Morbidity and mortality among children, adolescents, and young adults with cancer over six decades: a Swedish population-based cohort study (the Rebuc study).

Background: Despite progress in managing cancer in children, adolescents, and young adults (CAYAs), persistent complications may impact their quality of life. This study covers the morbidity and mortality, among CAYAs, with the aim to investigate the influence of socioeconomic factors on outcomes. Methods: This retrospective matched cohort study included the entire Swedish population of individuals under 25 with cancer 1958-2021. The population was identified from the Cancer Register, and controls were paired 1:5 based on age, sex, and residence. Multiple registers provided data on morbidity, mortality, and demographics. Findings: This survey covering 63 years, identified 65,173 CAYAs and matched controls, a total of 378,108 individuals (74% females). CAYAs exhibited a 3.04-times higher risk for subsequent cancer (Odds ratio (OR) 95% confidence interval (CI) 2.92-3.17, p < 0.0001), a 1.23-times higher risk for cardiovascular disease (OR 95% CI 1.20-1.26, p < 0.0001), and a 1.41-times higher risk for external affliction (OR 95% CI 1.34-1.49, p < 0.0001). CAYAs had a higher mortality hazard, and after adjusting for socioeconomic factors, males, individuals born outside Europe, and those with greater sick-leave had a higher association with mortality, while education and marriage showed a beneficial association. Interpretation: The Rebuc study, showed an increased risk for serious complications among young cancer patients in Sweden. Patient-specific variables, demographics, and socioeconomic factors influenced mortality. These results underscore the impact of cancer on the health and lifespan of young individuals and the necessity for further research to address socioeconomic disparities in cancer care. Funding: Grants from the Medical Research Council of Southeast Sweden (FORSS), ALF Grants, Region Ostergotland, and The Swedish Childhood Cancer Fund.

Effects of 3 months of detraining following cardiac rehabilitation in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation negatively impacts physical fitness and health-related quality of life. We recently showed that 3 months of physiotherapist-led exercise-based cardiac rehabilitation improves physical fitness and muscle function in elderly patients with permanent atrial fibrillation and concomitant diseases. Little is, however, known about the consequences for physical fitness, physical activity level, and health-related quality of life after ending the rehabilitation period. METHODS: Prospective 3 months follow-up study of 38 patients out of 40 eligible (10 women) who, as part of a randomized controlled trial, had completed a 3 months physiotherapist-led cardiac rehabilitation resulting in improved physical fitness,. In the current study, the participants were instructed to refrain from exercise for 3 months after completion of the rehabilitation period. Primary outcome measure was physical fitness measured as highest achieved workload using an exercise tolerance test. Secondary outcome measures were muscle function (muscle endurance tests), physical activity level (questionnaire and accelerometer), and health-related quality of life, (Short Form-36), as in the preceding intervention study. We used the Wilcoxon Signed Rank test to analyse differences between the end of rehabilitation and at follow-up. The effect size was determined using Cohen's d . RESULTS: Exercise capacity and exercise time significantly decresead between end of rehabilitation and at follow-up (p < .0001 for both). A significant reduction in shoulder flexion repetitions (p = .006) was observed as well as reduced health-related quality of life in the Short Form-36 dimensions Physical Function (p = .042), Mental Health (p = .030), and Mental Component Score (p = .035). There were, however, no changes regarding objective and subjective physical activity measurements. CONCLUSION: In older patients with permanent atrial fibrillation, previously achieved improvements from physiotherapist-led exercise-based cardiac rehabilitation in physical fitness and muscle function were lost, and health-related quality of life was impaired after ending the rehabilitation period. A strategy for conserving improvements after a rehabilitation period is essential.

Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody-Drug Conjugate in Patient-derived Xenografts.

Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).

[Training in chronic heart failure to improve the quality of life]. / Träning vid kronisk hjärtsvikt för att förbättra livskvaliteten.

Persons with chronic heart failure should be recommended aerobic and resistance exercise to be able to increase maximal oxygen uptake (VO2 max), walking distance, and health related quality of life (moderately strong scientific evidence - quality of evidence +++), and to reduce mortality and hospital admissions and increase muscle strength and endurance (low scientific evidence - quality of evidence ++). Prescription of exercise in chronic heart failure should always be preceded of assessments of aerobic and muscular fitness. The aerobic exercise could be conducted as continuous or interval exercise. In connection with ongoing exercise special attention is needed regarding heart rate, diverging blood pressure reactions, contingent occurrence of arrhythmias and the advent of symptoms such as dizziness and severe dyspnea.

A group-based exercise program did not improve physical activity in patients with chronic heart failure and comorbidity: a randomized controlled trial.

OBJECTIVE: To investigate how group-based exercise affects the levels of physical activity, physical fitness and health- related quality of life (HRQoL) in patients with chronic heart failure and comorbidities. DESIGN: Randomized controlled trial. PATIENTS: A total of 48 patients (10 women, 38 men), mean age 71 years (standard deviation 8 years), ejection fraction 27% (standard deviation 10%), and New York Heart Association functional class II-III. METHODS: A bicycle test, 6-min walk test (6MWT) and muscle endurance tests were performed. Physical activity was assessed with a pedometer and the International Physical Activity Questionnaire (IPAQ), HRQoL was evaluated with the Short Form-36 (SF-36). Patients were randomized to control or intervention groups. Intervention consisted of an individually designed group-based exercise programme twice a week, for a period of 3 months. Subjects in the control group were asked to continue with their usual lives. RESULTS: A total of 42 patients completed the study, and 6 dropped-out. Steps/day did not increase significantly after intervention (p = 0.351), but IPAQ score did (p = 0.008). Exercise tolerance (p = 0.001), 6MWT (p = 0.014), shoulder abduction (p = 0.028), heel lift (p < 0.0001) and HRQoL (p = 0.018) improved significantly in the intervention group compared with the control group. CONCLUSION: Group-based exercise did not improve the level of physical activity in patients with chronic heart failure and comorbidity; however, physical fitness and HRQoL were significantly improved.

4-(Pyrazol-4-yl)-pyrimidines as selective inhibitors of cyclin-dependent kinase 4/6.

Identification and structure-guided optimization of a series of 4-(pyrazol-4-yl)-pyrimidines as selective CDK4/6 inhibitors is reported herein. Several potency and selectivity determinants were established based on the X-ray crystallographic analysis of representative compounds bound to monomeric CDK6. Significant selectivity for CDK4/6 over CDK1 and CDK2 was demonstrated with several compounds in both enzymatic and cellular assays.