Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The Dam foundation Introduction Statin non-adherence remains a prevalent challenge in cardiovascular disease prevention and robust methods to monitor adherence are needed. Large variations in low-density-lipoprotein cholesterol (LDL-C) response to a given type and dose of statin have been reported. The LDL-C response to short-term discontinuation of statins is not well defined. Moreover, the relationship between the blood concentrations of statin metabolites and LDL-C, and how clinical factors interact, are unknown. Purpose To determine changes in LDL-C at an individual and group level during four-day discontinuation of atorvastatin, and to investigate whether clinical factors and atorvastatin metabolites concentration correlate with changes in LDL-C. Methods This clinical pharmacokinetic adherence study conducted in 2021, included 60 adult participants treated with atorvastatin 20 mg (n=20), 40 mg (n=20) or 80 mg (n=20). The participants were instructed to take atorvastatin daily between 07 and 10 am the week before study start, to ensure steady state drug concentrations. The last dose of atorvastatin was taken 24 hours prior to the first blood sampling (day zero). Atorvastatin doses were omitted until after blood sampling on the fourth day. The concentrations of atorvastatin metabolites (acid and lactone forms, including 2-OH- and 4-OH metabolite) were measured by a liquid chromatography–tandem mass spectrometry assay. Paired-samples T-tests, Spearman rank correlations and linear regression analyses were performed with SPSS. Results Mean age was 65 (SD 11) years, 18 (30%) were female, 45 (75%) had cardiovascular disease and 11 (18%) had diabetes mellitus. Mean LDL-C at steady state on day zero was 1.9 (SD 0.6) mmol/L. LDL-C increased on average by 0.5 (SD 0.3) mmol/L (30%) from day zero to day four, during the period with atorvastatin discontinuation. The increase of LDL-C was significant already after the first omitted dose (day one) (Figure 1). LDL-C increased from day zero to day four in 78 out of the 80 patients (97.5%). Higher Body Mass Index was significantly associated with lager increase in LDL-C during the four-day discontinuation (B 0.02, 95% CI 0.01 to 0.04, p=0.028), whereas age, sex, kidney function, cardiovascular disease and diabetes were not. Changes in atorvastatin plus metabolites concentration from day zero to day four were not associated with changes in LDL-C during discontinuation (Figure 2). This also applied if we assessed the individual atorvastatin metabolites. Conclusion Atorvastatin discontinuation for only four days resulted in a statistically significant 30% increase of LDL-C. Atorvastatin pharmacokinetics did not correlate with change in LDL-C during the discontinuation. Even short-term non-adherence may have unfavourable consequences, and deserves further attention.

Research on laparoscopic liver resection has shown shorter recovery time, a better quality of life, and fewer postoperative complications. Our previous report of the OSLO-COMET trial showed that laparoscopic surgery in patients with colorectal cancer liver metastases was equivalent to open resection regarding oncologic outcomes. The current report aimed to investigate the survival outcomes of this trial after a minimum follow-up of 6 years. Patients with resectable colorectal liver metastases from February 2012 to January 2016 were randomized between laparoscopic and open parenchyma-sparing liver resection with curative intent (ClinicalTrials.gov: NCT01516710). The trial's primary outcome was postoperative morbidity within 30 days, while overall survival was a predefined secondary endpoint. Patients received perioperative chemotherapy following Norwegian guidelines, at the discretion of the multidisciplinary team. Two hundred eighty patients were randomized to laparoscopic (n = 133) or open (n = 147) surgery. Current survival analysis was performed on January 20, 2022, with a minimum of 72 months follow-up and with a median follow-up of 94 months (95%CI, 91 to 97). Median overall survival was 71 months (95% CI 47 to 95) in the laparoscopic surgery group and 74 months (95%CI, 52 to 96) in the open surgery group (p=0.970), and the 5-year actual survival compiled 55% and 54%, respectively (HR 1.006 [0.738 to 1.372]). Median recurrence-free survival (RFS) was 17 months (95%CI, 10 to 23) after laparoscopy and 16 months (95%CI, 8 to 24) after open surgery, with a 5-year RFS of 33% and 31% (p = 0.705). These long-term outcomes after a minimum follow-up of six years, together with short-term results, further support the use of laparoscopic surgery to treat colorectal cancer liver metastases.

Abstract Background Statin associated muscle symptoms (SAMS) are commonly reported and constitute the principal reason for statin non-adherence and/or discontinuation. Understanding the determinants of SAMS may enhance the clinical management and form the basis of interventions. The association between psychological distress and the beliefs about statin treatment and SAMS have previously not been investigated under randomized, controlled conditions. Purpose To compare clinical and psychological factors among coronary patients with confirmed SAMS and non-SAMS. Methods This pre-planned exploratory study included 71 consecutively recruited patients with self-perceived SAMS enrolled in the MUscle Side-Effect of atorvastatin in coronary patients (MUSE) randomized double-blinded crossover trial. Muscle symptom (pain, weakness, tenderness, stiffness and/or cramps) intensity was registered weekly in a patient diary using a 0 (no symptoms) to 10 (worst imaginable) cm visual-analogue scale (VAS). Confirmed SAMS was predefined as a 25% higher individual mean VAS-scores during 7-weeks treatment with atorvastatin 40 mg/day versus 7-weeks treatment with placebo, and ≥1cm absolute difference. Clinical factors (10 variables), psychological factors (5 variables) and beliefs about medicine (3 variables) were obtained from a questionnaire and a clinical examination at study start. Results Mean age was 63 (SD 9.5) years, 32% were women, and each participant had tried average 1.3 (SD 0.6, range 1 to 3) statins prior to study start. In all, 28% (n=20) had confirmed SAMS and 72% (n=51) had non-SAMS. There were no differences in mean VAS score at study start between the groups (mean VAS score 4.5 vs. 4.7, p=0.20). More patients with confirmed SAMS than non-SAMS (25% vs. 6%, p<0.001) did not use statin treatment at study start, and mean LDL-cholesterol level was borderline higher (2.8 vs. 2.3 mmol/L, p=0.06). Patients with confirmed SAMS had a weaker belief in their statin use compared to patients with non-SAMS (3.1 vs. 3.6, p<0.001) using a 5-category scale from 1 (weak belief) to 5 (strongest belief). There were no differences in the sociodemographic, clinical (pre-existing muscle skeletal disorders, somatic comorbidity, cardiovascular risk factors) or psychological (symptoms of anxiety or depression, type D personality, worry, insomnia) factors explored between patients with confirmed SAMS or with non-SAMS. There were no associations between these factors and increasing VAS scores in continuous analyses among patients with confirmed SAMS and non-SAMS. Conclusions Patients with statin dependent muscle side-effects reported a weaker belief on the necessity to take statins than patients with muscle complaints not caused by the statin. Otherwise, we found no differences in clinical or psychological factors between these populations. The results indicate that these factors do not distinguish patients with and without associated muscle symptoms in clinical practice. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Vestfold Hospital Trust, research grant

Abstract Background: Mammographic density, a strong biomarker for breast cancer risk, represents epithelial and stromal proliferation. Insulin and insulin-like growth factor (IGF)-1 are suggested to influence cellular proliferation, while estrogen is a key factor in breast cancer development. However, whether the effects of these hormones among premenopausal women are mediated through mammographic density is less known. Material and Methods: Fasting serum insulin, IGF-1, and IGF binding protein (IGFBP)-3 were assessed among 202 healthy premenopausal women (Norwegian Energy Balance and Breast cancer Aspects study-I (EBBA-I). Daily salivary levels of 17β-estradiol throughout an entire menstrual cycle were measured at the reproductive Ecology Laboratory, Harvard University, USA. Computer-assisted mammographic density (Madena) was obtained from digitized mammograms taken at day 7–12 of the menstrual cycle. Uni- and multivariable regression models were used to study the associations between hormones and premenopausal percent mammographic density. Results: Among women with a mean age of 30,7 years, a mean premenopausal percent mammographic density of 29.8 % was observed. Throughout the menstrual cycle when comparing women with a high percent mammographic density (≥28.5%) to women with a low percent mammographic density (<28.5%), we observed insulin, IGF-1 and IGFBP-3 independently and in combination with cycling 17β-estradiol to predict premenopausal percent mammographic density. We observed among women with either serum insulin ≥89 pmol/, IGF-1 ≥24 nmol/l, IGFBP-3 ≥ 100 nmol/l, having a high (≥28.5%) versus a low (<28.5%) percent mammographic density was associated with an increase in overall average 17β-estradiol of 4.0 %, 10.9 % and 14.9%, respectively. Moreover, we observed a higher adjusted Odds Ratio (OR) for having a high percent mammographic density for each standard deviation (SD) increase in overall average 17β -estradiol, insulin, IGF-1 and IGFBP-3: 17β-estradiol, 1.55 (1.06–2.27); insulin, 1.62 (0.76–3.48), IGF-1, 1.90 (1.10–3.27); IGFBP-3, 1.88 (1.05–3.37) (adjusted for age, body mass index-BMI kg/m2)). Conclusion: Our study supports that insulin, IGF-1 and IGFBP-3 independently, and in combination with cycling estrogen, predicts premenopausal mammographic density. These hormones may be important biomarkers in breast cancer control and clinical practice. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-01-01.