05655715., Competing Interests: Competing interests: DLN, EVH, GA-F and ST have no conflict of interest. NJS has received conference participation from Pfizer Inc and a research grant from Herlev Hospital and Rigshospitalet, sponsored by Varian Medical Systems. Within the last two years IMS has received honoraria for consultancies and lectures from IO Biotech, Novartis, MSD, Pierre Fabre, BMS, Novo Nordisk, TILT Bio; research grants from IO Biotech, BMS, Lytix, Adaptimmune, TILT Bio. Within the last two years GFP has received conference participance from MSD, Daiichi Sankyo and Pfizer Pierre Fabre. Research grants from Varian Medical Systems and honoraria for consultancies and lectures from Astra Zeneca. RLE has received honoraria for consultancies and lectures from Amgen and received funding of study drugs from Bristol-Myers Squibb in the CheckPRO trial., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The World Federation of Ultrasound in Medicine and Biology (WFUMB) is addressing the issue of incidental findings with a series of position papers to give advice on characterization and management. The biliary system (gallbladder and biliary tree) is the third most frequent site for incidental findings. This first part of the position paper on incidental findings of the biliary system is related to general aspects, gallbladder polyps and other incidental findings of the gallbladder wall. Available evidence on prevalence, diagnostic work-up, malignancy risk, follow-up and treatment is summarized with a special focus on ultrasound techniques. Multiparametric ultrasound features of gallbladder polyps and other incidentally detected gallbladder wall pathologies are described, and their inclusion in assessment of malignancy risk and decision- making on further management is suggested., Competing Interests: Conflict of Interest disclosure The authors and participating institutions have no conflicts of interest related to this article. No funding was received to support data acquisition or preparation of this position paper. All fugures were provided by the authors, and data was acquired according to protocols approved by the institutional review boards of the authors. According to these protocols, participants gave consent for the use of their fully anonymized data (ultrasound images) in this article., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with refractory metastatic pancreatic cancer (mPC)., Methods: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status (ClinicalTrials.gov identifier: NCT02866383). The primary end point was the clinical benefit rate (CBR), defined as the percentage of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon's 2-stage phase II optimal design was used independently for both arms, with CBR determining expansion to the second stage. Secondary end points included safety, response rate, duration of response, progression-free survival, and overall survival. Exploratory analyses included biomarkers related to the benefits., Results: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (8.0 to 30.6) for patients receiving SBRT/nivolumab and 37.2% (24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient receiving SBRT/nivolumab and lasted for 4.6 months. Six patients receiving SBRT/nivolumab/ipilimumab achieved a PR with a median duration of response of 5.4 months (4.2 to not reached). Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) and 13 (30.2%) patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively. Programmed cell death ligand-1 expression by tumor proportion score or combined positivity score of ≥ 1% was not associated with clinical benefits. On-treatment decreased serum interleukin-6, interleukin-8, and C-reactive protein levels were associated with better overall survival., Conclusion: Clinically meaningful antitumor activity and favorable safety profiles were demonstrated after treatment with SBRT/nivolumab/ipilimumab in patients with refractory mPC. However, the contribution from SBRT is unknown. Further studies are warranted.

Background: Since the 1990's, structural transformations in the Norwegian economy have decreased employment opportunities for low-skilled young people lacking formal education credentials. In parallel with these economic changes, there has been a strong increase in the proportion of young disability pensioners. Preventing labour market exit requires a thorough understanding of the disability process. We aim to 1) identify the most typical trajectories into disability pension for young Norwegian inhabitants between 1993 and 2014 and 2) investigate if the trajectories and composition of young disability pensioners changed over time., Methods: Using high-quality Norwegian registry data, we established two population-based cohorts of Norwegian inhabitants aged 29-39 years in either 2003 (cohort 1) or 2014 (cohort 2) who were not disability pensioners during the first month of their cohort period but had been granted a disability pension by the cohort end-date. Cohort 1 was followed from the beginning of 1993 through 2003, cohort 2 from 2004 through 2014. We used sequence and cluster analyses to identify typical disability pension trajectories and investigate how they changed overtime., Results: The majority follow trajectories characterised by little or no previous work participation. Both the trajectories and composition of young disability pensioners changed overtime. Between the two cohorts there was 1) a doubling in the probability of following 'precarious income trajectories', 2) a decrease in the probability of following 'work and/or education trajectories' and 3) an increase in the proportion of early school leavers., Conclusion: Current initiatives such as the Norwegian Inclusive Workplace Agreement (IA) focus on preventing transitions from employment to disability benefits. However, such initiatives have little relevance for young disability pensioners as the majority have weak labour market attachment. Policymakers should therefore consider placing more emphasis on non-workplace interventions., Competing Interests: None., (© 2022 The Authors.)

Background: The increasing role of exercise training in cancer care is built on evidence that exercise can reduce side effects of treatment, improve physical functioning and quality of life. We and others have shown in mouse tumor models, that exercise leads to an adrenalin-mediated increased influx of T and NK cells into the tumor, altering the tumor microenvironment (TME) and leading to reduced tumor growth. These data suggest that exercise could improve immune responses against cancer cells by increase immune cell infiltration to the tumor and potentially having an impact on disease progression. Additionally, there are data to suggest that infiltration of T and NK cells into the TME is correlates with response to immune checkpoint inhibitors in patients. We have therefore initiated the clinical trial HI AIM, to investigate if high intensity exercise can mobilize and increase infiltration of immune cells in the TME in patients with lung cancer., Methods: HI AIM (NCT04263467) is a randomized controlled trial (70 patients, 1:1) for patients with non-small cell lung cancer. Patients in the treatment arm, receive an exercise-intervention consisting of supervised and group-based exercise training, comprising primarily intermediate to high intensity interval training three times per week over 6 weeks. All patients will also receive standard oncological treatments; checkpoint inhibitors, checkpoint inhibitors combined with chemotherapy or oncological surveillance. Blood samples and biopsies (ultrasound guided), harvested before, during and after the 6-week training program, will form basis for immunological measurements of an array of immune cells and markers. Primary outcome is circulating NK cells. Secondary outcome is other circulating immune cells, infiltration of immune cells in tumor, inflammatory markers, aerobic capacity measured by VO 2 max test, physical activity levels and quality of life measured by questionnaires, and clinical outcomes., Discussion: To our knowledge, HI AIM is the first project to combine supervised and monitored exercise in patients with lung cancer, with rigorous analyses of immune and cancer cell markers over the course of the trial. Data from the trial can potentially support exercise as a tool to mobilize cells of the immune system, which in turn could potentiate the effect of immunotherapy., Trial Registration: The study was prospectively registered at ClinicalTrials.gov on February 10 th 2020, ID: NCT04263467. https://clinicaltrials.gov/ct2/show/NCT04263467., (© 2022. The Author(s).)

Background: The increased use of neoadjuvant chemotherapy (NACT) facilitates an increase in breast-conserving surgery and immediate breast reconstruction. While NACT is considered to have the same oncological safety as adjuvant chemotherapy, evidence on the impact of NACT on surgical outcomes following breast surgery is unclear and varies across studies. The aim of this systematic review and meta-analysis was to assess the impact of NACT on surgical complications in breast cancer patients undergoing any kind of breast surgery., Methods: Database searches were conducted (March 26, 2021) to identify studies assessing the impact of NACT on postoperative complications. Studies were included if they compared a group of patients treated with NACT to a control group that was not, and if they reported at least one of our defined outcomes. Primary effect measures were odds ratios (ORs) and mean difference with a 95% confidence interval. Study quality was assessed by the Newcastle-Ottawa Scale., Results: Twenty-six studies comprising 134,191 patients were included. NACT was not associated with an increased complication rate for overall complications (OR: 1.13, 95% CI: 0.86 to 1.47, p = 0.38), individual postoperative complications, nor surgery duration. There was a non-significant trend towards NACT increasing the risk of seroma, wound complications, skin or nipple necrosis, flap ischemia or loss, and implant loss. A significant difference in blood loss was found, favouring NACT (MD = -75.85, 95% CI: -107.47 to -44.23, p < 0.00001). Heterogeneity was significant between the studies (I 2 >50%)., Conclusion: Compared to a control group, NACT was not found to affect the surgical complications adversely., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)