Myocardial injury and long-term oncological outcomes in patients undergoing surgery for colorectal cancer.

PURPOSE: Myocardial injury after noncardiac surgery (MINS) is associated with increased mortality and postoperative complications. In patients with colorectal cancer (CRC), postoperative complications are a risk factor for cancer recurrence and disease-free survival. This study investigates the association between MINS and long-term oncological outcomes in patients with CRC in an ERAS setting. METHODS: This retrospective cohort study was conducted at Zealand University Hospital, Denmark, between June 2015 and July 2017. Patients undergoing CRC surgery were included if troponin was measured twice after surgery. Outcomes were all-cause mortality, recurrence, and disease-free survival within five years of surgery. RESULTS: Among 586 patients, 42 suffered MINS. After five years, 36% of patients with MINS and 26% without MINS had died, p = 0.15. When adjusted for sex, age and UICC, the hazard ratio (aHR) for 1-year all-cause mortality, recurrence, and disease-free survival were 2.40 [0.93-6.22], 1.47 [0.19-11.29], and 2.25 [0.95-5.32] for patients with MINS compared with those without, respectively. Further adjusting for ASA status, performance status, smoking, and laparotomies, the aHR for 3- and 5-year all-cause mortality were 1.05 [0.51-2.15] and 1.11 [0.62-1.99], respectively. Similarly, the aHR for 3- and 5-year recurrence were 1.38 [0.46-4.51], and 1.49 [0.56-3.98] and for 3- and 5-year disease-free survival the aHR were 1.19 [0.63-2.23], and 1.19 [0.70-2.03]. CONCLUSION: In absolute numbers, we found no difference in all-cause mortality and recurrence in patients with and without MINS. In adjusted Cox regression analyses, the hazard was increased for all-cause mortality, recurrence, and disease-free survival in patients with MINS without reaching statistical significance.

Risk of Atopic Disorders in Patients with Chronic Urticaria: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic urticaria (CU) has been associated with several systemic and autoimmune disorders. The association with atopic disorders is however controversial. The objective of this study was to perform a systematic review and meta-analysis to assess the association between CU and the atopic disorders: atopic dermatitis (AD), asthma, and allergic rhinoconjunctivitis (ARC). METHODS: Search hits from PubMed, Embase, Cochrane Library, and Web of Science were systematically reviewed. English papers from 2000 to present, containing original data of the association (prevalence, incidence, or risk) between CU and any atopic disorder(s), were included. Pooled point prevalence and OR with 95% confidence intervals were calculated with a random effects model. RESULTS: A total of 8,108 search hits were screened and reviewed. Thirty-eight studies met all inclusion criteria. The estimated pooled point prevalence of AD, asthma, and ARC in CU was 7% (5-11%, I2 = 99%), 12% (9-15%, I2 = 100%), and 22% (16-29%, I2 = 100%), respectively. Pooled ORs were estimated to 2.75 (2.05-3.68, I2 = 94%) for AD, 1.87 (1.01-3.45, I2 = 100%) for asthma, and 2.94 (1.84-4.68, I2 = 100%) for ARC. CONCLUSION: Pooled point prevalences of atopic disorders in CU were comparable to the general population. However, studies that compared prevalences with controls from the same population all found a significantly increased risk of atopic disorders in CU. Results should however be interpreted with caution as high heterogeneity was found in all analyses.

The effect of melatonin on endothelial dysfunction in patients after acute coronary syndrome: The MEFACS randomized clinical trial.

Endothelial dysfunction (ED) precedes acute coronary syndrome. Oxidative stress results in ED but is reversible. Melatonin is aside from being a circadian hormone, also an antioxidant. The aim of this study was to investigate whether 25 mg melatonin administered for twelve weeks following acute coronary syndrome (ACS) could improve ED. In this placebo-controlled randomized trial, ED was measured as reactive hyperemia index (RHI) at baseline, day 14, and day 84. The effect was assessed using a generalized estimating equation adjusted for the baseline RHI. As secondary outcome, the concentrations of three biomarkers were measured: l-arginine, asymmetric dimethylarginine, and uric acid. Thirty-one patients were included in the study. The intention-to-treat analysis of the primary outcome had 26 patients due to missing data. The estimated marginal mean difference in RHI at day 14 and day 84 between the groups was 0.15 (95% CI: 0.29-0.01, P = .039) in favor of the placebo group. No significant differences in the biomarker concentrations were found. Melatonin treatment after ACS did not improve but may have aggravated ED. The significant difference between groups was in favor of placebo, but this might be due to the effect of missing data or uneven distribution of comorbidities.

Experiences with pre-graduate research among Danish medical students and doctors.

INTRODUCTION: Pre-graduate research is popular among medical students. Concerns about time constraints and lack of mentorship have been raised in international studies. The extent to which these issues affect Danish medical students remains unclear. We therefore aimed to assess the conditions and outcomes of pre-graduate research among medical students from the University of Copenhagen. METHODS: A descriptive, cross-sectional, questionnaire-based survey on experiences from pre-graduate research was distributed to medical students and recently graduated medical doctors from the University of Copenhagen who had engaged in full-time pre-graduate research. The survey covered 1) working hours and income, 2) publications and authorship and 3) work environment and well-being. RESULTS: A total of 437 pre-graduate researchers participated in the survey. Pre-graduate research often involved a period outside of medical school (88%) and typically lasted a year (56%), with clinical research being the most common focus (68%). Almost a third worked longer hours (29%) than agreed and additional hours were commonly provided after the research period. Scholarships of 10,000 DKK a month were the primary source of income (72%). Most participants achieved their publication goals (62%) and experiences on work environment and well-being were generally positive. CONCLUSION: Pre-graduate research provides a conducive environment for medical students to engage in scientific research. Hovewer, engaging in pre-graduate research entails long working hours, is inadequately remunerated and often requires students to take leave from medical school. FUNDING: None. TRIAL REGISTRATION: Not relevant.

Effect of melatonin in patients with low anterior resection syndrome (MELLARS): a study protocol for a randomised, placebo-controlled, crossover trial.

INTRODUCTION: After rectal cancer surgery, a majority of patients suffer from sequelae known as low anterior resection syndrome (LARS). It is a collection of symptoms consisting of flatus and/or stool incontinence, evacuation frequency, re-evacuation and urgency. The circadian hormone, melatonin, has shown to possess anti-inflammatory properties, and in high doses, it reduces bowel movements. The aim of the study is to investigate if locally administered melatonin has an alleviating effect on LARS. Secondarily, the effect of melatonin on bowel movements, other patient-reported symptoms, quality of life, depression, anxiety, sleep disturbances, motilin levels and rectal mucosa histology will be examined. METHODS AND ANALYSIS: This is a randomised, placebo-controlled, double-blinded, two-period crossover trial. The participants are randomised to 28 days of 25 mg melatonin administered rectally via an enema daily (or placebo) followed by a 28-day washout and then 28 days of placebo (or melatonin). Three participants will be included in an internal feasibility test. They will receive 25 mg of melatonin daily for 28 days. Data from these participants will be used to assess the feasibility of the rectally administered melatonin and to analyse the course of recruitment and outcome measurements. Afterwards, 18 participants will be included in the crossover trial. The severity of the LARS symptoms will be evaluated using the LARS Score on the first and last day of each treatment period. ETHICS AND DISSEMINATION: The Regional Ethics Committee, the Danish Medicines Agency and the Data and Development Support in Region Zealand approved this study. The study will be performed according to the Helsinki II declaration. Written informed consent will be obtained from all participants. The results of the study will be submitted to peer-reviewed journals for publication and presented at congresses. TRIAL REGISTRATION NUMBERS: EudraCT Registry (2020-004442-11) and ClinicalTrial.gov Registry (NCT05042700).

Neoadjuvant intratumoral influenza vaccine treatment in patients with proficient mismatch repair colorectal cancer leads to increased tumor infiltration of CD8+ T cells and upregulation of PD-L1: a phase 1/2 clinical trial.

BACKGROUND: In colorectal cancer, the effects of immune checkpoint inhibitors are mostly limited to patients with deficient mismatch repair tumors, characterized by a high grade infiltration of CD8+T cells. Interventions aimed at increasing intratumoral CD8+T-cell infiltration in proficient mismatch repair tumors are lacking. METHODS: We conducted a proof of concept phase 1/2 clinical trial, where patients with non-metastasizing sigmoid or rectal cancer, scheduled for curative intended surgery, were treated with an endoscopic intratumorally administered neoadjuvant influenza vaccine. Blood and tumor samples were collected before the injection and at the time of surgery. The primary outcome was safety of the intervention. Evaluation of pathological tumor regression grade, immunohistochemistry, flow cytometry of blood, tissue bulk transcriptional analyses, and spatial protein profiling of tumor regions were all secondary outcomes. RESULTS: A total of 10 patients were included in the trial. Median patient age was 70 years (range 54-78), with 30% women. All patients had proficient mismatch repair Union of International Cancer Control stage I-III tumors. No endoscopic safety events occurred, with all patients undergoing curative surgery as scheduled (median 9 days after intervention). Increased CD8+T-cell tumor infiltration was evident after vaccination (median 73 vs 315 cells/mm2, p<0.05), along with significant downregulation of messenger RNA gene expression related to neutrophils and upregulation of transcripts encoding cytotoxic functions. Spatial protein analysis showed significant local upregulation of programmed death-ligand 1 (PD-L1) (adjusted p value<0.05) and downregulation of FOXP3 (adjusted p value<0.05). CONCLUSIONS: Neoadjuvant intratumoral influenza vaccine treatment in this cohort was demonstrated to be safe and feasible, and to induce CD8+T-cell infiltration and upregulation of PD-L1 proficient mismatch repair sigmoid and rectal tumors. Definitive conclusions regarding safety and efficacy can only be made in larger cohorts. TRIAL REGISTRATION NUMBER: NCT04591379.

Prevention of depression in patients with cancer: A systematic review and meta-analysis of randomized controlled trials.

Depression and depressive symptoms are prevalent in patients with cancer. Depression is underdiagnosed and therefore, patients often receive inadequate treatment for depression. We have assessed the evidence of primary prophylactic treatment for depression in patients with cancer. The systematic review was prospectively registered at PROSPERO and was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Five electronic databases were searched on the 31st of May 2018 and two independent reviewers screened the papers. Randomized controlled trials of adult patients with cancer treated prophylactically with an antidepressive intervention of any kind using validated assessment tools to measure depression or depressive symptoms were included. No language or publication year restrictions were applied. Seven out of eighteen studies reported a statistically significant prophylactic effect on depression. The studies were classified into three groups based on the type of intervention. The meta-analyses showed a significant difference in favour of pharmacotherapy (RR 0.34, 95% CI 0.18; 0.63), psychotherapy (SMD -0.23,95% CI -0.46; 0.00), and other interventions (SMD -0.17, 95% CI -0.31; -0.03). Only one study had overall low risk of bias and the rest had high risk of bias predominantly due to blinding, incomplete data, or allocation concealment. Preventive measures have been examined in patients with cancer, but no convincing evidence for any specific intervention is present. Depression in patients with cancer can be prevented and prophylactic treatment should be given during oncological treatment but further high quality studies testing safe interventions are still needed.

The effect of melatonin on depressive symptoms and anxiety in patients after acute coronary syndrome: The MEDACIS randomized clinical trial.

BACKGROUND: Depression following acute coronary syndrome is prevalent and associated with increased mortality and morbidity. Melatonin may function as a primary prophylactic antidepressant substance and alleviate depressive symptoms. The study was undertaken to determine if melatonin administered following an acute coronary syndrome (ACS) could prevent development of depression. METHODS: The study was a double-blinded, placebo-controlled, multicenter, randomized clinical trial performed in five primary care cardiology departments at Zealand, Denmark. Included patients were adults patients, free of depression at baseline, included at the latest 4 weeks after acute coronary syndrome. Twenty-five mg melatonin or placebo was administered 1 h before participants' bedtime for 12 weeks. The primary outcome is Major Depression Inventory (MDI) measured every two weeks throughout the trial. Incidence of depression was apriori defined as MDI score ≥ 21 during the trial. Reported exploratory outcomes were patterns of dropout and safety outcomes. RESULTS: 1220 patients were screened and 252 participants were randomized in a 1:1 ratio. Baseline MDI score in the melatonin and placebo group were, respectively, 6.18 (CI 5.32-7.05) and 5.98 (CI 5.19-6.77). No significant intergroup differences were found during the study in the intention-to-treat analysis or per-protocol analysis. Cumulative events of depressive episodes during the 12 weeks were six in the melatonin group and four in the placebo group. A significant drop in depressive symptoms were present throughout the study period. No intergroup differences were present in dropouts or adverse events. CONCLUSIONS: Melatonin showed no prophylactic antidepressant effect following acute coronary syndrome. The non-significant results might be due to a type II error or melatonin might not be able to prevent development of depressive symptoms following ACS.