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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.

IntroductionEpithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease.Study designRegistry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE.ObjectivesTo improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern.MethodsSettings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression.ResultsThe registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.

IntroductionSolitary fibrous tumor (SFT) is a rare soft tissue tumor found at any site of the body. The treatment of choice is surgical resection, though 10%–30% of patients experience recurrent disease. Multiple risk factors and risk stratification systems have been investigated to predict which patients are at risk of recurrence. The main goal of this systematic review is to create an up-to-date systematic overview of risk factors and risk stratification systems predicting recurrence for patients with surgically resected SFT within torso and extremities.MethodWe prepared the review following the updated Prisma guidelines for systematic reviews (PRISMA-P). Pubmed, Embase, Cochrane Library, WHO international trial registry platform and ClinicalTrials.gov were systematically searched up to December 2022. All English studies describing risk factors for recurrence after resected SFT were included. We excluded SFT in the central nervous system and the oto-rhino-laryngology region.ResultsEighty-one retrospective studies were identified. Different risk factors including age, symptoms, sex, resection margins, anatomic location, mitotic index, pleomorphism, hypercellularity, necrosis, size, dedifferentiation, CD-34 expression, Ki67 index and TP53-expression, APAF1-inactivation, TERT promoter mutation and NAB2::STAT6 fusion variants were investigated in a narrative manner. We found that high mitotic index, Ki67 index and presence of necrosis increased the risk of recurrence after surgically resected SFT, whereas other factors had more varying prognostic value. We also summarized the currently available different risk stratification systems, and found eight different systems with a varying degree of ability to stratify patients into low, intermediate or high recurrence risk.ConclusionMitotic index, necrosis and Ki67 index are the most solid risk factors for recurrence. TERT promoter mutation seems a promising component in future risk stratification models. The Demicco risk stratification system is the most validated and widely used, however the G-score model may appear to be superior due to longer follow-up time.Systematic Review RegistrationCRD42023421358.

Abstract Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis‐based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double‐blinded, placebo‐controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21–67) were enrolled in this substudy. They received oral capsules containing Δ9‐tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra‐high‐performance liquid chromatography–tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half‐life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half‐life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group.

Introduction: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease. Study design: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE Objectives: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern. Methods: Settings and participants: It is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. Variables: Full details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methods: The data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression. Results: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual. [ABSTRACT FROM AUTHOR]

Movement integration (MI) has become a significant part of contemporary educational policy; it implies that teachers of any school subject are responsible for organizing movement activities that are of educative value. In this paper, we use Wolfgang Klafki's Bildung theoretical analysis to examine contemporary approaches to MI and clarify dominant theoretical and didactic ways of working with MI. We aim to suggest a new understanding of MI by applying Klafki's conception of categorial Bildung. We argue that it enables educators to emphasize the educative and existential potential of the embodied, social and emotional involvement with the academic content. Our analyses illustrates the thorough didactic consideration needed to transform an educational policy into real-world education.

Abstract Background Inflammation-scores based on general inflammation markers are suggested as prognostic markers of overall survival (OS) in lung cancer. However, whether these inflammation-scores improves the prognostication performed by well-established prognostic markers is unsettled. In a large register-based lung cancer patient cohort, nine different inflammation-scores were compared, and their ability to optimize the prognostication of OS was evaluated. Methods Lung cancer patients diagnosed from 2009–2018 in The Central Denmark Region were identified in the Danish Lung Cancer Registry. Pre-treatment inflammation markers were extracted from the clinical laboratory information system. Prognostication of OS was evaluated by Cox proportional hazard models. Comparison of the inflammation-scores and their added value to established prognostic markers were assessed by Akaike's information criteria and Harrel's C-index. Results In total, 5,320 patients with non-small cell lung cancer (NSCLC) and 890 patients with small cell lung cancer (SCLC) were identified. In NSCLC, the Aarhus composite biomarker score (ACBS), including albumin, C-reactive protein, neutrophil count, lymphocyte count and haemoglobin, and the neutrophil-lymphocyte-ratio (NLR) were superior. Furthermore, they improved the prognostication of OS significantly (p

Patients with multiple sclerosis (MS) and spinal cord injury (SCI) commonly sustain central neuropathic pain (NP) and spasticity. Despite a lack of consistent evidence, cannabis-based medicine (CBM) has been suggested as a supplement treatment. We aimed to investigate the effect of CBM on NP and spasticity in patients with MS or SCI. We performed a randomized, double-blinded, placebo-controlled trial in Denmark. Patients aged ≥18 years with NP (intensity >3, ≤9 on a numerical rating scale (NRS0-10) and/or spasticity (>3 on NRS0-10) were randomized to treatment consisting of either delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), a combination of THC&CBD in maximum doses of 22.5 mg, 45 mg and 22.5/45 mg per day, respectively, or placebo. A baseline registration was performed before randomization. Treatment duration was six weeks followed by a one-week phaseout. Primary endpoints were the intensity of patient-reported NP and/or spasticity. Between February 2019 and December 2021, 134 patients were randomized (MS n = 119, SCI n = 15), where 32 were assigned to THC, 31 to CBD, 31 to THC&CBD, and 40 to placebo. No significant difference was found for: mean pain intensity (THC 0.42 (−0.54–1.38), CBD 0.45 (−0.47–1.38) and THC&CBD 0.16 (−0.75–1.08)), mean spasticity intensity (THC 0.24 (−0.67–1.45), CBD 0.46 (−0.74–1.65), and THC&CBD 0.10 (−1.18–1.39), secondary outcomes (patient global impression of change and quality of life), or any tertiary outcomes. We aimed to include 448 patients in the trial; however, due to COVID-19 and recruitment challenges, fewer were included. Nevertheless, in this four-arm parallel trial, no effect was found between placebo and active treatment with THC or CBD alone or in combination on NP or spasticity in patients with either MS or SCI. The trial was registered with the EU Clinical Trials Register EudraCT (2018-002315-98).

Background: Soft-tissue sarcoma (STS) is a heterogeneous group of sarcomas with a low incidence. The treatment of advanced disease is poor, and mortality is high. We aimed to generate an overview of the clinical experiences with targeted treatments based on a pre-specified target in patients with STS. Methods: A systematic literature search was conducted in PubMed and Embase databases. The programs ENDNOTE and COVIDENCE were used for data management. The literature was screened to assess the article’s eligibility for inclusion. Results: Twenty-eight targeted agents were used to treat 80 patients with advanced STS and a known pre-specified genetic alteration. MDM2 inhibitors were the most-studied drug (n = 19), followed by crizotinib (n = 9), ceritinib (n = 8), and 90Y-OTSA (n = 8). All patients treated with the MDM2 inhibitor achieved a treatment response of stable disease (SD) or better with a treatment duration of 4 to 83 months. For the remaining drugs, a more mixed response was observed. The evidence is low because most studies were case reports or cohort studies, where only a few STS patients were included. Conclusions: Many targeted agents can precisely target specific genetic alterations in advanced STS. The MDM2 inhibitor has shown promising results.

Most soft tissue sarcoma (STS) patients do not respond to traditional checkpoint inhibitor treatment, which may be due to infiltrating immunosuppressive tumour-associated macrophages. This study investigated the prognostic value of four serum macrophage biomarkers. Methods: Blood samples were taken from 152 patients with STS at the time of diagnosis; clinical data were prospectively collected. The concentrations of four macrophage biomarkers (sCD163, sCD206, sSIRPα, sLILRB1) were measured in serum, dichotomised based on median concentration, and evaluated either individually or when combined with established prognostic markers. Results: All macrophage biomarkers were prognostic of overall survival (OS). However, only sCD163 and sSIRPα were prognostic for recurrent disease (sCD163: hazard ratio (HR): 1.97 (95% CI: 1.10–3.51) and sSIRPα: HR: 2.09 (95% CI: 1.16–3.77)). A prognostic profile was made based on sCD163 and sSIRPα; it also included c-reactive protein and tumour grade. Patients with intermediate- or high-risk prognostic profiles (adjusted for age and tumour size) had a higher risk of recurrent disease compared to low-risk patients (HR: 2.64 (95% CI: 0.97–7.19)) and (HR 4.3 (95% CI: 1.62–11.47)), respectively. Conclusion: This study demonstrated that serum biomarkers of immunosuppressive macrophages were prognostic for OS; when combined with well-established markers of recurrence they allowed for a clinically relevant categorising of patients.

Abstract Background Inflammation scores based on general inflammation markers as leucocyte count or C-reactive protein have been evaluated as prognostic markers of inferior survival in several cancers. In small cell lung cancer (SCLC), however, inflammation scores are less studied. In the present study, we set out to perform a systematic review and meta-analysis investigating reported associations between inflammation scores and overall survival (OS) in SCLC. Methods A literature search was performed in PubMed, Embase, Scopus, and Web of Science following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. Of the identified publications, only studies in English containing original data evaluating inflammation scores as a prognostic factor in SCLC patients were included. Hazard ratios (HRs) for OS were pooled in a random-effects model. Results In total, 33 articles were included evaluating eight different inflammation scores in 7762 SCLC patients. Seven of the identified scores were based on leucocyte count. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) ratio were the most frequently evaluated scores (NLR: n = 23; PLR: n = 22). For NLR, a meta-analysis including 16 studies demonstrated that patients with a high NLR had a significantly shorter OS compared to patients with a low NLR (pooled HR = 1.39 (95% CI, 1.23–1.56)). For PLR, an association with survival could not be confirmed in a meta-analysis performed based on eight studies (pooled HR = 1.20 (95% CI, 0.96–1.51)). Conclusions This review identifies that inflammation scores based on general inflammation markers have some potential as prognostic biomarkers in SCLC. The meta-analyses indicated that NLR is associated with inferior OS, whereas an association between PLR and OS could not be confirmed. Thus, NLR could be a useful biomarker of OS in SCLC patients. Systematic review registration The protocol for the study was submitted to the PROSPERO database (registration number CRD42020188553 ).

Indførelsen af kravet om 45 minutters daglig motion og bevægelse i folkeskolen har forandret lærernes undervisningspraksis. I dette kvalitative interviewstudie undersøger vi, hvilke didaktiske overvejelser lærere gør sig, når de integrerer bevægelse i deres undervisning. Undersøgelsen sigter på at nuancere forståelsen af og beskrive mulighederne i at integrere motion og bevægelse i undervisningen i folkeskolen. Studiets interviews peger på, at lærerne opfatter bevægelse som kropslige handlinger, der bidrager til indsigt i det faglige indhold frem for som fysiske aktiviteter, der fremmer eksekutive funktioner. Ifølge lærerne skal bevægelse i undervisningen give sansemotoriske, sociale og følelsesmæssige erfaringer, der bidrager til elevernes læring på en måde, som traditionel tavleundervisning ikke gør. Det er derfor lærernes didaktiske overvejelser om faglige mål og elevernes læring, der former bevægelsesaktiviteterne, og disse integreres således i lærernes fagdidaktik. Lærerne giver imidlertid udtryk for, at det er udfordrende at identificere berøringsflader mellem bevægelse og fagligt indhold. Ifølge lærerne øger bevægelsesaktiviteterne elevernes kropslige interaktion, hvilket gør undervisningen mere levende og engagerer eleverne. Det kan forstyrre undervisningen, men interviewene viser, at en handlingsorienteret bevægelsespraksis har potentiale til at skabe balance mellem bevægelsens vitalitet og den faglige styring.

Movement integration (MI) has become a significant part of contemporary educational policy; it implies that teachers of any school subject are responsible for organizing movement activities that are of educative value. In this paper, we use Wolfgang Klafki’s Bildung theoretical analysis to examine contemporary approaches to MI and clarify dominant theoretical and didactic ways of working with MI. We aim to suggest a new understanding of MI by applying Klafki’s conception of categorial Bildung. We argue that it enables educators to emphasize the educative and existential potential of the embodied, social and emotional involvement with the academic content. Our analyses illustrates the thorough didactic consideration needed to transform an educational policy into real-world education.

BACKGROUND: The effect of chemotherapy in metastatic bone sarcomas is poor and the condition is invariably fatal. Therefore, new treatment modalities are intensely needed. Pazopanib is a selective multitargeted tyrosine kinase inhibitor that has proven to be effective in the treatment of metastatic soft tissue sarcomas. The objective of this study was to evaluate the off-label use of pazopanib in patients with metastatic bone sarcomas who failed standard chemotherapy. METHODS: All patients with metastatic bone sarcomas treated with pazopanib between October 1st, 2011 and October 1st, 2017 at the Department of Oncology, Aarhus University Hospital were evaluated. Demographics, treatment, and survival outcomes were collected and analyzed. RESULTS: Nineteen patients were identified. The median age was 38 years (range 18–62). Most of the patients (50%) were diagnosed with osteosarcoma. All patients had documented disease progression at the time of initiating pazopanib treatment. The median overall survival was 11 months. Median progression free survival was 5.4 months. Out of 19 patients, 13 (68%) had either partial response or stable disease. In five patients, the dose of pazopanib was reduced because of toxicity. CONCLUSION: Off-label use of pazopanib is effective in the treatment of metastatic bone sarcomas of different histologies. Pazopanib was well tolerated in the treatment of patients with refractory bone sarcomas. Studies examining the effect of pazopanib alone or in combination with chemotherapy or other targeted therapies are needed.

Sarcomas are rare and have a high mortality rate. Further prognostic classification, with readily available parameters, is warranted, and several studies have examined circulating biomarkers and PET parameters separately. This single-site, retrospective study aimed to examine the prognostic values of several scoring systems in combination with PET parameters. We included 148 patients with sarcoma, who were treated and scanned at Aarhus University Hospital from 1 January 2016 to 31 December 2019. The Akaike information criterion and Harrell’s concordance index were used to evaluate whether the PET parameters added prognostic information to existing prognostic models using circulating biomarkers. Of the PET parameters, metabolic tumor volume (MTV) performed best, and when combined with the existing prognostic models, the prognostic value improved in all models. Backward stepwise selection was used to create a new model, SBSpib, which included albumin, lymphocytes, and one PET parameter, MTV. It has scores ranging from zero to three and increasing hazard ratios; HR = 4.83 (1.02–22.75) for group one, HR = 7.40 (1.6–33.42) for group two, and HR = 17.32 (3.45–86.93) for group three. Consequently, implementing PET parameters in prognostic models improved the prognostic value. SBSpib is a new prognostic model that includes both circulating biomarkers and PET parameters; however, validation in another sarcoma cohort is warranted.

Background: This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). Methods: Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. Results: No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. Conclusions: Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated.

Ninna Aggerholm-Pedersen1,2, Katja Maretty-Nielsen3, Steen Baerentzen3, Peter Holmberg Jørgensen4, Bjarne Hauge Hansen4, Thomas Baad-Hansen4, Johnny Keller4, Akmal Safwat1 1Department of Oncology, Sarcoma Centre of Aarhus University Hospital, Aarhus, Denmark; 2Department of Experimental Clinical Oncology, Sarcoma Centre of Aarhus University Hospital, Aarhus, Denmark; 3Department of Orthopaedic Surgery, Sarcoma Centre of Aarhus University Hospital, Aarhus, Denmark; 4Department of Pathology, Sarcoma Centre of Aarhus University Hospital, Aarhus, DenmarkCorrespondence: Ninna Aggerholm-PedersenDepartment of Oncology, Sarcoma Centre of Aarhus University Hospital, Palle Juul-Jensensens Boulevard 99, Aarhus N 8200, DenmarkEmail ninnpe@rm.dkBackground: Adjustment for comorbidity when investigating potential prognostic factors, especially in elderly cancer patients, is imperative. Patients diagnosed with chondrosarcoma are elderly and more comorbidity is expected for these patients. Demographic changes are awaited in the future resulting in more and more elderly patients with comorbidity. The aims of this study were to characterize patients with chondrosarcoma treated at a single institute and to evaluate various prognostic factors for survival adjusted for comorbidity.Material and methods: Between 1979 and 2008, 199 patients were treated at the Sarcoma Centre of Aarhus University Hospital, for chondrosarcoma. The incidence was calculated as a WHO age-standardized incidence rate (IR) per million per year. The endpoints were overall mortality and disease-specific mortality. Possible prognostic factors were analyzed for patients with intermediate/high-grade localized tumors by the uni- and multivariate Cox-proportional hazard method.Results: The WHO age-standardized IR in western Denmark in the period 1979–2008 was 2.4/million inhabitants/year (95% CI: 2.2;2.6). The 5-year overall and disease-specific mortality for the 199 patients were 29% (95% CI: 23;36) and 22% (95% CI: 16;27), respectively. The 5-year disease-specific mortality for patients with metastatic disease was significantly higher than for patients with localized disease. The median time to relapse was 2.0 years. Patients who relapse within 1 year after the primary diagnosis have a significantly higher 5-year overall mortality compared to patients who relapse after 1 year. The presence of comorbidity and high-grade tumors were independent prognostic factors for both the overall mortality and the disease-specific mortality of chondrosarcoma patients.Conclusion: Patients with comorbidity had a significantly increased overall mortality and disease-specific mortality. We found that adjusting for comorbidity is important when investigating a cohort of elderly patients.Keywords: chondrosarcoma, comorbidity, prognostic factors

Background: Checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, yielding long-term survival in a considerable proportion of the patients. Yet, 40–60% of patients do not achieve a long-term benefit from such therapy, emphasizing the urgent need to identify biomarkers that can predict response to immunotherapy and guide patients for the best possible treatment. Here, we exploited an unsupervised machine learning approach to identify potential inflammatory cytokine signatures from liquid biopsies, which could predict response to immunotherapy in melanoma. Methods: We studied a cohort of 77 patients diagnosed with unresectable advanced-stage melanoma undergoing treatment with first-line nivolumab plus ipilimumab or pembrolizumab. Baseline and on-treatment plasma samples were tested for levels of PD-1, PD-L1, IFNγ, IFNβ, CCL20, CXCL5, CXCL10, IL6, IL8, IL10, MCP1, and TNFα and analyzed by Uniform Manifold Approximation and Projection (UMAP) dimension reduction method and k-means clustering analysis. Results: Interestingly, using UMAP analysis, we found that treatment-induced cytokine changes measured as a ratio between baseline and on-treatment samples correlated significantly to progression-free survival (PFS). For patients treated with nivolumab plus ipilimumab we identified a group of patients with superior PFS that were characterized by significantly higher baseline-to-on-treatment increments of PD-1, PD-L1, IFNγ, IL10, CXCL10, and TNFα compared to patients with worse PFS. Particularly, a high PD-1 increment was a strong individual predictor for superior PFS (HR = 0.13; 95% CI 0.034–0.49; p = 0.0026). In contrast, decreasing levels of IFNγ and IL6 and increasing levels of CXCL5 were associated with superior PFS in the pembrolizumab group, although none of the cytokines were individually predictors for PFS. Conclusions: In short, our study demonstrates that a high increment of PD-1 is associated with superior PFS in advanced-stage melanoma patients treated with nivolumab plus ipilimumab. In contrast, decreasing levels of IFNγ and IL6, and increasing levels of CXCL5 are associated with response to pembrolizumab. These results suggest that using serial samples to monitor changes in cytokine levels early during treatment is informative for treatment response.

Multiple Myeloma (MM) often present with unspecific symptoms, which can lead to diagnostic delay. Serum-free light chain (sFLC) ratio is suggested to replace urine protein electrophoresis (UPE) in the diagnostic work-up of myeloma. We aimed to investigate the performance of the sFLC-ratio in general practice (GP) compared to UPE, just as we explored different sFLC-ratio cut-offs’ influence on diagnostic values. In a cohort of 13,210 patients from GP measures of sFLC-ratio, serum protein electrophoresis (SPE), or UPE were compared to diagnoses of incident M-component related diseases acquired from Danish health registers. UPE and sFLC-ratio equally improved diagnostic values when combined with SPE (sensitivity: SPE and UPE: 95.6 (90.6–98.4); SPE and sFLC-ratio: 95.1 (90.2–98.0)). The addition of the sFLC-ratio to SPE resulted in the identification of 13 patients with MGUS, light chain disease and amyloidosis, which was in line with the addition of UPE to SPE. The number of false-positive tests was UPE and SPE: 364 (11%) and sFLC-ratio and SPE: 677(19%). Expanding sFLC-ratio reference range to 0.26–4.32 resulted in a significant reduction in false positives n = 226 (6%) without loss of patients with clinical plasma cell dyscrasias. sFLC-ratio improves the diagnostic value of SPE in GP. However, due to low specificity and a large number of false positives, expanded cut-off values should be considered.

Introduction. Adult rhabdomyosarcoma is a rare tumour that has an inferior survival compared to the paediatric patient population. The reason for this consistently worse outcome remains mostly unknown. It has been suggested that this disparity may be related to biological and/or treatment-related factors, which in the literature has been shown to be distributed differently among paediatric and adult patients. The aim of this study was to clarify treatment outcome and clinicopathological factors for adult patients with rhabdomyosarcoma that were treated in Aarhus, Denmark, since 1979. Methods. By searching the Aarhus Sarcoma Registers, data for all rhabdomyosarcoma patients, aged 18 years or more, between 1979 and 2018, were retrieved and analysed. Results. Data from 50 patients were collected. No patients were lost to follow-up. For the entire cohort, 5- and 10-year overall survival rates were 30% and 18%, respectively. The median age was 46.5 years, and the median overall survival was 2.3 years. Tumour histology was embryonal 18%, alveolar 22%, pleomorphic 44%, and not otherwise specified 16%. The tumour site was unfavourable in more than 80% of the patients. Significant factors associated with inferior overall survival were histology and disease stage, although histological subtype was not significant in the multivariate model. Five-year overall survival was 40% for localised disease versus 15% for metastatic disease. Conclusion. Rhabdomyosarcoma in adults has a poorer prognosis than paediatric rhabdomyosarcoma and other high-grade sarcomas in adults. Adult rhabdomyosarcoma should continue to be treated aggressively, but new and tailored treatment strategies are needed to improve the long-term outcome. Previous predictors of poor survival in paediatric patients were valid in adults except for age, site (favourable versus unfavourable), and tumour size.

Background: Patients at high risk of medication errors will potentially benefit most from medication reviews. An algorithm, MERIS, can identify the patients who are at highest risk of medication errors. The aim of this study was to examine the effects of performing stratified medication reviews on patients who according to MERIS were at highest risk of medication errors. Methods: A randomised controlled trial was performed at the Acute Admissions Unit, Aarhus University Hospital, Denmark. Patients were included at admission to the hospital and were randomised to control or intervention. The intervention consisted of stratified medication review at admission on patients with a high MERIS score. Clinical pharmacists and clinical pharmacologists performed the medication reviews; the clinical pharmacologists performed the reviews on patients with the highest MERIS score. The primary outcome measure was the number of prescribing errors during the hospitalisation. Secondary outcomes included self-experienced quality of life, health-care utilisation and mortality measured at follow-up 90 days after discharge. Results: A total of 375 patients were included, of which medication reviews were performed in 64 patients. The medication reviews addressed 63 prescribing errors in 37 patients and 60 other drug-related problems. No difference in the number of prescribing errors during hospitalisation between the intervention group ( n = 165) and control group ( n = 153) was found, corresponding to 0.11 prescribing errors per drug (95% confidence interval (CI): 0.08–0.14) versus 0.13 per drug (95% CI: 0.09–0.16), respectively. No differences in secondary outcomes were observed. Conclusion: A stratified medication review approach based on the individual patient’s risk of medication errors did not show impact on the chosen outcomes. Plain language summary How does a medication review at admission affect patients who are in high risk of medication errors? Patients are at risk of medication errors at admission to hospital. Medication reviews aim to detect and solve these. Yet, due to limited resources in healthcare, it would be beneficial to detect the patients who are most at risk of medication errors and perform medication reviews on those patients. In this study we investigated whether an algorithm, MERIS, could detect patients who are at highest risk of medication errors; we also studied whether performing medication reviews on patients at highest risk of medication errors would have an effect on, for example, the number of medication errors during hospitalisation, qualify of life and number of readmissions. We included 375 patients in a Danish acute admission unit and they were divided into control group and intervention group. Patients in the intervention group received a medication review at admission if they were considered at high risk of medication errors, assessed with the aid of MERIS. In summary, 64 patients in the intervention group were most at risk of medication errors and therefore received a medication review. We conclude in the study that MERIS was useful in identifying relevant patients for medication reviews. Yet, the medication reviews performed at admission did not impact on the chosen outcomes.

Abstract Background The current literature on single cell genomic analyses on the DNA level is conflicting regarding requirements for cell quality, amplification success rates, allelic dropouts and resolution, lacking a systematic comparison of multiple cell input down to the single cell. We hypothesized that such a correlation assay would provide an approach to address the latter issues, utilizing the leukemic cell line OCI-AML3 with a known set of genetic aberrations. Results By analyzing single and multiple cell replicates (2 to 50 cells) purified by micromanipulation and serial dilution we stringently assessed the signal-to-noise ratio (SNR) from single as well as a discrete number of cells based on a multiple displacement amplification method, with whole exome sequencing as signal readout. In this setting, known OCI-AML3 mutations as well as large copy number alterations could be identified, adding to the current knowledge of cytogenetic status. The presence of DNMT3A R882C, NPM1 W288 fs and NRAS Q61L was consistent, in spite of uneven allelic read depths. In contrast, at the level of single cells, we observed that one-third to half of all variants were not reproduced in the replicate sample, and this allelic mismatch displayed an exponential function of cell input. Large signature duplications were discernible from 5 cells, whereas deletions were visible down to the single cell. Thus, even under highly optimized conditions, single cell whole genome amplification and interpretation must be taken with considerable caution, given that allelic change is frequent and displays low SNR. Allelic noise is rapidly alleviated with increased cell input, and the SNR is doubled from 2 to 50 cells. Conclusions In conclusion, we demonstrate noisy allele distributions, when analyzing genetic aberrations within single cells relative to multiple cells. Based on the presented data we recommend that single cell analyses should include replicate cell dilution assays for a given setup for relative assessment of procedure-specific SNR to ensure that the resolution supports the specific hypotheses.

The albumin-to-alkaline phosphatase ratio (AAPR) is a novel promising prognostic marker in cancer patients. However, the evidence for its significance in lung cancer is scarce. Therefore, we assessed the prognostic value of the AAPR in a large cohort of lung cancer patients. Data on lung cancer patients diagnosed from January 2009 to June 2018 were extracted from the Danish Lung Cancer Registry and combined with data on the pretreatment serum AAPR level extracted from the clinical laboratory information system (LABKA). AAPR tertiles were applied as cutoffs. Cox proportional hazard models assessed the prognostic value of the AAPR. In total, 5978 non-small cell lung cancer (NSCLC) patients and 1099 small cell lung cancer (SCLC) patients were included. Decreasing AAPR level was significantly associated with declining median overall survival (OS) in NSCLC patients (medium vs. low AAPR, adjusted HR = 0.73 (95% confidence interval (CI) 0.68–0.79); high vs. low AAPR, adjusted HR = 0.68 (95% CI 0.62–0.73)) and in SCLC patients (medium vs. low AAPR, adjusted HR = 0.62 (95% CI 0.52–0.74); high vs. low, adjusted HR = 0.59 (95% CI 0.50–0.70)). In conclusion, the AAPR was an independent prognostic factor in NSCLC and SCLC patients. The correlation seems to be level dependent, with reducing survival found to be associated with decreasing AAPR level.

BACKGROUND: The prognostic value of serum biomarkers in soft tissue sarcoma (STS) is limited, and its clinical applicability is compromised by a common inability to adjust for important confounders. The aim of this study was to determine the prognostic value of pretreatment biomarkers on disease-specific survival (DSS) adjusted for confounders. METHODS: The study included 818 patients with localized STS. Pretreatment levels of albumin, C-reactive protein, hemoglobin, neutrophils, and lymphocytes were tested individually and combined in prognostic scores: neutrophil/lymphocyte ratio (NLR), Glasgow Prognostic Score (GPS), and Aarhus Composite Biomarker Score (ACBS) which includes all five biomarkers. Patients were randomly split into a test cohort and a validation cohort. The prognostic value of biomarkers on DSS was estimated using crude and adjusted Cox proportional hazard models. The different biomarker scores were compared using Akaike's information criteria. RESULTS: In the test cohort of 403 patients, all biomarkers except lymphocyte count were significant prognostic factors for DSS also after adjusting for confounders. NLR, GPS, and ACBS were independently associated with decreased survival; however, ACBS was significantly superior to NLR (P = .02) and GPS (P = .002). These findings were validated in the randomly assigned validation cohort of 415 patients. In the pooled data of 818 patients, the ACBS performed better than GPS and NLR. ACBS 2 was independently associated with decreased DSS compared to ACBS 0, hazard ratio 2.3[95% confidence interval: 1.5-3.5], P

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis‐based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double‐blinded, placebo‐controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21–67) were enrolled in this substudy. They received oral capsules containing Δ9‐tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra‐high‐performance liquid chromatography–tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were Cmax 1.21 ng/mL, Tmax 2.68 h, and half‐life 2.75 h, and for CBD (10 mg) were Cmax 2.67 ng/mL, Tmax 0.10 h, and half‐life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group. [ABSTRACT FROM AUTHOR]

Disease or acquired damage to the central nervous system frequently causes disabling spasticity and central neuropathic pain (NP), both of which are frequent in multiple sclerosis (MS) and spinal cord injury (SCI). Patients with MS and SCI often request treatment with cannabis-based medicine (CBM). However, knowledge about effects, side effects, choice of active cannabinoids (Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) alone or in combination), and doses of CBM remains limited. Using a double-blind, parallel design in a national multicenter cohort, this study examines the effect of CBM on spasticity and NP. Patients are randomized to treatment with capsules containing either THC, CBD, THC and CBD, or placebo. Primary endpoints are patient-reported pain and spasticity on a numerical rating scale. Other endpoints include quality of life and sleep, depression and anxiety, and relief of pain and spasticity. Side-effects of CBM are described. In a sub-study, the pharmacodynamics (PD) and pharmacokinetics (PK) of oral capsule CBM are examined. We expect that the study will contribute to the literature by providing information on the effects and side-effects of CBD, THC, and the combination of the two for central neuropathic pain and spasticity. Furthermore, we will describe the PD/PK of THC and CBD in a patient population.

OBJECTIVE: Certain biomarkers such as the C-reactive protein, serum albumin, and the neutrophils to lymphocyte ratio are of prognostic significance regarding survival in different types of cancers. Data from sarcoma patients are sparse and mainly derived from soft tissue sarcoma and/or metastatic cases. Adjusting for confounders such as comorbidity and age is an essential safeguard against erroneous conclusions regarding the possible prognostic value of these biomarkers. The aim of this study was to assess the prognostic value of a battery of pretreatment biomarkers in the serum of patients with localized bone sarcomas and to adjust for potential confounders. MATERIAL AND METHODS: All patients diagnosed with localized intermediate and high-grade bone sarcoma during 1994 to 2008 were extracted from the Aarhus Sarcoma Registry. The serum levels of albumin, C-reactive protein, hemoglobin, neutrophils, lymphocytes, and sodium were collected from the patient records. The prognostic values of overall and disease-specific mortality were tested for each individual biomarker as well as for the Glasgow prognostic score (GPS) and for a new composite score incorporating five biomarkers (Aarhus composite biomarker score: ACBS). Adjustments were made for comorbidity as well as other possible prognostic factors, such as size, histological type, margin, chemotherapy, and soft tissue extension, using the Cox proportional hazard model. RESULTS: A total of 172 patients with high- or intermediate-grade localized bone sarcoma were included. Of these patients, 63 were diagnosed with chondrosarcoma and 109 patients with Ewing/osteosarcoma. The median age was 55 years for chondrosarcoma and 19 years for Ewing/osteosarcoma patients. The overall 5-year mortality was 31% [95% confidence interval (CI): 21-44] and 41% (95% CI: 33-51), whereas the 5-year disease-specific mortality was 21% (95% CI: 12-34) and 39% (95% CI: 31-49) for chondrosarcoma and Ewing/osteosarcoma, respectively. Comorbidities were present in 12% of the Ewing/osteosarcoma patients and in 24% of the chondrosarcoma patients. After adjustment for comorbidity and other confounders, it was found that elevated levels of CRP, low hemoglobin, low sodium, high GPS, and high ACBS were associated with increased overall mortality. Furthermore, elevated levels of CRP, low hemoglobin, high GPS, and high ACBS were associated with increased disease-specific mortality. CONCLUSION: Elevated levels of CRP, low hemoglobin, high GPS, and high ACBS were all independent prognostic factors for both overall and disease-specific mortality. ACBS is a new three-level score of five biomarkers, but its value has to be confirmed in an independent data set.

Purpose: Checkpoint inhibitors have significantly improved treatment of metastatic melanoma. However, 40–60% of patients do not respond to therapy, emphasizing the need for better predictive biomarkers for treatment response to immune checkpoint inhibitors. Prorammed death-ligand 1(PD-L1) expression in tumor cells is currently used as a predictive biomarker; however, it lacks specificity. Therefore, it is of utmost importance to identify other novel biomarkers that can predict treatment outcome. Experimental design: We studied a small cohort of 16 patients with advanced-stage melanoma treated with first-line checkpoint inhibitors. Plasma samples were collected prior to treatment initiation and continuously during the first year of treatment. Circulating tumor DNA (ctDNA) level and the expression of ten inflammatory cytokines were analyzed. Results: We found that the ctDNA-level in a blood sample collected after 6–8 weeks of therapy is predictive for response to checkpoint inhibitors. Patients with undetectable ctDNA had significantly longer progression-free survival (PFS) compared with patients with detectable ctDNA (median 26.3 vs. 2.1 months, p = 0.006). In parallel, we identified that high levels of the cytokines monocyte chemoattractant protein 1 (MCP1) and tumor necrosis factor α(TNFα) in baseline blood samples were significantly associated with longer PFS compared to low level of these cytokines (median not reached vs. 8.2 months p = 0.0008). Conclusions: These findings suggest that the levels of ctDNA, MCP1, and TNFα in baseline and early follow-up samples can predict disease progression in metastatic melanoma patients treated with checkpoint inhibitors. Potentially, these minimally invasive biomarkers may identify responders from non-responders.